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Sample records for adaptor trif contributes

  1. Seneca Valley Virus Suppresses Host Type I Interferon Production by Targeting Adaptor Proteins MAVS, TRIF, and TANK for Cleavage.

    Science.gov (United States)

    Qian, Suhong; Fan, Wenchun; Liu, Tingting; Wu, Mengge; Zhang, Huawei; Cui, Xiaofang; Zhou, Yun; Hu, Junjie; Wei, Shaozhong; Chen, Huanchun; Li, Xiangmin; Qian, Ping

    2017-08-15

    Seneca Valley virus (SVV) is an oncolytic RNA virus belonging to the Picornaviridae family. Its nucleotide sequence is highly similar to those of members of the Cardiovirus genus. SVV is also a neuroendocrine cancer-selective oncolytic picornavirus that can be used for anticancer therapy. However, the interaction between SVV and its host is yet to be fully characterized. In this study, SVV inhibited antiviral type I interferon (IFN) responses by targeting different host adaptors, including mitochondrial antiviral signaling (MAVS), Toll/interleukin 1 (IL-1) receptor domain-containing adaptor inducing IFN-β (TRIF), and TRAF family member-associated NF-κB activator (TANK), via viral 3C protease (3C pro ). SVV 3C pro mediated the cleavage of MAVS, TRIF, and TANK at specific sites, which required its protease activity. The cleaved MAVS, TRIF, and TANK lost the ability to regulate pattern recognition receptor (PRR)-mediated IFN production. The cleavage of TANK also facilitated TRAF6-induced NF-κB activation. SVV was also found to be sensitive to IFN-β. Therefore, SVV suppressed antiviral IFN production to escape host antiviral innate immune responses by cleaving host adaptor molecules. IMPORTANCE Host cells have developed various defenses against microbial pathogen infection. The production of IFN is the first line of defense against microbial infection. However, viruses have evolved many strategies to disrupt this host defense. SVV, a member of the Picornavirus genus, is an oncolytic virus that shows potential functions in anticancer therapy. It has been demonstrated that IFN can be used in anticancer therapy for certain tumors. However, the relationship between oncolytic virus and innate immune response in anticancer therapy is still not well known. In this study, we showed that SVV has evolved as an effective mechanism to inhibit host type I IFN production by using its 3C pro to cleave the molecules MAVS, TRIF, and TANK directly. These molecules are crucial for

  2. Sepsis Induces Hematopoietic Stem Cell Exhaustion and Myelosuppression through Distinct Contributions of TRIF and MYD88

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    Huajia Zhang

    2016-06-01

    Full Text Available Toll-like receptor 4 (TLR4 plays a central role in host responses to bacterial infection, but the precise mechanism(s by which its downstream signaling components coordinate the bone marrow response to sepsis is poorly understood. Using mice deficient in TLR4 downstream adapters MYD88 or TRIF, we demonstrate that both cell-autonomous and non-cell-autonomous MYD88 activation are major causes of myelosuppression during sepsis, while having a modest impact on hematopoietic stem cell (HSC functions. In contrast, cell-intrinsic TRIF activation severely compromises HSC self-renewal without directly affecting myeloid cells. Lipopolysaccharide-induced activation of MYD88 or TRIF contributes to cell-cycle activation of HSC and induces rapid and permanent changes in transcriptional programs, as indicated by persistent downregulation of Spi1 and CebpA expression after transplantation. Thus, distinct mechanisms downstream of TLR4 signaling mediate myelosuppression and HSC exhaustion during sepsis through unique effects of MyD88 and TRIF.

  3. Both TLR2 and TRIF contribute to interferon-β production during Listeria infection.

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    Camille Aubry

    Full Text Available Synthesis of interferon-β (IFN-β is an innate response to cytoplasmic infection with bacterial pathogens. Our recent studies showed that Listeria monocytogenes limits immune detection and IFN-β synthesis via deacetylation of its peptidoglycan, which renders the bacterium resistant to lysozyme degradation. Here, we examined signaling requirements for the massive IFN-β production resulting from the infection of murine macrophages with a mutant strain of L. monocytogenes, ΔpgdA, which is unable to modify its peptidoglycan. We report the identification of unconventional signaling pathways to the IFN-β gene, requiring TLR2 and bacterial internalization. Induction of IFN-β was independent of the Mal/TIRAP adaptor protein but required TRIF and the transcription factors IRF3 and IRF7. These pathways were stimulated to a lesser degree by wild-type L. monocytogenes. They operated in both resident and inflammatory macrophages derived from the peritoneal cavity, but not in bone marrow-derived macrophages. The novelty of our findings thus lies in the first description of TLR2 and TRIF as two critical components leading to the induction of the IFN-β gene and in uncovering that individual macrophage populations adopt different strategies to link pathogen recognition signals to IFN-β gene expression.

  4. TRIF promotes angiotensin II-induced cross-talk between fibroblasts and macrophages in atrial fibrosis

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    Chen, Xiao-Qing; Zhang, Dao-Liang [Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai (China); Zhang, Ming-Jian; Guo, Meng; Zhan, Yang-Yang; Liu, Fang [National Key Laboratory of Medical Immunology, Second Military Medical University, Shanghai (China); Jiang, Wei-Feng; Zhou, Li [Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai (China); Zhao, Liang, E-mail: zhaol_zg@163.com [Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai (China); Wang, Quan-Xing, E-mail: wqxejd@126.com [National Key Laboratory of Medical Immunology, Second Military Medical University, Shanghai (China); Liu, Xu, E-mail: liuxu_xk@163.com [Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai (China)

    2015-08-14

    Aims: Atrial fibroblasts and macrophages have long been thought to participate in atrial fibrillation (AF). However, which specific mediator may regulate the interaction between them remains unclear. Methods and results: We provided the evidence for the involvement of Toll/IL-1 receptor domain-containing adaptor inducing IFN-β (TRIF), an important inflammation-related molecule, in the pathophysiology of AF. Patients with AF showed higher levels of angiotensin II (AngII) and TRIF expression and larger number of macrophages infiltration in left atria appendage than individuals with sinus rhythm (SR). In the cell study, AngII induced chemokines expressions in mouse atrial fibroblasts and AngII-stimulated atrial fibroblasts induced the chemotaxis of macrophages, which were reduced by losartan and TRIF siRNA. Meanwhile, AngII-stimulated atrial fibroblasts proliferation was enhanced by macrophages. Conclusions: Our data demonstrated that TRIF may be a crucial factor promoting the interaction between atrial fibroblasts and macrophages, leading to atrial fibrosis. - Highlights: • Compared with SR, AF showed higher TRIF expression in left atrial appendage. • TRIF siRNA reversed macrophage chemotaxis induced by AngII-treated fibroblast. • TRIF siRNA reversed chemokines expressions induced by AngII in fibroblast. • AngII-stimulated atrial fibroblast proliferation was enhanced by macrophage.

  5. TRIF Differentially Regulates Hepatic Steatosis and Inflammation/Fibrosis in MiceSummary

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    Ling Yang

    2017-05-01

    Full Text Available Background & Aims: Toll-like receptor 4 (TLR4 signaling is activated through 2 adaptor proteins: MyD88 and TIR-domain containing adaptor-inducing interferon-β (TRIF. TLR4 and MyD88 are crucial in nonalcoholic steatohepatitis (NASH and fibrosis. However, the role of TRIF in TLR4-mediated NASH and fibrosis has been elusive. This study investigated the differential roles of TRIF in hepatic steatosis and inflammation/fibrosis. Methods: A choline-deficient amino acid defined (CDAA diet was used for the mouse NASH model. On this diet, the mice develop hepatic steatosis, inflammation, and fibrosis. TLR4 wild-type and TLR4-/- bone marrow chimeric mice and TRIF-/- mice were fed CDAA or a control diet for 22 weeks. Hepatic steatosis, inflammation, and fibrosis were examined. Results: In the CDAA diet–induced NASH, the mice with wild-type bone marrow had higher alanine aminotransferase and hepatic tumor necrosis factor levels than the mice with TLR4-/- bone marrow. The nonalcoholic fatty liver disease activity score showed that both wild-type and TLR4-/- bone marrow chimeras had reduced hepatic steatosis, and that both types of chimeras had similar levels of inflammation and hepatocyte ballooning to whole-body wild-type mice. Notably, wild-type recipients showed more liver fibrosis than TLR4-/- recipients. Although TRIF-/- mice showed reduced hepatic steatosis, these mice showed more liver injury, inflammation, and fibrosis than wild-type mice. TRIF-/- stellate cells and hepatocytes produced more C-X-C motif chemokine ligand 1 (CXCL1 and C-C motif chemokine ligand than wild-type cells in response to lipopolysaccharide. Consistently, TRIF-/- mice showed increased CXCL1 and CCL3 expression along with neutrophil and macrophage infiltration, which promotes liver inflammation and injury. Conclusions: In TLR4-mediated NASH, different liver cells have distinct roles in hepatic steatosis, inflammation, and fibrosis. TRIF promotes hepatic

  6. The TRIF-dependent signaling pathway is not required for acute cerebral ischemia/reperfusion injury in mice

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    Hua, Fang, E-mail: fhua2@emory.edu [Department of Emergency Medicine, Brain Research Laboratory, Emory University School of Medicine, 1365B Clifton Road, Suite 5100, Atlanta, GA 30322 (United States); Wang, Jun; Sayeed, Iqbal; Ishrat, Tauheed; Atif, Fahim; Stein, Donald G. [Department of Emergency Medicine, Brain Research Laboratory, Emory University School of Medicine, 1365B Clifton Road, Suite 5100, Atlanta, GA 30322 (United States)

    2009-12-18

    TIR domain-containing adaptor protein (TRIF) is an adaptor protein in Toll-like receptor (TLR) signaling pathways. Activation of TRIF leads to the activation of interferon regulatory factor 3 (IRF3) and nuclear factor kappa B (NF-{kappa}B). While studies have shown that TLRs are implicated in cerebral ischemia/reperfusion (I/R) injury and in neuroprotection against ischemia afforded by preconditioning, little is known about TRIF's role in the pathological process following cerebral I/R. The present study investigated the role that TRIF may play in acute cerebral I/R injury. In a mouse model of cerebral I/R induced by transient middle cerebral artery occlusion, we examined the activation of NF-{kappa}B and IRF3 signaling in ischemic cerebral tissue using ELISA and Western blots. Neurological function and cerebral infarct size were also evaluated 24 h after cerebral I/R. NF-{kappa}B activity and phosphorylation of the inhibitor of kappa B (I{kappa}B{alpha}) increased in ischemic brains, but IRF3, inhibitor of {kappa}B kinase complex-{epsilon} (IKK{epsilon}), and TANK-binding kinase1 (TBK1) were not activated after cerebral I/R in wild-type (WT) mice. Interestingly, TRIF deficit did not inhibit NF-{kappa}B activity or p-I{kappa}B{alpha} induced by cerebral I/R. Moreover, although cerebral I/R induced neurological and functional impairments and brain infarction in WT mice, the deficits were not improved and brain infarct size was not reduced in TRIF knockout mice compared to WT mice. Our results demonstrate that the TRIF-dependent signaling pathway is not required for the activation of NF-{kappa}B signaling and brain injury after acute cerebral I/R.

  7. The TRIF-dependent signaling pathway is not required for acute cerebral ischemia/reperfusion injury in mice

    International Nuclear Information System (INIS)

    Hua, Fang; Wang, Jun; Sayeed, Iqbal; Ishrat, Tauheed; Atif, Fahim; Stein, Donald G.

    2009-01-01

    TIR domain-containing adaptor protein (TRIF) is an adaptor protein in Toll-like receptor (TLR) signaling pathways. Activation of TRIF leads to the activation of interferon regulatory factor 3 (IRF3) and nuclear factor kappa B (NF-κB). While studies have shown that TLRs are implicated in cerebral ischemia/reperfusion (I/R) injury and in neuroprotection against ischemia afforded by preconditioning, little is known about TRIF's role in the pathological process following cerebral I/R. The present study investigated the role that TRIF may play in acute cerebral I/R injury. In a mouse model of cerebral I/R induced by transient middle cerebral artery occlusion, we examined the activation of NF-κB and IRF3 signaling in ischemic cerebral tissue using ELISA and Western blots. Neurological function and cerebral infarct size were also evaluated 24 h after cerebral I/R. NF-κB activity and phosphorylation of the inhibitor of kappa B (IκBα) increased in ischemic brains, but IRF3, inhibitor of κB kinase complex-ε (IKKε), and TANK-binding kinase1 (TBK1) were not activated after cerebral I/R in wild-type (WT) mice. Interestingly, TRIF deficit did not inhibit NF-κB activity or p-IκBα induced by cerebral I/R. Moreover, although cerebral I/R induced neurological and functional impairments and brain infarction in WT mice, the deficits were not improved and brain infarct size was not reduced in TRIF knockout mice compared to WT mice. Our results demonstrate that the TRIF-dependent signaling pathway is not required for the activation of NF-κB signaling and brain injury after acute cerebral I/R.

  8. Retinal dendritic cell recruitment, but not function, was inhibited in MyD88 and TRIF deficient mice.

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    Heuss, Neal D; Pierson, Mark J; Montaniel, Kim Ramil C; McPherson, Scott W; Lehmann, Ute; Hussong, Stacy A; Ferrington, Deborah A; Low, Walter C; Gregerson, Dale S

    2014-08-13

    Immune system cells are known to affect loss of neurons due to injury or disease. Recruitment of immune cells following retinal/CNS injury has been shown to affect the health and survival of neurons in several models. We detected close, physical contact between dendritic cells and retinal ganglion cells following an optic nerve crush, and sought to understand the underlying mechanisms. CD11c-DTR/GFP mice producing a chimeric protein of diphtheria toxin receptor (DTR) and GFP from a transgenic CD11c promoter were used in conjunction with mice deficient in MyD88 and/or TRIF. Retinal ganglion cell injury was induced by an optic nerve crush, and the resulting interactions of the GFPhi cells and retinal ganglion cells were examined. Recruitment of GFPhi dendritic cells to the retina was significantly compromised in MyD88 and TRIF knockout mice. GFPhi dendritic cells played a significant role in clearing fluorescent-labeled retinal ganglion cells post-injury in the CD11c-DTR/GFP mice. In the TRIF and MyD88 deficient mice, the resting level of GFPhi dendritic cells was lower, and their influx was reduced following the optic nerve crush injury. The reduction in GFPhi dendritic cell numbers led to their replacement in the uptake of fluorescent-labeled debris by GFPlo microglia/macrophages. Depletion of GFPhi dendritic cells by treatment with diphtheria toxin also led to their displacement by GFPlo microglia/macrophages, which then assumed close contact with the injured neurons. The contribution of recruited cells to the injury response was substantial, and regulated by MyD88 and TRIF. However, the presence of these adaptor proteins was not required for interaction with neurons, or the phagocytosis of debris. The data suggested a two-niche model in which resident microglia were maintained at a constant level post-optic nerve crush, while the injury-stimulated recruitment of dendritic cells and macrophages led to their transient appearance in numbers equivalent to or greater

  9. Th2 Regulation of Viral Myocarditis in Mice: Different Roles for TLR3 versus TRIF in Progression to Chronic Disease

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    Eric D. Abston

    2012-01-01

    Full Text Available Viral infections are able to induce autoimmune inflammation in the heart. Here, we investigated the role of virus-activated Toll-like receptor (TLR3 and its adaptor TRIF on the development of autoimmune coxsackievirus B3 (CVB3 myocarditis in mice. Although TLR3- or TRIF-deficient mice developed similarly worse acute CVB3 myocarditis and viral replication compared to control mice, disease was significantly worse in TRIF compared to TLR3-deficient mice. Interestingly, TLR3-deficient mice developed an interleukin (IL-4-dominant T helper (Th2 response during acute CVB3 myocarditis with elevated markers of alternative activation, while TRIF-deficient mice elevated the Th2-associated cytokine IL-33. Treatment of TLR3-deficient mice with recombinant IL-33 improved heart function indicating that elevated IL-33 in the context of a classic Th2-driven response protects against autoimmune heart disease. We show for the first time that TLR3 versus TRIF deficiency results in different Th2 responses that uniquely influence the progression to chronic myocarditis.

  10. Andrographolide suppresses TRIF-dependent signaling of toll-like receptors by targeting TBK1.

    Science.gov (United States)

    Kim, Ah-Yeon; Shim, Hyun-Jin; Shin, Hyeon-Myeong; Lee, Yoo Jung; Nam, Hyeonjeong; Kim, Su Yeon; Youn, Hyung-Sun

    2018-04-01

    Toll-like receptors (TLRs) play a crucial role in danger recognition and induction of innate immune response against bacterial and viral infections. The TLR adaptor molecule, toll-interleukin-1 receptor domain-containing adapter inducing interferon-β (TRIF), facilitates TLR3 and TLR4 signaling, leading to the activation of the transcription factor, NF-κB and interferon regulatory factor 3 (IRF3). Andrographolide, the active component of Andrographis paniculata, exerts anti-inflammatory effects; however, the principal molecular mechanisms remain unclear. The objective of this study was to investigate the role of andrographolide in TLR signaling pathways. Andrographolide suppressed NF-κB activation as well as COX-2 expression induced by TLR3 or TLR4 agonists. Andrographolide also suppressed the activation of IRF3 and the expression of interferon inducible protein-10 (IP-10) induced by TLR3 or TLR4 agonists. Andrographolide attenuated ligand-independent activation of IRF3 following overexpression of TRIF, TBK1, or IRF3. Furthermore, andrographolide inhibited TBK1 kinase activity in vitro. These results indicate that andrographolide modulates the TRIF-dependent pathway of TLRs by targeting TBK1 and represents a potential new anti-inflammatory candidate. Copyright © 2018 Elsevier B.V. All rights reserved.

  11. The TIR-domain containing adaptor TRAM is required for TLR7 mediated RANTES production.

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    Enda Shevlin

    Full Text Available Toll-like receptor 7 (TLR7 plays a vital role in the immune response to ssRNA viruses such as human rhinovirus (HRV and Influenza, against which there are currently no treatments or vaccines with long term efficacy available. Clearly, a more comprehensive understanding of the TLR7 signaling axis will contribute to its molecular targeting. TRIF related adaptor molecule (TRAM plays a vital role in TLR4 signaling by recruiting TRIF to TLR4, followed by endosomal trafficking of the complex and initiation of IRF3 dependent type I interferon production as well as NF-κB dependent pro-inflammatory cytokine production. Towards understanding the molecular mechanisms that regulate TLR7 functionality, we found that TRAM(-/- murine macrophages exhibited a transcriptional and translational impairment in TLR7 mediated RANTES, but not TNFα, production. Suppression of TRAM expression in human macrophages also resulted in an impairment in TLR7 mediated CCL5 and IFN-β, but not TNFα, gene induction. Furthermore, suppression of endogenous human TRAM expression in human macrophages significantly impaired RV16 induced CCL5 and IFNβ, but not TNFα gene induction. Additionally, TRAM-G2A dose-dependently inhibited TLR7 mediated activation of CCL5, IFNβ and IFNα reporter genes. TLR7-mediated phosphorylation and nuclear translocation of IRF3 was impaired in TRAM(-/- cells. Finally, co-immunoprecipitation studies indicated that TRAM physically interacts with MyD88 upon TLR7 stimulation, but not under basal conditions. Our results clearly demonstrate that TRAM plays a, hitherto unappreciated, role in TLR7 signaling through a novel signaling axis containing, but not limited to, MyD88, TRAM and IRF3 towards the activation of anti-viral immunity.

  12. Inversor Mc Murray trifásico

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    Rodríguez Chávez, Jaime Patricio

    1982-01-01

    El presente trabajo está encaminado a realizar un estudio teórico experimental del inversor trifásico Mc Murray. Una vez diseñado y construído el inversor se han realizado diferentes pruebas para demostrar las bondades de dicho circuito.

  13. Disruption of TLR3 signaling due to cleavage of TRIF by the hepatitis A virus protease-polymerase processing intermediate, 3CD.

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    Lin Qu

    2011-09-01

    Full Text Available Toll-like receptor 3 (TLR3 and cytosolic RIG-I-like helicases (RIG-I and MDA5 sense viral RNAs and activate innate immune signaling pathways that induce expression of interferon (IFN through specific adaptor proteins, TIR domain-containing adaptor inducing interferon-β (TRIF, and mitochondrial antiviral signaling protein (MAVS, respectively. Previously, we demonstrated that hepatitis A virus (HAV, a unique hepatotropic human picornavirus, disrupts RIG-I/MDA5 signaling by targeting MAVS for cleavage by 3ABC, a precursor of the sole HAV protease, 3C(pro, that is derived by auto-processing of the P3 (3ABCD segment of the viral polyprotein. Here, we show that HAV also disrupts TLR3 signaling, inhibiting poly(I:C-stimulated dimerization of IFN regulatory factor 3 (IRF-3, IRF-3 translocation to the nucleus, and IFN-β promoter activation, by targeting TRIF for degradation by a distinct 3ABCD processing intermediate, the 3CD protease-polymerase precursor. TRIF is proteolytically cleaved by 3CD, but not by the mature 3C(pro protease or the 3ABC precursor that degrades MAVS. 3CD-mediated degradation of TRIF depends on both the cysteine protease activity of 3C(pro and downstream 3D(pol sequence, but not 3D(pol polymerase activity. Cleavage occurs at two non-canonical 3C(pro recognition sequences in TRIF, and involves a hierarchical process in which primary cleavage at Gln-554 is a prerequisite for scission at Gln-190. The results of mutational studies indicate that 3D(pol sequence modulates the substrate specificity of the upstream 3C(pro protease when fused to it in cis in 3CD, allowing 3CD to target cleavage sites not normally recognized by 3C(pro. HAV thus disrupts both RIG-I/MDA5 and TLR3 signaling pathways through cleavage of essential adaptor proteins by two distinct protease precursors derived from the common 3ABCD polyprotein processing intermediate.

  14. A Novel Agonist of the TRIF Pathway Induces a Cellular State Refractory to Replication of Zika, Chikungunya, and Dengue Viruses

    Science.gov (United States)

    Pryke, Kara M.; Abraham, Jinu; Sali, Tina M.; Gall, Bryan J.; Archer, Iris; Liu, Andrew; Bambina, Shelly; Baird, Jason; Gough, Michael; Chakhtoura, Marita; Haddad, Elias K.; Kirby, Ilsa T.; Nilsen, Aaron; Streblow, Daniel N.; Hirsch, Alec J.; Smith, Jessica L.

    2017-01-01

    ABSTRACT The ongoing concurrent outbreaks of Zika, Chikungunya, and dengue viruses in Latin America and the Caribbean highlight the need for development of broad-spectrum antiviral treatments. The type I interferon (IFN) system has evolved in vertebrates to generate tissue responses that actively block replication of multiple known and potentially zoonotic viruses. As such, its control and activation through pharmacological agents may represent a novel therapeutic strategy for simultaneously impairing growth of multiple virus types and rendering host populations resistant to virus spread. In light of this strategy’s potential, we undertook a screen to identify novel interferon-activating small molecules. Here, we describe 1-(2-fluorophenyl)-2-(5-isopropyl-1,3,4-thiadiazol-2-yl)-1,2-dihydrochromeno[2,3-c]pyrrole-3,9-dione, which we termed AV-C. Treatment of human cells with AV-C activates innate and interferon-associated responses that strongly inhibit replication of Zika, Chikungunya, and dengue viruses. By utilizing genome editing, we investigated the host proteins essential to AV-C-induced cellular states. This showed that the compound requires a TRIF-dependent signaling cascade that culminates in IFN regulatory factor 3 (IRF3)-dependent expression and secretion of type I interferon to elicit antiviral responses. The other canonical IRF3-terminal adaptor proteins STING and IPS-1/MAVS were dispensable for AV-C-induced phenotypes. However, our work revealed an important inhibitory role for IPS-1/MAVS, but not TRIF, in flavivirus replication, implying that TRIF-directed viral evasion may not occur. Additionally, we show that in response to AV-C, primary human peripheral blood mononuclear cells secrete proinflammatory cytokines that are linked with establishment of adaptive immunity to viral pathogens. Ultimately, synthetic innate immune activators such as AV-C may serve multiple therapeutic purposes, including direct antimicrobial responses and facilitation of

  15. A Novel Agonist of the TRIF Pathway Induces a Cellular State Refractory to Replication of Zika, Chikungunya, and Dengue Viruses

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    Kara M. Pryke

    2017-05-01

    Full Text Available The ongoing concurrent outbreaks of Zika, Chikungunya, and dengue viruses in Latin America and the Caribbean highlight the need for development of broad-spectrum antiviral treatments. The type I interferon (IFN system has evolved in vertebrates to generate tissue responses that actively block replication of multiple known and potentially zoonotic viruses. As such, its control and activation through pharmacological agents may represent a novel therapeutic strategy for simultaneously impairing growth of multiple virus types and rendering host populations resistant to virus spread. In light of this strategy’s potential, we undertook a screen to identify novel interferon-activating small molecules. Here, we describe 1-(2-fluorophenyl-2-(5-isopropyl-1,3,4-thiadiazol-2-yl-1,2-dihydrochromeno[2,3-c]pyrrole-3,9-dione, which we termed AV-C. Treatment of human cells with AV-C activates innate and interferon-associated responses that strongly inhibit replication of Zika, Chikungunya, and dengue viruses. By utilizing genome editing, we investigated the host proteins essential to AV-C-induced cellular states. This showed that the compound requires a TRIF-dependent signaling cascade that culminates in IFN regulatory factor 3 (IRF3-dependent expression and secretion of type I interferon to elicit antiviral responses. The other canonical IRF3-terminal adaptor proteins STING and IPS-1/MAVS were dispensable for AV-C-induced phenotypes. However, our work revealed an important inhibitory role for IPS-1/MAVS, but not TRIF, in flavivirus replication, implying that TRIF-directed viral evasion may not occur. Additionally, we show that in response to AV-C, primary human peripheral blood mononuclear cells secrete proinflammatory cytokines that are linked with establishment of adaptive immunity to viral pathogens. Ultimately, synthetic innate immune activators such as AV-C may serve multiple therapeutic purposes, including direct antimicrobial responses and facilitation

  16. The Immune Signaling Adaptor LAT Contributes to the Neuroanatomical Phenotype of 16p11.2 BP2-BP3 CNVs

    NARCIS (Netherlands)

    Loviglio, Maria Nicla; Arbogast, Thomas; Jønch, Aia Elise; Collins, Stephan C.; Popadin, Konstantin; Bonnet, Camille S.; Giannuzzi, Giuliana; Maillard, Anne M.; Jacquemont, Sébastien; Loviglio, Maria Nicla; Jønch, Aia Elise; Popadin, Konstantin; Giannuzzi, Giuliana; Maillard, Anne M.; Fagerberg, Christina; Andersen, Charlotte Brasch; Doco-Fenzy, Martine; Delrue, Marie-Ange; Faivre, Laurence; Arveiler, Benoit; Geneviève, David; Schneider, Anouck; Gerard, Marion; Andrieux, Joris; El Chehadeh, Salima; Schaefer, Elise; Depienne, Christel; Van Haelst, Mieke; Brilstra, Eva H.; Van Binsbergen, Ellen; van Harssel, Jeske; van der Veken, Lars T.; Gusella, James F; Shen, Yiping; Mitchell, Elyse; Kini, Usha; Hawkes, Lara; Campbell, Carolyn; Butschi, Florence Niel; Addor, Marie Claude; Beckmann, Jacques S.; Jacquemont, Sébastien; Reymond, Alexandre; Yalcin, Binnaz; Katsanis, Nicholas; Golzio, Christelle; Reymond, Alexandre

    2017-01-01

    Copy-number changes in 16p11.2 contribute significantly to neuropsychiatric traits. Besides the 600 kb BP4-BP5 CNV found in 0.5%–1% of individuals with autism spectrum disorders and schizophrenia and whose rearrangement causes reciprocal defects in head size and body weight, a second distal 220 kb

  17. A Novel Agonist of the TRIF Pathway Induces a Cellular State Refractory to Replication of Zika, Chikungunya, and Dengue Viruses.

    Science.gov (United States)

    Pryke, Kara M; Abraham, Jinu; Sali, Tina M; Gall, Bryan J; Archer, Iris; Liu, Andrew; Bambina, Shelly; Baird, Jason; Gough, Michael; Chakhtoura, Marita; Haddad, Elias K; Kirby, Ilsa T; Nilsen, Aaron; Streblow, Daniel N; Hirsch, Alec J; Smith, Jessica L; DeFilippis, Victor R

    2017-05-02

    The ongoing concurrent outbreaks of Zika, Chikungunya, and dengue viruses in Latin America and the Caribbean highlight the need for development of broad-spectrum antiviral treatments. The type I interferon (IFN) system has evolved in vertebrates to generate tissue responses that actively block replication of multiple known and potentially zoonotic viruses. As such, its control and activation through pharmacological agents may represent a novel therapeutic strategy for simultaneously impairing growth of multiple virus types and rendering host populations resistant to virus spread. In light of this strategy's potential, we undertook a screen to identify novel interferon-activating small molecules. Here, we describe 1-(2-fluorophenyl)-2-(5-isopropyl-1,3,4-thiadiazol-2-yl)-1,2-dihydrochromeno[2,3- c ]pyrrole-3,9-dione, which we termed AV-C. Treatment of human cells with AV-C activates innate and interferon-associated responses that strongly inhibit replication of Zika, Chikungunya, and dengue viruses. By utilizing genome editing, we investigated the host proteins essential to AV-C-induced cellular states. This showed that the compound requires a TRIF-dependent signaling cascade that culminates in IFN regulatory factor 3 (IRF3)-dependent expression and secretion of type I interferon to elicit antiviral responses. The other canonical IRF3-terminal adaptor proteins STING and IPS-1/MAVS were dispensable for AV-C-induced phenotypes. However, our work revealed an important inhibitory role for IPS-1/MAVS, but not TRIF, in flavivirus replication, implying that TRIF-directed viral evasion may not occur. Additionally, we show that in response to AV-C, primary human peripheral blood mononuclear cells secrete proinflammatory cytokines that are linked with establishment of adaptive immunity to viral pathogens. Ultimately, synthetic innate immune activators such as AV-C may serve multiple therapeutic purposes, including direct antimicrobial responses and facilitation of pathogen

  18. Monophosphoryl lipid A induces protection against LPS in medullary thick ascending limb through a TLR4-TRIF-PI3K signaling pathway.

    Science.gov (United States)

    Watts, Bruns A; George, Thampi; Sherwood, Edward R; Good, David W

    2017-07-01

    Monophosphoryl lipid A (MPLA) is a detoxified derivative of LPS that induces tolerance to LPS and augments host resistance to bacterial infections. Previously, we demonstrated that LPS inhibits [Formula: see text] absorption in the medullary thick ascending limb (MTAL) through a basolateral Toll-like receptor 4 (TLR4)-myeloid differentiation factor 88 (MyD88)-ERK pathway. Here we examined whether pretreatment with MPLA would attenuate LPS inhibition. MTALs from rats were perfused in vitro with MPLA (1 µg/ml) in bath and lumen or bath alone for 2 h, and then LPS was added to (and MPLA removed from) the bath solution. Pretreatment with MPLA eliminated LPS-induced inhibition of [Formula: see text] absorption. In MTALs pretreated with MPLA plus a phosphatidylinositol 3-kinase (PI3K) or Akt inhibitor, LPS decreased [Formula: see text] absorption. MPLA increased Akt phosphorylation in dissected MTALs. The Akt activation was eliminated by a PI3K inhibitor and in MTALs from TLR4 -/- or Toll/IL-1 receptor domain-containing adaptor-inducing IFN-β (TRIF) -/- mice. The effect of MPLA to prevent LPS inhibition of [Formula: see text] absorption also was TRIF dependent. Pretreatment with MPLA prevented LPS-induced ERK activation; this effect was dependent on PI3K. MPLA alone had no effect on [Formula: see text] absorption, and MPLA pretreatment did not prevent ERK-mediated inhibition of [Formula: see text] absorption by aldosterone, consistent with MPLA's low toxicity profile. These results demonstrate that pretreatment with MPLA prevents the effect of LPS to inhibit [Formula: see text] absorption in the MTAL. This protective effect is mediated directly through MPLA stimulation of a TLR4-TRIF-PI3K-Akt pathway that prevents LPS-induced ERK activation. These studies identify detoxified TLR4-based immunomodulators as novel potential therapeutic agents to prevent or treat renal tubule dysfunction in response to bacterial infections. Copyright © 2017 the American Physiological

  19. Pioglitazone inhibits angiotensin II-induced atrial fibroblasts proliferation via NF-κB/TGF-β1/TRIF/TRAF6 pathway

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Xiao-qing [Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiaotong University, 241 west Huaihai Road, Shanghai 200030 (China); Liu, Xu, E-mail: xkliuxu@126.com [Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiaotong University, 241 west Huaihai Road, Shanghai 200030 (China); Wang, Quan-xing, E-mail: wqxejd@126.com [National Key Laboratory of Medical Immunology, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433 (China); Zhang, Ming-jian; Guo, Meng; Liu, Fang [National Key Laboratory of Medical Immunology, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433 (China); Jiang, Wei-feng; Zhou, Li [Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiaotong University, 241 west Huaihai Road, Shanghai 200030 (China)

    2015-01-01

    The exact mechanisms underlying inhibitory effects of pioglitazone (Pio) on Angiotensin II (AngII)-induced atrial fibrosis are complex and remain largely unknown. In the present study, we examined the effect of Pio on AngII-induced mice atrial fibrosis in vivo and atrial fibroblasts proliferation in vitro. In vivo study showed that AngII infusion induced atrial fibrosis and increased expressions of Toll/IL-1 receptor domain-containing adaptor inducing IFN-β (TRIF) and tumor necrosis factor receptor associated factor 6 (TRAF6) in mice models. However, those effects could be attenuated by Pio (P<0.01). As for in vitro experiment, Pio suppressed AngII-induced atrial fibroblasts proliferation via nuclear factor-κB/transforming growth factor-β1/TRIF/TRAF6 signaling pathway in primary cultured mice atrial fibroblasts (P<0.01). In conclusion, suppression of Pio on AngII-induced atrial fibrosis might be related to its inhibitory effects on above signaling pathway. - Highlights: • Angiotensin II increased atrial fibrosis and related gene expressions in mice. • Angiotensin II induced atrial fibroblasts proliferation by activating signaling pathway. • Pioglitazone reversed both aforementioned changes.

  20. Downstream Toll-like receptor signaling mediates adaptor-specific cytokine expression following focal cerebral ischemia

    Directory of Open Access Journals (Sweden)

    Bolanle Famakin

    2012-07-01

    Full Text Available Abstract Background Deletion of some Toll-like receptors (TLRs affords protection against cerebral ischemia, but disruption of their known major downstream adaptors does not. To determine whether compensation in the production of downstream effectors by one pathway when the other is disrupted can explain these findings, we examined cytokine/chemokine expression and inflammatory infiltrates in wild-type (WT, MyD88−/− and TRIF-mutant mice following permanent middle cerebral artery occlusion (pMCAO. Methods Cytokine/chemokine expression was measured with a 25-plex bead array in the serum and brains of all three groups of mice at baseline (no surgery/naïve and at 3 hours and 24 hours following pMCAO. Brain inflammatory and neutrophil infiltrates were examined 24 hours following pMCAO. Results IL-6, keratinocyte chemoattractant (KC, granulocyte colony-stimulating factor (G-CSF and IL-10 were significantly decreased in MyD88−/− mice compared to WT mice following pMCAO. Significantly, decreased levels of the neutrophil chemoattractants KC and G-CSF corresponded with a trend toward fewer neutrophils in the brains of MyD88−/− mice. IP-10 was significantly decreased when either pathway was disrupted. MIP-1α was significantly decreased in TRIF-mutant mice, consistent with TRIF-dependent production. MyD88−/− mice showed elevations of a number of Th2 cytokines, such as IL-13, at baseline, which became significantly decreased following pMCAO. Conclusions Both MyD88 and TRIF mediate pathway-specific cytokine production following focal cerebral ischemia. Our results also suggest a compensatory Th2-type skew at baseline in MyD88−/− mice and a paradoxical switch to a Th1 phenotype following focal cerebral ischemia. The MyD88 pathway directs the expression of neutrophil chemoattractants following cerebral ischemia.

  1. Carga eletrônica ativa trifásica

    OpenAIRE

    Heerdt, Joselito Anastácio

    2013-01-01

    Tese (doutorado) - Universidade Federal de Santa Catarina, Centro Tecnológico, Programa de Pós-Graduação em Engenharia Elétrica, Florianópolis, 2013. Neste trabalho estão apresentados os estudos efetuados do conversor trifásico bidirecional de três níveis (NPCm), aplicado a operação como Carga Eletrônica Ativa de corrente alternada. Os esforços de corrente e de tensão são analisados, modelados e comparados com o conversor NPC, bem como as perdas dos seus dispositivos semicondutores, para v...

  2. The ubiquitin-like protein PLIC-1 or ubiquilin 1 inhibits TLR3-Trif signaling.

    Directory of Open Access Journals (Sweden)

    Nabanita Biswas

    Full Text Available The innate immune responses to virus infection are initiated by either Toll-like receptors (TLR3/7/8/9 or cytoplasmic double-stranded RNA (dsRNA-recognizing RNA helicases RIG-I and MDA5. To avoid causing injury to the host, these signaling pathways must be switched off in time by negative regulators.Through yeast-two hybrid screening, we found that an ubiquitin-like protein named protein linking integrin-associated protein to cytoskeleton 1(PLIC-1 or Ubiquilin 1 interacted with the Toll/interleukin-1 receptor (TIR domain of TLR4. Interestingly, PLIC-1 had modest effect on TLR4-mediated signaling, but strongly suppressed the transcriptional activation of IFN-β promoter through the TLR3-Trif-dependent pathway. Concomitantly, reduction of endogenous PLIC-1 by short-hairpin interfering RNA (shRNA enhanced TLR3 activation both in luciferase reporter assays as well as in new castle disease virus (NDV infected cells. An interaction between PLIC-1 and Trif was confirmed in co-immunoprecipitation (Co-IP and GST-pull-down assays. Subsequent confocal microscopic analysis revealed that PLIC-1 and Trif colocalized with the autophagosome marker LC3 in punctate subcellular structures. Finally, overexpression of PLIC-1 decreased Trif protein abundance in a Nocodazole-sensitive manner.Our results suggest that PLIC-1 is a novel inhibitor of the TLR3-Trif antiviral pathway by reducing the abundance of Trif.

  3. A dimer of the Toll-like receptor 4 cytoplasmic domain provides a specific scaffold for the recruitment of signalling adaptor proteins.

    Directory of Open Access Journals (Sweden)

    Ricardo Núñez Miguel

    2007-08-01

    Full Text Available The Toll-like receptor 4 (TLR4 is a class I transmembrane receptor expressed on the surface of immune system cells. TLR4 is activated by exposure to lipopolysaccharides derived from the outer membrane of Gram negative bacteria and forms part of the innate immune response in mammals. Like other class 1 receptors, TLR4 is activated by ligand induced dimerization, and recent studies suggest that this causes concerted conformational changes in the receptor leading to self association of the cytoplasmic Toll/Interleukin 1 receptor (TIR signalling domain. This homodimerization event is proposed to provide a new scaffold that is able to bind downstream signalling adaptor proteins. TLR4 uses two different sets of adaptors; TRAM and TRIF, and Mal and MyD88. These adaptor pairs couple two distinct signalling pathways leading to the activation of interferon response factor 3 (IRF-3 and nuclear factor kappaB (NFkappaB respectively. In this paper we have generated a structural model of the TLR4 TIR dimer and used molecular docking to probe for potential sites of interaction between the receptor homodimer and the adaptor molecules. Remarkably, both the Mal and TRAM adaptors are strongly predicted to bind at two symmetry-related sites at the homodimer interface. This model of TLR4 activation is supported by extensive functional studies involving site directed mutagenesis, inhibition by cell permeable peptides and stable protein phosphorylation of receptor and adaptor TIR domains. Our results also suggest a molecular mechanism for two recent findings, the caspase 1 dependence of Mal signalling and the protective effects conferred by the Mal polymorphism Ser180Leu.

  4. A novel synthetic derivative of melatonin, 5-hydroxy-2’-isobutyl-streptochlorin (HIS), inhibits inflammatory responses via regulation of TRIF-dependent signaling and inflammasome activation

    Energy Technology Data Exchange (ETDEWEB)

    Shim, Do-Wan [Department of Biotechnology, Research Institute of Inflammatory Disease, Konkuk University, Chungju (Korea, Republic of); Shin, Hee Jae [Marine Natural Products Chemistry Laboratory, Korea Institute of Ocean Science & Technology, Ansan (Korea, Republic of); Han, Ji-Won; Ji, Young-Eun; Jang, Cheol-Hun; Koppula, Sushruta; Kang, Tae-Bong [Department of Biotechnology, Research Institute of Inflammatory Disease, Konkuk University, Chungju (Korea, Republic of); Lee, Kwang-Ho, E-mail: kwangho@kku.ac.kr [Department of Biotechnology, Research Institute of Inflammatory Disease, Konkuk University, Chungju (Korea, Republic of)

    2015-04-15

    Melatonin is substantially reported to possess anti-inflammatory properties. In the present study, we synthesized a novel melatonin derivative, 5-hydroxy-2′-isobutyl-streptochlorin (HIS), which displayed superior anti-inflammatory properties to its parent compound. Further, we explored its underlying mechanisms in cellular and experimental animal models. Lipopolysaccharide was used to induce in vitro inflammatory responses in RAW 264.7 macrophages. LPS-primed macrophages were pulsed with biologically unrelated toxic molecules to evaluate the role of HIS on inflammasome activation. In vivo verifications were carried out using acute lung injury (ALI) and Escherichia coli-induced septic shock mouse models. HIS inhibited the production of proinflammatory mediators and cytokines such as nitric oxide, cyclooxygenase 2, IL-1β, IL-6 and TNF-α in LPS-stimulated RAW 264.7 macrophages. HIS suppressed the infiltration of immune cells into the lung and the production of pro-inflammatory cytokines such as IL-6 and TNF-α in broncho-alveolar lavage fluid in the ALI mouse model. Mechanistic studies revealed that the inhibitory effects of HIS were mediated through the regulation of the TIR domain-containing, adaptor-inducing, interferon-β (TRIF)-dependent signaling pathway from toll-like receptors. Further, HIS attenuated IL-1β secretion via the inhibition of NLRP3 inflammasome activation independent of mitochondrial ROS production. Furthermore, HIS suppressed IL-1β, IL-6 and interferon-β production in peritoneal lavage in the Escherichia coli-induced sepsis mouse model. In conclusion, HIS exerted potent anti-inflammatory effects via the regulation of TRIF-dependent signaling and inflammasome activation. Notably, the superior anti-inflammatory properties of this derivative compared with its parent compound could be a promising lead for treating various inflammatory-mediated diseases. - Highlights: • Νovel compound, 5-hydroxy-2′-isobutyl-streptochlorin (HIS) was

  5. Role of adaptor proteins in secretory granule biogenesis and maturation

    Directory of Open Access Journals (Sweden)

    Mathilde L Bonnemaison

    2013-08-01

    Full Text Available In the regulated secretory pathway, secretory granules (SGs store peptide hormones that are released on demand. SGs are formed at the trans-Golgi network (TGN and must undergo a maturation process to become responsive to secretagogues. The production of mature SGs requires concentrating newly synthesized soluble content proteins in granules whose membranes contain the appropriate integral membrane proteins. The mechanisms underlying the sorting of soluble and integral membrane proteins destined for SGs from other proteins are not yet well understood. For soluble proteins, luminal pH and divalent metals can affect aggregation and interaction with surrounding membranes. The trafficking of granule membrane proteins can be controlled by both luminal and cytosolic factors. Cytosolic adaptor proteins, which recognize the cytosolic domains of proteins that span the SG membrane, have been shown to play essential roles in the assembly of functional SGs. Adaptor protein 1A (AP-1A is known to interact with specific motifs in its cargo proteins and with the clathrin heavy chain, contributing to the formation of a clathrin coat. AP-1A is present in patches on immature SG membranes, where it removes cargo and facilitates SG maturation. AP-1A recruitment to membranes can be modulated by PACS-1 (Phosphofurin Acidic Cluster Sorting protein 1, a cytosolic protein which interacts with both AP-1A and cargo that has been phosphorylated by casein kinase II. A cargo/PACS-1/AP-1A complex is necessary to drive the appropriate transport of several cargo proteins within the regulated secretory pathway. The GGA (Golgi-localized, -ear containing, ADP-ribosylation factor binding family of adaptor proteins serve a similar role. We review the functions of AP-1A, PACS-1 and GGAs in facilitating the retrieval of proteins from immature SGs and review examples of cargo proteins whose trafficking within the regulated secretory pathway is governed by adaptor proteins.

  6. Release of IL-12 by dendritic cells activated by TLR ligation is dependent on MyD88 signaling, whereas TRIF signaling is indispensable for TLR synergy.

    Science.gov (United States)

    Krummen, Mathias; Balkow, Sandra; Shen, Limei; Heinz, Stefanie; Loquai, Carmen; Probst, Hans-Christian; Grabbe, Stephan

    2010-07-01

    Recently, it has been shown that certain combinations of TLR ligands act in synergy to induce the release of IL-12 by DCs. In this study, we sought to define the critical parameters underlying TLR synergy. Our data show that TLR ligands act synergistically if MyD88- and TRIF-dependent ligands are combined. TLR4 uses both of these adaptor molecules, thus activation via TLR4 proved to be a synergistic event on its own. TLR synergy did not affect all aspects of DC activation but enhanced primarily the release of certain cytokines, particularly IL-12, whereas the expression of costimulatory molecules remained unchanged. Consequently, synergistic activation of DC did not affect their ability to induce T cell proliferation but resulted in T(H)1-biased responses in vitro and in vivo. Furthermore, we examined the impact of TLR ligand combinations on primary DC in vitro but observed only modest effects with a combination of CpG + Poly (I:C). However, noticeable synergy in terms of IL-12 production by DCs was detectable in vivo after systemic administration of CpG + Poly (I:C). Finally, we show that synergy is partially dependent on IFNAR signaling but does not require the release of IFNs to the enviroment, suggesting an autocrine action of type I IFNs.

  7. Styles of Creativity: Adaptors and Innovators in a Singapore Context

    Science.gov (United States)

    Ee, Jessie; Seng, Tan Oon; Kwang, Ng Aik

    2007-01-01

    Kirton (1976) described two creative styles, namely adaptors and innovators. Adaptors prefer to "do things better" whilst, innovators prefer to "do things differently". This study explored the relationship between two creative styles (adaptor and innovator) and the Big Five personality traits (extraversion, agreeableness, conscientiousness,…

  8. 21 CFR 870.3620 - Pacemaker lead adaptor.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Pacemaker lead adaptor. 870.3620 Section 870.3620...) MEDICAL DEVICES CARDIOVASCULAR DEVICES Cardiovascular Prosthetic Devices § 870.3620 Pacemaker lead adaptor. (a) Identification. A pacemaker lead adaptor is a device used to adapt a pacemaker lead so that it...

  9. Palmitoylated transmembrane adaptor proteins in leukocyte signaling

    Czech Academy of Sciences Publication Activity Database

    Štěpánek, Ondřej; Dráber, Peter; Hořejší, Václav

    2014-01-01

    Roč. 26, č. 5 (2014), s. 895-902 ISSN 0898-6568 R&D Projects: GA ČR(CZ) GBP302/12/G101 Institutional support: RVO:68378050 Keywords : Leukocyte * Adaptor * Palmitoylation Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 4.315, year: 2014

  10. PAG - a multipurpose transmembrane adaptor protein

    Czech Academy of Sciences Publication Activity Database

    Hrdinka, Matouš; Hořejší, Václav

    2014-01-01

    Roč. 33, č. 41 (2014), s. 4881-4892 ISSN 0950-9232 R&D Projects: GA ČR(CZ) GBP302/12/G101 Institutional support: RVO:68378050 Keywords : PAG * adaptor protein * membrane raft Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 8.459, year: 2014

  11. Mycobacterial Phenolic Glycolipids Selectively Disable TRIF-Dependent TLR4 Signaling in Macrophages

    Directory of Open Access Journals (Sweden)

    Reid Oldenburg

    2018-01-01

    Full Text Available Phenolic glycolipids (PGLs are cell wall components of a subset of pathogenic mycobacteria, with immunomodulatory properties. Here, we show that in addition, PGLs exert antibactericidal activity by limiting the production of nitric oxide synthase (iNOS in mycobacteria-infected macrophages. PGL-mediated downregulation of iNOS was complement receptor 3-dependent and comparably induced by bacterial and purified PGLs. Using Mycobacterium leprae PGL-1 as a model, we found that PGLs dampen the toll-like receptor (TLR4 signaling pathway, with macrophage exposure to PGLs leading to significant reduction in TIR-domain-containing adapter-inducing interferon-β (TRIF protein level. PGL-driven decrease in TRIF operated posttranscriptionally and independently of Src-family tyrosine kinases, lysosomal and proteasomal degradation. It resulted in the defective production of TRIF-dependent IFN-β and CXCL10 in TLR4-stimulated macrophages, in addition to iNOS. Our results unravel a mechanism by which PGLs hijack both the bactericidal and inflammatory responses of host macrophages. Moreover, they identify TRIF as a critical node in the crosstalk between CR3 and TLR4.

  12. Pepsin Digest of Wheat Gliadin Fraction Increases Production of IL-1β via TLR4/MyD88/TRIF/MAPK/NF-κB Signaling Pathway and an NLRP3 Inflammasome Activation

    Science.gov (United States)

    Palová-Jelínková, Lenka; Dáňová, Klára; Drašarová, Hana; Dvořák, Miloš; Funda, David P.; Fundová, Petra; Kotrbová-Kozak, Anna; Černá, Marie; Kamanová, Jana; Martin, Stefan F.; Freudenberg, Marina; Tučková, Ludmila

    2013-01-01

    Celiac disease (CD) is a gluten-responsive, chronic inflammatory enteropathy. IL-1 cytokine family members IL-1β and IL-18 have been associated with the inflammatory conditions in CD patients. However, the mechanisms of IL-1 molecule activation in CD have not yet been elucidated. We show in this study that peripheral blood mononuclear cells (PBMC) and monocytes from celiac patients responded to pepsin digest of wheat gliadin fraction (PDWGF) by a robust secretion of IL-1β and IL-1α and a slightly elevated production of IL-18. The analysis of the upstream mechanisms underlying PDWGF-induced IL-1β production in celiac PBMC show that PDWGF-induced de novo pro-IL-1β synthesis, followed by a caspase-1 dependent processing and the secretion of mature IL-1β. This was promoted by K+ efflux and oxidative stress, and was independent of P2X7 receptor signaling. The PDWGF-induced IL-1β release was dependent on Nod-like receptor family containing pyrin domain 3 (NLRP3) and apoptosis-associated speck like protein (ASC) as shown by stimulation of bone marrow derived dendritic cells (BMDC) from NLRP3−/− and ASC−/− knockout mice. Moreover, treatment of human PBMC as well as MyD88−/− and Toll-interleukin-1 receptor domain-containing adaptor-inducing interferon-β (TRIF)−/− BMDC illustrated that prior to the activation of caspase-1, the PDWGF-triggered signal constitutes the activation of the MyD88/TRIF/MAPK/NF-κB pathway. Moreover, our results indicate that the combined action of TLR2 and TLR4 may be required for optimal induction of IL-1β in response to PDWGF. Thus, innate immune pathways, such as TLR2/4/MyD88/TRIF/MAPK/NF-κB and an NLRP3 inflammasome activation are involved in wheat proteins signaling and may play an important role in the pathogenesis of CD. PMID:23658628

  13. Análisis de un sistema de distribución trifásico.

    OpenAIRE

    Cevallos Jácome, Luis Salvador; Medina González, Rubén Andrés

    2015-01-01

    Los sistemas trifásicos de distribución son la manera más eficiente que las empresas suministradoras de la energía eléctrica emplean para distribuir a los usuarios. Los parámetros regulados son: el nivel de voltaje en las instalaciones de los usuarios, bajo factor de potencia, corrientes parásitas o armónicas, etc. El análisis de los sistemas de distribución nos permitirá establecer soluciones viables, efectivas y económicas para solucionar o regular estos parámetros dentro de los rangos est...

  14. A role for cargo in Arf-dependent adaptor recruitment.

    Science.gov (United States)

    Caster, Amanda H; Sztul, Elizabeth; Kahn, Richard A

    2013-05-24

    Membrane traffic requires the specific concentration of protein cargos and exclusion of other proteins into nascent carriers. Critical components of this selectivity are the protein adaptors that bind to short, linear motifs in the cytoplasmic tails of transmembrane protein cargos and sequester them into nascent carriers. The recruitment of the adaptors is mediated by activated Arf GTPases, and the Arf-adaptor complexes mark sites of carrier formation. However, the nature of the signal(s) that initiates carrier biogenesis remains unknown. We examined the specificity and initial sites of recruitment of Arf-dependent adaptors (AP-1 and GGAs) in response to the Golgi or endosomal localization of specific cargo proteins (furin, mannose-6-phosphate receptor (M6PR), and M6PR lacking a C-terminal domain M6PRΔC). We find that cargo promotes the recruitment of specific adaptors, suggesting that it is part of an upstream signaling event. Cargos do not promote adaptor recruitment to all compartments in which they reside, and thus additional factors regulate the cargo's ability to promote Arf activation and adaptor recruitment. We document that within a given compartment different cargos recruit different adaptors, suggesting that there is little or no free, activated Arf at the membrane and that Arf activation is spatially and temporally coupled to the cargo and the adaptor. Using temperature block, brefeldin A, and recovery from each, we found that the cytoplasmic tail of M6PR causes the recruitment of AP-1 and GGAs to recycling endosomes and not at the Golgi, as predicted by steady state staining profiles. These results are discussed with respect to the generation of novel models for cargo-dependent regulation of membrane traffic.

  15. A Role for Cargo in Arf-dependent Adaptor Recruitment*

    Science.gov (United States)

    Caster, Amanda H.; Sztul, Elizabeth; Kahn, Richard A.

    2013-01-01

    Membrane traffic requires the specific concentration of protein cargos and exclusion of other proteins into nascent carriers. Critical components of this selectivity are the protein adaptors that bind to short, linear motifs in the cytoplasmic tails of transmembrane protein cargos and sequester them into nascent carriers. The recruitment of the adaptors is mediated by activated Arf GTPases, and the Arf-adaptor complexes mark sites of carrier formation. However, the nature of the signal(s) that initiates carrier biogenesis remains unknown. We examined the specificity and initial sites of recruitment of Arf-dependent adaptors (AP-1 and GGAs) in response to the Golgi or endosomal localization of specific cargo proteins (furin, mannose-6-phosphate receptor (M6PR), and M6PR lacking a C-terminal domain M6PRΔC). We find that cargo promotes the recruitment of specific adaptors, suggesting that it is part of an upstream signaling event. Cargos do not promote adaptor recruitment to all compartments in which they reside, and thus additional factors regulate the cargo's ability to promote Arf activation and adaptor recruitment. We document that within a given compartment different cargos recruit different adaptors, suggesting that there is little or no free, activated Arf at the membrane and that Arf activation is spatially and temporally coupled to the cargo and the adaptor. Using temperature block, brefeldin A, and recovery from each, we found that the cytoplasmic tail of M6PR causes the recruitment of AP-1 and GGAs to recycling endosomes and not at the Golgi, as predicted by steady state staining profiles. These results are discussed with respect to the generation of novel models for cargo-dependent regulation of membrane traffic. PMID:23572528

  16. Toll-like receptor 3 activation impairs excitability and synaptic activity via TRIF signalling in immature rat and human neurons.

    Science.gov (United States)

    Ritchie, Louise; Tate, Rothwell; Chamberlain, Luke H; Robertson, Graham; Zagnoni, Michele; Sposito, Teresa; Wray, Selina; Wright, John A; Bryant, Clare E; Gay, Nicholas J; Bushell, Trevor J

    2018-03-02

    Toll like receptor 3 (TLR3) belongs to a family of pattern recognition receptors that recognise molecules found on pathogens referred to as pathogen associated molecular patterns (PAMPs). Its involvement in innate immunity is well known but despite its presence in the central nervous system (CNS), our knowledge of its function is limited. Here, we have investigated whether TLR3 activation modulates synaptic activity in primary hippocampal cultures and induced pluripotent stem cell (iPSC)-derived neurons. Synaptically driven spontaneous action potential (AP) firing was significantly reduced by the TLR3 specific activator, poly I:C, in a concentration-dependent manner following both short (5 min) and long exposures (1h) in rat hippocampal cultures. Notably, the consequence of TLR3 activation on neuronal function was reproduced in iPSC-derived cortical neurons, with poly I:C (25 μg/ml, 1h) significantly inhibiting sAP firing. We examined the mechanisms underlying these effects, with poly I:C significantly reducing peak sodium current, an effect dependent on the MyD88-independent TRIF dependent pathway. Furthermore, poly I:C (25 μg/ml, 1h) resulted in a significant reduction in miniature excitatory postsynaptic potential (mEPSC) frequency and amplitude and significantly reduced surface AMPAR expression. These novel findings reveal that TLR3 activation inhibits neuronal excitability and synaptic activity through multiple mechanisms, with this being observed in both rat and human iPSC-derived neurons. These data might provide further insight into how TLR3 activation may contribute to neurodevelopmental disorders following maternal infection and in patients with increased susceptibility to herpes simplex encephalitis. Copyright © 2018. Published by Elsevier Ltd.

  17. Reconhecimento de padrões de falhas em motores trifásicos utilizando redes neurais

    OpenAIRE

    Reis, Aderson Jamier Santos

    2010-01-01

    Este trabalho apresenta um sistema de diagnóstico de falhas (rotor, estator e contaminação) do motor de indução trifásico através dos parâmetros do circuito equivalente e utilizando técnicas de reconhecimento de padrões. A tecnologia de detecção de falhas em motores está evoluindo e tornando cada vez mais importante na área de máquinas elétricas. As redes neurais possuem a habilidade de classificar relações não lineares entre sinais através da identificação de padrões dos sinai...

  18. Efectos de los huecos de tensión en las máquinas de inducción y en los transformadores trifásicos

    OpenAIRE

    Guasch Pesquer, Luis

    2006-01-01

    Este trabajo se enmarca dentro de la calidad del suministro de energía eléctrica y, en concreto, en el efecto que producen los huecos de tensión en las máquinas de inducción y en los transformadores trifásicos.En primer lugar se ha realizado una introducción al estudio de sistemas trifásicos mediante el método de las componentes simétricas que permiten obtener las ecuaciones de los huecos de tensión analizando las faltas que los originan (trifásica, trifásica-tierra, fase-tierra, fase-fas...

  19. Monitoreo de las variables eléctricas relacionadas con un generador trifásico

    Directory of Open Access Journals (Sweden)

    Flavio Humberto Fernández-Morales

    2014-01-01

    Full Text Available Los generadores trifásicos son máquinas ampliamente utilizadas como fuentes de energía eléctrica. Es común encontrarlos asociados a sistemas de alimentación alternativos como grupos electrógenos, microcentrales hidráulicas y generadores eólicos. Usualmente estos generadores, de baja y media potencia, no cuentan con la instrumentación adecuada para que el usuario pueda establecer su correcto funcionamiento. En este trabajo se describe el diseño y puesta a punto de un sistema para la medición de las variables asociadas a un generador trifásico. Se desarrollaron dos módulos: uno de tensión, que adicionalmente se encarga de medir la frecuencia y verificar la secuencia de fase; mientras que el otro módulo mide la corriente eléctrica. El procesamiento de la información se realiza con microcontroladores PIC 16F873, a los cuales se adaptaron los transformadores de medida y demás dispositivos para el acondicionamiento de las señales. Cada módulo permite la visualización de las variables a través de una pantalla de cristal líquido. El rango de operación del sistema es de 22 a 150 VAC, con un error relativo máximo de 7.6%; mientras que la corriente puede variar 100 A, con un error relativo máximo de 6.3%.

  20. DMPD: The SAP family of adaptors in immune regulation. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 15541655 The SAP family of adaptors in immune regulation. Latour S, Veillette A. Se...min Immunol. 2004 Dec;16(6):409-19. (.png) (.svg) (.html) (.csml) Show The SAP family of adaptors in immune ...regulation. PubmedID 15541655 Title The SAP family of adaptors in immune regulation. Authors Latour S, Veill

  1. Spiral biasing adaptor for use in Si drift detectors and Si drift detector arrays

    Science.gov (United States)

    Li, Zheng; Chen, Wei

    2016-07-05

    A drift detector array, preferably a silicon drift detector (SDD) array, that uses a low current biasing adaptor is disclosed. The biasing adaptor is customizable for any desired geometry of the drift detector single cell with minimum drift time of carriers. The biasing adaptor has spiral shaped ion-implants that generate the desired voltage profile. The biasing adaptor can be processed on the same wafer as the drift detector array and only one biasing adaptor chip/side is needed for one drift detector array to generate the voltage profiles on the front side and back side of the detector array.

  2. Análisis y diseño de un rectificador trifásico elevador PWM

    OpenAIRE

    García Bragado, Alejandro

    2010-01-01

    El principal objetivo de este proyecto es el de analizar, modelar, simular y validar experimentalmente un rectificador trifásico controlado tipo elevador, a partir de sus ecuaciones matemáticas. Para ello se utilizará la aplicación informática Matlab®, y su entorno Simulink®, junto con la herramienta de simulación PSIM®. Posteriormente se diseñará un sistema de control basado en la modulación por ancho de pulso (PWM) con las mismas herramientas para implementar dicho sistema de control en un ...

  3. Estrategias de inyección de potencia reactiva en un inversor trifásico conectado a red

    OpenAIRE

    Torres Martínez, Javier

    2013-01-01

    Se presenta un control de potencia reactiva, para plantas de generación eléctrica conectadas a red a través de inversores trifásicos, capaz de tratar la problemática de los huecos de tensión. Las redes de distribución eléctrica presentan unas normas que describen el comportamiento de la fuente de energía ante los fallos de red, con referencia a la inyección de potencia reactiva para permanecer conectado a la misma. Se detalla el funcionamiento del control y las limitaciones que este pre...

  4. A Big-Five Personality Profile of the Adaptor and Innovator.

    Science.gov (United States)

    Kwang, Ng Aik; Rodrigues, Daphne

    2002-01-01

    A study explored the relationship between two creative types (adaptor and innovator) and the Big Five personality traits (extraversion, agreeableness, conscientiousness, neuroticism, and openness to experience), in 164 teachers in Singapore. Adaptors were significantly more conscientious than innovators, while innovators were significantly more…

  5. 21 CFR 870.4290 - Cardiopulmonary bypass adaptor, stopcock, manifold, or fitting.

    Science.gov (United States)

    2010-04-01

    ..., or fitting. 870.4290 Section 870.4290 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF... Devices § 870.4290 Cardiopulmonary bypass adaptor, stopcock, manifold, or fitting. (a) Identification. A cardiopulmonary bypass adaptor, stopcock, manifold, or fitting is a device used in cardiovascular diagnostic...

  6. DMPD: Structure, function and regulation of the Toll/IL-1 receptor adaptor proteins. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17667936 Structure, function and regulation of the Toll/IL-1 receptor adaptor proteins... (.svg) (.html) (.csml) Show Structure, function and regulation of the Toll/IL-1 receptor adaptor proteins. ...PubmedID 17667936 Title Structure, function and regulation of the Toll/IL-1 receptor adaptor proteins

  7. Arabidopsis adaptor protein 1G is critical for pollen development.

    Science.gov (United States)

    Feng, Chong; Wang, Jia-Gang; Liu, Hai-Hong; Li, Sha; Zhang, Yan

    2017-09-01

    Pollen development is a pre-requisite for sexual reproduction of angiosperms, during which various cellular activities are involved. Pollen development accompanies dynamic remodeling of vacuoles through fission and fusion, disruption of which often compromises pollen viability. We previously reported that the Y subunit of adaptor protein 1 (AP1G) mediates synergid degeneration during pollen tube reception. Here, we demonstrate that AP1G is essential for pollen development. AP1G loss-of-function resulted in male gametophytic lethality due to defective pollen development. By ultrastructural analysis and fluorescence labeling, we demonstrate that AP1G loss-of-function compromised dynamic vacuolar remodeling during pollen development and impaired vacuolar acidification of pollen. Results presented here support a key role of vacuoles in gametophytic pollen development. © 2017 Institute of Botany, Chinese Academy of Sciences.

  8. Study on the isothermal forging process of MB26 magnesium alloy adaptor

    Directory of Open Access Journals (Sweden)

    Xu Wenchen

    2015-01-01

    Full Text Available The isothermal forging process is an effective method to manufacture complex-shaped components of hard-to-work materials, such as magnesium alloys. This study investigates the isothermal forging process of an MB26 magnesium alloy adaptor with three branches. The results show that two-step forging process is appropriate to form the adaptor forging, which not only improves the filling quality but also reduces the forging load compared with one-step forging process. Moreover, the flow line is distributed along the contour of the complex-shaped adaptor forging.

  9. Role of Crk Adaptor Proteins in Cellular Migration and Invasion in Human Breast Cancer

    National Research Council Canada - National Science Library

    Fathers, Kelly E

    2007-01-01

    The Crk adaptor proteins (CrkI, CrkII and CrkL) play an important role during cellular signalling by mediating the formation of protein-protein complexes and are involved in cellular migration, invasion, and adhesion...

  10. Role of Crk Adaptor Proteins in Cellular Migration and Invasion in Human Breast Cancer

    National Research Council Canada - National Science Library

    Fathers, Kelly E

    2008-01-01

    The Crk adaptor proteins (CrkI, CrkII and CrkL) play an important role during cellular signalling by mediating the formation of protein-protein complexes and are involved in cellular migration, invasion, and adhesion...

  11. Eps15: a multifunctional adaptor protein regulating intracellular trafficking

    Directory of Open Access Journals (Sweden)

    van Bergen en Henegouwen Paul MP

    2009-10-01

    Full Text Available Abstract Over expression of receptor tyrosine kinases is responsible for the development of a wide variety of malignancies. Termination of growth factor signaling is primarily determined by the down regulation of active growth factor/receptor complexes. In recent years, considerable insight has been gained in the endocytosis and degradation of growth factor receptors. A crucial player in this process is the EGFR Protein tyrosine kinase Substrate #15, or Eps15. This protein functions as a scaffolding adaptor protein and is involved both in secretion and endocytosis. Eps15 has been shown to bind to AP-1 and AP-2 complexes, to bind to inositol lipids and to several other proteins involved in the regulation of intracellular trafficking. In addition, Eps15 has been detected in the nucleus of mammalian cells. Activation of growth factor receptors induces tyrosine phosphorylation and mono-ubiquitination of Eps15. The role of these post translational modifications of Eps15 is still a mystery. It is proposed that Eps15 and its family members Eps15R and Eps15b are involved in the regulation of membrane morphology, which is required for intracellular vesicle formation and trafficking.

  12. The Role of the Clathrin Adaptor AP-1: Polarized Sorting and Beyond

    Directory of Open Access Journals (Sweden)

    Fubito Nakatsu

    2014-11-01

    Full Text Available The selective transport of proteins or lipids by vesicular transport is a fundamental process supporting cellular physiology. The budding process involves cargo sorting and vesicle formation at the donor membrane and constitutes an important process in vesicular transport. This process is particularly important for the polarized sorting in epithelial cells, in which the cargo molecules need to be selectively sorted and transported to two distinct destinations, the apical or basolateral plasma membrane. Adaptor protein (AP-1, a member of the AP complex family, which includes the ubiquitously expressed AP-1A and the epithelium-specific AP-1B, regulates polarized sorting at the trans-Golgi network and/or at the recycling endosomes. A growing body of evidence, especially from studies using model organisms and animals, demonstrates that the AP-1-mediated polarized sorting supports the development and physiology of multi-cellular units as functional organs and tissues (e.g., cell fate determination, inflammation and gut immune homeostasis. Furthermore, a possible involvement of AP-1B in the pathogenesis of human diseases, such as Crohn’s disease and cancer, is now becoming evident. These data highlight the significant contribution of AP-1 complexes to the physiology of multicellular organisms, as master regulators of polarized sorting in epithelial cells.

  13. Software para la determinación del comportamiento de un motor asincrónico trifásico

    Directory of Open Access Journals (Sweden)

    Héctor Brito Socarrás

    2011-02-01

    Full Text Available El motor asincrónico trifásico es uno de los convertidores más empleados en la industria, por lo cual es de unagran necesidad conocer el comportamiento de estas máquinas. Esto se puede valorar a través de las característicasde operación. Este tipo de máquina en ocasiones sufre averías, por lo cual tienen que ser reparadas y enmuchas situaciones posteriormente determinar nuevamente sus características de operación. En el presentetrabajo  se  elabora  un  paquete  de  programas  de  computación  que  permite  obtener  las  características  de:comportamiento contra potencia de salida y comportamiento en un punto de trabajo.  The asynchronous tree-phases motor is one of the converters more employee in the industry, reason why is of agreat necessity to know the behavior of these machines. This you can value through the operation characteris-tics. This machine type in occasions suffers mishaps, reason why they have to be repaired and in many situa-tions after the same ones is necessary to determine its operation characteristics again.  Presently work iselaborated a package of calculation programs that allows to obtain the characteristics of: of behavior against exitpower and their behavior in a work point.

  14. “Diseño e Implementación de un Convertidor Trifásico en Base a Tiristores Utilizando un DSP”

    OpenAIRE

    Tapia Tinoco, Guillermo

    2012-01-01

    En este trabajo de tesis se presenta el diseño y construcción de un prototipo de un convertidor controlado por tiristores, el cual es adecuado para utilizarse en aplicaciones industriales. La topología del convertidor desarrollado se basa en un arreglo trifásico de seis pulsos, el cual se construye con tres módulos de tiristores y tres disparadores de ángulo de fase comerciales, lo cual constituye la parte de potencia del convertidor. Las tareas asociadas al control y procesami...

  15. Prevención de las fallas de los motores trifásicos de inducción mediante una adecuada selección

    Directory of Open Access Journals (Sweden)

    Osvaldo Guerreo Castro

    2010-10-01

    Full Text Available En este trabajo se expone los aspectos de mayor importancia a considerar enuna adecuada selección de motores para prevenir las fallas, así como lasrepercusiones que puede tener tanto en la operación del equipo, como en la cantidad, frecuencia y tipo de falla de los motores trifásicos de inducción.Primeramente, se expondrán los aspectos que prevalecen o se usan con mayorfrecuencia en la selección de un motor trifásico de inducción y otros aspectosque se deben analizar con el cuidado correspondiente y que no se consideranpara prevenir las fallas de estos equipos.No se pretende que este trabajo sea una guía en la selección de motores eléctricos, ya que existen otros aspectos a tomar en cuenta que no serán analizados, sin embargo, sirve de complemento, especialmente si se pretende prevenir las fallas de estos equipos desde su compra.En este trabajo se expone los aspectos de mayor importancia a considerar en una adecuada selección de motores para prevenir las fallas, así como las repercusiones que puede tener tanto en la operación del equipo, como en la cantidad, frecuencia y tipo de falla de los motores trifásicos de inducción.Primeramente, se expondrán los aspectos que prevalecen o se usan con mayorfrecuencia en la selección de un motor trifásico de inducción y otros aspectoque se deben analizar con el cuidado correspondiente y que no se consideranpara prevenir las fallas de estos equipos. No se pretende que este trabajo sea una guía en la selección de motores eléctricos, ya que existen otros aspectos a tomar en cuenta que no serán analizados, sin embargo, sirve de complemento, especialmente si se pretende prevenir las fallas de estos equipos desde su compra.

  16. Insight into Phosphatidylinositol-Dependent Membrane Localization of the Innate Immune Adaptor Protein Toll/Interleukin 1 Receptor Domain-Containing Adaptor Protein

    Science.gov (United States)

    Patra, Mahesh Chandra; Choi, Sangdun

    2018-01-01

    The toll/interleukin 1 receptor (TIR) domain-containing adaptor protein (TIRAP) plays an important role in the toll-like receptor (TLR) 2, TLR4, TLR7, and TLR9 signaling pathways. TIRAP anchors to phosphatidylinositol (PI) 4,5-bisphosphate (PIP2) on the plasma membrane and PI (3,4,5)-trisphosphate (PIP3) on the endosomal membrane and assists in recruitment of the myeloid differentiation primary response 88 protein to activated TLRs. To date, the structure and mechanism of TIRAP’s membrane association are only partially understood. Here, we modeled an all-residue TIRAP dimer using homology modeling, threading, and protein–protein docking strategies. Molecular dynamics simulations revealed that PIP2 creates a stable microdomain in a dipalmitoylphosphatidylcholine bilayer, providing TIRAP with its physiologically relevant orientation. Computed binding free energy values suggest that the affinity of PI-binding domain (PBD) for PIP2 is stronger than that of TIRAP as a whole for PIP2 and that the short PI-binding motif (PBM) contributes to the affinity between PBD and PIP2. Four PIP2 molecules can be accommodated by distinct lysine-rich surfaces on the dimeric PBM. Along with the known PI-binding residues (K15, K16, K31, and K32), additional positively charged residues (K34, K35, and R36) showed strong affinity toward PIP2. Lysine-to-alanine mutations at the PI-binding residues abolished TIRAP’s affinity for PIP2; however, K34, K35, and R36 consistently interacted with PIP2 headgroups through hydrogen bond (H-bond) and electrostatic interactions. TIRAP exhibited a PIP2-analogous intermolecular contact and binding affinity toward PIP3, aided by an H-bond network involving K34, K35, and R36. The present study extends our understanding of TIRAP’s membrane association, which could be helpful in designing peptide decoys to block TLR2-, TLR4-, TLR7-, and TLR9-mediated autoimmune diseases. PMID:29434596

  17. Insight into Phosphatidylinositol-Dependent Membrane Localization of the Innate Immune Adaptor Protein Toll/Interleukin 1 Receptor Domain-Containing Adaptor Protein

    Directory of Open Access Journals (Sweden)

    Mahesh Chandra Patra

    2018-01-01

    Full Text Available The toll/interleukin 1 receptor (TIR domain-containing adaptor protein (TIRAP plays an important role in the toll-like receptor (TLR 2, TLR4, TLR7, and TLR9 signaling pathways. TIRAP anchors to phosphatidylinositol (PI 4,5-bisphosphate (PIP2 on the plasma membrane and PI (3,4,5-trisphosphate (PIP3 on the endosomal membrane and assists in recruitment of the myeloid differentiation primary response 88 protein to activated TLRs. To date, the structure and mechanism of TIRAP’s membrane association are only partially understood. Here, we modeled an all-residue TIRAP dimer using homology modeling, threading, and protein–protein docking strategies. Molecular dynamics simulations revealed that PIP2 creates a stable microdomain in a dipalmitoylphosphatidylcholine bilayer, providing TIRAP with its physiologically relevant orientation. Computed binding free energy values suggest that the affinity of PI-binding domain (PBD for PIP2 is stronger than that of TIRAP as a whole for PIP2 and that the short PI-binding motif (PBM contributes to the affinity between PBD and PIP2. Four PIP2 molecules can be accommodated by distinct lysine-rich surfaces on the dimeric PBM. Along with the known PI-binding residues (K15, K16, K31, and K32, additional positively charged residues (K34, K35, and R36 showed strong affinity toward PIP2. Lysine-to-alanine mutations at the PI-binding residues abolished TIRAP’s affinity for PIP2; however, K34, K35, and R36 consistently interacted with PIP2 headgroups through hydrogen bond (H-bond and electrostatic interactions. TIRAP exhibited a PIP2-analogous intermolecular contact and binding affinity toward PIP3, aided by an H-bond network involving K34, K35, and R36. The present study extends our understanding of TIRAP’s membrane association, which could be helpful in designing peptide decoys to block TLR2-, TLR4-, TLR7-, and TLR9-mediated autoimmune diseases.

  18. Stepping motor adaptor actuator for a commercial uhv linear motion feedthrough

    International Nuclear Information System (INIS)

    Iarocci, M.; Oversluizen, T.

    1989-01-01

    An adaptor coupling has been developed that will allow the attachment of a standard stepping motor to a precision commercial (Varian) uhv linear motion feedthrough. The assembly, consisting of the motor, motor adaptor, limit switches, etc. is clamped to the feedthrough body which can be done under vacuum conditions if necessary. With a 500 step/rev. stepping motor the resolution is 1.27 μm per step. We presently use this assembly in a remote location for the precise positioning of a beam sensing monitor. 2 refs., 3 figs

  19. Anti-inflammatory effects of extract from Haliotis discus hannai fermented with Cordyceps militaris mycelia in RAW264.7 macrophages through TRIF-dependent signaling pathway.

    Science.gov (United States)

    Joung, Hong-Joo; Kim, Yon-Suk; Hwang, Jin-Woo; Han, Young-Ki; Jeong, Jae-Hyun; Lee, Jung-Suck; Moon, Sang-Ho; Jeon, Byong-Tae; Park, Pyo-Jam

    2014-05-01

    In this study, Haliotis discus hannai (H. discus hannai) fermentation was attempted with Cordyceps militaris (C. militaris) mycelia using a solid culture. We tried to ferment H. discus hannai to determine the optimal conditions fermentation with regards to its anti-inflammatory effects. The extracts of H. discus hannai fermented with C. militaris mycelia (HFCM-5) showed higher nitric oxide inhibitory effects than H. discus hannai and C. militaris alone. HFCM-5 also decreased pro-inflammatory cytokines, TNF-α and IL-6 in a dose-dependent manner. HFCM-5 did not affect the MyD88-dependent pathway, but decreased phosphorylation of IRF3 and STAT1 which are involved in TRIF-dependent pathway. Taken together, our results suggest that HFCM-5 exerts its anti-inflammatory effects via TRIF signaling pathway and could potentially be used as a functional food in the regulation of inflammation. Copyright © 2014 Elsevier Ltd. All rights reserved.

  20. Glucose regulates clathrin adaptors at the trans-Golgi network and endosomes

    Science.gov (United States)

    Aoh, Quyen L.; Graves, Lee M.; Duncan, Mara C.

    2011-01-01

    Glucose is a rich source of energy and the raw material for biomass increase. Many eukaryotic cells remodel their physiology in the presence and absence of glucose. The yeast Saccharomyces cerevisiae undergoes changes in transcription, translation, metabolism, and cell polarity in response to glucose availability. Upon glucose starvation, translation initiation and cell polarity are immediately inhibited, and then gradually recover. In this paper, we provide evidence that, as in cell polarity and translation, traffic at the trans-Golgi network (TGN) and endosomes is regulated by glucose via an unknown mechanism that depends on protein kinase A (PKA). Upon glucose withdrawal, clathrin adaptors exhibit a biphasic change in localization: they initially delocalize from the membrane within minutes and later partially recover onto membranes. Additionally, the removal of glucose induces changes in posttranslational modifications of adaptors. Ras and Gpr1 signaling pathways, which converge on PKA, are required for changes in adaptor localization and changes in posttranslational modifications. Acute inhibition of PKA demonstrates that inhibition of PKA prior to glucose withdrawal prevents several adaptor responses to starvation. This study demonstrates that PKA activity prior to glucose starvation primes membrane traffic at the TGN and endosomes in response to glucose starvation. PMID:21832155

  1. SCIMP, a transmembrane adaptor protein involved in major histocompatibility complex class II signaling

    Czech Academy of Sciences Publication Activity Database

    Dráber, Peter; Vonková, Ivana; Štěpánek, Ondřej; Hrdinka, Matouš; Kucová, Markéta; Skopcová, Tereza; Otáhal, Pavel; Angelisová, Pavla; Hořejší, Václav; Yeung, M.; Weiss, A.; Brdička, Tomáš

    2011-01-01

    Roč. 31, č. 22 (2011), s. 4550-4562 ISSN 0270-7306 R&D Projects: GA MŠk 1M0506; GA ČR GEMEM/09/E011 Institutional research plan: CEZ:AV0Z50520514 Keywords : SCIMP * transmembrane adaptor protein * MHC II Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 5.527, year: 2011

  2. NTAL (non-T cell activation linker):a transmembrane adaptor protein involved in immunoreceptor signaling

    Czech Academy of Sciences Publication Activity Database

    Brdička, Tomáš; Imrich, Martin; Angelisová, Pavla; Brdičková, Naděžda; Horváth, Ondřej; Špička, Jiří; Hilgert, Ivan; Lusková, Petra; Dráber, Petr; Novák, P.; Engels, N.; Wienands, J.; Simeoni, L.; Osterreicher, J.; Aguado, E.; Malissen, M.; Schraven, B.; Hořejší, Václav

    2002-01-01

    Roč. 196, č. 12 (2002), s. 16180-16185 ISSN 0022-1007 R&D Projects: GA MŠk LN00A026 Keywords : NTAL * transmembrane adaptor * immunoreceptor signaling Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 15.838, year: 2002

  3. Deletion of the LIME adaptor protein minimally affects T and B cell development and function

    Czech Academy of Sciences Publication Activity Database

    Grégoire, C.; Šímová, Šárka; Wang, Y.; Sansoni, A.; Richelme, S.; Schmidr-Giese, A.; Simeoni, L.; Angelisová, Pavla; Reinhold, D.; Burkhart, S.; Hořejší, Václav; Malissen, B.; Malissen, M.

    2007-01-01

    Roč. 37, č. 11 (2007), s. 3259-3269 ISSN 0014-2980 R&D Projects: GA MŠk 1M0506 Institutional research plan: CEZ:AV0Z50520514 Keywords : LIME * adaptor protein * receptor Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 4.662, year: 2007

  4. The combination of maltose-binding protein and BCG-induced Th1 activation is involved in TLR2/9-mediated upregulation of MyD88-TRAF6 and TLR4-mediated downregulation of TRIF-TRAF3.

    Science.gov (United States)

    Liu, Guomu; Zhai, Xiaoyu; Zhou, Hongyue; Yang, Xiaoyu; Zhang, Nannan; Tai, Guixiang; Ni, Weihua

    2018-03-01

    Our previous study demonstrated that maltose-binding protein (MBP) activated Th1 through the TLR2-mediated MyD88-dependent pathway and the TLR4-mediated TRIF-dependent pathway. The combination of MBP and BCG synergistically induced Th1 activation, and the TLR2/9-mediated MyD88-dependent pathway is involved in this process. To further explore this mechanism, we stimulated purified mouse CD4 + T cells with MBP and BCG in vitro. The results demonstrated that MBP combined with BCG synergistically increased IFN-γ production and TLR2/4/9 expression, suggesting the involvement of TLR2/4/9 in the combination-induced Th1 activation. Next, TLRs 2/4/9 were blocked to analyze the effects of TLRs on Th1 activation. The results demonstrated that MBP induced a low level of Th1 activation by upregulating TLR2-mediated MyD88-TRAF6 and TLR4-mediated TRIF-TRAF3 expression, whereas MBP combined with BCG induced synergistic Th1 activation, which was not only triggered by strong upregulation of TLR2/9-mediated MyD88-TRAF6 expression but also by shifting TLR4-mediated TRIF-TRAF3 into the TRIF-TRAF6 pathway. Moreover, we observed that a TLR4 antibody upregulated MyD88 expression and a TLR9 inhibitor downregulated TRIF expression, indicating that there was cross-talk between TLRs 2/4/9 in MBP combined with BCG-induced Th1 activation. Our findings may expand the knowledge regarding TLR cross-talk involved in regulating the Th1 response. Copyright © 2018 Elsevier Inc. All rights reserved.

  5. A novel conserved phosphotyrosine motif in the Drosophila fibroblast growth factor signaling adaptor Dof with a redundant role in signal transmission.

    Science.gov (United States)

    Csiszar, Agnes; Vogelsang, Elisabeth; Beug, Hartmut; Leptin, Maria

    2010-04-01

    The fibroblast growth factor receptor (FGFR) signals through adaptors constitutively associated with the receptor. In Drosophila melanogaster, the FGFR-specific adaptor protein Downstream-of-FGFR (Dof) becomes phosphorylated upon receptor activation at several tyrosine residues, one of which recruits Corkscrew (Csw), the Drosophila homolog of SHP2, which provides a molecular link to mitogen-activated protein kinase (MAPK) activation. However, the Csw pathway is not the only link from Dof to MAPK. In this study, we identify a novel phosphotyrosine motif present in four copies in Dof and also found in other insect and vertebrate signaling molecules. We show that these motifs are phosphorylated and contribute to FGF signal transduction. They constitute one of three sets of phosphotyrosines that act redundantly in signal transmission: (i) a Csw binding site, (ii) four consensus Grb2 recognition sites, and (iii) four novel tyrosine motifs. We show that Src64B binds to Dof and that Src kinases contribute to FGFR-dependent MAPK activation. Phosphorylation of the novel tyrosine motifs is required for the interaction of Dof with Src64B. Thus, Src64B recruitment to Dof through the novel phosphosites can provide a new link to MAPK activation and other cellular responses. This may give a molecular explanation for the involvement of Src kinases in FGF-dependent developmental events.

  6. Nuclear adaptor Ldb1 regulates a transcriptional program essential for the maintenance of hematopoietic stem cells.

    Science.gov (United States)

    Li, LiQi; Jothi, Raja; Cui, Kairong; Lee, Jan Y; Cohen, Tsadok; Gorivodsky, Marat; Tzchori, Itai; Zhao, Yangu; Hayes, Sandra M; Bresnick, Emery H; Zhao, Keji; Westphal, Heiner; Love, Paul E

    2011-02-01

    The nuclear adaptor Ldb1 functions as a core component of multiprotein transcription complexes that regulate differentiation in diverse cell types. In the hematopoietic lineage, Ldb1 forms a complex with the non-DNA-binding adaptor Lmo2 and the transcription factors E2A, Scl and GATA-1 (or GATA-2). Here we demonstrate a critical and continuous requirement for Ldb1 in the maintenance of both fetal and adult mouse hematopoietic stem cells (HSCs). Deletion of Ldb1 in hematopoietic progenitors resulted in the downregulation of many transcripts required for HSC maintenance. Genome-wide profiling by chromatin immunoprecipitation followed by sequencing (ChIP-Seq) identified Ldb1 complex-binding sites at highly conserved regions in the promoters of genes involved in HSC maintenance. Our results identify a central role for Ldb1 in regulating the transcriptional program responsible for the maintenance of HSCs.

  7. Role of the epithelial cell-specific clathrin adaptor complex AP-1B in cell polarity

    Science.gov (United States)

    Fölsch, Heike

    2015-01-01

    Epithelial cells are important for organ development and function. To this end, they polarize their plasma membrane into biochemically and physically distinct membrane domains. The apical membrane faces the luminal site of an organ and the basolateral domain is in contact with the basement membrane and neighboring cells. To establish and maintain this polarity it is important that newly synthesized and endocytic cargos are correctly sorted according to their final destinations at either membrane. Sorting takes place at one of 2 major sorting stations in the cells, the trans-Golgi network (TGN) and recycling endosomes (REs). Polarized sorting may involve epithelial cell-specific sorting adaptors like the AP-1B clathrin adaptor complex. AP-1B facilitates basolateral sorting from REs. This review will discuss various aspects of basolateral sorting in epithelial cells with a special emphasis on AP-1B. PMID:27057418

  8. SR proteins are NXF1 adaptors that link alternative RNA processing to mRNA export.

    Science.gov (United States)

    Müller-McNicoll, Michaela; Botti, Valentina; de Jesus Domingues, Antonio M; Brandl, Holger; Schwich, Oliver D; Steiner, Michaela C; Curk, Tomaz; Poser, Ina; Zarnack, Kathi; Neugebauer, Karla M

    2016-03-01

    Nuclear export factor 1 (NXF1) exports mRNA to the cytoplasm after recruitment to mRNA by specific adaptor proteins. How and why cells use numerous different export adaptors is poorly understood. Here we critically evaluate members of the SR protein family (SRSF1-7) for their potential to act as NXF1 adaptors that couple pre-mRNA processing to mRNA export. Consistent with this proposal, >1000 endogenous mRNAs required individual SR proteins for nuclear export in vivo. To address the mechanism, transcriptome-wide RNA-binding profiles of NXF1 and SRSF1-7 were determined in parallel by individual-nucleotide-resolution UV cross-linking and immunoprecipitation (iCLIP). Quantitative comparisons of RNA-binding sites showed that NXF1 and SR proteins bind mRNA targets at adjacent sites, indicative of cobinding. SRSF3 emerged as the most potent NXF1 adaptor, conferring sequence specificity to RNA binding by NXF1 in last exons. Interestingly, SRSF3 and SRSF7 were shown to bind different sites in last exons and regulate 3' untranslated region length in an opposing manner. Both SRSF3 and SRSF7 promoted NXF1 recruitment to mRNA. Thus, SRSF3 and SRSF7 couple alternative splicing and polyadenylation to NXF1-mediated mRNA export, thereby controlling the cytoplasmic abundance of transcripts with alternative 3' ends. © 2016 Müller-McNicoll et al.; Published by Cold Spring Harbor Laboratory Press.

  9. Enhanced Toll-like receptor responses in the absence of signaling adaptor DAP12.

    OpenAIRE

    Hamerman, Jessica A; Tchao, Nadia K; Lowell, Clifford A; Lanier, Lewis L

    2005-01-01

    DAP12 is a signaling adaptor containing an immunoreceptor tyrosine-based activation motif (ITAM) that pairs with receptors on myeloid cells and natural killer cells. We examine here the responses of mice lacking DAP12 to stimulation through Toll-like receptors (TLRs). Unexpectedly, DAP12-deficient macrophages produced higher concentrations of inflammatory cytokines in response to a variety of pathogenic stimuli. Additionally, macrophages deficient in spleen tyrosine kinase (Syk), which signal...

  10. New Insights to Clathrin and Adaptor Protein 2 for the Design and Development of Therapeutic Strategies

    Directory of Open Access Journals (Sweden)

    Ebbe Toftgaard Poulsen

    2015-12-01

    Full Text Available The Amyloid Precursor Protein (APP has been extensively studied for its role as the precursor of the β-amyloid protein (Aβ in Alzheimer’s disease (AD. However, our understanding of the normal function of APP is still patchy. Emerging evidence indicates that a dysfunction in APP trafficking and degradation can be responsible for neuronal deficits and progressive degeneration in humans. We recently reported that the Y682 mutation in the 682YENPTY687 domain of APP affects its binding to specific adaptor proteins and leads to its anomalous trafficking, to defects in the autophagy machinery and to neuronal degeneration. In order to identify adaptors that influence APP function, we performed pull-down experiments followed by quantitative mass spectrometry (MS on hippocampal tissue extracts of three month-old mice incubated with either the 682YENPTY687 peptide, its mutated form, 682GENPTY687 or its phosphorylated form, 682pYENPTY687. Our experiments resulted in the identification of two proteins involved in APP internalization and trafficking: Clathrin heavy chain (hc and its Adaptor Protein 2 (AP-2. Overall our results consolidate and refine the importance of Y682 in APP normal functions from an animal model of premature aging and dementia. Additionally, they open the perspective to consider Clathrin hc and AP-2 as potential targets for the design and development of new therapeutic strategies.

  11. The Lnk adaptor protein: a key regulator of normal and pathological hematopoiesis.

    Science.gov (United States)

    Velazquez, Laura

    2012-12-01

    The development and function of blood cells are regulated by specific growth factors/cytokines and their receptors' signaling pathways. In this way, these factors influence cell survival, proliferation and differentiation of hematopoietic cells. Central to this positive and/or negative control are the adaptor proteins. Since their identification 10 years ago, members of the Lnk adaptor protein family have proved to be important activators and/or inhibitors in the hematopoietic, immune and vascular system. In particular, the generation of animal and cellular models for the Lnk and APS proteins has helped establish the physiological role of these molecules through the identification of their specific signaling pathways and the characterization of their binding partners. Moreover, the recent identification of mutations in the LNK gene in myeloproliferative disorders, as well as the correlation of a single nucleotide polymorphism on LNK with hematological, immune and vascular diseases have suggested its involvement in the pathophysiology of these malignancies. The latter findings have thus raised the possibility of addressing Lnk signaling for the treatment of certain human diseases. This review therefore describes the pathophysiological role of this adaptor protein in hematological malignancies and the potential benefits of Lnk therapeutic targeting.

  12. Bias in ligation-based small RNA sequencing library construction is determined by adaptor and RNA structure.

    Directory of Open Access Journals (Sweden)

    Ryan T Fuchs

    Full Text Available High-throughput sequencing (HTS has become a powerful tool for the detection of and sequence characterization of microRNAs (miRNA and other small RNAs (sRNA. Unfortunately, the use of HTS data to determine the relative quantity of different miRNAs in a sample has been shown to be inconsistent with quantitative PCR and Northern Blot results. Several recent studies have concluded that the major contributor to this inconsistency is bias introduced during the construction of sRNA libraries for HTS and that the bias is primarily derived from the adaptor ligation steps, specifically where single stranded adaptors are sequentially ligated to the 3' and 5'-end of sRNAs using T4 RNA ligases. In this study we investigated the effects of ligation bias by using a pool of randomized ligation substrates, defined mixtures of miRNA sequences and several combinations of adaptors in HTS library construction. We show that like the 3' adaptor ligation step, the 5' adaptor ligation is also biased, not because of primary sequence, but instead due to secondary structures of the two ligation substrates. We find that multiple secondary structural factors influence final representation in HTS results. Our results provide insight about the nature of ligation bias and allowed us to design adaptors that reduce ligation bias and produce HTS results that more accurately reflect the actual concentrations of miRNAs in the defined starting material.

  13. U1 Adaptor Oligonucleotides Targeting BCL2 and GRM1 Suppress Growth of Human Melanoma Xenografts In Vivo

    Directory of Open Access Journals (Sweden)

    Rafal Goraczniak

    2013-01-01

    Full Text Available U1 Adaptor is a recently discovered oligonucleotide-based gene-silencing technology with a unique mechanism of action that targets nuclear pre-mRNA processing. U1 Adaptors have two distinct functional domains, both of which must be present on the same oligonucleotide to exert their gene-silencing function. Here, we present the first in vivo use of U1 Adaptors by targeting two different human genes implicated in melanomagenesis, B-cell lymphoma 2 (BCL2 and metabotropic glutamate receptor 1 (GRM1, in a human melanoma cell xenograft mouse model system. Using a newly developed dendrimer delivery system, anti-BCL2 U1 Adaptors were very potent and suppressed tumor growth at doses as low as 34 µg/kg with twice weekly intravenous (iv administration. Anti-GRM1 U1 Adaptors suppressed tumor xenograft growth with similar potency. Mechanism of action was demonstrated by showing target gene suppression in tumors and by observing that negative control U1 Adaptors with just one functional domain show no tumor suppression activity. The anti-BCL2 and anti-GRM1 treatments were equally effective against cell lines harboring either wild-type or a mutant V600E B-RAF allele, the most common mutation in melanoma. Treatment of normal immune-competent mice (C57BL6 indicated no organ toxicity or immune stimulation. These proof-of-concept studies represent an in-depth (over 800 mice in ~108 treatment groups validation that U1 Adaptors are a highly potent gene-silencing therapeutic and open the way for their further development to treat other human diseases.

  14. TRAM is involved in IL-18 signaling and functions as a sorting adaptor for MyD88.

    Directory of Open Access Journals (Sweden)

    Hidenori Ohnishi

    Full Text Available MyD88, a Toll/interleukin-1 receptor homology (TIR domain-containing adaptor protein, mediates signals from the Toll-like receptors (TLR or IL-1/IL-18 receptors to downstream kinases. In MyD88-dependent TLR4 signaling, the function of MyD88 is enhanced by another TIR domain-containing adaptor, Mal/TIRAP, which brings MyD88 to the plasma membrane and promotes its interaction with the cytosolic region of TLR4. Hence, Mal is recognized as the "sorting adaptor" for MyD88. In this study, a direct interaction between MyD88-TIR and another membrane-sorting adaptor, TRAM/TICAM-2, was demonstrated in vitro. Cell-based assays including RNA interference experiments and TRAM deficient mice revealed that the interplay between MyD88 and TRAM in cells is important in mediating IL-18 signal transduction. Live cell imaging further demonstrated the co-localized accumulation of MyD88 and TRAM in the membrane regions in HEK293 cells. These findings suggest that TRAM serves as the sorting adaptor for MyD88 in IL-18 signaling, which then facilitates the signal transduction. The binding sites for TRAM are located in the TIR domain of MyD88 and actually overlap with the binding sites for Mal. MyD88, the multifunctional signaling adaptor that works together with most of the TLR members and with the IL-1/IL-18 receptors, can interact with two distinct sorting adaptors, TRAM and Mal, in a conserved manner in a distinct context.

  15. The Role of Crk Adaptor Proteins in Breast Tumorigenesis and Bone Metastasis

    Science.gov (United States)

    2012-09-01

    points indicated. Treatments included DMSO control or inhibition of Met (0.2uM PHA-665752), Abl (4uM Imatinib ), PI3K (20uM LY-294002), mTOR (0.1uM...CrkL over CrkII, Nat Chem Biol 8, 590–596 (2012). RESEARCH ARTICLE Open Access Crk adaptor proteins act as key signaling integrators for breast...R74 http://breast-cancer-research.com/content/14/3/R74 © 2012 Fathers et al.; licensee BioMed Central Ltd. This is an open access article distributed

  16. Transmembrane adaptor proteins in the high-affinity IgE receptor signaling

    Czech Academy of Sciences Publication Activity Database

    Dráber, Petr; Hálová, Ivana; Levi-Schaffer, F.; Dráberová, Lubica

    2012-01-01

    Roč. 2, 11.1. (2012), s. 95 ISSN 1664-3224 R&D Projects: GA MŠk 1M0506; GA ČR GA301/09/1826; GA ČR GAP302/10/1759; GA AV ČR KAN200520701 Grant - others:AV ČR(CZ) M200520901 Institutional research plan: CEZ:AV0Z50520514 Institutional support: RVO:68378050 Keywords : IgE receptor * LAT/LAT1 * LAX * NTAL/Lab/LAT2 * PAG/Cbp * mast cells * plasma membrane * transmembrane adaptor proteins Subject RIV: EB - Genetics ; Molecular Biology

  17. The role of small adaptor proteins in the control of oncogenic signaling driven by tyrosine kinases in human cancer

    Science.gov (United States)

    Naudin, Cécile; Chevalier, Clément; Roche, Serge

    2016-01-01

    Protein phosphorylation on tyrosine (Tyr) residues has evolved as an important mechanism to coordinate cell communication in multicellular organisms. The importance of this process has been revealed by the discovery of the prominent oncogenic properties of tyrosine kinases (TK) upon deregulation of their physiological activities, often due to protein overexpression and/or somatic mutation. Recent reports suggest that TK oncogenic signaling is also under the control of small adaptor proteins. These cytosolic proteins lack intrinsic catalytic activity and signal by linking two functional members of a catalytic pathway. While most adaptors display positive regulatory functions, a small group of this family exerts negative regulatory functions by targeting several components of the TK signaling cascade. Here, we review how these less studied adaptor proteins negatively control TK activities and how their loss of function induces abnormal TK signaling, promoting tumor formation. We also discuss the therapeutic consequences of this novel regulatory mechanism in human oncology. PMID:26788993

  18. The role of small adaptor proteins in the control of oncogenic signalingr driven by tyrosine kinases in human cancer.

    Science.gov (United States)

    Naudin, Cécile; Chevalier, Clément; Roche, Serge

    2016-03-08

    Protein phosphorylation on tyrosine (Tyr) residues has evolved as an important mechanism to coordinate cell communication in multicellular organisms. The importance of this process has been revealed by the discovery of the prominent oncogenic properties of tyrosine kinases (TK) upon deregulation of their physiological activities, often due to protein overexpression and/or somatic mutation. Recent reports suggest that TK oncogenic signaling is also under the control of small adaptor proteins. These cytosolic proteins lack intrinsic catalytic activity and signal by linking two functional members of a catalytic pathway. While most adaptors display positive regulatory functions, a small group of this family exerts negative regulatory functions by targeting several components of the TK signaling cascade. Here, we review how these less studied adaptor proteins negatively control TK activities and how their loss of function induces abnormal TK signaling, promoting tumor formation. We also discuss the therapeutic consequences of this novel regulatory mechanism in human oncology.

  19. Association of autoimmune hepatitis with Src homology 2 adaptor protein 3 gene polymorphisms in Japanese patients.

    Science.gov (United States)

    Umemura, Takeji; Joshita, Satoru; Hamano, Hideaki; Yoshizawa, Kaname; Kawa, Shigeyuki; Tanaka, Eiji; Ota, Masao

    2017-11-01

    Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease characterized by an autoimmune reaction to hepatocytes. The Src homology 2 adaptor protein 3 (SH2B3) gene is a member of the SH2B family of adaptor proteins that has been implicated in the integration and regulation of multiple signaling events. SH2B3 is involved in cytokine signaling pathways and serves as a negative mediator of T-cell receptor signaling. Genome-wide association analyses in Caucasians have linked a missense mutation at rs3184504 in SH2B3 with AIH. Accordingly, four selected single-nucleotide polymorphisms (SNPs) in the SH2B3 gene were genotyped in 158 patients with AIH, 327 patients with primary biliary cholangitis, 160 patients with autoimmune pancreatitis, and 325 healthy subjects of Japanese descent. Although the functional rs3184504 was non-polymorphic in 952 subjects, the frequency of the minor rs11065904 T allele was significantly decreased in AIH patients compared with healthy controls (odds ratio (OR)=0.68; corrected P=0.025). Haplotype 2 (rs2238154 A, rs11065904 T and rs739496 G) was associated with resistance to AIH (OR 0.67, P=0.021) as well as to autoimmune pancreatitis (OR=0.70, P=0.035). Our findings suggest that an SNP and haplotype in SH2B3 are associated with AIH.

  20. The Cytoplasmic Adaptor Protein Dok7 Activates the Receptor Tyrosine Kinase MuSK via Dimerization

    Energy Technology Data Exchange (ETDEWEB)

    Bergamin, E.; Hallock, P; Burden, S; Hubbard, S

    2010-01-01

    Formation of the vertebrate neuromuscular junction requires, among others proteins, Agrin, a neuronally derived ligand, and the following muscle proteins: LRP4, the receptor for Agrin; MuSK, a receptor tyrosine kinase (RTK); and Dok7 (or Dok-7), a cytoplasmic adaptor protein. Dok7 comprises a pleckstrin-homology (PH) domain, a phosphotyrosine-binding (PTB) domain, and C-terminal sites of tyrosine phosphorylation. Unique among adaptor proteins recruited to RTKs, Dok7 is not only a substrate of MuSK, but also an activator of MuSK's kinase activity. Here, we present the crystal structure of the Dok7 PH-PTB domains in complex with a phosphopeptide representing the Dok7-binding site on MuSK. The structure and biochemical data reveal a dimeric arrangement of Dok7 PH-PTB that facilitates trans-autophosphorylation of the kinase activation loop. The structure provides the molecular basis for MuSK activation by Dok7 and for rationalizing several Dok7 loss-of-function mutations found in patients with congenital myasthenic syndromes.

  1. ROS Control Mitochondrial Motility through p38 and the Motor Adaptor Miro/Trak

    Directory of Open Access Journals (Sweden)

    Valentina Debattisti

    2017-11-01

    Full Text Available Mitochondrial distribution and motility are recognized as central to many cellular functions, but their regulation by signaling mechanisms remains to be elucidated. Here, we report that reactive oxygen species (ROS, either derived from an extracellular source or intracellularly generated, control mitochondrial distribution and function by dose-dependently, specifically, and reversibly decreasing mitochondrial motility in both rat hippocampal primary cultured neurons and cell lines. ROS decrease motility independently of cytoplasmic [Ca2+], mitochondrial membrane potential, or permeability transition pore opening, known effectors of oxidative stress. However, multiple lines of genetic and pharmacological evidence support that a ROS-activated mitogen-activated protein kinase (MAPK, p38α, is required for the motility inhibition. Furthermore, anchoring mitochondria directly to kinesins without involvement of the physiological adaptors between the organelles and the motor protein prevents the H2O2-induced decrease in mitochondrial motility. Thus, ROS engage p38α and the motor adaptor complex to exert changes in mitochondrial motility, which likely has both physiological and pathophysiological relevance.

  2. The Adaptor Protein Rai/ShcC Promotes Astrocyte-Dependent Inflammation during Experimental Autoimmune Encephalomyelitis.

    Science.gov (United States)

    Ulivieri, Cristina; Savino, Maria Teresa; Luccarini, Ilaria; Fanigliulo, Emanuela; Aldinucci, Alessandra; Bonechi, Elena; Benagiano, Marisa; Ortensi, Barbara; Pelicci, Giuliana; D'Elios, Mario Milco; Ballerini, Clara; Baldari, Cosima Tatiana

    2016-07-15

    Th17 cells have been casually associated to the pathogenesis of autoimmune disease. We have previously demonstrated that Rai/ShcC, a member of the Shc family of adaptor proteins, negatively regulates Th17 cell differentiation and lupus autoimmunity. In this study, we have investigated the pathogenic outcome of the Th17 bias associated with Rai deficiency on multiple sclerosis development, using the experimental autoimmune encephalomyelitis (EAE) mouse model. We found that, unexpectedly, EAE was less severe in Rai(-/-) mice compared with their wild-type counterparts despite an enhanced generation of myelin-specific Th17 cells that infiltrated into the CNS. Nevertheless, when adoptively transferred into immunodeficient Rai(+/+) mice, these cells promoted a more severe disease compared with wild-type encephalitogenic Th17 cells. This paradoxical phenotype was caused by a dampened inflammatory response of astrocytes, which were found to express Rai, to IL-17. The results provide evidence that Rai plays opposite roles in Th17 cell differentiation and astrocyte activation, with the latter dominant over the former in EAE, highlighting this adaptor as a potential novel target for the therapy of multiple sclerosis. Copyright © 2016 by The American Association of Immunologists, Inc.

  3. Receptor tyrosine phosphatase R-PTP-alpha is tyrosine-phosphorylated and associated with the adaptor protein Grb2

    DEFF Research Database (Denmark)

    Su, J; Batzer, A; Sap, J

    1994-01-01

    Receptor tyrosine phosphatases (R-PTPases) have generated interest because of their suspected involvement in cellular signal transduction. The adaptor protein Grb2 has been implicated in coupling receptor tyrosine kinases to Ras. We report that a ubiquitous R-PTPase, R-PTP-alpha, is tyrosine-phos...

  4. Design and Calibration of a Dispersive Imaging Spectrometer Adaptor for a Fast IR Camera on NSTX-U

    Science.gov (United States)

    Reksoatmodjo, Richard; Gray, Travis; Princeton Plasma Physics Laboratory Team

    2017-10-01

    A dispersive spectrometer adaptor was designed, constructed and calibrated for use on a fast infrared camera employed to measure temperatures on the lower divertor tiles of the NSTX-U tokamak. This adaptor efficiently and evenly filters and distributes long-wavelength infrared photons between 8.0 and 12.0 microns across the 128x128 pixel detector of the fast IR camera. By determining the width of these separated wavelength bands across the camera detector, and then determining the corresponding average photon count for each photon wavelength, a very accurate measurement of the temperature, and thus heat flux, of the divertor tiles can be calculated using Plank's law. This approach of designing an exterior dispersive adaptor for the fast IR camera allows accurate temperature measurements to be made of materials with unknown emissivity. Further, the relative simplicity and affordability of this adaptor design provides an attractive option over more expensive, slower, dispersive IR camera systems. This work was made possible by funding from the Department of Energy for the Summer Undergraduate Laboratory Internship (SULI) program. This work is supported by the US DOE Contract No. DE-AC02-09CH11466.

  5. Alternatively spliced short and long isoforms of adaptor protein intersectin 1 form complexes in mammalian cells

    Directory of Open Access Journals (Sweden)

    Rynditch A. V.

    2012-12-01

    Full Text Available Intersectin 1 (ITSN1 is an adaptor protein involved in membrane trafficking and cell signaling. Long and short isoforms of ITSN1 (ITSN1-L and ITSN1-S are produced by alternative splicing. The aim of our study was to investigate whether ITSN1-L and ITSN1-S could interact in mammalian cells. Methods. During this study we employed immunoprecipitation and confocal microscopy. Results. We have shown that endogenous ITSN1-S co-precipitates with overexpressed ITSN1-L in PC12, 293 and 293T cells. Long and short isoforms of ITSN1 also co-localize in 293T cells. Conclusions. ITSN1-L and ITSN1-S form complexes in mammalian cells.

  6. Effectiveness of Needles Vial Adaptors and Blunt Cannulas for Drug Administration in a Microgravity Environment

    Science.gov (United States)

    Hailey, Melinda; Bayuse, Tina

    2009-01-01

    The need for a new system of injectable medications aboard the International Space Station (ISS) was identified. It is desired that this system fly medications in their original manufacturer's packaging, allowing the system to comply with United States Pharmacopeia (USP) guidelines while minimizing the resupply frequency due to medication expiration. Pre-filled syringes are desired, however, the evolving nature of the healthcare marketplace requires flexibility in the redesign. If medications must be supplied in a vial, a system is required that allows for the safe withdrawal of medication from the vial into a syringe for administration in microgravity. During two reduced gravity flights, the effectiveness of two versions of a blunt cannula and needleless vial adaptors was evaluated to facilitate the withdrawal of liquid medication from a vial into a syringe for injection. Other parameters assessed included the ability to withdraw the required amount of medication and whether this is dependent on vial size, liquid, or the total volume of fluid within the vial. Injectable medications proposed for flight on ISS were used for this evaluation. Due to differing sizes of vials and the fluid properties of the medications, the needleless vial adaptors proved to be too cumbersome to recommend for use on the ISS. The blunt cannula, specifically the plastic version, proved to be more effective at removing medication from the various sizes of vials and are the recommended hardware for ISS. Fluid isolation within the vials and syringes is an important step in preparing medication for injection regardless of the hardware used. Although isolation is a challenge in the relatively short parabolas during flight, it is not an obstacle for sustained microgravity. This presentation will provide an overview of the products tested as well as the challenges identified during the microgravity flights.

  7. The TLR4 D299G and T399I SNPs are constitutively active to up-regulate expression of Trif-dependent genes.

    Directory of Open Access Journals (Sweden)

    Georgina L Hold

    Full Text Available Dysregulated Toll-Like Receptor (TLR signalling and genetic polymorphisms in these proteins are linked to many human diseases. We investigated TLR4 functional variants D299G and T399I to assess the impact on LPS-induced responsiveness in comparison to wild-type TLR4. The mechanism by which this occurs in unclear as these SNPs do not lie within the lipid A binding domain or dimerisation sites of the LPS-TLR4/MD2 receptor complexes. Transfection of TLR4D299G, TLR4T399I or TLR4D299G. T399I into HEK cells resulted in constitutive activation of an NF-κB reporter gene and a blunting of the LPS-induced reporter activation compared to WT-TLR4. Unstimulated human monocyte/macrophages, from patients with the D299G and T399I SNPs demonstrated a downregulation of many genes, particularly Tram/Trif signalling pathway constitutents compared to the TLR4 wild-type subjects supporting the concept of basal receptor activity. Monocyte/macrophages from carriers of the TLR4 D299G and T399I polymorphisms stimulated with LPS showed >6 fold lower levels of NF-κB and ∼12 fold higher IFN-β gene expression levels compared to wild-type subjects (P<0.05; MWU test and dramatically altered resultant cytokine profiles. We conclude that these TLR4 SNPs affect constitutive receptor activity which impacts on the hosts ability to respond to LPS challenge leading to a dysregulated sub-optimal immune response to infection.

  8. Aplicación informática con Matlab para la modelización del transformador trifásico en régimen permanente y condiciones desequilibradas

    OpenAIRE

    Sánchez Navarro, Javier

    2007-01-01

    El objetivo principal de este proyecto es la realización de una aplicación informática qu resuelva una red radial trifásica de cuatro nudos propuesta por el IEEE ( The Institute of Electrical and Electronics Engineers), donde el elemento central de la red es el tranformador. El uso de la aplicación es sencillo e intuitivo, aunque se requieren ciertos conocimientos de los sistemas eléctricos de potencia. El programa incluye la posibilidad de sugerir los parámetros a introducir y de seleccio...

  9. Método para limitação de índices de desequilíbrio de máquinas elétricas trifásicas em sistemas de distribuição

    OpenAIRE

    Beneteli, Tatianna Aparecida Pereira

    2015-01-01

    Este trabalho propõe uma metodologia de fluxo de potência ótimo multifásico para a limitação dos desequilíbrios das tensões terminais e das correntes demandadas ou injetadas nas máquinas trifásicas girantes, geradores ou motores, com especial aplicação para os geradores conectados de forma dispersa aos sistemas de distribuição. A modelagem dos equipamentos é baseada no método de injeção de correntes em coordenadas retangulares. A metodologia foi implementada e a ferramenta computacional propo...

  10. Anti-Inflammatory Action of an Antimicrobial Model Peptide That Suppresses the TRIF-Dependent Signaling Pathway via Inhibition of Toll-Like Receptor 4 Endocytosis in Lipopolysaccharide-Stimulated Macrophages.

    Directory of Open Access Journals (Sweden)

    Do-Wan Shim

    Full Text Available Antimicrobial peptides (AMPs, also called host defense peptides, particularly those with amphipathic helical structures, are emerging as target molecules for therapeutic development due to their immunomodulatory properties. Although the antimicrobial activity of AMPs is known to be exerted primarily by permeation of the bacterial membrane, the mechanism underlying its anti-inflammatory activity remains to be elucidated. We report potent anti-inflammatory activity of WALK11.3, an antimicrobial model peptide with an amphipathic helical conformation, in lipopolysaccharide (LPS-stimulated RAW264.7 cells. This peptide inhibited the expression of inflammatory mediators, including nitric oxide, COX-2, IL-1β, IL-6, INF-β, and TNF-α. Although WALK11.3 did not exert a major effect on all downstream signaling in the MyD88-dependent pathway, toll-like receptor 4 (TLR4- mediated pro-inflammatory signals were markedly attenuated in the TRIF-dependent pathway due to inhibition of the phosphorylation of STAT1 by attenuation of IRF3 phosphorylation. WALK11.3 specifically inhibited the endocytosis of TLR4, which is essential for triggering TRIF-mediated signaling in macrophage cells. Hence, we suggest that specific interference with TLR4 endocytosis could be one of the major modes of the anti-inflammatory action of AMPs. Our designed WALK11 peptides, which possess both antimicrobial and anti-inflammatory activities, may be promising molecules for the development of therapies for infectious inflammation.

  11. Highly pathogenic avian influenza virus nucleoprotein interacts with TREX complex adaptor protein Aly/REF.

    Directory of Open Access Journals (Sweden)

    Vinod R M T Balasubramaniam

    Full Text Available We constructed a novel chicken (Gallus gallus lung cDNA library fused inside yeast acting domain vector (pGADT7. Using yeast two-hybrid screening with highly pathogenic avian influenza (HPAI nucleoprotein (NP from the strain (A/chicken/Malaysia/5858/2004(H5N1 as bait, and the Gallus gallus lung cDNA library as prey, a novel interaction between the Gallus gallus cellular RNA export adaptor protein Aly/REF and the viral NP was identified. This interaction was confirmed and validated with mammalian two hybrid studies and co-immunoprecipitation assay. Cellular localization studies using confocal microscopy showed that NP and Aly/REF co-localize primarily in the nucleus. Further investigations by mammalian two hybrid studies into the binding of NP of other subtypes of influenza virus such as the swine A/New Jersey/1976/H1N1 and pandemic A/Malaysia/854/2009(H1N1 to human Aly/REF, also showed that the NP of these viruses interacts with human Aly/REF. Our findings are also supported by docking studies which showed tight and favorable binding between H5N1 NP and human Aly/REF, using crystal structures from Protein Data Bank. siRNA knockdown of Aly/REF had little effect on the export of HPAI NP and other viral RNA as it showed no significant reduction in virus titer. However, UAP56, another component of the TREX complex, which recruits Aly/REF to mRNA was found to interact even better with H5N1 NP through molecular docking studies. Both these proteins also co-localizes in the nucleus at early infection similar to Aly/REF. Intriguingly, knockdown of UAP56 in A549 infected cells shows significant reduction in viral titer (close to 10 fold reduction. Conclusively, our study have opened new avenues for research of other cellular RNA export adaptors crucial in aiding viral RNA export such as the SRSF3, 9G8 and ASF/SF2 that may play role in influenza virus RNA nucleocytoplasmic transport.

  12. LIME: a new membrane raft-associated adaptor protein involved in CD4 and CD8 coreceptor signaling

    Czech Academy of Sciences Publication Activity Database

    Brdičková, Naděžda; Brdička, Tomáš; Angelisová, Pavla; Horváth, Ondřej; Špička, Jiří; Hilgert, Ivan; Pačes, Jan; Simeoni, L.; Kliche, S.; Merten, C.; Schraven, B.; Hořejší, Václav

    2003-01-01

    Roč. 198, č. 10 (2003), s. 1453-1462 ISSN 0022-1007 R&D Projects: GA MŠk LN00A079; GA MŠk LN00A026 Grant - others:Wellcome Trust(GB) J1116W24Z Institutional research plan: CEZ:AV0Z5052915 Keywords : immunology * T-lymphocyte * adaptor protein Subject RIV: EC - Immunology Impact factor: 15.302, year: 2003

  13. ATP binding to p97/VCP D1 domain regulates selective recruitment of adaptors to its proximal N-domain.

    Directory of Open Access Journals (Sweden)

    Wei Sheng Chia

    Full Text Available p97/Valosin-containing protein (VCP is a member of the AAA-ATPase family involved in many cellular processes including cell division, intracellular trafficking and extraction of misfolded proteins in endoplasmic reticulum-associated degradation (ERAD. It is a homohexamer with each subunit containing two tandem D1 and D2 ATPase domains and N- and C-terminal regions that function as adaptor protein binding domains. p97/VCP is directed to its many different functional pathways by associating with various adaptor proteins. The regulation of the recruitment of the adaptor proteins remains unclear. Two adaptor proteins, Ufd1/Npl4 and p47, which bind exclusively to the p97/VCP N-domain and direct p97/VCP to either ERAD-related processes or homotypic fusion of Golgi fragments, were studied here. Surface plasmon resonance biosensor-based assays allowed the study of binding kinetics in real time. In competition experiments, it was observed that in the presence of ATP, Ufd1/Npl4 was able to compete more effectively with p47 for binding to p97/VCP. By using non-hydrolysable ATP analogues and the hexameric truncated p97/N-D1 fragment, it was shown that binding rather than hydrolysis of ATP to the proximal D1 domain strengthened the Ufd1/Npl4 association with the N-domain, thus regulating the recruitment of either Ufd1/Npl4 or p47. This novel role of ATP and an assigned function to the D1 AAA-ATPase domain link the multiple functions of p97/VCP to the metabolic status of the cell.

  14. The non-motor adaptor HMMR dampens Eg5-mediated forces to preserve the kinetics and integrity of chromosome segregation.

    Science.gov (United States)

    Chen, Helen; Connell, Marisa; Mei, Lin; Reid, Gregor S D; Maxwell, Christopher A

    2018-01-31

    Mitotic spindle assembly and organization require forces generated by motor proteins. The activity of these motors is regulated by non-motor adaptor proteins. However, there are limited studies reporting the functional importance of adaptors on the balance of motor forces and the promotion of faithful and timely cell division. Here, we show that genomic deletion or siRNA silencing of the non-motor adaptor Hmmr/ HMMR disturbs spindle microtubule organization and bipolar chromosome-kinetochore attachments with a consequent elevated occurrence of aneuploidy. Rescue experiments show a conserved motif in HMMR is required to generate inter-kinetochore tension and promote anaphase entry. This motif bears high homology with the kinesin Kif15 and is known to interact with TPX2, a spindle assembly factor. We find that HMMR is required to dampen kinesin Eg5-mediated forces through localizing TPX2 and promoting the formation of inhibitory TPX2-Eg5 complexes. In HMMR-silenced cells, K-fiber stability is reduced while the frequency of unattached chromosomes and the time needed for chromosome segregation are both increased. These defects can be alleviated in HMMR-silenced cells with chemical inhibition of Eg5, but not through the silencing of Kif15. Together, our findings indicate that HMMR balances Eg5-mediated forces to preserve the kinetics and integrity of chromosome segregation. © 2018 by The American Society for Cell Biology.

  15. APS, an adaptor molecule containing PH and SH2 domains, has a negative regulatory role in B cell proliferation

    International Nuclear Information System (INIS)

    Iseki, Masanori; Kubo-Akashi, Chiyomi; Kwon, Sang-Mo; Yamaguchi, Akiko; Takatsu, Kiyoshi; Takaki, Satoshi

    2005-01-01

    Adaptor molecule containing PH and SH2 domains (APS) is an intracellular adaptor protein that forms part of an adaptor family along with Lnk and SH2-B. APS transcripts are expressed in various tissues including brain, kidney, and muscle, as well as in splenic B cells but not in T cells. We investigated the functions of APS in B cell development and activation by generating APS-transgenic (APS-Tg) mice that overexpressed APS in lymphocytes. The number of B-1 cells in the peritoneal cavity was reduced in APS-Tg mice, as were B-2 cells in the spleen. B cell development in the bone marrow was partially impaired at the transition stage from proliferating large pre-B to small pre-B cells. B cell proliferation induced by B cell receptor (BCR) crosslinking but not by other B cell mitogens was also impaired in APS-Tg mice. APS co-localized with BCR complexes and filamentous actin in activated APS-Tg B cells. Thus, APS appears to play novel negative regulatory roles in BCR signaling, actin reorganization pathways, and control of compartment sizes of B-lineage cells

  16. Recruitment of the Mint3 adaptor is necessary for export of the amyloid precursor protein (APP) from the Golgi complex.

    Science.gov (United States)

    Caster, Amanda H; Kahn, Richard A

    2013-10-04

    The amyloid precursor protein (APP) is a ubiquitously expressed single-pass transmembrane protein that undergoes proteolytic processing by secretases to generate the pathogenic amyloid-β peptide, the major component in Alzheimer plaques. The traffic of APP through the cell determines its exposure to secretases and consequently the cleavages that generate the pathogenic or nonpathogenic peptide fragments. Despite the likely importance of APP traffic to Alzheimer disease, we still lack clear models for the routing and regulation of APP in cells. Like the traffic of most transmembrane proteins, the binding of adaptors to its cytoplasmic tail, which is 47 residues long and contains at least four distinct sorting motifs, regulates that of APP. We tested each of these for effects on the traffic of APP from the Golgi by mutating key residues within them and examining adaptor recruitment at the Golgi and traffic to post-Golgi site(s). We demonstrate strict specificity for recruitment of the Mint3 adaptor by APP at the Golgi, a critical role for Tyr-682 (within the YENPTY motif) in Mint3 recruitment and export of APP from the Golgi, and we identify LAMP1(+) structures as the proximal destination of APP after leaving the Golgi. Together, these data provide a detailed view of the first sorting step in its route to the cell surface and processing by secretases and further highlight the critical role played by Mint3.

  17. Recruitment of the Mint3 Adaptor Is Necessary for Export of the Amyloid Precursor Protein (APP) from the Golgi Complex*

    Science.gov (United States)

    Caster, Amanda H.; Kahn, Richard A.

    2013-01-01

    The amyloid precursor protein (APP) is a ubiquitously expressed single-pass transmembrane protein that undergoes proteolytic processing by secretases to generate the pathogenic amyloid-β peptide, the major component in Alzheimer plaques. The traffic of APP through the cell determines its exposure to secretases and consequently the cleavages that generate the pathogenic or nonpathogenic peptide fragments. Despite the likely importance of APP traffic to Alzheimer disease, we still lack clear models for the routing and regulation of APP in cells. Like the traffic of most transmembrane proteins, the binding of adaptors to its cytoplasmic tail, which is 47 residues long and contains at least four distinct sorting motifs, regulates that of APP. We tested each of these for effects on the traffic of APP from the Golgi by mutating key residues within them and examining adaptor recruitment at the Golgi and traffic to post-Golgi site(s). We demonstrate strict specificity for recruitment of the Mint3 adaptor by APP at the Golgi, a critical role for Tyr-682 (within the YENPTY motif) in Mint3 recruitment and export of APP from the Golgi, and we identify LAMP1+ structures as the proximal destination of APP after leaving the Golgi. Together, these data provide a detailed view of the first sorting step in its route to the cell surface and processing by secretases and further highlight the critical role played by Mint3. PMID:23965993

  18. Nrf2 reduces levels of phosphorylated tau protein by inducing autophagy adaptor protein NDP52

    Science.gov (United States)

    Jo, Chulman; Gundemir, Soner; Pritchard, Susanne; Jin, Youngnam N.; Rahman, Irfan; Johnson, Gail V. W.

    2014-03-01

    Nuclear factor erythroid 2-related factor 2 (Nrf2) is a pivotal transcription factor in the defence against oxidative stress. Here we provide evidence that activation of the Nrf2 pathway reduces the levels of phosphorylated tau by induction of an autophagy adaptor protein NDP52 (also known as CALCOCO2) in neurons. The expression of NDP52, which we show has three antioxidant response elements (AREs) in its promoter region, is strongly induced by Nrf2, and its overexpression facilitates clearance of phosphorylated tau in the presence of an autophagy stimulator. In Nrf2-knockout mice, phosphorylated and sarkosyl-insoluble tau accumulates in the brains concurrent with decreased levels of NDP52. Moreover, NDP52 associates with phosphorylated tau from brain cortical samples of Alzheimer disease cases, and the amount of phosphorylated tau in sarkosyl-insoluble fractions is inversely proportional to that of NDP52. These results suggest that NDP52 plays a key role in autophagy-mediated degradation of phosphorylated tau in vivo.

  19. The adaptor protein Grb2 is not essential for the establishment of the glomerular filtration barrier.

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    Nicolas Bisson

    Full Text Available The kidney filtration barrier is formed by the combination of endothelial cells, basement membrane and epithelial cells called podocytes. These specialized actin-rich cells form long and dynamic protrusions, the foot processes, which surround glomerular capillaries and are connected by specialized intercellular junctions, the slit diaphragms. Failure to maintain the filtration barrier leads to massive proteinuria and nephrosis. A number of proteins reside in the slit diaphragm, notably the transmembrane proteins Nephrin and Neph1, which are both able to act as tyrosine phosphorylated scaffolds that recruit cytoplasmic effectors to initiate downstream signaling. While association between tyrosine-phosphorylated Neph1 and the SH2/SH3 adaptor Grb2 was shown in vitro to be sufficient to induce actin polymerization, in vivo evidence supporting this finding is still lacking. To test this hypothesis, we generated two independent mouse lines bearing a podocyte-specific constitutive inactivation of the Grb2 locus. Surprisingly, we show that mice lacking Grb2 in podocytes display normal renal ultra-structure and function, thus demonstrating that Grb2 is not required for the establishment of the glomerular filtration barrier in vivo. Moreover, our data indicate that Grb2 is not required to restore podocyte function following kidney injury. Therefore, although in vitro experiments suggested that Grb2 is important for the regulation of actin dynamics, our data clearly shows that its function is not essential in podocytes in vivo, thus suggesting that Grb2 rather plays a secondary role in this process.

  20. The Kinesin Adaptor Calsyntenin-1 Organizes Microtubule Polarity and Regulates Dynamics during Sensory Axon Arbor Development

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    Mary C. Halloran

    2017-04-01

    Full Text Available Axon growth and branching, and development of neuronal polarity are critically dependent on proper organization and dynamics of the microtubule (MT cytoskeleton. MTs must organize with correct polarity for delivery of diverse cargos to appropriate subcellular locations, yet the molecular mechanisms regulating MT polarity remain poorly understood. Moreover, how an actively branching axon reorganizes MTs to direct their plus ends distally at branch points is unknown. We used high-speed, in vivo imaging of polymerizing MT plus ends to characterize MT dynamics in developing sensory axon arbors in zebrafish embryos. We find that axonal MTs are highly dynamic throughout development, and that the peripheral and central axons of sensory neurons show differences in MT behaviors. Furthermore, we show that Calsyntenin-1 (Clstn-1, a kinesin adaptor required for sensory axon branching, also regulates MT polarity in developing axon arbors. In wild type neurons the vast majority of MTs are directed in the correct plus-end-distal orientation from early stages of development. Loss of Clstn-1 causes an increase in MTs polymerizing in the retrograde direction. These misoriented MTs most often are found near growth cones and branch points, suggesting Clstn-1 is particularly important for organizing MT polarity at these locations. Together, our results suggest that Clstn-1, in addition to regulating kinesin-mediated cargo transport, also organizes the underlying MT highway during axon arbor development.

  1. Targeting 14-3-3 adaptor protein-protein interactions to stimulate central nervous system repair

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    Andrew Kaplan

    2017-01-01

    Full Text Available The goal of developing treatments for central nervous system (CNS injuries is becoming more attainable with the recent identification of various drugs that can repair damaged axons. These discoveries have stemmed from screening efforts, large expression datasets and an improved understanding of the cellular and molecular biology underlying axon growth. It will be important to continue searching for new compounds that can induce axon repair. Here we describe how a family of adaptor proteins called 14-3-3s can be targeted using small molecule drugs to enhance axon outgrowth and regeneration. 14-3-3s bind to many functionally diverse client proteins to regulate their functions. We highlight the recent discovery of the axon-growth promoting activity of fusicoccin-A, a fungus-derived small molecule that stabilizes 14-3-3 interactions with their client proteins. Here we discuss how fusicoccin-A could serve as a starting point for the development of drugs to induce CNS repair.

  2. Neuronal adaptor FE65 stimulates Rac1-mediated neurite outgrowth by recruiting and activating ELMO1.

    Science.gov (United States)

    Li, Wen; Tam, Ka Ming Vincent; Chan, Wai Wan Ray; Koon, Alex Chun; Ngo, Jacky Chi Ki; Chan, Ho Yin Edwin; Lau, Kwok-Fai

    2018-04-03

    Neurite outgrowth is a crucial process in developing neurons for neural network formation. Understanding the regulatory mechanisms of neurite outgrowth is essential for developing strategies to stimulate neurite regeneration after nerve injury and in neurodegenerative disorders. FE65 is a brain-enriched adaptor that stimulates Rac1-mediated neurite elongation. However, the precise mechanism by which FE65 promotes the process remains elusive. Here, we show that ELMO1, a subunit of ELMO1-DOCK180 bipartite Rac1 GEF, interacts with the FE65 N-terminal region. Overexpression of FE65 and/or ELMO1 enhances whereas knockdown of FE65 or ELMO1 inhibits neurite outgrowth and Rac1 activation. The effect of FE65 alone or together with ELMO1 is attenuated by an FE65 double mutation that disrupts FE65-ELMO1 interaction. Notably, FE65 is found to activate ELMO1 by diminishing ELMO1 intramolecular autoinhibitory interaction and to promote the targeting of ELMO1 to the plasma membrane where Rac1 is activated. We also show that FE65, ELMO1 and DOCK180 form a tripartite complex. Knockdown of DOCK180 reduces the stimulatory effect of FE65-ELMO1 on Rac1 activation and neurite outgrowth. Thus, we identify a novel mechanism that FE65 stimulates Rac1-mediated neurite outgrowth by recruiting and activating of ELMO1. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.

  3. The adaptor molecule SAP plays essential roles during invariant NKT cell cytotoxicity and lytic synapse formation.

    Science.gov (United States)

    Das, Rupali; Bassiri, Hamid; Guan, Peng; Wiener, Susan; Banerjee, Pinaki P; Zhong, Ming-Chao; Veillette, André; Orange, Jordan S; Nichols, Kim E

    2013-04-25

    The adaptor molecule signaling lymphocytic activation molecule-associated protein (SAP) plays critical roles during invariant natural killer T (iNKT) cell ontogeny. As a result, SAP-deficient humans and mice lack iNKT cells. The strict developmental requirement for SAP has made it difficult to discern its possible involvement in mature iNKT cell functions. By using temporal Cre recombinase-mediated gene deletion to ablate SAP expression after completion of iNKT cell development, we demonstrate that SAP is essential for T-cell receptor (TCR)-induced iNKT cell cytotoxicity against T-cell and B-cell leukemia targets in vitro and iNKT-cell-mediated control of T-cell leukemia growth in vivo. These findings are not restricted to the murine system: silencing RNA-mediated suppression of SAP expression in human iNKT cells also significantly impairs TCR-induced cytolysis. Mechanistic studies reveal that iNKT cell killing requires the tyrosine kinase Fyn, a known SAP-binding protein. Furthermore, SAP expression is required within iNKT cells to facilitate their interaction with T-cell targets and induce reorientation of the microtubule-organizing center to the immunologic synapse (IS). Collectively, these studies highlight a novel and essential role for SAP during iNKT cell cytotoxicity and formation of a functional IS.

  4. Development of STEP-NC Adaptor for Advanced Web Manufacturing System

    Science.gov (United States)

    Ajay Konapala, Mr.; Koona, Ramji, Dr.

    2017-08-01

    Information systems play a key role in the modern era of Information Technology. Rapid developments in IT & global competition calls for many changes in basic CAD/CAM/CAPP/CNC manufacturing chain of operations. ‘STEP-NC’ an enhancement to STEP for operating CNC machines, creating new opportunities for collaborative, concurrent, adaptive works across the manufacturing chain of operations. Schemas and data models defined by ISO14649 in liaison with ISO10303 standards made STEP-NC file rich with feature based, rather than mere point to point information of G/M Code format. But one needs to have a suitable information system to understand and modify these files. Various STEP-NC information systems are reviewed to understand the suitability of STEP-NC for web manufacturing. Present work also deals with the development of an adaptor which imports STEP-NC file, organizes its information, allowing modifications to entity values and finally generates a new STEP-NC file to export. The system is designed and developed to work on web to avail additional benefits through the web and also to be part of a proposed ‘Web based STEP-NC manufacturing platform’ which is under development and explained as future scope.

  5. Dengue Virus Targets the Adaptor Protein MITA to Subvert Host Innate Immunity

    Science.gov (United States)

    Yu, Chia-Yi; Chang, Tsung-Hsien; Liang, Jian-Jong; Chiang, Ruei-Lin; Lee, Yi-Ling; Liao, Ching-Len; Lin, Yi-Ling

    2012-01-01

    Dengue is one of the most important arboviral diseases caused by infection of four serotypes of dengue virus (DEN). We found that activation of interferon regulatory factor 3 (IRF3) triggered by viral infection and by foreign DNA and RNA stimulation was blocked by DEN-encoded NS2B3 through a protease-dependent mechanism. The key adaptor protein in type I interferon pathway, human mediator of IRF3 activation (MITA) but not the murine homologue MPYS, was cleaved in cells infected with DEN-1 or DEN-2 and with expression of the enzymatically active protease NS2B3. The cleavage site of MITA was mapped to LRR↓96G and the function of MITA was suppressed by dengue protease. DEN replication was reduced with overexpression of MPYS but not with MITA, while DEN replication was enhanced by MPYS knockdown, indicating an antiviral role of MITA/MPYS against DEN infection. The involvement of MITA in DEN-triggered innate immune response was evidenced by reduction of IRF3 activation and IFN induction in cells with MITA knockdown upon DEN-2 infection. NS2B3 physically interacted with MITA, and the interaction and cleavage of MITA could be further enhanced by poly(dA:dT) stimulation. Thus, we identified MITA as a novel host target of DEN protease and provide the molecular mechanism of how DEN subverts the host innate immunity. PMID:22761576

  6. Artificial Neural Network for the Prediction of Tyrosine-Based Sorting Signal Recognition by Adaptor Complexes

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    Debarati Mukherjee

    2012-01-01

    Full Text Available Sorting of transmembrane proteins to various intracellular compartments depends on specific signals present within their cytosolic domains. Among these sorting signals, the tyrosine-based motif (YXXØ is one of the best characterized and is recognized by μ-subunits of the four clathrin-associated adaptor complexes (AP-1 to AP-4. Despite their overlap in specificity, each μ-subunit has a distinct sequence preference dependent on the nature of the X-residues. Moreover, combinations of these residues exert cooperative or inhibitory effects towards interaction with the various APs. This complexity makes it impossible to predict a priori, the specificity of a given tyrosine-signal for a particular μ-subunit. Here, we describe the results obtained with a computational approach based on the Artificial Neural Network (ANN paradigm that addresses the issue of tyrosine-signal specificity, enabling the prediction of YXXØ-μ interactions with accuracies over 90%. Therefore, this approach constitutes a powerful tool to help predict mechanisms of intracellular protein sorting.

  7. Role of the AP-5 adaptor protein complex in late endosome-to-Golgi retrieval.

    Science.gov (United States)

    Hirst, Jennifer; Itzhak, Daniel N; Antrobus, Robin; Borner, Georg H H; Robinson, Margaret S

    2018-01-01

    The AP-5 adaptor protein complex is presumed to function in membrane traffic, but so far nothing is known about its pathway or its cargo. We have used CRISPR-Cas9 to knock out the AP-5 ζ subunit gene, AP5Z1, in HeLa cells, and then analysed the phenotype by subcellular fractionation profiling and quantitative mass spectrometry. The retromer complex had an altered steady-state distribution in the knockout cells, and several Golgi proteins, including GOLIM4 and GOLM1, were depleted from vesicle-enriched fractions. Immunolocalisation showed that loss of AP-5 led to impaired retrieval of the cation-independent mannose 6-phosphate receptor (CIMPR), GOLIM4, and GOLM1 from endosomes back to the Golgi region. Knocking down the retromer complex exacerbated this phenotype. Both the CIMPR and sortilin interacted with the AP-5-associated protein SPG15 in pull-down assays, and we propose that sortilin may act as a link between Golgi proteins and the AP-5/SPG11/SPG15 complex. Together, our findings suggest that AP-5 functions in a novel sorting step out of late endosomes, acting as a backup pathway for retromer. This provides a mechanistic explanation for why mutations in AP-5/SPG11/SPG15 cause cells to accumulate aberrant endolysosomes, and highlights the role of endosome/lysosome dysfunction in the pathology of hereditary spastic paraplegia and other neurodegenerative disorders.

  8. Dengue virus targets the adaptor protein MITA to subvert host innate immunity.

    Science.gov (United States)

    Yu, Chia-Yi; Chang, Tsung-Hsien; Liang, Jian-Jong; Chiang, Ruei-Lin; Lee, Yi-Ling; Liao, Ching-Len; Lin, Yi-Ling

    2012-01-01

    Dengue is one of the most important arboviral diseases caused by infection of four serotypes of dengue virus (DEN). We found that activation of interferon regulatory factor 3 (IRF3) triggered by viral infection and by foreign DNA and RNA stimulation was blocked by DEN-encoded NS2B3 through a protease-dependent mechanism. The key adaptor protein in type I interferon pathway, human mediator of IRF3 activation (MITA) but not the murine homologue MPYS, was cleaved in cells infected with DEN-1 or DEN-2 and with expression of the enzymatically active protease NS2B3. The cleavage site of MITA was mapped to LRR↓(96)G and the function of MITA was suppressed by dengue protease. DEN replication was reduced with overexpression of MPYS but not with MITA, while DEN replication was enhanced by MPYS knockdown, indicating an antiviral role of MITA/MPYS against DEN infection. The involvement of MITA in DEN-triggered innate immune response was evidenced by reduction of IRF3 activation and IFN induction in cells with MITA knockdown upon DEN-2 infection. NS2B3 physically interacted with MITA, and the interaction and cleavage of MITA could be further enhanced by poly(dA:dT) stimulation. Thus, we identified MITA as a novel host target of DEN protease and provide the molecular mechanism of how DEN subverts the host innate immunity.

  9. The ubiquitin ligase RNF5 regulates antiviral responses by mediating degradation of the adaptor protein MITA.

    Science.gov (United States)

    Zhong, Bo; Zhang, Lu; Lei, Caoqi; Li, Ying; Mao, Ai-Ping; Yang, Yan; Wang, Yan-Yi; Zhang, Xiao-Lian; Shu, Hong-Bing

    2009-03-20

    Viral infection activates transcription factors NF-kappaB and IRF3, which collaborate to induce type I interferons (IFNs) and elicit innate antiviral response. MITA (also known as STING) has recently been identified as an adaptor that links virus-sensing receptors to IRF3 activation. Here, we showed that the E3 ubiquitin ligase RNF5 interacted with MITA in a viral-infection-dependent manner. Overexpression of RNF5 inhibited virus-triggered IRF3 activation, IFNB1 expression, and cellular antiviral response, whereas knockdown of RNF5 had opposite effects. RNF5 targeted MITA at Lys150 for ubiquitination and degradation after viral infection. Both MITA and RNF5 were located at the mitochondria and endoplasmic reticulum (ER) and viral infection caused their redistribution to the ER and mitochondria, respectively. We further found that virus-induced ubiquitination and degradation of MITA by RNF5 occurred at the mitochondria. These findings suggest that RNF5 negatively regulates virus-triggered signaling by targeting MITA for ubiquitination and degradation at the mitochondria.

  10. Dengue virus targets the adaptor protein MITA to subvert host innate immunity.

    Directory of Open Access Journals (Sweden)

    Chia-Yi Yu

    Full Text Available Dengue is one of the most important arboviral diseases caused by infection of four serotypes of dengue virus (DEN. We found that activation of interferon regulatory factor 3 (IRF3 triggered by viral infection and by foreign DNA and RNA stimulation was blocked by DEN-encoded NS2B3 through a protease-dependent mechanism. The key adaptor protein in type I interferon pathway, human mediator of IRF3 activation (MITA but not the murine homologue MPYS, was cleaved in cells infected with DEN-1 or DEN-2 and with expression of the enzymatically active protease NS2B3. The cleavage site of MITA was mapped to LRR↓(96G and the function of MITA was suppressed by dengue protease. DEN replication was reduced with overexpression of MPYS but not with MITA, while DEN replication was enhanced by MPYS knockdown, indicating an antiviral role of MITA/MPYS against DEN infection. The involvement of MITA in DEN-triggered innate immune response was evidenced by reduction of IRF3 activation and IFN induction in cells with MITA knockdown upon DEN-2 infection. NS2B3 physically interacted with MITA, and the interaction and cleavage of MITA could be further enhanced by poly(dA:dT stimulation. Thus, we identified MITA as a novel host target of DEN protease and provide the molecular mechanism of how DEN subverts the host innate immunity.

  11. The adaptor protein MITA links virus-sensing receptors to IRF3 transcription factor activation.

    Science.gov (United States)

    Zhong, Bo; Yang, Yan; Li, Shu; Wang, Yan-Yi; Li, Ying; Diao, Feici; Lei, Caoqi; He, Xiao; Zhang, Lu; Tien, Po; Shu, Hong-Bing

    2008-10-17

    Viral infection triggers activation of transcription factors such as NF-kappaB and IRF3, which collaborate to induce type I interferons (IFNs) and elicit innate antiviral response. Here, we identified MITA as a critical mediator of virus-triggered type I IFN signaling by expression cloning. Overexpression of MITA activated IRF3, whereas knockdown of MITA inhibited virus-triggered activation of IRF3, expression of type I IFNs, and cellular antiviral response. MITA was found to localize to the outer membrane of mitochondria and to be associated with VISA, a mitochondrial protein that acts as an adaptor in virus-triggered signaling. MITA also interacted with IRF3 and recruited the kinase TBK1 to the VISA-associated complex. MITA was phosphorylated by TBK1, which is required for MITA-mediated activation of IRF3. Our results suggest that MITA is a critical mediator of virus-triggered IRF3 activation and IFN expression and further demonstrate the importance of certain mitochondrial proteins in innate antiviral immunity.

  12. Role of the AP-5 adaptor protein complex in late endosome-to-Golgi retrieval.

    Directory of Open Access Journals (Sweden)

    Jennifer Hirst

    2018-01-01

    Full Text Available The AP-5 adaptor protein complex is presumed to function in membrane traffic, but so far nothing is known about its pathway or its cargo. We have used CRISPR-Cas9 to knock out the AP-5 ζ subunit gene, AP5Z1, in HeLa cells, and then analysed the phenotype by subcellular fractionation profiling and quantitative mass spectrometry. The retromer complex had an altered steady-state distribution in the knockout cells, and several Golgi proteins, including GOLIM4 and GOLM1, were depleted from vesicle-enriched fractions. Immunolocalisation showed that loss of AP-5 led to impaired retrieval of the cation-independent mannose 6-phosphate receptor (CIMPR, GOLIM4, and GOLM1 from endosomes back to the Golgi region. Knocking down the retromer complex exacerbated this phenotype. Both the CIMPR and sortilin interacted with the AP-5-associated protein SPG15 in pull-down assays, and we propose that sortilin may act as a link between Golgi proteins and the AP-5/SPG11/SPG15 complex. Together, our findings suggest that AP-5 functions in a novel sorting step out of late endosomes, acting as a backup pathway for retromer. This provides a mechanistic explanation for why mutations in AP-5/SPG11/SPG15 cause cells to accumulate aberrant endolysosomes, and highlights the role of endosome/lysosome dysfunction in the pathology of hereditary spastic paraplegia and other neurodegenerative disorders.

  13. Expression of the Rai (Shc C) adaptor protein in the human enteric nervous system.

    Science.gov (United States)

    Villanacci, V; Bassotti, G; Ortensi, B; Fisogni, S; Cathomas, G; Maurer, C A; Galletti, A; Salerni, B; Pelicci, G

    2008-03-01

    The adaptor protein Rai (ShcC/N-Shc) is almost exclusively present in the nervous system, although little is documented about its expression in the gut and the enteric nervous system (ENS). As Rai is a physiological substrate of Ret, an important factor for the development of ENS, we have evaluated the expression of Rai in the ENS in various segments of the human gastrointestinal tract. The expression of Rai was assessed by immunohistochemistry in disease-free human gut samples (oesophagus, stomach, small bowel and colon) obtained from subjects undergoing surgical procedures. Rai was not expressed in the epithelia or lymphoid tissue, whereas a moderate level of expression was observed in the endothelial cells of blood vessels and on the outer membrane of smooth muscle cells in both the muscularis mucosae and the muscularis propria. In the ENS, strong positivity was observed only in enteric glial cells, overlapping with GFAP and S100. In conclusion, Rai is expressed in the human gut, especially in the enteric glial cells. We conclude that Rai may provide an additional marker for this cell type.

  14. Histone locus regulation by the Drosophila dosage compensation adaptor protein CLAMP.

    Science.gov (United States)

    Rieder, Leila E; Koreski, Kaitlin P; Boltz, Kara A; Kuzu, Guray; Urban, Jennifer A; Bowman, Sarah K; Zeidman, Anna; Jordan, William T; Tolstorukov, Michael Y; Marzluff, William F; Duronio, Robert J; Larschan, Erica N

    2017-07-15

    The conserved histone locus body (HLB) assembles prior to zygotic gene activation early during development and concentrates factors into a nuclear domain of coordinated histone gene regulation. Although HLBs form specifically at replication-dependent histone loci, the cis and trans factors that target HLB components to histone genes remained unknown. Here we report that conserved GA repeat cis elements within the bidirectional histone3-histone4 promoter direct HLB formation in Drosophila In addition, the CLAMP (chromatin-linked adaptor for male-specific lethal [MSL] proteins) zinc finger protein binds these GA repeat motifs, increases chromatin accessibility, enhances histone gene transcription, and promotes HLB formation. We demonstrated previously that CLAMP also promotes the formation of another domain of coordinated gene regulation: the dosage-compensated male X chromosome. Therefore, CLAMP binding to GA repeat motifs promotes the formation of two distinct domains of coordinated gene activation located at different places in the genome. © 2017 Rieder et al.; Published by Cold Spring Harbor Laboratory Press.

  15. FLORISTIC CONTRIBUTIONS

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    COSTACHE I.

    2006-10-01

    Full Text Available The paper represents a part of the research carried out in a five-year period (within my Ph.D. paper called: “The Flora and the Vegetation of the Lower Hydrographic Basin of the River Motru”, coordinated by Professor V. CIOCÂRLAN, Ph.D.. The material contains additional information for the diagnosis of the taxa: Agróstis canína L. subsp. canína, Círsium créticum (L. D' Urv.; it suggests a new variety for the species Trifólium stríctum L. var. pubéscens Costache var. nova; the following species are noticed to be new for the region of Oltenia: Achilléa roseo-álba Ehrend., Cárex guestphálica (Boenn. ex Rchb. Boenn. ex O. Lang (with taxonomic considerations, Galinsóga quadriradiáta Ruiz & Pav., Xánthium saccharátum Wallr.

  16. Interactions between the Hepatitis C Virus Nonstructural 2 Protein and Host Adaptor Proteins 1 and 4 Orchestrate Virus Release.

    Science.gov (United States)

    Xiao, Fei; Wang, Stanley; Barouch-Bentov, Rina; Neveu, Gregory; Pu, Szuyuan; Beer, Melanie; Schor, Stanford; Kumar, Sathish; Nicolaescu, Vlad; Lindenbach, Brett D; Randall, Glenn; Einav, Shirit

    2018-03-13

    Hepatitis C virus (HCV) spreads via secreted cell-free particles or direct cell-to-cell transmission. Yet, virus-host determinants governing differential intracellular trafficking of cell-free- and cell-to-cell-transmitted virus remain unknown. The host adaptor proteins (APs) AP-1A, AP-1B, and AP-4 traffic in post-Golgi compartments, and the latter two are implicated in basolateral sorting. We reported that AP-1A mediates HCV trafficking during release, whereas the endocytic adaptor AP-2 mediates entry and assembly. We demonstrated that the host kinases AAK1 and GAK regulate HCV infection by controlling these clathrin-associated APs. Here, we sought to define the roles of AP-4, a clathrin-independent adaptor; AP-1A; and AP-1B in HCV infection. We screened for interactions between HCV proteins and the μ subunits of AP-1A, AP-1B, and AP-4 by mammalian cell-based protein fragment complementation assays. The nonstructural 2 (NS2) protein emerged as an interactor of these adaptors in this screening and by coimmunoprecipitations in HCV-infected cells. Two previously unrecognized dileucine-based motifs in the NS2 C terminus mediated AP binding and HCV release. Infectivity and coculture assays demonstrated that while all three adaptors mediate HCV release and cell-free spread, AP-1B and AP-4, but not AP-1A, mediate cell-to-cell spread. Live-cell imaging revealed HCV cotrafficking with AP-1A, AP-1B, and AP-4 and that AP-4 mediates HCV trafficking in a post-Golgi compartment. Lastly, HCV cell-to-cell spread was regulated by AAK1 and GAK and thus susceptible to treatment with AAK1 and GAK inhibitors. These data provide a mechanistic understanding of HCV trafficking in distinct release pathways and reveal a requirement for APs in cell-to-cell viral spread. IMPORTANCE HCV spreads via cell-free infection or cell-to-cell contact that shields it from antibody neutralization, thereby facilitating viral persistence. Yet, factors governing this differential sorting remain unknown

  17. Genetic Deletion of the Clathrin Adaptor GGA3 Reduces Anxiety and Alters GABAergic Transmission.

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    Kendall R Walker

    Full Text Available Golgi-localized γ-ear-containing ARF binding protein 3 (GGA3 is a monomeric clathrin adaptor that has been shown to regulate the trafficking of the Beta-site APP-cleaving enzyme (BACE1, which is required for production of the Alzheimer's disease (AD-associated amyloid βpeptide. Our previous studies have shown that BACE1 is degraded via the lysosomal pathway and that depletion of GGA3 results in increased BACE1 levels and activity owing to impaired lysosomal trafficking and degradation. We further demonstrated the role of GGA3 in the regulation of BACE1 in vivo by showing that BACE1 levels are increased in the brain of GGA3 null mice. We report here that GGA3 deletion results in novelty-induced hyperactivity and decreased anxiety-like behaviors. Given the pivotal role of GABAergic transmission in the regulation of anxiety-like behaviors, we performed electrophysiological recordings in hippocampal slices and found increased phasic and decreased tonic inhibition in the dentate gyrus granule cells (DGGC. Moreover, we found that the number of inhibitory synapses is increased in the dentate gyrus of GGA3 null mice in further support of the electrophysiological data. Thus, the increased GABAergic transmission is a leading candidate mechanism underlying the reduced anxiety-like behaviors observed in GGA3 null mice. All together these findings suggest that GGA3 plays a key role in GABAergic transmission. Since BACE1 levels are elevated in the brain of GGA3 null mice, it is possible that at least some of these phenotypes are a consequence of increased processing of BACE1 substrates.

  18. Genetic Deletion of the Clathrin Adaptor GGA3 Reduces Anxiety and Alters GABAergic Transmission.

    Science.gov (United States)

    Walker, Kendall R; Modgil, Amit; Albrecht, David; Lomoio, Selene; Haydon, Philip G; Moss, Stephen J; Tesco, Giuseppina

    2016-01-01

    Golgi-localized γ-ear-containing ARF binding protein 3 (GGA3) is a monomeric clathrin adaptor that has been shown to regulate the trafficking of the Beta-site APP-cleaving enzyme (BACE1), which is required for production of the Alzheimer's disease (AD)-associated amyloid βpeptide. Our previous studies have shown that BACE1 is degraded via the lysosomal pathway and that depletion of GGA3 results in increased BACE1 levels and activity owing to impaired lysosomal trafficking and degradation. We further demonstrated the role of GGA3 in the regulation of BACE1 in vivo by showing that BACE1 levels are increased in the brain of GGA3 null mice. We report here that GGA3 deletion results in novelty-induced hyperactivity and decreased anxiety-like behaviors. Given the pivotal role of GABAergic transmission in the regulation of anxiety-like behaviors, we performed electrophysiological recordings in hippocampal slices and found increased phasic and decreased tonic inhibition in the dentate gyrus granule cells (DGGC). Moreover, we found that the number of inhibitory synapses is increased in the dentate gyrus of GGA3 null mice in further support of the electrophysiological data. Thus, the increased GABAergic transmission is a leading candidate mechanism underlying the reduced anxiety-like behaviors observed in GGA3 null mice. All together these findings suggest that GGA3 plays a key role in GABAergic transmission. Since BACE1 levels are elevated in the brain of GGA3 null mice, it is possible that at least some of these phenotypes are a consequence of increased processing of BACE1 substrates.

  19. A potential role for the clathrin adaptor GGA in Drosophila spermatogenesis

    Directory of Open Access Journals (Sweden)

    Carmichael Jenny

    2011-05-01

    Full Text Available Abstract Background GGAs (Golgi-localised, γ-ear containing, ADP ribosylation factor-binding are a family of clathrin adaptors that sort a number of biologically important transmembrane proteins into clathrin-coated vesicles. Knockout and knockdown studies to determine GGA function are confounded by the fact that there are 3 GGA genes in mammalian cells. Thus Drosophila melanogaster is a useful model system to study tissue expression profiles and knockdown phenotypes as there is a single GGA ortholog. Results Here we have quantified protein expression in Drosophila and show that there is >3-fold higher expression of GGA in male flies relative to female flies. In female flies the majority of GGA expression is in the head. In male flies GGA is not only expressed at high levels in the head but there is a gender specific increased expression which is due to the abundant expression of GGA in the testes. Using a highly specific antibody we have localised endogenous GGA protein in testes squashes, and visualised it in somatic and germ line cells. We show that GGA is expressed during multiple stages of sperm development, and co-stains with a marker of the trans-Golgi Network. This is most striking at the acroblast of early spermatids. In spite of the high expression of GGA in testes, knocking down its expression by >95% using transgenic RNAi fly lines did not affect male fertility. Therefore spermatogenesis in the male flies appears to progress normally with Conclusion In Drosophila we have uncovered a potential role for GGA in the testes of male flies. The gender specific higher expression of GGA, its specific enrichment in testes and its localisation to developing spermatocytes and at the acroblast of spermatids supports a role for GGA function in Drosophila spermatogenesis, even though spermatogenesis still occurs when GGA expression is depleted to

  20. Hydrological Modeling Reproducibility Through Data Management and Adaptors for Model Interoperability

    Science.gov (United States)

    Turner, M. A.

    2015-12-01

    Because of a lack of centralized planning and no widely-adopted standards among hydrological modeling research groups, research communities, and the data management teams meant to support research, there is chaos when it comes to data formats, spatio-temporal resolutions, ontologies, and data availability. All this makes true scientific reproducibility and collaborative integrated modeling impossible without some glue to piece it all together. Our Virtual Watershed Integrated Modeling System provides the tools and modeling framework hydrologists need to accelerate and fortify new scientific investigations by tracking provenance and providing adaptors for integrated, collaborative hydrologic modeling and data management. Under global warming trends where water resources are under increasing stress, reproducible hydrological modeling will be increasingly important to improve transparency and understanding of the scientific facts revealed through modeling. The Virtual Watershed Data Engine is capable of ingesting a wide variety of heterogeneous model inputs, outputs, model configurations, and metadata. We will demonstrate one example, starting from real-time raw weather station data packaged with station metadata. Our integrated modeling system will then create gridded input data via geostatistical methods along with error and uncertainty estimates. These gridded data are then used as input to hydrological models, all of which are available as web services wherever feasible. Models may be integrated in a data-centric way where the outputs too are tracked and used as inputs to "downstream" models. This work is part of an ongoing collaborative Tri-state (New Mexico, Nevada, Idaho) NSF EPSCoR Project, WC-WAVE, comprised of researchers from multiple universities in each of the three states. The tools produced and presented here have been developed collaboratively alongside watershed scientists to address specific modeling problems with an eye on the bigger picture of

  1. Metodologia de cálculo de parâmetros do circuito elétrico equivalente de motores de indução trifásico de gaiola de esquilo de baixa potência

    OpenAIRE

    Machado, Daimon Castilhos

    2014-01-01

    Dissertação (mestrado) - Universidade Federal de Santa Catarina, Centro Tecnológico, Programa de Pós-Graduação em Engenharia Elétrica, Florianópolis, 2014. Neste trabalho foi desenvolvido um modelo analítico para o levantamento dos parâmetros do circuito elétrico equivalente de um motor de indução trifásico, com rotor do tipo gaiola de esquilo, a partir das características construtivas e elétricas da máquina. O modelo foi desenvolvido com base nas Equações de Maxwell. O cálculo dos parâmet...

  2. The Shc Family Protein Adaptor, Rai, Negatively Regulates T Cell Antigen Receptor Signaling by Inhibiting ZAP-70 Recruitment and Activation

    OpenAIRE

    Ferro, Micol; Savino, Maria Teresa; Ortensi, Barbara; Finetti, Francesca; Genovese, Luca; Masi, Giulia; Ulivieri, Cristina; Benati, Daniela; Pelicci, Giuliana; Baldari, Cosima T.

    2011-01-01

    Rai/ShcC is a member of the Shc family of protein adaptors expressed with the highest abundance in the central nervous system, where it exerts a protective function by coupling neurotrophic receptors to the PI3K/Akt survival pathway. Rai is also expressed, albeit at lower levels, in other cell types, including T and B lymphocytes. We have previously reported that in these cells Rai attenuates antigen receptor signaling, thereby impairing not only cell proliferation but also, opposite to neuro...

  3. A Dictyostelium SH2 adaptor protein required for correct DIF-1 signaling and pattern formation.

    Science.gov (United States)

    Sugden, Christopher; Ross, Susan; Annesley, Sarah J; Cole, Christian; Bloomfield, Gareth; Ivens, Alasdair; Skelton, Jason; Fisher, Paul R; Barton, Geoffrey; Williams, Jeffrey G

    2011-05-15

    phototaxis defect, implying that the early and late functions of LrrB are affected in different ways. These observations, coupled with its domain structure, suggest that LrrB is an SH2 adaptor protein active in diverse developmental signaling pathways. Copyright © 2011 Elsevier Inc. All rights reserved.

  4. Molecular cloning and characterization of GhAPm, a gene encoding the μ subunit of the clathrin-associated adaptor protein complex that is associated with cotton (Gossypium hirsutum) fiber development.

    Science.gov (United States)

    Zhou, Tao; Zhang, Rui; Yang, Dawei; Guo, Sandui

    2011-06-01

    The clathrin-associated adaptor protein (AP) complexes are the primary clathrin adaptors that contribute to the formation of clathrin-coated vesicles (CCVs). The GhAPm gene (GenBank accession number: GU359054), which encodes the medium subunit of the AP complexes, was cloned from cotton by rapid amplification of cDNA ends-polymerase chain reaction (RACE-PCR). The full-length cDNA was 1590 bp in size and encoded an open reading frame (ORF) of 416 amino acids with a molecular weight of 46 kDa. The GhAPm protein shared 81-85% identity at the amino acid level with the AP complex μ subunits isolated from Vitis vinifera, Glycine max, Populus trichocarpa, Ricinus communis and Arabidopsis thaliana, respectively. The corresponding genomic DNA, containing eight exons and seven introns, was isolated and analyzed. Also, a 5'-flanking region was analyzed, and a group of putative cis-acting elements were identified. DNA gel blot analysis showed that there is only one GhAPm gene in the cotton genome. Real-time RT-PCR analysis revealed that GhAPm is expressed in the root, stem, leaf, petal, ovule, and fiber. However, the interesting finding is that GhAPm expression level was shown to increase steadily as the cotton fiber develops. In 30 DPA fibers, expression increases sharply and arrives at a peak then the expression levels decrease rapidly. Based on these data, we propose that GhAPm has a critical role in cotton membrane trafficking and fiber development.

  5. Espectro de gotas e idade de trifólios na taxa de absorção e efeito residual de fungicidas em soja Drops spectra and leaflets age on the fungicides absorption rate and residual effect in soybean

    Directory of Open Access Journals (Sweden)

    Giuvan Lenz

    2011-10-01

    Full Text Available O objetivo do presente trabalho foi avaliar o efeito de espectros de gotas (grossas, médias e finas na velocidade de absorção de fungicidas, para trifólios de diferentes idades através de medida indireta expressa pelo residual de controle de ferrugem asiática da soja (Phakopsora pachyrhizi. O delineamento experimental utilizado foi inteiramente casualizado, com quatro repetições, em arranjo fatorial (3x3x5x4, cujos fatores foram compostos por: três categorias de gotas (grossas, médias e finas; três diferentes posições de avaliação na planta (1°, 3° e 5° trifólios; quatro períodos de tempo entre a aplicação de fungicidas e aplicação de chuva simulada (0, 30, 60 e 120min, mais uma testemunha sem chuva; testemunha sem aplicação, mais os fungicidas azoxistrobina + ciproconazol (60+24g i.a. ha-1 + óleo mineral 0,6L ha-1, azoxistrobina (50g i.a. ha-1 + óleo mineral 0,6L ha-1 e ciproconazol (30g i.a. ha-1. Avaliou-se a densidade de gotas por centímetro quadrado, diâmetro mediano volumétrico, diâmetro mediano numérico e amplitude relativa, além do número de dias para o aparecimento da primeira pústula. Verificou-se que gotas de menor DMV proporcionam maior velocidade de absorção de fungicidas. Trifólios mais novos absorvem os fungicidas mais rapidamente. A utilização de azoxistrobina + ciproconazol + óleo mineral proporcionou o maior número de dias até o aparecimento da primeira pústula.This research aimed to evaluate the effect of large, medium and fine droplets spectra and its interaction with the fungicide absorption rate and leaflets age through indirect measurement expressed by the residual control of Asian soybean rust (Phakopsora pachyrhizi. The experimental design was completely randomized with four replications in a factorial scheme (3x3x5x4, which factors were composed of: three drops spectra (large, medium and fine; three different positions in the plant evaluated (1st, 3rd and 5th leaflets, four

  6. Análisis multirresolución del motor trifásico de inducción sometido a huecos de tensión Triphasic induction motor multiresolution analysis on voltage sags

    Directory of Open Access Journals (Sweden)

    M.G Macri

    2012-04-01

    Full Text Available Este documento presenta los resultados del estudio realizado de la descomposición wavelet multinivel 1D de las señales perturbadas del par electromagnético y de la velocidad del eje del motor trifásico de inducción, cuando este es sometido a diferentes tipologías de huecos de tensión según la caracterización ABC, Bollen (2000. Los huecos de tensión trifásicos (3 variables son analizados indirectamente en el efecto producido en una variable perturbada (el par electromagnético o la velocidad del eje que contiene indirectamente información del tipo de hueco de tensión trifásico producido en el estator. El estudio analiza el efecto de los siete diferentes tipos de huecos de tensión, considerando también la influencia de la duración y tensión retenida. Para cada caso se obtiene un vector cuyos elementos son los niveles de energía wavelet en los distintos niveles de descomposición de la variable analizada, mostrando que la forma en que se distribuye la energía de la señal 1D en los distintos niveles de descomposición establece una firma única para cada caso. Esta forma de descripción de los huecos de tensión producidos en el estator, basada en la descomposición multinivel de una variable perturbada, reduce la cantidad de variables a analizar y permite posteriormente la clasificación de las perturbaciones empleando técnicas de inteligencia artificial; es ventajosa pues el almacenamiento de los vectores de niveles de energía de aproximación en las bases de datos emplea menor cantidad de espacio que la necesaria para una señal temporal, y empleando una DWT reversible es posible, además, reconstruir la variable de estado temporal.This document presents the study results of the wavelet 1D multi-level decomposition of perturbed electromagnetic torque and shaft speed signals, of the three-phase induction motor, when it is subjected to different types of voltage sags, as characterization ABC, Bollen (2000. The three

  7. Transmembrane adaptor protein TRIM regulates T cell receptor (TCR) expression and TCR-mediated signaling via an association with the TCR zeta chain

    Czech Academy of Sciences Publication Activity Database

    Kirchgesser, H.; Dietrich, J.; Scherer, J.; Isomaki, P.; Kořínek, Vladimír; Hilgert, Ivan; Bruyns, E.; Leo, A.; Cope, A. P.; Schraven, B.

    2001-01-01

    Roč. 193, č. 11 (2001), s. 1269-1283 ISSN 0022-1007 R&D Projects: GA ČR GA204/99/0367 Institutional research plan: CEZ:AV0Z5052915 Keywords : receptor * adaptor protein * signaling Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 15.340, year: 2001

  8. LAT--an important raft-associated transmembrane adaptor protein. Delivered on 6 July 2009 at the 34th FEBS Congress in Prague, Czech Republic

    Czech Academy of Sciences Publication Activity Database

    Hořejší, Václav; Otáhal, Pavel; Brdička, Tomáš

    2010-01-01

    Roč. 277, č. 21 (2010), s. 4383-4397 ISSN 1742-464X R&D Projects: GA ČR GEMEM/09/E011; GA MŠk 1M0506 Institutional research plan: CEZ:AV0Z50520514 Keywords : LAT * transmembrane adaptor protein * membrane rafts Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.129, year: 2010

  9. Kit- and Fc epsilonRI-induced differential phosphorylation of the transmembrane adaptor molecule NTAL/LAB/LAT2 allows flexibility in its scaffolding function in mast cells

    DEFF Research Database (Denmark)

    Iwaki, Shoko; Spicka, Jiri; Tkaczyk, Christine

    2008-01-01

    The transmembrane adaptor protein (TRAP), NTAL, is phosphorylated in mast cells following FcvarepsilonRI aggregation whereby it cooperates with LAT to induce degranulation. The Kit ligand, stem cell factor (SCF), enhances antigen-induced degranulation and this also appears to be NTAL-dependent. H...

  10. Brain-derived neurotrophic factor modulation of Kv1.3 channel is disregulated by adaptor proteins Grb10 and nShc

    Directory of Open Access Journals (Sweden)

    Marks David R

    2009-01-01

    Full Text Available Abstract Background Neurotrophins are important regulators of growth and regeneration, and acutely, they can modulate the activity of voltage-gated ion channels. Previously we have shown that acute brain-derived neurotrophic factor (BDNF activation of neurotrophin receptor tyrosine kinase B (TrkB suppresses the Shaker voltage-gated potassium channel (Kv1.3 via phosphorylation of multiple tyrosine residues in the N and C terminal aspects of the channel protein. It is not known how adaptor proteins, which lack catalytic activity, but interact with members of the neurotrophic signaling pathway, might scaffold with ion channels or modulate channel activity. Results We report the co-localization of two adaptor proteins, neuronal Src homology and collagen (nShc and growth factor receptor-binding protein 10 (Grb10, with Kv1.3 channel as demonstrated through immunocytochemical approaches in the olfactory bulb (OB neural lamina. To further explore the specificity and functional ramification of adaptor/channel co-localization, we performed immunoprecipitation and Western analysis of channel, kinase, and adaptor transfected human embryonic kidney 293 cells (HEK 293. nShc formed a direct protein-protein interaction with Kv1.3 that was independent of BDNF-induced phosphorylation of Kv1.3, whereas Grb10 did not complex with Kv1.3 in HEK 293 cells. Both adaptors, however, co-immunoprecipitated with Kv1.3 in native OB. Grb10 was interestingly able to decrease the total expression of Kv1.3, particularly at the membrane surface, and subsequently eliminated the BDNF-induced phosphorylation of Kv1.3. To examine the possibility that the Src homology 2 (SH2 domains of Grb10 were directly binding to basally phosphorylated tyrosines in Kv1.3, we utilized point mutations to substitute multiple tyrosine residues with phenylalanine. Removal of the tyrosines 111–113 and 449 prevented Grb10 from decreasing Kv1.3 expression. In the absence of either adaptor protein

  11. TIRAP, an Adaptor Protein for TLR2/4, Transduces a Signal from RAGE Phosphorylated upon Ligand Binding

    Science.gov (United States)

    Sakaguchi, Masakiyo; Murata, Hitoshi; Yamamoto, Ken-ichi; Ono, Tomoyuki; Sakaguchi, Yoshihiko; Motoyama, Akira; Hibino, Toshihiko; Kataoka, Ken; Huh, Nam-ho

    2011-01-01

    The receptor for advanced glycation end products (RAGE) is thought to be involved in the pathogenesis of a broad range of inflammatory, degenerative and hyperproliferative diseases. It binds to diverse ligands and activates multiple intracellular signaling pathways. Despite these pivotal functions, molecular events just downstream of ligand-activated RAGE have been surprisingly unknown. Here we show that the cytoplasmic domain of RAGE is phosphorylated at Ser391 by PKCζ upon binding of ligands. TIRAP and MyD88, which are known to be adaptor proteins for Toll-like receptor-2 and -4 (TLR2/4), bound to the phosphorylated RAGE and transduced a signal to downstream molecules. Blocking of the function of TIRAP and MyD88 largely abrogated intracellular signaling from ligand-activated RAGE. Our findings indicate that functional interaction between RAGE and TLRs coordinately regulates inflammation, immune response and other cellular functions. PMID:21829704

  12. Receptor tyrosine phosphatase R-PTP-alpha is tyrosine-phosphorylated and associated with the adaptor protein Grb2

    DEFF Research Database (Denmark)

    Su, J; Batzer, A; Sap, J

    1994-01-01

    Receptor tyrosine phosphatases (R-PTPases) have generated interest because of their suspected involvement in cellular signal transduction. The adaptor protein Grb2 has been implicated in coupling receptor tyrosine kinases to Ras. We report that a ubiquitous R-PTPase, R-PTP-alpha, is tyrosine......-phosphorylated and associated in vivo with the Grb2 protein. This association can be reproduced in stably and transiently transfected cells, as well as in vitro using recombinant Grb2 protein. Association requires the presence of an intact SH2 domain in Grb2, as well as tyrosine phosphorylation of R-PTP-alpha. This observation...... links a receptor tyrosine phosphatase with a key component of a central cellular signalling pathway and provides a basis for addressing R-PTP-alpha function....

  13. Shc adaptor proteins are key transducers of mitogenic signaling mediated by the G protein-coupled thrombin receptor

    DEFF Research Database (Denmark)

    Chen, Y; Grall, D; Salcini, A E

    1996-01-01

    The serine protease thrombin activates G protein signaling systems that lead to Ras activation and, in certain cells, proliferation. Whereas the steps leading to Ras activation by G protein-coupled receptors are not well defined, the mechanisms of Ras activation by receptor tyrosine kinases have...... kinase activation, gene induction and cell growth. From these data, we conclude that Shc represents a crucial point of convergence between signaling pathways activated by receptor tyrosine kinases and G protein-coupled receptors....... recently been elucidated biochemically and genetically. The present study was undertaken to determine whether common signaling components are used by these two distinct classes of receptors. Here we report that the adaptor protein Shc, is phosphorylated on tyrosine residues following stimulation...

  14. Ionized calcium-binding adaptor molecule 1 positive macrophages and HO-1 up-regulation in intestinal muscularis resident macrophages

    DEFF Research Database (Denmark)

    Mikkelsen, Hanne B; Huizinga, Jan D; Larsen, Jytte O

    2017-01-01

    Small intestinal muscularis externa macrophages have been associated with interstitial cells of Cajal (ICC). They have been proposed to play various roles in motility disorders and to take part in a microbiota-driven regulation of gastrointestinal motility. Our objective was to understand...... the reaction of resident macrophages of the musculature to a pro-inflammatory stimulator, lipopolysaccharide (LPS). Mice were injected with LPS or saline and sacrificed after 6 hours. Whole mounts were stained with antibodies toward CD169, ionized calcium-binding adaptor molecule 1 (iba1) (microglial/macrophage...... marker) and heme oxygenase-1 (HO-1). Cell densities were measured using unbiased stereology. RESULTS: iba1(pos) cells showed an overall higher density than CD169(pos) and HO-1(pos) cells. Most HO-1(pos) and iba1(pos) cells were positive for CD 169 in serosa and at Auerbach's plexus (AP). At the deep...

  15. The structure and polymerase-recognition mechanism of the crucial adaptor protein AND-1 in the human replisome.

    Science.gov (United States)

    Guan, Chengcheng; Li, Jun; Sun, Dapeng; Liu, Yingfang; Liang, Huanhuan

    2017-06-09

    DNA replication in eukaryotic cells is performed by a multiprotein complex called the replisome, which consists of helicases, polymerases, and adaptor molecules. Human a cidic n ucleoplasmic D NA-binding protein 1 (AND-1), also known as WD repeat and high mobility group (HMG)-box DNA-binding protein 1 (WDHD1), is an adaptor molecule crucial for DNA replication. Although structural information for the AND-1 yeast ortholog is available, the mechanistic details for how human AND-1 protein anchors the lagging-strand DNA polymerase α (pol α) to the DNA helicase complex ( C dc45- M CM2-7- G INS, CMG) await elucidation. Here, we report the structures of the N-terminal WD40 and SepB domains of human AND-1, as well as a biochemical analysis of the C-terminal HMG domain. We show that AND-1 exists as a homotrimer mediated by the SepB domain. Mutant study results suggested that a positively charged groove within the SepB domain provides binding sites for pol α. Different from its ortholog protein in budding yeast, human AND-1 is recruited to the CMG complex, mediated by unknown participants other than Go Ichi Ni San. In addition, we show that AND-1 binds to DNA in vitro , using its C-terminal HMG domain. In conclusion, our findings provide important insights into the mechanistic details of human AND-1 function, advancing our understanding of replisome formation during eukaryotic replication. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  16. Probing the Energetics of Dynactin Filament Assembly and the Binding of Cargo Adaptor Proteins Using Molecular Dynamics Simulation and Electrostatics-Based Structural Modeling.

    Science.gov (United States)

    Zheng, Wenjun

    2017-01-10

    Dynactin, a large multiprotein complex, binds with the cytoplasmic dynein-1 motor and various adaptor proteins to allow recruitment and transportation of cellular cargoes toward the minus end of microtubules. The structure of the dynactin complex is built around an actin-like minifilament with a defined length, which has been visualized in a high-resolution structure of the dynactin filament determined by cryo-electron microscopy (cryo-EM). To understand the energetic basis of dynactin filament assembly, we used molecular dynamics simulation to probe the intersubunit interactions among the actin-like proteins, various capping proteins, and four extended regions of the dynactin shoulder. Our simulations revealed stronger intersubunit interactions at the barbed and pointed ends of the filament and involving the extended regions (compared with the interactions within the filament), which may energetically drive filament termination by the capping proteins and recruitment of the actin-like proteins by the extended regions, two key features of the dynactin filament assembly process. Next, we modeled the unknown binding configuration among dynactin, dynein tails, and a number of coiled-coil adaptor proteins (including several Bicaudal-D and related proteins and three HOOK proteins), and predicted a key set of charged residues involved in their electrostatic interactions. Our modeling is consistent with previous findings of conserved regions, functional sites, and disease mutations in the adaptor proteins and will provide a structural framework for future functional and mutational studies of these adaptor proteins. In sum, this study yielded rich structural and energetic information about dynactin and associated adaptor proteins that cannot be directly obtained from the cryo-EM structures with limited resolutions.

  17. “Filtro c” para la fuente de alimentación de un inversor trifásico. Una curiosidad técnica; “CAPACITOR FILTER” TO POWER SUPLAY FOR TREE-PHASE INVERTER. A TECHNICAL CURIOSITY.

    Directory of Open Access Journals (Sweden)

    Alberto Nilo Basanta Otero

    2011-02-01

    Full Text Available Se presenta el análisis para encontrar, a partir de algunas restricciones y criterios técnicos-prácticos, unaexpresión matemática útil y también, muy fácil de recordar, que permite calcular el “Filtro C” para el casodel Rectificador Monofásico Onda Completa, tipo Puente, que garantice la Tensión Media de Directa a laentrada del Inversor Trifásico, en versiones de Variadores de Velocidad para motores de pequeñapotencia, aunque también dicha expresión podría usarse en otras aplicaciones en la que se permita unrizado del 10%. A partir de esa expresión de cálculo se deriva otra más general que puede ser utilizada encualquier otra aplicación en la que también se permita un rizado del 10% de la Tensión Media de Directa. In this document you will find a useful and easy to remember mathematical expression that will help you tocalculate the capacitance value needed in the single-phase, full-wave, bridge rectifier to be used as apower supply for a three-phase inverter in a low power variable frequency motor drive application. Also thisexpression could be used in any other application where a 10% ripple in the power supply voltage signal ispermitted.

  18. PRR7 Is a transmembrane adaptor protein expressed in activated T cells involved in regulation of T cell receptor signaling and apoptosis

    Czech Academy of Sciences Publication Activity Database

    Hrdinka, Matouš; Dráber, Peter; Štěpánek, Ondřej; Ormsby, Tereza; Otáhal, Pavel; Angelisová, Pavla; Brdička, Tomáš; Pačes, Jan; Hořejší, Václav; Drbal, Karel

    2011-01-01

    Roč. 286, č. 22 (2011), s. 19617-19629 ISSN 0021-9258 R&D Projects: GA MŠk 1M0506 Grant - others:GAČR(CZ) MEM/09/E011 Institutional research plan: CEZ:AV0Z50520514 Keywords : PRR7 * transmembrane adaptor protein * apoptosis Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 4.773, year: 2011

  19. LST1/A is a myeloid leukocyte-specific transmembrane adaptor protein recruiting protein tyrosine phosphatases SHP-1 and SHP-2 to the plasma membrane

    Czech Academy of Sciences Publication Activity Database

    Dráber, Peter; Štěpánek, Ondřej; Hrdinka, Matouš; Drobek, Aleš; Chmátal, Lukáš; Malá, Linda; Ormsby, Tereza; Angelisová, Pavla; Hořejší, Václav; Brdička, Tomáš

    2012-01-01

    Roč. 287, č. 27 (2012), s. 22812-228221 ISSN 0021-9258 R&D Projects: GA ČR GEMEM/09/E011; GA ČR(CZ) GBP302/12/G101; GA MŠk 1M0506 Institutional research plan: CEZ:AV0Z50520514 Institutional support: RVO:68378050 Keywords : adaptor proteins * myeloid cell * signal transduction * tetraspanins * LST1/A Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 4.651, year: 2012

  20. Phospho-dependent binding of the clathrin AP2 adaptor complex to GABAA receptors regulates the efficacy of inhibitory synaptic transmission

    OpenAIRE

    Kittler, Josef T.; Chen, Guojun; Honing, Stephan; Bogdanov, Yury; McAinsh, Kristina; Arancibia-Carcamo, I. Lorena; Jovanovic, Jasmina N.; Pangalos, Menelas N.; Haucke, Volker; Yan, Zhen; Moss, Stephen J.

    2005-01-01

    The efficacy of synaptic inhibition depends on the number of γ-aminobutyric acid type A receptors (GABAARs) expressed on the cell surface of neurons. The clathrin adaptor protein 2 (AP2) complex is a critical regulator of GABAAR endocytosis and, hence, surface receptor number. Here, we identify a previously uncharacterized atypical AP2 binding motif conserved within the intracellular domains of all GABAAR β subunit isoforms. This AP2 binding motif (KTHLRRRSSQLK in the β3 subunit) incorporates...

  1. Downregulation of the NHE3-binding PDZ-adaptor protein PDZK1 expression during cytokine-induced inflammation in interleukin-10-deficient mice.

    Directory of Open Access Journals (Sweden)

    Henrike Lenzen

    Full Text Available BACKGROUND: Impaired salt and water absorption is an important feature in the pathogenesis of diarrhea in inflammatory bowel disease (IBD. We analyzed the expression of proinflammatory cytokines in the infiltrating immune cells and the function and expression of the Na(+/H(+ exchanger isoform 3 (NHE3 and its regulatory PDZ-adaptor proteins NHERF1, NHERF2, and PDZK1 in the colon of interleukin-10-deficient (IL-10(-/- mice. METHODOLOGY/PRINCIPAL FINDINGS: Gene and protein expression were analyzed by real-time reverse transcription polymerase chain reaction (qRT-PCR, in situ RT-PCR, and immunohistochemistry. NHE3 activity was measured fluorometrically in apical enterocytes within isolated colonic crypts. Mice developed chronic colitis characterized by a typical immune cell infiltration composed of T-lymphocytes and macrophages, with high levels of gene and protein expression of the proinflammatory cytokines interleukin-1β and tumor necrosis factor-α. In parallel, inducible nitric oxide synthase expression was increased while procaspase 3 expression was unaffected. Interferon-γ expression remained low. Although acid-activated NHE3 activity was significantly decreased, the inflammatory process did not affect its gene and protein expression or its abundance and localization in the apical membrane. However, expression of the PDZ-adaptor proteins NHERF2 and PDZK1 was downregulated. NHERF1 expression was unchanged. In a comparative analysis we observed the PDZK1 downregulation also in the DSS (dextran sulphate sodium model of colitis. CONCLUSIONS/SIGNIFICANCE: The impairment of the absorptive function of the inflamed colon in the IL-10(-/- mouse, in spite of unaltered NHE3 expression and localization, is accompanied by the downregulation of the NHE3-regulatory PDZ adaptors NHERF2 and PDZK1. We propose that the downregulation of PDZ-adaptor proteins may be an important factor leading to NHE3 dysfunction and diarrhea in the course of the cytokine

  2. Brucella TIR-like protein TcpB/Btp1 specifically targets the host adaptor protein MAL/TIRAP to promote infection.

    Science.gov (United States)

    Li, Wenna; Ke, Yuehua; Wang, Yufei; Yang, Mingjuan; Gao, Junguang; Zhan, Shaoxia; Xinying, Du; Huang, Liuyu; Li, Wenfeng; Chen, Zeliang; Li, Juan

    2016-08-26

    Brucella spp. are known to avoid host immune recognition and weaken the immune response to infection. Brucella like accomplish this by employing two clever strategies, called the stealth strategy and hijacking strategy. The TIR domain-containing protein (TcpB/Btp1) of Brucella melitensis is thought to be involved in inhibiting host NF-κB activation by binding to adaptors downstream of Toll-like receptors. However, of the five TIR domain-containing adaptors conserved in mammals, whether MyD88 or MAL, even other three adaptors, are specifically targeted by TcpB has not been identified. Here, we confirmed the effect of TcpB on B.melitensis virulence in mice and found that TcpB selectively targets MAL. By using siRNA against MAL, we found that TcpB from B.melitensis is involved in intracellular survival and that MAL affects intracellular replication of B.melitensis. Our results confirm that TcpB specifically targets MAL/TIRAP to disrupt downstream signaling pathways and promote intra-host survival of Brucella spp. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Adaptor Protein Complexes AP-1 and AP-3 Are Required by the HHV-7 Immunoevasin U21 for Rerouting of Class I MHC Molecules to the Lysosomal Compartment

    Science.gov (United States)

    Kimpler, Lisa A.; Glosson, Nicole L.; Downs, Deanna; Gonyo, Patrick; May, Nathan A.; Hudson, Amy W.

    2014-01-01

    The human herpesvirus-7 (HHV-7) U21 gene product binds to class I major histocompatibility complex (MHC) molecules and reroutes them to a lysosomal compartment. Trafficking of integral membrane proteins to lysosomes is mediated through cytoplasmic sorting signals that recruit heterotetrameric clathrin adaptor protein (AP) complexes, which in turn mediate protein sorting in post-Golgi vesicular transport. Since U21 can mediate rerouting of class I molecules to lysosomes even when lacking its cytoplasmic tail, we hypothesize the existence of a cellular protein that contains the lysosomal sorting information required to escort class I molecules to the lysosomal compartment. If such a protein exists, we expect that it might recruit clathrin adaptor protein complexes as a means of lysosomal sorting. Here we describe experiments demonstrating that the μ adaptins from AP-1 and AP-3 are involved in U21-mediated trafficking of class I molecules to lysosomes. These experiments support the idea that a cellular protein(s) is necessary for U21-mediated lysosomal sorting of class I molecules. We also examine the impact of transient versus chronic knockdown of these adaptor protein complexes, and show that the few remaining μ subunits in the cells are eventually able to reroute class I molecules to lysosomes. PMID:24901711

  4. Basolateral sorting of the coxsackie and adenovirus receptor through interaction of a canonical YXXPhi motif with the clathrin adaptors AP-1A and AP-1B.

    Science.gov (United States)

    Carvajal-Gonzalez, Jose Maria; Gravotta, Diego; Mattera, Rafael; Diaz, Fernando; Perez Bay, Andres; Roman, Angel C; Schreiner, Ryan P; Thuenauer, Roland; Bonifacino, Juan S; Rodriguez-Boulan, Enrique

    2012-03-06

    The coxsackie and adenovirus receptor (CAR) plays key roles in epithelial barrier function at the tight junction, a localization guided in part by a tyrosine-based basolateral sorting signal, (318)YNQV(321). Sorting motifs of this type are known to route surface receptors into clathrin-mediated endocytosis through interaction with the medium subunit (μ2) of the clathrin adaptor AP-2, but how they guide new and recycling membrane proteins basolaterally is unknown. Here, we show that YNQV functions as a canonical YxxΦ motif, with both Y318 and V321 required for the correct basolateral localization and biosynthetic sorting of CAR, and for interaction with a highly conserved pocket in the medium subunits (μ1A and μ1B) of the clathrin adaptors AP-1A and AP-1B. Knock-down experiments demonstrate that AP-1A plays a role in the biosynthetic sorting of CAR, complementary to the role of AP-1B in basolateral recycling of this receptor. Our study illustrates how two clathrin adaptors direct basolateral trafficking of a plasma membrane protein through interaction with a canonical YxxΦ motif.

  5. Reactores aeróbios de lecho fluidizado trifásico con circulación interna: caracterización hidrodinámica y del soporte

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    Iván Andrés Sánchez Ortiz

    2010-01-01

    Full Text Available Los reactores aerobios de lecho fluidizado con circulación interna utilizan biomasa activa adherida a un medio soporte (biopelícula, con la ventaja de retener gran concentración de la misma, utilizando poco espacio físico y pudiendo remover, en un mismo reactor, materia carbonácea y nitrogenada. La circulación del líquido ocurre debido a la diferencia de presión hidrostática producida por la inyección de aire en el tubo de subida. En la condición de medio bifásico fueron estudiadas las velocidades de circulación, fracción volumétrica de aire y coeficiente de transferencia de oxígeno, utilizando cuatro configuraciones de reactores. En medio trifásico se evaluaron las velocidades de circulación, la fracción volumétrica de aire y el coeficiente de transferencia de oxígeno en una de dichas configuraciones. También se realizó la caracterización de tres posibles medios de soporte granulares. Se determinó que la relación de áreas entre los tubos interno y externo y la concentración de medio soporte influencian los valores de velocidad de circulación del líquido, de la fracción volumétrica de aire y de la transferencia de oxígeno y se observaron y compararon características importantes de los medios de soporte.

  6. Estudio de técnicas de control de rectificadores Boost Trifásicos con filtro LCL para reducción de la distorsión armónica en corriente, aplicadas al procesado eficiente de energía en aerogeneradores síncronos de imanes permanentes operando a velocidad variable

    OpenAIRE

    Carranza Castillo, Oscar

    2012-01-01

    La tesis se plantea como objetivo principal el estudio y la aplicación de técnicas de corrección de armónicos a sistemas de generación eólica de pequeña potencia, enfocando el problema desde el punto de vista del aerogenerador, esto es, centrando los objetivos en la etapa de entrada del convertidor de potencia utilizado, el cual está constituido por un rectificador trifásico pasivo, un convertidor dc-dc tipo boost y un inversor de conexión a red. Para reducir el factor THDi de las corrientes ...

  7. The adaptor protein alpha-syntrophin is reduced in human non-alcoholic steatohepatitis but is unchanged in hepatocellular carcinoma.

    Science.gov (United States)

    Rein-Fischboeck, Lisa; Pohl, Rebekka; Haberl, Elisabeth M; Weiss, Thomas S; Buechler, Christa

    2017-10-01

    The adaptor protein alpha-syntrophin (SNTA) is differentially expressed in varying types of cancer and affects triglyceride levels, inflammatory response and cell proliferation. However, little is known about the expression of SNTA in liver diseases. Non-alcoholic steatohepatitis (NASH) is characterized by hepatic steatosis, inflammation and eventually fibrosis, and may progress to hepatocellular carcinoma (HCC). Here, SNTA mRNA was analyzed in liver tissues from 71 non-alcoholic fatty liver disease patients and 32 controls to assess associations with disease characteristics. SNTA mRNA expression was reduced in NASH liver and negatively correlated with steatosis, inflammation, fibrosis and NASH scores. In the NASH patients, those with type 2 diabetes had a higher fibrosis score, reduced inflammation and increased hepatic SNTA mRNA levels demonstrating a strong association of SNTA mRNA levels with inflammation. Recently, we have shown diminished expression of the high-density lipoprotein scavenger receptor BI (SR-BI) in the liver of syntrophin-deficient mice. Indeed, hepatic SNTA and SR-BI mRNA were positively correlated. SNTA protein was further determined in tumor and non-tumorous tissues of 21 HCC patients. Protein expression was unchanged in the tumor and not related to staging and grading. Present study identified associations of hepatic SNTA mRNA levels with SR-BI and features of NASH assuming a function of this protein in chronic liver disease and cholesterol metabolism. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Matrilin-2, an extracellular adaptor protein, is needed for the regeneration of muscle, nerve and other tissues

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    Éva Korpos

    2015-01-01

    Full Text Available The extracellular matrix (ECM performs essential functions in the differentiation, maintenance and remodeling of tissues during development and regeneration, and it undergoes dynamic changes during remodeling concomitant to alterations in the cell-ECM interactions. Here we discuss recent data addressing the critical role of the widely expressed ECM protein, matrilin-2 (Matn2 in the timely onset of differentiation and regeneration processes in myogenic, neural and other tissues and in tumorigenesis. As a multiadhesion adaptor protein, it interacts with other ECM proteins and integrins. Matn2 promotes neurite outgrowth, Schwann cell migration, neuromuscular junction formation, skeletal muscle and liver regeneration and skin wound healing. Matn2 deposition by myoblasts is crucial for the timely induction of the global switch toward terminal myogenic differentiation during muscle regeneration by affecting transforming growth factor beta/bone morphogenetic protein 7/Smad and other signal transduction pathways. Depending on the type of tissue and the pathomechanism, Matn2 can also promote or suppress tumor growth.

  9. Characterization of Toll-like receptors in primary lung epithelial cells: strong impact of the TLR3 ligand poly(I:C on the regulation of Toll-like receptors, adaptor proteins and inflammatory response

    Directory of Open Access Journals (Sweden)

    Weith Andreas

    2005-11-01

    Full Text Available Abstract Background Bacterial and viral exacerbations play a crucial role in a variety of lung diseases including COPD or asthma. Since the lung epithelium is a major source of various inflammatory mediators that affect the immune response, we analyzed the inflammatory reaction of primary lung epithelial cells to different microbial molecules that are recognized by Toll-like receptors (TLR. Methods The effects of TLR ligands on primary small airway epithelial cells were analyzed in detail with respect to cytokine, chemokine and matrix metalloproteinase secretion. In addition, the regulation of the expression of TLRs and their adaptor proteins in small airway epithelial cells was investigated. Results Our data demonstrate that poly(I:C, a synthetic analog of viral dsRNA, mediated the strongest proinflammatory effects among the tested ligands, including an increased secretion of IL-6, IL-8, TNF-α, GM-CSF, GRO-α, TARC, MCP-1, MIP-3α, RANTES, IFN-β, IP-10 and ITAC as well as an increased release of MMP-1, MMP-8, MMP-9, MMP-10 and MMP-13. Furthermore, our data show that poly(I:C as well as type-1 and type-2 cytokines have a pronounced effect on the expression of TLRs and molecules involved in TLR signaling in small airway epithelial cells. Poly(I:C induced an elevated expression of TLR1, TLR2 and TLR3 and increased the gene expression of the general TLR adaptor MyD88 and IRAK-2. Simultaneously, poly(I:C decreased the expression of TLR5, TLR6 and TOLLIP. Conclusion Poly(I:C, an analog of viral dsRNA and a TLR3 ligand, triggers a strong inflammatory response in small airway epithelial cells that is likely to contribute to viral exacerbations of pulmonary diseases like asthma or COPD. The pronounced effects of poly(I:C on the expression of Toll-like receptors and molecules involved in TLR signaling is assumed to influence the immune response of the lung epithelium to viral and bacterial infections. Likewise, the regulation of TLR expression by type

  10. The adaptor protein alpha-syntrophin regulates adipocyte lipid droplet growth

    Energy Technology Data Exchange (ETDEWEB)

    Eisinger, Kristina; Rein-Fischboeck, Lisa; Pohl, Rebekka; Meier, Elisabeth M.; Krautbauer, Sabrina; Buechler, Christa, E-mail: christa.buechler@klinik.uni-regensburg.de

    2016-07-01

    The scaffold protein alpha-syntrophin (SNTA) regulates lipolysis indicating a role in lipid homeostasis. Adipocytes are the main lipid storage cells in the body, and here, the function of SNTA has been analyzed in 3T3-L1 cells. SNTA is expressed in preadipocytes and is induced early during adipogenesis. Knock-down of SNTA in preadipocytes increases their proliferation. Proteins which are induced during adipogenesis like adiponectin and caveolin-1, and the inflammatory cytokine IL-6 are at normal levels in the mature cells differentiated from preadipocytes with low SNTA. This suggests that SNTA does neither affect differentiation nor inflammation. Expression of proteins with a role in cholesterol and triglyceride homeostasis is unchanged. Consequently, basal and epinephrine induced lipolysis as well as insulin stimulated phosphorylation of Akt and ERK1/2 are normal. Importantly, adipocytes with low SNTA form smaller lipid droplets and store less triglycerides. Stearoyl-CoA reductase and MnSOD are reduced upon SNTA knock-down but do not contribute to lower lipid levels. Oleate uptake is even increased in cells with SNTA knock-down. In summary, current data show that SNTA is involved in the expansion of lipid droplets independent of adipogenesis. Enhanced preadipocyte proliferation and capacity to store surplus fatty acids may protect adipocytes with low SNTA from lipotoxicity in obesity. - Highlights: • Alpha-syntrophin (SNTA) is expressed in 3T3-L1adipocytes. • SNTA knock-down in preadipocytes has no effect on adipogenesis. • Mature 3T3-L1 differentiated from cells with low SNTA form small lipid droplets. • SCD1 and MnSOD are reduced in adipocytes with low SNTA. • SCD1 knock-down does not alter triglyceride levels.

  11. Structure of a putative ClpS N-end rule adaptor protein from the malaria pathogen Plasmodium falciparum.

    Science.gov (United States)

    AhYoung, Andrew P; Koehl, Antoine; Vizcarra, Christina L; Cascio, Duilio; Egea, Pascal F

    2016-03-01

    The N-end rule pathway uses an evolutionarily conserved mechanism in bacteria and eukaryotes that marks proteins for degradation by ATP-dependent chaperones and proteases such as the Clp chaperones and proteases. Specific N-terminal amino acids (N-degrons) are sufficient to target substrates for degradation. In bacteria, the ClpS adaptor binds and delivers N-end rule substrates for their degradation upon association with the ClpA/P chaperone/protease. Here, we report the first crystal structure, solved at 2.7 Å resolution, of a eukaryotic homolog of bacterial ClpS from the malaria apicomplexan parasite Plasmodium falciparum (Pfal). Despite limited sequence identity, Plasmodium ClpS is very similar to bacterial ClpS. Akin to its bacterial orthologs, plasmodial ClpS harbors a preformed hydrophobic pocket whose geometry and chemical properties are compatible with the binding of N-degrons. However, while the N-degron binding pocket in bacterial ClpS structures is open and accessible, the corresponding pocket in Plasmodium ClpS is occluded by a conserved surface loop that acts as a latch. Despite the closed conformation observed in the crystal, we show that, in solution, Pfal-ClpS binds and discriminates peptides mimicking bona fide N-end rule substrates. The presence of an apicoplast targeting peptide suggests that Pfal-ClpS localizes to this plastid-like organelle characteristic of all Apicomplexa and hosting most of its Clp machinery. By analogy with the related ClpS1 from plant chloroplasts and cyanobacteria, Plasmodium ClpS likely functions in association with ClpC in the apicoplast. Our findings open new venues for the design of novel anti-malarial drugs aimed at disrupting parasite-specific protein quality control pathways. © 2016 The Protein Society.

  12. The Adaptor Protein SAP Directly Associates with CD3ζ Chain and Regulates T Cell Receptor Signaling

    Science.gov (United States)

    Proust, Richard; Bertoglio, Jacques; Gesbert, Franck

    2012-01-01

    Mutations altering the gene encoding the SLAM associated protein (SAP) are responsible for the X-linked lymphoproliferative disease or XLP1. Its absence is correlated with a defective NKT cells development, a decrease in B cell functions and a reduced T cells and NK cells cytotoxic activities, thus leading to an immunodeficiency syndrome. SAP is a small 128 amino-acid long protein that is almost exclusively composed of an SH2 domain. It has been shown to interact with the CD150/SLAM family of receptors, and in a non-canonical manner with SH3 containing proteins such as Fyn, βPIX, PKCθ and Nck1. It would thus play the role of a minimal adaptor protein. It has been shown that SAP plays an important function in the activation of T cells through its interaction with the SLAM family of receptors. Therefore SAP defective T cells display a reduced activation of signaling events downstream of the TCR-CD3 complex triggering. In the present work, we evidence that SAP is a direct interactor of the CD3ζ chain. This direct interaction occurs through the first ITAM of CD3ζ, proximal to the membrane. Additionally, we show that, in the context of the TCR-CD3 signaling, an Sh-RNA mediated silencing of SAP is responsible for a decrease of several canonical T cell signaling pathways including Erk, Akt and PLCγ1 and to a reduced induction of IL-2 and IL-4 mRNA. Altogether, we show that SAP plays a central function in the T cell activation processes through a direct association with the CD3 complex. PMID:22912825

  13. The Adaptor Protein SH2B3 (Lnk) Negatively Regulates Neurite Outgrowth of PC12 Cells and Cortical Neurons

    Science.gov (United States)

    Wang, Tien-Cheng; Chiu, Hsun; Chang, Yu-Jung; Hsu, Tai-Yu; Chiu, Ing-Ming; Chen, Linyi

    2011-01-01

    SH2B adaptor protein family members (SH2B1-3) regulate various physiological responses through affecting signaling, gene expression, and cell adhesion. SH2B1 and SH2B2 were reported to enhance nerve growth factor (NGF)-induced neuronal differentiation in PC12 cells, a well-established neuronal model system. In contrast, SH2B3 was reported to inhibit cell proliferation during the development of immune system. No study so far addresses the role of SH2B3 in the nervous system. In this study, we provide evidence suggesting that SH2B3 is expressed in the cortex of embryonic rat brain. Overexpression of SH2B3 not only inhibits NGF-induced differentiation of PC12 cells but also reduces neurite outgrowth of primary cortical neurons. SH2B3 does so by repressing NGF-induced activation of PLCγ, MEK-ERK1/2 and PI3K-AKT pathways and the expression of Egr-1. SH2B3 is capable of binding to phosphorylated NGF receptor, TrkA, as well as SH2B1β. Our data further demonstrate that overexpression of SH2B3 reduces the interaction between SH2B1β and TrkA. Consistent with this finding, overexpressing the SH2 domain of SH2B3 is sufficient to inhibit NGF-induced neurite outgrowth. Together, our data demonstrate that SH2B3, unlike the other two family members, inhibits neuronal differentiation of PC12 cells and primary cortical neurons. Its inhibitory mechanism is likely through the competition of TrkA binding with the positive-acting SH2B1 and SH2B2. PMID:22028877

  14. Impact of the adaptor protein GIPC1/Synectin on radioresistance and survival after irradiation of prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Singer, A. [University Hospital Dresden (Germany). Dept. of Radiation Oncology; Deuse, Y.; Koch, U. [University Hospital Dresden (Germany). Dept. of Radiation Oncology; OncoRay National Center for Radiation Research in Oncology (Germany)] [and others

    2012-12-15

    Purpose: Studies have shown that GIPC1/Synectin is an essential adaptor protein of receptors that play an important role in cancer progression and therapy resistance. This is the first study to explore the role of GIPC1/Synectin in radioresistance of prostate cancer and as a possible predictive marker for outcome of primary radiation therapy. Materials and methods: The effect of RNA interference-mediated GIPC1/Synectin depletion on clonogenic cell survival after irradiation with 0, 2, 4, or 6 Gy was assayed in two different GIPC1/Synectin-expressing human prostate cancer cell lines. The clinical outcome data of 358 men who underwent radiotherapy of prostate cancer with a curative intention were analyzed retrospectively. Uni- and multivariate analysis was performed of prostate-specific antigen recurrence-free survival and overall survival in correlation with protein expression in pretreatment biopsy specimens. Protein expression was evaluated by standard immunohistochemistry methods. Results: In cell culture experiments, no change was detected in radiosensitivity after depletion of GIPC1/Synectin in GIPC1/Synectin-expressing prostate cancer cell lines. Furthermore, there was no correlation between GIPC1/Synectin expression in human pretreatment biopsy samples and overall or biochemical recurrence-free survival after radiotherapy in a retrospective analysis of the study cohort. Conclusion: Our results do not show a predictive or prognostic function of GIPC1/Synectin expression for the outcome of radiotherapy in prostate cancer. Furthermore, our in vitro results do not support a role of GIPC1 in the cellular radiation response. However, the role of GIPC1 in the progression of prostate cancer and its precursors should be subject to further research. (orig.)

  15. Multiple regulatory roles of the mouse transmembrane adaptor protein NTAL in gene transcription and mast cell physiology.

    Directory of Open Access Journals (Sweden)

    Iva Polakovicova

    Full Text Available Non-T cell activation linker (NTAL; also called LAB or LAT2 is a transmembrane adaptor protein that is expressed in a subset of hematopoietic cells, including mast cells. There are conflicting reports on the role of NTAL in the high affinity immunoglobulin E receptor (FcεRI signaling. Studies carried out on mast cells derived from mice with NTAL knock out (KO and wild type mice suggested that NTAL is a negative regulator of FcεRI signaling, while experiments with RNAi-mediated NTAL knockdown (KD in human mast cells and rat basophilic leukemia cells suggested its positive regulatory role. To determine whether different methodologies of NTAL ablation (KO vs KD have different physiological consequences, we compared under well defined conditions FcεRI-mediated signaling events in mouse bone marrow-derived mast cells (BMMCs with NTAL KO or KD. BMMCs with both NTAL KO and KD exhibited enhanced degranulation, calcium mobilization, chemotaxis, tyrosine phosphorylation of LAT and ERK, and depolymerization of filamentous actin. These data provide clear evidence that NTAL is a negative regulator of FcεRI activation events in murine BMMCs, independently of possible compensatory developmental alterations. To gain further insight into the role of NTAL in mast cells, we examined the transcriptome profiles of resting and antigen-activated NTAL KO, NTAL KD, and corresponding control BMMCs. Through this analysis we identified several genes that were differentially regulated in nonactivated and antigen-activated NTAL-deficient cells, when compared to the corresponding control cells. Some of the genes seem to be involved in regulation of cholesterol-dependent events in antigen-mediated chemotaxis. The combined data indicate multiple regulatory roles of NTAL in gene expression and mast cell physiology.

  16. Pertussis toxin targets the innate immunity through DAP12, FcRγ, and MyD88 adaptor proteins.

    Science.gov (United States)

    Phongsisay, Vongsavanh; Iizasa, Ei'ichi; Hara, Hiromitsu; Yoshida, Hiroki

    2017-04-01

    Activation of the innate immunity by adjuvants, such as pertussis toxin (PTX), in the presence of autoreactive lymphocytes and antigen mimicry is sufficient to trigger autoimmunity. Toll-like, C-type lectin, and immunglobulin-like receptors play an important role in the innate immunity by sensing a variety of microbial products through several adaptor proteins, including MyD88, DAP12, and FcRγ. This study investigated the interaction between PTX and innate immune components. The direct interactions between coated PTX and receptor-fusion proteins were examined using ELISA-based binding assays. Functionally, PTX-binding receptors could be classified into two groups: inhibition (DAP12-coupled TREM2, ITIM-bearing SIRPα, SIGNR1/SIGNR3/DCSIGN) and activation (MyD88-associated TLR4, DAP12-coupled LMIR5/CD300b, FcRγ-coupled LMIR8/CD300c, CLEC9A, MGL-1). DAP12, MyD88, and FcRγ were selected for further investigation. A comprehensive analysis of gene transcription showed that PTX up-regulated the expression of various inflammatory mediators. DAP12 deficiency resulted in reduction or enhancement of inflammatory responses in a cytokine-specific manner. PTX was able to activate the TREM2-DAP12 signalling pathway. PTX induced lower expression of inflammatory mediators in the absence of FcRγ alone and substantially lost its inflammatory capacity in the absence of both FcRγ and MyD88. PTX was able to activate the MyD88-NF-κB signalling pathway in the presence of TLR2 or TLR4. The inflammatory activity of PTX was completely lost by heating. These results demonstrate that PTX targets the innate immunity through DAP12, FcRγ, and MyD88 providing new insights into the immunobiology of PTX. Copyright © 2016 Elsevier GmbH. All rights reserved.

  17. The adaptor molecule Nck localizes the WAVE complex to promote actin polymerization during CEACAM3-mediated phagocytosis of bacteria.

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    Stefan Pils

    Full Text Available BACKGROUND: CEACAM3 is a granulocyte receptor mediating the opsonin-independent recognition and phagocytosis of human-restricted CEACAM-binding bacteria. CEACAM3 function depends on an intracellular immunoreceptor tyrosine-based activation motif (ITAM-like sequence that is tyrosine phosphorylated by Src family kinases upon receptor engagement. The phosphorylated ITAM-like sequence triggers GTP-loading of Rac by directly associating with the guanine nucleotide exchange factor (GEF Vav. Rac stimulation in turn is critical for actin cytoskeleton rearrangements that generate lamellipodial protrusions and lead to bacterial uptake. PRINCIPAL FINDINGS: In our present study we provide biochemical and microscopic evidence that the adaptor proteins Nck1 and Nck2, but not CrkL, Grb2 or SLP-76, bind to tyrosine phosphorylated CEACAM3. The association is phosphorylation-dependent and requires the Nck SH2 domain. Overexpression of the isolated Nck1 SH2 domain, RNAi-mediated knock-down of Nck1, or genetic deletion of Nck1 and Nck2 interfere with CEACAM3-mediated bacterial internalization and with the formation of lamellipodial protrusions. Nck is constitutively associated with WAVE2 and directs the actin nucleation promoting WAVE complex to tyrosine phosphorylated CEACAM3. In turn, dominant-negative WAVE2 as well as shRNA-mediated knock-down of WAVE2 or the WAVE-complex component Nap1 reduce internalization of bacteria. CONCLUSIONS: Our results provide novel mechanistic insight into CEACAM3-initiated phagocytosis. We suggest that the CEACAM3 ITAM-like sequence is optimized to co-ordinate a minimal set of cellular factors needed to efficiently trigger actin-based lamellipodial protrusions and rapid pathogen engulfment.

  18. The Shc family protein adaptor, Rai, negatively regulates T cell antigen receptor signaling by inhibiting ZAP-70 recruitment and activation.

    Directory of Open Access Journals (Sweden)

    Micol Ferro

    Full Text Available Rai/ShcC is a member of the Shc family of protein adaptors expressed with the highest abundance in the central nervous system, where it exerts a protective function by coupling neurotrophic receptors to the PI3K/Akt survival pathway. Rai is also expressed, albeit at lower levels, in other cell types, including T and B lymphocytes. We have previously reported that in these cells Rai attenuates antigen receptor signaling, thereby impairing not only cell proliferation but also, opposite to neurons, cell survival. Here we have addressed the mechanism underlying the inhibitory activity of Rai on TCR signaling. We show that Rai interferes with the TCR signaling cascade one of the earliest steps--recruitment of the initiating kinase ZAP-70 to the phosphorylated subunit of the TCR/CD3 complex, which results in a generalized dampening of the downstream signaling events. The inhibitory activity of Rai is associated to its inducible recruitment to phosphorylated CD3, which occurs in the physiological signaling context of the immune synapse. Rai is moreover found as a pre-assembled complex with ZAP-70 and also constitutively interacts with the regulatory p85 subunit of PI3K, similar to neuronal cells, notwithstanding the opposite biological outcome, i.e. impairment of PI-3K/Akt activation. The data highlight the ability of Rai to establish interactions with the TCR and key signaling mediators which, either directly (e.g. by inhibiting ZAP-70 recruitment to the TCR or sequestering ZAP-70/PI3K in the cytosol or indirectly (e.g. by promoting the recruitment of effectors responsible for signal extinction prevent full triggering of the TCR signaling cascade.

  19. The Shc family protein adaptor, Rai, negatively regulates T cell antigen receptor signaling by inhibiting ZAP-70 recruitment and activation.

    Science.gov (United States)

    Ferro, Micol; Savino, Maria Teresa; Ortensi, Barbara; Finetti, Francesca; Genovese, Luca; Masi, Giulia; Ulivieri, Cristina; Benati, Daniela; Pelicci, Giuliana; Baldari, Cosima T

    2011-01-01

    Rai/ShcC is a member of the Shc family of protein adaptors expressed with the highest abundance in the central nervous system, where it exerts a protective function by coupling neurotrophic receptors to the PI3K/Akt survival pathway. Rai is also expressed, albeit at lower levels, in other cell types, including T and B lymphocytes. We have previously reported that in these cells Rai attenuates antigen receptor signaling, thereby impairing not only cell proliferation but also, opposite to neurons, cell survival. Here we have addressed the mechanism underlying the inhibitory activity of Rai on TCR signaling. We show that Rai interferes with the TCR signaling cascade one of the earliest steps--recruitment of the initiating kinase ZAP-70 to the phosphorylated subunit of the TCR/CD3 complex, which results in a generalized dampening of the downstream signaling events. The inhibitory activity of Rai is associated to its inducible recruitment to phosphorylated CD3, which occurs in the physiological signaling context of the immune synapse. Rai is moreover found as a pre-assembled complex with ZAP-70 and also constitutively interacts with the regulatory p85 subunit of PI3K, similar to neuronal cells, notwithstanding the opposite biological outcome, i.e. impairment of PI-3K/Akt activation. The data highlight the ability of Rai to establish interactions with the TCR and key signaling mediators which, either directly (e.g. by inhibiting ZAP-70 recruitment to the TCR or sequestering ZAP-70/PI3K in the cytosol) or indirectly (e.g. by promoting the recruitment of effectors responsible for signal extinction) prevent full triggering of the TCR signaling cascade.

  20. The Shc Family Protein Adaptor, Rai, Negatively Regulates T Cell Antigen Receptor Signaling by Inhibiting ZAP-70 Recruitment and Activation

    Science.gov (United States)

    Ferro, Micol; Savino, Maria Teresa; Ortensi, Barbara; Finetti, Francesca; Genovese, Luca; Masi, Giulia; Ulivieri, Cristina; Benati, Daniela; Pelicci, Giuliana; Baldari, Cosima T.

    2011-01-01

    Rai/ShcC is a member of the Shc family of protein adaptors expressed with the highest abundance in the central nervous system, where it exerts a protective function by coupling neurotrophic receptors to the PI3K/Akt survival pathway. Rai is also expressed, albeit at lower levels, in other cell types, including T and B lymphocytes. We have previously reported that in these cells Rai attenuates antigen receptor signaling, thereby impairing not only cell proliferation but also, opposite to neurons, cell survival. Here we have addressed the mechanism underlying the inhibitory activity of Rai on TCR signaling. We show that Rai interferes with the TCR signaling cascade one of the earliest steps –recruitment of the initiating kinase ZAP-70 to the phosphorylated subunit of the TCR/CD3 complex, which results in a generalized dampening of the downstream signaling events. The inhibitory activity of Rai is associated to its inducible recruitment to phosphorylated CD3, which occurs in the physiological signaling context of the immune synapse. Rai is moreover found as a pre-assembled complex with ZAP-70 and also constitutively interacts with the regulatory p85 subunit of PI3K, similar to neuronal cells, notwithstanding the opposite biological outcome, i.e. impairment of PI-3K/Akt activation. The data highlight the ability of Rai to establish interactions with the TCR and key signaling mediators which, either directly (e.g. by inhibiting ZAP-70 recruitment to the TCR or sequestering ZAP-70/PI3K in the cytosol) or indirectly (e.g. by promoting the recruitment of effectors responsible for signal extinction) prevent full triggering of the TCR signaling cascade. PMID:22242145

  1. Algoritmo robusto para el diagnóstico de fallas eléctricas en el motor de inducción trifásico basado en herramientas espectrales y ondeletas.

    Directory of Open Access Journals (Sweden)

    Francisco Javier Villalobos-Piña

    2015-07-01

    Full Text Available Resumen: En este trabajo se presenta un conjunto de herramientas basadas en la transformada rápida de Fourier (TRF y la transformada discreta ondeleta (TDO Haar, Daubechies y Coiflet utilizando el módulo del vector espacial instantáneo (VEI de las corrientes de estator del motor de inducción trifásico para diagnosticar fallas en el estator y en el rotor. Se efectúa un estudio en simulación y una validación experimental de fallas eléctricas del estator para cortocircuito entre espiras de un mismo devanado y problemas de fisura de barra y anillo de cortocircuito de rotor. El objetivo del trabajo es contar con una herramienta de tipo no invasiva que permita efectuar el diagnóstico de fallas incipientes (con un carácter preventivo con el fin de evitar pérdidas económicas importantes en diferentes procesos industriales que utilizan máquinas de inducción aprovechando para ello las virtudes que ofrece la TRF y la TDO mediante el análisis de las firmas de corriente del estator del motor de inducción (MI, así como el diagnóstico de fallas drásticas con fines correctivos. Abstract: This work present a group of tools based on the fast Fourier transform (FFT and Haar, Daubechies and Coiflet discrete wavelet transform (DWT, using the Park's instantaneous space phasor module (ISP of the three phase induction machine stator currents for electric stator and rotor fault diagnosis. A simulation and experimental validation for inter-turn stator short-circuit electric fault and end-ring broken rotor fault diagnosis was performed. The main objective of the work is to perform a non invasive electric fault diagnosis to avoid economical losses in the industrial process using the advantages of spectral and wavelet tools. Palabras clave: Diagnóstico de fallas, motores de inducción, vector espacial instantáneo, transformada rápida de Fourier, ondeletas., Keywords: Fault diagnosis, induction

  2. Adaptor Protein Complex-2 (AP-2) and Epsin-1 Mediate Protease-activated Receptor-1 Internalization via Phosphorylation- and Ubiquitination-dependent Sorting Signals*

    Science.gov (United States)

    Chen, Buxin; Dores, Michael R.; Grimsey, Neil; Canto, Isabel; Barker, Breann L.; Trejo, JoAnn

    2011-01-01

    Signaling by protease-activated receptor-1 (PAR1), a G protein-coupled receptor (GPCR) for thrombin, is regulated by desensitization and internalization. PAR1 desensitization is mediated by β-arrestins, like most classic GPCRs. In contrast, internalization of PAR1 occurs through a clathrin- and dynamin-dependent pathway independent of β-arrestins. PAR1 displays two modes of internalization. Constitutive internalization of unactivated PAR1 is mediated by the clathrin adaptor protein complex-2 (AP-2), where the μ2-adaptin subunit binds directly to a tyrosine-based motif localized within the receptor C-tail domain. However, AP-2 depletion only partially inhibits agonist-induced internalization of PAR1, suggesting a function for other clathrin adaptors in this process. Here, we now report that AP-2 and epsin-1 are both critical mediators of agonist-stimulated PAR1 internalization. We show that ubiquitination of PAR1 and the ubiquitin-interacting motifs of epsin-1 are required for epsin-1-dependent internalization of activated PAR1. In addition, activation of PAR1 promotes epsin-1 de-ubiquitination, which may increase its endocytic adaptor activity to facilitate receptor internalization. AP-2 also regulates activated PAR1 internalization via recognition of distal C-tail phosphorylation sites rather than the canonical tyrosine-based motif. Thus, AP-2 and epsin-1 are both required to promote efficient internalization of activated PAR1 and recognize discrete receptor sorting signals. This study defines a new pathway for internalization of mammalian GPCRs. PMID:21965661

  3. EAT-2, a SAP-like adaptor, controls NK cell activation through phospholipase Cγ, Ca++, and Erk, leading to granule polarization.

    Science.gov (United States)

    Pérez-Quintero, Luis-Alberto; Roncagalli, Romain; Guo, Huaijian; Latour, Sylvain; Davidson, Dominique; Veillette, André

    2014-04-07

    Ewing's sarcoma-associated transcript 2 (EAT-2) is an Src homology 2 domain-containing intracellular adaptor related to signaling lymphocytic activation molecule (SLAM)-associated protein (SAP), the X-linked lymphoproliferative gene product. Both EAT-2 and SAP are expressed in natural killer (NK) cells, and their combined expression is essential for NK cells to kill abnormal hematopoietic cells. SAP mediates this function by coupling SLAM family receptors to the protein tyrosine kinase Fyn and the exchange factor Vav, thereby promoting conjugate formation between NK cells and target cells. We used a variety of genetic, biochemical, and imaging approaches to define the molecular and cellular mechanisms by which EAT-2 controls NK cell activation. We found that EAT-2 mediates its effects in NK cells by linking SLAM family receptors to phospholipase Cγ, calcium fluxes, and Erk kinase. These signals are triggered by one or two tyrosines located in the carboxyl-terminal tail of EAT-2 but not found in SAP. Unlike SAP, EAT-2 does not enhance conjugate formation. Rather, it accelerates polarization and exocytosis of cytotoxic granules toward hematopoietic target cells. Hence, EAT-2 promotes NK cell activation by molecular and cellular mechanisms distinct from those of SAP. These findings explain the cooperative and essential function of these two adaptors in NK cell activation.

  4. The murine Nck SH2/SH3 adaptors are important for the development of mesoderm-derived embryonic structures and for regulating the cellular actin network.

    Science.gov (United States)

    Bladt, Friedhelm; Aippersbach, Elke; Gelkop, Sigal; Strasser, Geraldine A; Nash, Piers; Tafuri, Anna; Gertler, Frank B; Pawson, Tony

    2003-07-01

    Mammalian Nck1 and Nck2 are closely related adaptor proteins that possess three SH3 domains, followed by an SH2 domain, and are implicated in coupling phosphotyrosine signals to polypeptides that regulate the actin cytoskeleton. However, the in vivo functions of Nck1 and Nck2 have not been defined. We have mutated the murine Nck1 and Nck2 genes and incorporated beta-galactosidase reporters into the mutant loci. In mouse embryos, the two Nck genes have broad and overlapping expression patterns. They are functionally redundant in the sense that mice deficient for either Nck1 or Nck2 are viable, whereas inactivation of both Nck1 and Nck2 results in profound defects in mesoderm-derived notochord and embryonic lethality at embryonic day 9.5. Fibroblast cell lines derived from Nck1(-/-) Nck2(-/-) embryos have defects in cell motility and in the organization of the lamellipodial actin network. These data suggest that the Nck SH2/SH3 adaptors have important functions in the development of mesodermal structures during embryogenesis, potentially linked to a role in cell movement and cytoskeletal organization.

  5. MEX3C interacts with adaptor-related protein complex 2 and involves in miR-451a exosomal sorting.

    Directory of Open Access Journals (Sweden)

    Pin Lu

    Full Text Available Some RNA species, especially microRNAs, are non-randomly sorted into exosomes, but how selectivity of RNA exosomal sorting is achieved is unknown. We found that all three variants of RNA-binding ubiquitin E3 ligase (MEX3C-MEX3C-1, MEX3C-2, and MEX3C-3 -interact with adaptor-related protein complex 2 (AP-2, a cargo adaptor in clathrin-mediated endocytosis. MEX3C's C-terminal RING finger domain and the hnRNP K homology (KH domain shared by the three MEX3C variants are both necessary for MEX3C/AP-2 interaction. MEX3C associates with the endolysosomal compartment through an endocytosis-like process. siRNA-mediated inhibition of the MEX3C or AP-2 complex substantially decreased exosomal but not cellular microRNA miR-451a expression. Exosomal sorting is ceramide-dependent but not ESCRT-dependent in microRNA miR-451a. That RNA-binding protein associates with membrane trafficking machinery, and that its involvement in exosomal microRNA expression, suggest the existence of a mechanism for specific recruiting of RNA molecules to endosomes for subsequent exosomal sorting.

  6. Discovery of a Unique Clp Component, ClpF, in Chloroplasts: A Proposed Binary ClpF-ClpS1 Adaptor Complex Functions in Substrate Recognition and Delivery.

    Science.gov (United States)

    Nishimura, Kenji; Apitz, Janina; Friso, Giulia; Kim, Jitae; Ponnala, Lalit; Grimm, Bernhard; van Wijk, Klaas J

    2015-10-01

    Clp proteases are found in prokaryotes, mitochondria, and plastids where they play crucial roles in maintaining protein homeostasis (proteostasis). The plant plastid Clp machinery comprises a hetero-oligomeric ClpPRT proteolytic core, ATP-dependent chaperones ClpC and ClpD, and an adaptor protein, ClpS1. ClpS1 selects substrates to the ClpPR protease-ClpC chaperone complex for degradation, but the underlying substrate recognition and delivery mechanisms are currently unclear. Here, we characterize a ClpS1-interacting protein in Arabidopsis thaliana, ClpF, which can interact with the Clp substrate glutamyl-tRNA reductase. ClpF and ClpS1 mutually stimulate their association with ClpC. ClpF, which is only found in photosynthetic eukaryotes, contains bacterial uvrB/C and YccV protein domains and a unique N-terminal domain. We propose a testable model in which ClpS1 and ClpF form a binary adaptor for selective substrate recognition and delivery to ClpC, reflecting an evolutionary adaptation of the Clp system to the plastid proteome. © 2015 American Society of Plant Biologists. All rights reserved.

  7. An Interaction between KSHV ORF57 and UIF Provides mRNA-Adaptor Redundancy in Herpesvirus Intronless mRNA Export

    Science.gov (United States)

    Jackson, Brian R.; Boyne, James R.; Noerenberg, Marko; Taylor, Adam; Hautbergue, Guillaume M.; Walsh, Matthew J.; Wheat, Rachel; Blackbourn, David J.; Wilson, Stuart A.; Whitehouse, Adrian

    2011-01-01

    The hTREX complex mediates cellular bulk mRNA nuclear export by recruiting the nuclear export factor, TAP, via a direct interaction with the export adaptor, Aly. Intriguingly however, depletion of Aly only leads to a modest reduction in cellular mRNA nuclear export, suggesting the existence of additional mRNA nuclear export adaptor proteins. In order to efficiently export Kaposi's sarcoma-associated herpesvirus (KSHV) intronless mRNAs from the nucleus, the KSHV ORF57 protein recruits hTREX onto viral intronless mRNAs allowing access to the TAP-mediated export pathway. Similarly however, depletion of Aly only leads to a modest reduction in the nuclear export of KSHV intronless mRNAs. Herein, we identify a novel interaction between ORF57 and the cellular protein, UIF. We provide the first evidence that the ORF57-UIF interaction enables the recruitment of hTREX and TAP to KSHV intronless mRNAs in Aly-depleted cells. Strikingly, depletion of both Aly and UIF inhibits the formation of an ORF57-mediated nuclear export competent ribonucleoprotein particle and consequently prevents ORF57-mediated mRNA nuclear export and KSHV protein production. Importantly, these findings highlight that redundancy exists in the eukaryotic system for certain hTREX components involved in the mRNA nuclear export of intronless KSHV mRNAs. PMID:21814512

  8. Absence of the Adaptor Protein PEA-15 Is Associated with Altered Pattern of Th Cytokines Production by Activated CD4+ T Lymphocytes In Vitro, and Defective Red Blood Cell Alloimmune Response In Vivo.

    Directory of Open Access Journals (Sweden)

    Stéphane Kerbrat

    Full Text Available TCR-dependent and costimulation signaling, cell division, and cytokine environment are major factors driving cytokines expression induced by CD4(+ T cell activation. PEA-15 15 (Protein Enriched in Astrocyte / 15 kDa is an adaptor protein that regulates death receptor-induced apoptosis and proliferation signaling by binding to FADD and relocating ERK1/2 to the cytosol, respectively. By using PEA-15-deficient mice, we examined the role of PEA-15 in TCR-dependent cytokine production in CD4(+ T cells. TCR-stimulated PEA-15-deficient CD4(+ T cells exhibited defective progression through the cell cycle associated with impaired expression of cyclin E and phosphoRb, two ERK1/2-dependent proteins of the cell cycle. Accordingly, expression of the division cycle-dependent cytokines IL-2 and IFNγ, a Th1 cytokine, was reduced in stimulated PEA-15-deficient CD4(+ T cells. This was associated with abnormal subcellular compartmentalization of activated ERK1/2 in PEA-15-deficient T cells. Furthermore, in vitro TCR-dependent differentiation of naive CD4(+ CD62L(+ PEA-15-deficient T cells was associated with a lower production of the Th2 cytokine, IL-4, whereas expression of the Th17-associated molecule IL4I1 was enhanced. Finally, a defective humoral response was shown in PEA-15-deficient mice in a model of red blood cell alloimmunization performed with Poly IC, a classical adjuvant of Th1 response in vivo. Collectively, our data suggest that PEA-15 contributes to the specification of the cytokine pattern of activated Th cells, thus highlighting a potential new target to interfere with T cell functional polarization and subsequent immune response.

  9. Absence of the Adaptor Protein PEA-15 Is Associated with Altered Pattern of Th Cytokines Production by Activated CD4+ T Lymphocytes In Vitro, and Defective Red Blood Cell Alloimmune Response In Vivo.

    Science.gov (United States)

    Kerbrat, Stéphane; Vingert, Benoit; Junier, Marie-Pierre; Castellano, Flavia; Renault-Mihara, François; Dos Reis Tavares, Silvina; Surenaud, Mathieu; Noizat-Pirenne, France; Boczkowski, Jorge; Guellaën, Georges; Chneiweiss, Hervé; Le Gouvello, Sabine

    2015-01-01

    TCR-dependent and costimulation signaling, cell division, and cytokine environment are major factors driving cytokines expression induced by CD4(+) T cell activation. PEA-15 15 (Protein Enriched in Astrocyte / 15 kDa) is an adaptor protein that regulates death receptor-induced apoptosis and proliferation signaling by binding to FADD and relocating ERK1/2 to the cytosol, respectively. By using PEA-15-deficient mice, we examined the role of PEA-15 in TCR-dependent cytokine production in CD4(+) T cells. TCR-stimulated PEA-15-deficient CD4(+) T cells exhibited defective progression through the cell cycle associated with impaired expression of cyclin E and phosphoRb, two ERK1/2-dependent proteins of the cell cycle. Accordingly, expression of the division cycle-dependent cytokines IL-2 and IFNγ, a Th1 cytokine, was reduced in stimulated PEA-15-deficient CD4(+) T cells. This was associated with abnormal subcellular compartmentalization of activated ERK1/2 in PEA-15-deficient T cells. Furthermore, in vitro TCR-dependent differentiation of naive CD4(+) CD62L(+) PEA-15-deficient T cells was associated with a lower production of the Th2 cytokine, IL-4, whereas expression of the Th17-associated molecule IL4I1 was enhanced. Finally, a defective humoral response was shown in PEA-15-deficient mice in a model of red blood cell alloimmunization performed with Poly IC, a classical adjuvant of Th1 response in vivo. Collectively, our data suggest that PEA-15 contributes to the specification of the cytokine pattern of activated Th cells, thus highlighting a potential new target to interfere with T cell functional polarization and subsequent immune response.

  10. Contributions: SAGE

    Indian Academy of Sciences (India)

    First page Back Continue Last page Overview Graphics. Contributions: SAGE. Space Alternating Generalized Expectation (SAGE) Maximization algorithm provides an iterative approach to parameter estimation when direct maximization of the likelihood function may be infeasible. Complexity is less in those applications ...

  11. Various Contributions

    Indian Academy of Sciences (India)

    First page Back Continue Last page Overview Graphics. Various Contributions. Developed an Off –Diagonal MIMO Canceller to mitigate Upstream Crosstalk in VDSL. Developed a low complexity, Expectation Maximization based iterative Crosstalk cancellation. Developed an optimal way of computational complexity ...

  12. Sub-cellular distribution of UNC-104(KIF1A) upon binding to adaptors as UNC-16(JIP3), DNC-1(DCTN1/Glued) and SYD-2(Liprin-α) in C. elegans neurons.

    Science.gov (United States)

    Hsu, C-C; Moncaleano, J D; Wagner, O I

    2011-03-10

    The accumulation of cargo (tau, amyloid precursor protein, neurofilaments etc.) in neurons is a hallmark of various neurodegenerative diseases while we have only little knowledge how axonal transport is regulated. Kinesin-3 UNC-104(KIF1A) is the major transporter of synaptic vesicles and recent reports suggest that a cargo itself can affect the motor's activity. Inspecting an interactome map, we identify three putative UNC-104 interactors, namely UNC-16(JIP3), DNC-1(DCTN1/Glued) and SYD-2(Liprin-α), known to be adaptors in essential neuronal protein complexes. We then employed the novel method bimolecular fluorescence complementation (BiFC) assay to visualize motor-adaptor complexes in the nervous system of living C. elegans. Interestingly, the binding of UNC-104 to each adaptor protein results in different sub-cellular distributions and has distinctive effects on the motor's motility. Specifically, if UNC-104 bound to UNC-16, the motor is primarily localized in the soma of neurons while bound to DNC-1, the motor is basically found in axonal termini. On the other hand, if UNC-104 is bound to SYD-2 we identify motor populations mostly along axons. Therefore, these three adaptors inherit different functions in steering the motor to specific sub-cellular locations in the neuron. Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

  13. RECOMBINANT FLUORESCENT SENSOR OF HYDROGEN PEROXIDE HyPer FUSED WITH ADAPTOR PROTEIN Ruk/CIN85: DESIGNING OF EXPRESSION VECTOR AND ITS FUNCTIONAL CHARACTERIZATION

    Directory of Open Access Journals (Sweden)

    А. V. Bazalii

    2015-10-01

    Full Text Available The aim of this study was to design the expression vector encoding fluorescent sensor of hydrogen peroxide HyPer fused with adaptor protein Ruk/CIN85 as well as to check its subcellular distribution and ability to sense hydrogen peroxide. It was demonstrated that in transiently transfected HEK293 and MCF-7 cells Ruk/CIN85-HyPer is concentrated in dot-like vesicular structures of different size while HyPer is diffusely distributed throughout the cell. Using live cell fluorescence microscopy we observed gradual increase in hydrogen peroxide concentration in representative vesicular structures during the time of experiment. Thus, the developed genetic construction encoding the chimeric Ruk/CIN85-HyPer fluorescent protein represents a new tool to study localized H2O2 production in living cells.

  14. p130Cas scaffolds the signalosome to direct adaptor-effector cross talk during Kaposi's sarcoma-associated herpesvirus trafficking in human microvascular dermal endothelial cells.

    Science.gov (United States)

    Bandyopadhyay, Chirosree; Veettil, Mohanan Valiya; Dutta, Sujoy; Chandran, Bala

    2014-12-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) interacts with cell surface receptors, such as heparan sulfate, integrins (α3β1, αVβ3, and αVβ5), and EphrinA2 (EphA2), and activates focal adhesion kinase (FAK), Src, phosphoinositol 3-kinase (PI3-K), c-Cbl, and RhoA GTPase signal molecules early during lipid raft (LR)-dependent productive macropinocytic entry into human dermal microvascular endothelial cells. Our recent studies have identified CIB1 as a signal amplifier facilitating EphA2 phosphorylation and subsequent cytoskeletal cross talk during KSHV macropinocytosis. Although CIB1 lacks an enzymatic activity and traditional adaptor domain or known interacting sequence, it associated with the KSHV entry signal complex and the CIB1-KSHV association was sustained over 30 min postinfection. To identify factors scaffolding the EphA2-CIB1 signal axis, the role of major cellular scaffold protein p130Cas (Crk-associated substrate of Src) was investigated. Inhibitor and small interfering RNA (siRNA) studies demonstrated that KSHV induced p130Cas in an EphA2-, CIB1-, and Src-dependent manner. p130Cas and Crk were associated with KSHV, LRs, EphA2, and CIB1 early during infection. Live-cell microscopy and biochemical studies demonstrated that p130Cas knockdown did not affect KSHV entry but significantly reduced productive nuclear trafficking of viral DNA and routed KSHV to lysosomal degradation. p130Cas aided in scaffolding adaptor Crk to downstream guanine nucleotide exchange factor phospho-C3G possibly to coordinate GTPase signaling during KSHV trafficking. Collectively, these studies demonstrate that p130Cas acts as a bridging molecule between the KSHV-induced entry signal complex and the downstream trafficking signalosome in endothelial cells and suggest that simultaneous targeting of KSHV entry receptors with p130Cas would be an attractive potential avenue for therapeutic intervention in KSHV infection. Eukaryotic cell adaptor molecules, without any intrinsic

  15. Expression of the neuronal adaptor protein X11alpha protects against memory dysfunction in a transgenic mouse model of Alzheimer's disease.

    LENUS (Irish Health Repository)

    Mitchell, Jacqueline C

    2010-01-01

    X11alpha is a neuronal-specific adaptor protein that binds to the amyloid-beta protein precursor (AbetaPP). Overexpression of X11alpha reduces Abeta production but whether X11alpha also protects against Abeta-related memory dysfunction is not known. To test this possibility, we crossed X11alpha transgenic mice with AbetaPP-Tg2576 mice. AbetaPP-Tg2576 mice produce high levels of brain Abeta and develop age-related defects in memory function that correlate with increasing Abeta load. Overexpression of X11alpha alone had no detectable adverse effect upon behavior. However, X11alpha reduced brain Abeta levels and corrected spatial reference memory defects in aged X11alpha\\/AbetaPP double transgenics. Thus, X11alpha may be a therapeutic target for Alzheimer\\'s disease.

  16. Anti-inflammatory action of 2-carbomethoxy-2,3-epoxy-3-prenyl-1,4-naphthoquinone (CMEP-NQ) suppresses both the MyD88-dependent and TRIF-dependent pathways of TLR4 signaling in LPS-stimulated RAW264.7 cells.

    Science.gov (United States)

    Ju Woo, Hyun; Jun, Do Youn; Lee, Ji Young; Park, Hae Sun; Woo, Mi Hee; Park, Sook Jahr; Kim, Sang Chan; Yang, Chae Ha; Kim, Young Ho

    2017-06-09

    The roots of Rubia cordifolia L. have been widely used as a traditional herbal medicine in Northeast Asia for treating inflammatory diseases. To elucidate the anti-inflammatory mechanism of 2-carbomethoxy-2,3-epoxy-3- prenyl-1,4-naphthoquinone (CMEP-NQ), purified from the roots of R. cordifolia L. as the major anti-inflammatory component, in LPS-treated RAW264.7 murine macrophage cells. Anti-inflammatory activity of CMEP-NQ was investigated in LPS-treated RAW264.7 cells by measuring the levels of NO, PGE 2 , and cytokines (IL1β, IL-6, TNF-α) in the culture supernatants and the TLR4-mediated intracellular events including association of MyD88 with IRAK1, activation of IRAK1, TAK1, MAPKs, NF-κB/AP-1, and IRF3, and generation of ROS. Pretreatment of RAW264.7 cells with CMEP-NQ reduced LPS-induced production of NO and PGE 2 by suppressing iNOS and COX-2 gene expression. CMEP-NQ also reduced the secretion of IL-1β, IL-6, and TNF-α by down-regulating mRNA levels. Under these conditions, TLR4-mediated MyD88-dependent events were inhibited by CMEP-NQ, including the association of MyD88 with IRAK1, phosphorylation of IRAK1, TAK1, and MAPKs (ERK, JNK and p38 MAPK), and activation of NF-κB and AP-1. As TRIF-dependent events of TLR4 signaling, phosphorylation of IRF3 and induction of iNOS protein expression were also inhibited by CMEP-NQ. However, the binding of FITC-conjugated LPS to cell surface TLR4 was not affected by CMEP-NQ. Following LPS stimulation, intracellular ROS production was first detected by DCFH-DA staining at 1h; then it continuously increased until 16h. Although CMEP-NQ failed to exhibit DPPH radical- or ABTS radical-scavenging activity in vitro, LPS-induced ROS production in RAW264.7 cells was more efficiently blocked by CMEP-NQ than by NAC. These results demonstrate that the suppressive effect of CMEP-NQ on LPS-induced inflammatory responses in RAW264.7 cells was mainly exerted via its inhibition of TLR4-mediated proximal events, such as MyD88

  17. Human kidney anion exchanger 1 interacts with adaptor-related protein complex 1 μ1A (AP-1 mu1A)

    International Nuclear Information System (INIS)

    Sawasdee, Nunghathai; Junking, Mutita; Ngaojanlar, Piengpaga; Sukomon, Nattakan; Ungsupravate, Duangporn; Limjindaporn, Thawornchai; Akkarapatumwong, Varaporn; Noisakran, Sansanee; Yenchitsomanus, Pa-thai

    2010-01-01

    Research highlights: → Trafficking defect of kAE1 is a cause of dRTA but trafficking pathway of kAE1 has not been clearly described. → Adaptor-related protein complex 1 μ1A (AP-1 mu1A) was firstly reported to interact with kAE1. → The interacting site for AP-1 mu1A on Ct-kAE1 was found to be Y904DEV907, a subset of YXXO motif. → AP-1 mu1A knockdown showed a marked reduction of kAE1 on the cell membrane and its accumulation in endoplasmic reticulum. → AP-1 mu1A has a critical role in kAE1 trafficking to the plasma membrane. -- Abstract: Kidney anion exchanger 1 (kAE1) mediates chloride (Cl - ) and bicarbonate (HCO 3 - ) exchange at the basolateral membrane of kidney α-intercalated cells. Impaired trafficking of kAE1 leads to defect of the Cl - /HCO 3 - exchange at the basolateral membrane and failure of proton (H + ) secretion at the apical membrane, causing a kidney disease - distal renal tubular acidosis (dRTA). To gain a better insight into kAE1 trafficking, we searched for proteins physically interacting with the C-terminal region of kAE1 (Ct-kAE1), which contains motifs crucial for intracellular trafficking, by a yeast two-hybrid (Y2H) system. An adaptor-related protein complex 1 μ1A (AP-1 mu1A) subunit was found to interact with Ct-kAE1. The interaction between either Ct-kAE1 or full-length kAE1 and AP-1 mu1A were confirmed in human embryonic kidney (HEK) 293T by co-immunoprecipitation, affinity co-purification, co-localization, yellow fluorescent protein (YFP)-based protein fragment complementation assay (PCA) and GST pull-down assay. The interacting site for AP-1 mu1A on Ct-kAE1 was found to be Y904DEV907, a subset of YXXO motif. Interestingly, suppression of endogenous AP-1 mu1A in HEK 293T by small interfering RNA (siRNA) decreased membrane localization of kAE1 and increased its intracellular accumulation, suggesting for the first time that AP-1 mu1A is involved in the kAE1 trafficking of kidney α-intercalated cells.

  18. A conserved serine residue regulates the stability of Drosophila Salvador and human WW domain-containing adaptor 45 through proteasomal degradation

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Di, E-mail: DiWu@mail.nankai.edu.cn; Wu, Shian

    2013-04-19

    Highlights: •Ser-17 is key for the stability of Drosophila Sav. •Ala mutation of Ser-17 promotes the proteasomal degradation of Sav. •Ser-17 residue is not the main target of Hpo-induced Sav stabilization. •Hpo-dependent and -independent mechanisms regulate Sav stability. •This mechanism is conserved in the homologue of Sav, human WW45. -- Abstract: The Hippo (Hpo) pathway is a conserved tumor suppressor pathway that controls organ size through the coordinated regulation of apoptosis and proliferation. Drosophila Salvador (Sav), which limits organ size, is a core component of the Hpo pathway. In this study, Ser-17 was shown to be important for the stability of Sav. Alanine mutation of Ser-17 promoted the proteasomal degradation of Sav. Destabilization and stabilization of the Sav protein mediated by alanine mutation of Ser-17 and by Hpo, respectively, were independent of each other. This implies that the stability of Sav is controlled by two mechanisms, one that is Ser-17-dependent and Hpo-independent, and another that is Ser-17-independent and Hpo-dependent. These dual mechanisms also regulated the human counterpart of Drosophila Sav, WW domain-containing adaptor 45 (WW45). The conservation of this regulation adds to its significance in normal physiology and tumorigenesis.

  19. A Stretch of Negatively Charged Amino Acids of Linker for Activation of T-Cell Adaptor Has a Dual Role in T-Cell Antigen Receptor Intracellular Signaling

    Directory of Open Access Journals (Sweden)

    Mikel M. Arbulo-Echevarria

    2018-02-01

    Full Text Available The adaptor protein linker for activation of T cells (LAT has an essential role transducing activatory intracellular signals coming from the TCR/CD3 complex. Previous reports have shown that upon T-cell activation, LAT interacts with the tyrosine kinase Lck, leading to the inhibition of its kinase activity. LAT–Lck interaction seemed to depend on a stretch of negatively charged amino acids in LAT. Here, we have substituted this segment of LAT between amino acids 113 and 126 with a non-charged segment and expressed the mutant LAT (LAT-NIL in J.CaM2 cells in order to analyze TCR signaling. Substitution of this segment in LAT prevented the activation-induced interaction with Lck. Moreover, cells expressing this mutant form of LAT showed a statistically significant increase of proximal intracellular signals such as phosphorylation of LAT in tyrosine residues 171 and 191, and also enhanced ZAP70 phosphorylation approaching borderline statistical significance (p = 0.051. Nevertheless, downstream signals such as Ca2+ influx or MAPK pathways were partially inhibited. Overall, our data reveal that LAT–Lck interaction constitutes a key element regulating proximal intracellular signals coming from the TCR/CD3 complex.

  20. The adaptor protein SAP directly associates with PECAM-1 and regulates PECAM-1-mediated-cell adhesion in T-like cell lines.

    Science.gov (United States)

    Proust, Richard; Crouin, Catherine; Gandji, Leslie Yewakon; Bertoglio, Jacques; Gesbert, Franck

    2014-04-01

    SAP is a small cytosolic adaptor protein expressed in hematopoietic lineages whose main function is to regulate intracellular signaling pathways induced by the triggering of members of the SLAM receptor family. In this paper, we have identified the adhesion molecule PECAM-1 as a new partner for SAP in a conditional yeast two-hybrid screen. PECAM-1 is an immunoglobulin-like molecule expressed by endothelial cells and leukocytes, which possesses both pro- and anti-inflammatory properties. However, little is known about PECAM-1 functions in T cells. We show that SAP directly and specifically interacts with the cytosolic tyrosine 686 of PECAM-1. We generated different T-like cell lines in which SAP or PECAM-1 are expressed or down modulated and we demonstrate that a diminished SAP expression correlates with a diminished PECAM-1-mediated adhesion. Although SAP has mainly been shown to associate with SLAM receptors, we evidence here that SAP is a new actor downstream of PECAM-1. Copyright © 2013 Elsevier Ltd. All rights reserved.

  1. Signal-transducing adaptor protein-2 promotes generation of functional long-term memory CD8+ T cells by preventing terminal effector differentiation.

    Science.gov (United States)

    Muraoka, Daisuke; Seo, Naohiro; Hayashi, Tae; Hyuga-Amaike, Chisaki; Okamori, Kana; Tawara, Isao; Harada, Naozumi; Shiku, Hiroshi

    2017-05-09

    Long-surviving memory CD8+ T cells generated by stimulation with appropriate tumor-associated antigens are the most aggressive and persistent tumoricidal effectors. In this event of memory CD8+ T cell development, the signal transducer and activator of transcription (STAT) proteins function as the crucial intracellular signaling molecules, but the regulatory mechanism of STATs in CD8+ T cells is not fully understood. In this study, we report for the first time, by using murine vaccination models, that signal-transducing adaptor protein-2 (STAP2) maintains the cytotoxicity of long-lived memory CD8+ T cells by controlling a STAT3/suppressor of cytokine signaling 3 (SOCS3) cascade. Following T cell activation, STAP2 expression was transiently reduced but was subsequently recovered and augmented. Analysis using small-interfering RNA (siRNA) demonstrated that restored STAP2 expression was associated with the activation of STAT3/SOCS3 signals and maintenance of cytotoxic T lymphocytes (CTLs) secondary responses by preventing their differentiation into terminal effector cells. Notably, this STAP2-dependent memory differentiation was observed in the spleen, but not in the lymph nodes (LNs). These findings indicate an essential role for STAP2 in the generation of a high-quality memory CD8+ CTLs periphery, and suggest the therapeutic potential of STAP2 in cancer patients.

  2. The adaptor-like protein ROG-1 is required for activation of the Ras-MAP kinase pathway and meiotic cell cycle progression in Caenorhabditis elegans.

    Science.gov (United States)

    Matsubara, Yosuke; Kawasaki, Ichiro; Urushiyama, Seiichi; Yasuda, Tomoharu; Shirakata, Masaki; Iino, Yuichi; Shibuya, Hiroshi; Yamanashi, Yuji

    2007-03-01

    The Ras-MAP kinase pathway regulates varieties of fundamental cellular events. In Caenorhabditis elegans, this pathway is required for oocyte development; however, the nature of its up-stream regulators has remained elusive. Here, we identified a C. elegans gene, rog-1, which encodes the only protein having the IRS-type phosphotyrosine-binding (PTB) domain in the worms. ROG-1 has no obvious domain structure aside from the PTB domain, suggesting that it could serve as an adaptor down-stream of protein-tyrosine kinases (PTKs). RNA interference (RNAi)-mediated down-regulation of rog-1 mRNA significantly decreased brood size. rog-1(tm1031) truncation mutants showed a severe disruption in progression of developing oocytes from pachytene to diakinesis, as was seen in worms carrying a loss-of-function mutation in the let-60 Ras or mpk-1 MAP kinase gene. Furthermore, let-60 Ras-regulated activation of MPK-1 in the gonad is undetectable in rog-1(tm1031) mutants. Conversely, a gain-of-function mutation in the let-60 Ras gene rescues the brood size reduction and germ cell abnormality in rog-1(tm1031) worms. Consistently, rog-1 is preferentially expressed in the germ cells and its expression in the gonad is essential for oocyte development. Thus, ROG-1 is a key positive regulator of the Ras-MAP kinase pathway that permits germ cells to exit from pachytene.

  3. Loss of the adaptor protein ShcA in endothelial cells protects against monocyte macrophage adhesion, LDL-oxydation, and atherosclerotic lesion formation.

    Science.gov (United States)

    Jaoude, Antoine Abou; Badiqué, Lise; Mlih, Mohamed; Awan, Sara; Guo, Sunning; Lemle, Alexandre; Abboud, Clauda; Foppolo, Sophie; Host, Lionel; Terrand, Jérôme; Justiniano, Hélène; Herz, Joachim; Matz, Rachel L; Boucher, Philippe

    2018-03-14

    ShcA is an adaptor protein that binds to the cytoplasmic tail of receptor tyrosine kinases and of the Low Density Lipoprotein-related receptor 1 (LRP1), a trans-membrane receptor that protects against atherosclerosis. Here, we examined the role of endothelial ShcA in atherosclerotic lesion formation. We found that atherosclerosis progression was markedly attenuated in mice deleted for ShcA in endothelial cells, that macrophage content was reduced at the sites of lesions, and that adhesion molecules such as the intercellular adhesion molecule-1 (ICAM-1) were severely reduced. Our data indicate that transcriptional regulation of ShcA by the zinc-finger E-box-binding homeobox 1 (ZEB1) and the Hippo pathway effector YAP, promotes ICAM-1 expression independently of p-NF-κB, the primary driver of adhesion molecules expressions. In addition, ShcA suppresses endothelial Akt and nitric oxide synthase (eNOS) expressions. Thus, through down regulation of eNOS and ZEB1-mediated ICAM-1 up regulation, endothelial ShcA promotes monocyte-macrophage adhesion and atherosclerotic lesion formation. Reducing ShcA expression in endothelial cells may represent an obvious therapeutic approach to prevent atherosclerosis.

  4. Myelin protein zero/P0 phosphorylation and function require an adaptor protein linking it to RACK1 and PKC alpha.

    Science.gov (United States)

    Gaboreanu, Ana-Maria; Hrstka, Ronald; Xu, Wenbo; Shy, Michael; Kamholz, John; Lilien, Jack; Balsamo, Janne

    2007-05-21

    Point mutations in the cytoplasmic domain of myelin protein zero (P0; the major myelin protein in the peripheral nervous system) that alter a protein kinase Calpha (PKCalpha) substrate motif (198HRSTK201) or alter serines 199 and/or 204 eliminate P0-mediated adhesion. Mutation in the PKCalpha substrate motif (R198S) also causes a form of inherited peripheral neuropathy (Charcot Marie Tooth disease [CMT] 1B), indicating that PKCalpha-mediated phosphorylation of P0 is important for myelination. We have now identified a 65-kD adaptor protein that links P0 with the receptor for activated C kinase 1 (RACK1). The interaction of p65 with P0 maps to residues 179-197 within the cytoplasmic tail of P0. Mutations or deletions that abolish p65 binding reduce P0 phosphorylation and adhesion, which can be rescued by the substitution of serines 199 and 204 with glutamic acid. A mutation in the p65-binding sequence G184R occurs in two families with CMT, and mutation of this residue results in the loss of both p65 binding and adhesion function.

  5. Phospho-dependent binding of the clathrin AP2 adaptor complex to GABAA receptors regulates the efficacy of inhibitory synaptic transmission.

    Science.gov (United States)

    Kittler, Josef T; Chen, Guojun; Honing, Stephan; Bogdanov, Yury; McAinsh, Kristina; Arancibia-Carcamo, I Lorena; Jovanovic, Jasmina N; Pangalos, Menelas N; Haucke, Volker; Yan, Zhen; Moss, Stephen J

    2005-10-11

    The efficacy of synaptic inhibition depends on the number of gamma-aminobutyric acid type A receptors (GABA(A)Rs) expressed on the cell surface of neurons. The clathrin adaptor protein 2 (AP2) complex is a critical regulator of GABA(A)R endocytosis and, hence, surface receptor number. Here, we identify a previously uncharacterized atypical AP2 binding motif conserved within the intracellular domains of all GABA(A)R beta subunit isoforms. This AP2 binding motif (KTHLRRRSSQLK in the beta3 subunit) incorporates the major sites of serine phosphorylation within receptor beta subunits, and phosphorylation within this site inhibits AP2 binding. Furthermore, by using surface plasmon resonance, we establish that a peptide (pepbeta3) corresponding to the AP2 binding motif in the GABA(A)R beta3 subunit binds to AP2 with high affinity only when dephosphorylated. Moreover, the pepbeta3 peptide, but not its phosphorylated equivalent (pepbeta3-phos), enhanced the amplitude of miniature inhibitory synaptic current and whole cell GABA(A)R current. These effects of pepbeta3 on GABA(A)R current were occluded by inhibitors of dynamin-dependent endocytosis supporting an action of pepbeta3 on GABA(A)R endocytosis. Therefore phospho-dependent regulation of AP2 binding to GABA(A)Rs provides a mechanism to specify receptor cell surface number and the efficacy of inhibitory synaptic transmission.

  6. Skb5, an SH3 adaptor protein, regulates Pmk1 MAPK signaling by controlling the intracellular localization of the MAPKKK Mkh1.

    Science.gov (United States)

    Kanda, Yuki; Satoh, Ryosuke; Matsumoto, Saki; Ikeda, Chisato; Inutsuka, Natsumi; Hagihara, Kanako; Matzno, Sumio; Tsujimoto, Sho; Kita, Ayako; Sugiura, Reiko

    2016-08-15

    The mitogen-activated protein kinase (MAPK) cascade is a highly conserved signaling module composed of MAPK kinase kinases (MAPKKKs), MAPK kinases (MAPKK) and MAPKs. The MAPKKK Mkh1 is an initiating kinase in Pmk1 MAPK signaling, which regulates cell integrity in fission yeast (Schizosaccharomyces pombe). Our genetic screen for regulators of Pmk1 signaling identified Shk1 kinase binding protein 5 (Skb5), an SH3-domain-containing adaptor protein. Here, we show that Skb5 serves as an inhibitor of Pmk1 MAPK signaling activation by downregulating Mkh1 localization to cell tips through its interaction with the SH3 domain. Consistent with this, the Mkh1(3PA) mutant protein, with impaired Skb5 binding, remained in the cell tips, even when Skb5 was overproduced. Intriguingly, Skb5 needs Mkh1 to localize to the growing ends as Mkh1 deletion and disruption of Mkh1 binding impairs Skb5 localization. Deletion of Pck2, an upstream activator of Mkh1, impaired the cell tip localization of Mkh1 and Skb5 as well as the Mkh1-Skb5 interaction. Interestingly, both Pck2 and Mkh1 localized to the cell tips at the G1/S phase, which coincided with Pmk1 MAPK activation. Taken together, Mkh1 localization to cell tips is important for transmitting upstream signaling to Pmk1, and Skb5 spatially regulates this process. © 2016. Published by The Company of Biologists Ltd.

  7. Characterization of the liver kinase B1-mouse protein-25 -Ste-20-related adaptor protein complex in adult mouse skeletal muscle.

    Science.gov (United States)

    Smith, Cody D; Compton, Richard A; Bowler, Joshua S; Kemp, Jonathan T; Sudweeks, Sterling N; Thomson, David M; Winder, William W

    2011-12-01

    In liver, the AMP-activated protein kinase kinase (AMPKK) complex was identified as the association of liver kinase B1 (LKB1), mouse protein 25 (MO25α/β), and Ste-20-related adaptor protein (STRADα/β); however, this complex has yet to be characterized in skeletal muscle. We demonstrate the expression of the LKB1-MO25-STRAD complex in skeletal muscle, confirm the absence of mRNA splice variants, and report the relative mRNA expression levels of these proteins in control and muscle-specific LKB1 knockout (LKB1(-/-)) mouse muscle. LKB1 detection in untreated control and LKB1(-/-) muscle lysates revealed two protein bands (50 and 60 kDa), although only the heavier band was diminished in LKB1(-/-) samples [55 ± 2.5 and 13 ± 1.5 arbitrary units (AU) in control and LKB1(-/-), respectively, P protein liquid chromatography. Mass spectrometry confirmed LKB1 protein detection in the 60-kDa protein band, while none was detected in the 50-kDa band. Coimmunoprecipitation assays demonstrated LKB1-MO25-STRAD complex formation. Quantitative PCR revealed significantly reduced LKB1, MO25α, and STRADβ mRNA in LKB1(-/-) muscle. These findings demonstrate that the LKB1-MO25-STRAD complex is the principal AMPKK in skeletal muscle.

  8. Identification and Characterization of KCASH2 and KCASH3, 2 Novel Cullin3 Adaptors Suppressing Histone Deacetylase and Hedgehog Activity in Medulloblastoma

    Directory of Open Access Journals (Sweden)

    Enrico De Smaele

    2011-04-01

    Full Text Available Medulloblastoma is the most common pediatric malignant brain tumor, arising from aberrant cerebellar precursors' development, a process mainly controlled by Hedgehog (Hh signaling pathway. Histone deacetylase HDAC1 has been recently shown to modulate Hh signaling, deacetylating its effectors Gli1/2 and enhancing their transcriptional activity. Therefore, HDAC may represent a potential therapeutic target for Hh-dependent tumors, but still little information is available on the physiological mechanisms of HDAC regulation. The putative tumor suppressor RENKCTD11 acts through ubiquitination-dependent degradation of HDAC1, thereby affecting Hh activity and medulloblastoma growth. We identify and characterize here two RENKCTD11 homologues, defining a new family of proteins named KCASH, as “KCTD containing, Cullin3 adaptor, suppressor of Hedgehog.” Indeed, the novel genes (KCASH2KCTD21 and KCASH3KCTD6 share with RENKCTD11 a number of features, such as a BTB domain required for the formation of a Cullin3 ubiquitin ligase complex and HDAC1 ubiquitination and degradation capability, suppressing the acetylation-dependent Hh/Gli signaling. Expression of KCASH2 and -3 is observed in cerebellum, whereas epigenetic silencing and allelic deletion are observed in human medulloblastoma. Rescuing KCASHs expression reduces the Hedgehog-dependent medulloblastoma growth, suggesting that loss of members of this novel family of native HDAC inhibitors is crucial in sustaining Hh pathway-mediated tumorigenesis. Accordingly, they might represent a promising class of endogenous “agents” through which this pathway may be targeted.

  9. Interplays between Sumoylation, SUMO-Targeted Ubiquitin Ligases, and the Ubiquitin-Adaptor Protein Ufd1 in Fission Yeast

    DEFF Research Database (Denmark)

    Køhler, Julie Bonne

    their conformation or interactions with other macromolecules. Though, whereas the downstream consequence of ubiquitin conjugation is often protein degradation, the functional outcomes of sumoylation are less unifiable. A class of ubiquitin E3 ligases able to target sumoylated proteins for degradation by the 26S...... proteasome mediates direct cross-talk between the two modification systems. By contributing to the dynamic turnover of SUMO conjugated species these SUMO-targeted ubiquitin ligases (STUbLs) fulfills essential roles in both yeast and man. However, the specific sumoylated proteins affected by STUbL activity...... and the specific molecular interactions and sequence of events linking sumoylation, ubiquitylation and substrate degradation, has been largely uncovered. Using the fission yeast model organism I here present evidence for a role of the Ufd1 (ubiquitinfusion degradation 1) protein, and by extension of the Cdc48-Ufd1...

  10. The Adaptor Protein and Arf GTPase-activating Protein Cat-1/Git-1 Is Required for Cellular Transformation

    Science.gov (United States)

    Yoo, Sungsoo M.; Antonyak, Marc A.; Cerione, Richard A.

    2012-01-01

    Cat-1/Git-1 is a multifunctional protein that acts as a GTPase-activating protein (GAP) for Arf GTPases, as well as serves as a scaffold for a number of different signaling proteins. Cat-1 is best known for its role in regulating cell shape and promoting cell migration. However, whether Cat-1 might also contribute to cellular transformation is currently unknown. Here we show that ∼95% of cervical tumor samples examined overexpress Cat-1, suggesting that the up-regulation of Cat-1 expression is a frequent occurrence in this type of cancer. We demonstrate further that knocking down Cat-1 from NIH3T3 fibroblasts expressing an activated form of Cdc42 (Cdc42 F28L), or from the human cervical carcinoma (HeLa) cell line, inhibits the ability of these cells to form colonies in soft agar, an in vitro measure of tumorgenicity. The requirement for Cat-1 when assaying the anchorage-independent growth of transformed fibroblasts and HeLa cells is dependent on its ability to bind paxillin, while being negatively impacted by its Arf-GAP activity. Moreover, the co-expression of Cat-1 and an activated form of Arf6 in fibroblasts was sufficient to induce their transformation. These findings highlight novel roles for Cat-1 and its interactions with the Arf GTPases and paxillin in oncogenic transformation. PMID:22807447

  11. The Adaptor Protein SAP Regulates Type II NKT Cell Development, Cytokine Production and Cytotoxicity Against Lymphoma1

    Science.gov (United States)

    Weng, Xiufang; Liao, Chia-Min; Bagchi, Sreya; Cardell, Susanna L.; Stein, Paul L.; Wang, Chyung-Ru

    2014-01-01

    CD1d-restricted NKT cells represent a unique lineage of immunoregulatory T cells that are divided into two groups, type I and type II, based on their TCR usage. Because there are no specific tools to identify type II NKT cells, little is known about their developmental requirements and functional regulation. In our previous study, we showed that signaling lymphocytic activation molecule-associated protein (SAP) is essential for the development of type II NKT cells. Here, using a type II NKT cell TCR transgenic mouse model (24αβTg), we demonstrated that CD1d-expressing hematopoietic cells but not thymic epithelial cells meditate efficient selection of type II NKT cells. Further, we showed that SAP regulates type II NKT cell development by controlling Egr2 and PLZF expression. SAP-deficient 24αβ transgenic T cells (24αβ T cells) exhibited an immature phenotype with reduced Th2 cytokine-producing capacity and diminished cytotoxicity to CD1d-expressing lymphoma cells. The impaired IL-4 production by SAP-deficient 24αβ T cells was associated with reduced IRF4 and GATA-3 induction following TCR stimulation. Collectively, these data suggest that SAP is critical for regulating type II NKT cell responses. Aberrant responses of these T cells may contribute to the immune dysregulation observed in X-linked lymphoproliferative disease caused by mutations in SAP. PMID:25236978

  12. The Shc family protein adaptor, Rai, acts as a negative regulator of Th17 and Th1 cell development.

    Science.gov (United States)

    Savino, Maria Teresa; Ulivieri, Cristina; Emmi, Giacomo; Prisco, Domenico; De Falco, Giulia; Ortensi, Barbara; Beccastrini, Enrico; Emmi, Lorenzo; Pelicci, Giuliana; D'Elios, Mario M; Baldari, Cosima T

    2013-04-01

    Rai, a Shc adapter family member, acts as a negative regulator of antigen receptor signaling in T and B cells. Rai(-/-) mice develop lupus-like autoimmunity associated to the spontaneous activation of self-reactive lymphocytes. Here, we have addressed the potential role of Rai in the development of the proinflammatory Th1 and Th17 subsets, which are centrally implicated in the pathogenesis of a number of autoimmune diseases, including lupus. We show that Rai(-/-) mice display a spontaneous Th1/Th17 bias. In vitro polarization experiments on naive and effector/memory CD4(+) T cells demonstrate that Rai(-/-) favors the development and expansion of Th17 but not Th1 cells, indicating that Rai modulates TCR signaling to antagonize the pathways driving naive CD4(+) T cell differentiation to the Th17 lineage, while indirectly limiting Th1 cell development in vivo. Th1 and Th17 cell infiltrates were found in the kidneys of Rai(-/-) mice, providing evidence that Rai(-/-) contributes to the development of lupus nephritis, not only by enhancing lymphocyte activation but also by promoting the development and expansion of proinflammatory effector T cells. Interestingly, T cells from SLE patients were found to have a defect in Rai expression, suggesting a role for Rai in disease pathogenesis.

  13. The adaptor protein SAP regulates type II NKT-cell development, cytokine production, and cytotoxicity against lymphoma.

    Science.gov (United States)

    Weng, Xiufang; Liao, Chia-Min; Bagchi, Sreya; Cardell, Susanna L; Stein, Paul L; Wang, Chyung-Ru

    2014-12-01

    CD1d-restricted NKT cells represent a unique lineage of immunoregulatory T cells that are divided into two groups, type I and type II, based on their TCR usage. Because there are no specific tools to identify type II NKT cells, little is known about their developmental requirements and functional regulation. In our previous study, we showed that signaling lymphocytic activation molecule associated protein (SAP) is essential for the development of type II NKT cells. Here, using a type II NKT-cell TCR transgenic mouse model, we demonstrated that CD1d-expressing hematopoietic cells, but not thymic epithelial cells, meditate efficient selection of type II NKT cells. Furthermore, we showed that SAP regulates type II NKT-cell development by controlling early growth response 2 protein and promyelocytic leukemia zinc finger expression. SAP-deficient 24αβ transgenic T cells (24αβ T cells) exhibited an immature phenotype with reduced Th2 cytokine-producing capacity and diminished cytotoxicity to CD1d-expressing lymphoma cells. The impaired IL-4 production by SAP-deficient 24αβ T cells was associated with reduced IFN regulatory factor 4 and GATA-3 induction following TCR stimulation. Collectively, these data suggest that SAP is critical for regulating type II NKT cell responses. Aberrant responses of these T cells may contribute to the immune dysregulation observed in X-linked lymphoproliferative disease caused by mutations in SAP. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  14. The Pseudomonas aeruginosa lectin LecA triggers host cell signalling by glycosphingolipid-dependent phosphorylation of the adaptor protein CrkII.

    Science.gov (United States)

    Zheng, Shuangshuang; Eierhoff, Thorsten; Aigal, Sahaja; Brandel, Annette; Thuenauer, Roland; de Bentzmann, Sophie; Imberty, Anne; Römer, Winfried

    2017-07-01

    The human pathogen Pseudomonas aeruginosa induces phosphorylation of the adaptor protein CrkII by activating the non-receptor tyrosine kinase Abl to promote its uptake into host cells. So far, specific factors of P. aeruginosa, which induce Abl/CrkII signalling, are entirely unknown. In this research, we employed human lung epithelial cells H1299, Chinese hamster ovary cells and P. aeruginosa wild type strain PAO1 to study the invasion process of P. aeruginosa into host cells by using microbiological, biochemical and cell biological approaches such as Western Blot, immunofluorescence microscopy and flow cytometry. Here, we demonstrate that the host glycosphingolipid globotriaosylceramide, also termed Gb3, represents a signalling receptor for the P. aeruginosa lectin LecA to induce CrkII phosphorylation at tyrosine 221. Alterations in Gb3 expression and LecA function correlate with CrkII phosphorylation. Interestingly, phosphorylation of CrkII Y221 occurs independently of Abl kinase. We further show that Src family kinases transduce the signal induced by LecA binding to Gb3, leading to Crk Y221 phosphorylation. In summary, we identified LecA as a bacterial factor, which utilizes a so far unrecognized mechanism for phospho-CrkII Y221 induction by binding to the host glycosphingolipid receptor Gb3. The LecA/Gb3 interaction highlights the potential of glycolipids to mediate signalling processes across the plasma membrane and should be further elucidated to gain deeper insights into this non-canonical mechanism of activating host cell processes. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Fit-to-Flow (F2F) interconnects: universal reversible adhesive-free microfluidic adaptors for lab-on-a-chip systems.

    Science.gov (United States)

    Chen, Arnold; Pan, Tingrui

    2011-02-21

    World-to-chip (macro-to-micro) interface continues to be one of the most complicated, ineffective, and unreliable components in the development of emerging lab-on-a-chip systems involving integrated microfluidic operations. A number of irreversible (e.g., adhesive gluing) and reversible techniques (e.g., press fitting) have attempted to provide dedicated fluidic passage from standard tubing to miniature on-chip devices, none of which completely addresses the above concerns. In this paper, we present standardized adhesive-free microfluidic adaptors, referred to as Fit-to-Flow (F2F) Interconnects, to achieve reliable hermetic seal, high-density tube packing, self-aligned plug-in, reworkable connectivity, straightforward scalability and expandability, and applicability to broad lab-on-a-chip platforms; analogous to the modular plug-and-play USB architecture employed in modern electronics. Specifically, two distinct physical packaging mechanisms are applied, with one utilizing induced tensile stress in elastomeric socket to establish reversible seal and the other using negative pressure to provide on demand vacuum shield, both of which can be adapted to a variety of experimental configurations. The non-leaking performance (up to 336 kPa) along with high tube-packing density (of 1 tube/mm(2)) and accurate self-guided alignment (of 10 μm) have been characterized. In addition, a 3D microfluidic mixer and a 6-level chemical gradient generator paired with the corresponding F2F Interconnects have been devised to illustrate the applicability of the universal fluidic connections to classic lab-on-a-chip operations.

  16. Improved cytotoxic T-lymphocyte immune responses to a tumor antigen by vaccines co-expressing the SLAM-associated adaptor EAT-2.

    Science.gov (United States)

    Aldhamen, Y A; Seregin, S S; Kousa, Y A; Rastall, D P W; Appledorn, D M; Godbehere, S; Schutte, B C; Amalfitano, A

    2013-10-01

    The signaling lymphocytic activation molecule-associated adaptor Ewing's sarcoma's-activated transcript 2 (EAT-2) is primarily expressed in dendritic cells, macrophages and natural killer cells. Including EAT-2 in a vaccination regimen enhanced innate and adaptive immune responses toward pathogen-derived antigens, even in the face of pre-existing vaccine immunity. Herein, we investigate whether co-vaccinations with two recombinant Ad5 (rAd5) vectors, one expressing the carcinoembryonic antigen (CEA) and one expressing EAT-2, can induce more potent CEA-specific cytotoxic T lymphocyte (CTL) and antitumor activity in the therapeutic CEA-expressing MC-38 tumor model. Our results suggest that inclusion of EAT-2 significantly alters the kinetics of Th1-biasing proinflammatory cytokine and chemokine responses, and enhances anti-CEA-specific CTL responses. As a result, rAd5-EAT2-augmented rAd5-CEA vaccinations are more efficient in eliminating CEA-expressing target cells as measured by an in vivo CTL assay. Administration of rAd5-EAT2 vaccines also reduced the rate of growth of MC-38 tumor growth in vivo. Also, an increase in MC-38 tumor cell apoptosis (as measured by hematoxylin and eosin staining, active caspase-3 and granzyme B levels within the tumors) was observed. These data provide evidence that more efficient, CEA-specific effector T cells are generated by rAd5 vaccines expressing CEA, when augmented by rAd5 vaccines expressing EAT-2, and this regimen may be a promising approach for cancer immunotherapy in general.

  17. Regulation of protease-activated receptor 1 signaling by the adaptor protein complex 2 and R4 subfamily of regulator of G protein signaling proteins.

    Science.gov (United States)

    Chen, Buxin; Siderovski, David P; Neubig, Richard R; Lawson, Mark A; Trejo, Joann

    2014-01-17

    The G protein-coupled protease-activated receptor 1 (PAR1) is irreversibly proteolytically activated by thrombin. Hence, the precise regulation of PAR1 signaling is important for proper cellular responses. In addition to desensitization, internalization and lysosomal sorting of activated PAR1 are critical for the termination of signaling. Unlike most G protein-coupled receptors, PAR1 internalization is mediated by the clathrin adaptor protein complex 2 (AP-2) and epsin-1, rather than β-arrestins. However, the function of AP-2 and epsin-1 in the regulation of PAR1 signaling is not known. Here, we report that AP-2, and not epsin-1, regulates activated PAR1-stimulated phosphoinositide hydrolysis via two different mechanisms that involve, in part, a subset of R4 subfamily of "regulator of G protein signaling" (RGS) proteins. A significantly greater increase in activated PAR1 signaling was observed in cells depleted of AP-2 using siRNA or in cells expressing a PAR1 (420)AKKAA(424) mutant with defective AP-2 binding. This effect was attributed to AP-2 modulation of PAR1 surface expression and efficiency of G protein coupling. We further found that ectopic expression of R4 subfamily members RGS2, RGS3, RGS4, and RGS5 reduced activated PAR1 wild-type signaling, whereas signaling by the PAR1 AKKAA mutant was minimally affected. Intriguingly, siRNA-mediated depletion analysis revealed a function for RGS5 in the regulation of signaling by the PAR1 wild type but not the AKKAA mutant. Moreover, activation of the PAR1 wild type, and not the AKKAA mutant, induced Gαq association with RGS3 via an AP-2-dependent mechanism. Thus, AP-2 regulates activated PAR1 signaling by altering receptor surface expression and through recruitment of RGS proteins.

  18. Nck adaptors, besides promoting N-WASP mediated actin-nucleation activity at pedestals, influence the cellular levels of enteropathogenic Escherichia coli Tir effector.

    Science.gov (United States)

    Nieto-Pelegrin, Elvira; Kenny, Brendan; Martinez-Quiles, Narcisa

    2014-01-01

    Enteropathogenic Escherichia coli (EPEC) binding to human intestinal cells triggers the formation of disease-associated actin rich structures called pedestals. The latter process requires the delivery, via a Type 3 secretion system, of the translocated Intimin receptor (Tir) protein into the host plasma membrane where binding of a host kinase-modified form to the bacterial surface protein Intimin triggers pedestal formation. Tir-Intimin interaction recruits the Nck adaptor to a Tir tyrosine phosphorylated residue where it activates neural Wiskott-Aldrich syndrome protein (N-WASP); initiating the major pathway to actin polymerization mediated by the actin-related protein (Arp) 2/3 complex. Previous studies with Nck-deficient mouse embryonic fibroblasts (MEFs) identified a key role for Nck in pedestal formation, presumed to reflect a lack of N-WASP activation. Here, we show the defect relates to reduced amounts of Tir within Nck-deficient cells. Indeed, Tir delivery and, thus, pedestal formation defects were much greater for MEFs than HeLa (human epithelial) cells. Crucially, the levels of two other effectors (EspB/EspF) within Nck-deficient MEFs were not reduced unlike that of Map (Mitochondrial associated protein) which, like Tir, requires CesT chaperone function for efficient delivery. Interestingly, drugs blocking various host protein degradation pathways failed to increase Tir cellular levels unlike an inhibitor of deacetylase activity (Trichostatin A; TSA). Treatments with TSA resulted in significant recovery of Tir levels, potentiation of actin polymerization and improvement in bacterial attachment to cells. Our findings have important implications for the current model of Tir-mediated actin polymerization and opens new lines of research in this area.

  19. Dual role of the Toxoplasma gondii clathrin adaptor AP1 in the sorting of rhoptry and microneme proteins and in parasite division.

    Directory of Open Access Journals (Sweden)

    Kannan Venugopal

    2017-04-01

    Full Text Available Toxoplasma gondii possesses a highly polarized secretory system, which efficiently assembles de novo micronemes and rhoptries during parasite replication. These apical secretory organelles release their contents into host cells promoting parasite invasion and survival. Using a CreLox-based inducible knock-out strategy and the ddFKBP over-expression system, we unraveled novel functions of the clathrin adaptor complex TgAP1. First, our data indicate that AP1 in T. gondii likely functions as a conserved heterotetrameric complex composed of the four subunits γ, β, μ1, σ1 and interacts with known regulators of clathrin-mediated vesicular budding such as the unique ENTH-domain containing protein, which we named Epsin-like protein (TgEpsL. Disruption of the μ1 subunit resulted in the mis-sorting of microneme proteins at the level of the Trans-Golgi-Network (TGN. Furthermore, we demonstrated that TgAP1 regulates rhoptry biogenesis by activating rhoptry protein exit from the TGN, but also participates in the post-Golgi maturation process of preROP compartments into apically anchored club-shaped mature organelles. For this latter activity, our data indicate a specific functional relationship between TgAP1 and the Rab5A-positive endosome-like compartment. In addition, we unraveled an original role for TgAP1 in the regulation of parasite division. APμ1-depleted parasites undergo normal daughter cell budding and basal complex assembly but fail to segregate at the end of cytokinesis.

  20. Disruption of the podosome adaptor protein TKS4 (SH3PXD2B) causes the skeletal dysplasia, eye, and cardiac abnormalities of Frank-Ter Haar Syndrome.

    Science.gov (United States)

    Iqbal, Zafar; Cejudo-Martin, Pilar; de Brouwer, Arjan; van der Zwaag, Bert; Ruiz-Lozano, Pilar; Scimia, M Cecilia; Lindsey, James D; Weinreb, Robert; Albrecht, Beate; Megarbane, Andre; Alanay, Yasemin; Ben-Neriah, Ziva; Amenduni, Mariangela; Artuso, Rosangela; Veltman, Joris A; van Beusekom, Ellen; Oudakker, Astrid; Millán, José Luis; Hennekam, Raoul; Hamel, Ben; Courtneidge, Sara A; van Bokhoven, Hans

    2010-02-12

    Frank-Ter Haar syndrome (FTHS), also known as Ter Haar syndrome, is an autosomal-recessive disorder characterized by skeletal, cardiovascular, and eye abnormalities, such as increased intraocular pressure, prominent eyes, and hypertelorism. We have conducted homozygosity mapping on patients representing 12 FTHS families. A locus on chromosome 5q35.1 was identified for which patients from nine families shared homozygosity. For one family, a homozygous deletion mapped exactly to the smallest region of overlapping homozygosity, which contains a single gene, SH3PXD2B. This gene encodes the TKS4 protein, a phox homology (PX) and Src homology 3 (SH3) domain-containing adaptor protein and Src substrate. This protein was recently shown to be involved in the formation of actin-rich membrane protrusions called podosomes or invadopodia, which coordinate pericellular proteolysis with cell migration. Mice lacking Tks4 also showed pronounced skeletal, eye, and cardiac abnormalities and phenocopied the majority of the defects associated with FTHS. These findings establish a role for TKS4 in FTHS and embryonic development. Mutation analysis revealed five different homozygous mutations in SH3PXD2B in seven FTHS families. No SH3PXD2B mutations were detected in six other FTHS families, demonstrating the genetic heterogeneity of this condition. Interestingly however, dermal fibroblasts from one of the individuals without an SH3PXD2B mutation nevertheless expressed lower levels of the TKS4 protein, suggesting a common mechanism underlying disease causation. Copyright (c) 2010 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  1. Lentiviral Vpx accessory factor targets VprBP/DCAF1 substrate adaptor for cullin 4 E3 ubiquitin ligase to enable macrophage infection.

    Directory of Open Access Journals (Sweden)

    Smita Srivastava

    2008-05-01

    Full Text Available Vpx is a small virion-associated adaptor protein encoded by viruses of the HIV-2/SIVsm lineage of primate lentiviruses that enables these viruses to transduce monocyte-derived cells. This probably reflects the ability of Vpx to overcome an as yet uncharacterized block to an early event in the virus life cycle in these cells, but the underlying mechanism has remained elusive. Using biochemical and proteomic approaches, we have found that Vpx protein of the pathogenic SIVmac 239 strain associates with a ternary protein complex comprising DDB1 and VprBP subunits of Cullin 4-based E3 ubiquitin ligase, and DDA1, which has been implicated in the regulation of E3 catalytic activity, and that Vpx participates in the Cullin 4 E3 complex comprising VprBP. We further demonstrate that the ability of SIVmac as well as HIV-2 Vpx to interact with VprBP and its associated Cullin 4 complex is required for efficient reverse transcription of SIVmac RNA genome in primary macrophages. Strikingly, macrophages in which VprBP levels are depleted by RNA interference resist SIVmac infection. Thus, our observations reveal that Vpx interacts with both catalytic and regulatory components of the ubiquitin proteasome system and demonstrate that these interactions are critical for Vpx ability to enable efficient SIVmac replication in primary macrophages. Furthermore, they identify VprBP/DCAF1 substrate receptor for Cullin 4 E3 ubiquitin ligase and its associated protein complex as immediate downstream effector of Vpx for this function. Together, our findings suggest a model in which Vpx usurps VprBP-associated Cullin 4 ubiquitin ligase to enable efficient reverse transcription and thereby overcome a block to lentivirus replication in monocyte-derived cells, and thus provide novel insights into the underlying molecular mechanism.

  2. Role of adaptor proteins and clathrin in the trafficking of human kidney anion exchanger 1 (kAE1) to the cell surface.

    Science.gov (United States)

    Junking, Mutita; Sawasdee, Nunghathai; Duangtum, Natapol; Cheunsuchon, Boonyarit; Limjindaporn, Thawornchai; Yenchitsomanus, Pa-thai

    2014-07-01

    Kidney anion exchanger 1 (kAE1) plays an important role in acid-base homeostasis by mediating chloride/bicarbornate (Cl-/HCO3-) exchange at the basolateral membrane of α-intercalated cells in the distal nephron. Impaired intracellular trafficking of kAE1 caused by mutations of SLC4A1 encoding kAE1 results in kidney disease - distal renal tubular acidosis (dRTA). However, it is not known how the intracellular sorting and trafficking of kAE1 from trans-Golgi network (TGN) to the basolateral membrane occurs. Here, we studied the role of basolateral-related sorting proteins, including the mu1 subunit of adaptor protein (AP) complexes, clathrin and protein kinase D, on kAE1 trafficking in polarized and non-polarized kidney cells. By using RNA interference, co-immunoprecipitation, yellow fluorescent protein-based protein fragment complementation assays and immunofluorescence staining, we demonstrated that AP-1 mu1A, AP-3 mu1, AP-4 mu1 and clathrin (but not AP-1 mu1B, PKD1 or PKD2) play crucial roles in intracellular sorting and trafficking of kAE1. We also demonstrated colocalization of kAE1 and basolateral-related sorting proteins in human kidney tissues by double immunofluorescence staining. These findings indicate that AP-1 mu1A, AP-3 mu1, AP-4 mu1 and clathrin are required for kAE1 sorting and trafficking from TGN to the basolateral membrane of acid-secreting α-intercalated cells. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  3. G protein-coupled receptors regulate Na+,K+-ATPase activity and endocytosis by modulating the recruitment of adaptor protein 2 and clathrin

    Science.gov (United States)

    Ogimoto, Goichi; Yudowski, Guillermo A.; Barker, Christopher J.; Köhler, Martin; Katz, Adrian I.; Féraille, Eric; Pedemonte, Carlos H.; Berggren, Per-Olof; Bertorello, Alejandro M.

    2000-01-01

    Inhibition of Na+,K+-ATPase (NKA) activity in renal epithelial cells by activation of G protein-coupled receptors is mediated by phosphorylation of the catalytic α-subunit followed by endocytosis of active molecules. We examined whether agonists that counteract this effect do so by dephosphorylation of the α-subunit or by preventing its internalization through a direct interaction with the endocytic network. Oxymetazoline counteracted the action of dopamine on NKA activity, and this effect was achieved not by preventing α-subunit phosphorylation, but by impaired endocytosis of α-subunits into clathrin vesicles and early and late endosomes. Dopamine-induced inhibition of NKA activity and α-subunit endocytosis required the interaction of adaptor protein 2 (AP-2) with the catalytic α-subunit. Phosphorylation of the α-subunit is essential because dopamine failed to promote such interaction in cells lacking the protein kinase C phosphorylation residue (S18A). Confocal microscopy confirmed that oxymetazoline prevents incorporation of NKA molecules into clathrin vesicles by inhibiting the ability of dopamine to recruit clathrin to the plasma membrane. Dopamine decreased the basal levels of inositol hexakisphosphate (InsP6), whereas oxymetazoline prevented this effect. Similar increments (above basal) in the concentration of InsP6 induced by oxymetazoline prevented AP-2 binding to the NKA α-subunit in response to dopamine. In conclusion, inhibition of NKA activity can be reversed by preventing its endocytosis without altering the state of α-subunit phosphorylation; increased InsP6 in response to G protein-coupled receptor signals blocks the recruitment of AP-2 and thereby clathrin-dependent endocytosis of NKA. PMID:10716725

  4. Identification of Atg2 and ArfGAP1 as Candidate Genetic Modifiers of the Eye Pigmentation Phenotype of Adaptor Protein-3 (AP-3) Mutants in Drosophila melanogaster.

    Science.gov (United States)

    Rodriguez-Fernandez, Imilce A; Dell'Angelica, Esteban C

    2015-01-01

    The Adaptor Protein (AP)-3 complex is an evolutionary conserved, molecular sorting device that mediates the intracellular trafficking of proteins to lysosomes and related organelles. Genetic defects in AP-3 subunits lead to impaired biogenesis of lysosome-related organelles (LROs) such as mammalian melanosomes and insect eye pigment granules. In this work, we have performed a forward screening for genetic modifiers of AP-3 function in the fruit fly, Drosophila melanogaster. Specifically, we have tested collections of large multi-gene deletions--which together covered most of the autosomal chromosomes-to identify chromosomal regions that, when deleted in single copy, enhanced or ameliorated the eye pigmentation phenotype of two independent AP-3 subunit mutants. Fine-mapping led us to define two non-overlapping, relatively small critical regions within fly chromosome 3. The first critical region included the Atg2 gene, which encodes a conserved protein involved in autophagy. Loss of one functional copy of Atg2 ameliorated the pigmentation defects of mutants in AP-3 subunits as well as in two other genes previously implicated in LRO biogenesis, namely Blos1 and lightoid, and even increased the eye pigment content of wild-type flies. The second critical region included the ArfGAP1 gene, which encodes a conserved GTPase-activating protein with specificity towards GTPases of the Arf family. Loss of a single functional copy of the ArfGAP1 gene ameliorated the pigmentation phenotype of AP-3 mutants but did not to modify the eye pigmentation of wild-type flies or mutants in Blos1 or lightoid. Strikingly, loss of the second functional copy of the gene did not modify the phenotype of AP-3 mutants any further but elicited early lethality in males and abnormal eye morphology when combined with mutations in Blos1 and lightoid, respectively. These results provide genetic evidence for new functional links connecting the machinery for biogenesis of LROs with molecules implicated in

  5. The Adaptor Protein p62 Mediates Nuclear Factor κB Activation in Response to Inflammation and Facilitates the Formation of Prolabor Mediators in Human Myometrium.

    Science.gov (United States)

    Lappas, Martha

    2017-05-01

    Preventing spontaneous preterm birth is one of the most important issues facing perinatal medicine today. The pathophysiology of preterm labor, the single biggest cause of preterm birth, is poorly understood. Inflammation, however, plays a significant role in the terminal processes of human labor, which include myometrial contractions. Nuclear factor κB (NF-κB) drives the transcription of proinflammatory mediators involved in the terminal effector pathways of human labor and delivery. Recent studies in nongestational tissues have shown that the adaptor protein p62 interacts with NF-κB to induce inflammation. The aim of this study was to determine the role of p62 in the genesis of NF-κB-induced proinflammatory and prolabur mediators. Human spontaneous term labor was associated with increased p62 messenger RNA (mRNA) and protein expression in myometrium. Myometrial cells treated with proinflammatory cytokines interleukin 1β (IL-1β) and tumor necrosis factor alpha (TNF-α) also significantly increased p62 mRNA and protein expression. Functional studies using p62 small interfering RNA (siRNA) demonstrated a significant attenuation of TNF-α- and IL-1β-induced proinflammatory cytokines (IL-6) and chemokine (IL-8 and monocyte chemoattractant protein 1 [MCP-1]) mRNA expression and secretion, expression of cyclooxygenase 2, release of prostaglandin F 2α (PGF 2α ), and expression of the prostaglandin F receptor (FP). In addition, siRNA knockdown of p62 significantly suppressed IL-1β- and TNF-α-induced NF-κB activation. Collectively, these studies suggest that p62 is involved in the genesis of NF-κB-induced proinflammatory and prolabor mediators.

  6. Modelo práctico del transformador de distribución trifásico para análisis de transitorios de baja frecuencia: Identificación de parámetros Practical model of three-phase distribution transformer for low-frequency transients analysis: Parameter identification

    Directory of Open Access Journals (Sweden)

    Jorge E Celis-Montero

    2012-12-01

    Full Text Available Para el análisis de los fenómenos transitorios que se originan durante la operación de los transformadores eléctricos, se pueden emplear los modelos implantados en las herramientas de simulación tipo EMTP. Algunos de estos modelos requieren la especificación de parámetros que son difíciles de obtener a partir de ensayo como la característica de saturación de las piernas y los yugos, debido a la interconexión predeterminada de los devanados, o que pueden ser propiedad de los fabricantes de transformadores como las dimensiones relativas del núcleo. En este artículo se propone un modelo para el transformador trifásico de tres columnas que es útil para el análisis de transitorios de baja frecuencia y cuyos parámetros pueden ser determinados mediante pruebas de laboratorio convencionales. El modelo ha sido implantado en EMTP y validado por comparación de resultados obtenidos por simulación con resultados derivados mediante pruebas de laboratorio.In order to analyse transient phenomena originated during electrical transformers operation, models implemented in simulation tools EMTP-type can be used. Some of these models need the specification of parameters that can be difficult to obtain by testing, such as the saturation characteristic of the legs and the yokes, due to the predetermined interconnection of the windings or might be property of transformer's manufacturers, such as the relative dimensions of the core. This paper proposes a three-phase three-legged transformer model that can be used for analysis of low-frequency transients and whose parameters can be determined using conventional laboratory tests. The model has been implemented in an EMTP-type program and validated by comparing simulation results with real measurements obtained from laboratory tests.

  7. Identification of Atg2 and ArfGAP1 as Candidate Genetic Modifiers of the Eye Pigmentation Phenotype of Adaptor Protein-3 (AP-3 Mutants in Drosophila melanogaster.

    Directory of Open Access Journals (Sweden)

    Imilce A Rodriguez-Fernandez

    Full Text Available The Adaptor Protein (AP-3 complex is an evolutionary conserved, molecular sorting device that mediates the intracellular trafficking of proteins to lysosomes and related organelles. Genetic defects in AP-3 subunits lead to impaired biogenesis of lysosome-related organelles (LROs such as mammalian melanosomes and insect eye pigment granules. In this work, we have performed a forward screening for genetic modifiers of AP-3 function in the fruit fly, Drosophila melanogaster. Specifically, we have tested collections of large multi-gene deletions--which together covered most of the autosomal chromosomes-to identify chromosomal regions that, when deleted in single copy, enhanced or ameliorated the eye pigmentation phenotype of two independent AP-3 subunit mutants. Fine-mapping led us to define two non-overlapping, relatively small critical regions within fly chromosome 3. The first critical region included the Atg2 gene, which encodes a conserved protein involved in autophagy. Loss of one functional copy of Atg2 ameliorated the pigmentation defects of mutants in AP-3 subunits as well as in two other genes previously implicated in LRO biogenesis, namely Blos1 and lightoid, and even increased the eye pigment content of wild-type flies. The second critical region included the ArfGAP1 gene, which encodes a conserved GTPase-activating protein with specificity towards GTPases of the Arf family. Loss of a single functional copy of the ArfGAP1 gene ameliorated the pigmentation phenotype of AP-3 mutants but did not to modify the eye pigmentation of wild-type flies or mutants in Blos1 or lightoid. Strikingly, loss of the second functional copy of the gene did not modify the phenotype of AP-3 mutants any further but elicited early lethality in males and abnormal eye morphology when combined with mutations in Blos1 and lightoid, respectively. These results provide genetic evidence for new functional links connecting the machinery for biogenesis of LROs with

  8. SR proteins SRp20 and 9G8 contribute to efficient export of herpes simplex virus 1 mRNAs

    International Nuclear Information System (INIS)

    Escudero-Paunetto, Laurimar; Li Ling; Hernandez, Felicia P.; Sandri-Goldin, Rozanne M.

    2010-01-01

    Herpes simplex virus 1 (HSV-1) mRNAs are exported to the cytoplasm through the export receptor TAP/NFX1. HSV-1 multifunctional protein ICP27 interacts with TAP/NXF1, binds viral RNAs, and is required for efficient viral RNA export. In ICP27 mutant infections, viral RNA export is reduced but not ablated, indicating that other export adaptors can aid in viral RNA export. Export adaptor protein Aly/REF is recruited to viral replication compartments, however, Aly/REF knockdown has little effect on viral RNA export. SR proteins SRp20 and 9G8 interact with TAP/NXF1 and mediate export of some cellular RNAs. We report that siRNA knockdown of SRp20 or 9G8 resulted in about a 10 fold decrease in virus yields and in nuclear accumulation of poly(A+) RNA. In infected cells depleted of SRp20, newly transcribed Bromouridine-labeled RNA also accumulated in the nucleus. We conclude that SRp20 and 9G8 contribute to HSV-1 RNA export.

  9. Análisis del comportamiento dinámico del motor de inducción trifásico usando modelos en simulink del matlab; Three-phase induction motor dynamic behaivor analysis using the simulink of matlab models

    Directory of Open Access Journals (Sweden)

    Héctor Brito Socarrás

    2011-06-01

    Full Text Available La máquina de inducción se ha colocado como pilar del desarrollo de la industria moderna por su sencillezconstructiva, bajo mantenimiento, larga vida útil, versatilidad y bajo costo. Sin embargo, la regulación de lavelocidad y el par de dicha máquina ha presentado dificultades, por lo que no ha sido frecuente su controlhasta la década de los años ochenta del siglo XX, debido al desarrollo de los convertidores basados endispositivos electrónicos de potencia.En el presente trabajo se hace la propuesta de algunos arreglos hechosal modelo del motor de inducción trifásico en los ejes a-b empleando el Simulink de Matlab para la simulacióndel su comportamiento durante algunos regímenes de trabajo muy frecuentes en su explotación, como son elarranque estrella-delta, arranque introduciendo resistencia en el circuito de rotor de un motor de inducción derotor bobinado y el frenado por contracorriente, empleando un determinado tipo de carga.   The induction machine has been placed as pillar of the development of the modern industry due to itsconstructive simplicity, low maintenance, long useful life, versatility and low cost. However, the regulation of thespeed and the couple has presented difficulties and has not been frequent until the decade of the eighties ofthe XX century, due to the development of the converters based on power electronic devices.In this presentwork a proposal is made of some arrangements done of an induction three phase motor model on the a-b axesusing the Simulink of Matlab for the simulation of the behaviour of three-phase induction motor workingregimens in its exploitation, like they the outbreak star-delta, outbreak introducing resistance in the circuit of therotor of a motor induction of rotor winding and a braked by counter-current using a certain type of change.

  10. Análisis del comportamiento dinámico del motor de inducción trifásico usando modelos en simulink del matlab;Three-phase induction motor dynamic behaivor analysis using the simulink of matlab models

    Directory of Open Access Journals (Sweden)

    Héctor Brito - Socarrás

    2011-06-01

    Full Text Available La máquina de inducción se ha colocado como pilar del desarrollo de la industria moderna por su sencillez constructiva, bajo mantenimiento, larga vida útil, versatilidad y bajo costo. Sin embargo, la regulación de la velocidad y el par de dicha máquina ha presentado dificultades, por lo que no ha sido frecuente su control hasta la década de los años ochenta del siglo XX, debido al desarrollo de los convertidores basados en dispositivos electrónicos de potencia.En el presente trabajo se hace la propuesta de algunos arreglos hechos al modelo del motor de inducción trifásico en los ejes α-β empleando el Simulink de Matlab para la simulación del su comportamiento durante algunos regímenes de trabajo muy frecuentes en su explotación, como son el arranque estrella-delta, arranque introduciendo resistencia en el circuito de rotor de un motor de inducción de rotor bobinado y el frenado por contracorriente, empleando un determinado tipo de carga.The induction machine has been placed as pillar of the development of the modern industry due to its constructive simplicity, low maintenance, long useful life, versatility and low cost. However, the regulation of the speed and the couple has presented difficulties and has not been frequent until the decade of the eighties of the XX century, due to the development of the converters based on power electronic devices.In this present work a proposal is made of some arrangements done of an induction three phase motor model on the α-β axes using the Simulink of Matlab for the simulation of the behaviour of three-phase induction motor working regimens in its exploitation, like they the outbreak star-delta, outbreak introducing resistance in the circuit of the rotor of a motor induction of rotor winding and a braked by counter-current using a certain type of change.

  11. Social Contributions in Romania

    Directory of Open Access Journals (Sweden)

    Attila Gyorgy

    2012-12-01

    Full Text Available Social contributions have an important impact on payroll policy. Also, social contributions represent a significant budgetary revenue item which can be viewed at the edge between taxation and insurance. Social contributions in Romania experienced many changes which ended in 2008. Nowadays, they are within a long transaction period towards partial externalization of the insurance activity to privately managed funds. The aim of this paper is to analyse the homogeneity of Romanian social security public scheme using annual data extracted from 2002-2009.The main findings reveal that social contributions reached the pinnacle of diversification, being too many, some of them with a small contribution rates; fiscal reforms which reduced contribution rates advantaged employers, and state will be interested to externalize this activity as far private sector will be able to assume this responsibility and the budgetary effects are acceptable for the public finance.

  12. Major contributions to science

    International Nuclear Information System (INIS)

    Martin, Andre

    1991-01-01

    It may look difficult to describe the scientific contributions of Léon Van Hove, who started his career as a pure mathematician, and then a mathematical physicist, and ended it as a phenomenologist and an adseveral of Léon's students, in particular N. Hugenholtz. In this domain, his contributions were numerous and fundamental

  13. The Arabidopsis adaptor protein AP-3µ interacts with the G-protein β subunit AGB1 and is involved in abscisic acid regulation of germination and post-germination development

    Science.gov (United States)

    Tsugama, Daisuke; Takano, Tetsuo

    2013-01-01

    Heterotrimeric G-proteins (G-proteins) have been implicated in ubiquitous signalling mechanisms in eukaryotes. In plants, G-proteins modulate hormonal and stress responses and regulate diverse developmental processes. However, the molecular mechanisms of their functions are largely unknown. A yeast two-hybrid screen was performed to identify interacting partners of the Arabidopsis G-protein β subunit AGB1. One of the identified AGB1-interacting proteins is the Arabidopsis adaptor protein AP-3µ. The interaction between AGB1 and AP-3µ was confirmed by an in vitro pull-down assay and bimolecular fluorescence complementation assay. Two ap-3µ T-DNA insertional mutants were found to be hyposensitive to abscisic acid (ABA) during germination and post-germination growth, whereas agb1 mutants were hypersensitive to ABA. During seed germination, agb1/ap-3µ double mutants were more sensitive to ABA than the wild type but less sensitive than agb1 mutants. However, in post-germination growth, the double mutants were as sensitive to ABA as agb1 mutants. These data suggest that AP-3µ positively regulates the ABA responses independently of AGB1 in seed germination, while AP-3µ does require AGB1 to regulate ABA responses during post-germination growth. PMID:24098050

  14. Newton's Contributions to Optics

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 11; Issue 12. Newton's Contributions to Optics. Arvind Kumar. General Article Volume 11 Issue 12 December 2006 pp 10-20. Fulltext. Click here to view fulltext PDF. Permanent link: http://www.ias.ac.in/article/fulltext/reso/011/12/0010-0020. Keywords.

  15. Newton's Contributions to Optics

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 11; Issue 12. Newton's Contributions to Optics. Arvind Kumar. General Article Volume 11 Issue 12 December 2006 pp 10-20. Fulltext. Click here to view fulltext PDF. Permanent link: https://www.ias.ac.in/article/fulltext/reso/011/12/0010-0020. Keywords.

  16. Newton's Contributions to Optics

    Indian Academy of Sciences (India)

    Newton's Contributions to Optics. Arvind Kumar is Director,. Homi Bhabha Centre for. Science Education,. Mumbai. His main areas of interest are theoretical physics and physics education. He has been involved ... early 1666, when he was a scholar at Trinity College, Cambridge. He aligned a triangular prism in the path of a ...

  17. Fisher's Contributions to Statistics

    Indian Academy of Sciences (India)

    research workers of various disciplines in designing their studies and in analysing data thereof. He is also called upon to advise organisations like the ... such visual aids. It is believed that this situation helped him develop a keen geometrical sense. Fisher's contributions to statistics have also given rise to a number of bitter ...

  18. Abstracts of contributed papers

    Energy Technology Data Exchange (ETDEWEB)

    1994-08-01

    This volume contains 571 abstracts of contributed papers to be presented during the Twelfth US National Congress of Applied Mechanics. Abstracts are arranged in the order in which they fall in the program -- the main sessions are listed chronologically in the Table of Contents. The Author Index is in alphabetical order and lists each paper number (matching the schedule in the Final Program) with its corresponding page number in the book.

  19. Contributions to statistics

    CERN Document Server

    Mahalanobis, P C

    1965-01-01

    Contributions to Statistics focuses on the processes, methodologies, and approaches involved in statistics. The book is presented to Professor P. C. Mahalanobis on the occasion of his 70th birthday. The selection first offers information on the recovery of ancillary information and combinatorial properties of partially balanced designs and association schemes. Discussions focus on combinatorial applications of the algebra of association matrices, sample size analogy, association matrices and the algebra of association schemes, and conceptual statistical experiments. The book then examines latt

  20. Contributions to sampling statistics

    CERN Document Server

    Conti, Pier; Ranalli, Maria

    2014-01-01

    This book contains a selection of the papers presented at the ITACOSM 2013 Conference, held in Milan in June 2013. ITACOSM is the bi-annual meeting of the Survey Sampling Group S2G of the Italian Statistical Society, intended as an international  forum of scientific discussion on the developments of theory and application of survey sampling methodologies and applications in human and natural sciences. The book gathers research papers carefully selected from both invited and contributed sessions of the conference. The whole book appears to be a relevant contribution to various key aspects of sampling methodology and techniques; it deals with some hot topics in sampling theory, such as calibration, quantile-regression and multiple frame surveys, and with innovative methodologies in important topics of both sampling theory and applications. Contributions cut across current sampling methodologies such as interval estimation for complex samples, randomized responses, bootstrap, weighting, modeling, imputati...

  1. Vaccinia virus protein C6 is a virulence factor that binds TBK-1 adaptor proteins and inhibits activation of IRF3 and IRF7.

    Directory of Open Access Journals (Sweden)

    Leonie Unterholzner

    2011-09-01

    Full Text Available Recognition of viruses by pattern recognition receptors (PRRs causes interferon-β (IFN-β induction, a key event in the anti-viral innate immune response, and also a target of viral immune evasion. Here the vaccinia virus (VACV protein C6 is identified as an inhibitor of PRR-induced IFN-β expression by a functional screen of select VACV open reading frames expressed individually in mammalian cells. C6 is a member of a family of Bcl-2-like poxvirus proteins, many of which have been shown to inhibit innate immune signalling pathways. PRRs activate both NF-κB and IFN regulatory factors (IRFs to activate the IFN-β promoter induction. Data presented here show that C6 inhibits IRF3 activation and translocation into the nucleus, but does not inhibit NF-κB activation. C6 inhibits IRF3 and IRF7 activation downstream of the kinases TANK binding kinase 1 (TBK1 and IκB kinase-ε (IKKε, which phosphorylate and activate these IRFs. However, C6 does not inhibit TBK1- and IKKε-independent IRF7 activation or the induction of promoters by constitutively active forms of IRF3 or IRF7, indicating that C6 acts at the level of the TBK1/IKKε complex. Consistent with this notion, C6 immunoprecipitated with the TBK1 complex scaffold proteins TANK, SINTBAD and NAP1. C6 is expressed early during infection and is present in both nucleus and cytoplasm. Mutant viruses in which the C6L gene is deleted, or mutated so that the C6 protein is not expressed, replicated normally in cell culture but were attenuated in two in vivo models of infection compared to wild type and revertant controls. Thus C6 contributes to VACV virulence and might do so via the inhibition of PRR-induced activation of IRF3 and IRF7.

  2. DNAX-activating Protein 10 (DAP10) Membrane Adaptor Associates with Receptor for Advanced Glycation End Products (RAGE) and Modulates the RAGE-triggered Signaling Pathway in Human Keratinocytes*

    Science.gov (United States)

    Sakaguchi, Masakiyo; Murata, Hitoshi; Aoyama, Yumi; Hibino, Toshihiko; Putranto, Endy Widya; Ruma, I. Made Winarsa; Inoue, Yusuke; Sakaguchi, Yoshihiko; Yamamoto, Ken-ichi; Kinoshita, Rie; Futami, Junichiro; Kataoka, Ken; Iwatsuki, Keiji; Huh, Nam-ho

    2014-01-01

    The receptor for advanced glycation end products (RAGE) is involved in the pathogenesis of many inflammatory, degenerative, and hyperproliferative diseases, including cancer. Previously, we revealed mechanisms of downstream signaling from ligand-activated RAGE, which recruits TIRAP/MyD88. Here, we showed that DNAX-activating protein 10 (DAP10), a transmembrane adaptor protein, also binds to RAGE. By artificial oligomerization of RAGE alone or RAGE-DAP10, we found that RAGE-DAP10 heterodimer formation resulted in a marked enhancement of Akt activation, whereas homomultimeric interaction of RAGE led to activation of caspase 8. Normal human epidermal keratinocytes exposed to S100A8/A9, a ligand for RAGE, at a nanomolar concentration mimicked the pro-survival response of RAGE-DAP10 interaction, although at a micromolar concentration, the cells mimicked the pro-apoptotic response of RAGE-RAGE. In transformed epithelial cell lines, A431 and HaCaT, in which endogenous DAP10 was overexpressed, and S100A8/A9, even at a micromolar concentration, led to cell growth and survival due to RAGE-DAP10 interaction. Functional blocking of DAP10 in the cell lines abrogated the Akt phosphorylation from S100A8/A9-activated RAGE, eventually leading to an increase in apoptosis. Finally, S100A8/A9, RAGE, and DAP10 were overexpressed in the psoriatic epidermis. Our findings indicate that the functional interaction between RAGE and DAP10 coordinately regulates S100A8/A9-mediated survival and/or apoptotic response of keratinocytes. PMID:25002577

  3. The adaptor molecule signaling lymphocytic activation molecule (SLAM)-associated protein (SAP) is essential in mechanisms involving the Fyn tyrosine kinase for induction and progression of collagen-induced arthritis.

    Science.gov (United States)

    Zhong, Ming-Chao; Veillette, André

    2013-11-01

    Signaling lymphocytic activation molecule-associated protein (SAP) is an Src homology 2 domain-only adaptor involved in multiple immune cell functions. It has also been linked to immunodeficiencies and autoimmune diseases, such as systemic lupus erythematosus. Here, we examined the role and mechanism of action of SAP in autoimmunity using a mouse model of autoimmune arthritis, collagen-induced arthritis (CIA). We found that SAP was essential for development of CIA in response to collagen immunization. It was also required for production of collagen-specific antibodies, which play a key role in disease pathogenesis. These effects required SAP expression in T cells, not in B cells. In mice immunized with a high dose of collagen, the activity of SAP was nearly independent of its ability to bind the protein tyrosine kinase Fyn and correlated with the capacity of SAP to promote full differentiation of follicular T helper (TFH) cells. However, with a lower dose of collagen, the role of SAP was more dependent on Fyn binding, suggesting that additional mechanisms other than TFH cell differentiation were involved. Further studies suggested that this might be due to a role of the SAP-Fyn interaction in natural killer T cell development through the ability of SAP-Fyn to promote Vav-1 activation. We also found that removal of SAP expression during progression of CIA attenuated disease severity. However, it had no effect on disease when CIA was clinically established. Together, these results indicate that SAP plays an essential role in CIA because of Fyn-independent and Fyn-dependent effects on TFH cells and, possibly, other T cell types.

  4. The microRNA mir-71 inhibits calcium signaling by targeting the TIR-1/Sarm1 adaptor protein to control stochastic L/R neuronal asymmetry in C. elegans.

    Directory of Open Access Journals (Sweden)

    Yi-Wen Hsieh

    Full Text Available The Caenorhabditis elegans left and right AWC olfactory neurons communicate to establish stochastic asymmetric identities, AWC(ON and AWC(OFF, by inhibiting a calcium-mediated signaling pathway in the future AWC(ON cell. NSY-4/claudin-like protein and NSY-5/innexin gap junction protein are the two parallel signals that antagonize the calcium signaling pathway to induce the AWC(ON fate. However, it is not known how the calcium signaling pathway is downregulated by nsy-4 and nsy-5 in the AWC(ON cell. Here we identify a microRNA, mir-71, that represses the TIR-1/Sarm1 adaptor protein in the calcium signaling pathway to promote the AWC(ON identity. Similar to tir-1 loss-of-function mutants, overexpression of mir-71 generates two AWC(ON neurons. tir-1 expression is downregulated through its 3' UTR in AWC(ON, in which mir-71 is expressed at a higher level than in AWC(OFF. In addition, mir-71 is sufficient to inhibit tir-1 expression in AWC through the mir-71 complementary site in the tir-1 3' UTR. Our genetic studies suggest that mir-71 acts downstream of nsy-4 and nsy-5 to promote the AWC(ON identity in a cell autonomous manner. Furthermore, the stability of mature mir-71 is dependent on nsy-4 and nsy-5. Together, these results provide insight into the mechanism by which nsy-4 and nsy-5 inhibit calcium signaling to establish stochastic asymmetric AWC differentiation.

  5. Evidence against roles for phorbol binding protein Munc13-1, ADAM adaptor Eve-1, or vesicle trafficking phosphoproteins Munc18 or NSF as phospho-state-sensitive modulators of phorbol/PKC-activated Alzheimer APP ectodomain shedding

    Directory of Open Access Journals (Sweden)

    Lovestone Simon

    2007-12-01

    Full Text Available Abstract Background Shedding of the Alzheimer amyloid precursor protein (APP ectodomain can be accelerated by phorbol esters, compounds that act via protein kinase C (PKC or through unconventional phorbol-binding proteins such as Munc13-1. We have previously demonstrated that application of phorbol esters or purified PKC potentiates budding of APP-bearing secretory vesicles at the trans-Golgi network (TGN and toward the plasma membrane where APP becomes a substrate for enzymes responsible for shedding, known collectively as α-secretase(s. However, molecular identification of the presumptive "phospho-state-sensitive modulators of ectodomain shedding" (PMES responsible for regulated shedding has been challenging. Here, we examined the effects on APP ectodomain shedding of four phorbol-sensitive proteins involved in regulation of vesicular membrane trafficking of APP: Munc13-1, Munc18, NSF, and Eve-1. Results Overexpression of either phorbol-sensitive wildtype Munc13-1 or phorbol-insensitive Munc13-1 H567K resulted in increased basal APP ectodomain shedding. However, in contrast to the report of Roßner et al (2004, phorbol ester-dependent APP ectodomain shedding from cells overexpressing APP and Munc13-1 wildtype was indistinguishable from that observed following application of phorbol to cells overexpressing APP and Munc13-1 H567K mutant. This pattern of similar effects on basal and stimulated APP shedding was also observed for Munc18 and NSF. Eve-1, an ADAM adaptor protein reported to be essential for PKC-regulated shedding of pro-EGF, was found to play no obvious role in regulated shedding of sAPPα. Conclusion Our results indicate that, in the HEK293 system, Munc13-1, Munc18, NSF, and EVE-1 fail to meet essential criteria for identity as PMES for APP.

  6. Evidence against roles for phorbol binding protein Munc13-1, ADAM adaptor Eve-1, or vesicle trafficking phosphoproteins Munc18 or NSF as phospho-state-sensitive modulators of phorbol/PKC-activated Alzheimer APP ectodomain shedding.

    Science.gov (United States)

    Ikin, Annat F; Causevic, Mirsada; Pedrini, Steve; Benson, Lyndsey S; Buxbaum, Joseph D; Suzuki, Toshiharu; Lovestone, Simon; Higashiyama, Shigeki; Mustelin, Tomas; Burgoyne, Robert D; Gandy, Sam

    2007-12-09

    Shedding of the Alzheimer amyloid precursor protein (APP) ectodomain can be accelerated by phorbol esters, compounds that act via protein kinase C (PKC) or through unconventional phorbol-binding proteins such as Munc13-1. We have previously demonstrated that application of phorbol esters or purified PKC potentiates budding of APP-bearing secretory vesicles at the trans-Golgi network (TGN) and toward the plasma membrane where APP becomes a substrate for enzymes responsible for shedding, known collectively as alpha-secretase(s). However, molecular identification of the presumptive "phospho-state-sensitive modulators of ectodomain shedding" (PMES) responsible for regulated shedding has been challenging. Here, we examined the effects on APP ectodomain shedding of four phorbol-sensitive proteins involved in regulation of vesicular membrane trafficking of APP: Munc13-1, Munc18, NSF, and Eve-1. Overexpression of either phorbol-sensitive wildtype Munc13-1 or phorbol-insensitive Munc13-1 H567K resulted in increased basal APP ectodomain shedding. However, in contrast to the report of Rossner et al (2004), phorbol ester-dependent APP ectodomain shedding from cells overexpressing APP and Munc13-1 wildtype was indistinguishable from that observed following application of phorbol to cells overexpressing APP and Munc13-1 H567K mutant. This pattern of similar effects on basal and stimulated APP shedding was also observed for Munc18 and NSF. Eve-1, an ADAM adaptor protein reported to be essential for PKC-regulated shedding of pro-EGF, was found to play no obvious role in regulated shedding of sAPPalpha. Our results indicate that, in the HEK293 system, Munc13-1, Munc18, NSF, and EVE-1 fail to meet essential criteria for identity as PMES for APP.

  7. Tank waste isotope contributions

    International Nuclear Information System (INIS)

    VANKEUREN, J.C.

    1999-01-01

    This document presents the results of a calculation to determine the relative contribution of selected isotopes to the inhalation and ingestion doses for a postulated release of Hanford tank waste. The fraction of the dose due to 90 Sr, 90 Y, 137 Cs and the alpha emitters for single shell solids and liquids, double shell solids and liquids, aging waste solids and liquids and all solids and liquids. An effective dose conversion factor was also calculated for the alpha emitters for each composite of the tank waste

  8. dRYBP contributes to the negative regulation of the Drosophila Imd pathway.

    Directory of Open Access Journals (Sweden)

    Ricardo Aparicio

    Full Text Available The Drosophila humoral innate immune response fights infection by producing antimicrobial peptides (AMPs through the microbe-specific activation of the Toll or the Imd signaling pathway. Upon systemic infection, the production of AMPs is both positively and negatively regulated to reach a balanced immune response required for survival. Here, we report the function of the dRYBP (drosophila Ring and YY1 Binding Protein protein, which contains a ubiquitin-binding domain, in the Imd pathway. We have found that dRYBP contributes to the negative regulation of AMP production: upon systemic infection with Gram-negative bacteria, Diptericin expression is up-regulated in the absence of dRYBP and down-regulated in the presence of high levels of dRYBP. Epistatic analyses using gain and loss of function alleles of imd, Relish, or skpA and dRYBP suggest that dRYBP functions upstream or together with SKPA, a member of the SCF-E3-ubiquitin ligase complex, to repress the Imd signaling cascade. We propose that the role of dRYBP in the regulation of the Imd signaling pathway is to function as a ubiquitin adaptor protein together with SKPA to promote SCF-dependent proteasomal degradation of Relish. Beyond the identification of dRYBP as a novel component of Imd pathway regulation, our results also suggest that the evolutionarily conserved RYBP protein may be involved in the human innate immune response.

  9. Contributing to Functionality

    DEFF Research Database (Denmark)

    Törpel, Bettina

    2006-01-01

    advocated in this paper, emerges in the specific dynamic interplay of actors, objectives, structures, practices and means. In this view, functionality is the result of creating, harnessing and inhabiting computer supported joint action spaces. The successful creation and further development of a computer......The objective of this paper is the design of computer supported joint action spaces. It is argued against a view of functionality as residing in computer applications. In such a view the creation of functionality is equivalent to the creation of computer applications. Functionality, in the view...... supported joint action space comprises a whole range of appropriate design contributions. The approach is illustrated by the example of the creation of the computer supported joint action space "exchange network of voluntary union educators". As part of the effort a group of participants created...

  10. Ergonomics Contribution in Maintainability

    Science.gov (United States)

    Teymourian, Kiumars; Seneviratne, Dammika; Galar, Diego

    2017-09-01

    The objective of this paper is to describe an ergonomics contribution in maintainability. The economical designs, inputs and training helps to increase the maintainability indicators for industrial devices. This analysis can be helpful, among other cases, to compare systems, to achieve a better design regarding maintainability requirements, to improve this maintainability under specific industrial environment and to foresee maintainability problems due to eventual changes in a device operation conditions. With this purpose, this work first introduces the notion of ergonomics and human factors, maintainability and the implementation of assessment of human postures, including some important postures to perform maintenance activities. A simulation approach is used to identify the critical posture of the maintenance personnel and implements the defined postures with minimal loads on the personnel who use the equipment in a practical scenario. The simulation inputs are given to the designers to improve the workplace/equipment in order to high level of maintainability. Finally, the work concludes summarizing the more significant aspects and suggesting future research.

  11. Contribution to postnonclassical psychopathology.

    Directory of Open Access Journals (Sweden)

    Quintino-Aires J.

    2014-09-01

    Full Text Available Any psychological paradigm needs a psychopathological system that helps professionals to describe and explain the behavioral expressions that deviate from “normal” (whether this term is used with the semantic property of statistical or ideal adaptations. In this work, I seek to present the system that I have been developing since 1998 among the psychologists at the Instituto Vegotsky de Lisboa (Vygotsky Institute of Lisbon, Portugal, to understand psychopathology with regard to the vygotskian approach. It was conceived and designed according to the work of Rita Mendes Leal and her contribution to socioemotional development theory, AR Luria’s systemic and dynamic theory of the human brain, the theory of Activity (dyatel’nost of AN Leont’ev, and the psychopathological German school of E Kraepelin, presented and disseminated in Portugal in the early twentieth century by Professor Sobral Cid. It is intended to be a proposal to colleagues who are interested in postnonclassical psychology and a request for arguments.

  12. EMSL Contribution Plan

    Energy Technology Data Exchange (ETDEWEB)

    Campbell, Allison A.

    2008-12-01

    This Contribution Plan is EMSL’s template for achieving our vision of simultaneous excellence in all aspects of our mission as a national scientific user facility. It reflects our understanding of the long-term stewardship we must work toward to meet the scientific challenges faced by the Department of Energy (DOE) and the nation. During the next decade, we will implement the strategies contained in this Plan, working closely with the scientific community, our advisory committees, DOE’s Office of Biological and Environmental Research, and other key stakeholders. This Plan is fully aligned with the strategic plans of DOE, its Office of Science, and the Pacific Northwest National Laboratory (PNNL). We recognize that shifts in science and technology, national priorities, and resources made available through the Federal budget process create planning uncertainties and, ultimately, a highly dynamic planning environment. Accordingly, this Plan should be viewed as a living document and we continually evaluate the changing needs and opportunities posed by our stakeholders (i.e., DOE, users, staff, advisory committees), work closely with them to understand and respond to those changes, and align our strategy accordingly. This Plan is organized around two sections. Section 1 describes our vision and four strategic outcomes: 1) Scientific Innovation, 2) Capabilities that Transform Science, 3) Outstanding Management and Operations, and Engaged and Proactive Users. These outcomes provide the framework for seven critical actions we must take during the next 3 to 5 years: 1) Establishing leadership in EMSL science themes, 2) building and deploying transformational capabilities, 3) integrating computation with experiment, 4) ensuring EMSL’s workforce meets the scientific challenges of the future, 5) creating partnerships, 6) attracting and engaging users in EMSL’s long-term strategy, and 7) building a research infrastructure that meets emerging scientific needs. Section 2

  13. CONTRIBUTION OF INDIRECT TAXES

    Directory of Open Access Journals (Sweden)

    CHIRCULESCU MARIA FELICIA

    2015-08-01

    Full Text Available The work is based on the fact that at any time and in any society, taxation is regarded as undesirable for all taxpayers. The existence and it's manifestation is justified, because the operation of any company involves costs that must be covered by sufficient resources. Since ancient times, each state has adopted its own tax system, more or less perfected, as the state has experienced a greater or lesser economic and military power At the base of this work stays the fact that tax systems are a key factor influencing the overall efficiency of the economy. They determine the size tendency to save, invest and work, influencing the increase in production and employment, which is essential sights integral economic strategy, making tax reform an important component of economic reform. This paper aims to analyze the indirect taxes and their contribution to the public revenues in Romania, the purpose paper contains an analysis based on statistical series as indirect taxation is where tax harmonization was possible. Through analyzes, the paper aims to provide answers to the problem of the contradiction between the growing need for budgetary revenues, which entails a continuous amplification and diversification of taxation, on the one hand, and the need to stimulate economic development, on the other hand. The harmonization of indirect taxation had been achieved since this touches the free movement of goods and the freedom to supply services, not being able to say the same thing about direct taxation, which is why the European Community Treaty does not specify expressly the alignment of direct taxation, considering that direct taxation is a matter of Internal Policies that, for a country free option.

  14. Adaptors and Innovators: A Description and Measure

    Science.gov (United States)

    Kirton, Michael

    1976-01-01

    Describes development of the Kirton Adaption Innovation Inventory (KAI) for rating respondents on a continuum of adaptiveness-innovativeness, discusses tests of the validity and utility of the KAI model, and evaluates the KAI model's characteristics. For availability see EA 507 670. (Author/JG)

  15. Motors and Adaptors : Transport Regulation within Neurons

    NARCIS (Netherlands)

    van Spronsen, C.S.A.M.|info:eu-repo/dai/nl/337616655

    2012-01-01

    Human thoughts and behavior are the outcome of communication between neurons in our brains. There is an entire world inside each of these neurons where transactions are established and meeting points are set. By using molecular motors to transport proteins and organelles along cytoskeletal tracks,

  16. COP 21: the national contributions

    International Nuclear Information System (INIS)

    Jouette, Isabelle

    2015-01-01

    This article comments the content of the national contributions (the so-called Intended Nationally Determined Contributions or INDC) which every country should have transmitted to the UN before the COP 21. In fact, 148 contributions, i.e. 75 per cent of the expected ones, have been transmitted. The author recalls that the content of these contributions had to obey some principles which had been defined in Lima in 2014, and that each country must identify its objectives in terms of mitigation (reduction of greenhouse gas emissions) and adaptation (reduction of the vulnerability of natural and human systems). The author comments some specific commitments regarding climate, emission reduction, adaptation to climate change, and more particularly evokes the Ethiopian contribution which is considered as exemplary

  17. Introducing and modeling inefficiency contributions

    DEFF Research Database (Denmark)

    Asmild, Mette; Kronborg, Dorte; Matthews, Kent

    2016-01-01

    Whilst Data Envelopment Analysis (DEA) is the most commonly used non-parametric benchmarking approach, the interpretation and application of DEA results can be limited by the fact that radial improvement potentials are identified across variables. In contrast, Multi-directional Efficiency Analysis......-called inefficiency contributions, which are defined as the relative contributions from specific variables to the overall levels of inefficiencies. A statistical model for distinguishing the inefficiency contributions between subgroups is proposed and the method is illustrated on a data set on Chinese banks....

  18. ECN contributions to GLOBAL `95

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1995-06-01

    This report contains the 9 contributions of the Netherlands Energy Research Foundation ECN to the international conference on evaluation of emerging nuclear fuel cycle systems, GLOBAL `95, held in Versailles, France, on September 11-14, 1995. (orig./GL).

  19. Uncapacitated facility location problems: contributions

    Directory of Open Access Journals (Sweden)

    Galvão Roberto Diéguez

    2004-01-01

    Full Text Available The objective of the present paper is to review my personal contributions in the field of uncapacitated facility location problems. These contributions took place throughout my academic career, from the time I was a Ph.D. student at Imperial College to the present day. They cover approximately 30 years, from 1973 to 2003; they address: algorithms developed for the p-median problem and for a general formulation of uncapacitated location problems; the study of dynamic location models; covering and hierarchical location problems; queuing-based probabilistic location models. The contributions encompass theoretical developments, computational algorithms and practical applications. All work took place in an academic environment, with the invaluable collaboration of colleagues (both in Brazil and abroad and research students at COPPE. Each section in the paper is dedicated to a topic that involves a personal contribution. Every one of them is placed within the context of the existing literature.

  20. 75 FR 34388 - Employee Contribution Elections and Contribution Allocations

    Science.gov (United States)

    2010-06-17

    ... describes: (a) That default employee contributions equal to 3 percent of the employee's basic pay will be... From the Federal Register Online via the Government Publishing Office #0; #0;Proposed Rules #0... Employees' Retirement System Act of 1986 (FERSA), Public Law 99-335, 100 Stat. 514. The TSP provisions of...

  1. Charm contribution to bulk viscosity

    Science.gov (United States)

    Laine, M.; Sohrabi, Kiyoumars A.

    2015-02-01

    In the range of temperatures reached in future heavy ion collision experiments, hadronic pair annihilations and creations of charm quarks may take place within the lifetime of the plasma. As a result, charm quarks may increase the bulk viscosity affecting the early stages of hydrodynamic expansion. Assuming thermalisation, we estimate the charm contribution to bulk viscosity within the same effective kinetic theory framework in which the light parton contribution has been computed previously. The time scale at which this physics becomes relevant is related to the width of the transport peak associated with the trace anomaly correlator and is found to be fm/c for MeV.

  2. Maxwell's Contributions to Thermal Physics

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 8; Issue 5. Maxwell's Contributions to Thermal Physics. Sisir Bhanja. General Article Volume 8 Issue 5 May 2003 pp 57-72. Fulltext. Click here to view fulltext PDF. Permanent link: http://www.ias.ac.in/article/fulltext/reso/008/05/0057-0072. Keywords.

  3. The Jewish contribution to medicine

    African Journals Online (AJOL)

    1989-07-15

    Jul 15, 1989 ... History of Medicine. The Jewish contribution to medicine. Part 11. The 19th and 20th centuries. H.DUBOVSKY. Summary. Despite the opening of German universities to Jews in the .... private practice since religious prejudice prevented him from ..... investigations in orphanages and prisons he established a.

  4. Contributions of Maxwell to Electromagnetism

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 8; Issue 5. Contributions of Maxwell to Electromagnetism. P V Panat. General Article Volume 8 Issue 5 May 2003 pp 17-29. Fulltext. Click here to view fulltext PDF. Permanent link: http://www.ias.ac.in/article/fulltext/reso/008/05/0017-0029. Keywords.

  5. The Jewish contribution to medicine

    African Journals Online (AJOL)

    Their contribution to the an may be gauged by their forming 30%1 of Nobel Prize winners for medicine while constituting a fraction of 1% of the total world population. Garrison,2 Talbot,3 Roth4 and the Encyclopaedia Judaica5 were consulted for Jewish identification. The laner authority includes those of 'Jewish origin', ...

  6. Financial Network Systemic Risk Contributions

    NARCIS (Netherlands)

    Hautsch, N.; Schaumburg, J.; Schienle, M.

    2015-01-01

    We propose the realized systemic risk beta as a measure of financial companies' contribution to systemic risk, given network interdependence between firms' tail risk exposures. Conditional on statistically pre-identified network spillover effects and market and balance sheet information, we define

  7. CONTRIBUTIONS OF SUSHRUTA TO ANATOMY

    African Journals Online (AJOL)

    2005-08-08

    Aug 8, 2005 ... Probably, the exhaustive knowledge of basic sciences he had would have made him a versatile surgeon. This article has compiled the contributions of this great stalwart to anatomy and interprets his perspective towards teaching this subject. Keywords: Sushruta, Dissection, Cadaver, Anatomy, Preservation.

  8. JC Bose's Contributions to Chronobiology

    Indian Academy of Sciences (India)

    1122 printed pages offour monograph volumes. Reproduced here are his contributions to chronobiology in ... to J C Bose's work in the first monograph written on the subject of circadian clocks in German in 1958, ... account from his many passages in his inimitable English prose,. _ _ _ _ _ _ _ _ ,AAAAA, _ _ _ _ _ _ _ _. 54.

  9. Dendritic cells from oral cavity induce Foxp3(+ regulatory T cells upon antigen stimulation.

    Directory of Open Access Journals (Sweden)

    Sayuri Yamazaki

    Full Text Available Evidence is accumulating that dendritic cells (DCs from the intestines have the capacity to induce Foxp3(+CD4(+ regulatory T cells (T-regs and regulate immunity versus tolerance in the intestines. However, the contribution of DCs to controlling immunity versus tolerance in the oral cavity has not been addressed. Here, we report that DCs from the oral cavity induce Foxp3(+ T-regs as well as DCs from intestine. We found that oral-cavity-draining cervical lymph nodes contained higher frequencies of Foxp3(+ T-regs and ROR-γt(+ CD4(+T cells than other lymph nodes. The high frequency of Foxp3(+ T-regs in the oral-cavity-draining cervical lymph nodes was not dependent on the Toll like receptor (TLR adaptor molecules, Myd88 and TICAM-1 (TRIF. In contrast, the high frequency of ROR-γt(+ CD4(+T cells relies on Myd88 and TICAM-1. In vitro data showed that CD11c(+ DCs from oral-cavity-draining cervical lymph nodes have the capacity to induce Foxp3(+ T-regs in the presence of antigen. These data suggest that, as well as in the intestinal environment, antigen-presenting DCs may play a vital role in maintaining tolerance by inducing Foxp3(+ T-regs in the oral cavity.

  10. Processed foods: contributions to nutrition.

    Science.gov (United States)

    Weaver, Connie M; Dwyer, Johanna; Fulgoni, Victor L; King, Janet C; Leveille, Gilbert A; MacDonald, Ruth S; Ordovas, Jose; Schnakenberg, David

    2014-06-01

    Both fresh and processed foods make up vital parts of the food supply. Processed food contributes to both food security (ensuring that sufficient food is available) and nutrition security (ensuring that food quality meets human nutrient needs). This ASN scientific statement focuses on one aspect of processed foods: their nutritional impacts. Specifically, this scientific statement 1) provides an introduction to how processed foods contribute to the health of populations, 2) analyzes the contribution of processed foods to "nutrients to encourage" and "constituents to limit" in the American diet as recommended by the Dietary Guidelines for Americans, 3) identifies the responsibilities of various stakeholders in improving the American diet, and 4) reviews emerging technologies and the research needed for a better understanding of the role of processed foods in a healthy diet. Analyses of the NHANES 2003-2008 show that processed foods provide both nutrients to encourage and constituents to limit as specified in the 2010 Dietary Guidelines for Americans. Of the nutrients to encourage, processed foods contributed 55% of dietary fiber, 48% of calcium, 43% of potassium, 34% of vitamin D, 64% of iron, 65% of folate, and 46% of vitamin B-12. Of the constituents to limit, processed foods contributed 57% of energy, 52% of saturated fat, 75% of added sugars, and 57% of sodium. Diets are more likely to meet food guidance recommendations if nutrient-dense foods, either processed or not, are selected. Nutrition and food science professionals, the food industry, and other stakeholders can help to improve the diets of Americans by providing a nutritious food supply that is safe, enjoyable, affordable, and sustainable by communicating effectively and accurately with each other and by working together to improve the overall knowledge of consumers. © 2014 American Society for Nutrition.

  11. Genetic contribution to vestibular diseases.

    Science.gov (United States)

    Gallego-Martinez, Alvaro; Espinosa-Sanchez, Juan Manuel; Lopez-Escamez, Jose Antonio

    2018-03-26

    Growing evidence supports the contribution of allelic variation to vestibular disorders. Heritability attributed to rare allelic variants is found in familial vestibular syndromes such as enlarged vestibular aqueduct syndrome or familial Meniere disease. However, the involvement of common allelic variants as key regulators of physiological processes in common and rare vestibular diseases is starting to be deciphered, including motion sickness or sporadic Meniere disease. The genetic contribution to most of the vestibular disorders is still largely unknown. This review will outline the role of common and rare variants in human genome to episodic vestibular syndromes, progressive vestibular syndrome, and hereditary sensorineural hearing loss associated with vestibular phenotype. Future genomic studies and network analyses of omic data will clarify the pathway towards a personalized stratification of treatments.

  12. Kant's contribution to social theory

    OpenAIRE

    González, A.M. (Ana Marta)

    2009-01-01

    Although Kant is not usually counted among the forerunners of social sciences, any look at the work of the most prominent social theorists of the past century shows the pervasive influence of Kant’s philosophy. This influence is obvious and crucial at the epistemological level, if only because Kant himself set the frame for subsequent discussion of the difference between human and natural sciences. Yet, Kant’s work is also rich in substantive contributions to social theory, whi...

  13. Galileo's contribution to modern orthopaedics.

    Science.gov (United States)

    Jastifer, James R; Toledo-Pereyra, Luis H; Gustafson, Peter A

    2011-01-01

    Galileo Galilei (1564-1642), world-renowned Italian mathematician, astronomer, physicist and philosopher, made many contributions to science. The objective of this study is to demonstrate that Galileo's discovery of scaling principles permitted others to define and advance orthopaedic research and clinical sciences. The science and scaling principles of Galileo Galilei were extensively analyzed by reviewing his 1638 original work Discorsi e Demostrazioni Matematiche Intorno a Due Nuove Scienze. Works about Galileo's science were reviewed for the concept of the scaling principles and with the idea of shedding light on how his work influenced modern orthopaedics. Galileo strictly adhered to the Copernican heliocentric theory with the sun at the center of the universe, which caused him aggravation and made him the target of inquisition rage at the end of his prodigious life. With his attention away from the cosmos, Galileo--through the voices of Salviati, Sagredo and Simplicio in the Discourses on Two New Sciences--defined how scaling was important to the movement and function of objects. Galileo introduced important advances in scaling laws, which contributed to the development of the field of biomechanics. This discipline, in many ways, has defined modern clinical and research orthopaedics. Galileo, by introducing the principles of scaling, permitted their application to human physical capacity, to bone and tissue response after injury, and to clinical treatment of injuries. Galileo in this way made important contributions to the practice of modern orthopaedics.

  14. Toll-like receptor 4 signaling in neurons of trigeminal ganglion contributes to nociception induced by acute pulpitis in rats.

    Science.gov (United States)

    Lin, Jia-Ji; Du, Yi; Cai, Wen-Ke; Kuang, Rong; Chang, Ting; Zhang, Zhuo; Yang, Yong-Xiang; Sun, Chao; Li, Zhu-Yi; Kuang, Fang

    2015-07-30

    Pain caused by acute pulpitis (AP) is a common symptom in clinical settings. However, its underlying mechanisms have largely remained unknown. Using AP model, we demonstrated that dental injury caused severe pulp inflammation with up-regulated serum IL-1β. Assessment from head-withdrawal reflex thresholds (HWTs) and open-field test demonstrated nociceptive response at 1 day post injury. A consistent up-regulation of Toll-like receptor 4 (TLR4) in the trigeminal ganglion (TG) ipsilateral to the injured pulp was found; and downstream signaling components of TLR4, including MyD88, TRIF and NF-κB, and cytokines such as TNF-α and IL-1β, were also increased. Retrograde labeling indicated that most TLR4 positve neuron in the TG innnervated the pulp and TLR4 immunoreactivity was mainly in the medium and small neurons. Double labeling showed that the TLR4 expressing neurons in the ipsilateral TG were TRPV1 and CGRP positive, but IB4 negative. Furthermore, blocking TLR4 by eritoran (TLR4 antagonist) in TGs of the AP model significantly down-regulated MyD88, TRIF, NF-κB, TNF-α and IL-1β production and behavior of nociceptive response. Our findings suggest that TLR4 signaling in TG cells, particularly the peptidergic TRPV1 neurons, plays a key role in AP-induced nociception, and indicate that TLR4 signaling could be a potential therapeutic target for orofacial pain.

  15. Genes contributing to prion pathogenesis

    DEFF Research Database (Denmark)

    Tamgüney, Gültekin; Giles, Kurt; Glidden, David V

    2008-01-01

    incubation times, indicating that the conversion reaction may be influenced by other gene products. To identify genes that contribute to prion pathogenesis, we analysed incubation times of prions in mice in which the gene product was inactivated, knocked out or overexpressed. We tested 20 candidate genes...... show that many genes previously implicated in prion replication have no discernible effect on the pathogenesis of prion disease. While most genes tested did not significantly affect survival times, ablation of the amyloid beta (A4) precursor protein (App) or interleukin-1 receptor, type I (Il1r1...

  16. Nobel Prizes: Contributions to Cardiology

    International Nuclear Information System (INIS)

    Mesquita, Evandro Tinoco; Marchese, Luana de Decco; Dias, Danielle Warol; Barbeito, Andressa Brasil; Gomes, Jonathan Costa; Muradas, Maria Clara Soares; Lanzieri, Pedro Gemal; Gismondi, Ronaldo Altenburg

    2015-01-01

    The Nobel Prize was created by Alfred Nobel. The first prize was awarded in 1901 and Emil Adolf von Behring was the first laureate in medicine due to his research in diphtheria serum. Regarding cardiology, Nobel Prize’s history permits a global comprehension of progress in pathophysiology, diagnosis and therapeutics of various cardiac diseases in last 120 years. The objective of this study was to review the major scientific discoveries contemplated by Nobel Prizes that contributed to cardiology. In addition, we also hypothesized why Carlos Chagas, one of our most important scientists, did not win the prize in two occasions. We carried out a non-systematic review of Nobel Prize winners, selecting the main studies relevant to heart diseaseamong the laureates. In the period between 1901 and 2013, 204 researches and 104 prizes were awarded in Nobel Prize, of which 16 (15%) studies were important for cardiovascular area. There were 33 (16%) laureates, and two (6%) were women. Fourteen (42%) were American, 15 (45%) Europeans and four (13%) were from other countries. There was only one winner born in Brazil, Peter Medawar, whose career was all in England. Reviewing the history of the Nobel Prize in physiology or medicine area made possible to identify which researchers and studies had contributed to advances in the diagnosis, prevention and treatment of cardiovascular diseases. Most winners were North Americans and Europeans, and male

  17. Nobel Prizes: Contributions to Cardiology

    Energy Technology Data Exchange (ETDEWEB)

    Mesquita, Evandro Tinoco; Marchese, Luana de Decco; Dias, Danielle Warol; Barbeito, Andressa Brasil; Gomes, Jonathan Costa; Muradas, Maria Clara Soares; Lanzieri, Pedro Gemal; Gismondi, Ronaldo Altenburg, E-mail: ronaldo@floralia.com.br [Universidade Federal Fluminense, Niterói, RJ (Brazil)

    2015-08-15

    The Nobel Prize was created by Alfred Nobel. The first prize was awarded in 1901 and Emil Adolf von Behring was the first laureate in medicine due to his research in diphtheria serum. Regarding cardiology, Nobel Prize’s history permits a global comprehension of progress in pathophysiology, diagnosis and therapeutics of various cardiac diseases in last 120 years. The objective of this study was to review the major scientific discoveries contemplated by Nobel Prizes that contributed to cardiology. In addition, we also hypothesized why Carlos Chagas, one of our most important scientists, did not win the prize in two occasions. We carried out a non-systematic review of Nobel Prize winners, selecting the main studies relevant to heart diseaseamong the laureates. In the period between 1901 and 2013, 204 researches and 104 prizes were awarded in Nobel Prize, of which 16 (15%) studies were important for cardiovascular area. There were 33 (16%) laureates, and two (6%) were women. Fourteen (42%) were American, 15 (45%) Europeans and four (13%) were from other countries. There was only one winner born in Brazil, Peter Medawar, whose career was all in England. Reviewing the history of the Nobel Prize in physiology or medicine area made possible to identify which researchers and studies had contributed to advances in the diagnosis, prevention and treatment of cardiovascular diseases. Most winners were North Americans and Europeans, and male.

  18. Nobel Prizes: Contributions to Cardiology

    Directory of Open Access Journals (Sweden)

    Evandro Tinoco Mesquita

    2015-08-01

    Full Text Available The Nobel Prize was created by Alfred Nobel. The first prize was awarded in 1901 and Emil Adolf von Behring was the first laureate in medicine due to his research in diphtheria serum. Regarding cardiology, Nobel Prize’s history permits a global comprehension of progress in pathophysiology, diagnosis and therapeutics of various cardiac diseases in last 120 years. The objective of this study was to review the major scientific discoveries contemplated by Nobel Prizes that contributed to cardiology. In addition, we also hypothesized why Carlos Chagas, one of our most important scientists, did not win the prize in two occasions. We carried out a non-systematic review of Nobel Prize winners, selecting the main studies relevant to heart diseaseamong the laureates. In the period between 1901 and 2013, 204 researches and 104 prizes were awarded in Nobel Prize, of which 16 (15% studies were important for cardiovascular area. There were 33 (16% laureates, and two (6% were women. Fourteen (42% were American, 15 (45% Europeans and four (13% were from other countries. There was only one winner born in Brazil, Peter Medawar, whose career was all in England. Reviewing the history of the Nobel Prize in physiology or medicine area made possible to identify which researchers and studies had contributed to advances in the diagnosis, prevention and treatment of cardiovascular diseases. Most winners were North Americans and Europeans, and male.

  19. Nobel Prizes: Contributions to Cardiology

    Directory of Open Access Journals (Sweden)

    Evandro Tinoco Mesquita

    2015-01-01

    Full Text Available The Nobel Prize was created by Alfred Nobel. The first prize was awarded in 1901 and Emil Adolf von Behring was the first laureate in medicine due to his research in diphtheria serum. Regarding cardiology, Nobel Prize’s history permits a global comprehension of progress in pathophysiology, diagnosis and therapeutics of various cardiac diseases in last 120 years. The objective of this study was to review the major scientific discoveries contemplated by Nobel Prizes that contributed to cardiology. In addition, we also hypothesized why Carlos Chagas, one of our most important scientists, did not win the prize in two occasions. We carried out a non-systematic review of Nobel Prize winners, selecting the main studies relevant to heart diseaseamong the laureates. In the period between 1901 and 2013, 204 researches and 104 prizes were awarded in Nobel Prize, of which 16 (15% studies were important for cardiovascular area. There were 33 (16% laureates, and two (6% were women. Fourteen (42% were American, 15 (45% Europeans and four (13% were from other countries. There was only one winner born in Brazil, Peter Medawar, whose career was all in England. Reviewing the history of the Nobel Prize in physiology or medicine area made possible to identify which researchers and studies had contributed to advances in the diagnosis, prevention and treatment of cardiovascular diseases. Most winners were North Americans and Europeans, and male.

  20. Cerebellar Contribution to Social Cognition.

    Science.gov (United States)

    Hoche, Franziska; Guell, Xavier; Sherman, Janet C; Vangel, Mark G; Schmahmann, Jeremy D

    2016-12-01

    Emotion attribution (EA) from faces is key to social cognition, and deficits in perception of emotions from faces underlie neuropsychiatric disorders in which cerebellar pathology is reported. Here, we test the hypothesis that the cerebellum contributes to social cognition through EA from faces. We examined 57 patients with cerebellar disorders and 57 healthy controls. Thirty-one patients had complex cerebrocerebellar disease (complex cerebrocerebellar disease group (CD)); 26 had disease isolated to cerebellum (isolated cerebellar disease group (ID)). EA was measured with the Reading the Mind in the Eyes test (RMET), and informants were administered a novel questionnaire, the Cerebellar Neuropsychiatric Rating Scale (CNRS). EA was impaired in all patients (CD p social skills (p social skills (CD p social skills and autism spectrum behaviors and experienced psychosocial difficulties on the CNRS. This has relevance for ataxias, the cerebellar cognitive affective/Schmahmann syndrome, and neuropsychiatric disorders with cerebellar pathology.

  1. Hadron Contribution to Vacuum Polarisation

    CERN Document Server

    Davier, M; Malaescu, B; Zhang, Z

    2016-01-01

    Precision tests of the Standard Theory require theoretical predictions taking into account higher-order quantum corrections. Among these vacuum polarisation plays a predominant role. Vacuum polarisation originates from creation and annihilation of virtual particle–antiparticle states. Leptonic vacuum polarisation can be computed from quantum electrodynamics. Hadronic vacuum polarisation cannot because of the non-perturbative nature of QCD at low energy. The problem is remedied by establishing dispersion relations involving experimental data on the cross section for e+ e− annihilation into hadrons. This chapter sets the theoretical and experimental scene and reviews the progress achieved in the last decades thanks to more precise and complete data sets. Among the various applications of hadronic vacuum polarisation calculations, two are emphasised: the contribution to the anomalous magnetic moment of the muon, and the running of the fine structure constant α to the Z mass scale. They are fundamental ingre...

  2. 22 CFR 130.6 - Political contribution.

    Science.gov (United States)

    2010-04-01

    ... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Political contribution. 130.6 Section 130.6 Foreign Relations DEPARTMENT OF STATE INTERNATIONAL TRAFFIC IN ARMS REGULATIONS POLITICAL CONTRIBUTIONS, FEES AND COMMISSIONS § 130.6 Political contribution. Political contribution means any loan, gift...

  3. Uruguay geology contributions no. 2

    International Nuclear Information System (INIS)

    Preciozzi, F.

    1989-01-01

    This Group is characterized by a volcano-sedimentary sequence of low grade into which are found the main Pb, Zn, Cu, Mo occurrences and vast limestones deposits and a laterally associated sequence of medium metamorphism. From a structural point of view it is characterized by a poly phasic evolution. At low metamorphic sequence is distinguished a volcanic-sedimentary series (s.s.) and a sedimentogenous series. The synchronism between both series is showed by transition by lateral facies changes. There is a pelitic carbonate zone associated to a basic calc o-alkaline and tholeitic volcanism and the another zone represented by a carbonaceous platform subjected lo de tri tic contribution of varied nature. The Iithologic succession permits establishing at the volcano-sedimentary sequence, five levels from base to top: -a phyllitic and meta pelitic level (500 meters thick), with basic volcanic rocks intercalated, -a level of limestones which evolves to the top by detritic contributions to a flisch alternation (300 m. thick) with basic volcanic rocks intercalated, -a level of rit mic alternation of rnetapelites, melasandstones, limes tones and phyllites (200 m. thick), -a basic volcanic unit, with intercalation of acid vulcanite s, at the lop are intercalated volcanoclastic rocks as tuffs and breccia s, 1000 meters thick, -a n el sedimentary unit integrated by limestones and phyllites wich evolve to the top of the series lo levels of dolomites. coarse-grained phyllites and jasper, 300 m. thick. Laterally this level passes lo a set integrated by quartzites, metaarcoses, limestones, acid tuffs and rarely rhyolites. The sedimentogenous series has the following base to top sequence: -150 m. of quartzites and meta sandstones wich lay unconformbly over a qranitic-gneissic set, -100 m. 01 phyllites, coarse-grained phyllites and metaarcoses, -ritmic alternance of calcareous, phyllites, coarse-grained phyllites, 800 m. thick (flisch). The megastructures were formed al the second

  4. The microbial contribution to macroecology

    Science.gov (United States)

    Barberán, Albert; Casamayor, Emilio O.; Fierer, Noah

    2014-01-01

    There has been a recent explosion of research within the field of microbial ecology that has been fueled, in part, by methodological improvements that make it feasible to characterize microbial communities to an extent that was inconceivable only a few years ago. Furthermore, there is increasing recognition within the field of ecology that microorganisms play a critical role in the health of organisms and ecosystems. Despite these developments, an important gap still persists between the theoretical framework of macroecology and microbial ecology. We highlight two idiosyncrasies of microorganisms that are fundamental to understanding macroecological patterns and their mechanistic drivers. First, high dispersal rates provide novel opportunities to test the relative importance of niche, stochastic, and historical processes in structuring biological communities. Second, high speciation rates potentially lead to the convergence of ecological and evolutionary time scales. After reviewing these unique aspects, we discuss strategies for improving the conceptual integration of microbes into macroecology. As examples, we discuss the use of phylogenetic ecology as an integrative approach to explore patterns across the tree of life. Then we demonstrate how two general theories of biodiversity (i.e., the recently developed theory of stochastic geometry and the neutral theory) can be adapted to microorganisms. We demonstrate how conceptual models that integrate evolutionary and ecological mechanisms can contribute to the unification of microbial ecology and macroecology. PMID:24829564

  5. Student Scientific Conference, 2009. Proceedings of reviewed contributions

    International Nuclear Information System (INIS)

    2009-01-01

    The conference included the following sections: (i) Biology (145 contributions); (ii) Chemistry (42 contributions); (iii) Geology (42 contributions); (iv) Environment (40 contributions); (v) Geography (28 contributions); (vi) Didactics (13 contributions). Contributions relevant of INIS interest has been inputted to INIS.

  6. Student Scientific Conference, 2010. Proceedings of reviewed contributions

    International Nuclear Information System (INIS)

    2010-01-01

    The conference included the following sections: (i) Biology (154 contributions); (ii) Chemistry (39 contributions); (iii) Geography; (41 contributions); (iv) Geology (22 contributions); (v) Environment (45 contributions); (vi) Didactics (6 contributions). Contributions relevant of INIS interest has been inputted to INIS.

  7. TLR2-dependent MyD88 signaling contributes to early host defense in murine Enterococcus faecium peritonitis

    NARCIS (Netherlands)

    Leendertse, Masja; Willems, Rob J. L.; Giebelen, Ida A. J.; van den Pangaart, Petra S.; Wiersinga, W. Joost; de Vos, Alex F.; Florquin, Sandrine; Bonten, Marc J. M.; van der Poll, Tom

    2008-01-01

    The incidence of infections with Enterococcus faecium is increasing worldwide. TLRs have been implicated in the recognition of pathogens and the initiation of an adequate innate immune response. We here sought to determine the roles of MyD88, the common adaptor protein involved in TLR signaling,

  8. The GMOS contributions to GEOSS

    Directory of Open Access Journals (Sweden)

    Pirrone N.

    2013-04-01

    oceans, and in the UTLS will support the validation of regional and global atmospheric mercury models for use in evaluating different policy options for reducing mercury pollution and its impacts on human health and ecosystems. The data sets, the validated models, and the interoperable system that is produced within this program, will support the policymaking process in the framework of UNEP Governing Council activities, and in the UNECE-LRTAP convention. The task builds upon contributions from, among others, the Global Mercury Observation System (GMOS project, the UNEP Mercury Programme, the Hemispheric Transport of Air Pollutants Task Force (TF HTAP, the European Monitoring and Evaluation Program (EMEP, the MercNet/AMNet initiative in the USA, the CAMNet in Canada, and other international monitoring and modelling efforts.

  9. Quarkonium Contribution to Meson Molecules

    Energy Technology Data Exchange (ETDEWEB)

    Cincioglu, E.; Yilmazer, A.U. [Ankara University, Department of Physics Engineering, Ankara (Turkey); Nieves, J. [Instituto de Fisica Corpuscular (IFIC) Centro Mixto CSIC-Universidad de Valencia, Institutos de Investigacion de Paterna, Valencia (Spain); Ozpineci, A. [Middle East Technical University, Department of Physics, Ankara (Turkey)

    2016-10-15

    Starting from a molecular picture for the X(3872) resonance, this state and its J{sup PC} = 2{sup ++} heavy-quark spin symmetry partner [X{sub 2}(4012)] are analyzed within a model which incorporates possible mixings with 2P charmonium (c anti c) states. Since it is reasonable to expect the bare χ{sub c1}(2P) to be located above the D anti D{sup *} threshold, but relatively close to it, the presence of the charmonium state provides an effective attraction that will contribute to binding the X(3872), but it will not appear in the 2{sup ++} sector. Indeed in the latter sector, the χ{sub c2}(2P) should provide an effective small repulsion, because it is placed well below the D{sup *} anti D{sup *} threshold. We show how the 1{sup ++} and 2{sup ++} bare charmonium poles are modified due to the D{sup (*)} anti D{sup (*)} loop effects, and the first one is moved to the complex plane. The meson loops produce, besides some shifts in the masses of the charmonia, a finite width for the 1{sup ++} dressed charmonium state. On the other hand, X(3872) and X{sub 2}(4012) start developing some charmonium content, which is estimated by means of the compositeness Weinberg sum rule. It turns out that in the heavy-quark limit, there is only one coupling between the 2P charmonia and the D{sup (*)} anti D{sup (*)} pairs. We also show that, for reasonable values of this coupling, leading to X(3872) molecular probabilities of around 70-90 %, the X{sub 2} resonance destabilizes and disappears from the spectrum, becoming either a virtual state or one being located deep into the complex plane, with decreasing influence in the D{sup *} anti D{sup *} scattering line. Moreover, we also discuss how around 10-30 % charmonium probability in the X(3872) might explain the ratio of radiative decays of this resonance into ψ(2S)γ and J/ψγ. Finally, we qualitatively discuss within this scheme, the hidden bottom flavor sector, paying a special attention to the implications for the X{sub b} and X

  10. 7 CFR 966.45 - Contributions.

    Science.gov (United States)

    2010-01-01

    ... contributions but these shall only be used for production research, market research and development and..., or any person whose contributions would constitute a conflict of interest. Research and Development ...

  11. Scalar contribution to the BFKL kernel

    International Nuclear Information System (INIS)

    Gerasimov, R. E.; Fadin, V. S.

    2010-01-01

    The contribution of scalar particles to the kernel of the Balitsky-Fadin-Kuraev-Lipatov (BFKL) equation is calculated. A great cancellation between the virtual and real parts of this contribution, analogous to the cancellation in the quark contribution in QCD, is observed. The reason of this cancellation is discovered. This reason has a common nature for particles with any spin. Understanding of this reason permits to obtain the total contribution without the complicated calculations, which are necessary for finding separate pieces.

  12. Contributing Chemistry and Compelling Physics

    Directory of Open Access Journals (Sweden)

    Editorial

    2013-04-01

    transplantation for haematological disorders and malignancies. With these two original research articles throwing a light upon the influence of various factors on stem cell proliferation, homing and engraftment, the article by Telpalo-Carpio et al has attempted to provide a general scenario of the state of the art in the Induced Pluripotent Stem (iPS cells generation, giving a glimpse of the most important and promising emerging de-differentiation technologies of the various research groups all over the world who are extensively researching on this ‘most sought after cell type’. Though all ideas and innovations may not turn out to yield successful solutions and all researches may not end up in positive outcome, the article by Terunuma et al which provides an in-sight into the in vitro expansion of patients’ immune cells such as NK cells, and T cells using chemically synthesized culture media without any feeder layers, whose clinical outcome in tackling several tumours with long term follow-up is something really a tonic of encouragement to scientists. Contribution of chemical moieties having been studied and translated to clinical applications, the physical forces' real worth have not yet been explored to the fullest. Time has come to dig, hig or boson them! References: Engler AJ, Sen S, Sweeney HL, Discher DE. Matrix elasticity directs stem cell lineage specification. Cell. 2006 Aug 25;126(4:677-89. Adams DS. A new tool for tissue engineers: ions as regulators of morphogenesis during development and regeneration. Tissue Eng Part A. 2008 Sep;14(9:1461-8.

  13. Control escalar de un convertidor trifásico con una placa Arduino

    OpenAIRE

    García de Baquedano Mauleón, Iosu

    2014-01-01

    Este trabajo consistirá en el diseño e implantación del control escalar para una máquina de corriente alterna asíncrona, utilizando para ello una plataforma de hardware libre Arduino Graduado o Graduada en Ingeniería en Tecnologías Industriales por la Universidad Pública de Navarra Gradua Industria Teknologietako Ingeniaritzan

  14. Targeted Elimination of G Proteins and Arrestins Defines Their Specific Contributions to Both Intensity and Duration of G Protein-coupled Receptor Signaling.

    Science.gov (United States)

    Alvarez-Curto, Elisa; Inoue, Asuka; Jenkins, Laura; Raihan, Sheikh Zahir; Prihandoko, Rudi; Tobin, Andrew B; Milligan, Graeme

    2016-12-30

    G protein-coupled receptors (GPCRs) can initiate intracellular signaling cascades by coupling to an array of heterotrimeric G proteins and arrestin adaptor proteins. Understanding the contribution of each of these coupling options to GPCR signaling has been hampered by a paucity of tools to selectively perturb receptor function. Here we employ CRISPR/Cas9 genome editing to eliminate selected G proteins (Gα q and Gα 11 ) or arrestin2 and arrestin3 from HEK293 cells together with the elimination of receptor phosphorylation sites to define the relative contribution of G proteins, arrestins, and receptor phosphorylation to the signaling outcomes of the free fatty acid receptor 4 (FFA4). A lack of FFA4-mediated elevation of intracellular Ca 2+ in Gα q /Gα 11 -null cells and agonist-mediated receptor internalization in arrestin2/3-null cells confirmed previously reported canonical signaling features of this receptor, thereby validating the genome-edited HEK293 cells. FFA4-mediated ERK1/2 activation was totally dependent on G q / 11 but intriguingly was substantially enhanced for FFA4 receptors lacking sites of regulated phosphorylation. This was not due to a simple lack of desensitization of G q / 11 signaling because the G q / 11 -dependent calcium response was desensitized by both receptor phosphorylation and arrestin-dependent mechanisms, whereas a substantially enhanced ERK1/2 response was only observed for receptors lacking phosphorylation sites and not in arrestin2/3-null cells. In conclusion, we validate CRISPR/Cas9 engineered HEK293 cells lacking G q / 11 or arrestin2/3 as systems for GPCR signaling research and employ these cells to reveal a previously unappreciated interplay of signaling pathways where receptor phosphorylation can impact on ERK1/2 signaling through a mechanism that is likely independent of arrestins. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  15. The gut microbiota engages different signaling pathways to induce Duox2 expression in the ileum and colon epithelium

    DEFF Research Database (Denmark)

    Sommer, F; Bäckhed, Gert Fredrik

    2015-01-01

    , but not when germ-free mice were colonized with various commensal bacteria. Duox2 expression was more rapidly induced by the gut microbiota in the colon than in the ileum. Furthermore, we showed that regulation of Duox2 expression in the ileum involved TIR-domain-containing adaptor protein including interferon......-β (TRIF) and canonical nuclear factor-κB p50/p65 signaling, whereas regulation of Duox2 expression in the colon involved MyD88 and the p38 pathway. Collectively, these data indicate that the gut microbiota uses two distinct signaling pathways to induce Duox2 expression in the ileum and colon epithelium....

  16. Contribution behavior of 401(k) plan participants.

    Science.gov (United States)

    Holden, S; VanDerhei, J

    2001-10-01

    This Issue Brief examines the 1999 contribution behavior of 1.7 million 401(k) plan participants drawn from the EBRI/ICI Participant-Directed Retirement Plan Data Collection Project. The findings in this paper build on previous academic research examining the contribution activity of 401(k) participants, by using a large sample of participants in a wide range of plan sizes and by examining in detail the factors that influence contribution activity. Eighty-five percent of participants in the sample only made before-tax contributions to their plans, and 97 percent of all dollars contributed by employees were contributed on a before-tax basis. On average, participants contributed 6.8 percent of their salaries on a before-tax basis. Before-tax contribution activity varied among participants. About 61 percent of participants contributed more than 5 percent of their salaries on a before-tax basis and about 21 percent set aside more than 10 percent of their salaries on a before-tax basis. Eleven percent of participants analyzed in this study earning more than $40,000 a year contributed at the $10,000 before-tax IRC limit in 1999. Thirteen percent of participants with salaries between $70,000 and $80,000 contributed at the cap, and 18 percent of those with salaries between $80,000 and $90,000 were at the limit. However, it appears that among participants not contributing at the IRC limit, 52 percent could not have done so because of formal plan-imposed contribution limits below the IRC limit. Older participants tended to contribute a higher percentage of their salaries to plans than did younger participants, even after factoring out differences in salary and job tenure. Participants tended to increase the share of their salary (and amounts) contributed to their 401(k) plan as their salaries rose until salaries reached $80,000. For individuals with salaries above $80,000, before-tax contribution rates (though not the amounts contributed) tended to fall as salaries rose

  17. Public libraries' contribution to Sustainable Development Goals

    OpenAIRE

    Telo, Paula Alexandra Ochoa de Carvalho; Pinto, Leonor Gaspar

    2017-01-01

    UID/HIS/04666/2013 Initiated in November 2016, the project Public Libraries and Sustainability: Gathering Evidences of Contribution to SDGs (Project PLS) aims to develop a framework for evaluating public libraries’ contribution to Sustainable Development Goals (SDGs) and tailor it to Portuguese public libraries. This paper discusses the role of impact evaluation practices and competencies in evidence gathering and advocacy processes of libraries’ contribution to the UN 2030 Agenda, focusin...

  18. 44 CFR 361.4 - Matching contributions.

    Science.gov (United States)

    2010-10-01

    ... HOMELAND SECURITY PREPAREDNESS NATIONAL EARTHQUAKE HAZARDS REDUCTION ASSISTANCE TO STATE AND LOCAL GOVERNMENTS Earthquake Hazards Reduction Assistance Program § 361.4 Matching contributions. (a) All State...

  19. 7 CFR 550.15 - Resource contribution.

    Science.gov (United States)

    2010-01-01

    ... completion of the project. Required resource contributions must be substantial enough to substantiate a true... true stake in the project as determined by the ADO. The Cooperator's contribution must be maintained at... cost sharing or matching share shall be reasonable and shall not exceed the fair market value of the...

  20. 11 CFR 9034.2 - Matchable contributions.

    Science.gov (United States)

    2010-01-01

    ... one the principal purpose of which is political speech or discussion, such as the traditional... Federal Elections FEDERAL ELECTION COMMISSION PRESIDENTIAL ELECTION CAMPAIGN FUND: PRESIDENTIAL PRIMARY... requirements will be considered matchable campaign contributions. (1) The contribution shall be a gift of money...

  1. National contributions to observed global warming

    International Nuclear Information System (INIS)

    Matthews, H Damon; Graham, Tanya L; Keverian, Serge; Lamontagne, Cassandra; Seto, Donny; Smith, Trevor J

    2014-01-01

    There is considerable interest in identifying national contributions to global warming as a way of allocating historical responsibility for observed climate change. This task is made difficult by uncertainty associated with national estimates of historical emissions, as well as by difficulty in estimating the climate response to emissions of gases with widely varying atmospheric lifetimes. Here, we present a new estimate of national contributions to observed climate warming, including CO 2 emissions from fossil fuels and land-use change, as well as methane, nitrous oxide and sulfate aerosol emissions While some countries’ warming contributions are reasonably well defined by fossil fuel CO 2 emissions, many countries have dominant contributions from land-use CO 2 and non-CO 2 greenhouse gas emissions, emphasizing the importance of both deforestation and agriculture as components of a country’s contribution to climate warming. Furthermore, because of their short atmospheric lifetime, recent sulfate aerosol emissions have a large impact on a country’s current climate contribution We show also that there are vast disparities in both total and per-capita climate contributions among countries, and that across most developed countries, per-capita contributions are not currently consistent with attempts to restrict global temperature change to less than 2 °C above pre-industrial temperatures. (paper)

  2. 6-quark contribution to nuclear magnetic moments

    International Nuclear Information System (INIS)

    Ito, H.

    1985-01-01

    The magnetic moments of nuclei with LS closed shell +/-1 particle are calculated. Core polarization and meson exchange current are treated realistically in order to single out the 6-quark contribution. Overall agreement with experimental values is quite good. It is shown that the 6-quark system contributes to the respective iso-vector and iso-scalar moments with reasonable magnitudes

  3. Contributions of Psychology to War and Peace

    Science.gov (United States)

    Christie, Daniel J.; Montiel, Cristina J.

    2013-01-01

    The contributions of American psychologists to war have been substantial and responsive to changes in U.S. national security threats and interests for nearly 100 years. These contributions are identified and discussed for four periods of armed conflict: World Wars I and II, the Cold War, and the Global War on Terror. In contrast, about 50 years…

  4. 13 CFR 120.910 - Borrower contributions.

    Science.gov (United States)

    2010-01-01

    ... 13 Business Credit and Assistance 1 2010-01-01 2010-01-01 false Borrower contributions. 120.910 Section 120.910 Business Credit and Assistance SMALL BUSINESS ADMINISTRATION BUSINESS LOANS Development... must contribute to the Project cash (or property acceptable to SBA obtained with the cash) or land...

  5. 7 CFR 983.72 - Contributions.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 8 2010-01-01 2010-01-01 false Contributions. 983.72 Section 983.72 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements..., ARIZONA, AND NEW MEXICO Expenses and Assessments § 983.72 Contributions. The committee may accept...

  6. Contribution of Renewables to Energy Security

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2007-07-01

    The environmental benefits of renewable energy are well known. But the contribution that they can make to energy security is less widely recognised. This report aims to redress the balance, showing how in electricity generation, heat supply, and transport, renewables can enhance energy security and suggesting policies that can optimise this contribution.

  7. THE CONTRIBUTION OF AGROFORESTRY TREE PRODUCTS TO ...

    African Journals Online (AJOL)

    philiph

    A study to evaluate the contributions and economic benefits of agro-forestry tree products to rural farmers in Karim-Lamido Local ... derivable from this practice and its contributions and economic benefit to farmers' livelihood should be intensified ..... and fast growing tree species, and replacement for every tree felled. Gideon ...

  8. HEALTH INSURANCE: FIXED CONTRIBUTION AND REIMBURSEMENT MAXIMA

    CERN Multimedia

    Human Resources Division

    2001-01-01

    Affected by the salary adjustments on 1 January 2001 and the evolution of the staff members and fellows population, the average reference salary, which is used as an index for fixed contributions and reimbursement maxima, has changed significantly. An adjustment of the amounts of the reimbursement maxima and the fixed contributions is therefore necessary, as from 1 January 2001. Reimbursement maxima The revised reimbursement maxima will appear on the leaflet summarizing the benefits for the year 2001, which will be sent out with the forthcoming issue of the CHIS Bull'. This leaflet will also be available from the divisional secretariats and from the UNIQA office at CERN. Fixed contributions The fixed contributions, applicable to some categories of voluntarily insured persons, are set as follows (amounts in CHF for monthly contributions) : voluntarily insured member of the personnel, with normal health insurance cover : 910.- (was 815.- in 2000) voluntarily insured member of the personnel, with reduced heal...

  9. The contribution of technology to added value

    CERN Document Server

    Fernandes, António S C

    2013-01-01

    There is a wide consensus that introduction of technology to the production process contributes to an overall economic value, however, confusion between technology, knowledge and capital often makes value calculations ambiguous and non-objective. The Contribution of Technology to Added Value addresses not only this issue of definition but also provides a production model to assess the value contribution of technology within the production process. A clarification  of fundamental semantics  provides a significant taxonomy for technology dependence, and allows understanding and modeling of how knowledge, technology and capital individually contribute to production and to value adding. A new technology dependence taxonomy is proposed and assessed following chapters explaining growth models, the KTC model and technology index values. Balancing theoretical knowledge with real-world data and applications The Contribution of Technology to Added Value clarifies the issue of value adding for a range of different vie...

  10. Clockwork graviton contributions to muon g -2

    Science.gov (United States)

    Hong, Deog Ki; Kim, Du Hwan; Shin, Chang Sub

    2018-02-01

    The clockwork mechanism for gravity introduces a tower of massive graviton modes, clockwork gravitons, with a very compressed mass spectrum, whose interaction strengths are much stronger than those of massless gravitons. In this work, we compute the lowest order contributions of the clockwork gravitons to the anomalous magnetic moment, g -2 , of muon in the context of an extra dimensional model with a five-dimensional Planck mass, M5. We find that the total contributions are rather insensitive to the detailed model parameters and are determined mostly by the value of M5. To account for the current muon g -2 anomaly, M5 should be around 0.2 TeV, and the size of the extra dimension has to be quite large, l5≳10-7 m . For M5≳1 TeV , the clockwork graviton contributions are too small to explain the current muon g -2 anomaly. We also compare the clockwork graviton contributions with other extra dimensional models such as Randall-Sundrum models or large extra dimensional models. We find that the leading contributions in the small curvature limit are universal, but the cutoff-independent subleading contributions vary for different background geometries and the clockwork geometry gives the smallest subleading contributions.

  11. Polyclonal type II natural killer T cells require PLZF and SAP for their development and contribute to CpG-mediated antitumor response

    Science.gov (United States)

    Zhao, Jie; Weng, Xiufang; Bagchi, Sreya; Wang, Chyung-Ru

    2014-01-01

    CD1d-restricted natural killer T (NKT) cells are innate-like T cells with potent immunomodulatory function via rapid production of both Th1 and Th2 cytokines. NKT cells comprise well-characterized type I NKT cells, which can be detected by α-galactosylceramide-loaded CD1d tetramers, and less-studied type II NKT cells, which do not recognize α-galactosylceramide. Here we characterized type II NKT cells on a polyclonal level by using a Jα18-deficient IL-4 reporter mouse model. This model allows us to track type II NTK cells by the GFP+TCRβ+ phenotype in the thymus and liver. We found type II NKT cells, like type I NKT cells, exhibit an activated phenotype and are dependent on the transcriptional regulator promyelocytic leukemia zinc finger (PLZF) and the adaptor molecule signaling lymphocyte activation molecule-associated protein (SAP) for their development. Type II NKT cells are potently activated by β-D-glucopyranosylceramide (β-GlcCer) but not sulfatide or phospholipids in a CD1d-dependent manner, with the stimulatory capacity of β-GlcCer influenced by acyl chain length. Compared with type I NKT cells, type II NKT cells produce lower levels of IFN-γ but comparable amounts of IL-13 in response to polyclonal T-cell receptor stimulation, suggesting they may play different roles in regulating immune responses. Furthermore, type II NKT cells can be activated by CpG oligodeoxynucletides to produce IFN-γ, but not IL-4 or IL-13. Importantly, CpG-activated type II NKT cells contribute to the antitumor effect of CpG in the B16 melanoma model. Taken together, our data reveal the characteristics of polyclonal type II NKT cells and their potential role in antitumor immunotherapy. PMID:24550295

  12. Indian - American contributions to psychiatric research.

    Science.gov (United States)

    Pandurangi, Anand K

    2010-01-01

    The Indian Diaspora, especially in North America, is a visible force in the field of psychiatric medicine. An estimated 5000 persons of Indian origin practice psychiatry in the USA and Canada, and an estimated 10% of these are in academic psychiatry. Wide ranging contributions, from molecular biology of psychiatric disorders to community and cultural psychiatry, are being made by this vibrant group of researchers. This article is a brief summary and work-in-progress report of the contributions by Indian - American psychiatric researchers. Although not exhaustive in coverage, it is meant to give the reader an overview of the contributions made by three waves of researchers over a span of 50 years.

  13. Theodore Millon's Contributions to Conceptualizing Personality Disorders.

    Science.gov (United States)

    Pincus, Aaron L; Krueger, Robert F

    2015-01-01

    We review Theodore Millon's contributions to conceptualizing personality disorders in contemporary clinical science and practice. Millon worked tirelessly across professional domains and theoretical orientations, developing a rich integrative theory of personality and its pathology, directly and indirectly impacting the evolving iterations of the Diagnostic and Statistical Manual of Mental Disorders (DSM-III through DSM-5), and advocating for the personality disorders through his contributions to cofounding the International Society for the Study of Personality Disorders and the Journal of Personality Disorders. We conclude with a closer look at Millon's final major contributions to conceptualizing personality disorders as well as the strengths and limitations of his approach.

  14. Children's contributions to pediatric outpatient encounters.

    NARCIS (Netherlands)

    Dulmen, A.M. van

    1998-01-01

    Objective: Generally, increasing attention is being paid to the quality of doctor-patient communication. However, children's contributions have been, until now, primarily ignored in communication research, although there are indications that considering their views increases satisfaction and

  15. Frederick National Laboratory's Contribution to ATOM | FNLCR

    Science.gov (United States)

    As a founding member organization of ATOM, the Frederick National Laboratory will contribute scientific expertise in precision oncology, computational chemistry and cancer biology, as well as support for open sharing of data sets and predictive model

  16. Quantifying arthropod contributions to wood decay

    Science.gov (United States)

    Michael Ulyshen; Terry Wagner

    2013-01-01

    Termites carry large amounts of soil into dead wood, and this behaviour complicates efforts to measure their contributions to wood decay. A novel method for isolating termite soil by burning the wood is described, and some preliminary results are presented.

  17. 12 CFR 1291.2 - Required annual AHP contributions; allocation of contributions.

    Science.gov (United States)

    2010-01-01

    ... 12 Banks and Banking 7 2010-01-01 2010-01-01 false Required annual AHP contributions; allocation of contributions. 1291.2 Section 1291.2 Banks and Banking FEDERAL HOUSING FINANCE AGENCY HOUSING... future annual required AHP contributions an amount up to the greater of $5 million or 20% of its annual...

  18. Hybridization characteristics of biomolecular adaptors, covalent DNA streptavidin conjugates

    NARCIS (Netherlands)

    Niemeyer, CM; Burger, W; Hoedemakers, RMJ

    1998-01-01

    Semisynthetic, covalent streptavidin-DNA adducts are versatile molecular connectors for the fabrication of both nano-and microstructured protein arrays by use of DNA hybridization. In this study, the hybridization characteristics of six adduct species, each containing a different DNA sequence of 21

  19. Suppression of systemic autoimmunity by the innate immune adaptor STING

    Science.gov (United States)

    Sharma, Shruti; Campbell, Allison M.; Chan, Jennie; Schattgen, Stefan A.; Orlowski, Gregory M.; Nayar, Ribhu; Huyler, Annie H.; Nündel, Kerstin; Mohan, Chandra; Berg, Leslie J.; Shlomchik, Mark J.; Marshak-Rothstein, Ann; Fitzgerald, Katherine A.

    2015-01-01

    Cytosolic DNA-sensing pathways that signal via Stimulator of interferon genes (STING) mediate immunity to pathogens and also promote autoimmune pathology in DNaseII- and DNaseIII-deficient mice. In contrast, we report here that STING potently suppresses inflammation in a model of systemic lupus erythematosus (SLE). Lymphoid hypertrophy, autoantibody production, serum cytokine levels, and other indicators of immune activation were markedly increased in STING-deficient autoimmune-prone mice compared with STING-sufficient littermates. As a result, STING-deficient autoimmune-prone mice had significantly shorter lifespans than controls. Importantly, Toll-like receptor (TLR)-dependent systemic inflammation during 2,6,10,14-tetramethylpentadecane (TMPD)-mediated peritonitis was similarly aggravated in STING-deficient mice. Mechanistically, STING-deficient macrophages failed to express negative regulators of immune activation and thus were hyperresponsive to TLR ligands, producing abnormally high levels of proinflammatory cytokines. This hyperreactivity corresponds to dramatically elevated numbers of inflammatory macrophages and granulocytes in vivo. Collectively these findings reveal an unexpected negative regulatory role for STING, having important implications for STING-directed therapies. PMID:25646421

  20. Role of adaptor proteins in motor regulation and membrane transport

    NARCIS (Netherlands)

    M.A. Schlager (Max)

    2010-01-01

    markdownabstract__Abstract__ Active transport along the cytoskeleton is a process essential for proper cellular function. Although much is known about the motor proteins that generate the necessary force and the cytoskeleton that provides the cellular infrastructure, many questions still

  1. Whole-body vibration improves the anti-inflammatory status in elderly subjects through toll-like receptor 2 and 4 signaling pathways.

    Science.gov (United States)

    Rodriguez-Miguelez, Paula; Fernandez-Gonzalo, Rodrigo; Collado, Pilar S; Almar, Mar; Martinez-Florez, Susana; de Paz, José A; González-Gallego, Javier; Cuevas, María J

    2015-09-01

    Regular physical exercise has anti-inflammatory effects in elderly subjects. Yet, the inflammatory responses after whole body vibration (WBV) training, a popular exercise paradigm for the elderly, remain to be elucidated. This study assessed the effects of WBV training on the inflammatory response associated with toll-like receptors (TLRs) signaling pathways. Twenty-eight subjects were randomized to a training group (TG) or a control group (CG). TG followed an 8-week WBV training program. Blood samples were obtained before and after the training period in both groups. Peripheral blood mononuclear cells were isolated, and mRNA and protein levels of makers involved in the TLR2/TLR4 myeloid differentiation primary response gen 88 (MyD88) and TIR domain-containing adaptor inducing interferon (TRIF)-dependent pathways were analyzed. Plasma TNFα and C-reactive protein levels were also assessed. The WBV program reduced protein expression of TLR2, TLR4, MyD88, p65, TRIF and heat shock protein (HSP) 60, while HSP70 content increased. IL-10 mRNA level and protein concentration were upregulated, and TNFα protein content decreased, after WBV training. Plasma concentration of C-reactive protein and TNFα decreased in the TG. The current data suggest WBV may improve the anti-inflammatory status of elderly subjects through an attenuation of MyD88- and TRIF-dependent TLRs signaling pathways. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  2. HSV-2 increases TLR4-dependent phosphorylated IRFs and IFN-β induction in cervical epithelial cells.

    Directory of Open Access Journals (Sweden)

    Hongya Liu

    Full Text Available Our previous studies demonstrated that HSV-2 infection up-regulates TLR4 expression and induces NF-kB activity, thereby facilitating innate immune response in human cervical epithelial cells. This process requires involvement of TLR4 adaptors, Mal and MyD88. In the current study, we found that HSV-2 infection increases levels of phosphoryalted IRF3 and IRF7, then regulating expression of type I IFN. As expected, these changes induced by HSV-2 infection depended upon TLR4. Knockdown of TRIF and/or TRAM by siRNAs indicated that TRIF/TRAM might be involved in expression of IFN-β. Our results demonstrate for the first time that IRF3 and IRF7 are both involved in inducing TLR4-dependent IFN-β expression in response to HSV-2 in its primary infected genital epithelial cells. Thus, TLR4-Mal/MyD88 and TLR4-TRIF/TRAM signaling may synergize and/or cooperate in innate immune response of cervical epithelial cells to HSV-2 infection.

  3. How sonochemistry contributes to green chemistry?

    Science.gov (United States)

    Chatel, Gregory

    2018-01-01

    Based on the analyses of papers from the literature, and especially those published in Ultrasonics Sonochemistry journal, the contribution of sonochemistry to green chemistry area has been discussed here. Important reminders and insights on the good practices and considerations have been made to understand and demonstrate how sonochemistry can continue to efficiently contribute to green chemistry area in the further studies. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Estimating tourism contribution to Macedonian economy

    OpenAIRE

    Petrevska, Biljana

    2014-01-01

    In the past few years, tourism became an emerging sector in Macedonia. This research intends to investigate and estimate the impact of several factors that may be important in explaining tourism contribution to Macedonian economy. Moreover, this empirical study attempts to discover the relationship and the level of significance of several commonly applied variables representing tourism contribution. In this line, the investigation identifies the impacts of capital investment, foreign tourist ...

  5. Rules regarding voluntary contributions to the Agency

    International Nuclear Information System (INIS)

    2004-01-01

    The texts of the following Rules Regarding Voluntary Contributions to the Agency are reproduced for the information of all Members of the Agency. Rules to Govern the Acceptance of Gifts of Services, Equipment and Facilities - adopted by the Board of Governors on 10 March 2004; Rules Regarding the Acceptance of Voluntary Contributions of Money to the Agency - approved by the General Conference on 21 September 2001 (GC (45)/RES/9)

  6. Factors Contributing to School Bus Crashes

    OpenAIRE

    Yasmin, Shamsunnahar; Anowar, Sabreena; Tay, Richard

    2013-01-01

    School bus safety is a community concern because parents expect their children to be transported to and from school safely. However, relatively few studies have been devoted to examining the factors contributing to school bus crashes. In this study, a logistic regression model is used to delineate the factors that contribute to school bus collisions from collisions involving other types of buses. As expected, we find significant differences in crash factors arising from differences in exposur...

  7. OPTIMAL PORTFOLIOS IN DEFINED CONTRIBUTION PENSION SYSTEMS

    OpenAIRE

    EDUARDO WALKER

    2006-01-01

    We study optimal portfolios for defined contribution (possibly mandatory) pension systems, which maximize expected pensions subject to a risk level. By explicitly considering the present value of future individual contributions and changing the risk-return numeraire to future pension units we obtain interesting insights, consistent with the literature, in a simpler context. Results naturally imply that the local indexed (inflation-adjusted) currency is the benchmark and that the investment ho...

  8. Jakob Nielsen and His Contributions to Topology

    DEFF Research Database (Denmark)

    Hansen, Vagn Lundsgaard

    1999-01-01

    The Danish mathematician Jakob Nielsen won international recognition as one of the developers of combinatorial group theory and the topology of surfaces. This article describes the life and work of Jakob Nielsen with emphasis on his contributions to topology.......The Danish mathematician Jakob Nielsen won international recognition as one of the developers of combinatorial group theory and the topology of surfaces. This article describes the life and work of Jakob Nielsen with emphasis on his contributions to topology....

  9. Genomic contributions in livestock gene introgression programmes

    Directory of Open Access Journals (Sweden)

    Hospital Frédéric

    2005-05-01

    Full Text Available Abstract The composition of the genome after introgression of a marker gene from a donor to a recipient breed was studied using analytical and simulation methods. Theoretical predictions of proportional genomic contributions, including donor linkage drag, from ancestors used at each generation of crossing after an introgression programme agreed closely with simulated results. The obligate drag, the donor genome surrounding the target locus that cannot be removed by subsequent selection, was also studied. It was shown that the number of backcross generations and the length of the chromosome affected proportional genomic contributions to the carrier chromosomes. Population structure had no significant effect on ancestral contributions and linkage drag but it did have an effect on the obligate drag whereby larger offspring groups resulted in smaller obligate drag. The implications for an introgression programme of the number of backcross generations, the population structure and the carrier chromosome length are discussed. The equations derived describing contributions to the genome from individuals from a given generation provide a framework to predict the genomic composition of a population after the introgression of a favourable donor allele. These ancestral contributions can be assigned a value and therefore allow the prediction of genetic lag.

  10. Incentives to Encourage Scientific Web Contribution (Invited)

    Science.gov (United States)

    Antunes, A. K.

    2010-12-01

    We suggest improvements to citation standards and creation of remuneration opportunities to encourage career scientist contributions to Web2.0 and social media science channels. At present, agencies want to accomplish better outreach and engagement with no funding, while scientists sacrifice their personal time to contribute to web and social media sites. Securing active participation by scientists requires career recognition of the value scientists provide to web knowledge bases and to the general public. One primary mechanism to encourage participation is citation standards, which let a contributor improve their reputation in a quantifiable way. But such standards must be recognized by their scientific and workplace communities. Using case studies such as the acceptance of web in the workplace and the growth of open access journals, we examine what agencies and individual can do as well as the time scales needed to secure increased active contribution by scientists. We also discuss ways to jumpstart this process.

  11. Greenhouse effect contributions of US landfill methane

    International Nuclear Information System (INIS)

    Augenstein, D.

    1991-01-01

    The greenhouse effect has recently been receiving a great deal of scientific and popular attention. The term refers to a cause-and-effect relationship in which ''heat blanketing'' of the earth, due to trace gas increases in the atmosphere, is expected to result in global warming. The trace gases are increasing as the result of human activities. Carbon dioxide (CO 2 ) is the trace gas contributing most importantly to the ''heat blanketing'' and currently receives the most attention. Less widely recognized has been the high importance of methane (CH 4 ). Methane's contribution to the increased heat blanketing occurring since 1980 is estimated to be over a third as much as that of carbon dioxide. Gas from landfills has in turn been recognized to be a source of methane to the atmospheric buildup. However the magnitude of the landfill methane contribution, and the overall significance of landfill methane to the greenhouse phenomenon has been uncertain and the subject of some debate. (Author)

  12. Formalized search strategies for human risk contributions

    International Nuclear Information System (INIS)

    Rasmussen, J.; Pedersen, O.M.

    1982-07-01

    For risk management, the results of a probabilistic risk analysis (PRA) as well as the underlying assumptions can be used as references in a closed-loop risk control; and the analyses of operational experiences as a means of feedback. In this context, the need for explicit definition and documentation of the PRA coverage, including the search strategies applied, is discussed and aids are proposed such as plant description in terms of a formal abstraction hierarchy and use of cause-consequence-charts for the documentation of not only the results of PRA but also of its coverage. Typical human risk contributions are described on the basis of general plant design features relevant for risk and accident analysis. With this background, search strategies for human risk contributions are treated: Under the designation ''work analysis'', procedures for the analysis of familiar, well trained, planned tasks are proposed. Strategies for identifying human risk contributions outside this category are outlined. (author)

  13. Contribution to encyclopedia of thermal stresses

    Science.gov (United States)

    Taler, Jan; Ocłoń, Pawel

    2015-06-01

    This paper lists the contribution in the international interdisciplinary reference - Encyclopedia of Thermal Stresses (ETS). The ETS, edited by the world famous expert in field of Thermal Stresses - Professor Richard Hetnarski from Rochester Institute of Technology, was published by Springer in 2014. This unique Encyclopedia, subdivided into 11 volumes is the most extensive and comprehensive work related to the Thermal Stresses topic. The entries were carefully prepared by specialists in the field of thermal stresses, elasticity, heat conduction, optimization among others. The Polish authors' contribution within this work is significant; over 70 entries were prepared by them.

  14. ZEUS contributed papers to CHEP92

    International Nuclear Information System (INIS)

    1992-10-01

    At the Computing in High Energy Physics conference, CHEP92 Annecy 21st - 25th September 1992, the ZEUS data acquisition groups contributed a number of papers, as a result of plenary, parallel and poster session contributions. These papers are appended after the index list and a figure which gives a schematic overview of the acquisition system. The papers give up-to-date information concerning the ZEUS data acquisition system and the experience gained during the first HERA running period in 1992. (orig.)

  15. Jakob Nielsen and his Contributions to Topology

    DEFF Research Database (Denmark)

    Hansen, Vagn Lundsgaard

    1996-01-01

    The Danish mathematician Jakob Nielsen won international recognitionas one of the developers of combinatiorial group theory and the topologyof surfaces. This article describes the life and work of Jakob Nielsenwith emphasis on his contributions to topology.The biography is to be included in the b......The Danish mathematician Jakob Nielsen won international recognitionas one of the developers of combinatiorial group theory and the topologyof surfaces. This article describes the life and work of Jakob Nielsenwith emphasis on his contributions to topology.The biography is to be included...

  16. Formalized Search Strategies for Human Risk Contributions

    DEFF Research Database (Denmark)

    Rasmussen, Jens; Pedersen, O. M.

    and documentation of the PRA coverage, including the search strategies applied, is discussed and aids are proposed such as plant description in terms of a formal abstraction hierarchy and use of cause-consequence-charts for the documentation of not only the results of PRA but also of its coverage. Typical human...... risk contributions are described on the basis of general plant design features relevant for risk and accident analysis. With this background, search strategies for human risk contributions are treated: Under the designation "work analysis", procedures for the analysis of familiar, well trained, planned...

  17. DEDUCTIBILITY OF CONTRIBUTIONS TO VOLUNTARY PRIVATE PENSIONS

    Directory of Open Access Journals (Sweden)

    LILIANA MUNTEAN

    2011-01-01

    Full Text Available The present paper approaches the notion of public and private pension in Romania. Pension can be seen in terms of a replacement income to individuals whose age no longer affords to operate in the labour market. Pension reform in Romania has allowed besides the public pension system, called Pillar I, which is a distributive system based on solidarity between generations also a private pension system that records the contributions of participants in individual accounts, based on capitalization, investment and accumulation of these contributions.

  18. Evidence for ProTα-TLR4/MD-2 binding: molecular dynamics and gravimetric assay studies.

    Science.gov (United States)

    Omotuyi, Olaposi; Matsunaga, Hayato; Ueda, Hiroshi

    2015-01-01

    During preconditioning, lipopolysaccharide (LPS) selectively activates TLR4/MD-2/Toll/IL-1 receptor-domain-containing adaptor inducing IFN-β (TRIF) pathway instead of pro-inflammatory myeloid differentiation protein-88 (MyD88)/MyD88-adaptor-like protein (MAL) pathway. Extracellular prothymosin alpha (ProTα) is also known to selectively activate the TLR4/MD2/TRIF-IRF3 pathway in certain diseased conditions. In the current study, biophysical evidence for ProTα/TLR4/MD-2 complex formation and its interaction dynamics have been studied. Gravimetric assay was used to investigate ProTα/TLR4/MD-2 complex formation while molecular dynamics (MD) simulation was used to study its interaction dynamics. Through electrostatic interaction, full-length ProTα (F-ProTα) C-terminal peptide (aa 91 - 111) superficially interacts with similar TLR4/MD-2 (KD = 273.36 nm vs 16.07 μg/ml [LPS]) conformation with LPS at an overlapping three-dimensional space while F-ProTα is hinged to the TLR4 scaffold by one-amino acid shift-Mosoian domain (aa-51 - 90). Comparatively, F-ProTα better stabilizes MD-2 metastable states transition and mediates higher TLR4/MD-2 interaction than LPS. ProTα via its C-terminal peptide (aa 91 - 111) exhibits in vitro biophysical contact with TLR4/MD-2 complex conformation recognized by LPS at overlapping LPS-binding positions.

  19. Intergenerational Practice: Contributing to a Conceptual Framework

    Science.gov (United States)

    Vieira, Sacha; Sousa, Liliana

    2016-01-01

    The ageing of the European population is creating a new demographic mix, increasing the relevance of intergenerational practice (IGP). To date, however, this field lacks an appropriate conceptual framework. This study aims to contribute to such a framework through an integrative review of peer-reviewed papers reporting on IGPs. Fifteen papers were…

  20. Arab Contributions to Civilization. ADC Issues #6.

    Science.gov (United States)

    Macron, Mary

    This booklet, designed to provide educational materials on Arab history and culture, describes the contributions of Islamic civilization to western civilization. To be Arab, like American, was and is a cultural trait rather than a racial mark. To be Arab meant to be from the Arabic speaking world of common traditions, customs, and values shaped by…

  1. Elements that contribute to healthy building design

    NARCIS (Netherlands)

    Loftness, V.; Hakkinen, B.; Adan, O.; Nevalainen, A.

    2007-01-01

    Background: The elements that contribute to a healthy building are multifactorial and can be discussed from different perspectives. Objectives: We present three viewpoints of designing a healthy building: the importance of sustainable development, the role of occupants for ensuring indoor air

  2. Land science contributions to ecosystem services

    NARCIS (Netherlands)

    Crossman, N.D.; Brett, A.; Bryan, A.; Groot, de R.S.; Lin, Y.P.; Minang, P.A.

    2013-01-01

    We provide an overview of the contribution of land science to improving ecosystem service quantification, valuation and management. We briefly review the impacts of land use and land management change on ecosystem services, the complexity of relationships between the land system and the supply and

  3. Protestant ethic: Contributing towards a meaningful workplace ...

    African Journals Online (AJOL)

    ... the Protestant ethic can indeed contribute towards a meaningful experience whilst performing work-related tasks in workspace. The Protestant work ethic is more than a cultural norm that places a positive moral value on doing a good job. Based on a belief that work has intrinsic value for its own sake, it represents a value ...

  4. Mapping Academic Library Contributions to Campus Internationalization

    Science.gov (United States)

    Witt, Steven W.; Kutner, Laurie; Cooper, Liz

    2015-01-01

    This study surveyed academic libraries across the United States to establish baseline data on their contributions to campus internationalization. Supplementing data from the American Council on Education (ACE) on internationalization of higher education, this research measured the level of international activities taking place in academic…

  5. ENERGY SYSTEM CONTRIBUTIONS DURING INCREMENTAL EXERCISE TEST

    Directory of Open Access Journals (Sweden)

    Rômulo Bertuzzi

    2013-09-01

    Full Text Available The main purpose of this study was to determine the relative contributions of the aerobic and glycolytic systems during an incremental exercise test (IET. Ten male recreational long-distance runners performed an IET consisting of three-minute incremental stages on a treadmill. The fractions of the contributions of the aerobic and glycolytic systems were calculated for each stage based on the oxygen uptake and the oxygen energy equivalents derived by blood lactate accumulation, respectively. Total metabolic demand (WTOTAL was considered as the sum of these two energy systems. The aerobic (WAER and glycolytic (WGLYCOL system contributions were expressed as a percentage of the WTOTAL. The results indicated that WAER (86-95% was significantly higher than WGLYCOL (5-14% throughout the IET (p < 0.05. In addition, there was no evidence of the sudden increase in WGLYCOL that has been previously reported to support to the "anaerobic threshold" concept. These data suggest that the aerobic metabolism is predominant throughout the IET and that energy system contributions undergo a slow transition from low to high intensity

  6. 215 ECONOMIC CONTRIBUTION OF CASSAVA PRODUCTION (A ...

    African Journals Online (AJOL)

    DR. AMINU

    2010-06-01

    Jun 1, 2010 ... ECONOMIC CONTRIBUTION OF CASSAVA PRODUCTION (A CASE STUDY OF. KUJE AREA COUNCIL FEDERAL ... transportation were found to be affecting cassava production in the area. It was recommended ... of the Federal Government policy on cassava production for both local and international.

  7. Contributions to Analytic Number Theory | Lucht | Quaestiones ...

    African Journals Online (AJOL)

    This paper reports on some recent contributions to the theory of multiplicative arithmetic semigroups, which have been initiated by John Knopfmacher's work on analytic number theory. They concern weighted inversion theorems of the. Wiener type, mean-value theorems for multiplicative functions, and, Ramanujan

  8. Work-related Musculoskeletal Disorders: Prevalence, contributing ...

    African Journals Online (AJOL)

    The majority of the participants indicated that the following work factors contributed to WRMDs: treating a large number of patients per day (97.5%), repeatedly performing the same task (94.9%), performing manual therapy techniques (93.2%), working in the same position for long periods (92.1%), and lifting and transferring ...

  9. Neutron contribution to nuclear DVCS asymmetries

    Energy Technology Data Exchange (ETDEWEB)

    Vadim Guzey

    2008-01-22

    Using a simple model for nuclear GPDs, we study the role of the neutron contribution to nuclear DVCS observables. As an example, we use the beam-spin asymmetry $A_{LU}^A$ measured in coherent and incoherent DVCS on a wide range of nuclear targets in the HERMES and JLab kinematics. We find that at small values of the momentum transfer $t$, $A_{LU}^A$ is dominated by the coherent-enriched contribution, which enhances $A_{LU}^A$ compared to the free proton asymmetry $A_{LU}^p$, $A_{LU}^A(\\phi)/A_{LU}^p(\\phi)=1.8-2.2$. At large values of $t$, the nuclear asymmetry is dominated by the incoherent contribution and $A_{LU}^A/(\\phi)A_{LU}^p(\\phi)=0.66-0.74$. The deviation of $A_{LU}^A(\\phi)/A_{LU}^p(\\phi)$ from unity at large $t$ is a result of the neutron contribution, which gives a possibility to constain neutron GPDs in incoherent nuclear DVCS. A similar trend is expected for other DVCS asymmetries.

  10. contributions to a physiotherapy HIV curriculum

    African Journals Online (AJOL)

    2013-11-04

    Nov 4, 2013 ... 2 AJHPE. Micro, meso and macro issues emerging from focus group discussions: Contributions to a physiotherapy HIV curriculum. H Myezwa,1 PhD; A Stewart,1 PhD; P Solomon,2 PhD. 1 Department of Physiotherapy, Faculty of Health Sciences,University of the Witwatersrand, Johannesburg, South Africa.

  11. Do School Lunches Contribute to Childhood Obesity?

    Science.gov (United States)

    Schanzenbach, Diane Whitmore

    2009-01-01

    This paper assesses whether school lunches contribute to childhood obesity. I employ two methods to isolate the causal impact of school lunches on obesity. First, using panel data, I ?nd that children who consume school lunches are more likely to be obese than those who brown bag their lunches even though they enter kindergarten with the same…

  12. Health Care Workers Contribution to Missed Immunization ...

    African Journals Online (AJOL)

    This study was aimed at identifying the health workers' knowledge and inappropriate practices that potentially contribute to missed immunization opportunities in children. A cross-sectional survey was conducted in August 2007 among Primary Health Care workers in Khana Local Government Area of Rivers State, Nigeria ...

  13. Resource Contributions, Gender Orientation, and Childbearing ...

    African Journals Online (AJOL)

    Resource Contributions, Gender Orientation, and Childbearing Decision Making in Ghana; The case of Urban Couples. Akosua Adomako Ampofo. Full Text: EMAIL FULL TEXT EMAIL FULL TEXT · DOWNLOAD FULL TEXT DOWNLOAD FULL TEXT · http://dx.doi.org/10.4314/rrias.v15i2.22886 · AJOL African Journals Online.

  14. Neuromuscular contributions to age-related weakness

    Science.gov (United States)

    Age-related physiological change of neuromuscular function is not a linear process and is likely influenced by various biological and behavioral factors (e.g., genetics, nutrition, physical activity level, comorbidities, etc.). These factors contribute to heterogeneity among older adults, which chal...

  15. Nutrient composition and contribution of plantain ( Musa ...

    African Journals Online (AJOL)

    Some plantain (Musa paradisiacea) products, which serve as dietary staple in Nigeria were studied for their nutrient composition and contribution to dietary diversification of consumers. Unripe plantain was purchased from Oje market in Ibadan, Nigeria. Proximate, mineral and vitamin composition of raw, sundried, ...

  16. Mathematical Contributions of Archimedes: Some Nuggets

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 11; Issue 10. Mathematical Contributions of Archimedes: Some Nuggets. C S Yogananda. General Article Volume 11 Issue 10 October 2006 pp 8-17. Fulltext. Click here to view fulltext PDF. Permanent link:

  17. The Manchester contribution to peritoneal dialysis

    NARCIS (Netherlands)

    Krediet, Raymond T.

    2011-01-01

    Two names emerge when considering the contribution of Manchester in the development of peritoneal dialysis (PD). The first is Ram Gokal; the second is icodextrin. As there will be a separate article on icodextrin, this one will focus more on other aspects of the activities performed by the Renal

  18. Perceived Contribution of Agricultural Transformation Agenda to ...

    African Journals Online (AJOL)

    USER

    through ATA would enhance participation. Keyword: Perception of ATA, contribution of ATA, farm families. Introduction. The Agricultural Transformation Agenda (ATA) was designed to achieve a hunger-free Nigeria through an agricultural sector that drives income growth, accelerates achievement of food and nutrition ...

  19. Mode Contributions to the Casimir Effect

    Science.gov (United States)

    Intravaia, F.; Henkel, C.

    2010-04-01

    Applying a sum-over-modes approach to the Casimir interaction between two plates with finite conductivity, we isolate and study the contributions of surface plasmons and Foucault (eddy current) modes. We show in particular that for the TE-polarization eddy currents provide a repulsive force that cancels, at high temperatures, the Casimir free energy calculated with the plasma model.

  20. Can Inferentialism Contribute to Social Epistemology?

    Science.gov (United States)

    Derry, Jan

    2013-01-01

    This article argues that Robert Brandom's work can be used to develop ideas in the area of social epistemology. It suggests that this work, precisely because it was influenced by Hegel, can make a significant contribution with philosophical anthropology at its centre. The argument is developed using illustrations from education: the first, from…

  1. AACSB Standards and Accounting Faculty's Intellectual Contributions

    Science.gov (United States)

    Lee, B. Brian; Quddus, Munir

    2008-01-01

    The authors performed a content analysis of intellectual contribution portfolios of accounting faculty at various business schools that Association to Advance Collegiate Schools of Business International recently accredited. The results showed a significant divergence in faculty research (e.g., areas, topics) and their teaching assignments. This…

  2. 13 CFR 120.911 - Land contributions.

    Science.gov (United States)

    2010-01-01

    ... 13 Business Credit and Assistance 1 2010-01-01 2010-01-01 false Land contributions. 120.911 Section 120.911 Business Credit and Assistance SMALL BUSINESS ADMINISTRATION BUSINESS LOANS Development... Project Property) previously acquired by the Borrower. [68 FR 57987, Oct. 7, 2003] ...

  3. Gender Differences among Contributing Leadership Development Resources

    Science.gov (United States)

    Thompson, Michael D.

    2012-01-01

    Gender differences among contributing student leadership development resources were examined within the context of theory-based perspectives of leadership-related attributes. The findings suggest that students' increased engagement with institutional constituencies cultivates an environment conducive to students' cognitive development toward…

  4. Our contributions to the study of carbonatites

    Indian Academy of Sciences (India)

    First page Back Continue Last page Overview Graphics. Our contributions to the study of carbonatites. Carbonatite magmatism in flood basalt provinces has important implications. Liquid immiscibility is responsible for evolution of carbonate and silicate parental magmas. Crustal contamination of the primary magma is ...

  5. Contributions of Psychology to Limiting Climate Change

    Science.gov (United States)

    Stern, Paul C.

    2011-01-01

    Psychology can make a significant contribution to limiting the magnitude of climate change by improving understanding of human behaviors that drive climate change and human reactions to climate-related technologies and policies, and by turning that understanding into effective interventions. This article develops a framework for psychological…

  6. Contribution of Bilingualism in Language Teaching

    Science.gov (United States)

    Sipra, Muhammad Aslam

    2013-01-01

    This study is an investigation into the contribution of the use of bilingualism as an aid in learning/teaching English as a foreign language and bilingualism in EFL classroom does not reduce students' communicative abilities but in effect can assist in teaching and learning process. The study employed a qualitative, interpretive research design…

  7. In the suppression of regge cut contributions

    International Nuclear Information System (INIS)

    Chia, S.P.

    1975-07-01

    It is shown that contributions of reggeon-pomeron cuts are suppressed in amplitudes with opposite natural to the reggeon. This suppression grows logarithmically with energy. The suppression in the πP cut is, however, found to be weak. Consequence on conspiracy is discussed

  8. Instanton contributions in reggeon quantum mechanics

    International Nuclear Information System (INIS)

    Ciafaloni, M.

    1978-01-01

    The full semiclassical approximation to reggeon field theory without transverse dimensions is derived. By using Polyakov's method in Lagrangian form and paying due attention to the quantum terms of the potential it is shown that instanton contributions are able to explain the tunnel-like energy gap for α(0)-1>>lambda. (Auth.)

  9. The economic contribution of tourism in Mozambique

    DEFF Research Database (Denmark)

    Jones, Edward Samuel

    2010-01-01

    How much tourism contributes to the economies of developing countries is controversial and often not measured rigorously. Focusing on Mozambique, this study presents a simple accounting tool – a tourist-focused Social Accounting Matrix – which makes it possible to estimate the economic contributi...... are already evident and careful attention must be paid to the full tourism value chain....

  10. Exploring the contribution of Klippies Kritzinger

    African Journals Online (AJOL)

    2016-05-30

    May 30, 2016 ... This article explores the contribution of Klippies Kritzinger, a South African missiologist and theologian, to a white critical and anti-racist theology. As will be pointed out below, this emphasis has been central to Kritzinger's academic work since his doctoral studies (completed in 1988) but has not been ...

  11. The value contribution of strategic foresight

    DEFF Research Database (Denmark)

    Rohrbeck, René; Schwarz, Jan Oliver

    2013-01-01

    This paper focuses on exploring the potential and empirically observable value creation of strategic foresight activities in firms. We first review the literature on strategic foresight, innovation management and strategic management in order to identify the potential value contributions. We use ...

  12. CONTRIBUTIONS TO THE BIOLOGY OF THE PANGA ...

    African Journals Online (AJOL)

    CONTRIBUTIONS TO THE BIOLOGY OF THE PANGA, PTEROGYMNUS. LA NIARIUS (PISCES: SPARIDAE): AGE, GROWTH AND REPRODUCTION. T HECHT AND D BAIRD. Department of Zoology, University of Port Elizabeth. Accepted: April 1977. ABSTRACT. All the fish used in this investigation were caught by ...

  13. Employer involvement in defined contribution investment education.

    Science.gov (United States)

    Blau, G; VanDerhei, J L

    2000-01-01

    In this paper the authors consider the personnel problems that may arise for defined contribution plan sponsors if major market corrections cause older employees to delay retirement beyond previous expectations. We move from that basic premise to argue that, given the continued evolution from defined benefit (DB) to defined contribution (DC) retirement plans, employers need to be more "proactive" in educating their employees about their retirement planning. A human resources perspective is used to support this argument, apart from and in addition to legal considerations such as ERISA Section 404(c). Specifics of employer involvement and its place as a component of an organization's culture are discussed. Finally, recommendations are given for employers to consider.

  14. Contributions of Public Health to nursing practice

    Directory of Open Access Journals (Sweden)

    Káren Mendes Jorge de Souza

    Full Text Available ABSTRACT Objective: Analyze the perceptions of undergraduate nursing students about the contributions of public health to nursing practice in the Unified Health System. Method: Qualitative Descriptive Study. Data collection was carried out through semi-directed interviews with 15 students. The language material was analyzed according to content and thematic analysis. Results: Thematic categories were established, namely: "Perceptions about Public Health" and "Contribution of Public Health to nursing practice in the Unified Health System". Final considerations: Perceptions about Public Health are diversified, but converge to the recognition of this field as the basis for training nurses qualified to work in the SUS with technical competence, autonomy and focusing on the integrality in health care.

  15. CONTRIBUTING FACTORS TO THE STUDENTS’ SPEAKING ABILITY

    Directory of Open Access Journals (Sweden)

    Irwan

    2017-09-01

    Full Text Available The use of English in Indonesia has developed quickly in all of the fields. It is affected by many things in many ways. The need of English has also increased quickly in many parts of Indonesian life. To face it, teaching English at young ages or studentseems like the solution. Speaking is one of the skills that should be tough to the student. To get effective learning, it's useful to know what are factors contributing to the student speaking development. This research showed that there are some contributing factors to the students’ speaking development. Those factors are Teacher, Daily Practice, Listening to English Music, Family Support, Watching English Video and Movie, Motivation to Learn, Classroom Environment, Learning Material. Such as a good teacher would provide good learning. Support of the family would also give an effective outcome for the student's development. So, the factors should be known to get a better outcome for the students

  16. Contribution to Numerical Simulation of Laser Welding

    Science.gov (United States)

    Turňa, Milan; Taraba, Bohumil; Ambrož, Petr; Sahul, Miroslav

    Contribution deals with numerical simulation of thermal and stress fields in welding tubes made of austenitic stainless CrNi steel type AISI 304 with a pulsed Nd:YAG laser. Process simulation was realised by use of ANSYS 10 software. Experiments were aimed at solution of asymptotic, standard and the so-called shell model. Thermally dependent properties of AISI 304 steel were considered. Thermal fields developed in the course of welding process and also shape of weld pool were assessed. Contribution is aimed at simulation of technological welding process with input parameters regarding the thermal and strain task and comparison of attained results with real experiment. The achieved results of numerical simulation were almost identical with a real weldment thermally affected by welding process.

  17. Forgotten intrauterine device contributing to infertility

    Directory of Open Access Journals (Sweden)

    Gabriel O. Igberase

    2011-10-01

    Full Text Available The aim of the study is to show that long standing forgotten intrauterine device contributes to infertility, reporting three cases presented at Central Hospital Warri, Nigeria, a government tertiary health center. Three cases of forgotten intrauterine contraceptive device (IUCD contributing to infertility were seen. Two were inserted for contraceptive reasons while one was inserted while being managed for uterine synechae. Health care providers should ensure proper documentation of all procedures carried out, adequate counseling which should include taking an informed consent and also ensuring both short and long term follow up of their clients. Also all patients being evaluated for infertility and clients with past history of intrauterine device must have a speculum examination and ultrasound scan carried out.

  18. Some feminist contributions to community social psychology

    Directory of Open Access Journals (Sweden)

    Claudia Mayorga

    2014-02-01

    Full Text Available This article analyzes the contributions of feminist debate about intersectionality of social categories for Community Social Psychology in Brazil. This was set up as dedicated to theoretical analyze the social inequalities that characterize contemporary societies and propose methodological processes of intervention for questioning and processing of these realities. We discuss how the emergence of new actors and demands on public space, as distinct from the 60/70, is required to understand the oppression from various power systems such as gender, race and sexuality. We conclude that intersectional analysis should consider different levels of relationships between categories, the history of the same differential and common aspects of different systems of power as naturalization of inequality, the relationship between public and private relationship between equality and difference. Analyses based on intersectionality can contribute to processes of social intervention that considers the complexity of contemporary societies.

  19. Making a meaningful contribution to theory

    DEFF Research Database (Denmark)

    Boer, Harry; Holweg, Matthias; Kilduff, Martin

    2015-01-01

    matters. The authors further argue that the choice of theory is critical, as a common mistake is trying to contribute to high-level theories borrowed from other fields. Finally, the authors recommend using theory parsimoniously, yet with confidence. Originality/value – The paper presents a collection...... discussed in the “OM Theory” workshop in Dublin in 2011 and the special sessions at the 2011 and the 2013 EurOMA Conferences in Cambridge and Dublin. Design/methodology/approach – This paper presents six short essays that explore the role and use of theory in management research, and specifically ask what...... is a good or meaningful contribution to theory. The authors comment on the current state of theory in OperationsManagement (OM) (Harry Boer), the type of theories the authors have in OM (Chris Voss), the role of theory in increasing the general understanding of OM problems (Roger Schmenner), whether...

  20. General relativistic contributions in transformation optics

    International Nuclear Information System (INIS)

    Thompson, Robert T

    2012-01-01

    One potentially realistic specification for devices designed with transformation optics is that they operate with high precision in curved space–time, such as Earth orbit. This raises the question of what, if any, role does space–time curvature play in determining transformation media? Transformation optics has been based on a 3-vector representation of Maxwell's equations in flat Minkowski space–time. I discuss a completely covariant, manifestly four-dimensional approach that enables transformations in arbitrary space–times, and demonstrate this approach for stable circular orbits in the spherically symmetric Schwarzschild geometry. Finally, I estimate the magnitude of curvature induced contributions to satellite-borne transformation media in Earth orbit and comment on the level of precision required for metamaterial fabrication before such contributions become important

  1. Japan's yen contribution to UNFPA unchanged.

    Science.gov (United States)

    1998-02-01

    As a result of the Japanese government's cabinet decision to cut Japan's total official development assistance (ODA) budget by 10%, the UNFPA expected to receive less financial support from Japan for 1998. In 1997, Japan provided 18% of UNFPA's budget. However, despite the government's announcement that the 10% cut would be applied across the board without exception, the Japanese government announced on December 24 that its yen contribution to UNFPA in 1998 will stay at its 1997 level. This decision was announced following top-level negotiations with the prime minister involving the Ministry of Foreign Affairs (MOFA) and the Ministry of Finance, and reflects the success of a major advocacy effort both inside and outside of Japan. In yen, the budgets of neither the UNFPA, UNICEF, nor UNHCR were reduced. However, in real terms, Japan will contribute fewer US dollars to UNFPA due to the depreciation of the yen.

  2. Contributions of Literature to Social Psychology

    Directory of Open Access Journals (Sweden)

    Anastasio Ovejero

    2012-11-01

    Full Text Available There are two main kind of psychology: a intuitive psychology, and an academic and professional psychology. These two psychologies are different, but they can make important reciprocals contributions. And the best of the intuitive psychology, that in my opinion is in the literature and overall in the romance, can be very useful for professional psychologists. The main end of this paper is to show how the social psychologists can learn from the intuitive psychology of the great romances. This contribution of the romance to the social psychology is, at least, at these two levels. At the level of construction of the subjectivity and the modern subject and the, therefore, of the psychology’s arise, and at the level of some concrete subjects studied by the psychologists (romantic love, jealousy, infidelity, compunction, emotions, vengeance, human relations…

  3. The Contribution of Festivals to City Branding

    OpenAIRE

    Lim, H.

    2016-01-01

    The economic contribution of festivals and events has been widely acknowledged, but the relationship between a festival and city branding has received little attention. This thesis explores the role of festival stakeholders in the development of a city brand, providing a detailed account of city branding and festival sponsorship. The research focuses particular attention on cultural festivals by examining their role in the city branding process. To this end, one city (Seoul) and two festivals...

  4. MR contribution in surgery of epilepsy

    International Nuclear Information System (INIS)

    Meiners, L.C.; Valk, J.; Jansen, G.H.; Veelen, C.W.M. van

    1999-01-01

    The contribution of MR imaging in patients with drug-resistant epilepsy considered for surgical therapy is discussed. In this review we focus on: (a) focal abnormalities (mesial temporal sclerosis, focal migration disorders, hamartomatous lesions and low-grade tumours, phakomatosis and vascular malformations) associated with therapy-resistant partial epilepsy, requiring resective surgery; (b) abnormalities leading to generalized seizures that require more drastic surgical procedures, such as callosotomy and functional hemispherectomy; and (c) localisation of implanted depth-electrodes. (orig.)

  5. Contributing to Peace, Health and Prosperity

    International Nuclear Information System (INIS)

    Amano, Yukiya

    2013-01-01

    This issue of the IAEA Bulletin edition considers the ideas and innovations that led to the IAEA’s formation and influenced its evolution. In this issue of the IAEA Bulletin, you will learn more about how countries use nuclear technology to improve health and prosperity and protect the environment through the technical cooperation programme. Together, the Member States and the IAEA are making a lasting contribution to achieving the Millennium Development Goals that challenge us to significantly reduce hunger, poverty and disease

  6. Who Contributes to the Knowledge Sharing Economy?

    OpenAIRE

    Ramachandran, Arthi; Chaintreau, Augustin

    2015-01-01

    Information sharing dynamics of social networks rely on a small set of influencers to effectively reach a large audience. Our recent results and observations demonstrate that the shape and identity of this elite, especially those contributing \\emph{original} content, is difficult to predict. Information acquisition is often cited as an example of a public good. However, this emerging and powerful theory has yet to provably offer qualitative insights on how specialization of users into active ...

  7. Assessing ambition of nationally determined contributions

    International Nuclear Information System (INIS)

    Höhne, Niklas

    2015-01-01

    A key for a successful new international climate agreement by December 2015 will be the collective assessment of ambition of individual proposals by countries on how and how much to reduce their greenhouse gas emissions. We conclude that there is nothing right or wrong in choosing one or several of these approaches to assess the level of ambition of contributions. An approach using several of many methods described can take into account the difference in national circumstances.

  8. THE CONTEXTUAL CONTRIBUTION TO INDIVIDUAL HEALTH.

    OpenAIRE

    GIANNANTONI, PATRIZIA

    2013-01-01

    Background Many Countries consider health as a fundamental right for their citizens. In terms of health policy, this means equal opportunity of prevention and access to care guaranteed to all. Thus, a major concern in research has been given to health inequalities and their determinants. A body of evidence has shown that individual characteristics primary affect health, however contextual factors also substantially contribute to the final perception of health and/or mediate the effect of t...

  9. Occipito-temporal contributions to reading

    OpenAIRE

    Kawabata Duncan, K. J.

    2010-01-01

    The debate regarding the role of ventral occipito-temporal cortex (vOTC) in visual word recognition arises in part from difficulty delineating the functional contributions of vOTC as separate from other areas of the reading network. Successful transcranial magnetic stimulation (TMS) of the area could provide a novel source of information regarding the area’s function, by offering the possibility of temporarily, non-invasively perturbing its information processing and assessing the consequence...

  10. Contribution to Asterisk Open Source Project

    OpenAIRE

    González Martín, Sergio

    2009-01-01

    With this final master thesis we are going to contribute to the Asterisk open source project. Asterisk is an open source project that started with the main objective of develop an IP telephony platform, completely based on Software (so not hardware dependent) and under an open license like GPL. This project was started on 1999 by the software engineer Mark Spencer at Digium. The main motivation of that open source project was that the telecommunications sector is lack of open solutions, and m...

  11. Human Resource Development's Contribution to Continuous Improvement

    DEFF Research Database (Denmark)

    Jørgensen, Frances; Hyland, Paul

    2007-01-01

    Continuous Improvement (CI) is an approach to organizational change that requires active involvement of skilled and motivated employees, which implies an important role for HRD practitioners. The findings from a literature review and a survey of 168 Danish manufacturing companies indicate however...... that HRD is rarely integrated with CI. The paper contributes by offering a model that depicts how HR and HRD functions could be exploited to support successful CI development and implementation....

  12. Gluonic contributions in the chiral hyperbag

    International Nuclear Information System (INIS)

    Park, B.Y.; Vento, V.; Valencia Univ./CSIC, Valencia

    1990-01-01

    We incorporate into a non-perturbative chiral bag model scheme the gluons and the η' in a perturbative fashion. We analyze in this context the proton matrix element for the flavor singlet axial current, where due account is taken of the anomaly, and the delta-nucleon mass difference. Our results show that the contribution due to the gluons is significant for large bag radii and that they are crucial in order to establish the Cheshire cat principle. (orig.)

  13. [Epilepsy with normal CT: the MR contribution].

    Science.gov (United States)

    Garcia Asensio, S; Guelbenzu, S; Barrena, R; López del Val, J; Mazas, L; Macho, J

    1995-01-01

    We present a study of 165 patients with fits with normal brain computerized tomography (CT) scan or else who showed no evidence as to the etiology of such attacks. We analyzed the magnetic resonance (MR) results obtained. In 36.6% of cases MR was pathological, the most frequent finding in our series being cerebral atrophy (12.8%). We comment on the most important pathology groups, highlighting the contribution MR made in our patients.

  14. CONTRIBUTION OF CULTURAL TOURISM ON TURKISH ECONOMY

    OpenAIRE

    Demet ÇAK; Þeref BOZOKLU; Faruk ALAEDDÝNOÐLU; Murat ÇAK

    2015-01-01

    The positive effects of Turkey’s tourism sector on the economy are increasing with each passing day. To increase tourism revenues that have a positive contribution on Turkey’s current account balance year by year, have a great importance. Therefore, the diversification of tourism types and expansion of deseasonalized cultural tourism applications are necessary. For such purposes within this work, cultural tourism has been introduced by mentioning about the place of the tourism in the economy....

  15. Contributions of psychology to war and peace.

    Science.gov (United States)

    Christie, Daniel J; Montiel, Cristina J

    2013-10-01

    The contributions of American psychologists to war have been substantial and responsive to changes in U.S. national security threats and interests for nearly 100 years. These contributions are identified and discussed for four periods of armed conflict: World Wars I and II, the Cold War, and the Global War on Terror. In contrast, about 50 years ago, largely in reaction to the threat of nuclear war, some psychologists in the United States and around the world broke with the tradition of supporting war and began focusing their scholarship and activism on the prevention of war and promotion of peace. Today, peace psychology is a vibrant area of psychology, with theory and practice aimed at understanding, preventing, and mitigating both episodes of organized violence and the pernicious worldwide problem of structural violence. The growth, scope, and content of peace psychology are reviewed along with contributions to policies that promote peace, social justice, and human well-being. PsycINFO Database Record (c) 2013 APA, all rights reserved

  16. Health Care Ergonomics: Contributions of Thomas Waters.

    Science.gov (United States)

    Poole Wilson, Tiffany; Davis, Kermit G

    2016-08-01

    The aim of this study was to assess the contributions of Thomas Waters's work in the field of health care ergonomics and beyond. Waters's research of safe patient handling with a focus on reducing musculoskeletal disorders (MSDs) in health care workers contributed to current studies and prevention strategies. He worked with several groups to share his research and assist in developing safe patient handling guidelines and curriculum for nursing students and health care workers. The citations of articles that were published by Waters in health care ergonomics were evaluated for quality and themes of conclusions. Quality was assessed using the Mixed Methods Appraisal Tool and centrality to original research rating. Themes were documented by the type of population the citing articles were investigating. In total, 266 articles that referenced the top seven cited articles were evaluated. More than 95% of them were rated either medium or high quality. The important themes of these citing articles were as follows: (a) Safe patient handling is effective in reducing MSDs in health care workers. (b) Shift work has negative impact on nurses. (c) There is no safe way to manually lift a patient. (d) Nurse curriculums should contain safe patient handling. The research of Waters has contributed significantly to the health care ergonomics and beyond. His work, in combination with other pioneers in the field, has generated multiple initiatives, such as a standard safe patient-handling curriculum and safe patient-handling programs. © 2016, Human Factors and Ergonomics Society.

  17. U.S. Contributions to ITER

    International Nuclear Information System (INIS)

    Sauthoff, Ned R.

    2005-01-01

    The United States participates in the ITER project and program to enable the study of the science and technology of burning plasmas, a key programmatic element missing from the world fusion program. The 2003 U.S. decision to enter the ITER negotiations followed an extensive series of community and governmental reviews of the benefits, readiness, and approaches to the study of burning plasmas. This paper describes both the technical and the organizational preparations and plans for U.S. participation in the ITER construction activity: in-kind contributions, staff contributions, and cash contributions as well as supporting physics and technology research. Near-term technical activities focus on the completion of R and D and design and mitigation of risks in the areas of the central solenoid magnet, shield/blanket, diagnostics, ion cyclotron system, electron cyclotron system, pellet fueling system, vacuum system, tritium processing system, and conventional systems. Outside the project, the U .S. is engaged in preparations for the test blanket module program. Organizational activities focus on preparations of the project management arrangements to maximize the overall success of the ITER Project; elements include refinement of U.S. directions on the international arrangements, the establishment of the U.S. Domestic Agency, progress along the path of the U.S. Department of Energy's Project Management Order, and overall preparations for commencement of the fabrication of major items of equipment and for provision of staff and cash as specified in the upcoming ITER agreement

  18. CODE's contribution to the IGS MGEX

    Science.gov (United States)

    Prange, Lars; Dach, Rolf; Lutz, Simon; Schaer, Stefan; Jäggi, Adrian

    2014-05-01

    The Center for Orbit Determination in Europe (CODE) is contributing as a global analysis center to the International GNSS Service (IGS) since many years. The processing of GPS and GLONASS data is well established in CODE's ultra-rapid, rapid, and final product lines. Since 2012 CODE contributes to the "Multi GNSS EXperiment" (MGEX), launched by the IGS as a testbed for the incorporation of new GNSS and their signals into the existing IGS processing chains and software packages. The focus of CODE's MGEX activities was on Galileo so far. Comparisons with other groups results proved the quality of CODE's Galileo orbit (based on a 3-day long-arc solution) and clock products. The MGEX processing at CODE is currently extended to the BeiDou system, which will result in a fully consistent quadruple-system solution including GPS, GLONASS, Galileo, and BeiDou. We present the latest status of the CODE MGEX processing. The quality of the orbit and clock solutions will be evaluated. The characteristics and the impact of the contributing GNSS on the products will be assessed. The CODE MGEX orbit and clock products are publicly available in the IGS MGEX products directory at the CDDIS data center: ftp://cddis.gsfc.nasa.gov/gnss/products/mgex (the solution ID "com" stands for CODE-MGEX).

  19. Active and passive contributions to spatial learning.

    Science.gov (United States)

    Chrastil, Elizabeth R; Warren, William H

    2012-02-01

    It seems intuitively obvious that active exploration of a new environment will lead to better spatial learning than will passive exposure. However, the literature on this issue is decidedly mixed-in part, because the concept itself is not well defined. We identify five potential components of active spatial learning and review the evidence regarding their role in the acquisition of landmark, route, and survey knowledge. We find that (1) idiothetic information in walking contributes to metric survey knowledge, (2) there is little evidence as yet that decision making during exploration contributes to route or survey knowledge, (3) attention to place-action associations and relevant spatial relations contributes to route and survey knowledge, although landmarks and boundaries appear to be learned without effort, (4) route and survey information are differentially encoded in subunits of working memory, and (5) there is preliminary evidence that mental manipulation of such properties facilitates spatial learning. Idiothetic information appears to be necessary to reveal the influence of attention and, possibly, decision making in survey learning, which may explain the mixed results in desktop virtual reality. Thus, there is indeed an active advantage in spatial learning, which manifests itself in the task-dependent acquisition of route and survey knowledge.

  20. Group Contribution Methods for Phase Equilibrium Calculations.

    Science.gov (United States)

    Gmehling, Jürgen; Constantinescu, Dana; Schmid, Bastian

    2015-01-01

    The development and design of chemical processes are carried out by solving the balance equations of a mathematical model for sections of or the whole chemical plant with the help of process simulators. For process simulation, besides kinetic data for the chemical reaction, various pure component and mixture properties are required. Because of the great importance of separation processes for a chemical plant in particular, a reliable knowledge of the phase equilibrium behavior is required. The phase equilibrium behavior can be calculated with the help of modern equations of state or g(E)-models using only binary parameters. But unfortunately, only a very small part of the experimental data for fitting the required binary model parameters is available, so very often these models cannot be applied directly. To solve this problem, powerful predictive thermodynamic models have been developed. Group contribution methods allow the prediction of the required phase equilibrium data using only a limited number of group interaction parameters. A prerequisite for fitting the required group interaction parameters is a comprehensive database. That is why for the development of powerful group contribution methods almost all published pure component properties, phase equilibrium data, excess properties, etc., were stored in computerized form in the Dortmund Data Bank. In this review, the present status, weaknesses, advantages and disadvantages, possible applications, and typical results of the different group contribution methods for the calculation of phase equilibria are presented.

  1. Understanding the CDM's contribution to technology transfer

    International Nuclear Information System (INIS)

    Schneider, Malte; Holzer, Andreas; Hoffmann, Volker H.

    2008-01-01

    Developing countries are increasingly contributing to global greenhouse gas emissions and, consequently, climate change as a result of their rapid economic growth. In order to reduce their impact, the private sector needs to be engaged in the transfer of low-carbon technology to those countries. The Clean Development Mechanism (CDM) is currently the only market mechanism aimed at triggering changes in the pattern of emissions-intensive activities in developing countries and is likely to play a role in future negotiations. In this paper, we analyse how the CDM contributes to technology transfer. We first develop a framework from the literature that delineates the main factors which characterise technology transfer. Second, we apply this framework to the CDM by assessing existing empirical studies and drawing on additional expert interviews. We find that the CDM does contribute to technology transfer by lowering several technology-transfer barriers and by raising the transfer quality. On the basis of this analysis, we give preliminary policy recommendations

  2. Perturbative QCD contributions to inclusive processes

    Energy Technology Data Exchange (ETDEWEB)

    Ritbergen, T. van

    1996-09-24

    This thesis treats the calculation of quantum corrections to a number of high energy processes that are measured in current and future accelerator experiments. The main objective of these experiments is to accurately verify the generally accepted theory of electro-weak and strong interactions, known as the Standard model, and to look for possible deviations. Most of the processes that are treated in this thesis are of a type for which the final state of of a highly energetic scattering or decay process is measured inclusively. The higher order quantum corrections discussed in this thesis are due to strong interactions. To the inclusive decay rate of Z{sup 0} bosons into all possible final states consisting of hadrons third order QCD contributions have been obtained. Also in the third order QCD an expansion for the inclusive hadronic decay rate of a {tau}-lepton was obtained. Then the top-quark-mass effects on the decay channels of a Higgs boson: Higgs{yields}b-quarks and Higgs{yields}gluons, were investigated. Thereafter the calculation of 3-loop contributions to the deep-inelastic lepton-nucleon scattering process is discussed. Finally the 3-loop contributions to the q{sup 2}-dependence of the lower moments {integral}{sub 0}{sup 1}x{sup N-1}F(x,q{sup 2})dx, N=2,4,6,8 of the structure functions F{sub 2} and F{sub L} were obtained. (orig./HSI).

  3. Knowledge Contribution in Knowledge Networks: Effects of Participants’ Central Positions on Contribution Quality

    NARCIS (Netherlands)

    Sedighi, M.; Hamedi, Mohsen

    2016-01-01

    Knowledge networks play a crucial role in contemporary organisations to improve participation for knowledge sharing. Examining employees’ knowledge contribution play an important role for in success implementing knowledgenetworks. Whereas most part of studies emphasis on the quantity aspect of

  4. Contribution mapping: a method for mapping the contribution of research to enhance its impact

    Directory of Open Access Journals (Sweden)

    Kok Maarten O

    2012-07-01

    Full Text Available Abstract Background At a time of growing emphasis on both the use of research and accountability, it is important for research funders, researchers and other stakeholders to monitor and evaluate the extent to which research contributes to better action for health, and find ways to enhance the likelihood that beneficial contributions are realized. Past attempts to assess research 'impact' struggle with operationalizing 'impact', identifying the users of research and attributing impact to research projects as source. In this article we describe Contribution Mapping, a novel approach to research monitoring and evaluation that aims to assess contributions instead of impacts. The approach focuses on processes and actors and systematically assesses anticipatory efforts that aim to enhance contributions, so-called alignment efforts. The approach is designed to be useful for both accountability purposes and for assisting in better employing research to contribute to better action for health. Methods Contribution Mapping is inspired by a perspective from social studies of science on how research and knowledge utilization processes evolve. For each research project that is assessed, a three-phase process map is developed that includes the main actors, activities and alignment efforts during research formulation, production and knowledge extension (e.g. dissemination and utilization. The approach focuses on the actors involved in, or interacting with, a research project (the linked actors and the most likely influential users, who are referred to as potential key users. In the first stage, the investigators of the assessed project are interviewed to develop a preliminary version of the process map and first estimation of research-related contributions. In the second stage, potential key-users and other informants are interviewed to trace, explore and triangulate possible contributions. In the third stage, the presence and role of alignment efforts is

  5. Contribution mapping: a method for mapping the contribution of research to enhance its impact

    Science.gov (United States)

    2012-01-01

    Background At a time of growing emphasis on both the use of research and accountability, it is important for research funders, researchers and other stakeholders to monitor and evaluate the extent to which research contributes to better action for health, and find ways to enhance the likelihood that beneficial contributions are realized. Past attempts to assess research 'impact' struggle with operationalizing 'impact', identifying the users of research and attributing impact to research projects as source. In this article we describe Contribution Mapping, a novel approach to research monitoring and evaluation that aims to assess contributions instead of impacts. The approach focuses on processes and actors and systematically assesses anticipatory efforts that aim to enhance contributions, so-called alignment efforts. The approach is designed to be useful for both accountability purposes and for assisting in better employing research to contribute to better action for health. Methods Contribution Mapping is inspired by a perspective from social studies of science on how research and knowledge utilization processes evolve. For each research project that is assessed, a three-phase process map is developed that includes the main actors, activities and alignment efforts during research formulation, production and knowledge extension (e.g. dissemination and utilization). The approach focuses on the actors involved in, or interacting with, a research project (the linked actors) and the most likely influential users, who are referred to as potential key users. In the first stage, the investigators of the assessed project are interviewed to develop a preliminary version of the process map and first estimation of research-related contributions. In the second stage, potential key-users and other informants are interviewed to trace, explore and triangulate possible contributions. In the third stage, the presence and role of alignment efforts is analyzed and the preliminary

  6. The Contribution of Fusion to Sustainable Development

    International Nuclear Information System (INIS)

    Ward, D.

    2006-01-01

    The world demand for energy is projected to more than double over the next 50 years, indeed this will be essential to bring much of the world out of poverty. At the same time there is increasing pressure to substantially reduce atmospheric pollution, most notably of carbon dioxide. Together, these conflicting goals drive a need to produce enormous amounts of non-carbon energy supply, much greater than our total present energy supply. This presents an enormous challenge. As one of very few options for large-scale, non-carbon future supply of energy, fusion has the potential to make an important contribution to sustained energy supplies. Fusion's advantages of large fuel reserves, low atmospheric emissions and high levels of safety make it an important consideration in future energy strategies. - Fuel supplies are sufficient for at least thousands of years, and probably up to millions of years, of energy use. - Atmospheric emissions of CO 2 are very low and minor emissions of other pollutants are less harmful than those from most existing energy sources. - Hazards to the public will be very low because of the high levels of passive safety. - Waste materials will require little, or no, use of repository storage. Conceptual designs of fusion power plants have been optimised against safety and environmental criteria. The optimum designs vary both with the assessed progress in the development programme and according to the weight given to different criteria. The impact of this weighting on design, and the comparison of the outcomes with other energy sources, is described. To make a contribution to sustainable development, fusion must also be economically viable to enter the energy market. The calculated cost of electricity from fusion and other technologies, both new and existing, show that, particularly in an energy market where environmental constraints are playing an increasing role, fusion can make an important contribution. (author)

  7. Audits contribute to pride, productivity and profit

    International Nuclear Information System (INIS)

    White, Q.

    1984-01-01

    The object of this writing is to demonstrate that audits (in general) when used as a ''management tool' can contribute to pride, productivity, and profit. The goal of ''pride'' achievement is demonstrated through the use of techniques developed from behavioral sciences. Discussed is dealing with people and their basic needs. This is intended to point out the fact that satisfying individual needs and concerns is the first step to achieving the goals of pride, productivity, and profit. Also discussed are the basic needs of safety (security), social, ego/esteem, and self-fulfillment as well as providing some basic techniques of auditing which will help assure general satisfaction of these needs. Also noted are reporting methods. The goal of ''productivity'' is approached by demonstrating that objectives must be clear and workable. Objectives must be translated into specific action and that action must be compatible with the overall company objectives. All objectives must be known and understood by those affected. Consideration must be given to men, money, and machines (present technology). All of the objectives must also be weighed against external constraints. The goal of ''profit'' then becomes the product of a combination of ''pride'' and ''productivity''. Audits must be cost conscious. Value engineer the problem, the cause, and the solution. Discussion continues with quality cost programs briefly indicating that ''Q'' costs could be considered a type of audit. Identifying deficiencies and weaknesses, then correcting them, contributes to profit. Increased pride and productivity contributes to profit. Consider the employee's awareness and commitment for doing a good job when auditing

  8. Autophagy contributes to degradation of Hirano bodies.

    Science.gov (United States)

    Kim, Dong-Hwan; Davis, Richard C; Furukawa, Ruth; Fechheimer, Marcus

    2009-01-01

    Hirano bodies are actin-rich inclusions reported most frequently in the hippocampus in association with a variety of conditions including neurodegenerative diseases, and aging. We have developed a model system for formation of Hirano bodies in Dictyostelium and cultured mammalian cells to permit detailed studies of the dynamics of these structures in living cells. Model Hirano bodies are frequently observed in membrane-enclosed vesicles in mammalian cells consistent with a role of autophagy in the degradation of these structures. Clearance of Hirano bodies by an exocytotic process is supported by images from electron microscopy showing extracellular release of Hirano bodies, and observation of Hirano bodies in the culture medium of Dictyostelium and mammalian cells. An autophagosome marker protein Atg8-GFP, was co-localized with model Hirano bodies in wild type Dictyostelium cells, but not in atg5(-) or atg1-1 autophagy mutant strains. Induction of model Hirano bodies in Dictyostelium with a high level expression of 34 kDa DeltaEF1 from the inducible discoidin promoter resulted in larger Hirano bodies and a cessation of cell doubling. The degradation of model Hirano bodies still occurred rapidly in autophagy mutant (atg5(-)) Dictyostelium, suggesting that other mechanisms such as the ubiquitin-mediated proteasome pathway could contribute to the degradation of Hirano bodies. Chemical inhibition of the proteasome pathway with lactacystin, significantly decreased the turnover of Hirano bodies in Dictyostelium providing direct evidence that autophagy and the proteasome can both contribute to degradation of Hirano bodies. Short term treatment of mammalian cells with either lactacystin or 3-methyl adenine results in higher levels of Hirano bodies and a lower level of viable cells in the cultures, supporting the conclusion that both autophagy and the proteasome contribute to degradation of Hirano bodies.

  9. Neuromarketing and consumer neuroscience: contributions to neurology.

    Science.gov (United States)

    Javor, Andrija; Koller, Monika; Lee, Nick; Chamberlain, Laura; Ransmayr, Gerhard

    2013-02-06

    'Neuromarketing' is a term that has often been used in the media in recent years. These public discussions have generally centered around potential ethical aspects and the public fear of negative consequences for society in general, and consumers in particular. However, positive contributions to the scientific discourse from developing a biological model that tries to explain context-situated human behavior such as consumption have often been neglected. We argue for a differentiated terminology, naming commercial applications of neuroscientific methods 'neuromarketing' and scientific ones 'consumer neuroscience'. While marketing scholars have eagerly integrated neuroscientific evidence into their theoretical framework, neurology has only recently started to draw its attention to the results of consumer neuroscience. In this paper we address key research topics of consumer neuroscience that we think are of interest for neurologists; namely the reward system, trust and ethical issues. We argue that there are overlapping research topics in neurology and consumer neuroscience where both sides can profit from collaboration. Further, neurologists joining the public discussion of ethical issues surrounding neuromarketing and consumer neuroscience could contribute standards and experience gained in clinical research. We identify the following areas where consumer neuroscience could contribute to the field of neurology:First, studies using game paradigms could help to gain further insights into the underlying pathophysiology of pathological gambling in Parkinson's disease, frontotemporal dementia, epilepsy, and Huntington's disease.Second, we identify compulsive buying as a common interest in neurology and consumer neuroscience. Paradigms commonly used in consumer neuroscience could be applied to patients suffering from Parkinson's disease and frontotemporal dementia to advance knowledge of this important behavioral symptom.Third, trust research in the medical context lacks

  10. BRAND POLICY INSTRUMENTS:CONTRIBUTIONS TO BRANDEQUITY

    OpenAIRE

    Roxana Dumitriu

    2013-01-01

    In this paper we attempted to establish the contributions of brand elements to the brand equity. Building brand equity is realized and is based on a series of visible elements, easy to recognize and to remember by the public. A name, a symbol, a slogan are just a part of the visible elements of the brand meaning. The brand elements are a shortcut of clients’ perception regarding the brand utility and brand image, suggesting some benefices of performance and competence. The brand elements that...

  11. Fermionic NNLO contributions to Bhabha scattering

    International Nuclear Information System (INIS)

    Actis, S.; Riemann, T.; Czakon, M.; Uniwersytet Slaski, Katowice; Gluza, J.

    2007-10-01

    We derive the two-loop corrections to Bhabha scattering from heavy fermions using dispersion relations. The double-box contributions are expressed by three kernel functions. Convoluting the perturbative kernels with fermionic threshold functions or with hadronic data allows to determine numerical results for small electron mass m e , combined with arbitrary values of the fermion mass m f in the loop, m 2 e 2 f , or with hadronic insertions. We present numerical results for m f =m μ , m τ ,m top at typical small- and large-angle kinematics ranging from 1 GeV to 500 GeV. (orig.)

  12. Factors Contributing to Crashes among Young Drivers

    Directory of Open Access Journals (Sweden)

    Lyndel J. Bates

    2014-08-01

    Full Text Available Young drivers are the group of drivers most likely to crash. There are a number of factors that contribute to the high crash risk experienced by these drivers. While some of these factors are intrinsic to the young driver, such as their age, gender or driving skill, others relate to social factors and when and how often they drive. This article reviews the factors that affect the risk of young drivers crashing to enable a fuller understanding of why this risk is so high in order to assist in developing effective countermeasures.

  13. Microwave filters and circuits contributions from Japan

    CERN Document Server

    Matsumoto, Akio

    1970-01-01

    Microwave Filters and Circuits: Contributions from Japan covers ideas and novel circuits used to design microwave filter that have been developed in Japan, as well as network theory into the field of microwave transmission networks. The book discusses the general properties and synthesis of transmission-line networks; transmission-line filters on the image-parameter basis; and experimental results on a class of transmission-line filter constructed only with commensurate TEM lossless transmission lines. The text describes lines constants, approximation problems in transmission-line networks, as

  14. [Contribution of animal experimentation to pharmacology].

    Science.gov (United States)

    Sassard, Jean; Hamon, Michel; Galibert, Francis

    2009-11-01

    Animal experimentation is of considerable importance in pharmacology and cannot yet be avoided when studying complex, highly integrated physiological functions. The use of animals has been drastically reduced in the classical phases of pharmacological research, for example when comparing several compounds belonging to the same pharmacological class. However, animal experiments remain crucial for generating and validating new therapeutic concepts. Three examples of such research, conducted in strict ethical conditions, will be used to illustrate the different ways in which animal experimentation has contributed to human therapeutics.

  15. Neuromarketing and consumer neuroscience: contributions to neurology

    Science.gov (United States)

    2013-01-01

    Background ‘Neuromarketing’ is a term that has often been used in the media in recent years. These public discussions have generally centered around potential ethical aspects and the public fear of negative consequences for society in general, and consumers in particular. However, positive contributions to the scientific discourse from developing a biological model that tries to explain context-situated human behavior such as consumption have often been neglected. We argue for a differentiated terminology, naming commercial applications of neuroscientific methods ‘neuromarketing’ and scientific ones ‘consumer neuroscience’. While marketing scholars have eagerly integrated neuroscientific evidence into their theoretical framework, neurology has only recently started to draw its attention to the results of consumer neuroscience. Discussion In this paper we address key research topics of consumer neuroscience that we think are of interest for neurologists; namely the reward system, trust and ethical issues. We argue that there are overlapping research topics in neurology and consumer neuroscience where both sides can profit from collaboration. Further, neurologists joining the public discussion of ethical issues surrounding neuromarketing and consumer neuroscience could contribute standards and experience gained in clinical research. Summary We identify the following areas where consumer neuroscience could contribute to the field of neurology: First, studies using game paradigms could help to gain further insights into the underlying pathophysiology of pathological gambling in Parkinson’s disease, frontotemporal dementia, epilepsy, and Huntington’s disease. Second, we identify compulsive buying as a common interest in neurology and consumer neuroscience. Paradigms commonly used in consumer neuroscience could be applied to patients suffering from Parkinson’s disease and frontotemporal dementia to advance knowledge of this important behavioral symptom

  16. [Nursing contribution in health decision making].

    Science.gov (United States)

    Mosqueda-Díaz, Angélica; Mendoza-Parra, Sara; Jofré-Aravena, Viviane

    2014-01-01

    Decision making in health is a frequent situation, although potentially difficult, depending on patient/user characteristics and the context or the situation of health. This causes decisional conflicts in patients/users. The present study proposes to analyze the decision making process in health, conceptually, and nurses' contributions to understand and confront the phenomenon. The Ottawa the Model of Decisions Making in Health, proposed by Annette O'Connor, arises as a useful tool that enables nurses to carry out effective interventions with persons who face decision problems. Patients/users can assume a more active participation in the decisions on their own health.

  17. Medical contribution to the comprehensive approach.

    Science.gov (United States)

    Fletcher, J M

    2011-12-01

    The coordination of the Military, Diplomatic and Economic/Development levers of power, the so-called "hard" and "soft" powers, to bring about the strategic aims of governments, supported by Non-Governmental Organisations and international organisations, is commonly known as the Comprehensive Approach (CA). The CA is now part of both NATO and UK military doctrine and concepts development. This article describes how medical branch HQ Allied Rapid Reaction Corp, as part of the HQs work to operationalise the CA, has sought and developed training opportunities to improve individual skill-sets to enable the branch to better contribute to the CA process.

  18. [Placebo effect: a contribution of social psychology].

    Science.gov (United States)

    Balez, R; Leroyer, C; Couturaud, F

    2014-10-01

    This article reviews the psychosocial variables, which are of interest in the relationship between the patient and the physician. According to a classical model of social psychology, such a relationship might contribute to the placebo/nocebo effects. We develop herein various relational and contextual variables, taking into account four dimensions (intra-individual, interpersonal, positional and ideological) and their potential effects on therapeutic responses. This applies both in the setting of daily clinical practice and of clinical trials. The placebo effect offers an opportunity for collaboration and dialogue between social scientists and physicians.

  19. Capitalizing the contribution of the nuclear industry

    International Nuclear Information System (INIS)

    Donnadieu, G.

    1984-01-01

    The main contributions of the French nuclear industry to the country, and ways to make the most of them are presented. The advantages acquired include the nuclear power stations built; mastering of the combustion cycle; a powerful, well structured nuclear construction industry; and a nuclear-industrial complex giving France an important industrial potential. It is recommended that the industrial and research effort be maintained. The proposed strategy consists of defining an electronuclear program and associated economic development program and sticking to them; promoting exports; possibly merging certain industrial capacities; and strengthening the national position and independence concerning the fuel cycle [fr

  20. Climate change - the contribution from air travel

    International Nuclear Information System (INIS)

    Beesley, Colin

    2000-01-01

    The paper discusses the Intergovernment Panel on Climate Change (IPCC) report on Aviation and the Global Atmosphere (published in 1999). It was considered necessary to treat air transport on its own since aircraft are unique in delivering emissions into the upper atmosphere rather than at ground level. The study was commissioned at the request of the International Civil Aviation Organisation and the Montreal Protocol. More than 300 experts contributed and the report has quantified the effect of aviation on the atmosphere on a world wide basis and highlighted areas where improved data are required. (UK)

  1. Adam Smith’s contribution to secularisation

    Directory of Open Access Journals (Sweden)

    Petrus Simons

    2013-06-01

    Full Text Available This article examined several crucial themes in Adam Smith’s philosophy with the purpose of highlighting and assessing his contribution to the secularisation of Western society. The article, written from the perspective of reformational philosophy, begins with a brief biography and sketch of Adam Smith’s influence on modern society, followed by a summary of Ponti Venter’s view on Smith. This sets the scene for a discussion of Adam Smith’s project, his method of tackling it, and his views on systems, philosophy of history and the concept of philosophy.

  2. Research for the thermal change. Contributions

    International Nuclear Information System (INIS)

    Szczepanski, Petra; Wunschick, Franziska; Martin, Niklas

    2016-01-01

    The energy transition in the heating sector is not a sure-fire success and it is too slow. This is alarming since the heating / cooling sector is responsible for more than half of the final energy demand. That the ''thermal change'' has accelerated hardly despite many efforts by politics, industry and research in recent years, is the reason for the scientists the FVEE institutes to examine the perspectives of renewable energy and the need to increase efficiency in the heating sector systematically. therefore FVEE-2015 Annual Meeting, is entitled ''Research for the thermal change''. The contributions of this conference proceedings present the latest research results and show ways to implement the heat change technically, economically and politically. They are dedicated to the drivers, but also the barriers of heat change. The authors report on innovative projects to provide buildings with heat from geothermal energy, biomass and solar thermal energy. Several contributions are dedicated to the application of efficient components, such as thermal insulation, thermal storage and heat pumps. [de

  3. Gut Microbiota: A Contributing Factor to Obesity

    Science.gov (United States)

    Harakeh, Steve M.; Khan, Imran; Kumosani, Taha; Barbour, Elie; Almasaudi, Saad B.; Bahijri, Suhad M.; Alfadul, Sulaiman M.; Ajabnoor, Ghada M. A.; Azhar, Esam I.

    2016-01-01

    Obesity, a global epidemic of the modern era, is a risk factor for cardiovascular diseases (CVD) and diabetes. The pervasiveness of obesity and overweight in both developed as well as developing populations is on the rise and placing a huge burden on health and economic resources. Consequently, research to control this emerging epidemic is of utmost importance. Recently, host interactions with their resident gut microbiota (GM) have been reported to be involved in the pathogenesis of many metabolic diseases, including obesity, diabetes, and CVD. Around 1014 microorganisms reside within the lower human intestine and many of these 1014 microorganisms have developed mutualistic or commensal associations with the host and actively involved in many physiological processes of the host. However, dysbiosis (altered gut microbial composition) with other predisposing genetic and environmental factors, may contribute to host metabolic disorders resulting in many ailments. Therefore, delineating the role of GM as a contributing factor to obesity is the main objective of this review. Obesity research, as a field is expanding rapidly due to major advances in nutrigenomics, metabolomics, RNA silencing, epigenetics, and other disciplines that may result in the emergence of new technologies and methods to better interpret causal relationships between microbiota and obesity. PMID:27625997

  4. Gut Microbiota: a contributing factor to obesity

    Directory of Open Access Journals (Sweden)

    Steve M Harakeh

    2016-08-01

    Full Text Available Obesity, a global epidemic of the modern era, is a risk factor for cardiovascular diseases (CVD and diabetes. The pervasiveness of obesity and overweight in both developed as well as developing populations is on the rise and placing a huge burden on health and economic resources. Consequently, research to control this emerging epidemic is of utmost importance. Recently, host interactions with their resident gut microbiota (GM have been reported to be involved in the pathogenesis of many metabolic diseases, including obesity, diabetes, and CVD. Around 1014 microorganisms reside within the lower human intestine and many of these 1014microorganisms have developed mutualistic or commensal associations with the host and actively involved in many physiological processes of the host. However, dysbiosis (altered gut microbial composition with other predisposing genetic and environmental factors, may contribute to host metabolic disorders resulting in many ailments. Therefore, delineating the role of GM as a contributing factor to obesity is the main objective of this review.Obesity research, as a field is expanding rapidly due to major advances in nutrigenomics, metabolomics, RNA silencing, epigenetics and other disciplines that may result in the emergence of new technologies and methods to better interpret causal relationships between microbiota and obesity.

  5. Deep Ocean Contribution to Sea Level Rise

    Science.gov (United States)

    Chang, L.; Sun, W.; Tang, H.; Wang, Q.

    2017-12-01

    The ocean temperature and salinity change in the upper 2000m can be detected by Argo floats, so we can know the steric height change of the ocean. But the ocean layers above 2000m represent only 50% of the total ocean volume. Although the temperature and salinity change are small compared to the upper ocean, the deep ocean contribution to sea level might be significant because of its large volume. There has been some research on the deep ocean rely on the very sparse situ observation and are limited to decadal and longer-term rates of change. The available observational data in the deep ocean are too spares to determine the temporal variability, and the long-term changes may have a bias. We will use the Argo date and combine the situ data and topographic data to estimate the temperature and salinity of the sea water below 2000m, so we can obtain a monthly data. We will analyze the seasonal and annual change of the steric height change due to the deep ocean between 2005 and 2016. And we will evaluate the result combination the present-day satellite and in situ observing systems. The deep ocean contribution can be inferred indirectly as the difference between the altimetry minus GRACE and Argo-based steric sea level.

  6. Control practices contribute to premature transformer failures

    Energy Technology Data Exchange (ETDEWEB)

    Jauch, E.T. [Beckwith Electric Company Inc., Largo, FL (United States)

    2007-07-01

    Studies of premature load tap changer (LTC) transformer failures on utility systems have shown the tap changers to be the primary contributing factor. Some of the LTC factors that lead to transformer failures include oil quality and particulate contamination; LTC contact temperature rise; contact coking; carbon film build-up; short circuit mechanical forces; and contact wear and arcing. These factors create increasing contact resistance thereby increasing voltage drop, localized heating, contact pitting, oil contamination and general deterioration. This paper discussed utility tapchanger control practices and methods of determining control functions to be activated as well as the determination of optimum settings contributing to excessive or untimely tap change operations. The transformer applications that were considered included transmission tie transformers as well as transmission distribution interface transformers. The paper discussed the circulating current paralleling method and the circulating reactive current or var sharing paralleling method. Several common practices were discussed, including basic voltage control ranges and setting effects; timing options available; LDC misapplications; first house protection methods; and various paralleling techniques. It was concluded that although there are several other methods of paralleling power transformers, many are not applicable under certain system configurations. In these applications, improper use of a paralleling method or improper setting and commissioning may cause hunting for appropriate tap positions and dramatically increase the number of tap changes, causing wear and degradation of the tap changer contacts. 3 refs., 5 figs.

  7. The contribution of adhesion signaling to lactogenesis.

    Science.gov (United States)

    Morrison, Bethanie; Cutler, Mary Lou

    2010-10-01

    The mammary gland undergoes hormonally controlled cycles of pubertal maturation, pregnancy, lactation, and involution, and these processes rely on complex signaling mechanisms, many of which are controlled by cell-cell and cell-matrix adhesion. The adhesion of epithelial cells to the extracellular matrix initiates signaling mechanisms that have an impact on cell proliferation, survival, and differentiation throughout lactation. The control of integrin expression on the mammary epithelial cells, the composition of the extracellular matrix and the presence of secreted matricellular proteins all contribute to essential adhesion signaling during lactogenesis. In vitro and in vivo studies, including the results from genetically engineered mice, have shed light on the regulation of these processes at the cell and tissue level and have led to increased understanding of the essential signaling components that are regulated in temporal and cell specific manner during lactogenesis. Recent studies suggest that a secreted matricellular protein, CTGF/CCN2, may play a role in lactogenic differentiation through binding to β1 integrin complexes, enhancing the production of extracellular matrix components and contributions to cell adhesion signaling.

  8. What causes autism? Exploring the environmental contribution.

    Science.gov (United States)

    Landrigan, Philip J

    2010-04-01

    Autism is a biologically based disorder of brain development. Genetic factors--mutations, deletions, and copy number variants--are clearly implicated in causation of autism. However, they account for only a small fraction of cases, and do not easily explain key clinical and epidemiological features. This suggests that early environmental exposures also contribute. This review explores this hypothesis. Indirect evidence for an environmental contribution to autism comes from studies demonstrating the sensitivity of the developing brain to external exposures such as lead, ethyl alcohol and methyl mercury. But the most powerful proof-of-concept evidence derives from studies specifically linking autism to exposures in early pregnancy - thalidomide, misoprostol, and valproic acid; maternal rubella infection; and the organophosphate insecticide, chlorpyrifos. There is no credible evidence that vaccines cause autism. Expanded research is needed into environmental causation of autism. Children today are surrounded by thousands of synthetic chemicals. Two hundred of them are neurotoxic in adult humans, and 1000 more in laboratory models. Yet fewer than 20% of high-volume chemicals have been tested for neurodevelopmental toxicity. I propose a targeted discovery strategy focused on suspect chemicals, which combines expanded toxicological screening, neurobiological research and prospective epidemiological studies.

  9. Crystal field contribution to Moessbauer isomer shift

    International Nuclear Information System (INIS)

    Singh, Avtar; Shrivastava, K.N.

    1975-01-01

    A new temperature dependent contribution to isomer shift in Fe 3+ (ed 5 ) is proposed. The static crystal field gives rise to a new second-order correction to Mossbauer resonance line and crystal field hamiltonian Hc=B 2 0 Y 2 0 +B 2 2 (Y 22 ) usually used in the study of electronspin resonance is employed. The electron charge density at the nuclear site, responsible for the isomer shift is affected by the crystal field through excitation of an electron from 3d to 4s subshell. Further, temperature dependence is analysed by the variation of crystal field parameters with temperature which occurs as a square in the final result. The importance of the sign of the field parameter (KD) is also realised in the isomer shift studies. Although the proposed new second-order contribution to Moessbauer isomer shift is static in nature, yet it is expected to have important implications in the study of temperature depedence of centre shift of a Moessbauer line. Numerical estimates of the shift are also presented. (author)

  10. Eijkman's contribution to the discovery of vitamins.

    Science.gov (United States)

    Carpenter, K J; Sutherland, B

    1995-02-01

    The work by Christiaan Eijkman in Batavia (now Djakarta, the capital of Indonesia) between 1890 and 1900, for which he received a Nobel Prize, is reviewed. While searching for a microorganism responsible for beriberi, he found that a condition of polyneuritis, with similarities to beriberi, could be produced consistently in chickens by feeding them polished rice, and that addition of the silverskin removed during polishing prevented this. He showed further that the silverskin did not act by physically preventing the entry of microorganisms into the endosperm, nor was its action explained by the protein and salts that it contributed. His tentative hypothesis was that this fraction contributed an antidote to a nerve poison produced by the fermentation of starch in the chickens' crop. However, his successor continued to use Eijkman's animal model and was able to show that silverskin supplied some unknown factor(s) that was required regardless of whether or not the diet contained starch. Fractionation eventually showed thiamin to be the active factor.

  11. Contribution to the strategy of energy efficiency

    International Nuclear Information System (INIS)

    Ciconkov, Risto

    2003-01-01

    An explanation for the greenhouse effect, i.e.global warming and reasons which contribute to this effect. Greenhouse gasses (GHG) and GWP (Global Warming Potential) as a factor for estimating their contributing on the greenhouse effect. Indicators of the climate change in the previous period and projecting of likely scenarios for the future. Consequences on the environment and human activities: industry, energy, agriculture, water resource. The main lines of the Kyoto Protocol and problems in its realization. Suggestions to the country strategy concerning to the acts of the Kyoto Protocol. A special attention is pointed out on the energy, its resource, the structure of energy consumption and energy efficiency. Main sectors of the energy efficiency: buildings, industry and transport. Buildings: importance of heat insulation. District heating, suggestions for space heating. Heat pumps and CHP. Air conditioning and refrigeration. Industry: process heating, and integrated energy system heat recovery, refrigeration, compressed air. Need of quality maintenance and servicing. Monitoring and automatic control. Education for energy and its saving. (Original)

  12. Ted Irving's early contributions to paleomagnetism

    Science.gov (United States)

    Frankel, H. R.

    2014-12-01

    Edward (Ted) Irving (1927 - 2014) was one of the most deeply and widely respected paleomagnetists, making significant contributions to the field throughout his career which spanned six decades. Restricting attention to the first decade of his career, the 1950s, he discovered from work on the Torridonian (1951-1953) that fine-grained red sandstones were generally suitable for paleomagnetic work (1951-1952). He rediscovered (1951) that paleomagnetism could be used to test continental drift, and initiated (1951) the first paleomagnetic test of whether India had drifted northward relative to Asia and argued (1954) that it had. He also made significant contributions to the first APW path for Great Britain (Creer, Irving, and Runcorn, 1954). He was the first to draw two APW paths to explain results from Great Britain and North America (1956) and to use paleomagnetism and paleoclimatology together to argue for continental drift (1954, 1956). With Ron Green, his first student, he first APW path for Australia (1958). He was the first to invoke axial rotations to explain away an apparent anomaly with an APW path (1959). His work on the Torridonian led to the first description of stratigraphically sequential reversals in sedimentary rocks. Moreover, his 1959 superb review of the paleomagnetic support for continental drift was instrumental in Hess's becoming a continental drifter before he came up with the idea of seafloor spreading.

  13. Gut Microbiota: A Contributing Factor to Obesity.

    Science.gov (United States)

    Harakeh, Steve M; Khan, Imran; Kumosani, Taha; Barbour, Elie; Almasaudi, Saad B; Bahijri, Suhad M; Alfadul, Sulaiman M; Ajabnoor, Ghada M A; Azhar, Esam I

    2016-01-01

    Obesity, a global epidemic of the modern era, is a risk factor for cardiovascular diseases (CVD) and diabetes. The pervasiveness of obesity and overweight in both developed as well as developing populations is on the rise and placing a huge burden on health and economic resources. Consequently, research to control this emerging epidemic is of utmost importance. Recently, host interactions with their resident gut microbiota (GM) have been reported to be involved in the pathogenesis of many metabolic diseases, including obesity, diabetes, and CVD. Around 10(14) microorganisms reside within the lower human intestine and many of these 10(14) microorganisms have developed mutualistic or commensal associations with the host and actively involved in many physiological processes of the host. However, dysbiosis (altered gut microbial composition) with other predisposing genetic and environmental factors, may contribute to host metabolic disorders resulting in many ailments. Therefore, delineating the role of GM as a contributing factor to obesity is the main objective of this review. Obesity research, as a field is expanding rapidly due to major advances in nutrigenomics, metabolomics, RNA silencing, epigenetics, and other disciplines that may result in the emergence of new technologies and methods to better interpret causal relationships between microbiota and obesity.

  14. A Contribution Towards A Grammar of Code

    Directory of Open Access Journals (Sweden)

    David M. Berry

    2008-01-01

    Full Text Available Over the past thirty years there has been an increasing interest in the social and cultural implications of digital technologies and ‘informationalism’ from the social sciences and humanities. Generally this has concentrated on the implications of the “convergence” of digital devices and services, understood as linked to the discrete processing capabilities of computers, which rely on logical operations, binary processing and symbolic representation. In this paper, I wish to suggest that a ‘grammar of code’ might provide a useful way of thinking about the way in which digital technologies operate as a medium and can contribute usefully to this wider debate. I am interested in the way in which the dynamic properties of code can be understood as operating according to a grammar reflected in its materialisation and operation in the lifeworld – the discretisation of the phenomenal world. As part of that contribution in this paper I develop some tentative Weberian ‘ideal-types’. These ideal-types are then applied to the work of the Japanese composer, Masahiro Miwa, whose innovative ‘Reverse-Simulation music’ models the operation of basic low-level digital circuitry for the performance and generation of musical pieces.

  15. Factors Contributing Decreased Performance Of Slow Learners

    Directory of Open Access Journals (Sweden)

    Dr. L. Kannan

    2015-03-01

    Full Text Available Back ground Even experienced teaching faculty and administrators can be challenged by learners who have not able to perform up to expected need in their annual performance of their students these students are called as slow learnersStruggle learners. There should be a designed study to foster discussion about diagnosing particular problems that contribute with meeting objectives of slow learners. Methodology The study was performed on the entire current first year of Medical students were all the three internal assessments of 250 students performance is taken in to consideration for the study. This study is of cross section type.After obtaining the list of all students marks in internal examination from medical education unit supporting mentors are contacted to meet the students and confidentiality is maintained throughout the study. After obtaining informed consent a questionnaire was administered to the students by the investigator. The questionnaire contains the following sections. Section I will be on the background characteristics of the student name age sex type of family. Section II will be on the details of their learning capabilities. Section III will focus on the awareness of the slow learners in which the precipitating factors contributing to them. Results The prevalence of slow learners as low achievers were contributed to be 32.4 percentages.The performance of the students is based on combination of all three internal assessment marks including theory and practical performance. In this the students age ranges from 17 to 21 years the mean age of student was contributed to be 17.81 and majority of the students were in the age group of 18 years which contributed to be 16867.2.In the present study majority were males 13252.8 compared to females 11847.2.but when study is compared to percentage of attendance majority of the individual 15177 scored more than 50 percentage of marks have more than 80 percentage of attendance but when

  16. Malaysia's contributions towards global climate change concerns

    International Nuclear Information System (INIS)

    Yuzlaini Mohd Yusop; Yvonne Lunsong; Norhayati Kamaruddin

    2000-01-01

    Concerns about Green House Gas (GHG) emissions and global climate change were voiced by the scientific community as far back as the International Geophysical year in 1957 when climate changes scenarios and impacts were analysed. More recently, the United Nations Framework Convention on climate change (UNFCCC) was adopted in 1992, renewing a global acknowledgement and commitment towards curbing GHG emissions. Little progress was made until the adoption of Kyoto Protocol in December 1997, over 5 years later. Basically, developed countries would not commit to strong measures if there were no global effort (i. e. corresponding efforts by developing countries) while developing countries are waiting for developed countries to show concrete results first. Since 1950, developed countries cumulatively produced more than 80% of worldwide GHG emissions. Between 1950 and 1990, North America alone contributed 40 billion tons of carbon while Western and Eastern Europe contributed 57 billion tons. Developing countries produced only 24 billion tons of carbon emissions during the same period. At present, per capita emission in developed countries are also about ten times higher than those of developing countries. This imbalance has caused most developing countries to adopt a wait till others do it stance and justifiably so. Nonetheless, curbing GHG emissions should be a larger community effort (which includes business and the public) and not just the efforts of Governments and officials. Thus, the deciding factors should make more business or economic sense. It is likely that business and the general public would listen and contribute positively if they are made aware of potential cost savings and international competitiveness to be derived from these efforts. During the current economic slowdown, especially in East Asia, it makes business sense to defer the capital investment in new electricity generating capacity and related energy supply infrastructure. Pusat Tenaga Malaysia

  17. Worldwide academic contributions of Japanese neurosurgeons.

    Science.gov (United States)

    Sasaki, Tomio; Hashiguchi, Kimiaki; Yoshimoto, Koji; Nakamizo, Akira; Mizoguchi, Masahiro

    2011-01-01

    Based on the data reported in the National Institute of Science and Technology Policy 2010, Japan is ranked in fourth place in the world in terms of the numbers of the articles in the fields of clinical medicine. However, there had not been any objective data regarding the numbers of publications by neurosurgeons. As it is important for neurosurgeons to realize the extent of academic contributions by the neurosurgeons in different countries, the numbers of publications in the major journals by the members of the Japan Neurosurgical Society and those from neurosurgical institutions around the world were analyzed using both the biomedical literature database PubMed and the publication database "ISI Web of Knowledge." Parts of the results were presented in the 69th Annual Meeting of the Japan Neurosurgical Society. As to the number of neurosurgical publications in English from the top 9 countries, the US has been consistently in first place and Japan in second. However, the number of publications from Japan has been decreasing since 2000. With regards to the "top 8 journals" such as the Lancet and the Journal of the American Medical Association, the number of first-author publications by Japanese neurosurgeons increased in the late 1980s and had been 2-9 articles per year until recently. In the "top 12 neuroscience journals" which include Stroke, Neuro-Oncology, Cancer Research, and others, Japan had been in the third next to the US and UK till 2004, but Germany surpassed Japan in 2005. In the "top 6 clinical journals" such as the Journal of Neurosurgery and Neurosurgery, the US has been consistently keeping first place and Japan second place since 1977. Searches using the key word elucidated that Japanese neurosurgeons are greatly contributing in the field of "aneurysm." Regarding the number of publications per neurosurgeon, Canada and UK are in the forefront and Japan is down to eighth place. Japanese neurosurgeons have been contributing greatly next to the

  18. Contributions to In Silico Genome Annotation

    KAUST Repository

    Kalkatawi, Manal M.

    2017-11-30

    Genome annotation is an important topic since it provides information for the foundation of downstream genomic and biological research. It is considered as a way of summarizing part of existing knowledge about the genomic characteristics of an organism. Annotating different regions of a genome sequence is known as structural annotation, while identifying functions of these regions is considered as a functional annotation. In silico approaches can facilitate both tasks that otherwise would be difficult and timeconsuming. This study contributes to genome annotation by introducing several novel bioinformatics methods, some based on machine learning (ML) approaches. First, we present Dragon PolyA Spotter (DPS), a method for accurate identification of the polyadenylation signals (PAS) within human genomic DNA sequences. For this, we derived a novel feature-set able to characterize properties of the genomic region surrounding the PAS, enabling development of high accuracy optimized ML predictive models. DPS considerably outperformed the state-of-the-art results. The second contribution concerns developing generic models for structural annotation, i.e., the recognition of different genomic signals and regions (GSR) within eukaryotic DNA. We developed DeepGSR, a systematic framework that facilitates generating ML models to predict GSR with high accuracy. To the best of our knowledge, no available generic and automated method exists for such task that could facilitate the studies of newly sequenced organisms. The prediction module of DeepGSR uses deep learning algorithms to derive highly abstract features that depend mainly on proper data representation and hyperparameters calibration. DeepGSR, which was evaluated on recognition of PAS and translation initiation sites (TIS) in different organisms, yields a simpler and more precise representation of the problem under study, compared to some other hand-tailored models, while producing high accuracy prediction results. Finally

  19. Contribution of autophagy to antiviral immunity.

    Science.gov (United States)

    Rey-Jurado, Emma; Riedel, Claudia A; González, Pablo A; Bueno, Susan M; Kalergis, Alexis M

    2015-11-14

    Although identified in the 1960's, interest in autophagy has significantly increased in the past decade with notable research efforts oriented at understanding as to how this multi-protein complex operates and is regulated. Autophagy is commonly defined as a "self-eating" process evolved by eukaryotic cells to recycle senescent organelles and expired proteins, which is significantly increased during cellular stress responses. In addition, autophagy can also play important roles during human diseases, such as cancer, neurodegenerative and autoimmune disorders. Furthermore, novel findings suggest that autophagy contributes to the host defense against microbial infections. In this article, we review the role of macroautophagy in antiviral immune responses and discuss molecular mechanisms evolved by viral pathogens to evade this process. A role for autophagy as an effector mechanism used both, by innate and adaptive immunity is also discussed. Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  20. Citizen Science: Contributions to Astronomy Research

    Science.gov (United States)

    Christian, Carol; Lintott, Chris; Smith, Arfon; Fortson, Lucy; Bamford, Steven

    2012-08-01

    The contributions of everyday individuals to significant research has grown dramatically beyond the early days of classical birdwatching and endeavors of amateurs of the 19th century. Now people who are casually interested in science can participate directly in research covering diverse scientific fields. Regarding astronomy, volunteers, either as individuals or as networks of people, are involved in a variety of types of studies. Citizen Science is intuitive, engaging, yet necessarily robust in its adoption of scientific principles and methods. Herein, we discuss Citizen Science, focusing on fully participatory projects such as Zooniverse (by several of the authors CL, AS, LF, SB), with mention of other programs. In particular, we make the case that citizen science (CS) can be an important aspect of the scientific data analysis pipelines provided to scientists by observatories.

  1. NASA contributions to the global habitability program

    Science.gov (United States)

    Mcconnell, D. G.

    1984-01-01

    As a result of developments occurring over the last two decades, the data acquisition, storage, analysis, and transmission facilities are now available for a concerted long-term interdisciplinary and international study of the global environmental system. Such a study is the essence of the 'Global Habitability' concept introduced in 1982. The aims of Global Habitability research are considered, taking into account an understanding of the vital global processes of the earth's energy balance, the global hydrological cycle, and the biogeochemical cycling of carbon, nitrogen, phosphorus, and sulfur. Details of NASA planning for Global Habitability are discussed along with international data exchange arrangements. Attention is given to the possible contributions of satellite data and associated techniques to Global Habitability, examples of specific research conducted by NASA in support of the Global Habitability and the international sharing of data and results for Global Habitability.

  2. Contributions from the CYGNUS/Milagro Collaboration

    Energy Technology Data Exchange (ETDEWEB)

    Allen, G.E.; Chang, C.Y.; Chen, M.L.

    1995-09-01

    This document consists of eleven reports contributed to the XXIV International Cosmic Ray Conference (Rome, Italy, August 28--September 8, 1995) from the CYGNUS/Milagro Collaboration: ``Search for Ultra-High-Energy Radiation from Gamma-Ray Bursts``, ``Gamma-Ray Bursts: Detection and Distance Estimates with Milagro``, ``Searching for Gamma-Ray Bursts with Water-Cerenkov-Detector Single-Particle Rates``, ``The Milagro Detector``, ``The Milagro Data Acquisition System``, ``Source Searches Using the CYGNUS Water-Cerenkov Array``, ``Search for UHE Emission from Supernova Remnants``, ``Solar Physics with the Milagro Telescope``, ``An Experiment to Detect Correlations Between Cerenkov and Muon Lateral Distributions in EAS``, ``A Study of Large-Zenith-Angle Air Showers with the CYGNUS Experiment``, and ``Mass Resolution of Ground Based Air Shower Experiments in the 10 to 10000 TeV range.``

  3. The Amtex DAMA Project: The Brookhaven contribution

    Energy Technology Data Exchange (ETDEWEB)

    Peskin, A.M.

    1995-01-01

    The Amtex Partnership organized in 1993 as a Technology Transfer Collaboration among members of the integrated textile industry, the DOE National Laboratories, a number of universities, and several research/education/technology transfer organizations (RETTs). Under the Amtex umbrella organization, a number of technology areas were defined and individual projects were launched addressing various aspects of improving the health and competitiveness of the American textile industry. The first and, to date, the largest of these has been the computer-based Demand Activated Manufacturing Architecture (DAMA) project. Brookhaven National Laboratory became involved in DAMA beginning in March of 1993 and remained an active participant through January of 1995. It was staffed almost exclusively with personnel of the Computing and Communications Division. This document summarizes the activities and accomplishments of the Brookhaven team in working with the larger collaboration. Detailed information about the Amtex Partnership, the DAMA Project, and specific BNL contributions are documented elsewhere.

  4. Global climate: Methane contribution to greenhouse effect

    International Nuclear Information System (INIS)

    Metalli, P.

    1992-01-01

    The global atmospheric concentration of methane greatly contributes to the severity of the greenhouse effect. It has been estimated that this concentration, due mainly to human activities, is growing at the rate of roughly 1.1% per year. Environmental scientists suggest that a reduction, even as small as 10%, in global methane emissions would be enough to curtail the hypothetical global warning scenarios forecasted for the up-coming century. Through the recovery of methane from municipal and farm wastes, as well as, through the control of methane leaks and dispersions in coal mining and petrochemical processes, substantial progress towards the abatement of greenhouse gas effects could be achieved without having to resort to economically detrimental limitations on the use of fossil fuels

  5. Ions and their contribution for living space

    Directory of Open Access Journals (Sweden)

    Jaroslav Svoboda

    2008-01-01

    Full Text Available This contribution is dealing with more than up to date topic. Nowadays more than one third of human population suffers from some form of allergies – dust, pollen or mites. The air we breathe the whole day does not come from outside, on the contrary it comes from closed rooms used for living. the important part of air are the negative ions which are neccessary for life. Therefore, the optimal level of ions should be maintained. Living enviroment which does not contain enough negative ions causes various diseases, such as allergies, asthma, headache, tiredness and depressions. Increased concentration of negative ions inside a house is the basic prevention of tiredness and other diseases.

  6. Contributions of the communication sciences to physiology.

    Science.gov (United States)

    Siebert, W M

    1978-05-01

    This paper reviews the impact on physiology of the revolutions in the communication sciences and technology that have occurred in the last 35 years. Particular attention is given to the significance of the cybernetic suggestions of Norbert Wiener--specifically, the ideas of negative feedback, of the computer as a brain metaphor, and of signal-and-noise considerations in information processing. It is argued that the first two of these have not in fact made much lasting contribution to physiology beyond providing loose analogies. On the other hand, the ready availability of a wide variety of electronic measuring and signal-processing devices from communication technology has clearly had a substantial impact. And it is proposed that the kind of models and concepts that are necessary for the characterization of the nervous system as an information-processing device play now, and will continue to play in the future, a major role in physiology.

  7. Contribution of neutrophils to acute lung injury.

    Science.gov (United States)

    Grommes, Jochen; Soehnlein, Oliver

    2011-01-01

    Treatment of acute lung injury (ALI) and its most severe form, acute respiratory distress syndrome (ARDS), remain unsolved problems of intensive care medicine. ALI/ARDS are characterized by lung edema due to increased permeability of the alveolar-capillary barrier and subsequent impairment of arterial oxygenation. Lung edema, endothelial and epithelial injury are accompanied by an influx of neutrophils into the interstitium and broncheoalveolar space. Hence, activation and recruitment of neutrophils are regarded to play a key role in progression of ALI/ARDS. Neutrophils are the first cells to be recruited to the site of inflammation and have a potent antimicrobial armour that includes oxidants, proteinases and cationic peptides. Under pathological circumstances, however, unregulated release of these microbicidal compounds into the extracellular space paradoxically can damage host tissues. This review focuses on the mechanisms of neutrophil recruitment into the lung and on the contribution of neutrophils to tissue damage in ALI.

  8. The enduring scientific contributions of Sigmund Freud.

    Science.gov (United States)

    Gedo, John E

    2002-01-01

    Through the development of a novel observational method, Sigmund Freud made possible the collection of reliable data about man's inner life. The scientific hypotheses he formulated about these formed the initial version of psychoanalysis. Many of these first thoughts have had to be revised in the light of subsequent scientific findings about the operations of the central nervous system, but even these refuted propositions often had much heuristic value. Despite the passage of a whole century, many Freudian hypotheses have retained their scientific standing. Most important among these was Freud's realization that human thought is usually unconscious. His understanding of the role of the automatic repetition of basic patterns of behavior, of the fateful consequences of early childhood emotional vicissitudes in structuring enduring mental dispositions, and of the distinction between two distinct modes of thinking are the most significant among his many contributions.

  9. Contribution of Lean Management to Excellence

    Directory of Open Access Journals (Sweden)

    López-Fresno Palmira

    2014-11-01

    Full Text Available To continuously and systematically improve efficiency and efficacy of processes, organizations need the implication of all employees in continuous improvement and innovation through suitable Quality Management Programs (QMPs. Effectiveness of these programs is directly linked to the requirement employees understand the methodologies and tools used for QM and the benefits that will derivate from their implementation, individually and collectively, so they can commit and implicate. Lean Management is a friendly methodology to continuously and systematically achieve process improvement, so helping the organization seeking operational excellence that contributes to overall excellence. This paper identifies Critical Success Factors (CSFs for an effective implementation of QMPs, suggests Lean Management as an easy-to-understand, powerful and friendly methodology for operational excellence and overall excellence, and presents a case experience of implementation of Lean Management in a health care organization that applies the EFQM model, and the lessons learnt.

  10. How could haloalkaliphilic microorganisms contribute to biotechnology?

    Science.gov (United States)

    Zhao, Baisuo; Yan, Yanchun; Chen, Shulin

    2014-11-01

    Haloalkaliphiles are microorganisms requiring Na(+) concentrations of at least 0.5 mol·L(-1) and an alkaline pH of 9 for optimal growth. Their unique features enable them to make significant contributions to a wide array of biotechnological applications. Organic compatible solutes produced by haloalkaliphiles, such as ectoine and glycine betaine, are correlated with osmoadaptation and may serve as stabilizers of intracellular proteins, salt antagonists, osmoprotectants, and dermatological moisturizers. Haloalkaliphiles are an important source of secondary metabolites like rhodopsin, polyhydroxyalkanoates, and exopolysaccharides that play essential roles in biogeocycling organic compounds. These microorganisms also can secrete unique exoenzymes, including proteases, amylases, and cellulases, that are highly active and stable in extreme haloalkaline conditions and can be used for the production of laundry detergent. Furthermore, the unique metabolic pathways of haloalkaliphiles can be applied in the biodegradation and (or) biotransformation of a broad range of toxic industrial pollutants and heavy metals, in wastewater treatment, and in the biofuel industry.

  11. Hysteria to conversion disorders: Babinski's contributions

    Directory of Open Access Journals (Sweden)

    Marleide da Mota Gomes

    2014-04-01

    Full Text Available The main objective of this paper is to present the importance of hysteria on Babinski's oeuvre, and the conceptions of pithiatism from Babinski until the one of conversion disorder. Babinski gave a mental basis for hysteria in the place of Charcot's encephalopatic one, and several important semiotic tools to differentiate organic from hysterical manifestations based on studies from 1893-1917/8. His teachings were spread worldwide, and in Brazil they were also appreciated in the work on hysteria by Antonio Austregesilo, the first Brazilian neurology chairman. The neurobiological basis of hysteria conceived by Charcot is nowadays reappraised, and Babinski's neurosemiological contribution is everlasting. The patients believed to be hysterical, and the two outstanding neurologists, Charcot and Babinski, gave support for the development of the modern neurology.

  12. Hysteria to conversion disorders: Babinski's contributions.

    Science.gov (United States)

    Gomes, Marleide da Mota; Engelhardt, Eliasz

    2014-04-01

    The main objective of this paper is to present the importance of hysteria on Babinski's oeuvre, and the conceptions of pithiatism from Babinski until the one of conversion disorder. Babinski gave a mental basis for hysteria in the place of Charcot's encephalopatic one, and several important semiotic tools to differentiate organic from hysterical manifestations based on studies from 1893-1917/8. His teachings were spread worldwide, and in Brazil they were also appreciated in the work on hysteria by Antonio Austregesilo, the first Brazilian neurology chairman. The neurobiological basis of hysteria conceived by Charcot is nowadays reappraised, and Babinski's neurosemiological contribution is everlasting. The patients believed to be hysterical, and the two outstanding neurologists, Charcot and Babinski, gave support for the development of the modern neurology.

  13. Pregnant teenagers' group: contributions to prenatal care.

    Science.gov (United States)

    Queiroz, Maria Veraci Oliveira; Menezes, Giselle Maria Duarte; Silva, Thaís Jormanna Pereira; Brasil, Eysler Gonçalves Maia; Silva, Raimunda Magalhães da

    2017-06-05

    To describe changes in nurses' care following the implementation of a group of pregnant teenagers in prenatal care based on the expectations and experiences of pregnant teenagers. Qualitative and descriptive study conducted from February to November 2013 at a Primary Care Unit in Fortaleza, Ceará, Brazil, through focus groups with 16 adolescents from the group of pregnant women in the second or third trimester of pregnancy. The analysis identified central ideas and units of meanings that formed the categories. The strategy of a group of pregnant teenagers, which provides a space for coexistence and the establishment of ties encourages these individuals to talk about their needs, re-signifying their ties. Educational strategies to promote self-care of pregnant teenagers and care for their babies involve the sharing of experiences, doubts and beliefs. Considerations and suggestions of the adolescents contributed to guide nurses' practice and provide a strategic space of care and support for pregnant adolescents in primary care.

  14. PSI contribution to the EU project ECOMONT

    Energy Technology Data Exchange (ETDEWEB)

    Portmann, W.; Siegwolf, R.T.; Saurer, M.; Scheidegger, Y.; Geissbuehler, P.; Furger, M.; Poggio, L.; Erne, R.; Richter, R.; Buerki, D.; Graber, W.K. [Paul Scherrer Inst. (PSI), Villigen (Switzerland)

    1997-06-01

    Land-use changes (intensification, extensification and abandonment) in agriculture and forestry are considered to be the major driving forces for changes in ecosystem function and dynamics, and in landscape patterns in Europe. The aim of the EU project ECOMONT is to investigate the potential risks due to land-use change in the mountainous ecosystem. Fluxes of sensible and latent heat, water vapour, CO{sub 2} and pollutants between the vegetation and the atmosphere are sensitive and critical factors characterising landscape function. The Atmospheric Pollution Section of the PSI contributes to this project with the measurements of these fluxes. The measuring techniques, the experimental setup and first results are presented. (author) 4 figs., 3 refs.

  15. Contributions to the 1999 particle accelerator conference

    International Nuclear Information System (INIS)

    Bernard, M.; Fartoukh, S.; Jablonka, M.; Joly, J.M.; Lalot, M.; Magne, C.; Napoly, O.; Baboi, N.; Schreiber, S.; Simrock, S.; Weise, H.

    2000-06-01

    This document puts together the 10 contributions of the laboratory to the 1999 particle accelerator conference. The titles of the papers are: 1) Evidence for a strongly coupled dipole mode with insufficient damping in the first accelerating module of the TESLA test facility (TTF); 2) An alternative scheme for stiffening superconducting RF cavities by plasma spraying; 3) A laser triggered electron source for pulsed radiolysis; 4) A cure for the energy spread increasing related bunch lengthening in electron storage rings; 5) Single bunch longitudinal instabilities in proton storage rings; 6) Analytical investigation on the halo formation in space charge dominated beams; 7) Analytical investigation on the dynamic apertures of circular accelerators; 8) The intrinsic upper limit to the beam energy of an electron-positron circular collider; 9) Coaxial disc windows for a high power superconducting cavity input coupler; and 10) RF pulsed tests on 3 GHz niobium cavities

  16. Japan's contribution to nuclear medical research

    International Nuclear Information System (INIS)

    Rahman, M.; Sakamoto, Junichi; Fukui, Tsuguya

    2002-01-01

    We investigated the degree of Japan's contribution to the nuclear medical research in the last decade. Articles published in 1991-2000 in highly reputed nuclear medical journals were accessed through the MEDLINE database. The number of articles having affiliation with a Japanese institution was counted along with publication year. In addition, shares of top-ranking countries were determined along with their trends over time. Of the total number of articles (7,788), Japan's share of articles in selected nuclear medical journals was 11.4% (889 articles) and ranked 2nd in the world after the USA (2,645 articles). The recent increase in the share was statistically significant for Japan (p=0.02, test for trend). Japan's share in nuclear medical research output is much higher than that in other biomedical fields. (author)

  17. The Contributions of Immigrants to American Culture.

    Science.gov (United States)

    Hirschman, Charles

    2013-01-01

    The standard account of American immigration focuses on the acculturation and assimilation of immigrants and their children to American society. This analysis typically ignores the significant contributions of immigrants to the creation of American culture through the performing arts, sciences, and other cultural pursuits. Immigrants and their children are not born with more creative talents than native-born citizens, but their selectivity and marginality may have pushed and pulled those with ability into high-risk career paths that reward creative work. The presence of large numbers of talented immigrants in Hollywood, academia, and the high-tech industries has pushed American institutions to be more meritocratic and open to innovation than they would be otherwise.

  18. Rapidly moving contact lines and damping contributions

    Science.gov (United States)

    Xia, Yi; Daniel, Susan; Steen, Paul

    2017-11-01

    Contact angle varies dynamically with contact line (CL) speed when a liquid moves across a solid support, as when a liquid spreads rapidly. For sufficiently rapid spreading, inertia competes with capillarity to influence the interface shape near the support. We use resonant-mode plane-normal support oscillations of droplets to drive lateral contact-line motion. Reynolds numbers based on CL speeds are high and capillary numbers are low. These are inertial-capillary motions. By scanning the driving frequency, we locate the frequency at peak amplification (resonance), obtain the scaled peak height (amplification factor) and a measure of band-width (damping ratio). We report how a parameter for CL mobility depends on these scanning metrics, with the goal of distinguishing contributions from the bulk- and CL-dissipation to overall damping.

  19. AJO Centennial: AJO contributions to Ophthalmic Genetics.

    Science.gov (United States)

    MacDonald, Ian M; Sieving, Pamela C

    2018-03-09

    To review the contributions to ophthalmic genetics through the American Journal of OphthalmologyDesign: Perspective. A literature search to retrieve original articles, letters, editorials, and published lectures from 1966 to 2017, providing a 50 year review. Titles were excluded that gave no reference to genetics or presented findings related to a non-genetic ocular condition. From a search of the Scopus database, 719 articles were ascertained. Of these 115 were excluded as the title did not reference a genetic condition or have a focus on genetic factors. Of these, four were excluded describing animal phenotypes (1966-7) and four were excluded having received no citations up to and including 2015. The highest number of citations was 283 times for a single article on familial aggregation in age-related macular degeneration. The Web of Science database yielded 771 articles; of these, 118 were excluded as not reporting human genetic studies; 55 received no citations. The highest number of citations was 307 for a single article, a 1991 paper on Leber hereditary optic neuropathy. The Journal's contributions to our understanding of the heritability of human ocular traits have been broad and deep, with international reach. The development of new techniques fostered new concepts and new approaches to rapidly expand the number of known single gene disorders with a defined molecular genetic cause. Reports on Mendelian and complex traits in the Journal abound along with six Edward Jackson Memorial Lectures on retinal dystrophies, Leber congenital amaurosis, age-related macular degeneration and glaucoma. Copyright © 2018 Elsevier Inc. All rights reserved.

  20. Contribution of Donana wetlands to carbon sequestration.

    Directory of Open Access Journals (Sweden)

    Edward P Morris

    Full Text Available Inland and transitional aquatic systems play an important role in global carbon (C cycling. Yet, the C dynamics of wetlands and floodplains are poorly defined and field data is scarce. Air-water CO2 fluxes in the wetlands of Doñana Natural Area (SW Spain were examined by measuring alkalinity, pH and other physiochemical parameters in a range of water bodies during 2010-2011. Areal fluxes were calculated and, using remote sensing, an estimate of the contribution of aquatic habitats to gaseous CO2 transport was derived. Semi-permanent ponds adjacent to the large Guadalquivir estuary acted as mild sinks, whilst temporal wetlands were strong sources of CO2 (-0.8 and 36.3 mmol(CO2 m(-2 d(-1. Fluxes in semi-permanent streams and ponds changed seasonally; acting as sources in spring-winter and mild sinks in autumn (16.7 and -1.2 mmol(CO2 m(-2 d(-1. Overall, Doñana's water bodies were a net annual source of CO2 (5.2 mol(C m(-2 y(-1. Up-scaling clarified the overwhelming contribution of seasonal flooding and allochthonous organic matter inputs in determining regional air-water gaseous CO2 transport (13.1 Gg(C y(-1. Nevertheless, this estimate is about 6 times < local marsh net primary production, suggesting the system acts as an annual net CO2 sink. Initial indications suggest longer hydroperiods may favour autochthonous C capture by phytoplankton. Direct anthropogenic impacts have reduced the hydroperiod in Doñana and this maybe exacerbated by climate change (less rainfall and more evaporation, suggesting potential for the modification of C sequestration.

  1. Contribution of Latin America to pharmacovigilance.

    Science.gov (United States)

    González, Juan Camilo; Arango, Victoria E; Einarson, Thomas R

    2006-01-01

    Pharmacovigilance activities have been ongoing for 4 decades. However, little is known (especially outside of the area) about the contribution of Latin America to this field. To review and quantify the published literature on pharmacovigilance in Latin American countries. We searched electronic databases including MEDLINE (1966-2004), EMBASE (1980-2004), International Pharmaceutical Abstracts (1970-2004), Toxline (1992-2004), Literatura Latino-Americana e do Caribe em Ciências da Saúde (1982-2004), Sistema de Información Esencial en Terapéutica y Salud (1980-2004), and the Pan American Health Organization Web site (1970-2004) for articles on pharmacovigilance or adverse drug reactions in any of the 19 major Latin American countries. Papers were retrieved and categorized according to content and country of origin by 2 independent reviewers. There were 195 usable articles from 13 countries. Fifty-one of the papers retrieved dealt with pharmacovigilance centers (15 national centers, 10 hospitals, 26 other), 55 covered pharmacovigilance itself (21 theoretical papers, 9 with description of models, 25 educational papers), and 89 were pharmacoepidemiologic studies of adverse drug reactions (69 case reports, 13 observational cohorts, 2 cohort studies, 1 randomized clinical trial, 4 clinical papers on adverse reaction management). Studies have increased exponentially since 1980. Five countries (Argentina, Brazil, Chile, Costa Rica, Venezuela) published reports from national centers. No studies were found from 6 countries: Dominican Republic, El Salvador, Honduras, Nicaragua, Paraguay, or Uruguay. Most studied categories were antiinfectives and drugs affecting the central nervous system, cardiovascular system, and musculoskeletal system. Contributions of Latin American countries to the field of pharmacovigilence have been remarkable, considering the constraints on these countries. A need exists for an increased number of formal pharmacovigilance studies and research

  2. Vascular Contributions to Cognitive Impairment and Dementia

    Science.gov (United States)

    Gorelick, Philip B.; Scuteri, Angelo; Black, Sandra E.; DeCarli, Charles; Greenberg, Steven M.; Iadecola, Costantino; Launer, Lenore J.; Laurent, Stephane; Lopez, Oscar L.; Nyenhuis, David; Petersen, Ronald C.; Schneider, Julie A.; Tzourio, Christophe; Arnett, Donna K.; Bennett, David A.; Chui, Helena C.; Higashida, Randall T.; Lindquist, Ruth; Nilsson, Peter M.; Roman, Gustavo C.; Sellke, Frank W.; Seshadri, Sudha

    2013-01-01

    Background and Purpose This scientific statement provides an overview of the evidence on vascular contributions to cognitive impairment and dementia. Vascular contributions to cognitive impairment and dementia of later life are common. Definitions of vascular cognitive impairment (VCI), neuropathology, basic science and pathophysiological aspects, role of neuroimaging and vascular and other associated risk factors, and potential opportunities for prevention and treatment are reviewed. This statement serves as an overall guide for practitioners to gain a better understanding of VCI and dementia, prevention, and treatment. Methods Writing group members were nominated by the writing group co-chairs on the basis of their previous work in relevant topic areas and were approved by the American Heart Association Stroke Council Scientific Statement Oversight Committee, the Council on Epidemiology and Prevention, and the Manuscript Oversight Committee. The writing group used systematic literature reviews (primarily covering publications from 1990 to May 1, 2010), previously published guidelines, personal files, and expert opinion to summarize existing evidence, indicate gaps in current knowledge, and, when appropriate, formulate recommendations using standard American Heart Association criteria. All members of the writing group had the opportunity to comment on the recommendations and approved the final version of this document. After peer review by the American Heart Association, as well as review by the Stroke Council leadership, Council on Epidemiology and Prevention Council, and Scientific Statements Oversight Committee, the statement was approved by the American Heart Association Science Advisory and Coordinating Committee. Results The construct of VCI has been introduced to capture the entire spectrum of cognitive disorders associated with all forms of cerebral vascular brain injury—not solely stroke—ranging from mild cognitive impairment through fully developed

  3. Biomass burning contribution to Beijing aerosol

    Directory of Open Access Journals (Sweden)

    Y. Cheng

    2013-08-01

    Full Text Available Biomass burning, the largest global source of elemental carbon (EC and primary organic carbon (OC, is strongly associated with many subjects of great scientific concern, such as secondary organic aerosol and brown carbon which exert important effects on the environment and on climate in particular. This study investigated the relationships between levoglucosan and other biomass burning tracers (i.e., water soluble potassium and mannosan based on both ambient samples collected in Beijing and source samples. Compared with North America and Europe, Beijing was characterized by high ambient levoglucosan concentrations and low winter to summer ratios of levoglucosan, indicating significant impact of biomass burning activities throughout the year in Beijing. Comparison of levoglucosan and water soluble potassium (K+ levels suggested that it was acceptable to use K+ as a biomass burning tracer during summer in Beijing, while the contribution of fireworks to K+ could be significant during winter. Moreover, the levoglucosan to K+ ratio was found to be lower during the typical summer period (0.21 ± 0.16 compared with the typical winter period (0.51 ± 0.15. Levoglucosan correlated strongly with mannosan (R2 = 0.97 throughout the winter and the levoglucosan to mannosan ratio averaged 9.49 ± 1.63, whereas levoglucosan and mannosan exhibited relatively weak correlation (R2 = 0.73 during the typical summer period when the levoglucosan to mannosan ratio averaged 12.65 ± 3.38. Results from positive matrix factorization (PMF model analysis showed that about 50% of the OC and EC in Beijing were associated with biomass burning processes. In addition, a new source identification method was developed based on the comparison of the levoglucosan to K+ ratio and the levoglucosan to mannosan ratio among different types of biomass. Using this method, the major source of biomass burning aerosol in Beijing was suggested to be the combustion of crop residuals, while the

  4. Satellite Contributions to Global Change Studies

    Science.gov (United States)

    Parkinson, Claire L.

    2009-01-01

    By providing a global view with a level playing field (no region missed because of unfavorable surface conditions or political boundaries), satellites have made major contributions to improved monitoring and understanding of our constantly changing planet. The global view has allowed surprising realizations like the relative sparsity of lightning strikes over oceans and the large-scale undulations on the massive Antarctic ice sheet. It has allowed the tracking of all sorts of phenomena, including aerosols, both natural and anthropogenic, as they move with the atmospheric circulation and impact weather and human health. But probably nothing that the global view allows is more important in the long term than its provision. of unbiased data sets to address the issue of global change, considered by many to be among the most important issues facing humankind today. With satellites we can monitor atmospheric temperatures at all latitudes and longitudes, and obtain a global average that lessens the likelihood of becoming endlessly mired in the confusions brought about by the certainty of regional differences. With satellites we can monitor greenhouse gases such as CO2 not just above individual research stations but around the globe. With satellites we can monitor the polar sea ice covers, as we have done since the late 1970s, determining and quantifying the significant reduction in Arctic sea ice and the slight growth in Antarctic sea ice over that period, With satellites we can map the full extent and changes in the Antarctic stratospheric ozone depletions that were first identified from using a single ground station; and through satellite data we have witnessed from afar land surface changes brought about by humans both intentionally, as with wide-scale deforestation, and unintentionally, as with the decay of the Aral Sea. The satellite data are far from sufficient for all that we need in order to understand the global system and forecast its changes, as we also need

  5. Quantifying emission reduction contributions by emerging economics

    Energy Technology Data Exchange (ETDEWEB)

    Moltmann, Sara; Hagemann, Markus; Eisbrenner, Katja; Hoehne, Niklas [Ecofys GmbH, Koeln (Germany); Sterk, Wolfgang; Mersmann, Florian; Ott, Hermann E.; Watanabe, Rie [Wuppertal Institut (Germany)

    2011-04-15

    Further action is needed that goes far beyond what has been agreed so far under the United Nations Framework Convention on Climate Change (UNFCCC) and the Kyoto Protocol to 'prevent dangerous anthropogenic interference with the climate system', the ultimate objective of the UNFCCC. It is out of question that developed countries (Annex I countries) will have to take a leading role. They will have to commit to substantial emission reductions and financing commitments due to their historical responsibility and their financial capability. However, the stabilisation of the climate system will require global emissions to peak within the next decade and decline well below half of current levels by the middle of the century. It is hence a global issue and, thus, depends on the participation of as many countries as possible. This report provides a comparative analysis of greenhouse gas (GHG) emissions, including their national climate plans, of the major emitting developing countries Brazil, China, India, Mexico, South Africa and South Korea. It includes an overview of emissions and economic development, existing national climate change strategies, uses a consistent methodology for estimating emission reduction potential, costs of mitigation options, provides an estimate of the reductions to be achieved through the national climate plans and finally provides a comparison of the results to the allocation of emission rights according to different global effort-sharing approaches. In addition, the report discusses possible nationally appropriate mitigation actions (NAMAs) the six countries could take based on the analysis of mitigation options. This report is an output of the project 'Proposals for quantifying emission reduction contributions by emerging economies' by Ecofys and the Wuppertal Institute for the Federal Environment Agency in Dessau. It builds upon earlier joint work ''Proposals for contributions of emerging economies to the climate

  6. Inflammasome and Fas-Mediated IL-1β Contributes to Th17/Th1 Cell Induction in Pathogenic Bacterial Infection In Vivo.

    Science.gov (United States)

    Uchiyama, Ryosuke; Yonehara, Shin; Taniguchi, Shun'ichiro; Ishido, Satoshi; Ishii, Ken J; Tsutsui, Hiroko

    2017-08-01

    CD4 + Th cells play crucial roles in orchestrating immune responses against pathogenic microbes, after differentiating into effector subsets. Recent research has revealed the importance of IFN-γ and IL-17 double-producing CD4 + Th cells, termed Th17/Th1 cells, in the induction of autoimmune and inflammatory diseases. In addition, Th17/Th1 cells are involved in the regulation of infection caused by the intracellular bacterium Mycobacterium tuberculosis in humans. However, the precise mechanism of Th17/Th1 induction during pathogen infection is unclear. In this study, we showed that the inflammasome and Fas-dependent IL-1β induces Th17/Th1 cells in mice, in response to infection with the pathogenic intracellular bacterium Listeria monocytogenes In the spleens of infected wild-type mice, Th17/Th1 cells were induced, and expressed T-bet and Rorγt. In Pycard -/- mice, which lack the adaptor molecule of the inflammasome (apoptosis-associated speck-like protein containing a caspase recruitment domain), Th17/Th1 induction was abolished. In addition, the Fas-mediated IL-1β production was required for Th17/Th1 induction during bacterial infection: Th17/Th1 induction was abolished in Fas -/- mice, whereas supplementation with recombinant IL-1β restored Th17/Th1 induction via IL-1 receptor 1 (IL-1R1), and rescued the mortality of Fas -/- mice infected with Listeria IL-1R1, but not apoptosis-associated speck-like protein containing a caspase recruitment domain or Fas on T cells, was required for Th17/Th1 induction, indicating that IL-1β stimulates IL-1R1 on T cells for Th17/Th1 induction. These results indicate that IL-1β, produced by the inflammasome and Fas-dependent mechanisms, contributes cooperatively to the Th17/Th1 induction during bacterial infection. This study provides a deeper understanding of the molecular mechanisms underlying Th17/Th1 induction during pathogenic microbial infections in vivo. Copyright © 2017 by The American Association of Immunologists

  7. Contribution inequality in the spatial public goods game: Should the rich contribute more?

    Science.gov (United States)

    Tu, Jing

    2018-04-01

    Scale-free property exists in resource distribution, and the rich pay more in public goods is commonplace in reality. What will happen if the rich are expected to contribute more in the spatial public goods game? This paper therefore proposes a new contribution paradigm, in which individual contribution is determined by his payoff in the last evolution step. Tunable parameter w is used to characterize the contribution rate of nodes whose payoff is larger than the average. The results of simulations reveal that the impact of w on cooperation is associated with the enhancement factor r. When r is low, the higher w is, the lower the cooperation rate is. With the increment of r, the value of w to optimize cooperation rate increases with r. The relationship of cooperation rate and wealth on the network has also been investigated. Interestingly, higher cooperation rate does not always lead to higher wealth. Finally, the impact of w on the wealth distribution on the network is explored. The higher w reduces the inequality in wealth distribution by the shrinking of lower-class, which is enhanced by a higher r.

  8. [Cognitive neuroscience of aging. Contributions and challenges].

    Science.gov (United States)

    Díaz, Fernando; Pereiro, Arturo X

    The cognitive neuroscience of aging is a young discipline that has emerged as a result of the combination of: A) the theoretical and explanatory frameworks proposed by the cognitive psychology perspective throughout the second half of the twentieth century; B) the designs and methodological procedures arising from experimental psychology and the need to test the hypotheses proposed from the cognitive psychology perspective; C) the contributions of the computer sciences to the explanation of brain functions; and D) the development and use of neuroimaging techniques that have enabled the recording of brain activity in humans while tasks that test some cognitive process or function are performed. An analysis on the impact of research conducted from this perspective over the last 3decades has been carried out, including its shortcomings, as well as the potential directions and usefulness that will advantageously continue to drive this discipline in its description and explanation of the process es of cerebral and cognitive aging. Copyright © 2017 SEGG. Publicado por Elsevier España, S.L.U. All rights reserved.

  9. Centers of Excellence Contribution to Knowledge Augmentation

    International Nuclear Information System (INIS)

    Mignone, O.

    2016-01-01

    Full text: Knowledge management is a key need of the nuclear industry to cope with the knowledge limited augmentation and the risks of knowledge loss due to a number of reasons, such as: staff attrition, organizational changes, upgraded technologies, new projects implementation, and the nuclear power evolution in recent years (i.e., post-Fukushima upgrades). This document describes the contribution of nuclear centers of excellence to knowledge augmentation. The effective implementation of nuclear centers of excellence is a key success factor for the knowledge management programme of nuclear organizations. This document, is based on a real example of operating organization approach in launching such initiative for staff knowledge augmentation and performance improvement. Eventually, any type of organizations in the nuclear sector could apply the proposed technique to reach better knowledge usage. The nuclear centers of excellence are a key knowledge management initiative for the learning organizations that are caring about organizational intellectual capital and striving for performance improvement. The nuclear centers of excellence can be realized as a forum to exchange ideas, knowledge, information, experiences; to collect lessons learned; and to identify areas for improvement where further organizational competence building is needed. Usual realization of this initiative is going through an active staff involvement in knowledge sharing in a form of different technical communities of practice focusing on specific knowledge domains. (author

  10. Does coring contribute to tree mortality?

    Science.gov (United States)

    van Mantgem, P.J.; Stephenson, N.L.

    2004-01-01

    We assess the potential of increment coring, a common method for measuring tree ages and growth, to contribute to mortality. We used up to 21 years of annual censuses from two cored and two uncored permanent plots in the Sierra Nevada of California, to detect changes in mortality rates 12 years following coring for individuals >5 cm DBH from two coniferous species, Abies concolor (Gordon & Glend.) Lindl. (white fir) and Abies magnifica A. Murr. (red fir). Using a randomized before-after control impact (BACI) design, we found no differences in mortality rates following coring for 825 cored and 525 uncored A. concolor and 104 cored and 66 uncored A. magnifica. These results support the view that collecting tree cores can be considered nondestructive sampling, but we emphasize that our 12-year postcoring records are short compared with the maximum life-span of these trees and that other species in different environments may prove to be more sensitive to coring. ?? 2004 NRC Canada.

  11. Epibiotic pressure contributes to biofouling invader success.

    Science.gov (United States)

    Leonard, Kaeden; Hewitt, Chad L; Campbell, Marnie L; Primo, Carmen; Miller, Steven D

    2017-07-12

    Reduced competition is a frequent explanation for the success of many introduced species. In benthic marine biofouling communities, space limitation leads to high rates of overgrowth competition. Some species can utilise other living organisms as substrate (epibiosis), proffering a competitive advantage for the epibiont. Additionally, some species can prevent or reduce epibiotic settlement on their surfaces and avoid being basibionts. To test whether epibiotic pressure differs between native and introduced species, we undertook ex situ experiments comparing bryozoan larval settlement to determine if introduced species demonstrate a greater propensity to settle as epibionts, and a reduced propensity to be basibionts, than native species. Here we report that introduced species opportunistically settle on any space (bare, native, or introduced), whereas native species exhibit a strong tendency to settle on and near other natives, but avoid settling on or near introduced basibionts. In addition, larvae of native species experience greater larval wastage (mortality) than introduced species, both in the presence and absence of living substrates. Introduced species' ability to settle on natives as epibionts, and in turn avoid epibiosis as basibionts, combined with significantly enhanced native larval wastage, provides a comprehensive suite of competitive advantages contributing to the invasion success of these biofouling species.

  12. Dan Joseph's contributions to disperse multiphase flow

    Science.gov (United States)

    Prosperetti, Andrea

    2012-11-01

    During his distinguished career, Dan Joseph worked on a vast array of problems. One of these, which occupied him off and on over the last two decades of his life, was that of flows with suspended finite-size particles at finite Reynolds numbers. He realized early on that progress in this field had to rely on the insight gained from numerical simulation, an area in which he was a pioneer. On the basis of the early numerical results he recognized the now famous ``drafting, kissing and tumbling'' mechanism of particle-particle interaction, the possibility of fluidization by lift and many others. With a number of colleagues and a series of gifted students he produced a significant body of work summarized in his on-line book Interrogations of Direct Numerical Simulation of Solid-Liquid Flows available from http://www.efluids.com/efluids/books/joseph.htm. This presentation will describe Joseph's contribution to the understanding of disperse multiphase flow and conclude with some examples from the author's recent work in this area. Supported by NSF.

  13. Towards psychoanalytic contribution to linguistic metaphor theory.

    Science.gov (United States)

    Caspi, Tair

    2017-07-05

    This paper lays out a formulation of the psychoanalytical contribution to linguistic metaphor theory. The author's main argument is that psychoanalysis can help enrich and shed light on linguistic metaphor theories, since these have focused on the cognitive aspect, to the exclusion of the role played by affect. Based on the tight link between metaphor and symbol - both configurations of figurative language - the author shall apply ideas sourced from some of the key psychoanalytic symbolization theories, focusing in particular on Klein, Winnicott, and Ogden. The course of exploration will serve to trace the unconscious emotional aspects that participate in the metaphor's mechanism, just as they participate in the symbol's workings. The study leads to the main conclusion that the intersubjective transitional space is of substantial importance to metaphor's constitution, particularly in regard to novel metaphors. Expanding the understanding of metaphor's modus operandi has important implications in conceptual clarification and for an in-depth analytical work, and is of immense significance when it comes to analytical work with patients who suffer impairment of their metaphoric ability. Copyright © 2017 Institute of Psychoanalysis.

  14. Rock mechanics contributions from defense programs

    International Nuclear Information System (INIS)

    Heuze, F.E.

    1992-02-01

    An attempt is made at illustrating the many contributions to rock mechanics from US defense programs, over the past 30-plus years. Large advances have been achieved in the technology-base area covering instrumentation, material properties, physical modeling, constitutive relations and numerical simulations. In the applications field, much progress has been made in understanding and being able to predict rock mass behavior related to underground explosions, cratering, projectile penetration, and defense nuclear waste storage. All these activities stand on their own merit as benefits to national security. But their impact is even broader, because they have found widespread applications in the non-defense sector; to name a few: the prediction of the response of underground structures to major earthquakes, the physics of the earth's interior at great depths, instrumentation for monitoring mine blasting, thermo-mechanical instrumentation useful for civilian nuclear waste repositories, dynamic properties of earthquake faults, and transient large-strain numerical modeling of geological processes, such as diapirism. There is not pretense that this summary is exhaustive. It is meant to highlight success stories representative of DOE and DOD geotechnical activities, and to point to remaining challenges

  15. The Contribution of IVS to IGGOS

    Science.gov (United States)

    Nothnagel, A.

    2002-05-01

    Since its inauguration in 1999, the International VLBI Service for Geodesy and Astrometry has made significant progress in the coordination and utilisation of worldwide VLBI resources. Improving the visibility of the IVS components to a wider public in turn led to a higher motivation of the individuals to contribute to the global effort. Not only the number of IVS components but also their investments in terms of funds and manpower demonstrate the increased awareness of the importance of this joint international endeavour. The different demands of the users but also of the contributors often require the definition of priorities which are only being acceptable due to the existence of a strong umbrella organisation like the IVS. Significant progress has also been made in the area of routine data analysis and combination of results. By now, six IVS Analysis Centers provide the redundancy necessary for a robust combination of the results. The use of ITRF2000 station coordinates as the basis for the IVS combined EOP series is the most recent step towards the generation of a consistent chain from the quasi-inertial frame of radio sources to system Earth.

  16. Contribution of Gut Bacteria to Liver Pathobiology

    Directory of Open Access Journals (Sweden)

    Gakuhei Son

    2010-01-01

    Full Text Available Emerging evidence suggests a strong interaction between the gut microbiota and health and disease. The interactions of the gut microbiota and the liver have only recently been investigated in detail. Receiving approximately 70% of its blood supply from the intestinal venous outflow, the liver represents the first line of defense against gut-derived antigens and is equipped with a broad array of immune cells (i.e., macrophages, lymphocytes, natural killer cells, and dendritic cells to accomplish this function. In the setting of tissue injury, whereby the liver is otherwise damaged (e.g., viral infection, toxin exposure, ischemic tissue damage, etc., these same immune cell populations and their interactions with the infiltrating gut bacteria likely contribute to and promote these pathologies. The following paper will highlight recent studies investigating the relationship between the gut microbiota, liver biology, and pathobiology. Defining these connections will likely provide new targets for therapy or prevention of a wide variety of acute and chronic liver pathologies.

  17. Assessing Urban Landscape Variables’ Contributions to Microclimates

    Directory of Open Access Journals (Sweden)

    Tammy E. Parece

    2016-01-01

    Full Text Available The well-known urban heat island (UHI effect recognizes prevailing patterns of warmer urban temperatures relative to surrounding rural landscapes. Although UHIs are often visualized as single features, internal variations within urban landscapes create distinctive microclimates. Evaluating intraurban microclimate variability presents an opportunity to assess spatial dimensions of urban environments and identify locations that heat or cool faster than other locales. Our study employs mobile weather units and fixed weather stations to collect air temperatures across Roanoke, Virginia, USA, on selected dates over a two-year interval. Using this temperature data, together with six landscape variables, we interpolated (using Kriging and Random Forest air temperatures across the city for each collection period. Our results estimated temperatures with small mean square errors (ranging from 0.03 to 0.14; landscape metrics explained between 60 and 91% of temperature variations (higher when the previous day’s average temperatures were included as a variable. For all days, similar spatial patterns appeared for cooler and warmer areas in mornings, with distinctive patterns as landscapes warmed during the day and over successive days. Our results revealed that the most potent landscape variables vary according to season and time of day. Our analysis contributes new dimensions and new levels of spatial and temporal detail to urban microclimate research.

  18. THE CONTRIBUTION OF GESTURES TO PERSONAL BRANDING

    Directory of Open Access Journals (Sweden)

    Brînduşa-Mariana Amălăncei

    2015-07-01

    Full Text Available A form of (self-promotion but also an authentic strategic choice, the personal brand has become a topical preoccupation of marketing specialists. Personal branding or self-marketing represents an innovative concept that associates the efficiency of personal development with the effectiveness of communication and marketing techniques adapted to the individual and that comprises the entire collection of techniques allowing the identification and promotion of the self/individual. The main objective is a clear communication with regard to personal identity, no matter by means of which method, so that it gives uniqueness and offers a competitive advantage. Although online promotion is increasingly gaining ground for the creation of a personal brand, an individual’s verbal and nonverbal behaviour represent very important differentiating elements. Starting from the premise that gestures often complement, anticipate, substitute or contradict the verbal, we will endeavour to highlight a number of significations that can be attributed to the various body movements and that can successfully contribute to the creation of a powerful personal brand.

  19. Quantification of social contributions to earthquake mortality

    Science.gov (United States)

    Main, I. G.; NicBhloscaidh, M.; McCloskey, J.; Pelling, M.; Naylor, M.

    2013-12-01

    Death tolls in earthquakes, which continue to grow rapidly, are the result of complex interactions between physical effects, such as strong shaking, and the resilience of exposed populations and supporting critical infrastructures and institutions. While it is clear that the social context in which the earthquake occurs has a strong effect on the outcome, the influence of this context can only be exposed if we first decouple, as much as we can, the physical causes of mortality from our consideration. (Our modelling assumes that building resilience to shaking is a social factor governed by national wealth, legislation and enforcement and governance leading to reduced levels of corruption.) Here we attempt to remove these causes by statistically modelling published mortality, shaking intensity and population exposure data; unexplained variance from this physical model illuminates the contribution of socio-economic factors to increasing earthquake mortality. We find that this variance partitions countries in terms of basic socio-economic measures and allows the definition of a national vulnerability index identifying both anomalously resilient and anomalously vulnerable countries. In many cases resilience is well correlated with GDP; people in the richest countries are unsurprisingly safe from even the worst shaking. However some low-GDP countries rival even the richest in resilience, showing that relatively low cost interventions can have a positive impact on earthquake resilience and that social learning between these countries might facilitate resilience building in the absence of expensive engineering interventions.

  20. FACTORS CONTRIBUTING TO PERINATAL MORTALITY : OPTIMIZING OUTCOME

    Directory of Open Access Journals (Sweden)

    Lakshmi

    2015-03-01

    Full Text Available OBJECTIVE: To evaluate the various causes of perinatal deaths and adopt strategies to improve perinatal outcome at a referral teaching hospital in North Kerala. METHODS: A prospective observational study conducted at Institute of Maternal and Child Health, Government Medical College, Kozhikode. All perinatal deaths during the period January 2013 to December 2014 were analysed and from this factors responsible for perinatal deaths were identified. RESULTS: Out of total 30,042 deliveries , there were 966 perinatal deaths during the study period. 566 were still births and 400 early neonatal deaths. The perinatal mortality rate was 31.1 per 1000 live births. Perinatal asphyxia was the major cause of perinatal mortality. The important factors contributing to perinatal asphyxia were prematurity (39%, abruptio placenta (19% and MSAF ( 12%. Among the antenatal factors, hypertensive disorders of pregnancy leading to iatrogenic elective preterm delivery were the most important. CONCLUSION: Perinatal asphyxia due to prematurity and low birth weight emerged as the most important cause of perinatal mortality in this study and hypertensive disorders of pregnancy were the most important antenatal complication leading to prematurity

  1. Retinal dendritic cell recruitment, but not function, was inhibited in MyD88 and TRIF deficient mice

    OpenAIRE

    Heuss, Neal D; Pierson, Mark J; Montaniel, Kim Ramil C; McPherson, Scott W; Lehmann, Ute; Hussong, Stacy A; Ferrington, Deborah A; Low, Walter C; Gregerson, Dale S

    2014-01-01

    Background Immune system cells are known to affect loss of neurons due to injury or disease. Recruitment of immune cells following retinal/CNS injury has been shown to affect the health and survival of neurons in several models. We detected close, physical contact between dendritic cells and retinal ganglion cells following an optic nerve crush, and sought to understand the underlying mechanisms. Methods CD11c-DTR/GFP mice producing a chimeric protein of diphtheria toxin receptor (DTR) and GF...

  2. The Contribution of Missionaries to Shona Lexicography*

    Directory of Open Access Journals (Sweden)

    Advice Viriri

    2011-10-01

    Full Text Available

    Abstract: The article discusses the developments in Shona lexicography during the colonial eraand the contribution made by the missionaries in general and Father M. Hannan in particularwhich later resulted in the on-going process of compiling monolingual dictionaries by the AfricanLanguages Research Institute (ALRI (into which the ALLEX project has been transformed. Themissionaries employed various methods that did not only signal the beginning of an economicallyexploitative relationship between "the West and the rest of us" but also had ancillary cultural consequences(Dathorne 1975: 3. Their motives towards the development of African literature in generaland Zimbabwean lexicographic work in particular were primarily evangelical and not to furthercreative writing. This caused Father Hannan to experience problems not only in his translationof the Shona Bible but also in his Standard Shona Dictionary. Hannan is used as an example becausehis translation problems were typical of those experienced by all missionaries. Hannan's dictionarywas a welcome new development using the orthography introduced in 1931 and revised in 1955.The aim of his dictionary was "to record Shona words in Standard Shona spelling" (Hannan 1959:ix. Hannan's dictionary has made a considerable contribution to standardising Shona orthography.

    Keywords: LEXICOGRAPHY, MISSIONARY, COBUILD, SHONA DICTIONARY, MONOLINGUALDICTIONARY, BILINGUAL DICTIONARY, CULTURE, TRANSLATION, STANDARDORTHOGRAPHY, COLONIALISM, CULTURAL IMPERIALISM, SHONA PROVERBS,AFRICAN LANGUAGES RESEARCH INSTITUTE (ALRI, INFLUENCE.

    Opsomming: Die bydrae van sendelinge tot die Sjonaleksikografie. Die artikelbespreek die ontwikkelinge in Sjonaleksikografie gedurende die koloniale tydperk en die bydraegemaak deur die sendelinge in die algemeen en Vader M. Hannan in die besonder, wat later uitgeloophet op die voortgaande proses van die samestelling van eentalige woordeboeke deur dieAfrican Languages

  3. Neuronal glycogen synthesis contributes to physiological aging.

    Science.gov (United States)

    Sinadinos, Christopher; Valles-Ortega, Jordi; Boulan, Laura; Solsona, Estel; Tevy, Maria F; Marquez, Mercedes; Duran, Jordi; Lopez-Iglesias, Carmen; Calbó, Joaquim; Blasco, Ester; Pumarola, Marti; Milán, Marco; Guinovart, Joan J

    2014-10-01

    Glycogen is a branched polymer of glucose and the carbohydrate energy store for animal cells. In the brain, it is essentially found in glial cells, although it is also present in minute amounts in neurons. In humans, loss-of-function mutations in laforin and malin, proteins involved in suppressing glycogen synthesis, induce the presence of high numbers of insoluble polyglucosan bodies in neuronal cells. Known as Lafora bodies (LBs), these deposits result in the aggressive neurodegeneration seen in Lafora's disease. Polysaccharide-based aggregates, called corpora amylacea (CA), are also present in the neurons of aged human brains. Despite the similarity of CA to LBs, the mechanisms and functional consequences of CA formation are yet unknown. Here, we show that wild-type laboratory mice also accumulate glycogen-based aggregates in the brain as they age. These structures are immunopositive for an array of metabolic and stress-response proteins, some of which were previously shown to aggregate in correlation with age in the human brain and are also present in LBs. Remarkably, these structures and their associated protein aggregates are not present in the aged mouse brain upon genetic ablation of glycogen synthase. Similar genetic intervention in Drosophila prevents the accumulation of glycogen clusters in the neuronal processes of aged flies. Most interestingly, targeted reduction of Drosophila glycogen synthase in neurons improves neurological function with age and extends lifespan. These results demonstrate that neuronal glycogen accumulation contributes to physiological aging and may therefore constitute a key factor regulating age-related neurological decline in humans. © 2014 The Authors. Aging cell published by the Anatomical Society and John Wiley & Sons Ltd.

  4. Contribution of systematic reviews to management decisions.

    Science.gov (United States)

    Cook, Carly N; Possingham, Hugh P; Fuller, Richard A

    2013-10-01

    Systematic reviews comprehensively summarize evidence about the effectiveness of conservation interventions. We investigated the contribution to management decisions made by this growing body of literature. We identified 43 systematic reviews of conservation evidence, 23 of which drew some concrete conclusions relevant to management. Most reviews addressed conservation interventions relevant to policy decisions; only 35% considered practical on-the-ground management interventions. The majority of reviews covered only a small fraction of the geographic and taxonomic breadth they aimed to address (median = 13% of relevant countries and 16% of relevant taxa). The likelihood that reviews contained at least some implications for management tended to increase as geographic coverage increased and to decline as taxonomic breadth increased. These results suggest the breadth of a systematic review requires careful consideration. Reviews identified a mean of 312 relevant primary studies but excluded 88% of these because of deficiencies in design or a failure to meet other inclusion criteria. Reviews summarized on average 284 data sets and 112 years of research activity, yet the likelihood that their results had at least some implications for management did not increase as the amount of primary research summarized increased. In some cases, conclusions were elusive despite the inclusion of hundreds of data sets and years of cumulative research activity. Systematic reviews are an important part of the conservation decision making tool kit, although we believe the benefits of systematic reviews could be significantly enhanced by increasing the number of reviews focused on questions of direct relevance to on-the-ground managers; defining a more focused geographic and taxonomic breadth that better reflects available data; including a broader range of evidence types; and appraising the cost-effectiveness of interventions. © 2013 The Authors. Conservation Biology published by Wiley

  5. Ketogenesis contributes to intestinal cell differentiation.

    Science.gov (United States)

    Wang, Qingding; Zhou, Yuning; Rychahou, Piotr; Fan, Teresa W-M; Lane, Andrew N; Weiss, Heidi L; Evers, B Mark

    2017-03-01

    The intestinal epithelium undergoes a continual process of proliferation, differentiation and apoptosis. Previously, we have shown that the PI3K/Akt/mTOR pathway has a critical role in intestinal homeostasis. However, the downstream targets mediating the effects of mTOR in intestinal cells are not known. Here, we show that the ketone body β-hydroxybutyrate (βHB), an endogenous inhibitor of histone deacetylases (HDACs) induces intestinal cell differentiation as noted by the increased expression of differentiation markers (Mucin2 (MUC2), lysozyme, IAP, sucrase-isomaltase, KRT20, villin, Caudal-related homeobox transcription factor 2 (CDX2) and p21 Waf1 ). Conversely, knockdown of the ketogenic mitochondrial enzyme hydroxymethylglutaryl CoA synthase 2 (HMGCS2) attenuated spontaneous differentiation in the human colon cancer cell line Caco-2. Overexpression of HMGCS2, which we found is localized specifically in the more differentiated portions of the intestinal mucosa, increased the expression of CDX2, thus further suggesting the contributory role of HMGCS2 in intestinal differentiation. In addition, mice fed a ketogenic diet demonstrated increased differentiation of intestinal cells as noted by an increase in the enterocyte, goblet and Paneth cell lineages. Moreover, we showed that either knockdown of mTOR or inhibition of mTORC1 with rapamycin increases the expression of HMGCS2 in intestinal cells in vitro and in vivo, suggesting a possible cross-talk between mTOR and HMGCS2/βHB signaling in intestinal cells. In contrast, treatment of intestinal cells with βHB or feeding mice with a ketogenic diet inhibits mTOR signaling in intestinal cells. Together, we provide evidence showing that HMGCS2/βHB contributes to intestinal cell differentiation. Our results suggest that mTOR acts cooperatively with HMGCS2/βHB to maintain intestinal homeostasis.

  6. FAM5C contributes to aggressive periodontitis.

    Directory of Open Access Journals (Sweden)

    Flavia M Carvalho

    2010-04-01

    Full Text Available Aggressive periodontitis is characterized by a rapid and severe periodontal destruction in young systemically healthy subjects. A greater prevalence is reported in Africans and African descendent groups than in Caucasians and Hispanics. We first fine mapped the interval 1q24.2 to 1q31.3 suggested as containing an aggressive periodontitis locus. Three hundred and eighty-nine subjects from 55 pedigrees were studied. Saliva samples were collected from all subjects, and DNA was extracted. Twenty-one single nucleotide polymorphisms were selected and analyzed by standard polymerase chain reaction using TaqMan chemistry. Non-parametric linkage and transmission distortion analyses were performed. Although linkage results were negative, statistically significant association between two markers, rs1935881 and rs1342913, in the FAM5C gene and aggressive periodontitis (p = 0.03 was found. Haplotype analysis showed an association between aggressive periodontitis and the haplotype A-G (rs1935881-rs1342913; p = 0.009. Sequence analysis of FAM5C coding regions did not disclose any mutations, but two variants in conserved intronic regions of FAM5C, rs57694932 and rs10494634, were found. However, these two variants are not associated with aggressive periodontitis. Secondly, we investigated the pattern of FAM5C expression in aggressive periodontitis lesions and its possible correlations with inflammatory/immunological factors and pathogens commonly associated with periodontal diseases. FAM5C mRNA expression was significantly higher in diseased versus healthy sites, and was found to be correlated to the IL-1beta, IL-17A, IL-4 and RANKL mRNA levels. No correlations were found between FAM5C levels and the presence and load of red complex periodontopathogens or Aggregatibacter actinomycetemcomitans. This study provides evidence that FAM5C contributes to aggressive periodontitis.

  7. Physical Design Factors Contributing to Patient Falls.

    Science.gov (United States)

    Pati, Debajyoti; Valipoor, Shabboo; Cloutier, Aimee; Yang, James; Freier, Patricia; Harvey, Thomas E; Lee, Jaehoon

    2017-02-03

    The aim of this study was to identify physical design elements that contribute to potential falls in patient rooms. An exploratory, physical simulation-based approach was adopted for the study. Twenty-seven subjects, older than 70 years (11 male and 16 female subjects), conducted scripted tasks in a mockup of a patient bathroom and clinician zone. Activities were captured using motion-capture technology and video recording. After biomechanical data processing, video clips associated with potential fall moments were extracted and then examined and coded by a group of registered nurses and health care designers. Exploratory analyses of the coded data were conducted followed by a series of multivariate analyses using regression models. In multivariate models with all personal, environmental, and postural variables, only the postural variables demonstrated statistical significance-turning, grabbing, pushing, and pulling in the bathroom and pushing and pulling in the clinician zone. The physical elements/attributes associated with the offending postures include bathroom configuration, intravenous pole, door, toilet seat height, flush, grab bars, over-bed table, and patient chair. Postural changes, during interactions with the physical environment, constitute the source of most fall events. Physical design must include simultaneous examination of postural changes in day-to-day activities in patient rooms and bathrooms. Among discussed testable recommendations in the article, the followings design strategies should be considered: (a) designing bathrooms to reduce turning as much as possible and (b) designing to avoid motions that involve 2 or more of the offending postures, such as turning and grabbing or grabbing and pulling, and so on.

  8. Traits contributing to the autistic spectrum.

    Directory of Open Access Journals (Sweden)

    Colin D Steer

    2010-09-01

    Full Text Available It is increasingly recognised that traits associated with autism reflect a spectrum with no clear boundary between typical and atypical behaviour. Dimensional traits are needed to investigate the broader autism phenotype.Ninety-three individual measures reflecting components of social, communication and repetitive behaviours characterising autistic spectrum disorder (ASD were identified between the ages of 6 months and 9 years from the ALSPAC database. Using missing value imputation, data for 13,138 children were analysed. Factor analysis suggested the existence of 7 factors explaining 85% of the variance. The factors were labelled: verbal ability, language acquisition, social understanding, semantic-pragmatic skills, repetitive-stereotyped behaviour, articulation and social inhibition. Four factors (1, 3, 5 and 7 were specific to ASD being more strongly associated with this phenotype than other co-morbid conditions while other factors were more associated with learning difficulties and specific language impairment. Nevertheless, all 7 factors contributed independently to the explanation of ASD (p<0.001. Exploration of putative genetic causal factors such as variants in the CNTNAP2 gene showed a varying pattern of associations with these traits. An alternative predictive model of ASD was derived using four individual measures: the coherence subscale of the Children's Communication Checklist (9y, the Social and Communication Disorders Checklist (91 m, repetitive behaviour (69 m and the sociability subscale of the Emotionality Activity and Sociability measure (38 m. Although univarably these traits performed better than some factors, their combined explanations of ASD were similar (R(2 =  0.48.These results support the fractional nature of ASD with different aetiological origins for these components despite pleiotropic genetic effects being observed. These traits are likely to be useful in the exploration of ASD.

  9. Elements that contribute to healthy building design.

    Science.gov (United States)

    Loftness, Vivian; Hakkinen, Bert; Adan, Olaf; Nevalainen, Aino

    2007-06-01

    The elements that contribute to a healthy building are multifactorial and can be discussed from different perspectives. WE PRESENT THREE VIEWPOINTS OF DESIGNING A HEALTHY BUILDING: the importance of sustainable development, the role of occupants for ensuring indoor air quality, and ongoing developments related to indoor finishes with low chemical emissions and good fungal resistance. Sustainable design rediscovers the social, environmental, and technical values of pedestrian and mixed-use communities, using existing infrastructures including "main streets" and small-town planning principles and recapturing indoor-outdoor relationships. This type of design introduces nonpolluting materials and assemblies with lower energy requirements and higher durability and recyclability. Building occupants play a major role in maintaining healthy indoor environments, especially in residences. Contributors to indoor air quality include cleaning habits and other behaviors; consumer products, furnishings, and appliances purchases, as well as where and how the occupants use them. Certification of consumer products and building materials as low-emitting products is a primary control measure for achieving good indoor air quality. Key products in this respect are office furniture, flooring, paints and coatings, adhesives and sealants, wall coverings, wood products, textiles, insulation, and cleaning products. Finishing materials play a major role in the quality of indoor air as related to moisture retention and mold growth. Sustainable design emphasizes the needs of infrastructure, lower energy consumption, durability, and recyclability. To ensure good indoor air quality, the product development for household use should aim to reduce material susceptibility to contaminants such as mold and should adopt consumer-oriented product labeling.

  10. Clinical Research Informatics Contributions from 2015.

    Science.gov (United States)

    Daniel, C; Choquet, R

    2016-11-10

    To summarize key contributions to current research in the field of Clinical Research Informatics (CRI) and to select best papers published in 2015. A bibliographic search using a combination of MeSH and free terms search over PubMed on Clinical Research Informatics (CRI) was performed followed by a double-blind review in order to select a list of candidate best papers to be then peer-reviewed by external reviewers. A consensus meeting between the two section editors and the editorial team was finally organized to conclude on the selection of best papers. Among the 579 returned papers published in the past year in the various areas of Clinical Research Informatics (CRI) - i) methods supporting clinical research, ii) data sharing and interoperability, iii) re-use of healthcare data for research, iv) patient recruitment and engagement, v) data privacy, security and regulatory issues and vi) policy and perspectives - the full review process selected four best papers. The first selected paper evaluates the capability of the Clinical Data Interchange Standards Consortium (CDISC) Operational Data Model (ODM) to support the representation of case report forms (in both the design stage and with patient level data) during a complete clinical study lifecycle. The second selected paper describes a prototype for secondary use of electronic health records data captured in non-standardized text. The third selected paper presents a privacy preserving electronic health record linkage tool and the last selected paper describes how big data use in US relies on access to health information governed by varying and often misunderstood legal requirements and ethical considerations. A major trend in the 2015 publications is the analysis of observational, "nonexperimental" information and the potential biases and confounding factors hidden in the data that will have to be carefully taken into account to validate new predictive models. In addiction, researchers have to understand

  11. The soil physics contributions of Edgar Buckingham

    Science.gov (United States)

    Nimmo, J.R.; Landa, E.R.

    2005-01-01

    During 1902 to 1906 as a soil physicist at the USDA Bureau of Soils (BOS), Edgar Buckingham originated the concepts of matric potential, soil-water retention curves, specific water capacity, and unsaturated hydraulic conductivity (K) as a distinct property of a soil. He applied a formula equivalent to Darcy's law (though without specific mention of Darcy's work) to unsaturated flow. He also contributed significant research on quasi-empirical formulas for K as a function of water content, water flow in capillary crevices and in thin films, and scaling. Buckingham's work on gas flow in soils produced paradigms that are consistent with our current understanding. His work on evaporation elucidated the concept of self-mulching and produced sound and sometimes paradoxical generalizations concerning conditions that favor or retard evaporation. Largely overshadowing those achievements, however, is that he launched a theory, still accepted today, that could predict transient water content as a function of time and space. Recently discovered documents reveal some of the arguments Buckingham had with BOS officials, including the text of a two-paragraph conclusion of his famous 1907 report on soil water, and the official letter documenting rejection of that text. Strained interpersonal relations motivated the departure of Buckingham and other brilliant physicists (N.E. Dorsey, F.H. King, and Lyman Briggs) from the BOS during 1903 to 1906. Given that Buckingham and his BOS colleagues had been rapidly developing the means of quantifying unsaturated flow, these strained relations probably slowed the advancement of unsaturated flow theory. ?? Soil Science Society of America.

  12. French contribution to develop Prussian blue.

    Science.gov (United States)

    Besse Bardot, Isabelle; Bardot, Sebastien; Menetrier, Florence; Leiterer, Alexandra; Pech, Annick

    2014-11-01

    Prussian blue is an antidote indicated for the treatment of internal cesium radioisotope contamination. The French armed forces develop and manufacture some antidotal drugs meeting regulatory, analytical and pharmaceutical requirements in order to submit marketing authorization documentation. Prior to an initial meeting with the French National Agency for Medicines and Health Products Safety (ANSM) in 2011, the authors were following regulatory developments in free cyanide release, active pharmaceutical ingredient (API) synthesis, API specifications, ability of cesium/Prussian blue binding products and collection of pre-clinical data. Free cyanide release was assessed by ultraviolet-visible (UV-Vis) spectrometry at 615 nm. The kinetics of cesium were evaluated in vitro by flame atomic absorption. Good laboratory practice (GLP) and mutagenic assays were examined in rat studies to assess 'no absorption'. A validated method makes it possible to assess the free cyanide in API according to the published tolerability in humans. The French synthesizer meets good manufacturing practice (GMP) to give a drug that is compliant with all specifications, ensuring its high quality. Two standard mutagenic assays showed mutagenic potential, leading to further tests to obtain more information on any induced chromosomal aberrations. Absorption could be an important factor in determining the risk posed by the drug. The French health service provides the country with several antidotal drugs reducing Chemical, Biological, Radiological and Nuclear (CBRN) risks. Using their GMP manufacturing facilities and pharmaceutical expertise, the French armed forces have contributed to developing drugs with marketing authorization, such as pentetate calcium trisodium (Ca-DTPA) for infusion, or under development with the French Alternative Energies and Atomic Energy Commission (CEA), such as Ca-DTPA by inhalation.

  13. Serotonergic contribution to boys' behavioral regulation.

    Directory of Open Access Journals (Sweden)

    Amélie Nantel-Vivier

    Full Text Available Animal and human adult studies reveal a contribution of serotonin to behavior regulation. Whether these findings apply to children is unclear. The present study investigated serotonergic functioning in boys with a history of behavior regulation difficulties through a double-blind, acute tryptophan supplementation procedure.Participants were 23 boys (age 10 years with a history of elevated physical aggression, recruited from a community sample. Eleven were given a chocolate milkshake supplemented with 500 mg tryptophan, and 12 received a chocolate milkshake without tryptophan. Boys engaged in a competitive reaction time game against a fictitious opponent, which assessed response to provocation, impulsivity, perspective taking, and sharing. Impulsivity was further assessed through a Go/No-Go paradigm. A computerized emotion recognition task and a staged instrumental help incident were also administered.Boys, regardless of group, responded similarly to high provocation by the fictitious opponent. However, boys in the tryptophan group adjusted their level of responding optimally as a function of the level of provocation, whereas boys in the control group significantly decreased their level of responding towards the end of the competition. Boys in the tryptophan group tended to show greater perspective taking, tended to better distinguish facial expressions of fear and happiness, and tended to provide greater instrumental help to the experimenter.The present study provides initial evidence for the feasibility of acute tryptophan supplementation in children and some effect of tryptophan supplementation on children's behaviors. Further studies are warranted to explore the potential impact of increased serotonergic functioning on boys' dominant and affiliative behaviors.

  14. Salivary contribution to exhaled nitric oxide.

    Science.gov (United States)

    Zetterquist, W; Pedroletti, C; Lundberg, J O; Alving, K

    1999-02-01

    Dietary and metabolic nitrate is distributed from the blood to the saliva by active uptake in the salivary glands, and is reduced to nitrite in the oral cavity by the action of certain bacteria. Since it has been reported that nitric oxide may be formed nonenzymatically from nitrite this study aimed to determine whether salivary nitrite could influence measurements of exhaled NO. Ten healthy subjects fasted overnight and ingested 400 mg potassium nitrate, equivalent to approximately 200 g spinach. Exhaled NO and nasal NO were regularly measured with a chemiluminescence technique up to 3 h after the ingestion. Measurements of exhaled NO were performed with a single-breath procedure, standardized to a 20-s exhalation, at a flow of 0.15 L x s(-1), and oral pressure of 8-10 cmH2O. Values of NO were registered as NO release rate (pmol x s(-1)) during the plateau of exhalation. Exhaled NO increased steadily over time after nitrate load and a maximum was seen at 120 min (77.0+/-15.2 versus 31.2+/-3.0 pmol x s(-1), pnitrite concentrations increased in parallel; at 120 min there was a four-fold increase compared with baseline (1.56+/-0.44 versus 0.37+/-0.09 mM, pnitrite-reducing conditions in the oral cavity were also manipulated by the use of different mouthwash procedures. The antibacterial agent chlorhexidine acetate (0.2%) decreased NO release by almost 50% (pnitrate loading and reduced the preload control levels by close to 30% (pnitric oxide formation contributes to nitric oxide in exhaled air and a large intake of nitrate-rich foods before the investigation might be misinterpreted as an elevated inflammatory activity in the airways. This potential source of error and the means for avoiding it should be considered in the development of a future standardized method for measurements of exhaled nitric oxide.

  15. Contributions to Pursuit-Evasion Game Theory

    Science.gov (United States)

    Oyler, Dave Wilson

    is developed that requires minimal information and highlights a limitation of dominance regions. These contributions extend pursuit-evasion game theory to a number of games that have not previously been solved, and in some cases, the solutions presented are more amenable to implementation than previous methods.

  16. CERN Health Insurance Scheme (CHIS): Monthly Contributions for 2016

    CERN Multimedia

    HR Department

    2015-01-01

    For 2016, the contribution rate for active and retired CHIS members will be 4.86%. The amounts of the fixed contributions for voluntarily insured members (e.g. users and other associates), as well as the supplementary contributions for spouses with income from a professional activity or with a retirement pension (including a CERN pension), are thus as follows:   1. Voluntary contributions The full contribution based on Reference Salary II is 1218 CHF per month. This fixed contribution is applied to voluntarily affiliated users and other associates with normal coverage. Half of this amount, 609 CHF, is applied to voluntarily affiliated users and other associates with reduced coverage. Finally, an amount of 487 CHF is applied to children maintaining their insurance cover on a voluntary and temporary basis. 2. Supplementary contributions The supplementary contribution for the spouse or registered partner of a staff member, fellow or pensioner is now as follows, according to the spouse’s month...

  17. Japanese contributions to IAEA INTOR Workshop, phase IIA

    International Nuclear Information System (INIS)

    Tomabechi, Ken; Hiraoka, Tohru; Fujisawa, Noboru; Nishio, Satoshi; Sawada, Yoshio; Kobayashi, Takeshi.

    1982-11-01

    Japanese contributions at INTOR Phase 2A are summarized as a first three chapters of the report, Japanese Contributions to INTOR Workshop, Phase 2A. This report contains Introduction, Summary of the total report and INTOR Concepts. (author)

  18. The contributions of construction material waste to project cost ...

    African Journals Online (AJOL)

    Material wastage on construction sites can contribute to cost overruns. Research to provide evidence of the extent of material wastages' contribution to cost overruns on construction sites is based mostly on surveys. Thus, the actual contribution is not yet ascertained. The purpose of this article is to report the results of an ...

  19. 26 CFR 1.408A-5 - Recharacterized contributions.

    Science.gov (United States)

    2010-04-01

    ... transfers to a traditional IRA the $160,000 plus allocable net income. No other contributions have been made... the FIRST IRA, and any net income transferred with the recharacterized contribution is treated as..., then is moved (with net income attributable to the contribution) in a tax-free transfer to another IRA...

  20. 5 CFR 831.405 - Interest on voluntary contributions.

    Science.gov (United States)

    2010-01-01

    ....405 Section 831.405 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT (CONTINUED) CIVIL SERVICE... contributions stop earning interest on the earliest of— (1) The date when OPM authorizes payment to the... voluntary contributions to purchase additional annuity, voluntary contributions stop earning interest on the...

  1. 76 FR 18490 - Contributions to the Telecommunications Relay Service Fund

    Science.gov (United States)

    2011-04-04

    ...] Contributions to the Telecommunications Relay Service Fund AGENCY: Federal Communications Commission. ACTION... service to participate in and contribute to the Telecommunications Relay Services (TRS) Fund. The law... INFORMATION: This is a summary of the Commission's Contributions to the Telecommunications Relay Service Fund...

  2. Shear Strength of Concrete I-Beams - Contributions of Flanges

    DEFF Research Database (Denmark)

    Teoh, B. K.; Hoang, Cao Linh; Nielsen, Mogens Peter

    1999-01-01

    The contribution of flanges to the shear strength of reinforced concrete beams has up to now either been neglected or evaluated by very simple empirical formulas. However, the contribution may sometimes be large, up to 20-30%. In this paper the flange contribution for shear reinforced I-beams has...

  3. 26 CFR 1.704-4 - Distribution of contributed property.

    Science.gov (United States)

    2010-04-01

    ... fact that A was entitled to 50 percent of the $20,000 post-contribution appreciation in Property B. The... 26 Internal Revenue 8 2010-04-01 2010-04-01 false Distribution of contributed property. 1.704-4... TAX (CONTINUED) INCOME TAXES Partners and Partnerships § 1.704-4 Distribution of contributed property...

  4. 75 FR 39034 - Public Housing Annual Contributions Contract

    Science.gov (United States)

    2010-07-07

    ... Contributions Contract AGENCY: Office of the Chief Information Officer, HUD. ACTION: Notice. SUMMARY: The... Contributions Contract (ACC) with certain requirements applicable to all project and other requirements... Contributions Contract. OMB Approval Number: 2577-New. Form Numbers: Certain information collections do not have...

  5. 26 CFR 31.3231(e)-2 - Contribution base.

    Science.gov (United States)

    2010-04-01

    ... 26 Internal Revenue 15 2010-04-01 2010-04-01 false Contribution base. 31.3231(e)-2 Section 31.3231... Contribution base. The term compensation does not include any remuneration paid during any calendar year by an employer to an employee for services rendered in excess of the applicable contribution base. For rules...

  6. Contributions of GRACE to Climate Monitoring

    Science.gov (United States)

    Rodell, Matthew; Famiglietti, James; Chambers, Don P.; Wahr, John

    2011-01-01

    western Antarctica. For 2002 to present, the rate of ice mass loss has been 200 to 300 GT/yr in Greenland and 70 to 210 GT/yr in Antarctica, and some scientists are suggesting that the rates are accelerating. Similarly, GRACE has been used to monitor mass changes in alpine glaciers. Tamisiea et al. first characterized glacier melt along the southern coast of Alaska, more recently estimated to be occurring at a rate of 84 GT/yr. Chen et al. estimated that Patagonian glaciers are melting at a rate of 28 GT/yr, and estimated that the high mountains of central Asia lose ice at a rate of 47 GT/yr. Tapley et al. and Wahr et al. presented the first GRACE based estimates of changes in column-integrated terrestrial water storage (TWS; the sum of ground-water, soil moisture, surface waters, snow, ice, and water stored in vegetation) at continental scales. Since then, dozens of studies have shown that GRACE based estimates of regional to continental scale TWS variations agree with independent information, and some innovative uses of GRACE data have been developed. Rodell et al. (2004) and Swenson and Wahr (2006) demonstrated that by combining GRACE derived terrestrial water storage changes with observations of precipitation and runoff in a river basin scale water budget, it was possible to produce new estimates of evapotranspiration and atmospheric moisture convergence, essential climate variables that are difficult to estimate accurately. Similarly, GRACE has been used to constrain estimates of global river discharge and the contribution of changes in TWS to sea level rise. Crowley et al. observed a negative correlation between interannual TWS anomalies in the Amazon and the Congo River basin. Yeh et al. and Rodell et al. estimated regionally averaged groundwater storage variations based on GRACE and auxiliary observations. Rodell et al. and Tiwari et al. applied that method to quantify massive groundwater depletion in northern India caused by over reliance on aquifers for irration

  7. The Italian contribution to the CSES satellite

    Science.gov (United States)

    Conti, Livio

    2016-04-01

    We present the Italian contribution to the CSES (China Seismo-Electromagnetic Satellite) mission. The CSES satellite aims at investigating electromagnetic field, plasma and particles in the near-Earth environment in order to study in particular seismic precursors, particles fluxes (from Van Allen belts, cosmic rays, solar wind, etc.), anthropogenic electromagnetic pollution and more in general the atmosphere-ionosphere-magnetosphere coupling mechanisms that can affect the climate changes. The launch of CSES - the first of a series of several satellite missions - is scheduled by the end of 2016. The CSES satellite has been financed by the CNSA (China National Space Agency) and developed by CEA (China Earthquake Administration) together with several Chinese research institutes and private companies such as the DFH (that has developed the CAST2000 satellite platform). Italy participates to the CSES satellite mission with the LIMADOU project funded by ASI (Italian Space Agency) in collaboration with the Universities of Roma Tor Vergata, Uninettuno, Trento, Bologna and Perugia, as well as the INFN (Italian National Institute of Nuclear Physics), INGV (Italian National Institute of Geophysics and Volcanology) and INAF-IAPS (Italian National Institute of Astrophysics and Planetology). Many analyses have shown that satellite observations of electromagnetic fields, plasma parameters and particle fluxes in low Earth orbit may be useful in order to study the existence of electromagnetic emissions associated with the occurrence of earthquakes of medium and high magnitude. Although the earthquakes forecasting is not possible today, it is certainly a major challenge - and perhaps even a duty - for science in the near future. The claims that the reported anomalies (of electromagnetic, plasma and particle parameters) are seismic precursors are still intensely debated and analyses for confirming claimed correlations are still lacking. In fact, ionospheric currents, plasma

  8. Less work, less respect: authors' perceived importance of research contributions and their declared contributions to research articles.

    Science.gov (United States)

    Ivaniš, Ana; Hren, Darko; Marušić, Matko; Marušić, Ana

    2011-01-01

    Attitudes towards authorship are connected with authors' research experience and with knowledge of authorship criteria of International Committee of Medical Journal Editors (ICMJE). The objective of this study was to assess association between authors' perceived importance of contributions for authorship qualification and their participation in manuscripts submitted to a journal. Authors (n = 1181) of 265 manuscripts submitted to the Croatian Medical Journal were asked to identify and rate their contribution in the preparation of the submitted manuscript (0-none to 4-full for 11 listed contributions) and the importance of these contributions as authorship qualifications (0-none to 4-full). They were randomly allocated into 3 groups: the first (n = 90 manuscripts, n = 404 authors) first received the contribution disclosure form and then contribution importance-rating questionnaire; the second (n = 88 manuscripts, n = 382 authors) first received the rating questionnaire and then the contribution disclosure form, and the third group (n = 87 manuscripts, n = 395 authors) received both questionnaires at the same time. We compared authors' perception of importance of contribution categories. 1014 (85.9%) authors of 235 manuscripts responded. Authors who declared contribution to a specific category rated it as more important for authorship than those authors who did not contribute to the same category (P>0.005 for all contribution categories, Mann-Withney test). Authors qualifying for ICMJE authorship rated all contribution categories higher than non-qualifying authors. For all contributions, associations between perceived importance of contribution and actual author's contribution were statistically significant. Authorship seems to be not a normative issue subjective to categorization into criteria, but also a very personal view of the importance and value of one's contributions.

  9. Measurement of the contribution of neutrons to hadron calorimeter signals

    International Nuclear Information System (INIS)

    Akchurin, N.; Berntzon, L.; Cardini, A.; Ferrari, R.; Gaudio, G.; Hauptman, J.; Kim, H.; La Rotonda, L.; Livan, M.; Meoni, E.; Paar, H.; Penzo, A.; Pinci, D.; Policicchio, A.; Popescu, S.; Susinno, G.; Roh, Y.; Vandelli, W.; Wigmans, R.

    2007-01-01

    The contributions of neutrons to hadronic signals from the DREAM calorimeter are measured by analyzing the time structure of these signals. The neutrons, which mainly originate from the evaporation stage of nuclear breakup in the hadronic shower development process, contribute through elastic scattering off protons in the plastic scintillating fibers which provide the dE/dx information in this calorimeter. This contribution is characterized by an exponential tail in the pulse shape, with a time constant of ∼25ns. The relative contribution of neutrons to the signals increases with the distance from the shower axis. As expected, the neutrons do not contribute to the DREAM Cherenkov signals

  10. Decreased SAP expression in T cells from patients with SLE contributes to early signaling abnormalities and reduced IL-2 production

    Science.gov (United States)

    Karampetsou, Maria P.; Comte, Denis; Kis-Toth, Katalin; Terhorst, Cox; Kyttaris, Vasileios C.; Tsokos, George C.

    2016-01-01

    T cells from patients with systemic lupus erythematosus (SLE) display a number of functions including increased early signaling events following engagement of the T cell receptor (TCR). Signaling lymphocytic activation molecule family (SLAMF) cell surface receptors and the X-chromosome-defined signaling lymphocytic activation molecule-associated protein (SAP) adaptor are important in the development of several immunocyte lineages and modulating immune response. Here we present evidence that SAP protein levels are decreased in T cells and in their main subsets isolated from 32 women and 3 men with SLE independently of disease activity. In SLE T cells the SAP protein is also subject to increased degradation by a caspase-3. Forced expression of SAP in SLE T cells simultaneously heightened IL-2 production, calcium (Ca2+) responses and tyrosine phosphorylation of a number of proteins. Exposure of normal T cells to SLE serum IgG, known to contain anti-CD3/TCR antibodies, resulted in SAP downregulation. We conclude that SLE T cells display reduced levels of the adaptor protein SAP probably as a result of continuous T cell activation and degradation by caspase-3. Restoration of SAP levels in SLE T cells corrects the overexcitable lupus T cell phenotype. PMID:27183584

  11. Contribution of Systematic Reviews to Management Decisions

    Science.gov (United States)

    COOK, CARLY N; POSSINGHAM, HUGH P; FULLER, RICHARD A

    2014-01-01

    Systematic reviews comprehensively summarize evidence about the effectiveness of conservation interventions. We investigated the contribution to management decisions made by this growing body of literature. We identified 43 systematic reviews of conservation evidence, 23 of which drew some concrete conclusions relevant to management. Most reviews addressed conservation interventions relevant to policy decisions; only 35% considered practical on-the-ground management interventions. The majority of reviews covered only a small fraction of the geographic and taxonomic breadth they aimed to address (median = 13% of relevant countries and 16% of relevant taxa). The likelihood that reviews contained at least some implications for management tended to increase as geographic coverage increased and to decline as taxonomic breadth increased. These results suggest the breadth of a systematic review requires careful consideration. Reviews identified a mean of 312 relevant primary studies but excluded 88% of these because of deficiencies in design or a failure to meet other inclusion criteria. Reviews summarized on average 284 data sets and 112 years of research activity, yet the likelihood that their results had at least some implications for management did not increase as the amount of primary research summarized increased. In some cases, conclusions were elusive despite the inclusion of hundreds of data sets and years of cumulative research activity. Systematic reviews are an important part of the conservation decision making tool kit, although we believe the benefits of systematic reviews could be significantly enhanced by increasing the number of reviews focused on questions of direct relevance to on-the-ground managers; defining a more focused geographic and taxonomic breadth that better reflects available data; including a broader range of evidence types; and appraising the cost-effectiveness of interventions. Contribuciones de las Revisiones Sistemáticas a las

  12. CHIS - Annual adjustment of benefits and fixed contributions

    CERN Multimedia

    HR Department

    2010-01-01

    As foreseen by the CHIS Rules, an annual adjustment is applied to: ceilings for certain benefits contributions for voluntary membership as well as supplementary contributions for spouses/partners. Benefits The ceilings have been maintained at the level of 2009. The full list of benefits is available on the CHIS Website.   Voluntary contributions The full contribution based on reference salary II is now 975 CHF per month. This fixed amount contribution is applied to voluntary affiliated users and associates with normal coverage. Half of this rate (487 CHF) is applied to apprentices as well as to voluntary affiliated users and associates with reduced coverage. A rate of 390 CHF is applied to children maintaining their insurance cover on a voluntary and temporarily basis.   Supplementary contributions From 1st January 2010 the supplementary contribution for the spouse or registered partner of a staff member, fellow or pensioner is as follow...

  13. Contribution of Heavy Water Board in nuclear fuel cycle technologies. Contributed Paper IT-03

    International Nuclear Information System (INIS)

    Mohanty, P.R.

    2014-01-01

    The three stage Indian nuclear power programme envisages use of closed nuclear fuel cycle and thorium utilization as its mainstay for long term energy security on sustainable basis. India is committed to realize this objective through the development and deployment of frontier technologies pertaining to all aspects of a closed nuclear fuel cycle. Comprehensive indigenous capabilities have been developed in all aspects of nuclear power and associated fuel cycles. Heavy Water Board (HWB), with its abiding objective of fulfilling demand of heavy water for India's flourishing nuclear power program, is one of the frontrunner in Nuclear Fuel Cycle Technology. HWB is now engaged in wide spectrum of activities in various facets of fuel cycle covering all the three stages of Indian Nuclear Power Programme. HWB is contributing to Nuclear Fuel Cycle through large scale production and sustained supply of key input materials including heavy water, solvents for nuclear hydrometallurgy, 10 B enriched boron etc

  14. CERN Health Insurance Scheme (CHIS) Contributions – Changes for 2012

    CERN Multimedia

    HR Department

    2012-01-01

    Following the 2010 five-yearly review of financial and social conditions, which included the CERN Health Insurance Scheme (CHIS), the CERN Council decided in December 2010 to progressively increase the level of contributions over the period 2011-2015.   For 2012, the contribution rate of active and retired CHIS members will be 4.41%. The amounts of the fixed premiums for voluntarily insured members (e.g. users and associates) as well as the supplementary contributions for spouses with income from a professional activity increase accordingly : Voluntary contributions The full contribution based on Reference Salary II is now 1094 CHF per month. This fixed amount contribution is applied to voluntarily affiliated users and associates with normal coverage. Half of this amount (547 CHF) is applied to apprentices as well as to voluntarily affiliated users and associates with reduced coverage. Finally, an amount of 438 CHF is applied to children maintaining their insurance cover on a voluntary and tempo...

  15. Proposed level of Member States' contributions as from 2006

    CERN Document Server

    2005-01-01

    The document "The scientific activities of CERN and budget estimates for the years 2006-2009 and Projections for the year 2010" was presented to the Finance Committee in June. At its June Session, the Council requested the Management to prepare the Preliminary Draft Budget for 2006 on the basis of an income level corresponding to the 2005 contributions at 2005 prices, excluding the additional income resulting from the exceptional indexation of the two Host States. This document contains a proposal for a contribution level that takes account of these constraints, and expresses the need for a decision on the special cases of three Member States contributions. The Finance Committee is invited to recommend and the Council to approve the minimum level of contributions of 977.3 MCHF in 2006, with the consideration of possible transition measures for the contributions of Finland, Greece and Portugal. Additional voluntary contributions from the Host States and application of agreed transition measures will allow the ...

  16. Dissociating contributions of head and torso to spatial reference frames

    DEFF Research Database (Denmark)

    Alsmith, Adrian J T; Ferrè, Elisa R; Longo, Matthew R.

    2017-01-01

    contribution of each part to spatial judgments. Both the head and the torso contributed to judgements, though with greater contributions from the torso. A second experiment manipulating visual contrast of the torso showed that this does not reflect low-level differences in visual salience between body parts....... Our results demonstrate that spatial perspective-taking relies on a weighted combination of reference frames centred on different parts of the body....

  17. Contribution of different body segments in Sit and Reach Test

    OpenAIRE

    Andrea Perin; Leandra Ulbricht; Eduardo Borba Neves

    2015-01-01

    This research aims to determine the contributions of the hip joint, lumbar and thoracic spine in the execution of Sit and Reach (SR) in young Brazilians. Subjects were 195 boys from 18 to 19 years., Sit and Reach  was evaluated with angular kinematic analysis through of Photogrammetry to identify the contribution of body segments in trunk flexion.  A protocol was developed for evaluating reference angles that were transformed into percentage contribution of the segments. Based on the results,...

  18. Contributions from Women to the Radiation Sciences: A Brief History.

    Science.gov (United States)

    Martinez, Nicole E

    2017-04-01

    Contributions from men to radiation science are well known, particularly the early contributions from such luminaries as William Roentgen, James Chadwick, Niels Bohr, Robert Oppenheimer, and the like. Although not ignored per se, beyond Marie Curie and Lise Meitner, the contributions of female nuclear scientists are not as widely recognized. This paper provides a concise historical summary of contributions to radiation science from the discovery of radiation through the current status of international leadership within the radiation protection community. Beyond lead scientists and academics, this paper also considers support personnel as well as the role women have played in the advancement of radiation epidemiology.

  19. Influence Of The Social Contributions On The Enterprise Behaviour

    Directory of Open Access Journals (Sweden)

    Nicoleta MIHĂILĂ

    2012-06-01

    Full Text Available The current fiscal system comprises a multitude of taxes, dues and contributions which the enterprise has to pay. The large number of taxes and dues to be paid put a high fiscal pressure on the enterprise and the social contributions are a determining factor in the manifestation of the fiscal behaviour of the enterprises. The employer has to pay to the state a significant proportion of the gross wage of the employee, almost 30%, which includes: the contribution to the social insurances, the contribution to the unemployment fund, the contribution to the Single National Fund for Health Social Insurance, the contribution to the guarantee fund for wages, the contribution to the health insurances, the contribution to the fund for accidents and the fee for the Chamber of Labour. The employee must also pay the state a total of 32.5% which consists of the contribution to the social insurances, the contribution to the unemployment fund, the contribution to the health insurances and the income tax. A simple calculation shows that the net income of the employee from his/her gross income is much lower than the revenue to the state from this wage. The state charges a burdening 45% on each job, while the employee earns almost 55%. This percentage is an obstacle for business development in Romania, where the labour force is overtaxed. Within this context, the pressure presumed by any increase of the minimal national wage is very strong for the employers and it generates unemployment, informal work and tax evasion.

  20. Melatonin inhibits type 1 interferon signaling of toll-like receptor 4 via heme oxygenase-1 induction in hepatic ischemia/reperfusion.

    Science.gov (United States)

    Kang, Jung-Woo; Lee, Sun-Mee

    2012-08-01

    The cytoprotective mechanisms of melatonin in hepatic ischemia/reperfusion (I/R) injury associated with heme oxygenase-1 (HO-1) induction and type 1 interferon (IFN) signaling pathway downstream of toll-like receptor 4 (TLR4) were investigated. Rats were subjected to 60min of ischemia followed by 5-hr reperfusion. Melatonin (10mg/kg) or vehicle (5% ethanol in saline) was administered intraperitoneally 15min prior to ischemia and immediately before reperfusion. Rats were pretreated with zinc protoporphyrin (ZnPP, 10mg/kg, i.p.), a HO-1 inhibitor, at 16 and 3hr prior to ischemia. Melatonin attenuated the I/R-induced increase in serum alanine aminotransferase activity, and ZnPP reversed this attenuation. Melatonin augmented the levels of HO activity and HO-1 protein and mRNA expression, and this enhancement was reversed by ZnPP. Melatonin enhanced the level of NF-E2-related factor-2 (Nrf2) nuclear translocation, and ZnPP reversed this increase. Overexpression of TLR4 and its adaptor proteins, toll-receptor-associated activator of interferon (TRIF), and myeloid differentiation factor 88 (MyD88), induced by I/R, was attenuated by melatonin; ZnPP reversed the effect of melatonin on TLR4 and TRIF expression. Melatonin suppressed the increased interaction between TLR4/TRIF and TLR4/MyD88, which was reversed by ZnPP. Melatonin attenuated the increased levels of JAK2 and STAT1 activation as well as IFN-β, and ZnPP reversed these inhibitory effects of melatonin. Melatonin inhibited the level of chemokine (C-X-C motif) ligand 10 (CXCL-10), and ZnPP reversed this inhibition. Our findings suggest that melatonin protects the liver against I/R injury by HO-1 overexpression, which suppresses the type 1 IFN signaling pathway downstream of TLR4. © 2012 John Wiley & Sons A/S.