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  1. Decreased Expression of T-Cell Costimulatory Molecule CD28 on CD4 and CD8 T Cells of Mexican Patients with Pulmonary Tuberculosis

    PubMed Central

    Bernal-Fernandez, German; Espinosa-Cueto, Patricia; Leyva-Meza, Rosario; Mancilla, Nathalie; Mancilla, Raul

    2010-01-01

    Patients with tuberculosis frequently develop anergy, a state of T-cell hyporesponsiveness in which defective T-cell costimulation could be a factor. To know if the expression of T-cell costimulatory molecules was altered in tuberculosis, we analyzed the peripheral blood T-cell phenotype of 23 Mexican patients with pulmonary tuberculosis. There was severe CD4 (P < .001) and CD8 (P < .01) lymphopenia and upregulation of costimulatory molecule CD30 on CD4 and CD8 T cells (P < .05); this increase was higher in relapsing tuberculosis. The main finding was severe downregulation of the major costimulatory molecule CD28 on both CD8 and CD4 T cells (P < .001). Depletion of the CD4/CD28 subset, a hitherto undescribed finding, is relevant because CD4 T cells constitute the main arm of the cell-mediated antimycobacterial immune response. PMID:22567259

  2. CD28: a signalling perspective.

    PubMed Central

    Ward, S G

    1996-01-01

    CD28 and the related molecule cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), together with their natural ligands B7.1 and B7.2, have been implicated in the differential regulation of several immune responses. CD28 provides signals during T cell activation which are required for the production of interleukin 2 and other cytokines and chemokines, and it has also been implicated in the regulation of T cell anergy and programmed T cell death. The biochemical signals provided by CD28 are cyclosporin A-resistant and complement those provided by the T cell antigen receptor to allow full activation of T cells. Multiple signalling cascades which may be independent of, or dependent on, protein tyrosine kinase activation have been demonstrated to be activated by CD28, including activation of phospholipase C, p21ran, phosphoinositide 3-kinase, sphingomyelinase/ceramide and 5-lipoxygenase. The relative contributions of these cascades to overall CD28 signalling are still unknown, but probably depend on the state of activation of the T cell and the level of CD28 activation. The importance of these signalling cascades (in particular the phosphoinositide 3-kinase-mediated cascade) to functional indications of CD28 activation, such as interleukin 2 gene regulation, has been investigated using pharmacological and genetic manipulations. These approaches have demonstrated that CD28-activated signalling cascades regulate several transcription factors involved in interleukin 2 transcriptional activation. This review describes in detail the structure and expression of the CD28 and B7 families, the functional outcomes of CD28 ligation and the signalling events that are thought to mediate these functions. PMID:8809021

  3. From TGN1412 to TAB08: the return of CD28 superagonist therapy to clinical development for the treatment of rheumatoid arthritis.

    PubMed

    Tyrsin, Dmitry; Chuvpilo, Sergey; Matskevich, Alexey; Nemenov, Daniil; Römer, Paula S; Tabares, Paula; Hünig, Thomas

    2016-01-01

    CD28 superagonists (CD28SA) are CD28-specific monoclonal antibodies which are able to activate T-cells without overt TCR engagement. In rodents, CD28SA efficiently activate regulatory T-cells and are therapeutically effective in multiple models of autoimmunity, inflammation and transplantation. However, a phase I study of the human CD28SA TGN1412 in 2006 resulted in a life-threatening cytokine storm. This brief review summarises preclinical work before and since the failed phase I trial with an emphasis on understanding the reasons why there had been no warning of toxicity, and how a novel assay paved the way for a new phase I, phase Ib (both completed), and an ongoing phase II study.

  4. [Construction of a recombinant baculovirus transfer vector with two promoters expressing the anti-human CD28 chimeric antibody by using TP-PCR method].

    PubMed

    Zhu, Yan; Chen, Yong-Jing; Qiu, Yu-Hua; Zheng, Feng-Feng; Zhu, Jiang

    2005-09-01

    CD28, a cell surface glycoprotein, predominantly expressed on T cells, belongs to the Ig superfamily and provides critical co-stimulatory signals. The data which have published indicate that the monoclonal antibody against CD28 can decrease curative effects when it was applied in vivo for a long time. In order to avoid the human-anti-mouse action, anti-CD28 mAb must be humanized before it can be used in clinical study. Chimeric antibody, consisting of variable regions of mouse antibody and the constant regions of human IgG1, is often chosen by designers in generating humanized antibody. In this study, to prepare the anti-human CD28 chimeric antibody, the genes coding variable regions of anti-CD28 mAb and the constant regions of human IgG1 were cloned by PCR method. Then, the target genes were assembled by TP-PCR, a novel method developed for fusing genes without designing endonuclease sites at the both end of the target genes, and inserted into the baculovirus transfer vector pAcUW3 respectively. Thus, the recombinant baculovirus transfer vector with two strong promoters, ph and p10 was successfully constructed, which can express two different foreign genes at the same time. The recombinant vector was identified by the methods of restriction digesting, electrophoresis, PCR amplification and further verified by DNA sequence analysis. This work will contribute to expressing the chimeric CD28 antibody in insect cells.

  5. CD28 Family and Chronic Rejection: “To Belatacept...and Beyond!”

    PubMed Central

    Silva, Marcos V.; Machado, Juliana R.; Rocha, Laura P.; Castellano, Lúcio R.; Reis, Marlene A.; Corrêa, Rosana R. M.

    2012-01-01

    Kidneys are one of the most frequently transplanted human organs. Immunosuppressive agents may prevent or reverse most acute rejection episodes; however, the graft may still succumb to chronic rejection. The immunological response involved in the chronic rejection process depends on both innate and adaptive immune response. T lymphocytes have a pivotal role in chronic rejection in adaptive immune response. Meanwhile, we aim to present a general overview on the state-of-the-art knowledge of the strategies used for manipulating the lymphocyte activation mechanisms involved in allografts, with emphasis on T-lymphocyte costimulatory and coinhibitory molecules of the B7-CD28 superfamily. A deeper understanding of the structure and function of these molecules improves both the knowledge of the immune system itself and their potential action as rejection inducers or tolerance promoters. In this context, the central role played by CD28 family, especially the relationship between CD28 and CTLA-4, becomes an interesting target for the development of immune-based therapies aiming to increase the survival rate of allografts and to decrease autoimmune phenomena. Good results obtained by the recent development of abatacept and belatacept with potential clinical use aroused better expectations concerning the outcome of transplanted patients. PMID:22720132

  6. Unusual CD4+CD28− T Cells and Their Pathogenic Role in Chronic Inflammatory Disorders

    PubMed Central

    Lee, Ga Hye

    2016-01-01

    CD28 is a primary co-stimulatory receptor that is essential for successful T cell activation, proliferation, and survival. While ubiquitously expressed on naive T cells, the level of CD28 expression on memory T cells is largely dependent on the T-cell differentiation stage in humans. Expansion of circulating T cells lacking CD28 was originally considered a hallmark of age-associated immunological changes in humans, with a progressive loss of CD28 following replicative senescence with advancing age. However, an increasing body of evidence has revealed that there is a significant age-inappropriate expansion of CD4+CD28− T cells in patients with a variety of chronic inflammatory diseases, suggesting that these cells play a role in their pathogenesis. In fact, expanded CD4+CD28− T cells can produce large amounts of proinflammatory cytokines such as IFN-γ and TNF-α and also have cytotoxic potential, which may cause tissue damage and development of pathogenesis in many inflammatory disorders. Here we review the characteristics of CD4+CD28− T cells as well as the recent advances highlighting the contribution of these cells to several disease conditions. PMID:28035207

  7. Autoantibodies against CD28 are associated with atopic diseases

    PubMed Central

    Neuber, K; Mähnss, B; Hübner, C; Gergely, H; Weichenthal, M

    2006-01-01

    The B7-1/B7-2-CD28/CTLA-4 pathway is crucial in regulating T cell activation and tolerance. Autoantibodies to surface molecules on lymphocytes have already been described in various immune conditions, such as autoimmune diseases, infections and blood transfusions. The objective of this study was to test sera from healthy individuals and from patients for association of CD28 autoantibodies with inflammatory and non-inflammatory diseases. First, CD28 was obtained by digestion of CD28-Ig fusion protein with trypsin. The cleavage products were separated by sodium dodecyl sulphate–page gel electrophoresis. Additionally, a CD28/GST fusion protein was expressed in Escherichia coli and was used to establish an enzyme-linked immunosorbent assay for detection of autoantibodies against CD28. Sera from healthy individuals (n = 72) and patients with different inflammatory and non-inflammatory skin diseases (n = 196) were tested for the presence of autoantibodies against CD28. Using mixed lymphocyte reaction (MLR), purified autoantibodies against CD28 were tested for their effects on CTLA-4-Ig-induced T cell anergy. In this study, for the first time, we describe the existence of autoantibodies against CD28 in humans which are associated with atopic diseases, e.g. allergic rhinitis and asthma. These antibodies stimulate T cells and overcome the CTLA-4-Ig-induced anergy of T cells in an MLR. The existence of autoantibodies against CD28, which may have a T cell-stimulating function, has been shown. The data indicate that autoantibodies against CD28 could be a new immunological mechanism in allergic inflammation. Additionally, autoantibodies against CD28 could be an important new marker to discriminate between atopic diseases and other inflammatory skin diseases. PMID:17034578

  8. Association of CD28 IVS3 +17T/C Polymorphism with Soluble CD28 in Rheumatoid Arthritis

    PubMed Central

    Ledezma-Lozano, I. Y.; Padilla-Martínez, J. J.; Leyva-Torres, S. D.; Parra-Rojas, I.; Ramírez-Dueñas, M. G.; Pereira-Suárez, Ana Laura; Rangel-Villalobos, H.; Ruiz-Quezada, S. L.; Sánchez-Hernández, P. E.; Muñoz-Valle, J. F.

    2011-01-01

    Objective: Rheumatoid arthritis (RA) is an autoimmune disease of unknown etiology in which inflammatory pathology involves T cell activation and the CD28 costimulatory molecule involved in T cell presentation. The gene includes the CD28 IVS3 +17T/C polymorphism that could be associated with susceptibility to RA whereas the soluble concentrations of CD28 (sCD28) could be related to clinical activity. Methods: We investigated the CD28 IVS3 +17T/C polymorphism in 200 RA patients and 200 healthy subjects (HS). Furthermore, we quantified the sCD28 concentrations in 77 samples of each group. We applied indexes focused to determine the activity and disability (DAS28 and Spanish HAQ-DI, respectively) in RA patients. Methods: We investigated the CD28 IVS3 +17T/C polymorphism in 200 RA patients and 200 healthy subjects (HS). Furthermore, we quantified the sCD28 concentrations in 77 samples of each group. We applied indexes focused to determine the activity and disability (DAS28 and Spanish HAQ-DI, respectively) in RA patients. Results: RA patients had significantly higher frequencies of the CD28 T allele compared to HS (p = 0.032 OR = 1.59, C.I. 1.02–2.49). In addition, the IVS3 +17 T/T genotype frequency was also increased in RA vs. HS (p = 0.026). The RA patients showed higher sCD28 serum levels than HS (p = 0.001). Carriers of the T/T genotype in RA patients showed higher sCD28 levels than C/C carriers (p = 0.047). In addition, a correlation between sCD28 and Spanish HAQ-DI (correlation, 0.272; p = 0.016), was found. Conclusion: The T allele in CD28 IVS3 +17T/C polymorphism is associated with a susceptibility to RA in Western Mexico. In addition, increased sCD28 levels are related to T/T genotype in RA patients. PMID:21508506

  9. Neonatal activation of CD28 signaling overcomes T cell anergy and prevents autoimmune diabetes by an IL-4-dependent mechanism.

    PubMed Central

    Arreaza, G A; Cameron, M J; Jaramillo, A; Gill, B M; Hardy, D; Laupland, K B; Rapoport, M J; Zucker, P; Chakrabarti, S; Chensue, S W; Qin, H Y; Singh, B; Delovitch, T L

    1997-01-01

    Optimal T cell responsiveness requires signaling through the T cell receptor (TCR) and CD28 costimulatory receptors. Previously, we showed that T cells from autoimmune nonobese diabetic (NOD) mice display proliferative hyporesponsiveness to TCR stimulation, which may be causal to the development of insulin-dependent diabetes mellitus (IDDM). Here, we demonstrate that anti-CD28 mAb stimulation restores complete NOD T cell proliferative responsiveness by augmentation of IL-4 production. Whereas neonatal treatment of NOD mice with anti-CD28 beginning at 2 wk of age inhibits destructive insulitis and protects against IDDM by enhancement of IL-4 production by islet-infiltrating T cells, administration of anti-CD28 beginning at 5-6 wk of age does not prevent IDDM. Simultaneous anti-IL-4 treatment abrogates the preventative effect of anti-CD28 treatment. Thus, neonatal CD28 costimulation during 2-4 wk of age is required to prevent IDDM, and is mediated by the generation of a Th2 cell-enriched nondestructive environment in the pancreatic islets of treated NOD mice. Our data support the hypothesis that a CD28 signal is requisite for activation of IL-4-producing cells and protection from IDDM. PMID:9410902

  10. MiR-150 impairs inflammatory cytokine production by targeting ARRB-2 after blocking CD28/B7 costimulatory pathway

    PubMed Central

    Sang, Wei; Wang, Ying; Zhang, Cong; Zhang, Dianzheng; Sun, Cai; Niu, Mingshan; Zhang, Zhe; Wei, Xiangyu; Pan, Bin; Chen, Wei; Yan, Dongmei; Zeng, Lingyu; Loughran, Thomas P.; Xu, Kailin

    2016-01-01

    MiR-150, a major modulator negatively regulating the development and differentiation of various immune cells, is widely involved in orchestrating inflammation. In transplantation immunity, miR-150 can effectively induce immune tolerance, although the underlying mechanisms have not been fully elucidated. In the current study, we found that miR-150 is elevated after blocking CD28/B7 co-stimulatory signaling pathway and impaired IL-2 production by targeting ARRB2. Further investigation suggested that miR-150 not only repressed the level of ARRB2/PDE4 directly but also prevented AKT/ARRB2/PDE4 trimer recruitment into the lipid raft by inhibiting the activities of PI3K and AKT through the cAMP-PKA-Csk signaling pathway. This leads to the interruption of cAMP degradation and subsequently results in inhibition of the NF-kB pathway and reduced production of both IL-2 and TNF. In conclusion, our study demonstrated that miR-150 can effectively prevent CD28/B7 co-stimulatory signaling transduction, decrease production of inflammatory cytokines, such as IL-2 and TNF, and elicit the induction of immune tolerance. Therefore, miR-150 could become a novel potential therapeutic target in transplantation immunology. PMID:26549736

  11. Gr-1+ myeloid cells derived from tumor-bearing mice inhibit primary T cell activation induced through CD3/CD28 costimulation.

    PubMed

    Kusmartsev, S A; Li, Y; Chen, S H

    2000-07-15

    Activation of T cells is a necessary step in the development of a specific antitumor immune response. In the present study, we evaluated the ability of Gr-1+ myeloid cells, derived from the bone marrow or spleen of tumor-bearing mice, to inhibit CD3/CD28-mediated T cell activation. Using flow cytometry, we found that growth of a murine colon carcinoma (MCA-26) induces a significant increase in the number of Gr-1+ and Gr-1+/Mac-1+ myeloid cells in both bone marrow and spleen of the tumor host. The proliferative response of T cells was dramatically decreased when naive T cells were activated by anti-CD3 and anti-CD28 Abs in the presence of a myeloid-enriched cell fraction derived from spleen or bone marrow of tumor-bearing mice vs the bone marrow of naive mice. Reversal of the inhibitory effect could be achieved by adding a combination of MnTBAP (manganese [III] tetrakis [4-benzoic acid]) porphyrin and l -NMMA (NG-monomethyl-l -arginine), a superoxide dismutase mimetic and inducible NO synthase inhibitor, respectively, or by depletion of the Gr-1-positive cells. IFN-gamma, which is endogenously produced by CD3/CD28-stimulated naive T cells, is involved in induction of the inhibitory activity of myeloid cells. Importantly, when T cells pre-activated with anti-CD3 Abs were used as responder cells, the bone marrow- or spleen-derived Gr-1+ myeloid cells were unable to suppress CD3/CD28-induced T cell proliferation. Our findings suggest that one mechanism by which an increased number of immune suppressive Gr-1+ cells can induce T cell unresponsiveness or immune tolerance in tumor hosts could be through peroxynitrite production upon primary T cell activation.

  12. Analysis of CD28 and bcl-2 expression on peripheral blood and liver-infiltrating mononuclear cells in patients with autoimmune hepatitis.

    PubMed

    Kurokohchi, Kazutaka; Arima, Keiji; Masaki, Tsutomu; Deguchi, Akiihiro; Nakai, Seiji; Morishita, Asahiro; Yoneyama, Hirohito; Ohgi, Tomohiro; Ono, Masahiro; Yoshitake, Akira; Maeta, Tsuyoshi; Mori, Yoshihiro; Kohi, Fumikazu; Nishioka, Mikio; Kuriyama, Shigeki

    2006-07-01

    Because the underlying mechanism of hepatocellular damages in autoimmune hepatitis (AIH) still remains unclear, analysis of CD28 and bcl-2 molecules, which are critical for T cell activation and survival, was performed in patients with AIH. The number of CD28(+)CD4(+) peripheral blood mononuclear cells (PBMC) in corticosteroid (CS)-treated patients was comparable to normal control individuals but decreased in untreated AIH patients. In contrast, the number of CD28(+)CD8(+) PBMC was decreased in both CS-treated and untreated AIH patients. Analysis of liver-infiltrating mononuclear cells (LIMC) showed that the number of CD28(+)CD4(+) and CD28(-)CD8(+) LIMC were positively correlated with the histology activity index score. Bcl-2(+)CD4(+) LIMC were observed in the portal area of the liver and the numbers fluctuated with disease activity during the time course after CS administration. By contrast, CD8(+) LIMC were shown not to express bcl-2. Taken collectively, these results suggest that bcl-2(+)CD28(+)CD4(+) and bcl-2(-)CD28(-)CD8(+) cells may play critical and distinct roles in hepatocellular damage in AIH.

  13. Characterization of CD4+CD28null T cells in patients with coronary artery disease and individuals with risk factors for atherosclerosis.

    PubMed

    Téo, Fábio Haach; de Oliveira, Rômulo Tadeu Dias; Mamoni, Ronei Luciano; Ferreira, Maria Carolina Salmora; Nadruz, Wilson; Coelho, Otávio Rizzi; Fernandes, Juliano de Lara; Blotta, Maria Heloisa Souza Lima

    2013-01-01

    Risk factors for atherosclerosis may contribute to chronic low-grade inflammation. A highly cytotoxic and inflammatory CD4(+) cell subset (CD4(+)CD28(null) cells) has been associated with inflammatory diseases, including acute coronary syndromes (ACS). The aim of this study was to quantify and characterize CD4(+)CD28(null) cells in individuals with risk factors for atherosclerosis and patients with coronary artery disease (CAD). In order to achieve this goal, peripheral blood mononuclear cells (PBMCs) from individuals with risk factors for atherosclerosis and patients with CAD were analyzed using flow cytometry to detect cytotoxic molecules and evaluate the expression of homing receptors and inflammatory cytokines in CD4(+) cell subsets. The cells were evaluated ex vivo and after stimulation in culture. We found no differences in the proportions of CD4(+)CD28(null) cells among the groups. Compared with the CD4(+)CD28(+) population, the ex vivo CD4(+)CD28(null) subset from all groups expressed higher levels of granzymes A and B, perforin, granulysin and interferon-γ (IFN-γ). Individuals with risk factors and patients with ACS showed the highest levels of cytotoxic molecules. After stimulation, tumor necrosis factor-α (TNF-α) expression in the CD4(+)CD28(null) subset from these groups increased more than in the other groups. Stimulation with LPS decreased the expression of cytotoxic molecules by CD4(+)CD28(null) cells in all groups. In conclusion, our results show that risk factors for atherosclerosis may alter the CD4(+)CD28(null) cells phenotype, increasing their cytotoxic potential. Our findings also suggest that CD4(+)CD28(null) cells may participate in the early phases of atherosclerosis.

  14. CD28− and CD28lowCD8+ Regulatory T Cells: Of Mice and Men

    PubMed Central

    Vuddamalay, Yirajen; van Meerwijk, Joost P. M.

    2017-01-01

    Since the rebirth of regulatory (formerly known as suppressor) T cells in the early 1990s, research in the field of immune-regulation by various T cell populations has quickly gained momentum. While T cells expressing the transcription factor Foxp3 are currently in the spotlight, several other T cell populations endowed with potent immunomodulatory capacities have been identified in both the CD8+ and CD4+ compartment. The fundamental difference between CD4+ and CD8+ T cells in terms of antigen recognition suggests non-redundant, and perhaps complementary, functions of regulatory CD4+ and CD8+ T cells in immunoregulation. This emphasizes the importance and necessity of continuous research on both subpopulations of regulatory T cells (Tregs) so as to decipher their complex physiological relevance and possible synergy. Two distinct CD8-expressing Treg populations can be distinguished based on expression of the co-stimulatory receptor CD28. Here, we review the literature on these (at least in part) thymus-derived CD28low and peripherally induced CD28−CD8+ Tregs. PMID:28167946

  15. Apoptotic Effects of Antilymphocyte Globulins on Human Pro-inflammatory CD4+CD28− T-cells

    PubMed Central

    Duftner, Christina; Dejaco, Christian; Hengster, Paul; Bijuklic, Klaudija; Joannidis, Michael; Margreiter, Raimund; Schirmer, Michael

    2012-01-01

    Background Pro-inflammatory, cytotoxic CD4+CD28− T-cells with known defects in apoptosis have been investigated as markers of premature immuno-senescence in various immune-mediated diseases. In this study we evaluated the influence of polyclonal antilymphocyte globulins (ATG-Fresenius, ATG-F) on CD4+CD28− T-cells in vivo and in vitro. Principal Findings Surface and intracellular three colour fluorescence activated cell sorting analyses of peripheral blood mononuclear cells from 16 consecutive transplant recipients and short-term cell lines were performed. In vivo, peripheral levels of CD3+CD4+CD28− T-cells decreased from 3.7±7.1% before to 0±0% six hours after ATG-F application (P = 0.043) in 5 ATG-F treated but not in 11 control patients (2.9±2.9% vs. 3.9±3.0%). In vitro, ATG-F induced apoptosis even in CD4+CD28− T-cells, which was 4.3-times higher than in CD4+CD28+ T-cells. ATG-F evoked apoptosis was partially reversed by the broad-spectrum caspase inhibitor benzyloxycarbonyl (Cbz)-Val-Ala-Asp(OMe)-fluoromethylketone (zVAD-fmk) and prednisolon-21-hydrogensuccinate. ATG-F triggered CD25 expression and production of pro-inflammatory cytokines, and induced down-regulation of the type 1 chemokine receptors CXCR-3, CCR-5, CX3CR-1 and the central memory adhesion molecule CD62L predominately in CD4+CD28− T-cells. Conclusion In summary, in vivo depletion of peripheral CD3+CD4+CD28− T-cells by ATG-F in transplant recipients was paralleled in vitro by ATG-F induced apoptosis. CD25 expression and chemokine receptor down-regulation in CD4+CD28− T-cells only partly explain the underlying mechanism. PMID:22479483

  16. The B7 and CD28 Receptor Families

    DTIC Science & Technology

    1994-01-01

    34- .•t _" immunology Today 323 Vol 1 No. 71994 177 `1 -. 1 " T review (LPS) (Ref. 18). On human B cells, B7-2 expression CD8’ cells, and in nearly...established differences concerning Immunology Today 324 V.L 15 No. 71994 0 .- ¶ . review T-cell activation and CsA sensitivity, co-stimulation is limited...71994 Va C ,.-;,’. *.-,.. a •• *•.•-’"• review is maximal, and there is evidence that CD28 may not Committee on Immunology , U~niversity’ of Chicago

  17. Cutting edge: monovalency of CD28 maintains the antigen dependence of T cell costimulatory responses.

    PubMed

    Dennehy, Kevin M; Elias, Fernando; Zeder-Lutz, Gabrielle; Ding, Xin; Altschuh, Danièle; Lühder, Fred; Hünig, Thomas

    2006-05-15

    CD28 and CTLA-4 are the major costimulatory receptors on naive T cells. But it is not clear why CD28 is monovalent whereas CTLA-4 is bivalent for their shared ligands CD80/86. We generated bivalent CD28 constructs by fusing the extracellular domains of CTLA-4 or CD80 with the intracellular domains of CD28. Bivalent or monovalent CD28 constructs were ligated with recombinant ligands with or without TCR coligation. Monovalent CD28 ligation did not induce responses unless the TCR was coligated. By contrast, bivalent CD28 ligation induced responses in the absence of TCR engagement. To extend these findings to primary cells, we used novel superagonistic and conventional CD28 Abs. Superagonistic Ab D665, but not conventional Ab E18, predominantly ligates CD28 bivalently at low CD28/Ab ratios and induces Ag-independent T cell proliferation. Monovalency of CD28 for its natural ligands is thus essential to provide costimulation without inducing responses in the absence of TCR engagement.

  18. Reducing progression of experimental lupus nephritis via inhibition of the B7/CD28 signaling pathway

    PubMed Central

    HUANG, LI; KONG, YONG; WANG, JING; SUN, JIE; SHI, QIN; QIU, YU-HUA

    2015-01-01

    The aim of the present study was to evaluate the effects of the B7/cluster of differentiation (CD)28 signaling pathway on experimental lupus nephritis and examine the molecular mechanism involved by inhibiting the B7/CD28 signaling pathway. A lupus nephritis model in C57BL/6 J mice was induced via intraperitoneal injection of pristane. A recombinant B7-1 short hairpin RNA (shRNA) lentivirus vector was constructed by synthesis and splicing. A neutralizing mouse anti-human B7-1 antibody termed 4E5 was also prepared. The mouse model of lupus nephritis was treated with B7-1 shRNA and 4E5 via injection through the tail vein. The silencing effects of B7-1 shRNA lentiviral infection on target molecules were evaluated using immunofluorescence and flow cytometry. The levels of protein in the urine were detected using Albustix test paper each month over 10 months. The concentration of interleukin (IL)-4 and interferon-γ in the serum was determined using an ELISA. The immune complex (IC) deposits in the kidney were analyzed using direct immunofluorescence. The results demonstrated that the C57BL/6 J mouse lupus nephritis model was successfully constructed with immune cells activated in the spleen of the mice, increases in the concentration of anti-nuclear antibody (ANA) and anti-double stranded DNA antibodies as well as positive IC formation. Following B7-1 shRNA lentivirus or 4E5 treatment, CD11b+B7-1+, CD11c+B7-1+ and CD21+B7-1+ cells in the spleen of the mice were significantly reduced. The concentration of ANA and IL-4 in the serum was also decreased. The concentration of urine protein was reduced and it was at its lowest level in the 4E5 early intervention group. It was also revealed that the immunofluorescence intensity of the IC deposits was weak in the 4E5 early intervention group. In conclusion, inhibiting the B7-1/CD28 signaling pathway is able to alleviate experimental lupus nephritis and provides an experimental basis for the therapeutic use of blocking the B7

  19. Single CD28 stimulation induces stable and polyclonal expansion of human regulatory T cells

    PubMed Central

    He, Xuehui; Smeets, Ruben L.; van Rijssen, Esther; Boots, Annemieke M. H.; Joosten, Irma; Koenen, Hans J. P. M.

    2017-01-01

    CD4+FOXP3+ Treg are essential for immune tolerance. Phase-1 clinical trials of Treg-therapy to treat graft-versus-host-disease reported safety and potential therapeutic efficacy. Treg-based trials have started in organ-transplant patients. However, efficient ex vivo expansion of a stable Treg population remains a challenge and exploring novel ways for Treg expansion is a pre-requisite for successful immunotherapy. Based on the recent finding that CD28-signaling is crucial for survival and proliferation of mouse Treg, we studied single-CD28 stimulation of human Treg, without T cell receptor stimulation. Single-CD28 stimulation of human Treg in the presence of recombinant human IL-2(rhIL-2), as compared to CD3/CD28/rhIL-2 stimulation, led to higher expression levels of FOXP3. Although the single-CD28 expanded Treg population was equally suppressive to CD3/CD28 expanded Treg, pro-inflammatory cytokine (IL-17A/IFNγ) production was strongly inhibited, indicating that single-CD28 stimulation promotes Treg stability. As single-CD28 stimulation led to limited expansion rates, we examined a CD28-superagonist antibody and demonstrate a significant increased Treg expansion that was more efficient than standard anti-CD3/CD28-bead stimulation. CD28-superagonist stimulation drove both naïve and memory Treg proliferation. CD28-superagonist induction of stable Treg appeared both PI3K and mTOR dependent. Regarding efficient and stable expansion of Treg for adoptive Treg-based immunotherapy, application of CD28-superagonist stimulation is of interest. PMID:28223693

  20. Single CD28 stimulation induces stable and polyclonal expansion of human regulatory T cells.

    PubMed

    He, Xuehui; Smeets, Ruben L; van Rijssen, Esther; Boots, Annemieke M H; Joosten, Irma; Koenen, Hans J P M

    2017-02-22

    CD4+FOXP3+ Treg are essential for immune tolerance. Phase-1 clinical trials of Treg-therapy to treat graft-versus-host-disease reported safety and potential therapeutic efficacy. Treg-based trials have started in organ-transplant patients. However, efficient ex vivo expansion of a stable Treg population remains a challenge and exploring novel ways for Treg expansion is a pre-requisite for successful immunotherapy. Based on the recent finding that CD28-signaling is crucial for survival and proliferation of mouse Treg, we studied single-CD28 stimulation of human Treg, without T cell receptor stimulation. Single-CD28 stimulation of human Treg in the presence of recombinant human IL-2(rhIL-2), as compared to CD3/CD28/rhIL-2 stimulation, led to higher expression levels of FOXP3. Although the single-CD28 expanded Treg population was equally suppressive to CD3/CD28 expanded Treg, pro-inflammatory cytokine (IL-17A/IFNγ) production was strongly inhibited, indicating that single-CD28 stimulation promotes Treg stability. As single-CD28 stimulation led to limited expansion rates, we examined a CD28-superagonist antibody and demonstrate a significant increased Treg expansion that was more efficient than standard anti-CD3/CD28-bead stimulation. CD28-superagonist stimulation drove both naïve and memory Treg proliferation. CD28-superagonist induction of stable Treg appeared both PI3K and mTOR dependent. Regarding efficient and stable expansion of Treg for adoptive Treg-based immunotherapy, application of CD28-superagonist stimulation is of interest.

  1. Enhancement of soluble CD28 levels in the serum of Graves' disease.

    PubMed

    Sun, Zhongwen; Yi, Lixian; Tao, Hong; Huang, Jingfang; Jin, Zhenghong; Xiao, Yang; Feng, Caiyun; Sun, Jing

    2014-01-01

    Graves' disease is an autoimmune disease of the thyroid gland mediated by T cells. CD28, a member of costimulatory molecules, plays a pivotal role in regulating T-cell responses. Plasma-soluble CD28 is one form of CD28 in peripheral blood. To investigate the concentrations of soluble CD28 in patients with Graves' disease, we used a sensitive dual monoclonal antibody sandwich enzyme-linked immunosorbent assay (ELISA) to detect the soluble form of CD28. Our results suggested that mean concentrations of soluble CD28 in plasma of patients with Graves' disease were 1.79 ±1.52 ng/ml, and levels of soluble CD28 in healthy subjects were only 0.83 ±1.35 ng/ml. Concentrations of soluble CD28 detected in patients with Graves' disease were significantly higher than those of healthy subjects (p < 0.01). Moreover, there was a significant positive correlation between the concentrations of soluble CD28 in plasma and levels of FT3 (r = 0.663), FT4 (r = 0.624) and TRAb (r = 0.728) in serum, but a negative correlation was found between sCD28 levels and TSH (r = -0.726). Through in vitro experiments we observed that engagement of soluble CD28 protein and B7-1/B7-2 molecules expressed on dendritic cells could exert the secretion of cytokine IL-6, which may promote the production of autoantibody and aggravate Graves' disease. Therefore, aberrant elevation of plasma-soluble CD28 in patients with Graves' disease may reflect the dysregulation of immune system, and may serve as a useful biomarker in Graves' disease diagnosis.

  2. CD3+CD8+CD28− T Lymphocytes in Patients with Lupus Nephritis

    PubMed Central

    Krajewska, Magdalena

    2016-01-01

    The results of studies on the CD3+CD8+CD28− cells in SLE are inconsistent since several analyses describe CD3+CD8+CD28− as either immunosuppressive or cytotoxic. The aim of this study is to inquire whether the quantitative changes of CD3+CD8+CD28− T lymphocytes subpopulation are related to the clinical status of patients with lupus nephritis. Evaluation of Foxp3 expression on CD3+CD8+CD28− cells may shed some light on functional properties of these cells. 54 adult SLE patients and 19 sex and age matched healthy volunteers were enrolled in the study. There were 15 patients in inactive (SLEDAI ≤ 5) and 39 in active (SLEDAI > 5) phase of disease. We determined absolute count of CD3+CD8+CD28− and CD3+CD8+CD28−Foxp3+ subpopulations by flow cytometry. We observed a statistically significant increase in absolute count and percentage of CD3+CD8+CD28− in SLE patients compared to HC (p < 0.001). Moreover there was significant positive correlation between increasing absolute count of CD3+CD8+CD28− cells and disease activity measured by SLEDAI (rs = 0.281, p = 0.038). Active LN patients had increased absolute count of CD3+CD8+CD28− cells compared to HC. Positive correlation of CD3+CD8+CD28− number with disease activity, and lack of Foxp3 expression on these cells, suggests that CD3+CD8+CD28− lymphocytes might be responsible for an increased proinflammatory response in the exacerbation of SLE. PMID:27446964

  3. Costimulatory receptors in a teleost fish: Typical CD28, elusive CTLA4

    USGS Publications Warehouse

    Bernard, D.; Riteau, B.; Hansen, J.D.; Phillips, R.B.; Michel, F.; Boudinot, P.; Benmansour, A.

    2006-01-01

    T cell activation requires both specific recognition of the peptide-MHC complex by the TCR and additional signals delivered by costimulatory receptors. We have identified rainbow trout sequences similar to CD28 (rbtCD28) and CTLA4 (rbtCTLA4). rbtCD28 and rbtCTLA4 are composed of an extracellular Ig-superfamily V domain, a transmembrane region, and a cytoplasmic tail. The presence of a conserved ligand binding site within the V domain of both molecules suggests that these receptors likely recognize the fish homologues of the B7 family. The mRNA expression pattern of rbtCD28 and rbtCTLA4 in naive trout is reminiscent to that reported in humans and mice, because rbtCTLA4 expression within trout leukocytes was quickly up-regulated following PHA stimulation and virus infection. The cytoplasmic tail of rbtCD28 possesses a typical motif that is conserved in mammalian costimulatory receptors for signaling purposes. A chimeric receptor made of the extracellular domain of human CD28 fused to the cytoplasmic tail of rbtCD28 promoted TCR-induced IL-2 production in a human T cell line, indicating that rbtCD28 is indeed a positive costimulator. The cytoplasmic tail of rtrtCTLA4 lacked obvious signaling motifs and accordingly failed to signal when fused to the huCD28 extracellular domain. Interestingly, rbtCTLA4 and rbtCD28 are not positioned on the same chromosome and thus do not belong to a unique costimulatory cluster as in mammals. Finally, oar results raise questions about the origin and evolution of positive and negative costimulation in vertebrate immune systems. Copyright ?? 2006 by The American Association of Immunologists, Inc.

  4. The effect of single course high dose dexamethasone on CD28/CTLA-4 balance in the treatment of patients with newly diagnosed primary immune thrombocytopenia

    PubMed Central

    Guo, Xinhong; Yasen, Halida; Zhao, Fang; Wang, Lei; Sun, Mingling; Pang, Nannan; Wang, Xiujuan; Zhang, Ying; Ding, Jianbing; Ma, Xiumin

    2016-01-01

    To evaluate the effect of a single course of high dose dexamethasone (HD-DXM) on CD28 and CTLA-4 expression in patients with newly-diagnosed primary immune thrombocytopenia (ITP). Twenty-8 ITP patients (18 females and 10 males, age range 18–65 years, median age 38.5 years) enrolled in this study and 26 healthy volunteers (19 women and 7 men, age range 16–66 years, median age 37 years) served as a control group. The patients were treated with HD-DXM (40 mg/day) for 4 consecutive days. CD28 and CTLA-4 expression was assessed by flow cytometry once-monthly for 6 months. Plasma levels of the cytokines IFN-γ and IL-10 were determined by enzyme-linked immunosorbent assay. One month after treatment, a platelet response was observed in 23 (82%) of the patients. The response rates over the next 5 months were 71%, 57%, 53%, 46%, and 39%, chronologically. We observed a significant decrease in CD28 expression after the first month (34.7 ± 4.8% vs. 44.5 ± 4.4% before treatment), after which the CD28 levels gradually increased. In contrast, CTLA-4 expression increased after the first month (3.2 ± 0.5% vs. 0.8 ± 0.4 before treatment), after which the CTLA-4 levels gradually decreased. Similar dynamic changes were seen in the levels of IFN-γ and IL-10. The dynamic changes of CD28 and CTLA-4 were consistent with those of IFN-γ and IL-10 and with the effectiveness of HD-DXM in the treatment of ITP. Our results suggest that a disturbed CD28/CTLA-4 balance may contribute to the immunopathogenesis of ITP. PMID:26211942

  5. Intrinsic and extrinsic control of peripheral T-cell tolerance by costimulatory molecules of the CD28/B7 family

    PubMed Central

    Bour-Jordan, Hélène; Esensten, Jonathan H.; Martinez-Llordella, Marc; Penaranda, Cristina; Stumpf, Melanie; Bluestone, Jeffrey A.

    2011-01-01

    Summary Positive and negative costimulation by members of the CD28 family is critical for the development of productive immune responses against foreign pathogens and their proper termination to prevent inflammation-induced tissue damage. In addition, costimulatory signals are critical for the establishment and maintenance of peripheral tolerance. This paradigm has been established in many animal models and has led to the development of immunotherapies targeting costimulation pathways for the treatment of cancer, autoimmune disease, and allograft rejection. During the last decade, the complexity of the biology of costimulatory pathways has greatly increased due to the realization that costimulation does not affect only effector T cells but also influences regulatory T cells and antigen-presenting cells. Thus, costimulation controls T-cell tolerance through both intrinsic and extrinsic pathways. In this review, we discuss the influence of costimulation on intrinsic and extrinsic pathways of peripheral tolerance, with emphasis on members of the CD28 family, CD28, cytotoxic T-lymphocyte antigen-4 (CTLA-4), and programmed death-1 (PD-1), as well as the downstream cytokine interleukin-1 (IL-2). PMID:21488898

  6. Costimulatory receptors in jawed vertebrates: Conserved CD28, odd CTLA4 and multiple BTLAs

    USGS Publications Warehouse

    Bernard, D.; Hansen, J.D.; Du, Pasquier L.; Lefranc, M.-P.; Benmansour, A.; Boudinot, P.

    2007-01-01

    CD28 family of costimulatory receptors is comprised of molecules with a single V-type extracellular Ig domain, a transmembrane and an intracytoplasmic region with signaling motifs. CD28 and cytotoxic T lymphocyte antigen-4 (CTLA4) homologs have been recently identified in rainbow trout. Other sequences similar to mammalian CD28 family members have now been identified using teleost, Xenopus and chicken databases. CD28- and CTLA4 homologs were found in all vertebrate classes whereas inducible costimulatory signal (ICOS) was restricted to tetrapods, and programmed cell death-1 (PD1) was limited to mammals and chicken. Multiple B and T Lymphocyte Attenuator (BTLA) sequences were found in teleosts, but not in Xenopus or in avian genomes. The intron/exon structure of btlas was different from that of cd28 and other members of the family. The Ig domain encoded in all the btla genes has features of the C-type structure, which suggests that BTLA does not belong to the CD28 family. The genomic localization of these genes in vertebrate genomes supports the split between the BTLA and CD28 families. ?? 2006 Elsevier Ltd. All rights reserved.

  7. The Story of CD4+CD28− T Cells Revisited: Solved or Still Ongoing?

    PubMed Central

    Maly, Kathrin

    2015-01-01

    CD4+CD28− T cells are a unique type of proinflammatory T cells characterised by blockade of costimulatory CD28 receptor expression at the transcriptional level, which is still reversible by IL-12. In healthy individuals older than 65 years, these cells may accumulate to up to 50% of total CD4+ T lymphocytes as in many immune-mediated diseases, immunodeficiency, and specific infectious diseases. Here we focus on CD4+CD28− T cells in chronic immune-mediated diseases, summarizing various phenotypic and functional characteristics, which vary depending on the underlying disease, disease activity, and concurrent treatment. CD4+CD28− T cells present as effector/memory cells with increased replicative history and oligoclonality but reduced apoptosis. As an alternative costimulatory signal instead of CD28, not only natural killer cell receptors and Toll-like receptors, but also CD47, CTLA-4, OX40, and 4-1BB have to be considered. The proinflammatory and cytotoxic capacities of these cells indicate an involvement in progression and maintenance of chronic immune-mediated disease. So far it has been shown that treatment with TNF-α blockers, abatacept, statins, and polyclonal antilymphocyte globulins (ATG) mediates reduction of the CD4+CD28− T cell level. The clinical relevance of targeting CD4+CD28− T cells as a therapeutic option has not been examined so far. PMID:25834833

  8. CD28/B7 Deficiency Attenuates Systolic Overload-Induced Congestive Heart Failure, Myocardial and Pulmonary Inflammation, and Activated T Cell Accumulation in the Heart and Lungs.

    PubMed

    Wang, Huan; Kwak, Dongmin; Fassett, John; Hou, Lei; Xu, Xin; Burbach, Brandon J; Thenappan, Thenappan; Xu, Yawei; Ge, Jun-Bo; Shimizu, Yoji; Bache, Robert J; Chen, Yingjie

    2016-09-01

    The inflammatory response regulates congestive heart failure (CHF) development. T cell activation plays an important role in tissue inflammation. We postulate that CD28 or B7 deficiency inhibits T cell activation and attenuates CHF development by reducing systemic, cardiac, and pulmonary inflammation. We demonstrated that chronic pressure overload-induced end-stage CHF in mice is characterized by profound accumulation of activated effector T cells (CD3(+)CD44(high) cells) in the lungs and a mild but significant increase of these cells in the heart. In knockout mice lacking either CD28 or B7, there was a dramatic reduction in the accumulation of activated effector T cells in both hearts and lungs of mice under control conditions and after transverse aortic constriction. CD28 or B7 knockout significantly attenuated transverse aortic constriction-induced CHF development, as indicated by less increase of heart and lung weight and less reduction of left ventricle contractility. CD28 or B7 knockout also significantly reduced transverse aortic constriction-induced CD45(+) leukocyte, T cell, and macrophage infiltration in hearts and lungs, lowered proinflammatory cytokine expression (such as tumor necrosis factor-α and interleukin-1β) in lungs. Furthermore, CD28/B7 blockade by CTLA4-Ig treatment (250 μg/mouse every 3 days) attenuated transverse aortic constriction-induced T cell activation, left ventricle hypertrophy, and left ventricle dysfunction. Our data indicate that CD28/B7 deficiency inhibits activated effector T cell accumulation, reduces myocardial and pulmonary inflammation, and attenuates the development of CHF. Our findings suggest that strategies targeting T cell activation may be useful in treating CHF.

  9. Peripheral Frequency of CD4+ CD28− Cells in Acute Ischemic Stroke

    PubMed Central

    Tuttolomondo, Antonino; Pecoraro, Rosaria; Casuccio, Alessandra; Di Raimondo, Domenico; Buttà, Carmelo; Clemente, Giuseppe; Corte, Vittoriano della; Guggino, Giuliana; Arnao, Valentina; Maida, Carlo; Simonetta, Irene; Maugeri, Rosario; Squatrito, Rosario; Pinto, Antonio

    2015-01-01

    Abstract CD4+ CD28− T cells also called CD28 null cells have been reported as increased in the clinical setting of acute coronary syndrome. Only 2 studies previously analyzed peripheral frequency of CD28 null cells in subjects with acute ischemic stroke but, to our knowledge, peripheral frequency of CD28 null cells in each TOAST subtype of ischemic stroke has never been evaluated. We hypothesized that CD4+ cells and, in particular, the CD28 null cell subset could show a different degree of peripheral percentage in subjects with acute ischemic stroke in relation to clinical subtype and severity of ischemic stroke. The aim of our study was to analyze peripheral frequency of CD28 null cells in subjects with acute ischemic stroke in relation to TOAST diagnostic subtype, and to evaluate their relationship with scores of clinical severity of acute ischemic stroke, and their predictive role in the diagnosis of acute ischemic stroke and diagnostic subtype We enrolled 98 consecutive subjects admitted to our recruitment wards with a diagnosis of ischemic stroke. As controls we enrolled 66 hospitalized patients without a diagnosis of acute ischemic stroke. Peripheral frequency of CD4+ and CD28 null cells has been evaluated with a FACS Calibur flow cytometer. Subjects with acute ischemic stroke had a significantly higher peripheral frequency of CD4+ cells and CD28 null cells compared to control subjects without acute ischemic stroke. Subjects with cardioembolic stroke had a significantly higher peripheral frequency of CD4+ cells and CD28 null cells compared to subjects with other TOAST subtypes. We observed a significant relationship between CD28 null cells peripheral percentage and Scandinavian Stroke Scale and NIHSS scores. ROC curve analysis showed that CD28 null cell percentage may be useful to differentiate between stroke subtypes. These findings seem suggest a possible role for a T-cell component also in acute ischemic stroke clinical setting showing a different

  10. CD28–B7 Interaction Modulates Short- and Long-Lived Plasma Cell Function

    PubMed Central

    Njau, Modesta N.; Kim, Jin Hyang; Chappell, Craig P.; Ravindran, Rajesh; Thomas, Leela; Pulendran, Bali; Jacob, Joshy

    2016-01-01

    The interaction of CD28, which is constitutively expressed on T cells, with B7.1/B7.2 expressed on APCs is critical for T cell activation. CD28 is also expressed on murine and human plasma cells but its function on these cells remains unclear. There are two types of plasma cells: short-lived ones that appear in the secondary lymphoid tissue shortly after Ag exposure, and long-lived plasma cells that mainly reside in the bone marrow. We demonstrate that CD28-deficient murine short- and long-lived plasma cells produce significantly higher levels of Abs than do their wild-type counterparts. This was owing to both increased frequencies of plasma cells as well as increased Ab production per plasma cell. Plasma cells also express the ligand for CD28, B7.1, and B7.2. Surprisingly, deficiency of B7.1 and B7.2 in B cells also led to higher Ab levels, analogous to Cd28−/− plasma cells. Collectively, our results suggest that the CD28–B7 interaction operates as a key modulator of plasma cell function. PMID:22908331

  11. CD28 Promotes Plasma Cell Survival, Sustained Antibody Responses, and BLIMP-1 Upregulation through Its Distal PYAP Proline Motif

    PubMed Central

    Rozanski, Cheryl H.; Utley, Adam; Carlson, Louise M.; Farren, Matthew R.; Murray, Megan; Russell, Lisa M.; Nair, Jayakumar R.; Yang, ZhengYu; Brady, William; Garrett-Sinha, Lee Ann; Schoenberger, Stephen P.; Green, Jonathan M.; Boise, Lawrence H.

    2015-01-01

    In health, long-lived plasma cells (LLPC) are essential for durable protective humoral immunity, and, conversely, in disease are a major source of pathogenic Abs in autoimmunity, graft rejection, and allergy. However, the molecular basis for their longevity is largely unknown. We have recently found that CD28 signaling in plasma cells (PC) is essential for sustaining Ab titers, by supporting the survival of LLPC, but not short-lived PC (SLPC). We now find that, unlike SLPC, CD28 activation in LLPC induces prosurvival downstream Vav signaling. Knockin mice with CD28 cytoplasmic tail mutations that abrogate Vav signaling (CD28-AYAA) had significantly fewer LLPC but unaffected SLPC numbers, whereas mice with mutations that abrogate PI3K signaling (CD28-Y170F) were indistinguishable from wild-type controls. This was consistent with the loss of CD28’s prosurvival effect in LLPC from CD28-AYAA, but not CD28-Y170F, mice. Furthermore, the CD28 Vav motif in the B lineage was essential for the long-term maintenance of Ag-specific LLPC populations and Ab titers in vivo. Signaling downstream of the CD28 Vav motif induced previously undescribed transcriptional regulation of B lymphocyte–induced maturation protein-1, a key mediator of PC differentiation and maintenance. These findings suggest CD28 signaling in LLPC modulates the central B lymphocyte–induced maturation protein-1 transcriptional nexus involved in long-term survival and function. PMID:25833397

  12. Peripheral and site-specific CD4(+) CD28(null) T cells from rheumatoid arthritis patients show distinct characteristics.

    PubMed

    Pieper, J; Johansson, S; Snir, O; Linton, L; Rieck, M; Buckner, J H; Winqvist, O; van Vollenhoven, R; Malmström, V

    2014-02-01

    Proinflammatory CD4(+) CD28(null) T cells are frequently found in the circulation of patients with rheumatoid arthritis (RA), but are less common in the rheumatic joint. In the present study, we sought to identify functional differences between CD4(+) CD28(null) T cells from blood and synovial fluid in comparison with conventional CD28-expressing CD4(+) T cells. Forty-four patients with RA, displaying a distinct CD4(+) CD28(null) T cell population in blood, were recruited for this study; the methylation status of the IFNG locus was examined in isolated T cell subsets, and intracellular cytokine production (IFN-γ, TNF, IL-17) and chemokine receptor expression (CXCR3, CCR6 and CCR7) were assessed by flow cytometry on T cells from the two compartments. Circulating CD4(+) CD28(null) T cells were significantly more hypomethylated in the CNS-1 region of the IFNG locus than conventional CD4(+) CD28(+) T cells and produced higher levels of both IFN-γ and TNF after TCR cross-linking. CD4(+) CD28(null) T cells from the site of inflammation expressed significantly more CXCR3 and CCR6 compared to their counterparts in blood. While IL-17A production could hardly be detected in CD4(+) CD28(null) cells from the blood, a significant production was observed in CD4(+) CD28(null) T cells from synovial fluid. CD4(+) CD28(null) T cells were not only found to differ from conventional CD4(+) CD28(+) T cells in the circulation, but we could also demonstrate that synovial CD4(+) CD28(null) T cells showed additional effector functions (IL-17 coproduction) as compared to the same subset in peripheral blood, suggesting an active role for these cells in the perpetuation of inflammation in the subset of patients having a CD28(null) population.

  13. Co-stimulatory CD28 and transcription factor NFKB1 gene variants affect idiopathic recurrent miscarriages.

    PubMed

    Misra, Maneesh Kumar; Singh, Bharti; Mishra, Aditi; Agrawal, Suraksha

    2016-12-01

    Co-stimulatory CD28 and transcription factor NFKB1 genes are considered as a crucial player in the determination of inflammatory responses; genetic variability in these may modulate the risk for idiopathic recurrent miscarriages (IRM). We investigated the association of functional variants of CD28 (rs3116496 T/C) and NFKB1 (rs28362491 ins/del and rs696 A/G) with IRM cases. We recruited 200 IRM women with a history of at least three consecutive pregnancy losses before 20th week of pregnancy and 300 fertile control women. Determination of CD28 (rs3116496 T/C) and NFKB1 (rs28362491 ins/del and rs696 A/G) gene variants were based on the polymerase chain reaction pursued by restriction fragment length polymorphism analysis and validated with Sanger sequencing. Single marker analysis and multifactor dimensionality reduction (MDR) model used to predict the IRM risk. We observed nearly three- to twofold increased risk in single marker analysis for minor homozygous genotypes of rs3116496 T/C, rs28362491 ins/del and rs696 A/G tag-SNPs in IRM cases, suggesting the risk association. In MDR analysis, we observed 10.5-fold augmented risk among IRM women in three-SNP model (rs3116496 T/C, rs28362491 ins/del and rs696 A/G). The eQTL mapping analyses was performed to strengthen the results of our study. The eQTL mapping analysis revealed that the variations in CD28 and NFKB1 gene content might affect the abundance of transcripts of CD28 and Family with sequence similarity 177 member A1 (FAM177A1) genes, respectively. These results suggest that CD28 and NFKB1 gene variants may be associated with increased risks to IRM.

  14. CD4⁺CD28null T lymphocytes resemble CD8⁺CD28null T lymphocytes in their responses to IL-15 and IL-21 in HIV-infected patients.

    PubMed

    Echeverría, Ainara; Moro-García, Marco A; Asensi, Víctor; Cartón, José A; López-Larrea, Carlos; Alonso-Arias, Rebeca

    2015-09-01

    HIV-infected individuals suffer from accelerated immunologic aging. One of the most prominent changes during T lymphocyte aging is the accumulation of CD28(null) T lymphocytes, mainly CD8(+) but also CD4(+) T lymphocytes. Enhancing the functional properties of these cells may be important because they provide antigen-specific defense against chronic infections. The objective of this study was to compare the responses of CD4(+)CD28(null) and CD8(+)CD28(null) T lymphocytes from HIV-infected patients to the immunomodulatory effects of cytokines IL-15 and IL-21. We quantified the frequencies of CD4(+)CD28(null) and CD8(+)CD28(null) T lymphocytes in peripheral blood from 110 consecutive, HIV-infected patients and 25 healthy controls. Patients showed increased frequencies of CD4(+)CD28(null) and CD8(+)CD28(null). Both subsets were positively correlated to each other and showed an inverse correlation with the absolute counts of CD4(+) T lymphocytes. Higher frequencies of HIV-specific and CMV-specific cells were found in CD28(null) than in CD28(+) T lymphocytes. Activation of STAT5 by IL-15 and STAT3 by IL-21 was higher in CD28(null) compared with CD28(+) T lymphocytes. Proliferation, expression of CD69, and IFN-γ production in CD28(null) T lymphocytes were increased after treatment with IL-15, and IL-21 potentiated most of those effects. Nevertheless, IL-21 alone reduced IFN-γ production in response to anti-CD3 stimulation but increased CD28 expression, even counteracting the inhibitory effect of IL-15. Intracytoplasmic stores of granzyme B and perforin were increased by IL-15, whereas IL-21 and simultaneous treatment with the 2 cytokines also significantly enhanced degranulation in CD4(+)CD28(null) and CD8(+)CD28(null) T lymphocytes. IL-15 and IL-21 could have a role in enhancing the effector response of CD28(null) T lymphocytes against their specific chronic antigens in HIV-infected patients.

  15. CD28 is an Inducible T Cell Surface Antigen that Transduces a Proliferative Signal in CD3(+) Mature Thymocytes

    DTIC Science & Technology

    1990-03-01

    CD3-C28"" l . Despite the 99% of T cells die within the thymus and thus never ability of PMA to induce high density CD28 expres- achieve functional...density of the CD3 surface Ag. In this thymus . few cells stained with anti-CD28 alone, and the intensity of staining In the CD3- cells was less than that...activation alone is sufficient to Induce thymus . We and others (28: present report) have now expression of the CD28 gene. CD28" T cells were cultured with

  16. Forsythoside A Inhibits BVDV Replication via TRAF2-Dependent CD28–4-1BB Signaling in Bovine PBMCs

    PubMed Central

    Song, Quan-Jiang; Weng, Xiao-Gang; Cai, Dong-Jie; Zhang, Wang; Wang, Jiu-Feng

    2016-01-01

    Bovine viral diarrhea virus (BVDV), the causative agent of bovine viral diarrhea/mucosal disease (BVD/MD), is an important pathogen of cattle and other wild animals throughout the world. BVDV infection typically leads to an impaired immune response in cattle. In the present study, we investigated the effect of Forsythoside A (FTA) on BVDV infection of bovine peripheral blood mononuclear cells (PBMCs). We found that Forsythoside A could not only promote proliferation of PBMCs and T cells activation but also inhibit the replication of BVDV as well as apoptosis induced by BVDV. FTA treatment could counteract the BVDV-induced overproduction of IFN-γ to maintain the immune homeostasis in bovine PBMCs. At same time, FTA can enhance the secretion of IL-2. What’s more, BVDV promotes the expression of CD28, 4-1BB and TRAF-2, which can be modulated by FTA. Our data suggest that FTA protects PBMCs from BVDV infection possibly via TRAF2-dependent CD28–4-1BB signaling, which may activate PBMCs in response to BVDV infection. Therefore, this aids in the development of an effective adjuvant for vaccines against BVDV and other specific FTA-based therapies for preventing BVDV infection. PMID:27617959

  17. Expansion of cytotoxic CD8+ CD28- T cells in healthy ageing people, including centenarians.

    PubMed Central

    Fagnoni, F F; Vescovini, R; Mazzola, M; Bologna, G; Nigro, E; Lavagetto, G; Franceschi, C; Passeri, M; Sansoni, P

    1996-01-01

    Ageing is associated with complex remodelling in the phenotypic and functional profiles of T lymphocytes. We investigated whether expression of CD28 antigen on T cells is conserved throughout adulthood and ageing in humans. For this purpose we analysed T cells obtained from peripheral blood of 102 healthy people of ages ranging from 20 to 105 years. We found an age-related increase of CD28- T cells in percentage and absolute number, predominantly among CD8+ T cells. CD28- T cells from aged donors analysed by flow cytometry appeared as resting cells (not expressing CD25, CD38, CD69, CD71, DR), bearing markers of cytotoxic activity (CD 11b and CD 57) and with a phenotype compatible with 'memory' cells (up-regulated CD2 and CD11a; CD62L absent). At the functional level, freshly isolated purified CD28- CD8+ T cells showed high anti-CD3 redirected cytotoxic activity against Fc-bearing P815 cells. The same activity tested on freshly isolated bulk T lymphocytes was significantly augmented with age. We found a positive correlation between age, number of CD8+ CD28- T cells and anti-CD3 redirected cytotoxicity by freshly isolated T cells. These data suggest that an activation of unknown nature within the cytotoxic arm of the immune system occurs with age. We speculate that these cytotoxic T lymphocytes (CTL) in vivo may constitute armed effector cells for immediate killing of targets bearing peptides from pathogens of intracellular origin. PMID:8881749

  18. CD28/CTLA-4/ICOS haplotypes confers susceptibility to Graves' disease and modulates clinical phenotype of disease.

    PubMed

    Pawlak-Adamska, Edyta; Frydecka, Irena; Bolanowski, Marek; Tomkiewicz, Anna; Jonkisz, Anna; Karabon, Lidia; Partyka, Anna; Nowak, Oskar; Szalinski, Marek; Daroszewski, Jacek

    2017-01-01

    Graves' disease, an autoimmune disease with heterogeneous symptoms including Graves' orbitopathy, has a combined genetic/environmental background, where variations within CD28/CTLA-4/ICOS genes are considered as disease markers.Association of CD28c.17+3T>C(rs3116496), CTLA-4g.319C>T(rs5742909), CTLA-4c.49A>G(rs231775), CTLA-4g.*642AT(8_33), CT60(rs3087243), Jo31(rs11571302), ICOSc.1554+4GT(8_15) polymorphisms with susceptibility to Graves' disease and clinical outcome was investigated. The study group comprised of 561 Polish Caucasians, including 172 unrelated Graves' disease patients. CTLA-4c.49A>G, CTLA-4g.319C>T, and CT60 were genotyped by PCR-RFLP; Jo31 and CD28c.17+3C>T by minisequencing; CTLA-4g.*642AT(8_33) and ICOSc.1554+4GT(8_15)-PCR and fluorescence-based technique. CD28c.17+3T>C(rs3116496)T/CTLA-4g.319C>T(rs5742909)C/CTLA-4c.49A>G(rs231775)G/CTLA-4g.*642AT(8_33)(AT16-21)/CT60(rs3087243)G/Jo31(rs11571302)G/ICOSc.1554+4GT(8_15)(m) and TCA(AT<16)GT(m) haplotypes increased risk of Graves' disease, especially in males, as well as overall Graves' orbitopathy development with severe outcome. TCG(AT16-21)GG(l) haplotype increased risk of Graves' disease and reduced the chance of successful medical treatment. Although this haplotype was mainly observed in patients without signs of Graves' orbitopathy, if Graves' orbitopathy developed it favored a Graves' orbitopathy outcome. Haplotype TCA(AT>21)GT(m) increased Graves' disease risk in women and, in all patients, was linked to Graves' disease without Graves' orbitopathy. TCG(AT<16)GG(m) haplotype was predominantly observed in patients without Graves' orbitopathy, whereas TCA(AT16-21)GG(m) was absent in those patients. TCA(AT16-21)GG(m) occurred in patients with a mild Graves' orbitopathy outcome. The marker CTLA-4g.*642AT(8_33) was the only independent Graves' disease risk factor, whereas CT60 was an independent factor for disease progression. Sporadic Graves' disease was related to presence of CTLA-4c.49A>G[A] and

  19. Thymic medullary epithelium and thymocyte self tolerance require cooperation between CD28-CD80/86 and CD40-CD40L costimulatory pathways

    PubMed Central

    Williams, Joy A.; Zhang, Jingjing; Jeon, Hyein; Nitta, Takeshi; Ohigashi, Izumi; Klug, David; Kruhlak, Michael J.; Choudhury, Baishakhi; Sharrow, Susan O.; Granger, Larry; Adams, Anthony; Eckhaus, Michael A.; Jenkinson, S. Rhiannon; Richie, Ellen R.; Gress, Ronald E.; Takahama, Yousuke; Hodes, Richard J.

    2014-01-01

    A critical process during thymic development of the T cell repertoire is the induction of self-tolerance. Tolerance in developing T cells is highly dependent on medullary thymic epithelial cells (mTEC) and mTEC development in turn requires signals from mature single positive (SP) thymocytes, a bidirectional relationship termed thymus crosstalk. We show that CD28-CD80/86 and CD40-CD40L costimulatory interactions, which mediate negative selection and self-tolerance, upregulate expression of LTα, LTβ and RANK in the thymus and are necessary for medullary development. Combined absence of CD28-CD80/86 and CD40-CD40L results in profound deficiency in mTEC development comparable to that observed in the absence of SP thymocytes. This requirement for costimulatory signaling is maintained even in a TCR transgenic model of high affinity TCR-ligand interactions. CD4 thymocytes maturing in the altered thymic epithelial environment of CD40/CD80/86 KO mice are highly autoreactive in vitro and are lethal in congenic adoptive transfer in vivo, demonstrating a critical role for these costimulatory pathways in self-tolerance as well as thymic epithelial development. These findings demonstrate that cooperativity between CD28-CD80/86 and CD40-CD40L pathways is required for normal medullary epithelium and for maintenance of self-tolerance in thymocyte development. PMID:24337745

  20. Folate-modified Chitosan Nanoparticles Containing the IP-10 Gene Enhance Melanoma-specific Cytotoxic CD8+CD28+ T Lymphocyte Responses

    PubMed Central

    He, Jian; Duan, Siliang; Yu, Xia; Qian, Zhiyong; Zhou, Sufang; Zhang, Zhiyong; Huang, Xianing; Huang, Yong; Su, Jing; Lai, Chunhui; Meng, Jinyu; Zhou, Nuo; Lu, Xiaoling; Zhao, Yongxiang

    2016-01-01

    Background: Adoptive immunotherapy with cytotoxic T lymphocytes (CTLs) has great potential for the treatment of some malignant cancers. Therefore, augmenting the responses of tumor-specific CTLs is significant for the adoptive immunotherapy of melanoma. This study aimed to investigate the anti-tumor response of a combination therapy employing folate-modified chitosan nanoparticles containing IP-10 (interferon-γ-inducible protein-10) plus melanoma TRP2-specific CD8+CD28+ T cells. Methods: We prepared folate-modified chitosan nanoparticles containing the mouse IP-10 gene (FA-CS-mIP-10), and induced melanoma TRP2-specific CD8+CD28+ T cells by co-culturing them with artificial antigen-presenting cells. B16-bearing mice were treated with FA-CS-mIP-10, melanoma TRP2-specific CD8+CD28+ T cells, a combination of both, and the saline control. Tumor volumes and the survival time of mice were recorded. The proportion of myeloid-derived suppressor cells (MDSCs) infiltrating the tumor microenvironment and regulatory T cells (Tregs) in the spleen was analyzed by flow cytometry. We also detected the proliferation and angiogenesis of tumors by immunohistochemistry and apoptosis by TUNEL. Results: The combination therapy inhibited the progression of melanoma in vivo. Compared with other treatments, it more efficiently inhibited tumor growth and increased the survival time of mice. After treatment with combination therapy, the proportion of MDSCs and Tregs decreased, while the percentage of CXCR3+CD8+ T cells increased. Furthermore, combination therapy inhibited proliferation and promoted apoptosis of tumor cells and significantly inhibited tumor angiogenesis in vivo. Conclusion: We describe a novel strategy for improving the anti-tumor response of CD8+CD28+ CTLs by combining them with FA-CS-mIP-10 nanoparticles. PMID:27022421

  1. Functional Dichotomy between NKG2D and CD28-Mediated Co-Stimulation in Human CD8+ T Cells

    PubMed Central

    Rajasekaran, Kamalakannan; Xiong, Va; Fong, Lee; Gorski, Jack; Malarkannan, Subramaniam

    2010-01-01

    Both CD28 and NKG2D can function as co-stimulatory receptors in human CD8+ T cells. However, their independent functional contributions in distinct CD8+ T cell subsets are not well understood. In this study, CD8+ T cells in human peripheral blood- and lung-derived lymphocytes were analyzed for CD28 and NKG2D expression and function. We found a higher level of CD28 expression in PBMC-derived naïve (CD45RA+CD27+) and memory (CD45RA−CD27+) CD8+ T cells (CD28Hi), while its expression was significantly lower in effector (CD45RA+CD27−) CD8+ T cells (CD28Lo). Irrespective of the differences in the CD28 levels, NKG2D expression was comparable in all three CD8+ T cell subsets. CD28 and NKG2D expressions followed similar patterns in human lung-resident GILGFVFTL/HLA-A2-pentamer positive CD8+ T cells. Co-stimulation of CD28Lo effector T cells via NKG2D significantly increased IFN-γ and TNF-α levels. On the contrary, irrespective of its comparable levels, NKG2D-mediated co-stimulation failed to augment IFN-γ and TNF-α production in CD28Hi naïve/memory T cells. Additionally, CD28-mediated co-stimulation was obligatory for IL-2 generation and thereby its production was limited only to the CD28Hi naïve/memory subsets. MICA, a ligand for NKG2D was abundantly expressed in the tracheal epithelial cells, validating the use of NKG2D as the major co-stimulatory receptor by tissue-resident CD8+ effector T cells. Based on these findings, we conclude that NKG2D may provide an expanded level of co-stimulation to tissue-residing effector CD8+ T cells. Thus, incorporation of co-stimulation via NKG2D in addition to CD28 is essential to activate tumor or tissue-infiltrating effector CD8+ T cells. However, boosting a recall immune response via memory CD8+ T cells or vaccination to stimulate naïve CD8+ T cells would require CD28-mediated co-stimulation. PMID:20844584

  2. Alterations in levels of CD28-/CD8+ suppressor cell precursor and CD45RO+/CD4+ memory T lymphocytes in the peripheral blood of multiple sclerosis patients.

    PubMed Central

    Crucian, B; Dunne, P; Friedman, H; Ragsdale, R; Pross, S; Widen, R

    1995-01-01

    A comprehensive peripheral blood immunophenotype analysis of 16 multiple sclerosis (MS) patients was performed by three-color flow cytometric analysis, and the results were compared with those for age-matched healthy controls. The cell subsets quantified included T cells (CD3+), B cells (CD19+), NK cells (CD56+), CD4+ and CD8+ T cells, cytotoxic (CD28+) and suppressor precursor (CD28-) CD8+ T cells, CD45RA+ and CD45RO+ T cells (CD4+ and CD8+), and CD5+ T and B cells. Analysis of MS patients' peripheral blood revealed essentially normal levels of total T, B, and NK cells. In agreement with results obtained by other investigators, it was found that MS patients had an increased CD4/CD8 ratio, primarily due to a decrease in CD8+ T cells. MS patients were found to have a significantly decreased level of suppressor precursor (CD28-) CD8+ T cells compared with that of controls but to have normal levels of cytotoxic (CD28+) CD8+ T cells. These data indicate that MS patients do not have a general decrease in CD8+ T cells but that they have a specific decrease in the suppressor precursor subset only and normal levels of cytotoxic CD8+ T cells. MS patients also had a significant increase in memory (CD45RO+) CD4+ T cells and displayed a trend towards a decrease in naive (CD45RA+) T cells in the peripheral blood. PMID:7697540

  3. Generation of autologous tumor-specific T cells for adoptive transfer based on vaccination, in vitro restimulation and CD3/CD28 dynabead-induced T cell expansion.

    PubMed

    Brimnes, Marie Klinge; Gang, Anne Ortved; Donia, Marco; Thor Straten, Per; Svane, Inge Marie; Hadrup, Sine Reker

    2012-08-01

    Adoptive cell transfer (ACT) of in vitro expanded autologous tumor-infiltrating lymphocytes (TIL) has been shown to exert therapeutic efficacy in melanoma patients. We aimed to develop an ACT protocol based on tumor-specific T cells isolated from peripheral blood and in vitro expanded by Dynabeads® ClinExVivo™CD3/CD28. We show here that the addition of an in vitro restimulation step with relevant peptides prior to bead expansion dramatically increased the proportion of tumor-specific T cells in PBMC-cultures. Importantly, peptide-pulsed dendritic cells (DCs) as well as allogeneic tumor lysate-pulsed DCs from the DC vaccine preparation could be used with comparable efficiency to peptides for in vitro restimulation, to increase the tumor-specific T-cell response. Furthermore, we tested the use of different ratios and different types of Dynabeads® CD3/CD28 and CD3/CD28/CD137 T-cell expander, for optimized expansion of tumor-specific T cells. A ratio of 1:3 of Dynabeads® CD3/CD28 T-cell expander to T cells resulted in the maximum number of tumor-specific T cells. The addition of CD137 did not improve functionality or fold expansion. Both T-cell expansion systems could generate tumor-specific T cells that were both cytotoxic and effective cytokine producers upon antigen recognition. Dynabeads®-expanded T-cell cultures shows phenotypical characteristics of memory T cells with potential to migrate and expand in vivo. In addition, they possess longer telomeres compared to TIL cultures. Taken together, we demonstrate that in vitro restimulation of tumor-specific T cells prior to bead expansion is necessary to achieve high numbers of tumor-specific T cells. This is effective and easily applicable in combination with DC vaccination, by use of vaccine-generated DCs, either pulsed with peptide or tumor-lysate.

  4. Selective CD28 Antagonist Blunts Memory Immune Responses and Promotes Long-Term Control of Skin Inflammation in Nonhuman Primates.

    PubMed

    Poirier, Nicolas; Chevalier, Melanie; Mary, Caroline; Hervouet, Jeremy; Minault, David; Baker, Paul; Ville, Simon; Le Bas-Bernardet, Stephanie; Dilek, Nahzli; Belarif, Lyssia; Cassagnau, Elisabeth; Scobie, Linda; Blancho, Gilles; Vanhove, Bernard

    2016-01-01

    Novel therapies that specifically target activation and expansion of pathogenic immune cell subsets responsible for autoimmune attacks are needed to confer long-term remission. Pathogenic cells in autoimmunity include memory T lymphocytes that are long-lived and present rapid recall effector functions with reduced activation requirements. Whereas the CD28 costimulation pathway predominantly controls priming of naive T cells and hence generation of adaptive memory cells, the roles of CD28 costimulation on established memory T lymphocytes and the recall of memory responses remain controversial. In contrast to CD80/86 antagonists (CTLA4-Ig), selective CD28 antagonists blunt T cell costimulation while sparing CTLA-4 and PD-L1-dependent coinhibitory signals. Using a new selective CD28 antagonist, we showed that Ag-specific reactivation of human memory T lymphocytes was prevented. Selective CD28 blockade controlled both cellular and humoral memory recall in nonhuman primates and induced long-term Ag-specific unresponsiveness in a memory T cell-mediated inflammatory skin model. No modification of memory T lymphocytes subsets or numbers was observed in the periphery, and importantly no significant reactivation of quiescent viruses was noticed. These findings indicate that pathogenic memory T cell responses are controlled by both CD28 and CTLA-4/PD-L1 cosignals in vivo and that selectively targeting CD28 would help to promote remission of autoimmune diseases and control chronic inflammation.

  5. CD28 and KIR2D receptors as sensors of the immune status in heart and liver transplantation.

    PubMed

    Blanco-García, R M; López-Álvarez, M R; Garrido, I P; Salgado-Cecilia, G; Campillo, J A; Bolarín, J M; Legaz, I; Muro, M; García-Alonso, A M; Martínez-Sánchez, M V; Moral, J M de la Peña; Pascual-Figal, D A; Alvarez-López, M R; Miras, M; Minguela, A

    2011-10-01

    Viral infections and cellular acute rejection (AR) condition immunosuppressive therapy and compromise the evolution of allografts. Immune monitoring can be useful for ascertaining rejection and for differentiating allo-reaction from activation induced by infections. This work analyzes the usefulness of monitoring the expression of CD28 and KIR2D receptors in peripheral blood T lymphocytes by flow cytometry, to ascertain the immune response in heart and liver transplant recipients. In both types of transplant, the up-regulation of CD28 in CD4(+) lymphocytes in the periods of greatest AR frequency indicates an effective allo-response, whereas the post-transplantation emergence of circulating CD8(+)CD28(-) and CD8(+)CD28(-)KIR2D(+) T cells correlates with better early clinical results. Cytomegalovirus (CMV) infection, but not hepatitis C virus (HCV) or other infections, abrogated both CD28 up-regulation and CD8(+)CD28(-)KIR2D(+) T-cell expansion. Our results show that monitoring the expression of CD28 and KIR2D receptors on T lymphocytes might be considered as sensors of the immune status of heart and liver recipients.

  6. Co-Stimulatory Blockade of the CD28/CD80-86/CTLA-4 Balance in Transplantation: Impact on Memory T Cells?

    PubMed Central

    Ville, Simon; Poirier, Nicolas; Blancho, Gilles; Vanhove, Bernard

    2015-01-01

    CD28 and CTLA-4 are prototypal co-stimulatory and co-inhibitory cell surface signaling molecules interacting with CD80/86, known to be critical for immune response initiation and regulation, respectively. Initial “bench-to-beside” translation, two decades ago, resulted in the development of CTLA4-Ig, a biologic that targets CD80/86 and prevents T-cell costimulation. In spite of its proven effectiveness in inhibiting allo-immune responses, particularly in murine models, clinical experience in kidney transplantation with belatacept (high-affinity CTLA4-Ig molecule) reveals a high incidence of acute, cell-mediated rejection. Originally, the etiology of belatacept-resistant graft rejection was thought to be heterologous immunity, i.e., the cross-reactivity of the pool of memory T cells from pathogen-specific immune responses with alloantigens. Recently, the standard view that memory T cells arise from effector cells after clonal contraction has been challenged by a “developmental” model, in which less differentiated memory T cells generate effector cells. This review delineates how this shift in paradigm, given the differences in co-stimulatory and co-inhibitory signal depending on the maturation stage, could profoundly affect our understanding of the CD28/CD80-86/CTLA-4 blockade and highlights the potential advantages of selectively targeting CD28, instead of CD80/86, to control post-transplant immune responses. PMID:26322044

  7. Novel CD28 antagonist mPEG PV1-Fab’ mitigates experimental autoimmune uveitis by suppressing CD4+ T lymphocyte activation and IFN-γ production

    PubMed Central

    Papotto, Pedro Henrique; Marengo, Eliana Blini; Sardinha, Luiz Roberto; Carvalho, Karina Inácio; de Carvalho, Ana Eduarda Zulim; Castillo-Mendez, Sheyla; Jank, Carina Calixto; Vanhove, Bernard; Goldberg, Anna Carla; Rizzo, Luiz Vicente

    2017-01-01

    Autoimmune Uveitis is an important chronic inflammatory disease and a leading cause of impaired vision and blindness. This ocular autoimmune disorder is mainly mediated by T CD4+ lymphocytes poising a TH1 phenotype. Costimulatory molecules are known to play an important role on T cell activation and therefore represent interesting therapeutical targets for autoimmune disorders. CD28 is the prototypical costimulatory molecule for T lymphocytes, and plays a crucial role in the initiation, and maintenance of immune responses. However, previous attempts to use this molecule in clinical practice achieved no success. Thus, we evaluated the efficacy of mPEG PV1-Fab’ (PV1), a novel selective CD28 antagonist monovalent Fab fragment in the treatment of Experimental Autoimmune Uveitis (EAU). Here, we showed that PV1 treatment decreases both average disease score and incidence of EAU. A decrease in the activation profile of both T CD4+ and T CD8+ eye-infiltrating lymphocytes was evidenced. In the periphery, T CD4+ cells from PV1-treated mice also showed a decrease in their activation status, with reduced expression of CD69, CD25, and PD-1 molecules. This suppression was not dependent on Treg cells, as both their frequency and absolute number were lower in PV1-treated mice. In addition, frequency of CD4+IFN-γ+ T cells was significantly lower in PV1-treated group, but not of IL-17-producing T cells. Moreover, after specific restimulation, PV1 blockade selectively blocked IFN-γ production by CD4+ lymphocytes Taken together, our data suggest that mPEG PV1-Fab’ acts mainly on IFN-γ-producing CD4+ T cells and emphasize that this specific CD28 blockade strategy is a potential specific and alternative tool for the treatment of autoimmune disorders in the eye. PMID:28248972

  8. T-Cell Proliferation Involving the CD28 Pathway is Associated with Cyclosporine-Resistant Interleukin 2 Gene Expression

    DTIC Science & Technology

    1987-12-01

    Security Classification) T-CELL PROLIFERATION INVOLVING THE CD28 PATHWAY IS ASSOCIATED WITH CYCLOSPORINE-RESISTANT INTERLEUKIN 2 GENE EXPRESSION 12. PERSONAL...Cyclosporins,. T Lymphocytes) r’jh ,,.. "’’ .. - | Gene Expression 19. ABSTRACT (Continue on reverse if necessary and identify by block num’ber) DTIC...American Society tor Microbiology T-Cell Proliferation Involving the CD28 Pathway Is Associated with Cyclosporine-Resistant Interleukin 2 Gene Expression

  9. Human mast cells costimulate T cells through a CD28-independent interaction.

    PubMed

    Suurmond, Jolien; Dorjée, Annemarie L; Huizinga, Tom W J; Toes, René E M

    2016-05-01

    Mast cells are innate immune cells usually residing in peripheral tissues, where they are likely to activate T-cell responses. Similar to other myeloid immune cells, mast cells can function as antigen-presenting cells. However, little is known about the capacity of human mast cells to costimulate CD4(+) T cells. Here, we studied the T-cell stimulatory potential of human mast cells. Peripheral blood derived mast cells were generated and cocultured with isolated CD4(+) T cells. In the presence of T-cell receptor triggering using anti-CD3, mast cells promoted strong proliferation of T cells, which was two- to fivefold stronger than the "T-cell promoting capacity" of monocytes. The interplay between mast cells and T cells was dependent on cell-cell contact, suggesting that costimulatory molecules on the mast cell surface are responsible for the effect. However, in contrast to monocytes, the T-cell costimulation by mast cells was independent of the classical costimulatory molecule CD28, or that of OX40L, ICOSL, or LIGHT. Our data show that mast cells can costimulate human CD4(+) T cells to induce strong T-cell proliferation, but that therapies aiming at disrupting the interaction of CD28 and B7 molecules do not inhibit mast cell mediated T-cell activation.

  10. Divide, Conquer, and Sense: CD8+CD28− T Cells in Perspective

    PubMed Central

    Arosa, Fernando A.; Esgalhado, André J.; Padrão, Carolina A.; Cardoso, Elsa M.

    2017-01-01

    Understanding the rationale for the generation of a pool of highly differentiated effector memory CD8+ T cells displaying a weakened capacity to scrutinize for peptides complexed with major histocompatibility class I molecules via their T cell receptor, lacking the “signal 2” CD28 receptor, and yet expressing a highly diverse array of innate receptors, from natural killer receptors, interleukin receptors, and damage-associated molecular pattern receptors, among others, is one of the most challenging issues in contemporary human immunology. The prevalence of these differentiated CD8+ T cells, also known as CD8+CD28−, CD8+KIR+, NK-like CD8+ T cells, or innate CD8+ T cells, in non-lymphoid organs and tissues, in peripheral blood of healthy elderly, namely centenarians, but also in stressful and chronic inflammatory conditions suggests that they are not merely end-of-the-line dysfunctional cells. These experienced CD8+ T cells are highly diverse and capable of sensing a variety of TCR-independent signals, which enables them to respond and fine-tune tissue homeostasis. PMID:28096804

  11. Divide, Conquer, and Sense: CD8(+)CD28(-) T Cells in Perspective.

    PubMed

    Arosa, Fernando A; Esgalhado, André J; Padrão, Carolina A; Cardoso, Elsa M

    2016-01-01

    Understanding the rationale for the generation of a pool of highly differentiated effector memory CD8(+) T cells displaying a weakened capacity to scrutinize for peptides complexed with major histocompatibility class I molecules via their T cell receptor, lacking the "signal 2" CD28 receptor, and yet expressing a highly diverse array of innate receptors, from natural killer receptors, interleukin receptors, and damage-associated molecular pattern receptors, among others, is one of the most challenging issues in contemporary human immunology. The prevalence of these differentiated CD8(+) T cells, also known as CD8(+)CD28(-), CD8(+)KIR(+), NK-like CD8(+) T cells, or innate CD8(+) T cells, in non-lymphoid organs and tissues, in peripheral blood of healthy elderly, namely centenarians, but also in stressful and chronic inflammatory conditions suggests that they are not merely end-of-the-line dysfunctional cells. These experienced CD8(+) T cells are highly diverse and capable of sensing a variety of TCR-independent signals, which enables them to respond and fine-tune tissue homeostasis.

  12. CD28 ligation increases macrophage suppression of T-cell proliferation.

    PubMed

    Silberman, Daniel; Bucknum, Amanda; Bartlett, Thomas; Composto, Gabriella; Kozlowski, Megan; Walker, Amanda; Werda, Amy; Cua, Jackelyn; Sharpe, Arlene H; Somerville, John E; Riggs, James E

    2012-07-01

    When compared to spleen or lymph node cells, resident peritoneal cavity cells respond poorly to T-cell activation in vitro. The greater proportional representation of macrophages in this cell source has been shown to actively suppress the T-cell response. Peritoneal macrophages exhibit an immature phenotype (MHC class II(lo), B7(lo)) that reduces their efficacy as antigen-presenting cells. Furthermore, these cells readily express inducible nitric oxide synthase (iNOS), an enzyme that promotes T-cell tolerance by catabolism of the limiting amino acid arginine. Here, we investigate the ability of exogenous T-cell costimulation to recover the peritoneal T-cell response. We show that CD28 ligation failed to recover the peritoneal T-cell response and actually suppressed responses that had been recovered by inhibiting iNOS. As indicated by cytokine ELISpot and neutralizing monoclonal antibody (mAb) treatment, this 'cosuppression' response was due to CD28 ligation increasing the number of interferon (IFN)-γ-secreting cells. Our results illustrate that cellular composition and cytokine milieu influence T-cell costimulation biology.Cellular & Molecular Immunology advance online publication, 23 April 2012; doi:10.1038/cmi.2012.13.

  13. CD45RA-Foxp3(low) non-regulatory T cells in the CCR7-CD45RA-CD27+CD28+ effector memory subset are increased in synovial fluid from patients with rheumatoid arthritis.

    PubMed

    Matsuki, Fumichika; Saegusa, Jun; Nishimura, Keisuke; Miura, Yasushi; Kurosaka, Masahiro; Kumagai, Shunichi; Morinobu, Akio

    2014-07-01

    Increased numbers of regulatory T (Treg) cells are found in synovial fluid from patients with rheumatoid arthritis (RASF) compared with peripheral blood. However, Treg cells in RASF have been shown to have a decreased capacity to suppress T cells. Here we phenotypically classified CD4+ T cells in RASF into six subsets based on the expression of CD45RA, CCR7, CD27 and CD28, and demonstrated that the CCR7-CD45RA-CD27+CD28+ TEM subset was significantly increased in synovial fluid compared with peripheral blood. In addition, the proportion of Foxp3+ Treg cells in the CCR7-CD45RA-CD27+CD28+ TEM subset was significantly increased in RASF. Furthermore, most of the Foxp3+ Treg cells in RASF were non-suppressive CD45RA-Foxp3(low) non-Treg cells, and the frequency of the non-Treg cells in the CCR7-CD45RA-CD27+CD28+ TEM subset was significantly increased in RASF. Our findings suggest that the pro-inflammatory environment in RA joints may induce the increase of CD45RA-Foxp3(low) non-Treg cells in synovial fluid.

  14. Nonantigen specific CD8+ T suppressor lymphocytes originate from CD8+CD28- T cells and inhibit both T-cell proliferation and CTL function.

    PubMed

    Filaci, Gilberto; Fravega, Marco; Negrini, Simone; Procopio, Francesco; Fenoglio, Daniela; Rizzi, Marta; Brenci, Sabrina; Contini, Paola; Olive, Daniel; Ghio, Massimo; Setti, Maurizio; Accolla, Roberto S; Puppo, Francesco; Indiveri, Francesco

    2004-02-01

    Nonantigen specific CD8+ suppressor T lymphocytes (CD8+ Ts) inhibit T-cell proliferation of antigen-specific T lymphocytes. The impossibility to generate in vitro these cells has been correlated with the appearance of relapses in patients affected by autoimmune diseases, suggesting the involvement of these cells in immune regulation. This study was aimed to identify circulating precursors and to characterize the phenotype and mechanism of action of CD8+ Ts. We found that CD8+ Ts can be generated in vitro from CD8+CD28- T lymphocytes, but not from CD8+CD28+ T cells. A key role in their generation is played by monocytes that secrete interleukin-10 (IL-10) after granulocyte macrophage-colony-stimulating factor (GM-CSF) stimulation. Cell-to-cell direct interaction between CD8+CD28- T cells and monocytes does not play a role in the generation of CD8+ Ts. CD8+ Ts have a CD45RA+, CD27-, CCR7-, IL-10Ralpha+ phenotype and a TCR Vbeta chain repertoire overlapping that of autologous circulating CD8+ T cells. This phenotype is typical of T lymphocytes previously expanded due to antigen stimulation. Their suppressive effect on T-cell proliferation targets both antigen presenting cells, such as dendritic cells, and antigen-specific T lymphocytes, and is mediated by IL-10. CD8+ Ts suppress also the antigen-specific cytotoxic activity of CTL decreasing the expression of HLA class I molecules on target cells through IL-10 secretion. These findings can be helpful for the better understanding of immune regulatory circuits and for the definition of new pathogenic aspects in autoimmunity and tumor immunology.

  15. Gold- and silver-induced murine autoimmunity--requirement for cytokines and CD28 in murine heavy metal-induced autoimmunity.

    PubMed

    Havarinasab, S; Pollard, K M; Hultman, P

    2009-03-01

    Treatment with gold in the form of aurothiomaleate, silver or mercury (Hg) in genetically susceptible mouse strains (H-2(s)) induces a systemic autoimmune condition characterized by anti-nuclear antibodies targeting the 34-kDa nucleolar protein fibrillarin, as well as lymphoproliferation and systemic immune-complex (IC) deposits. In this study we have examined the effect of single-gene deletions for interferon (IFN)-gamma, interleukin (IL)-4, IL-6 or CD28 in B10.S (H-2(s)) mice on heavy metal-induced autoimmunity. Targeting of the genes for IFN-gamma, IL-6 or CD28 abrogated the development of both anti-fibrillarin antibodies (AFA) and IC deposits using a modest dose of Hg (130 microg Hg/kg body weight/day). Deletion of IL-4 severely reduced the IgG1 AFA induced by all three metals, left the total IgG AFA response intact, but abrogated the Hg-induced systemic IC deposits. In conclusion, intact IFN-gamma and CD28 genes are necessary for induction of AFA with all three metals and systemic IC deposits using Hg, while lack of IL-4 distinctly skews the metal-induced AFA response towards T helper type 1. In a previous study using a higher dose of Hg (415 microg Hg/kg body weight/day), IC deposits were preserved in IL-4(-/-) and IL-6(-/-) mice, and also AFA in the latter mice. Therefore, the attenuated autoimmunity following loss of IL-4 and IL-6 is dose-dependent, as higher doses of Hg are able to override the attenuation observed using lower doses.

  16. CD27 Promotes Survival of Activated T Cells and Complements CD28 in Generation and Establishment of the Effector T Cell Pool

    PubMed Central

    Hendriks, Jenny; Xiao, Yanling; Borst, Jannie

    2003-01-01

    CD27, like CD28, acts in concert with the T cell receptor to support T cell expansion. Using CD27−/− mice, we have shown earlier that CD27 determines the magnitude of primary and memory T cell responses to influenza virus. Here, we have examined the relative contributions of CD27 and CD28 to generation of the virus-specific effector T cell pool and its establishment at the site of infection (the lung), using CD27−/−, CD28−/−, and CD27/CD28−/− mice. We find that primary and memory CD8+ T cell responses to influenza virus are dependent on the collective contribution of both receptors. In the primary response, CD27 and CD28 impact to a similar extent on expansion of virus-specific T cells in draining lymph nodes. CD27 is the principle determinant for accumulation of virus-specific T cells in the lung because it can sustain this response in CD28−/− mice. Unlike CD28, CD27 does not affect cell cycle activity, but promotes survival of activated T cells throughout successive rounds of division at the site of priming and may do so at the site of infection as well. CD27 was found to rescue CD28−/− T cells from death at the onset of division, explaining its capacity to support a T cell response in absence of CD28. PMID:14581610

  17. Differential effects of CD28 costimulation upon cytokine production by CD4+ and CD8+ T cells.

    PubMed

    Rochford, Rosemary; Riggs, James E; Clavo, Anaira; Ernst, David N; Hobbs, Monte V

    2004-01-01

    The impact of CD28 ligation upon CD4+ and CD8+ T lymphocyte proliferation and cytokine production was assessed. Although costimulation increased the proliferative response of both T cell subsets, cytokine production was most markedly increased in the CD4+ subset, as evidenced by a 40-fold increase in interleukin-2 (IL-2), a 14-fold increase in interleukin-3 (IL-3) and 5-fold increases in interferon gamma and GM-colony-stimulating factor (CSF) production. The CD8+ T cell response to CD28 ligation was less marked, maxima being a 5-fold increase in IL-2 production and 2-fold increases in IL-3 and GM-CSF production. Resolution of CD4+ and CD8+ T cells into their CD44lo (naïve) and CD44hi (memory/effector) subsets revealed that naive CD4+ T cells were the most CD28-responsive subsets. CD28-mediated costimulation promotes distinct differentiation programs in CD4+ versus CD8+ T cells.

  18. Vstm3 is a Member of the CD28 Family and an Important Modulator of T Cell Function

    PubMed Central

    Taft, David W.; Brandt, Cameron S.; Bucher, Christoph; Howard, Edward D.; Chadwick, Eric M.; Johnston, Janet; Hammond, Angela; Bontadelli, Kristen; Ardourel, Daniel; Hebb, LuAnn; Wolf, Anitra; Bukowski, Thomas R.; Rixon, Mark W.; Kuijper, Joseph L.; Ostrander, Craig D.; West, James W.; Bilsborough, Janine; Fox, Brian; Gao, Zeren; Xu, Wenfeng; Ramsdell, Fred; Blazar, Bruce R.; Lewis, Katherine E.

    2013-01-01

    Summary Members of the CD28 family play important roles in regulating T cell functions and share a common gene structure profile. We have identified VSTM3 as a protein whose gene structure matches that of the other CD28 family members. This protein (also known as TIGIT and WUCAM) has been previously shown to affect immune responses and is expressed on NK cells, activated and memory T cells, and regulatory T cells. The nectin-family proteins CD155 and CD112 serve as counter-structures for VSTM3 and CD155 and CD112 also bind to the activating receptor CD226 on T cells and NK cells. Hence, this group of interacting proteins forms a network of molecules similar to the well-characterized CD28-CTLA4-CD80-CD86 network. In the same way that soluble CTLA4 can be used to block T cell responses, we show that soluble Vstm3 attenuates T cell responses in vitro and in vivo. Moreover, animals deficient in Vstm3 are more sensitive to autoimmune challenges indicating that this new member of the CD28 family is an important regulator of T cell responses. PMID:21416464

  19. Interleukin-7 is a potent co-stimulus of the adhesion pathway involving CD2 and CD28 molecules.

    PubMed Central

    Costello, R; Brailly, H; Mallet, F; Mawas, C; Olive, D

    1993-01-01

    Co-stimulation of highly purified peripheral T lymphocytes from healthy blood donors with the adhesion molecules CD2 and CD28 in association with recombinant interleukin-7 (rIL-7) induced T-cell proliferation, multiple cytokine secretion and IL-2 receptivity. We demonstrated that rIL-7 is as potent as rIL-2 in inducing the proliferation of unseparated, CD4+ and CD8+ T cells. In contrast to low or undetectable levels of IL-1 alpha, IL-6 and IL-2, high levels of tumour necrosis factor-alpha (TNF-alpha), IL-4 and granulocyte-macrophage colony-stimulating factor (GM-CSF) were secreted. Experiments using blocking antibodies suggested a direct mechanism for rIL-7 co-stimulatory effect, although induction of the CD25/IL-2 receptor alpha-chain (CD25/IL-2R alpha) was observed. Monoclonal antibodies (mAb) against the adhesion molecules CD2 and CD28 are likely to mimic the interaction with their respective physiological ligands [lymphocyte function-associated antigen-3 (LFA-3)/CD58, CD59 and CD48 for CD2, B7/BB1 for CD28]. Taken together, these in vitro data suggest that IL-7 could participate in paracrine interactions between T lymphocytes and thymic stromal cells or dendritic cells, via its potent co-stimulatory activity with CD2 and CD28 adhesion molecules. PMID:7904590

  20. Presence of HIV-1 Gag-specific IFN-gamma+IL-2+ and CD28+IL-2+ CD4 T cell responses is associated with nonprogression in HIV-1 infection.

    PubMed

    Boaz, Mark J; Waters, Anele; Murad, Shahed; Easterbrook, Philippa J; Vyakarnam, Annapurna

    2002-12-01

    HIV immunity is likely CD4 T cell dependent. HIV-specific CD4 T cell proliferative responses are reported to correlate inversely with virus load and directly with specific CD8 responses. However, the phenotype and cytokine profile of specific CD4 T cells that correlate with disease is unknown. We compared the number/function of Gag p24-specific CD4 T cells in 17 HIV-infected long-term nonprogressors (LTNPs) infected for a median of 14.6 years with those of 16 slow progressors (SPs), also HIV infected for a median of 14 years but whose CD4 count had declined to <500 cells/ micro l. Compared with SPs, LTNPs had higher numbers of specific CD4s that were double positive for IFN-gamma and IL-2 as well as CD28 and IL-2. However, CD4 T cells that produced IL-2 alone (IL-2(+)IFN-gamma(-)) or IFN-gamma alone (IFN-gamma(+)IL-2(-)) did not differ between LTNPs and SPs. The decrease in p24-specific CD28(+)IL-2(+) cells with a concomitant increase of p24-specific CD28(-)IL-2(+) cells occurred before those specific for a non-HIV Ag, CMV. p24-specific CD28(-)IL-2(+) cells were evident in LTNPs and SPs, whereas the CMV-specific CD28(-)IL-2(+) response was confined to SPs. The difference between LTNPs and SPs in the Gag p24 IFN-gamma(+)IL-2(+) response was maintained when responses to total Gag (p17 plus p24) were measured. The percentage and absolute number of Gag-specific IFN-gamma(+)IL-2(+) but not of IFN-gamma(+)IL-2(-) CD4s correlated inversely with virus load. The Gag-specific IFN-gamma(+)IL-2(+) CD4 response also correlated positively with the percentage of Gag-specific IFN-gamma(+) CD8 T cells in these subjects. Accumulation of specific CD28(-)IL-2(+) helpers and loss of IFN-gamma(+)IL-2(+) CD4 T cells may compromise specific CD8 responses and, in turn, immunity to HIV.

  1. The effect of CTLA-4Ig, a CD28/B7 antagonist, on the lung inflammation and T cell subset profile during murine hypersensitivity pneumonitis.

    PubMed

    Jiménez-Alvarez, Luis; Arreola, José Luis; Ramírez-Martínez, Gustavo; Ortiz-Quintero, Blanca; Gaxiola, Miguel; Reynoso-Robles, Rafael; Avila-Moreno, Federico; Urrea, Francisco; Pardo, Annie; Selman, Moisés; Zuñiga, Joaquín

    2011-12-01

    Hypersensitivity pneumonitis (HP) is an inflammatory lung disease characterized by an influx of activated T cells to the lung, in which the CD28/B7 costimulatory signals are essential for the T cell activation and the outcome of the inflammatory response. In this study, we investigated the effect of the CD28/B7 antagonist, CTLA-4Ig, on the lung inflammation and the T cell subset profile in experimental Saccharopolyspora recivirgula (SR)-induced HP. C57BL/6 mice were treated with SR or saline during two and three weeks and in addition of CTLA-4Ig was administrated after either the second or third week and mice were sacrificed seven days later. The extent of the lung inflammation was quantified by histopathology and the lung T cell subsets (Treg, Th17, γδT and NKT) were analyzed by flow cytometry. Mice treated with CTLA-4Ig showed a significant decrease in the extent of lung damage (p<0.05), and exhibited a decreased number of inflammatory cells in the bronchoalveolar lavage (BAL) with diminished CD4/CD8 T cell ratio. Also, a significant increase in the percentage of lung γδT (p<0.01) and NKT (p<0.05) cells was observed in two weeks SR-treated mice with the administration of CTLA-4Ig/SR. At 3 weeks, SR-treated mice showed an increased percentage of regulatory T cells but no significantly differences were found in the percentage of Th17 cells when compared with CTLA-4Ig/SR-treated mice. Our findings suggest that the treatment with CTLA-4Ig affects the HP progression and the lung T cell subset kinetics in mice.

  2. Bacterial superantigen toxins induce a lethal cytokine storm by enhancing B7-2/CD28 costimulatory receptor engagement, a critical immune checkpoint

    PubMed Central

    Kaempfer, Raymond; Popugailo, Andrey; Levy, Revital; Arad, Gila; Hillman, Dalia; Rotfogel, Ziv

    2017-01-01

    Formation of the costimulatory axis between the B7-2 and CD28 coreceptors is critical for T-cell activation. Superantigens, Gram-positive bacterial virulence factors, cause toxic shock and sepsis by hyperinducing inflammatory cytokines. We report a novel role for costimulatory receptors CD28 and B7-2 as obligatory receptors for superantigens, rendering them therapeutic targets. We show that by engaging not only CD28 but also its coligand B7-2 directly, superantigens potently enhance the interaction between B7-2 and CD28, inducing thereby T-cell hyperactivation. Using a conserved twelve amino-acid domain, superantigens engage both B7-2 and CD28 at their homodimer interfaces, sites far removed from where these receptors interact, implying that inflammatory signaling can be controlled through the receptor homodimer interfaces. Short B7-2 and CD28 dimer interface mimetic peptides bind diverse superantigens, prevent superantigen binding to cell-surface B7-2 or CD28, attenuate inflammatory cytokine overexpression, and protect mice from lethal superantigen challenge. Thus, superantigens induce a cytokine storm by mediating not only the interaction between MHC-II molecule and T-cell receptor but critically, by promoting B7-2/CD28 coreceptor engagement, forcing the principal costimulatory axis to signal excessively. Our findings highlight the B7/CD28 interaction as a bottleneck in signaling for expression of inflammatory cytokines. B7-2 and CD28 homodimer interface mimetic peptides prevent superantigen lethality by blocking the superantigen-host costimulatory receptor interaction. PMID:28286804

  3. T cells coactivated with immobilized anti-CD3 and anti-CD28 as potential immunotherapy for cancer.

    PubMed

    Garlie, N K; LeFever, A V; Siebenlist, R E; Levine, B L; June, C H; Lum, L G

    1999-07-01

    This report describes the generation of T cells with characteristics that may prove useful for the immunotherapy of cancer. Peripheral blood mononuclear cells obtained from healthy donors were cultured in the presence of anti-CD3/anti-CD28 mAb-coated beads (3/28 beads) at a 3:1 bead to cell ratio. The 3/28 beads were removed after 14 days of culture. Optimal growth conditions for CD3/CD28 coactivated T cells (COACTS) were determined to be X-VIVO 15 containing 5% human AB serum and 100 IU/ml of interleukin-2. The median fold expansion after 14 days was 84-fold. Flow cytometric analyses demonstrated that all cultures were > 90% CD3+ with an increase in the proportion of CD8+ cells. CD28 expression was maintained at very high levels on CD4+ cells and augmented on CD8+ cells. COACTS were induced to secrete high levels of Th1-type cytokines (IFN-gamma and TNF-alpha) after a 24-h restimulation with fresh 3/28 beads and displayed nonmajor histocompatibility complex-restricted lytic activity against a variety of human tumor cell lines in standard 51Cr-release assays. Bead removal from COACT cultures before day 14 greatly enhanced the cell growth and cytokine production without significantly affecting the lytic potential. In summary, large numbers of T cells can be generated by coactivation with anti-CD3/anti-CD28-coated beads for 14 days. This method may provide an advantage over current forms of cellular immunotherapy for cancer because of the ability of COACTS to secrete tumoricidal cytokines and generate antitumor cytotoxicity.

  4. 1,25(OH)2D3 Promotes the Efficacy of CD28 Costimulation Blockade by Abatacept

    PubMed Central

    Gardner, David H.; Jeffery, Louisa E.; Soskic, Blagoje; Briggs, Zoe; Hou, Tie Zheng; Raza, Karim

    2015-01-01

    Inhibition of the CD28:CD80/CD86 T cell costimulatory pathway has emerged as an effective strategy for the treatment of T cell–mediated inflammatory diseases. However, patient responses to CD28-ligand blockade by abatacept (CTLA-4-Ig) in conditions such as rheumatoid arthritis are variable and often suboptimal. In this study, we show that the extent to which abatacept suppresses T cell activation is influenced by the strength of TCR stimulation, with high-strength TCR stimulation being associated with relative abatacept insensitivity. Accordingly, cyclosporin A, an inhibitor of T cell stimulation via the TCR, synergized with abatacept to inhibit T cell activation. We also observed that 1,25-dihydroxyvitamin D3 enhanced the inhibition of T cell activation by abatacept, strongly inhibiting T cell activation driven by cross-linked anti-CD3, but with no effect upon anti-CD28 driven stimulation. Thus, like cyclosporin A, 1,25-dihydroxyvitamin D3 inhibits TCR-driven activation, thereby promoting abatacept sensitivity. Vitamin D3 supplementation may therefore be a useful adjunct for the treatment of conditions such as rheumatoid arthritis in combination with abatacept to promote the efficacy of treatment. PMID:26276872

  5. Stimulus dependence of the action of small-molecule inhibitors in the CD3/CD28 signalling network.

    PubMed

    Köhler, Karsten; Ganser, Alexander; André, Thomas; Roth, Günter; Grosse-Hovest, Ludger; Jung, Gundram; Brock, Roland

    2008-09-01

    Cells in the body are exposed simultaneously to a multitude of various signals. Inside a cell, molecular signalling networks integrate this information into a physiologically meaningful response. Interestingly, in the cellular testing of drug candidates, this complexity is largely ignored. Compounds are tested for cells that are challenged with one stimulus only. The activation of T lymphocytes through engagement of the T cell receptor (TCR)-CD3 complex and CD28 coreceptor is a prominent example for a cellular response that depends on the integration of signals. We investigated the cellular response characteristics of this network at different strengths of receptor and coreceptor activation. A novel cellular microarray-based approach, in which various combinations of antibodies directed against the CD3 complex and CD28 were spotted, was employed for analysing the stimulus dependence of activation of the transcription factor NFAT and actin reorganisation. For both responses, quantitative differences in inhibitor activity were observed. Remarkably, for IL-2 expression, which was detected by standard ELISA, low doses of the Src-family kinase inhibitor PP2 strongly potentiated IL-2 expression at high-level, but not at low-level, CD28 co-engagement. Therefore, for a physiologically highly relevant signalling network, the cellular response might vary qualitatively with only quantitative variations of a stimulus. This level of complexity should be considered in early cellular drug testing.

  6. AP-1 is involved in ICOS gene expression downstream of TCR/CD28 and cytokine receptor signaling.

    PubMed

    Watanabe, Masashi; Nakajima, Shinsuke; Ohnuki, Kazunobu; Ogawa, Shuhei; Yamashita, Masakatsu; Nakayama, Toshinori; Murakami, Yasufumi; Tanabe, Kazunari; Abe, Ryo

    2012-07-01

    It has been proposed that sustained ICOS expression in chronic inflammatory immune conditions, such as autoimmunity and allergy, contributes to symptom exacerbation. Therefore modulation of ICOS gene expression could be a potential therapeutic strategy for such immune diseases. However, the precise molecular mechanisms controlling ICOS gene expression remain poorly understood. In this study, we explored transcription factors involving in ICOS gene expression and examined their roles in a physiological situation. Microarray analysis revealed that one AP-1 molecule, Fos-related antigen-2 (Fra2), was highly correlated with ICOS expression. Ectopic expression of Fra2 and other AP-1 molecules upregulated ICOS expression on T cells. We identified an AP-1-responsive site (AP1-RE) within the ICOS promoter region and demonstrated AP-1 actually binds to AP1-RE upon TCR/CD28 stimulation. Meanwhile, we found several cytokines could upregulate ICOS expression on both naïve and effector T cells in a manner independent of TCR/CD28 stimulation. These cytokine stimuli induced AP-1 binding to AP1-RE. Together, our results indicate AP-1 transcription factors are involved in ICOS gene expression downstream of both TCR/CD28 signaling and cytokine receptor signaling, and suggest AP-1 activation via cytokine receptor signaling may be one of the mechanisms maintaining high level ICOS expression in chronic inflammatory immune responses.

  7. Phenotypic characteristics of aged CD4(+) CD28(null) T lymphocytes are determined by changes in the whole-genome DNA methylation pattern.

    PubMed

    Suarez-Álvarez, Beatriz; Rodríguez, Ramón M; Schlangen, Karin; Raneros, Aroa Baragaño; Márquez-Kisinousky, Leonardo; Fernández, Agustín F; Díaz-Corte, Carmen; Aransay, Ana M; López-Larrea, Carlos

    2017-04-01

    Aging is associated with a progressive loss of the CD28 costimulatory molecule in CD4(+) lymphocytes (CD28(null) T cells), which is accompanied by the acquisition of new biological and functional properties that give rise to an impaired immune response. The regulatory mechanisms that govern the appearance and function of this cell subset during aging and in several associated inflammatory disorders remain controversial. Here, we present the whole-genome DNA methylation and gene expression profiles of CD28(null) T cells and its CD28(+) counterpart. A comparative analysis revealed that 296 genes are differentially methylated between the two cell subsets. A total of 160 genes associated with cytotoxicity (e.g. GRZB, TYROBP, and RUNX3) and cytokine/chemokine signaling (e.g. CX3CR1, CD27, and IL-1R) are demethylated in CD28(null) T cells, while 136 de novo-methylated genes matched defects in the TCR signaling pathway (e.g. ITK, TXK, CD3G, and LCK). TCR-landscape analysis confirmed that CD28(null) T cells have an oligo/monoclonal expansion over the polyclonal background of CD28(+) T cells, but feature a Vβ family repertoire specific to each individual. We reported that CD28(null) T cells show a preactivation state characterized by a higher level of expression of inflammasome-related genes that leads to the release of IL-1β when activated. Overall, our results demonstrate that CD28(null) T cells have a unique DNA methylation landscape, which is associated with differences in gene expression, contributing to the functionality of these cells. Understanding these epigenetic regulatory mechanisms could suggest novel therapeutic strategies to prevent the accumulation and activation of these cells during aging.

  8. TIM-3 Suppresses Anti-CD3/CD28-Induced TCR Activation and IL-2 Expression through the NFAT Signaling Pathway.

    PubMed

    Tomkowicz, Brian; Walsh, Eileen; Cotty, Adam; Verona, Raluca; Sabins, Nina; Kaplan, Fred; Santulli-Marotto, Sandy; Chin, Chen-Ni; Mooney, Jill; Lingham, Russell B; Naso, Michael; McCabe, Timothy

    2015-01-01

    TIM-3 (T cell immunoglobulin and mucin-domain containing protein 3) is a member of the TIM family of proteins that is preferentially expressed on Th1 polarized CD4+ and CD8+ T cells. Recent studies indicate that TIM-3 serves as a negative regulator of T cell function (i.e. T cell dependent immune responses, proliferation, tolerance, and exhaustion). Despite having no recognizable inhibitory signaling motifs, the intracellular tail of TIM-3 is apparently indispensable for function. Specifically, the conserved residues Y265/Y272 and surrounding amino acids appear to be critical for function. Mechanistically, several studies suggest that TIM-3 can associate with interleukin inducible T cell kinase (ITK), the Src kinases Fyn and Lck, and the p85 phosphatidylinositol 3-kinase (PI3K) adaptor protein to positively or negatively regulate IL-2 production via NF-κB/NFAT signaling pathways. To begin to address this discrepancy, we examined the effect of TIM-3 in two model systems. First, we generated several Jurkat T cell lines stably expressing human TIM-3 or murine CD28-ECD/human TIM-3 intracellular tail chimeras and examined the effects that TIM-3 exerts on T cell Receptor (TCR)-mediated activation, cytokine secretion, promoter activity, and protein kinase association. In this model, our results demonstrate that TIM-3 inhibits several TCR-mediated phenotypes: i) NF-kB/NFAT activation, ii) CD69 expression, and iii) suppression of IL-2 secretion. To confirm our Jurkat cell observations we developed a primary human CD8+ cell system that expresses endogenous levels of TIM-3. Upon TCR ligation, we observed the loss of NFAT reporter activity and IL-2 secretion, and identified the association of Src kinase Lck, and PLC-γ with TIM-3. Taken together, our results support the conclusion that TIM-3 is a negative regulator of TCR-function by attenuating activation signals mediated by CD3/CD28 co-stimulation.

  9. Implications of learning theory for developing programs to decrease overeating.

    PubMed

    Boutelle, Kerri N; Bouton, Mark E

    2015-10-01

    Childhood obesity is associated with medical and psychological comorbidities, and interventions targeting overeating could be pragmatic and have a significant impact on weight. Calorically dense foods are easily available, variable, and tasty which allows for effective opportunities to learn to associate behaviors and cues in the environment with food through fundamental conditioning processes, resulting in measurable psychological and physiological food cue reactivity in vulnerable children. Basic research suggests that initial learning is difficult to erase, and that it is vulnerable to a number of phenomena that will allow the original learning to re-emerge after it is suppressed or replaced. These processes may help explain why it may be difficult to change food cue reactivity and overeating over the long term. Extinction theory may be used to develop effective cue-exposure treatments to decrease food cue reactivity through inhibitory learning, although these processes are complex and require an integral understanding of the theory and individual differences. Additionally, learning theory can be used to develop other interventions that may prove to be useful. Through an integration of learning theory, basic and translational research, it may be possible to develop interventions that can decrease the urges to overeat, and improve the weight status of children.

  10. Implications of learning theory for developing programs to decrease overeating

    PubMed Central

    Boutelle, Kerri N.; Bouton, Mark E.

    2015-01-01

    Childhood obesity is associated with medical and psychological comorbidities, and interventions targeting overeating could be pragmatic and have a significant impact on weight. Calorically dense foods are easily available, variable, and tasty which allows for effective opportunities to learn to associate behaviors and cues in the environment with food through fundamental conditioning processes, resulting in measurable psychological and physiological food cue reactivity in vulnerable children. Basic research suggests that initial learning is difficult to erase, and that it is vulnerable to a number of phenomena that will allow the original learning to re-emerge after it is suppressed or replaced. These processes may help explain why it may be difficult to change food cue reactivity and overeating over the long term. Extinction theory may be used to develop effective cue-exposure treatments to decrease food cue reactivity through inhibitory learning, although these processes are complex and require an integral understanding of the theory and individual differences. Additionally, learning theory can be used to develop other interventions that may prove to be useful. Through an integration of learning theory, basic and translational research, it may be possible to develop interventions that can decrease the urges to overeat, and improve the weight status of children. PMID:25998235

  11. Cytomegalovirus-Associated CD4(+) CD28(null) Cells in NKG2D-Dependent Glomerular Endothelial Injury and Kidney Allograft Dysfunction.

    PubMed

    Shabir, S; Smith, H; Kaul, B; Pachnio, A; Jham, S; Kuravi, S; Ball, S; Chand, S; Moss, P; Harper, L; Borrows, R

    2016-04-01

    Emerging data suggest that expansion of a circulating population of atypical, cytotoxic CD4(+) T cells lacking costimulatory CD28 (CD4(+) CD28(null) cells) is associated with latent cytomegalovirus (CMV) infection. The purpose of the current study was to increase the understanding of the relevance of these cells in 100 unselected kidney transplant recipients followed prospectively for a median of 54 months. Multicolor flow cytometry of peripheral blood mononuclear cells before transplantation and serially posttransplantation was undertaken. CD4(+) CD28(null) cells were found predominantly in CMV-seropositive patients and expanded in the posttransplantation period. These cells were predominantly effector-memory phenotype and expressed markers of endothelial homing (CX3CR1) and cytotoxicity (NKG2D and perforin). Isolated CD4(+) CD27(-) CD28(null) cells proliferated in response to peripheral blood mononuclear cells previously exposed to CMV-derived (but not HLA-derived) antigens and following such priming incubation with glomerular endothelium resulted in signs of endothelial damage and apoptosis (release of fractalkine and von Willebrand factor; increased caspase 3 expression). This effect was mitigated by NKG2D-blocking antibody. Increased CD4(+) CD28(null) cell frequencies were associated with delayed graft function and lower estimated glomerular filtration rate at end follow-up. This study suggests an important role for this atypical cytotoxic CD4(+) CD28(null) cell subset in kidney transplantation and points to strategies that may minimize the impact on clinical outcomes.

  12. Expansions of Cytotoxic CD4+CD28− T Cells Drive Excess Cardiovascular Mortality in Rheumatoid Arthritis and Other Chronic Inflammatory Conditions and Are Triggered by CMV Infection

    PubMed Central

    Broadley, Iain; Pera, Alejandra; Morrow, George; Davies, Kevin A.; Kern, Florian

    2017-01-01

    A large proportion of cardiovascular (CV) pathology results from immune-mediated damage, including systemic inflammation and cellular proliferation, which cause a narrowing of the blood vessels. Expansions of cytotoxic CD4+ T cells characterized by loss of CD28 (“CD4+CD28− T cells” or “CD4+CD28null cells”) are closely associated with cardiovascular disease (CVD), in particular coronary artery damage. Direct involvement of these cells in damaging the vasculature has been demonstrated repeatedly. Moreover, CD4+CD28− T cells are significantly increased in rheumatoid arthritis (RA) and other autoimmune conditions. It is striking that expansions of this subset beyond 1–2% occur exclusively in CMV-infected people. CMV infection itself is known to increase the severity of autoimmune diseases, in particular RA and has also been linked to increased vascular pathology. A review of the recent literature on immunological changes in CVD, RA, and CMV infection provides strong evidence that expansions of cytotoxic CD4+CD28− T cells in RA and other chronic inflammatory conditions are limited to CMV-infected patients and driven by CMV infection. They are likely to be responsible for the excess CV mortality observed in these situations. The CD4+CD28− phenotype convincingly links CMV infection to CV mortality based on a direct cellular-pathological mechanism rather than epidemiological association. PMID:28303136

  13. Simultaneous ligation of CD5 and CD28 with monoclonal antibodies restores impaired immunostimulatory function in human renal cell carcinoma.

    PubMed

    Siebels, M; Meyer, G; Habicht, A; Meuer, S C; Moebius, U

    2001-10-01

    Tumor cells, including renal cell carcinoma (RCC) cells, do not effectively stimulate T lymphocyte responses against specific antigens presented on their surface. Reasons for this low immunogenicity may include low or absent expression of MHC class I and/or class II molecules, as well as accessory and costimulatory molecules. We used tumor cell pretreatment with cytokines, together with monoclonal antibodies (mAbs) directed at receptors for costimulatory molecules, to render RCC cells immunostimulatory. Interferon-gamma or tumor necrosis factor-alpha pretreatment enhanced expression of MHC class I and class II molecules, as well as CD54, but had only minimal effects on T cell activation. A CD28 mAb, or an even more effective combination of CD28 and CD5 mAb, induced strong primary proliferative responses of allogeneic resting T lymphocytes. Cytokine pretreatment further augmented this T cell response in vitro and allowed T cell expansion and establishment of T cell lines. Stimulation of T cells with autologous RCC cells resulted in a similar T cell activation but with the expansion of cytolytic T cells directed at autologous MHC class II molecules. These experiments demonstrate that cytokines combined with costimulatory mAbs are useful for increasing the immunogenicity of tumor cells. They also indicate. however, that autologous MHC class II expression on tumor cells, together with strong costimulation, may lead to the activation of autoreactive T cells.

  14. TRAF3 is required for T cell-mediated immunity and T cell receptor/CD28 signaling1

    PubMed Central

    Xie, Ping; Kraus, Zachary J.; Stunz, Laura L.; Liu, Yan; Bishop, Gail A.

    2011-01-01

    We recently reported that TRAF3, a ubiquitously expressed adaptor protein, promotes mature B cell apoptosis. However, the specific function of TRAF3 in T cells has remained unclear. Here we report the generation and characterization of T cell-specific TRAF3−/− mice, in which the TRAF3 gene was deleted from thymocytes and T cells. Ablation of TRAF3 in the T cell-lineage did not affect the numbers or proportions of CD4+,CD8+ or double positive or negative thymocytes, or CD4 or CD8 T cell populations in secondary lymphoid organs except that the T cell specific TRAF3−/− mice had a two-fold increase in FoxP3+ T cells.. In striking contrast to mice lacking TRAF3 in B cells, the T cell TRAF3 deficient mice exhibited defective IgG1 responses to a T dependent antigen, and impaired T cell-mediated immunity to infection with Listeria monocytogenes. Surprisingly, we found that TRAF3 was recruited to the TCR/CD28 signaling complex upon co-stimulation, and that TCR/CD28-mediated proximal and distal signaling events were compromised by TRAF3 deficiency. These findings provide new insights into the roles played by TRAF3 in T cell activation and T cell-mediated immunity. PMID:21084666

  15. Inhibition of ZAP-70 Kinase Activity via an Analog-sensitive Allele Blocks T Cell Receptor and CD28 Superagonist Signaling*S⃞

    PubMed Central

    Levin, Susan E.; Zhang, Chao; Kadlecek, Theresa A.; Shokat, Kevan M.; Weiss, Arthur

    2008-01-01

    ZAP-70 is a cytoplasmic protein tyrosine kinase that is required for T cell antigen receptor (TCR) signaling. Both mice and humans deficient in ZAP-70 fail to develop functional T cells, thus demonstrating its necessity for T cell development and function. There is currently no highly specific, cell-permeable, small molecule inhibitor for ZAP-70; therefore, we generated a mutant ZAP-70 allele that retains kinase activity but is sensitive to inhibition by a mutant-specific inhibitor. We validated the chemical genetic inhibitor system in Jurkat T cell lines, where the inhibitor blocked ZAP-70-dependent TCR signaling in cells expressing the analog-sensitive allele. Interestingly, the inhibitor also ablated CD28 superagonist signaling, thereby demonstrating the utility of this system in dissecting the requirement for ZAP-70 in alternative mechanisms of T cell activation. Thus, we have developed the first specific chemical means of inhibiting ZAP-70 in cells, which serves as a valuable tool for studying the function of ZAP-70 in T cells. PMID:18378687

  16. CD28⁻ CD8⁺ T cells are significantly reduced and correlate with disease duration in juveniles with type 1 diabetes.

    PubMed

    Yarde, Danielle N; Lorenzo-Arteaga, Kristina; Corley, Kevin P; Cabrera, Monina; Sarvetnick, Nora E

    2014-10-01

    Type 1 diabetes (T1D) is a chronic disease caused by autoimmune destruction of insulin-producing pancreatic β-cells. T1D is typically diagnosed in children, but information regarding immune cell subsets in juveniles with T1D is scarce. Therefore, we studied various lymphocytic populations found in the peripheral blood of juveniles with T1D compared to age-matched controls (ages 2-17). One population of interest is the CD28(-) CD8(+) T cell subset, which are late-differentiated cells also described as suppressors. These cells are altered in a number of disease states and have been shown to be reduced in adults with T1D. We found that the proportion of CD28(-) cells within the CD8(+) T cell population is significantly reduced in juvenile type 1 diabetics. Furthermore, this reduction is not correlated with age in T1D juveniles, although a significant negative correlation between proportion CD28(-) CD8(+) T cells and age was observed in the healthy controls. Finally, correlation analysis revealed a significant and negative correlation between the proportion of CD28(-) CD8(+) T cells and T1D disease duration. These findings show that the CD28(-) CD8(+) T cell population is perturbed following onset of disease and may prove to be a valuable marker for monitoring the progression of T1D.

  17. Differentiation and activation of γδ T Lymphocytes: Focus on CD27 and CD28 costimulatory receptors.

    PubMed

    Ribot, Julie C; Silva-Santos, Bruno

    2013-01-01

    γδ T lymphocytes are major providers of the pro-inflammatory cytokines interferon-γ (IFN-γ) and interleukin-17 (IL-17) at early stages of (auto)immune responses. We and others have recently described the phenotype and differentiation requirements of two distinct murine γδ T cell subsets producing either IFN-γ or IL-17. Here we summarize our current understanding of the molecular mechanisms that control γδ T cell differentiation, which is programmed in the thymus, and peripheral activation upon infection. We focus on the costimulatory receptors CD27 and CD28, which play independent and non-redundant roles in the physiology of γδ T cells in mice and in humans.

  18. Locoregional treatment of low-grade B-cell lymphoma with CD3xCD19 bispecific antibodies and CD28 costimulation. II. Assessment of cellular immune responses.

    PubMed

    Manzke, O; Tesch, H; Lorenzen, J; Diehl, V; Bohlen, H

    2001-02-15

    Ten patients with advanced B-cell lymphoma were treated with a single locoregional injection of CD3xCD19 bispecific and costimulating CD28 monospecific antibodies to activate tumor-infiltrating T-lymphocytes. Antibodies were administered at 4 different dose levels (30 microg, 270 microg, 810 microg, 1,600 microg of each antibody) either by intratumoral or intralymphatic injection. Most patients developed responses within different compartments of the immune systems (T cells, NK cells) subsequent to the antibody application. Comparative studies in 2 patients of which treated as well as untreated lymph nodes were available revealed the up-regulation of T-cell activation markers induced by the antibody injection. Additionally, in 1 patient the induction of apoptosis of lymphoma B cells in the antibody-treated lymph node was observed. Specificity analyses of peripheral blood T cells by means of IFN-gamma ELISpot measurement indicated the recruitment of idiotype-specific T cells, as in 1 out of 3 investigated patients an increased T-cell response toward autologous idiotype peptides could be demonstrated. We conclude that a single injection of CD3xCD19 bispecific antibodies is capable to induce an activation of autologous T lymphocytes if simultaneous costimulatory signaling by CD28 antibodies is provided. Furthermore, our data suggest that at least in some patients lymphoma-specific T cells can be recruited by this immunotherapeutic approach toward B-cell lymphoma.

  19. CTLA-4 ligation blocks CD28-dependent T cell activation [published erratum appears in J Exp Med 1996 Jul 1;184(1):301

    PubMed Central

    1996-01-01

    CTLA-4 is a CD28 homologue believed to be a negative regulator of T cell function. However, the mechanism of this downregulatory activity is not well understood. The present study was designed to examine the effect of CTLA-4 ligation on cytokine production, cell survival, and cell cycle progression. The results demonstrate that the primary effect of CTLA-4 ligation is not the induction of apoptosis. Instead, CTLA-4 signaling blocks IL-2 production, IL-2 receptor expression, and cell cycle progression of activated T cells. Moreover, the effect of CTLA-4 signaling was manifested after initial T cell activation. Inhibition of IL-2 receptor expression and cell cycle progression was more pronounced at late (72 h) time points after initial activation. The effects of anti-CTLA-4 mAbs were most apparent in the presence of optimal CD28- mediated costimulation consistent with the finding that CTLA-4 upregulation was CD28-dependent. Finally, the addition of exogenous IL- 2 to the cultures restored IL-2 receptor expression and T cell proliferation. These results suggest that CTLA-4 signaling does not regulate cell survival or responsiveness to IL-2, but does inhibit CD28- dependent IL-2 production. PMID:8676075

  20. PD-1/PDL1 and CD28/CD80 pathways modulate natural killer T cell function to inhibit hepatitis B virus replication.

    PubMed

    Wang, X F; Lei, Y; Chen, M; Chen, C B; Ren, H; Shi, T D

    2013-04-01

    α-Galactosylceramide (α-GalCer)-activated natural killer T (NKT) cells have antiviral properties against hepatitis B virus (HBV). However, α-GalCer activation of NKT cells can induce anergy. We hypothesized that this effect may be overcome by a treatment strategy that includes manipulation of CD28/CD80 costimulatory and PD-1/PDL1 coinhibitory signals of NKT cells, thereby enhancing the anti-HBV effect of α-GalCer. We established a transgenic mouse model of chronic HBV infection and investigated hepatic NKT cell frequencies, functions and expression of immunomodulatory factors. Our results showed that compared with uninfected control mice, hepatic NKT cells from HBV transgenic mice displayed lower frequencies (7.91% vs 16.74%, P < 0.05), impaired capabilities to produce interferon (IFN)-γ (5.6% vs 1.4%, P < 0.05) and interleukin (IL)-4 (6.8% vs 0.3%, P < 0.05), higher expression of PD-1 (9.64% vs 6.36%, P < 0.05) and lower expression of CD28 (5.05% vs 28.88%, P < 0.05). However, when hepatic mononuclear cells (MNCs) were isolated from HBV transgenic mice, α-GalCer exposure in culture remarkably upregulated both PD-1(+) NKT cells (P < 0.05) and CD28(+) NKT cells (P < 0.05). Furthermore, when HBV transgenic mice were treated with combination therapies consisting of α-GalCer and anti-PDL1 monoclonal antibody (mAb) and/or anti-CD80/anti-CD28 mAbs, IFN-γ(+) NKT cell frequency was selectively increased (P < 0.05) and HBV replication was suppressed; these effects were accompanied by varying degrees and types of liver damage. Surprisingly, activating CD28/CD80 signal in HBV transgenic mice was more effective but caused less liver injury than blocking PD-1/PDL1 signal in modulating αGalCer-activated NKT cell function to inhibit HBV infection. Our findings also show that combined therapy with blocking PD-1/PDL1 and activating CD28/CD80 signal in the presence of aGalCer cannot superimpose the effect of antivirus. α-GalCer combination therapy that

  1. Ndrg1 is a T-cell clonal anergy factor negatively regulated by CD28 costimulation and interleukin-2.

    PubMed

    Oh, Yu Mi; Park, Hyung Bae; Shin, Jae Hun; Lee, Ji Eun; Park, Ha Young; Kho, Dhong Hyo; Lee, Jun Sung; Choi, Heonsik; Okuda, Tomohiko; Kokame, Koichi; Miyata, Toshiyuki; Kim, In-Hoo; Lee, Seung Hoon; Schwartz, Ronald H; Choi, Kyungho

    2015-10-28

    Induction of T-cell clonal anergy involves serial activation of transcription factors, including NFAT and Egr2/3. However, downstream effector mechanisms of these transcription factors are not fully understood yet. Here we identify Ndrg1 as an anergy factor induced by Egr2. Ndrg1 is upregulated by anergic signalling and maintained at high levels in resting anergic T cells. Overexpression of Ndrg1 mimics the anergic state and knockout of the gene prevents anergy induction. Interestingly, Ndrg1 is phosphorylated and degraded by CD28 signalling in a proteasome-dependent manner, explaining the costimulation dependence of anergy prevention. Similarly, IL-2 treatment of anergic T cells, under conditions that lead to the reversal of anergy, also induces Ndrg1 phosphorylation and degradation. Finally, older Ndrg1-deficient mice show T-cell hyperresponsiveness and Ndrg1-deficient T cells aggravate inducible autoimmune inflammation. Thus, Ndrg1 contributes to the maintenance of clonal anergy and inhibition of T-cell-mediated inflammation.

  2. Ndrg1 is a T-cell clonal anergy factor negatively regulated by CD28 costimulation and interleukin-2

    PubMed Central

    Oh, Yu Mi; Park, Hyung Bae; Shin, Jae Hun; Lee, Ji Eun; Park, Ha Young; Kho, Dhong Hyo; Lee, Jun Sung; Choi, Heonsik; Okuda, Tomohiko; Kokame, Koichi; Miyata, Toshiyuki; Kim, In-Hoo; Lee, Seung Hoon; Schwartz, Ronald H.; Choi, Kyungho

    2015-01-01

    Induction of T-cell clonal anergy involves serial activation of transcription factors, including NFAT and Egr2/3. However, downstream effector mechanisms of these transcription factors are not fully understood yet. Here we identify Ndrg1 as an anergy factor induced by Egr2. Ndrg1 is upregulated by anergic signalling and maintained at high levels in resting anergic T cells. Overexpression of Ndrg1 mimics the anergic state and knockout of the gene prevents anergy induction. Interestingly, Ndrg1 is phosphorylated and degraded by CD28 signalling in a proteasome-dependent manner, explaining the costimulation dependence of anergy prevention. Similarly, IL-2 treatment of anergic T cells, under conditions that lead to the reversal of anergy, also induces Ndrg1 phosphorylation and degradation. Finally, older Ndrg1-deficient mice show T-cell hyperresponsiveness and Ndrg1-deficient T cells aggravate inducible autoimmune inflammation. Thus, Ndrg1 contributes to the maintenance of clonal anergy and inhibition of T-cell-mediated inflammation. PMID:26507712

  3. Vav1 regulates T cell activation through a feedback mechanism and crosstalk between the T cell receptor and CD28

    PubMed Central

    Helou, Ynes A.; Petrashen, Anna P.; Salomon, Arthur R.

    2015-01-01

    Vavl, a Rac/Rho guanine nucleotide exchange factor and a critical component of the T cell receptor (TCR) signaling cascade, is rapidly tyrosine phosphorylated in response to T cell activation. Vav1 has established roles in proliferation, cytokine secretion, Ca2+ responses, and actin cytoskeleton regulation, however, its function in the regulation of phosphorylation of TCR components, including the ζ chain, the CD3 δ, ε, γ chains, and the associated kinases Lck, and ZAP-70 is not well established. To obtain a more comprehensive picture of the role of Vav1 in receptor proximal signaling, we performed a wide-scale characterization of Vav1-dependent tyrosine phosphorylation events using quantitative phosphoproteomic analysis of Vav1-deficient T cells across a time course of TCR stimulation. Importantly, this study revealed a new function for Vav1 in the negative feedback regulation of the phosphorylation of immunoreceptor tyrosine-based activation motifs within the ζ chains, CD3 δ, ε, γ chains, as well as activation sites on the critical T cell tyrosine kinases Itk, Lck, and ZAP-70. Our study also uncovered a previously unappreciated role for Vav1 in crosstalk between the CD28 and TCR signaling pathways. PMID:26043137

  4. Decreased roundabout 1 expression promotes development of intrahepatic cholangiocarcinoma.

    PubMed

    Mano, Yohei; Aishima, Shinichi; Fukuhara, Takasuke; Tanaka, Yuki; Kubo, Yuichiro; Motomura, Takashi; Toshima, Takeo; Iguchi, Tomohiro; Shirabe, Ken; Maehara, Yoshihiko; Oda, Yoshinao

    2013-11-01

    Roundabout 1 (Robo1) is a transmembrane receptor of the immunoglobulin family. Slit2 is one of its ligands. The function of Slit2/Robo1 signaling in the development of intrahepatic cholangiocarcinoma (ICC) remains to be elucidated. We examined the immunohistochemical expression of Robo1 and Slit2 and their clinicopathologic implications in 132 cases of ICC. Also, small interfering RNA of Robo1 was transfected into a high-expression ICC cell line, and a Robo1 vector was transfected into a low-Robo1 expression ICC cell line. The effect of Robo1 suppression and overexpression in cell proliferation and migration of cultured ICC cells with Slit2 stimulation was investigated. Immunohistochemical study of ICC in the low-Robo1 expression group showed larger tumors (P = .015), a higher Ki-67 labeling index (P = .021), and low expression of Slit2 (P = .0005). The low-Slit2 expression group frequently showed perineural invasion (P = .036) and lymph node metastases (P = .013). Low Robo1 expression was associated with a poor prognosis (P = .0207). Robo1 suppression in Huh28 cells tended to promote cell proliferation and migration, whereas Robo1 overexpression in RBE cells significantly suppressed cell proliferation and migration. Low Robo1 expression was associated with cell proliferation and migration in ICC and was one of the adverse prognostic factors in patients with these tumors.

  5. TCRs genetically linked to CD28 and CD3ε do not mispair with endogenous TCR chains and mediate enhanced T cell persistence and anti-melanoma activity.

    PubMed

    Govers, Coen; Sebestyén, Zsolt; Roszik, János; van Brakel, Mandy; Berrevoets, Cor; Szöőr, Árpád; Panoutsopoulou, Konstantina; Broertjes, Marieke; Van, Tan; Vereb, György; Szöllősi, János; Debets, Reno

    2014-11-15

    Adoptive transfer of T cells that are gene engineered to express a defined TCR represents a feasible and promising therapy for patients with tumors. However, TCR gene therapy is hindered by the transient presence and effectiveness of transferred T cells, which are anticipated to be improved by adequate T cell costimulation. In this article, we report the identification and characterization of a novel two-chain TCR linked to CD28 and CD3ε (i.e., TCR:28ε). This modified TCR demonstrates enhanced binding of peptide-MHC and mediates enhanced T cell function following stimulation with peptide compared with wild-type TCR. Surface expression of TCR:28ε depends on the transmembrane domain of CD28, whereas T cell functions depend on the intracellular domains of both CD28 and CD3ε, with IL-2 production showing dependency on CD28:LCK binding. TCR:28ε, but not wild-type TCR, induces detectable immune synapses in primary human T cells, and such immune synapses show significantly enhanced accumulation of TCR transgenes and markers of early TCR signaling, such as phosphorylated LCK and ERK. Importantly, TCR:28ε does not show signs of off-target recognition, as evidenced by lack of TCR mispairing, as well as preserved specificity. Notably, when testing TCR:28ε in immune-competent mice, we observed a drastic increase in T cell survival, which was accompanied by regression of large melanomas with limited recurrence. Our data argue that TCR transgenes that contain CD28, and, thereby, may provide T cell costimulation in an immune-suppressive environment, represent candidate receptors to treat patients with tumors.

  6. A double mutant knockin of the CD28 YMNM and PYAP motifs reveals a critical role for the YMNM motif in regulation of T cell proliferation and Bcl-Xl expression1

    PubMed Central

    Boomer, Jonathan S.; Deppong, Christine M.; Shah, Dulari D.; Bricker, Traci L.; Green, Jonathan M.

    2014-01-01

    CD28 is a critical regulator of T cell function, augmenting proliferation, cytokine secretion and cell survival. Our previous work using knockin mice expressing point mutations in CD28 had demonstrated that the distal proline motif was primarily responsible for much of CD28 function, whereas in marked contrast to prior studies, mutation of the PI3-kinase binding motif had little discernible effect. In this study, we examined the phenotype of mice in which both motifs are simultaneously mutated. We found that mutation of the PYAP motif unmasks a critical role for the proximal tyrosine motif in regulating T cell proliferation and expression of Bcl-Xl, but not cytokine secretion. In addition, we demonstrated that while function is more severely impaired in the double mutant than in either single mutant, there remained residual CD28-dependent responses, definitively establishing that additional motifs can partially mediate CD28 function. PMID:24639356

  7. Potent costimulation of human CD8 T cells by anti-4-1BB and anti-CD28 on synthetic artificial antigen presenting cells.

    PubMed

    Rudolf, Despina; Silberzahn, Tobias; Walter, Steffen; Maurer, Dominik; Engelhard, Johanna; Wernet, Dorothee; Bühring, Hans-Jörg; Jung, Gundram; Kwon, Byoung S; Rammensee, Hans-Georg; Stevanović, Stefan

    2008-02-01

    The in vitro generation of cytotoxic T lymphocytes (CTLs) for anticancer immunotherapy is a promising approach to take patient-specific therapy from the bench to the bedside. Two criteria must be met by protocols for the expansion of CTLs: high yield of functional cells and suitability for good manufacturing practice (GMP). The antigen presenting cells (APCs) used to expand the CTLs are the key to achieving both targets but they pose a challenge: Unspecific stimulation is not feasible because only memory T cells are expanded and not rare naïve CTL precursors; in addition, antigen-specific stimulation by cell-based APCs is cumbersome and problematic in a clinical setting. However, synthetic artificial APCs which can be loaded reproducibly with MHC-peptide monomers and antibodies specific for costimulatory molecules could resolve these problems. The purpose of this study was to investigate the potential of complex synthetic artificial APCs in triggering the costimulatory molecules CD28 and 4-1BB on the T cell. Anti-4-1BB antibodies were added to an established system of microbeads coated with MHC-peptide monomers and anti-CD28. Triggering via CD28 and 4-1BB resulted in strong costimulatory synergy. The quantitative ratio between these signals determined the outcome of the stimulation with optimal results when anti-4-1BB and anti-CD28 were applied in a 3:1 ratio. Functional CTLs of an effector memory subtype (CD45RA(-) CCR7(-)) were generated in high numbers. We present a highly defined APC platform using off-the-shelf reagents for the convenient generation of large numbers of antigen-specific CTLs.

  8. T-Cell Receptor/CD28 Engagement When Combined with Prostaglandin E2 Treatment Leads to Potent Activation of Human T-Cell Leukemia Virus Type 1

    PubMed Central

    Dumais, Nancy; Paré, Marie-Ève; Mercier, Simon; Bounou, Salim; Marriot, Susan J.; Barbeau, Benoit; Tremblay, Michel J.

    2003-01-01

    Infection with human T-cell leukemia virus type 1 (HTLV-1) is characterized by long latency periods, indicating that viral gene expression is under tight control. There is presently little information available regarding the nature of extracellular stimuli that can transactivate the regulatory elements of HTLV-1 (i.e., long terminal repeat [LTR]). To gain insight into the biological importance of externally induced activation pathways in virus gene expression, primary and established T cells were transfected with HTLV-1-based reporter gene vectors and then were treated with agents that cross-linked the T-cell receptor (TCR) or the costimulatory CD28 molecule with prostaglandin E2 (PGE2). We demonstrated that a potent induction of HTLV-1 LTR-driven reporter gene activity was seen only when the three agents were used in combination. Interestingly, similar observations were made when using C91/PL, a cell line that carries integrated HTLV-1 proviral DNA. This TCR-CD28-PGE2-mediated increase in virus transcription was dependent on protein kinase A activation and induction of the cAMP response element binding protein. Experiments with a mutated reporter construct further revealed the importance of the Tax-responsive elements in the HTLV-1 LTR in the observed up regulation of virus gene expression when TCR/CD28 engagement was combined with PGE2 treatment. The protein tyrosine kinases p56lck and the transmembrane tyrosine phosphatase CD45 were all found to be involved in TCR-CD28-PGE2-directed increase in HTLV-1 LTR activity. This study presents new information on the possible mechanisms underlying reactivation of this retrovirus. PMID:14512564

  9. T-cell receptor/CD28 engagement when combined with prostaglandin E2 treatment leads to potent activation of human T-cell leukemia virus type 1.

    PubMed

    Dumais, Nancy; Paré, Marie-Eve; Mercier, Simon; Bounou, Salim; Marriot, Susan J; Barbeau, Benoit; Tremblay, Michel J

    2003-10-01

    Infection with human T-cell leukemia virus type 1 (HTLV-1) is characterized by long latency periods, indicating that viral gene expression is under tight control. There is presently little information available regarding the nature of extracellular stimuli that can transactivate the regulatory elements of HTLV-1 (i.e., long terminal repeat [LTR]). To gain insight into the biological importance of externally induced activation pathways in virus gene expression, primary and established T cells were transfected with HTLV-1-based reporter gene vectors and then were treated with agents that cross-linked the T-cell receptor (TCR) or the costimulatory CD28 molecule with prostaglandin E(2) (PGE(2)). We demonstrated that a potent induction of HTLV-1 LTR-driven reporter gene activity was seen only when the three agents were used in combination. Interestingly, similar observations were made when using C91/PL, a cell line that carries integrated HTLV-1 proviral DNA. This TCR-CD28-PGE(2)-mediated increase in virus transcription was dependent on protein kinase A activation and induction of the cAMP response element binding protein. Experiments with a mutated reporter construct further revealed the importance of the Tax-responsive elements in the HTLV-1 LTR in the observed up regulation of virus gene expression when TCR/CD28 engagement was combined with PGE(2) treatment. The protein tyrosine kinases p56(lck) and the transmembrane tyrosine phosphatase CD45 were all found to be involved in TCR-CD28-PGE(2)-directed increase in HTLV-1 LTR activity. This study presents new information on the possible mechanisms underlying reactivation of this retrovirus.

  10. Use of anti-CD3/CD28 mAb coupled magnetic beads permitting subsequent phenotypic analysis of activated human T cells by indirect immunofluorescence.

    PubMed

    Pène, Jérôme; Rahmoun, Massilva; Temmerman, Stéphane; Yssel, Hans

    2003-12-01

    Functional analysis of T lymphocytes requires in vitro stimulation of these cells under experimental conditions that mimic as closely as possible physiological in vivo stimulation and that involve antigen/T cell receptor (TCR)-mediated activation. Because of the low frequency of antigen-specific T cells in human clinical samples, stimulation with a combination of anti-CD3 and anti-CD28 monoclonal antibodies (mAbs) is a preferred method. Interaction of these mAbs with their ligand results in modulation of the mAb-ligand complex from the cell surface. However, as a result of incomplete modulation, CD3/CD28 mAb complexes often remain at the cell surface, thereby precluding subsequent indirect immunofluorescence and flow cytometry analysis using mouse immunoglobulin (Ig)-specific antibodies. This is of importance in situations in which no specific fluorochrome-conjugated mAbs are available, such as in screening procedures of Ig-containing hybridoma culture supernatants. We propose here the use of CD3/CD28 mAbs, linked to magnetic beads allowing standardization of the activation conditions, optimal activation of T cells and complete modulation of antigen-antibody complexes from the cell surface.

  11. CD28-stimulated ERK2 phosphorylation is required for polarization of the microtubule organizing center and granules in YTS NK cells

    PubMed Central

    Chen, Xi; Allan, David S. J.; Krzewski, Konrad; Ge, Baoxue; Kopcow, Hernan; Strominger, Jack L.

    2006-01-01

    Activation of natural killer (NK) cell cytotoxicity requires adhesion and formation of a conjugate with a susceptible target cell, followed by actin polymerization, and polarization of the microtubule organizing center (MTOC) and cytolytic granules to the NK cell immune synapse. Here, by using the YTS NK cell line as a model, CD28 is shown to be an activating receptor. It signals cytotoxicity in a process dependent on phosphoinositide-3 kinase activation, leading to sustained extracellular signal-regulated kinase 2 (ERK2) phosphorylation. ERK and phospho-ERK localize to microtubule filaments. Neither conjugation with targets nor actin polymerization is affected by blocking ERK2 activation. However, both polarization of the MTOC and cytolytic granules to the synaptic region and NK cell cytotoxicity are strongly reduced by blocking ERK2 activation. A role for the CD28/CD80 interaction in cytotoxicity of human peripheral NK cells also was established. By contrast, lymphocyte function-associated antigen 1 (LFA-1) ligation transduces only a transient ERK2 activation and fails to induce killing in YTS cells. Thus, in YTS cells, a CD28 signal is used to polarize the MTOC and cytolytic granules to the NK cell immune synapse by stimulating sustained ERK2 activation. PMID:16801532

  12. CD28 is required for induction and maintenance of immunological memory in toxin-reactive CD4+ T cells in vivo.

    PubMed

    Fukada, Kenji; Koyanagi, Madoka; Arimura, Yutaka; Ogiuchi, Hideki; Uchiyama, Takehiko; Yagi, Junji

    2005-12-01

    We previously reported that Vbeta3+ CD4+ T cells maintained a protracted expansion, with the phenotypes of memory Th2 cells, for 30 days in C57BL/6 (B6) mice implanted with SEA-containing mini-osmotic pumps. In the present study, we followed the fate of Vbeta3+ CD4+ T cells in CD28-/- mice. Vbeta3+ CD4+ T cells increased to a degree similar to that of B6 Vbeta3+ CD4+ T cells until day 10 after implantation, then declined rapidly reaching the control level by 28 days. Remaining Vbeta3+ CD4+ T cells at that time did not exhibit memory phenotypes nor Th2-deviated responses. The rapid drop in Vbeta3+ CD4+ T cells in CD28-/- mice was attributable to upregulated induction of apoptosis owing to marginal inductions of Bcl-2 and Bcl-xL. Collectively, these data indicate CD28 to play critical roles in the generation and maintenance of SEA-reactive CD4+ T cells in vivo.

  13. Dietary strawberries increase the proliferative response of CD3/CD28-activated CD8⁺ T cells and the production of TNF-α in lipopolysaccharide-stimulated monocytes from obese human subjects.

    PubMed

    Zunino, Susan J; Storms, David H; Freytag, Tammy L; Mackey, Bruce E; Zhao, Ling; Gouffon, Julia S; Hwang, Daniel H

    2013-12-14

    Obesity increases the risk of developing bacterial and viral infections compared with normal weight. In a 7-week double-blind, randomised, cross-over trial, twenty obese volunteers (BMI between 30 and 40 kg/m²) were fed freeze-dried strawberry powder or strawberry-flavoured placebo preparations to determine the effects of dietary strawberries on immune function. Blood was collected at six time points during the study and peripheral blood mononuclear cells (PBMC) were isolated at each time point and activated with CD3 plus CD28 antibodies (T-lymphocyte activation) or lipopolysaccharide (LPS, monocyte activation). Interferon-γ, TNF-α, IL-4 and IL-10 were measured in supernatants from the activated T cells. Supernatants from the activated monocytes were analysed for the production of TNF-α, IL-1β, IL-6 and IL-8. PBMC were pre-stained with PKH (Paul Karl Horan) dye and activated with CD3 plus CD28 antibodies to determine the proliferative responses of CD4⁺ and CD8⁺ T-lymphocytes by flow cytometry. To detect global changes in gene expression, microarray analysis was performed on LPS- and vehicle-treated PBMC from two subjects before and after the strawberry intervention. No difference was observed for the production of T-cell cytokines between the intervention groups. The production of TNF-α was increased in the supernatants from LPS-activated PBMC in the group consuming strawberries compared with the placebo. A modest increase in the proliferation of the CD8⁺ T-lymphocyte population was observed at 24 h post-activation. These data suggest that dietary strawberries may increase the immunological response of T-lymphocytes and monocytes in obese people who are at greater risk for developing infections.

  14. Characterisation of an epigenetically altered CD4+ CD28+ Kir+ T cell subset in autoimmune rheumatic diseases by multiparameter flow cytometry

    PubMed Central

    Strickland, Faith M; Patel, Dipak; Somers, Emily; Robida, Aaron M; Pihalja, Michael; Swartz, Richard; Marder, Wendy; Richardson, Bruce

    2016-01-01

    Objectives Antigen-specific CD4+ T cells epigenetically modified with DNA methylation inhibitors overexpress genes normally suppressed by this mechanism, including CD11a, CD70, CD40L and the KIR gene family. The altered cells become autoreactive, losing restriction for nominal antigen and responding to self-class II major histocompatibility complex (MHC) molecules without added antigen, and are sufficient to cause a lupus-like disease in syngeneic mice. T cells overexpressing the same genes are found in patients with active lupus. Whether these genes are co-overexpressed on the same or different cells is unknown. The goal of this study was to determine whether these genes are overexpressed on the same or different T cells and whether this subset of CD4+ T cells is also present in patients with lupus and other rheumatic diseases. Methods Multicolour flow cytometry was used to compare CD11a, CD70, CD40L and KIR expression on CD3+CD4+CD28+ T cells to their expression on experimentally demethylated CD3+CD4+CD28+ T cells and CD3+CD4+CD28+ T cells from patients with active lupus and other autoimmune diseases. Results Experimentally demethylated CD4+ T cells and T cells from patients with active lupus have a CD3+CD4+CD28+CD11ahiCD70+CD40LhiKIR+ subset, and the subset size is proportional to lupus flare severity. A similar subset is found in patients with other rheumatic diseases including rheumatoid arthritis, systemic sclerosis and Sjögren's syndrome but not retroperitoneal fibrosis. Conclusions Patients with active autoimmune rheumatic diseases have a previously undescribed CD3+CD4+CD28+CD11ahiCD70+CD40LhiKIR+ T cell subset. This subset may play an important role in flares of lupus and related autoimmune rheumatic diseases, provide a biomarker for disease activity and serve as a novel therapeutic target for the treatment of lupus flares. PMID:27099767

  15. Efficient Nef-mediated downmodulation of TCR-CD3 and CD28 is associated with high CD4+ T cell counts in viremic HIV-2 infection.

    PubMed

    Khalid, Mohammad; Yu, Hangxing; Sauter, Daniel; Usmani, Shariq M; Schmokel, Jan; Feldman, Jerome; Gruters, Rob A; van der Ende, Marchina E; Geyer, Matthias; Rowland-Jones, Sarah; Osterhaus, Albert D; Kirchhoff, Frank

    2012-05-01

    The role of the multifunctional accessory Nef protein in the immunopathogenesis of HIV-2 infection is currently poorly understood. Here, we performed comprehensive functional analyses of 50 nef genes from 21 viremic (plasma viral load, >500 copies/ml) and 16 nonviremic (<500) HIV-2-infected individuals. On average, nef alleles from both groups were equally active in modulating CD4, TCR-CD3, CD28, MHC-I, and Ii cell surface expression and in enhancing virion infectivity. Thus, many HIV-2-infected individuals efficiently control the virus in spite of efficient Nef function. However, the potency of nef alleles in downmodulating TCR-CD3 and CD28 to suppress the activation and apoptosis of T cells correlated with high numbers of CD4(+) T cells in viremic patients. No such correlations were observed in HIV-2-infected individuals with undetectable viral load. Further functional analyses showed that the Nef-mediated downmodulation of TCR-CD3 suppressed the induction of Fas, Fas-L, PD-1, and CTLA-4 cell surface expression as well as the secretion of gamma interferon (IFN-γ) by primary CD4(+) T cells. Moreover, we identified a single naturally occurring amino acid variation (I132T) in the core domain of HIV-2 Nef that selectively disrupts its ability to downmodulate TCR-CD3 and results in functional properties highly reminiscent of HIV-1 Nef proteins. Taken together, our data suggest that the efficient Nef-mediated downmodulation of TCR-CD3 and CD28 help viremic HIV-2-infected individuals to maintain normal CD4(+) T cell homeostasis by preventing T cell activation and by suppressing the induction of death receptors that may affect the functionality and survival of both virally infected and uninfected bystander cells.

  16. Definition of the HLA-A2 restricted peptides recognized by human CD8+ effector T cells by flow-assisted sorting of the CD8+ CD45RA+ CD28- T cell subpopulation.

    PubMed

    Höhn, H; Jülch, M; Pilch, H; Kortsik, C; Tully, G; Neukirch, C; Freitag, K; Maeurer, M

    2003-01-01

    In response to antigenic stimulation, naive MHC-class I restricted and antigen-specific CD8+ CD45RA+ CD28+ T cells undergo clonal expansion, differentiate into CD8+ CD45RO+ memory T cells and convert to CD8+ CD45RA+ CD28- T cells displaying potent immune effector functions upon re-encounter with the nominal antigen. We show that the effector CD8+ CD45RA+ CD28- T cell subset is expanded in peripheral blood lymphocytes (PBL) from patients with human papilloma virus (HPV)+ cervical lesions as well as in PBL from patients with pulmonary tuberculosis. Flow-cytometric cell sorted CD8+ CD45RA+ CD28- and CD8+ CD45RA+ CD28- T cells were tested for recognition of HLA-A2 restricted peptides derived either from the human papillomavirus (HPV)16-E7 gene product, or from M. tuberculosis antigens. Mostly CD8+ CD45+ CD28- T cells define antigen/peptide-specific and MHC-restricted responses. These data were confirmed in PBL from patients with tuberculosis using HLA-A2 tetramer-complexes loaded with a peptide from the M. tuberculosis Ag85b antigen by flow cytometry. The sorting of this T cell subset enables to determine the fine specificity of CD8+ effector T cells without the need for in vitro manipulation.

  17. Engagement of transgenic Ly49A inhibits mouse CD4 cell activation by disrupting T cell receptor, but not CD28, signaling.

    PubMed

    Leavenworth, Jianmei W; Pauza, Mary E

    2009-01-01

    Islet specific CD4 cells expressing inhibitory receptors may be a useful therapeutic tool for treating type 1 diabetes (T1D). Engagement of transgenic Ly49A inhibits CD4 cell activation and delays onset of T1D in mice. However, in vitro studies suggest the inhibitory effect of Ly49A is incomplete. Here we report that following simultaneous TCR and Ly49A engagement, phosphorylation of Zap70, Erk1/2 and c-Jun were significantly diminished. Kinetic studies indicated that Ly49A did not simply delay activation but had a long-lasting effect. In contrast, when only costimulatory signals were provided through CD28, Ly49A engagement did not block p38 MapK or Akt phosphorylation. Likewise, expression of the downstream targets Bcl-xl and Baff were unaffected. Together these data suggest that engagement of Ly49A selectively inhibits signals downstream of the TCR but spares those unique to CD28. These results suggest that when considering its use as an immunotherapy, the potency of inhibitory receptors such as Ly49A may be further improved by pairing them with costimulatory blockade.

  18. FR255734, a humanized, Fc-Silent, Anti-CD28 antibody, improves psoriasis in the SCID mouse-psoriasis xenograft model.

    PubMed

    Raychaudhuri, Siba P; Kundu-Raychaudhuri, Smriti; Tamura, Kouichi; Masunaga, Taro; Kubo, Kaori; Hanaoka, Kaori; Jiang, Wen-Yue; Herzenberg, Leonore A; Herzenberg, Leonard A

    2008-08-01

    In psoriasis, CD28/B7 costimulatory molecules are well characterized. Here, using the severe combined immunodeficient (SCID) mouse-psoriasis xenograft model, we report therapeutic efficacy of a humanized anti-CD28 monoclonal antibody (FR255734; Astellas Pharmaceuticals Inc., Tokyo, Japan). Transplanted psoriasis plaques on the SCID mouse were treated weekly for 4 weeks with intraperitoneal injections of FR255734 at 10, 3, and 1-mg kg(-1) doses. Groups treated with doses of 10 and 3 mg kg(-1) had significant thinning of the epidermis and reduced HLA-DR-positive lymphocytic infiltrates. The length of the rete pegs changed from 415.2+/-59.6 to 231.4+/-40.4 microm (P<0.005) in the 10-mg kg(-1) group, and from 323.4+/-69.6 to 237.5+/-73.6 microm in the 3-mg kg(-1) group (P=0.002). Positive controls treated with CTLA4-Ig and cyclosporine had significant histological improvement, whereas plaques treated with saline and isotype controls (human and mouse IgG2) remained unchanged. In vitro studies have shown that FR255734 effectively blocked T-cell proliferation and proinflammatory cytokine production. These observations warrant studies to evaluate the efficacy of FR255734 in human autoimmune diseases.

  19. Augmentation of immune response by chicoric acid through the modulation of CD28/CTLA-4 and Th1 pathway in chronically stressed mice.

    PubMed

    Kour, Kiranjeet; Bani, Sarang

    2011-05-01

    This study demonstrates the protective effect of chicoric acid (CA) on chronic restraint stress-induced altered T lymphocyte subset distribution and corresponding cytokine secretion patterns in experimental Swiss albino mice. CA has the potential to restore diminished immune response and Th1/Th2 homeostasis in chronically stressed mice as evident by significant increase in lymphocyte proliferation and CD3(+), CD4(+) and CD8(+) T cell population. Interestingly, chicoric acid imparted immunostimulation mainly by upregulating the expression of CD28 and CD80 and downregulating CTLA-4. It exerted stimulatory effect on IL-12, IFN-gamma and IL-2 and suppressed the increased IL-10 levels in chronically stressed mice. It also exhibited a significant lowering effect on raised corticosterone levels and reversed the chronic stress-induced hypertrophy of adrenal glands and atrophy of thymus and spleen, thereby showing its normalizing effect on HPA axis. Our results reveal that CA has the potential to reverse the impact of chronic restraint stress on immune status by normalizing corticosterone levels and augmenting Th1 cytokine profile along with the co-stimulatory molecules particularly CD28/CTLA-4 pathway that plays a very important role in generation of an effective immune response in immune compromised situations.

  20. Loss of CD28 within CD4(+) T cell subsets from cervical cancer patients is accompanied by the acquisition of intracellular perforin, and is further enhanced by NKG2D expression.

    PubMed

    Escarra-Senmarti, Marta; Bueno-Topete, Miriam Ruth; Jave-Suarez, Luis Felipe; Gomez-Bañuelos, Eduardo; Gutierrez-Franco, Jorge; Vega-Magaña, Natali; Aguilar-Lemarroy, Adriana; Pereira-Suarez, Ana Laura; Haramati, Jesse; Del Toro-Arreola, Susana

    2017-02-01

    CD28 is well characterized as an essential co-stimulatory receptor critical for activation, proliferation and survival processes in CD4(+) T cells. Populations of CD4(+)CD28(null) T cells, with apparently contradictory physiological roles, have recently been reported, along with the co-expression of the NK activating receptor NKG2D, in autoimmune diseases and chronic viral inflammation. Paradoxically, studies in cancer suggest that an expanded CD4(+)NKG2D(+) population may be armed with immunosuppressive properties. We have recently reported the existence of two separate CD4(+)NKG2D(+) T cell populations, which were defined by the presence or absence of the co-stimulatory molecule CD28, with the CD4(+)CD28(null)NKG2D(+) population more frequently observed in women with cervical cancer. This has led to the present effort to further characterize this population and to determine if the loss of CD28 influences the acquisition of cytotoxic or regulatory markers. In the present work, a multicolor flow cytometry protocol was used to analyze the expression of cytotoxic and immunoregulatory markers on circulating CD4(+) T cells characterized by the presence or absence of CD28 and NKG2D in patients with invasive cervical carcinoma and age/gender-matched healthy controls. A noticeable expansion of CD4(+)CD28(null) cells, many of them NKG2D(+), were observed in selected cervical cancer samples. This CD4(+)CD28(null) T cell population was characterized by a lack of immunoregulatory markers, as well as very low basal levels of intracellular IFN-γ, TNF-α, TGF-β, and IL-10. Intracellular perforin, however, was found to be significantly increased in this CD4(+)CD28(null) population, and increases in the mean fluorescence intensity of perforin were found to be enhanced by the presence of NKG2D. In conclusion, our data provide the first evidence of a strict link between the absence of CD28 and the expression of perforin, which is likewise enhanced by the expression of NKG2D

  1. Blockade of both CD28/B7 and OX40/OX40L co-stimulatory signal pathways prolongs the survival of islet xenografts.

    PubMed

    Wang, G M; Yang, Y; Jin, Y Z; Li, A L; Hao, J; Gao, X; Xie, S S

    2005-12-01

    CTLA4Ig, a recombinant fusion protein composed of the extracellular domain of human CTLA4 and the constant region of human IgG1, inhibits the interaction of CD28/B7 pathway by binding the B7 molecule. OX40Ig, a recombinant fusion protein composed of the extracellular domain of human OX40 and the constant region of human IgG1, abrogates the interaction of OX40/OX40L pathway by binding the OX40L on APCs. So blockade of CD28/B7 or OX40/OX40L co-stimulatory pathways alone in mice with CTLA4Ig or OX40Ig can result in finitely prolonging the survival of islet grafts (43.2 +/- 4.81 and 67.7 +/- 7.74 days, respectively). In this study, a novel replication-defective adenovirus containing both of the CTLA4Ig and OX40Ig genes, AdCTLA4Ig-IRES-OX40Ig, was constructed by homologous recombination and injected into the streptozocin-rendered diabetic BalB/c mouse recipients (H-2d) through the tail vein, at the same day, the freshly isolated islets from Lewis rats (RT-1) were transplanted under the left kidney capsule of the recipients. The results showed that the mean survival time of the islet xenografts in the AdCTLA4Ig-IRES-OX40Ig-treated diabetic mice was significantly prolonged (100.3 +/- 14.94 days), while those in the untreated or AdEGFP-treated mice were rejected in normal fashion (6.7 +/- 0.94 and 7.0 +/- 1.0 days, respectively). In conclusion, utilizing AdCTLA4Ig-IRES-OX40Ig in vivo which can simultaneously express CTLA4Ig and OX40Ig proteins can improve the survival of Lewis-->BalB/c islet xenografts.

  2. Usability Design Strategies for Children: Developing Children's Learning and Knowledge in Decreasing Their Dental Anxiety

    ERIC Educational Resources Information Center

    Yahaya, Wan Ahmad Jaafar Wan; Salam, Sobihatun Nur Abdul

    2010-01-01

    This paper presents an example of how usability design strategies for children can be designed into educational material using CD-ROM based multimedia application for assisting parents and teachers to develop children's learning and knowledge in decreasing as well as motivate children aged 7-9 years old to reduce their anxious feelings towards…

  3. Decreased SBPase activity alters growth and development in transgenic tobacco plants.

    PubMed

    Lawson, T; Bryant, B; Lefebvre, S; Lloyd, J C; Raines, C A

    2006-01-01

    The effects of reduced SBPase activity on growth and development were examined in a set of transgenic tobacco plants produced using an antisense construct driven by the ribulose bisphosphate carboxylase, small subunit promoter. Photosynthetic carbon assimilation rates and carbohydrate levels in source leaves were decreased in the antisense plants. Growth rate and total shoot biomass were reduced in the SBPase antisense plants, even in plants where SBPase activity was reduced by only 25%. Floral biomass also decreased in response to reductions in SBPase activity and the onset of flowering was delayed by 5-10 d. This is the first demonstration of a link between reproductive biomass and reductions in Calvin cycle enzyme activity using antisense plants. Furthermore, unexpected changes in the growth and development of the antisense plants were evident. Small reductions in SBPase activity (above 50% wild type) resulted in shorter plants with only a small decrease in stem biomass and specific leaf area. In contrast, plants with larger reductions in SBPase activity had an increase in specific leaf area and attained heights similar to that of the wild-type plants but with a much reduced stem biomass, largely due to a decrease in xylem tissue. This bi-modal response of growth to reductions in SBPase activity has similarities to changes in leaf and stem anatomy and morphology that accompany light acclimation.

  4. A Critical Precursor Frequency of Donor-Reactive CD4+ T Cell Help is Required for CD8+ T Cell-Mediated CD28/CD154-Independent Rejection

    PubMed Central

    Ford, Mandy L.; Wagener, Maylene E.; Hanna, Samantha S.; Pearson, Thomas C.; Kirk, Allan D.; Larsen, Christian P.

    2008-01-01

    Antigen-specific precursor frequency is increasingly being appreciated as an important factor in determining the kinetics, magnitude, and degree of differentiation of T cell responses, and recently was found to play a critical role in determining the relative requirement of CD8+ T cells for CD28- and CD154-mediated costimulatory signals during transplantation. We addressed the possibility that variations in CD4+ T cell precursor frequency following transplantation might affect CD4+ T cell proliferation, effector function, and provision of help for donor-reactive B cell and CD8+ T cell responses. Using a transgenic model system wherein increasing frequencies of donor-reactive CD4+ T cells were transferred into skin graft recipients, we observed that a critical CD4+ T cell threshold precursor frequency was necessary to provide help following blockade of the CD28 and CD154 costimulatory pathways, as measured by increased B cell and CD8+ T cell responses and precipitation of graft rejection. In contrast to high-frequency CD8+ T cell responses, this effect was observed even though the proliferative and cytokine responses of Ag-specific CD4+ T cells were inhibited. Thus, we conclude that an initial high frequency of donor-reactive CD4+ T cells uncouples T cell proliferative and effector cytokine production from the provision of T cell help. This is an author-produced version of a manuscript accepted for publication in The Journal of Immunology (The JI). The American Association of Immunologists, Inc. (AAI), publisher of The JI, holds the copyright to this manuscript. This version of the manuscript has not yet been copyedited or subjected to editorial proofreading by The JI; hence, it may differ from the final version published in The JI (online and in print). AAI (The JI) is not liable for errors or omissions in this author-produced version of the manuscript or in any version derived from it by the U.S. National Institutes of Health or any other third party. The final

  5. NSOM/QD-based direct visualization of CD3-induced and CD28-enhanced nanospatial coclustering of TCR and coreceptor in nanodomains in T cell activation.

    PubMed

    Zhong, Liyun; Zeng, Gucheng; Lu, Xiaoxu; Wang, Richard C; Gong, Guangming; Yan, Lin; Huang, Dan; Chen, Zheng W

    2009-06-17

    Direct molecular imaging of nano-spatial relationship between T cell receptor (TCR)/CD3 and CD4 or CD8 co-receptor before and after activation of a primary T cell has not been reported. We have recently innovated application of near-field scanning optical microscopy (NSOM) and immune-labeling quantum dots (QD) to image Ag-specific TCR response during in vivo clonal expansion, and now up-graded the NSOM/QD-based nanotechnology through dipole-polarization and dual-color imaging. Using this imaging system scanning cell-membrane molecules at a best-optical lateral resolution, we demonstrated that CD3, CD4 or CD8 molecules were distinctly distributed as single QD-bound molecules or nano-clusters equivalent to 2-4 QD fluorescence-intensity/size on cell-membrane of un-stimulated primary T cells, and approximately 6-10% of CD3 were co-clustering with CD4 or CD8 as 70-110 nm nano-clusters without forming nano-domains. The ligation of TCR/CD3 on CD4 or CD8 T cells led to CD3 nanoscale co-clustering or interaction with CD4 or CD8 co-receptors forming 200-500 nm nano-domains or >500 nm micro-domains. Such nano-spatial co-clustering of CD3 and CD4 or CD3 and CD8 appeared to be an intrinsic event of TCR/CD3 ligation, not purely limited to MHC engagement, and be driven by Lck phosphorylation. Importantly, CD28 co-stimulation remarkably enhanced TCR/CD3 nanoscale co-clustering or interaction with CD4 co-receptor within nano- or micro-domains on the membrane. In contrast, CD28 co-stimulation did not enhance CD8 clustering or CD3-CD8 co-clustering in nano-domains although it increased molecular number and density of CD3 clustering in the enlarged nano-domains. These nanoscale findings provide new insights into TCR/CD3 interaction with CD4 or CD8 co-receptor in T-cell activation.

  6. Chronic inflammation contributes to the development of hepatocellular carcinoma by decreasing miR-122 levels

    PubMed Central

    Li, Changfei; Deng, Mengmeng; Hu, Jun; Li, Xin; Chen, Lizhao; Ju, Ying; Hao, Junli; Meng, Songdong

    2016-01-01

    Persistent inflammation in chronic hepatitis plays a major role in the development of hepatocellular carcinoma (HCC). In this study, the major inflammatory cytokines expressed in chronic hepatitis, IL-6 and TNF-α, induced a marked decrease in microRNA-122 (miR-122) levels, and miR-122 expression was downregulated in the livers of chronic hepatitis B (CHB) patients. The decrease of miR-122 caused upregulation of the proinflammatory chemokine CCL2. IL-6 and TNF-α suppressed miR-122 both by directly downregulating the transcription factor C/EBPα and indirectly upregulating c-myc, which blocks C/EBPα-mediated miR-122 transcription. In addition, IL-6 and TNF-α levels were elevated and miR-122 levels were decreased in mouse and rat models of diethylnitrosamine (DEN)-induced HCC. Restoration of miR-122 levels through delivery of agomir-122 suppressed DEN-induced hepatocarcinogenesis in mice. Our results show that inflammation-induced miR-122 downregulation in hepatitis contributes to carcinogenesis and suggest that increasing miR-122 may be an effective strategy for preventing HCC development in CHB patients. PMID:26933995

  7. Cyclosporin A improves murine pregnancy outcome in abortion-prone matings: involvement of CD80/86 and CD28/CTLA-4.

    PubMed

    Zhou, Wen-Hui; Dong, Lin; Du, Mei-Rong; Zhu, Xiao-Yong; Li, Da-Jin

    2008-03-01

    Immune regulation during pregnancy is complex, and thus an optimal therapy for pregnancy complications is always a big challenge to reproductive medicine. Cyclosporin A (CsA), a potent immunosuppressant, prevents rejection of allografts by hosts, but little is known about the modulating effect of CsA on the materno-fetal relationship. Here, pregnant CBA/J females mated with DBA/2 males as an abortion-prone model were administered with CsA on day 4.5 of gestation, and the pregnant CBA/J females mated with BALB/c males were established as successful pregnancy control. It was demonstrated that administration of CsA at the window of implantation significantly up-regulated the expression of CTLA-4, while down-regulating the levels of CD80, CD86, and CD28 at the materno-fetal interface in the CBA/J x DBA/2 abortion-prone matings, and the embryo resorption rate of the abortion-prone matings reduced significantly after CsA treatment, implying that modulation of costimulatory molecule expression by CsA might contribute to preventing the fetus from maternal immune attack. In addition, treatment with CsA induced enhanced growth and reduced cell apoptosis of the murine trophoblast cells. Together, these findings indicate that CsA has a beneficial effect on the materno-fetal interface in abortion-prone matings, leading to a pregnancy outcome improvement, which might provide new therapeutics for spontaneous pregnancy wastage.

  8. Inhibition of prolactin in the last trimester of gestation decreases mammary gland development in gilts.

    PubMed

    Farmer, C; Sorensen, M T; Petitclerc, D

    2000-05-01

    Prolactin is required for mammary development in various species but its possible role for mammogenesis in pigs is not known. The goal of the present study was therefore to determine the effect of prolactin inhibition by bromocriptine during the last third of gestation on mammary gland development in gilts. Twenty-eight primigravid gilts were assigned as controls (n = 15) or received 10 mg of bromocriptine orally thrice daily (n = 13) from d 70 to 110 of gestation. Jugular blood samples were collected on d 70 of gestation and every 8 d thereafter and were assayed for prolactin, IGF-I, estradiol, and progesterone. Gilts were slaughtered on d 110 of gestation and fetuses were counted and weighed. One row of mammary glands was used for dissection of parenchymal and extraparenchymal tissues and for determination of DNA, RNA, dry matter, protein, and fat contents. Tissue from the other row was used for measures of prolactin receptor number and affinity. Concentrations of prolactin were drastically reduced throughout the bromocriptine treatment period (P < .001), whereas there was no overall treatment effect on progesterone and IGF-I levels (P > .10). Total weight and extraparenchymal tissue weight of the mammary glands were unaffected by treatment (P > or = .1), but weight of parenchymal tissue, total DNA, and total RNA decreased (P < .01) with bromocriptine treatment. Percentages of fat and dry matter in parenchymal tissue increased with bromocriptine treatment (P < .01) and the percentage of protein decreased (P < .01). Number of prolactin receptors in parenchymal tissue decreased with bromocriptine treatment (P < .001) and receptor affinity increased (P < .001). Average fetal weight was lower in gilts receiving bromocriptine than in control gilts (P = .05), but fetal number did not differ (P > .1). These results clearly demonstrate that prolactin is essential for normal mammary gland development and can affect fetal growth during the last third of gestation in gilts.

  9. DECREASE Final Technical Report: Development of a Commercial Ready Enzyme Application System for Ethanol

    SciTech Connect

    Teter, Sarah A

    2012-04-18

    Conversion of biomass to sugars plays a central in reducing our dependence on petroleum, as it allows production of a wide range of biobased fuels and chemicals, through fermentation of those sugars. The DECREASE project delivers an effective enzyme cocktail for this conversion, enabling reduced costs for producing advanced biofuels such as cellulosic ethanol. Benefits to the public contributed by growth of the advanced biofuels industry include job creation, economic growth, and energy security. The DECREASE primary project objective was to develop a two-fold improved enzyme cocktail, relative to an advanced cocktail (CZP00005) that had been developed previously (from 2000- 2007). While the final milestone was delivery of all enzyme components as an experimental mixture, a secondary objective was to deploy an improved cocktail within 3 years following the close of the project. In February 2012, Novozymes launched Cellic CTec3, a multi-enzyme cocktail derived in part from components developed under DECREASE. The externally validated performance of CTec3 and an additional component under project benchmarking conditions indicated a 1.8-fold dose reduction in enzyme dose required for 90% conversion (based on all available glucose and xylose sources) of NREL dilute acid pretreated PCS, relative to the starting advanced enzyme cocktail. While the ability to achieve 90% conversion is impressive, targeting such high levels of biomass digestion is likely not the most cost effective strategy. Novozymes techno economic modeling showed that for NREL's dilute acid pretreated corn stover (PCS), 80% target conversion enables a lower total production cost for cellulosic ethanol than for 90% conversion, and this was also found to be the case when cost assumptions were based on the NREL 2002 Design Report. A 1.8X dose-reduction was observed for 80% conversion in the small scale (50 g) DECREASE benchmark assay for CTec3 and an additional component. An upscaled experiment (in 0.5 kg

  10. Neonatal Colonization of Mice with LGG Promotes Intestinal Development and Decreases Susceptibility to Colitis in Adulthood

    PubMed Central

    Yan, Fang; Liu, Liping; Cao, Hailong; Moore, Daniel J.; Washington, M. Kay; Wang, Bangmao; Peek, Richard M.; Acra, Sari A.; Polk, D. Brent

    2016-01-01

    Development of the intestinal microbiota during early life serves a key regulatory stage in establishing the host-microbial relationship. This symbiotic relationship contributes to developing host immunity and maintaining health throughout the life span. This study was to develop an approach to colonize conventionally raised mice with a model probiotic bacterium, Lactobacillus rhamnosus GG (LGG), and determine the effects of LGG colonization on intestinal development and prevention of colitis in adulthood. LGG colonization in conventionally raised was established by administering LGG to pregnant mice starting at gestational day 18 and pups at postnatal day 1 to day 5. LGG colonization promoted bodyweight gain and increased diversity and richness of the colonic mucosa-associated microbiota prior to weaning. Intestinal epithelial cell proliferation, differentiation, tight junction formation and mucosal IgA production were all significantly enhanced in LGG colonized mice. Adult mice colonized with LGG showed increased IgA production and decreased susceptibility to intestinal injury and inflammation induced in the dextran sodium sulphate model of colitis. Thus, neonatal colonization of mice with LGG enhances intestinal functional maturation and IgA production and confers life long health consequences on protection from intestinal injury and inflammation. This strategy might be applied for benefiting health in the host. PMID:27095077

  11. Dexamethasone Treatment of Newborn Rats Decreases Cardiomyocyte Endowment in the Developing Heart through Epigenetic Modifications.

    PubMed

    Gay, Maresha S; Li, Yong; Xiong, Fuxia; Lin, Thant; Zhang, Lubo

    2015-01-01

    The potential adverse effect of synthetic glucocorticoid, dexamethasone therapy on the developing heart remains unknown. The present study investigated the effects of dexamethasone on cardiomyocyte proliferation and binucleation in the developing heart of newborn rats and evaluated DNA methylation as a potential mechanism. Dexamethasone was administered intraperitoneally in a three day tapered dose on postnatal day 1 (P1), 2 and 3 to rat pups in the absence or presence of a glucocorticoid receptor antagonist Ru486, given 30 minutes prior to dexamethasone. Cardiomyocytes from P4, P7 or P14 animals were analyzed for proliferation, binucleation and cell number. Dexamethasone treatment significantly increased the percentage of binucleated cardiomyocytes in the hearts of P4 pups, decreased myocyte proliferation in P4 and P7 pups, reduced cardiomyocyte number and increased the heart to body weight ratio in P14 pups. Ru486 abrogated the effects of dexamethasone. In addition, 5-aza-2'-deoxycytidine (5-AZA) blocked the effects of dexamethasone on binucleation in P4 animals and proliferation at P7, leading to recovered cardiomyocyte number in P14 hearts. 5-AZA alone promoted cardiomyocyte proliferation at P7 and resulted in a higher number of cardiomyocytes in P14 hearts. Dexamethasone significantly decreased cyclin D2, but not p27 expression in P4 hearts. 5-AZA inhibited global DNA methylation and blocked dexamethasone-mediated down-regulation of cyclin D2 in the heart of P4 pups. The findings suggest that dexamethasone acting on glucocorticoid receptors inhibits proliferation and stimulates premature terminal differentiation of cardiomyocytes in the developing heart via increased DNA methylation in a gene specific manner.

  12. Aquaporin-4 expression contributes to decreases in brain water content during mouse postnatal development.

    PubMed

    Li, Xiumiao; Gao, Junying; Ding, Jiong; Hu, Gang; Xiao, Ming

    2013-05-01

    The water channel protein aquaporin-4 (AQP4) is implicated to facilitate water efflux from the brain parenchyma into the blood and CSF, playing a critical role in maintaining brain water homeostasis. Nevertheless, its contribution to decreases in brain water content during postnatal development remains unknown. A quantitative Western blot analysis was performed to investigate developmental expression of AQP4 in the whole mouse brain and showed that AQP4 expression level in 1 week-old brain was only 21.3% of that in the adult brain, but significantly increased to 67.4% of the adult level by 2 weeks after birth. Statistical analysis demonstrated that increased AQP4 expression partially relates to decreased brain water content in postnatal mice (r(2)=0.92 and P=0.002). Moreover, AQP4 null mice had greater brain water content than littermate controls from 2 weeks up to adult age. Consistently, mature pattern of AQP4 localization at the brain-blood and brain-CSF interfaces were completed at approximately at 2 weeks after birth. In addition, AQP4 expression in the brain stem and hypothalamus was earlier than that in the cerebral cortex and cerebellum, suggesting a brain regional variation in developmental expression of AQP4. These results characterize the developmental feature of AQP4 expression in the postnatal brain and provide direct evidence for a role of AQP4 in postnatal brain water uptake.

  13. Decreasing CNPY2 Expression Diminishes Colorectal Tumor Growth and Development through Activation of p53 Pathway.

    PubMed

    Yan, Ping; Gong, Hui; Zhai, Xiaoyan; Feng, Yi; Wu, Jun; He, Sheng; Guo, Jian; Wang, Xiaoxia; Guo, Rui; Xie, Jun; Li, Ren-Ke

    2016-04-01

    Neovascularization drives tumor development, and angiogenic factors are important neovascularization initiators. We recently identified the secreted angiogenic factor CNPY2, but its involvement in cancer has not been explored. Herein, we investigate CNPY2's role in human colorectal cancer (CRC) development. Tumor samples were obtained from CRC patients undergoing surgery. Canopy 2 (CNPY2) expression was analyzed in tumor and adjacent normal tissue. Stable lines of human HCT116 cells expressing CNPY2 shRNA or control shRNA were established. To determine CNPY2's effects on tumor xenografts in vivo, human CNPY2 shRNA HCT116 cells and controls were injected into nude mice, separately. Cellular apoptosis, growth, and angiogenesis in the xenografts were evaluated. CNPY2 expression was significantly higher in CRC tissues. CNPY2 knockdown in HCT116 cells inhibited growth and migration and promoted apoptosis. In xenografts, CNPY2 knockdown prevented tumor growth and angiogenesis and promoted apoptosis. Knockdown of CNPY2 in the HCT116 CRC cell line reversibly increased p53 activity. The p53 activation increased cyclin-dependent kinase inhibitor p21 and decreased cyclin-dependent kinase 2, thereby inhibiting tumor cell growth, inducing cell apoptosis, and reducing angiogenesis both in vitro and in vivo. CNPY2 may play a critical role in CRC development by enhancing cell proliferation, migration, and angiogenesis and by inhibiting apoptosis through negative regulation of the p53 pathway. Therefore, CNPY2 may represent a novel CRC therapeutic target and prognostic indicator.

  14. VEGF receptor expression decreases during lung development in congenital diaphragmatic hernia induced by nitrofen

    PubMed Central

    Sbragia, L.; Nassr, A.C.C.; Gonçalves, F.L.L.; Schmidt, A.F.; Zuliani, C.C.; Garcia, P.V.; Gallindo, R.M.; Pereira, L.A.V.

    2014-01-01

    Changes in vascular endothelial growth factor (VEGF) in pulmonary vessels have been described in congenital diaphragmatic hernia (CDH) and may contribute to the development of pulmonary hypoplasia and hypertension; however, how the expression of VEGF receptors changes during fetal lung development in CDH is not understood. The aim of this study was to compare morphological evolution with expression of VEGF receptors, VEGFR1 (Flt-1) and VEGFR2 (Flk-1), in pseudoglandular, canalicular, and saccular stages of lung development in normal rat fetuses and in fetuses with CDH. Pregnant rats were divided into four groups (n=20 fetuses each) of four different gestational days (GD) 18.5, 19.5, 20.5, 21.5: external control (EC), exposed to olive oil (OO), exposed to 100 mg nitrofen, by gavage, without CDH (N-), and exposed to nitrofen with CDH (CDH) on GD 9.5 (term=22 days). The morphological variables studied were: body weight (BW), total lung weight (TLW), left lung weight, TLW/BW ratio, total lung volume, and left lung volume. The histometric variables studied were: left lung parenchymal area density and left lung parenchymal volume. VEGFR1 and VEGFR2 expression were determined by Western blotting. The data were analyzed using analysis of variance with the Tukey-Kramer post hoc test. CDH frequency was 37% (80/216). All the morphological and histometric variables were reduced in the N- and CDH groups compared with the controls, and reductions were more pronounced in the CDH group (P<0.05) and more evident on GD 20.5 and GD 21.5. Similar results were observed for VEGFR1 and VEGFR2 expression. We conclude that N- and CDH fetuses showed primary pulmonary hypoplasia, with a decrease in VEGFR1 and VEGFR2 expression. PMID:24519134

  15. VEGF receptor expression decreases during lung development in congenital diaphragmatic hernia induced by nitrofen.

    PubMed

    Sbragia, L; Nassr, A C C; Gonçalves, F L L; Schmidt, A F; Zuliani, C C; Garcia, P V; Gallindo, R M; Pereira, L A V

    2014-02-01

    Changes in vascular endothelial growth factor (VEGF) in pulmonary vessels have been described in congenital diaphragmatic hernia (CDH) and may contribute to the development of pulmonary hypoplasia and hypertension; however, how the expression of VEGF receptors changes during fetal lung development in CDH is not understood. The aim of this study was to compare morphological evolution with expression of VEGF receptors, VEGFR1 (Flt-1) and VEGFR2 (Flk-1), in pseudoglandular, canalicular, and saccular stages of lung development in normal rat fetuses and in fetuses with CDH. Pregnant rats were divided into four groups (n=20 fetuses each) of four different gestational days (GD) 18.5, 19.5, 20.5, 21.5: external control (EC), exposed to olive oil (OO), exposed to 100 mg nitrofen, by gavage, without CDH (N-), and exposed to nitrofen with CDH (CDH) on GD 9.5 (term=22 days). The morphological variables studied were: body weight (BW), total lung weight (TLW), left lung weight, TLW/BW ratio, total lung volume, and left lung volume. The histometric variables studied were: left lung parenchymal area density and left lung parenchymal volume. VEGFR1 and VEGFR2 expression were determined by Western blotting. The data were analyzed using analysis of variance with the Tukey-Kramer post hoc test. CDH frequency was 37% (80/216). All the morphological and histometric variables were reduced in the N- and CDH groups compared with the controls, and reductions were more pronounced in the CDH group (P<0.05) and more evident on GD 20.5 and GD 21.5. Similar results were observed for VEGFR1 and VEGFR2 expression. We conclude that N- and CDH fetuses showed primary pulmonary hypoplasia, with a decrease in VEGFR1 and VEGFR2 expression.

  16. Induction of granzyme B expression in T-cell receptor/CD28-stimulated human regulatory T cells is suppressed by inhibitors of the PI3K-mTOR pathway

    PubMed Central

    2009-01-01

    Background Regulatory T cells (Tregs) can employ a cell contact- and granzyme B-dependent mechanism to mediate suppression of bystander T and B cells. Murine studies indicate that granzyme B is involved in the Treg-mediated suppression of anti-tumor immunity in the tumor microenvironment and in the Treg-mediated maintenance of allograft survival. In spite of its central importance, a detailed study of granzyme B expression patterns in human Tregs has not been performed. Results Our data demonstrated that natural Tregs freshly isolated from the peripheral blood of normal adults lacked granzyme B expression. Tregs subjected to prolonged TCR and CD28 triggering, in the presence of IL-2, expressed high levels of granzyme B but CD3 stimulation alone or IL-2 treatment alone failed to induce granzyme B. Treatment of Tregs with the mammalian target of rapamycin (mTOR) inhibitor, rapamycin or the PI3 kinase (PI3K) inhibitor LY294002 markedly suppressed granzyme B expression. However, neither rapamycin, as previously reported by others, nor LY294002 inhibited Treg proliferation or induced significant cell death in TCR/CD28/IL-2 stimulated cells. The proliferation rate of Tregs was markedly higher than that of CD4+ conventional T cells in the setting of rapamycin treatment. Tregs expanded by CD3/CD28/IL-2 stimulation without rapamycin demonstrated increased in vitro cytotoxic activity compared to Tregs expanded in the presence of rapamycin in both short term (6 hours) and long term (48 hours) cytotoxicity assays. Conclusion TCR/CD28 mediated activation of the PI3K-mTOR pathway is important for granyzme B expression but not proliferation in regulatory T cells. These findings may indicate that suppressive mechanisms other than granzyme B are utilized by rapamycin-expanded Tregs. PMID:19930596

  17. Construction of Anti-CD20 Single-Chain Antibody-CD28-CD137-TCRζ Recombinant Genetic Modified T Cells and its Treatment Effect on B Cell Lymphoma

    PubMed Central

    Chen, Fei; Fan, Chuming; Gu, Xuezhong; Zhang, Haixi; Liu, Qian; Gao, Xiaoli; Lu, Jie; He, Baoli; Lai, Xun

    2015-01-01

    Background Immunotherapy has been explored as a new therapy for B cell lymphoma, which is a non-Hodgkin’s lymphoma. Because CD20 is a B lymphocyte-specific marker, anti-CD20 single chain-tagged T lymphocytes have already begun to be experimentally used in B cell lymphoma treatment, but its use is still limited because of its unspecific targeting. T cells transfected with CD28 and CD137 can significantly improve the ability of cytokines secretion and anti-tumor effect, as well as extending T cell survival time and improving their proliferation ability. Material/Methods Genes containing anti-CD20-CD28-CD137-TCRζ were constructed. After cloning and sequencing, the plasmid was constructed and packaged by lentivirus. It was transfected to the peripheral blood T lymphocyte after identification transfection to induce the fusion protein expression. The cells were incubated with Raji cells and the LDH test was performed to detect the cytotoxic effect of CAR-T cells; the tumor volume and survival rate were measured to observe its inhibitory effect on B cell lymphoma in nude mice. Results Gene with anti-CD20-CD28-CD137-TCRζ was successfully constructed and transfected to the T cell surface. LDH assay revealed that CAR-T cells can kill the Raji cells with a killing rate of 32.89±6.26%. It can significantly inhibit B cell lymphoma growth in nude mice. Conclusions T lymphocytes transfected with anti-CD20-CD28-CD137-TCRζ fusion gene can kill B cell lymphoma, which could provide a new strategy for tumor treatment. PMID:26195067

  18. Decrease in plasminogen activator correlates with synapse elimination during neonatal development of mouse skeletal muscle.

    PubMed Central

    Hantaï, D; Rao, J S; Kahler, C; Festoff, B W

    1989-01-01

    Previous studies have implicated proteases, acting extracellularly, in the mechanism of polyneuronal synapse elimination. Most studies have focused on mammalian, especially rodent, skeletal muscle, where retraction of subordinate nerve terminals occurs during a narrow time window 2-3 weeks after birth. To date no specific protease(s) has been detected that (i) coincides in time with maximal synapse elimination and (ii) is known to act extracellularly on specific extracellular matrix proteins. In previous studies of denervation in adult mouse muscle, rapid activation of urokinase-type plasminogen activator, a neutral serine protease, was detected. This enzyme, by activation of plasminogen to plasmin, specifically degrades matrix components such as fibronectin, type IV collagen, and laminin in muscle. We now present evidence for an initial increase and subsequent decrease in soluble urokinase-type PA--and, to a lesser extent, tissue PA--in developing muscle, suggesting postnatal developmental regulation of these enzymes during the period of maximal synapse elimination. Although considerably higher in specific activity, membrane-bound PA activity followed the wave of synapse elimination, possibly indicating a longer half-life of membrane-bound enzyme(s). Images PMID:2492103

  19. Benzo[a]pyrene decreases global and gene specific DNA methylation during zebrafish development

    Technology Transfer Automated Retrieval System (TEKTRAN)

    DNA methylation is important for gene regulation and is vulnerable to early-life exposure to environmental contaminants. We found that direct waterborne benzo[a]pyrene (BaP) exposure at 24 'g/L from 2.5 to 96 hours post fertilization (hpf) to zebrafish embryos significantly decreased global cytosine...

  20. Rotenone Decreases Hatching Success in Brine Shrimp Embryos by Blocking Development: Implications for Zooplankton Egg Banks

    PubMed Central

    Hutchison, Evan R.; Neumeyer, Courtney H.; Gunderson, Matthew D.

    2016-01-01

    While many zooplankton species recover quickly after the treatment of water resources with the piscicide, rotenone, some fail to reach pretreatment population density or, in rare cases, do not reappear at all. The variable impact of rotenone on zooplankton populations could stem from differences in the capacity of species to switch entirely to anaerobic catabolic pathways in the presence of rotenone, which blocks mitochondrial electron transport. Alternatively, variable responses among species could originate from differences in permeability of dormant life-stages to lipophilic chemicals like rotenone. The purpose of the present study was to determine the effects of rotenone on development, emergence and hatching of zooplankton embryos that lack both the anaerobic capacity to develop in the presence of rotenone and a permeability barrier to prevent the entry of rotenone during dormancy. Post-diapause embryos of the brine shrimp, Artemia franciscana, were employed as a model system, because they are permeable to lipophilic compounds when dechorionated and require aerobic conditions to support development. Early development in this species is also well characterized in the literature. Brine shrimp embryos were exposed to rotenone while development was either slowed by chilling or suspended by anoxia. Development, emergence and hatching were then observed in rotenone-free artificial seawater. The data presented demonstrate that rotenone freely diffuses across the embryonic cuticle in a matter of hours, and prevents development and emergence after brief exposures to ecologically relevant concentrations (0.025–0.5 mg L-1) of the piscicide. Neither the removal of rotenone from the environment, nor the removal of embryonic water with a hypertonic solution, are sufficient to reverse this block on development and emergence. These data indicate that rotenone could impair recruitment from egg banks for species of zooplankton that lack both an embryonic barrier to the entry

  1. Decreasing costs of ground data processing system development using a software product line

    NASA Technical Reports Server (NTRS)

    Chaffin, Brian

    2005-01-01

    In this paper, I describe software product lines and why a Ground Data Processing System should use one. I also describe how to develop a software product line, using examples from an imaginary Ground Data Processing System.

  2. Fixed-time teacher attention to decrease off-task behaviors of typically developing third graders.

    PubMed

    Austin, Jennifer L; Soeda, Jennifer M

    2008-01-01

    Evidence to validate the use of fixed-time (FT) reinforcer delivery (i.e., noncontingent reinforcement) with typically developing populations has been relatively rare in the behavioral literature. In those studies that have provided validation, reinforcer delivery schedules appeared to be prohibitively dense for sustained implementation of procedures. This study demonstrated the efficacy of using FT reinforcer delivery to reduce off-task behavior of 2 typically developing third graders using a teacher-selected schedule (FT 4 min). Immediate reductions in off-task behavior were observed for both children. Challenges in identifying the operative mechanism of FT schedules in natural settings are discussed.

  3. N, N-Dimethylglycine decreases oxidative stress and improves in vitro development of bovine embryos

    PubMed Central

    TAKAHASHI, Toshikiyo; SASAKI, Kouya; SOMFAI, Tamas; NAGAI, Takashi; MANABE, Noboru; EDASHIGE, Keisuke

    2016-01-01

    The antioxidant effect of N, N-dimethylglycine (DMG) on in vitro-produced (IVP) bovine embryos was examined. After in vitro fertilization, presumptive zygotes were cultured with or without 0.1 μM DMG under different oxygen tensions. The percentage of embryos developing to the blastocyst stage was lowest under a 20% oxygen concentration without DMG, and it was significantly increased (P < 0.05) by applying a 5% oxygen concentration. Under the 20% oxygen concentration, supplementation of the medium with DMG significantly improved blastocyst development, which was nearly equal to that achieved under 5% oxygen without DMG. Furthermore, a tendentious increase (P = 0.06) in blastocyst cell numbers was observed when DMG was applied. In the second experiment, addition of H2O2 (0.5 mM) to the culture medium significantly (P < 0.01) reduced the percentage of embryos developing to the blastocyst stage. However, DMG supplementation prevented this reduction. In conclusion, DMG enhanced the in vitro development of IVP bovine embryos by acting as an antioxidant. PMID:26875568

  4. Benzo[a]pyrene decreases global and gene specific DNA methylation during zebrafish development

    PubMed Central

    Fang, Xiefan; Thornton, Cammi; Scheffler, Brian E.; Willett, Kristine L.

    2013-01-01

    DNA methylation is important for gene regulation and is vulnerable to early-life exposure to environmental contaminants. We found that direct waterborne benzo[a]pyrene (BaP) exposure at 24 μg/L from 2.5 to 96 hours post fertilization (hpf) to zebrafish embryos significantly decreased global cytosine methylation by 44.8% and promoter methylation in vasa by 17%. Consequently, vasa expression was significantly increased by 33%. In contrast, BaP exposure at environmentally relevant concentrations did not change CpG island methylation or gene expression in cancer genes such as ras-association domain family member 1 (rassf1), telomerase reverse transcriptase (tert), c-jun, and c-myca. Similarly, BaP did not change gene expression of DNA methyltransferase 1 (dnmt1) and glycine N-methyltransferase (gnmt). While total DNMT activity was not affected, GNMT enzyme activity was moderately increased. In summary, BaP is an epigenetic modifier for global and gene specific DNA methylation status in zebrafish larvae. PMID:23542452

  5. Loss of Core 1-derived O-Glycans Decreases Breast Cancer Development in Mice*

    PubMed Central

    Song, Kai; Herzog, Brett H.; Fu, Jianxin; Sheng, Minjia; Bergstrom, Kirk; McDaniel, J. Michael; Kondo, Yuji; McGee, Samuel; Cai, Xiaofeng; Li, Ping; Chen, Hong; Xia, Lijun

    2015-01-01

    Mucin-type core 1-derived O-glycans, one of the major types of O-glycans, are highly expressed in mammary gland epithelium. Abnormal O-glycans such as Tn antigen are found in over 90% of breast cancers; however, the in vivo role of these aberrant O-glycans in the etiology of breast cancer is unclear. We generated mice with mammary epithelial specific deletion of core 1-derived O-glycans. By crossing with two spontaneous mouse breast cancer models, we determined that loss of core 1-derived O-glycans delays the onset and progression of breast cancer development. Deficiency of core 1 O-glycosylation impaired the localization of Muc1, a major O-glycoprotein, on the apical surfaces of mammary epithelium. Signaling mediated by Muc1, which is critical for breast cancer development, was also defective in the absence of core 1 O-glycans. This study reveals an unexpected role of core 1-derived O-glycans in breast cancer development in mice. PMID:26124270

  6. Monocyte development inhibitor PRM-151 decreases corneal myofibroblast generation in rabbits.

    PubMed

    Santhiago, M R; Singh, V; Barbosa, F L; Agrawal, V; Wilson, S E

    2011-11-01

    This study investigated whether PRM-151 (Promedior, Inc., Malvern, PA), a recombinant form of human pentraxin-2 (PTX-2, also referred to as serum amyloid P, hSAP), that inhibits differentiation of circulating monocytes into fibrocytes and profibrotic macrophages, could modulate generation of myofibroblasts after opacity-producing corneal injury in rabbits, and, therefore, have potential to reduce or prevent haze after PRK. Nine diopter PRK for myopia was performed with the VISX S4 IR laser. Four groups of 6 animals were treated in masked fashion: Group 1: 30 μl of topical PRM-151 (20 mg/ml) 6 times a day for 5 days; Group 2: 30 μl topical vehicle 6 times a day for 5 days; Group 3: 200 μl sub-conjunctival PRM-151 (total injection of 4 mg) immediately after surgery and every other day until day 8; Group 4: 200 μl sub-conjunctival injections of vehicle according to the same schedule as group 3. At one month after PRK, the animals were euthanized and immunohistochemistry was performed for the myofibroblast marker α-smooth muscle actin (SMA). The density of SMA+ cells/400× field in the central stroma was determined in each cornea. Myofibroblast density at one month after surgery was significantly lower (p = 0.006) after sub-conjunctival PRM-151 treatment (5.8 ± 2.8 cells/400× stromal field) compared to sub-conjunctival vehicle treatment (15.3 ± 2.9 cells/400× stromal field). There was no significant (p = 0.27) decrease in stromal myofibroblasts triggered by topical PRM-151 treatment (11.8 ± 6.6 cells/400× stromal field) compared to the topical vehicle treatment (14.2.8 ± 6.2 cells/400× stromal field). PRM-151 inhibits myofibroblast generation when administered by sub-conjunctival injection, but not when administered topically, after opacity-producing corneal injury. This study provides additional confirmation that bone marrow-derived cells contribute to corneal myofibroblast generation.

  7. When development and learning decrease memory. Evidence against category-based induction in children.

    PubMed

    Sloutsky, Vladimir M; Fisher, Anna V

    2004-08-01

    Inductive inference is crucial for learning: If one learns that a cat has a particular biological property, one could expand this knowledge to other cats. We argue that young children perform induction on the basis of similarity of compared entities, whereas adults may induce on the basis of category information. If different processes underlie induction at different points in development, young children and adults would form different memory traces during induction, and would subsequently have different memory accuracy. Experiment 1 demonstrates that after performing an induction task, 5-year-olds exhibit more accurate memory than adults. Experiment 2 indicates that after 5-year-olds are trained to perform induction in an adultlike manner, their memory accuracy drops to the level of adults. These results, indicating that sometimes 5-year-olds exhibit better memory than adults, support the claim that, unlike adults, young children perform similarity-based rather than category-based induction.

  8. Induction of T regulatory cells by the superagonistic anti-CD28 antibody D665 leads to decreased pathogenic IgG autoantibodies against desmoglein 3 in a HLA-transgenic mouse model of pemphigus vulgaris.

    PubMed

    Schmidt, Thomas; Willenborg, Sebastian; Hünig, Thomas; Deeg, Cornelia A; Sonderstrup, Grete; Hertl, Michael; Eming, Rüdiger

    2016-04-01

    Pemphigus vulgaris (PV) is a potentially life-threatening autoimmune disease of the skin and mucous membranes. Its pathogenesis is based on IgG autoantibodies that target the desmosomal cadherins, desmoglein 3 (Dsg3) and desmoglein 1 (Dsg1) and induce intra-epidermal loss of adhesion. Although the PV pathogenesis is well-understood, therapeutic options are still limited to immunosuppressive drugs, particularly corticosteroids, which are associated with significant side effects. Dsg3-reactive T regulatory cells (Treg) have been previously identified in PV and healthy carriers of PV-associated HLA class II alleles. Ex vivo, Dsg3-specific Treg cells down-regulated the activation of pathogenic Dsg3-specific T-helper (Th) 2 cells. In this study, in a HLA-DRB1*04:02 transgenic mouse model of PV, peripheral Treg cells were modulated by the use of Treg-depleting or expanding monoclonal antibodies, respectively. Our findings show that, in vivo, although not statistically significant, Treg cells exert a clear down-regulatory effect on the Dsg3-driven T-cell response and, accordingly, the formation of Dsg3-specific IgG antibodies. These observations confirm the powerful immune regulatory functions of Treg cells and identify Treg cells as potential therapeutic modulators in PV.

  9. Shading the whole vines during young fruit development decreases ascorbate accumulation in kiwi.

    PubMed

    Li, Mingjun; Ma, Fengwang; Liu, Jun; Li, Juan

    2010-11-01

    We investigated how different lighting conditions affected the levels of ascorbate (AsA), sugar contents, the mRNA expression of genes involved in AsA biosynthesis and recycling and enzyme activity in kiwi fruits. Shaded leaves had dramatically less AsA as well as altered transcript levels and enzyme activities. In contrast, fruits that had been covered directly at various developmental stages showed no changes in those parameters. Fruits had significantly less AsA content before 40 days after anthesis (DAA) when whole vines were shaded only from 0 to 40 DAA, whereas transcript levels of most related genes (except those for GDP-L-galactose-1-phosphate phosphorylase and GDP-mannose pyrophosphorylase) followed a parallel trend. When the shading was removed after 40 DAA, values for the ripening fruits returned to those measured for the control. Such a response, however, was not observed when shading treatments were delayed until after 40 DAA. Fruits were also smaller at harvest when vines were shaded at the earliest time point. The present results suggest that lighting conditions can indirectly affect the capacity of biosynthesis and recycling of AsA in young fruits of kiwi, and this regulation might occur via the interaction of signal from leaves and development of fruit.

  10. Do Development and Learning Really Decrease Memory? On Similarity and Category-Based Induction in Adults and Children

    ERIC Educational Resources Information Center

    Wilburn, Catherine; Feeney, Aidan

    2008-01-01

    In a recently published study, Sloutsky and Fisher [Sloutsky, V. M., & Fisher, A.V. (2004a). When development and learning decrease memory: Evidence against category-based induction in children. "Psychological Science", 15, 553-558; Sloutsky, V. M., & Fisher, A. V. (2004b). Induction and categorization in young children: A similarity-based model.…

  11. The nature of the decrease in blood-cerebrospinal fluid barrier exchange during postnatal brain development in the rat.

    PubMed Central

    Habgood, M D; Knott, G W; Dziegielewska, K M; Saunders, N R

    1993-01-01

    1. The blood-cerebrospinal fluid (CSF) exchange of a wide range of passively transported lipid insoluble compounds (0.43-5.4 nm molecular radius) has been investigated in rats at different stages of postnatal development (2 days old to adult). A novel 'litter-based' model for investigating blood-CSF barrier exchange in immature animals is described. 2. At each age investigated there was a clear inverse correlation between molecular radius and blood-CSF barrier exchange, in addition to an overall decrease in blood-CSF barrier exchange with increasing age. 3. The decrease in blood-CSF barrier exchange with age was not consistent with a reduction in pore diameters, nor does it appear to be due to an increase in the CSF sink effect with age. It seems likely to be due to a relative decrease in the number of a population of large diameter pores. PMID:8254533

  12. The contribution of Kv2.2-mediated currents decreases during the postnatal development of mouse dorsal root ganglion neurons.

    PubMed

    Regnier, Glenn; Bocksteins, Elke; Van de Vijver, Gerda; Snyders, Dirk J; van Bogaert, Pierre-Paul

    2016-03-01

    Delayed rectifier voltage-gated K(+)(Kv) channels play an important role in the regulation of the electrophysiological properties of neurons. In mouse dorsal root ganglion (DRG) neurons, a large fraction of the delayed rectifier current is carried by both homotetrameric Kv2 channels and heterotetrameric channels consisting of Kv2 and silent Kv (KvS) subunits (i.e., Kv5-Kv6 and Kv8-Kv9). However, little is known about the contribution of Kv2-mediated currents during the postnatal development ofDRGneurons. Here, we report that the Stromatoxin-1 (ScTx)-sensitive fraction of the total outward K(+)current (IK) from mouseDRGneurons gradually decreased (~13%,P < 0.05) during the first month of postnatal development. Because ScTx inhibits both Kv2.1- and Kv2.2-mediated currents, this gradual decrease may reflect a decrease in currents containing either subunit. However, the fraction of Kv2.1 antibody-sensitive current that only reflects the Kv2.1-mediated currents remained constant during that same period. These results suggested that the fractional contribution of Kv2.2-mediated currents relative toIKdecreased with postnatal age. SemiquantitativeRT-PCRanalysis indicated that this decrease can be attributed to developmental changes in Kv2.2 expression as themRNAlevels of the Kv2.2 subunit decreased gradually between 1 and 4 weeks of age. In addition, we observed age-dependent fluctuations in themRNAlevels of the Kv6.3, Kv8.1, Kv9.1, and Kv9.3 subunits. These results support an important role of both Kv2 and KvS subunits in the postnatal maturation ofDRGneurons.

  13. Knife cuts of entorhinal cortex: effects on development of amygdaloid kindling and seizure-induced decrease of muscarinic cholinergic receptors

    SciTech Connect

    Savage, D.D.; Rigsbee, L.C.; McNamara, J.O.

    1985-02-01

    This report examines the effect of transection of the entorhinal hippocampal projection on amygdaloid kindling. We found that: bilateral knife cuts of entorhinal cortex but not of dorsal neocortex antagonize the development of amygdaloid kindling; and bilateral knife cuts of entorhinal cortex eliminate the seizure-induced decrease in number of muscarinic receptors of dentate granule cells. We suggest the following interpretations of these data: the hippocampal formation circuitry facilitates the development of amygdaloid kindling; and the decline of muscarinic receptors after kindled seizures is due to excessive activation of granule cells by axons from entorhinal cortex, a noncholinergic afferent.

  14. Natural and lesion-induced decrease in cell proliferation in the medial nucleus of the trapezoid body during hearing development.

    PubMed

    Saliu, Aminat; Adise, Shana; Xian, Sandy; Kudelska, Kamila; Rodríguez-Contreras, Adrián

    2014-04-01

    The functional interactions between neurons and glial cells that are important for nervous system function are presumably established during development from the activity of progenitor cells. In this study we examined proliferation of progenitor cells in the medial nucleus of the trapezoid body (MNTB) located in the rat auditory brainstem. We performed DNA synthesis labeling experiments to demonstrate changes in cell proliferation activity during postnatal stages of development. An increase in cell proliferation correlated with MNTB growth and the presence of S100β-positive astrocytes among MNTB neurons. In additional experiments we analyzed the fate of newly born cells. At perinatal ages, newly born cells colabeled with the astrocyte marker S100β in higher numbers than when cells were generated at postnatal day 6. Furthermore, we identified newly born cells that were colabeled with caspase-3 immunohistochemistry and performed comparative experiments to demonstrate that there is a natural decrease in cell proliferation activity during postnatal development in rats, mice, gerbils, and ferrets. Lastly, we found that there is a stronger decrease in MNTB cell proliferation after performing bilateral lesions of the auditory periphery in rats. Altogether, these results identify important stages in the development of astrocytes in the MNTB and provide evidence that the proliferative activity of the progenitor cells is developmentally regulated. We propose that the developmental reduction in cell proliferation may reflect coordinated signaling between the auditory brainstem and the auditory periphery.

  15. Appetite - decreased

    MedlinePlus

    ... cancer Ovarian cancer Stomach cancer Pancreatic cancer Other causes of decreased appetite include: Chronic liver disease Chronic kidney disease Chronic obstructive pulmonary disease (COPD) Dementia Heart failure ...

  16. Gonadotropin-inhibitory hormone inhibits gonadal development and maintenance by decreasing gonadotropin synthesis and release in male quail.

    PubMed

    Ubuka, Takayoshi; Ukena, Kazuyoshi; Sharp, Peter J; Bentley, George E; Tsutsui, Kazuyoshi

    2006-03-01

    Until recently, any neuropeptide that directly inhibits gonadotropin secretion had not been identified. We recently identified a novel hypothalamic dodecapeptide that directly inhibits gonadotropin release in quail and termed it gonadotropin-inhibitory hormone (GnIH). The action of GnIH on the inhibition of gonadotropin release is mediated by a novel G protein-coupled receptor in the quail pituitary. This new gonadotropin inhibitory system is considered to be a widespread property of birds and provides us with an unprecedented opportunity to study the regulation of avian reproduction from an entirely novel standpoint. To understand the physiological role(s) of GnIH in avian reproduction, we investigated GnIH actions on gonadal development and maintenance in male quail. Continuous administration of GnIH to mature birds via osmotic pumps for 2 wk decreased the expressions of gonadotropin common alpha and LHbeta subunit mRNAs in a dose-dependent manner. Plasma LH and testosterone concentrations were also decreased dose dependently. Furthermore, administration of GnIH to mature birds induced testicular apoptosis and decreased spermatogenic activity in the testis. In immature birds, daily administration of GnIH for 2 wk suppressed normal testicular growth and rise in plasma testosterone concentrations. An inhibition of juvenile molt also occurred after GnIH administration. These results indicate that GnIH inhibits gonadal development and maintenance through the decrease in gonadotropin synthesis and release. GnIH may explain the phenomenon of photoperiod-induced gonadal regression before an observable decline in hypothalamic GnRH in quail. To our knowledge, GnIH is the first identified hypothalamic neuropeptide inhibiting reproductive function in any vertebrate class.

  17. NKCC1 knockdown decreases neuron production through GABA(A)-regulated neural progenitor proliferation and delays dendrite development.

    PubMed

    Young, Stephanie Z; Taylor, M Morgan; Wu, Sharon; Ikeda-Matsuo, Yuri; Kubera, Cathryn; Bordey, Angélique

    2012-09-26

    Signaling through GABA(A) receptors controls neural progenitor cell (NPC) development in vitro and is altered in schizophrenic and autistic individuals. However, the in vivo function of GABA(A) signaling on neural stem cell proliferation, and ultimately neurogenesis, remains unknown. To examine GABA(A) function in vivo, we electroporated plasmids encoding short-hairpin (sh) RNA against the Na-K-2Cl cotransporter NKCC1 (shNKCC1) in NPCs of the neonatal subventricular zone in mice to reduce GABA(A)-induced depolarization. Reduced GABA(A) depolarization identified by a loss of GABA(A)-induced calcium responses in most electroporated NPCs led to a 70% decrease in the number of proliferative Ki67(+) NPCs and a 60% reduction in newborn neuron density. Premature loss of GABA(A) depolarization in newborn neurons resulted in truncated dendritic arborization at the time of synaptic integration. However, by 6 weeks the dendritic tree had partially recovered and displayed a small, albeit significant, decrease in dendritic complexity but not total dendritic length. To further examine GABA(A) function on NPCs, we treated animals with a GABA(A) allosteric agonist, pentobarbital. Enhancement of GABA(A) activity in NPCs increased the number of proliferative NPCs by 60%. Combining shNKCC1 and pentobarbital prevented the shNKCC1 and the pentobarbital effects on NPC proliferation, suggesting that these manipulations affected NPCs through GABA(A) receptors. Thus, dysregulation in GABA(A) depolarizing activity delayed dendritic development and reduced NPC proliferation resulting in decreased neuronal density.

  18. Trypanosoma cruzi Immune Response Modulation Decreases Microbiota in Rhodnius prolixus Gut and Is Crucial for Parasite Survival and Development

    PubMed Central

    Castro, Daniele P.; Moraes, Caroline S.; Gonzalez, Marcelo S.; Ratcliffe, Norman A.; Azambuja, Patrícia; Garcia, Eloi S.

    2012-01-01

    Trypanosoma cruzi in order to complete its development in the digestive tract of Rhodnius prolixus needs to overcome the immune reactions and microbiota trypanolytic activity of the gut. We demonstrate that in R. prolixus following infection with epimastigotes of Trypanosoma cruzi clone Dm28c and, in comparison with uninfected control insects, the midgut contained (i) fewer bacteria, (ii) higher parasite numbers, and (iii) reduced nitrite and nitrate production and increased phenoloxidase and antibacterial activities. In addition, in insects pre-treated with antibiotic and then infected with Dm28c, there were also reduced bacteria numbers and a higher parasite load compared with insects solely infected with parasites. Furthermore, and in contrast to insects infected with Dm28c, infection with T. cruzi Y strain resulted in a slight decreased numbers of gut bacteria but not sufficient to mediate a successful parasite infection. We conclude that infection of R. prolixus with the T. cruzi Dm28c clone modifies the host gut immune responses to decrease the microbiota population and these changes are crucial for the parasite development in the insect gut. PMID:22574189

  19. Lack of Maternal Glutamate Cysteine Ligase Modifier Subunit (Gclm) Decreases Oocyte Glutathione Concentrations and Disrupts Preimplantation Development in Mice

    PubMed Central

    Nakamura, Brooke N.; Fielder, Thomas J.; Hoang, Yvonne D.; Lim, Jinhwan; McConnachie, Lisa A.; Kavanagh, Terrance J.

    2011-01-01

    Glutathione (GSH) is the most abundant intracellular thiol and an important regulator of cellular redox status. Mice that lack the modifier subunit of glutamate cysteine ligase (Gclm), the rate-limiting enzyme in GSH synthesis, have decreased GSH synthesis. Nicotinamide nucleotide transhydrogenase, an inner mitochondrial membrane protein, catalyzes the interconversion of reduced nicotinamide adenine dinucleotide and reduced nicotinamide adenine dinucleotide phosphate; reduced nicotinamide adenine dinucleotide phosphate is required for reduction of GSH disulfide. Previous work supports roles for GSH in preimplantation development. We hypothesized that Gclm−/− mice have increased preimplantation embryonic mortality and that this effect is enhanced by absence of a functioning Nnt gene. Gclm−/− females produced significantly fewer pups per litter than Gclm+/+ littermates. Numbers of oocytes ovulated in a natural estrous cycle or upon superovulation did not differ by genotype. Fewer uterine implantation sites were observed in the Gclm−/− females. Prepubertal Gclm−/− and Gclm+/+ females were superovulated, then mated overnight with a Gclm+/+ male. At 0.5 d postcoitum, Gclm−/− females had significantly lower percentages of zygotes with two pronuclei and higher percentages of zygotes with one pronucleus than Gclm+/+ or Gclm+/− females. At 3.5 d postcoitum, a significantly lower percentage of blastocyst stage embryos was recovered from uteri of Gclm−/− females than Gclm+/+ females. Embryonic development to the blastocyst stage, but not the two-cell stage, was significantly decreased after in vitro fertilization of oocytes from Gclm−/− females compared with Gclm+/+ females. The Nnt mutation did not enhance the effects of Gclm genotype on female fertility. These results demonstrate critical roles for maternal GSH in supporting normal preimplantation development. PMID:21558310

  20. Third-generation CD28/4-1BB chimeric antigen receptor T cells for chemotherapy relapsed or refractory acute lymphoblastic leukaemia: a non-randomised, open-label phase I trial protocol

    PubMed Central

    Tang, Xiao-Yi; Sun, Yao; Zhang, Ang; Hu, Guo-Liang; Cao, Wei; Wang, Dan-Hong; Zhang, Bin; Chen, Hu

    2016-01-01

    Introduction There is no curative treatment available for patients with chemotherapy relapsed or refractory CD19+ B cells-derived acute lymphoblastic leukaemia (r/r B-ALL). Although CD19-targeting second-generation (2nd-G) chimeric antigen receptor (CAR)-modified T cells carrying CD28 or 4-1BB domains have demonstrated potency in patients with advanced B-ALL, these 2 signalling domains endow CAR-T cells with different and complementary functional properties. Preclinical results have shown that third-generation (3rd-G) CAR-T cells combining 4-1BB and CD28 signalling domains have superior activation and proliferation capacity compared with 2nd-G CAR-T cells carrying CD28 domain. The aim of the current study is therefore to investigate the safety and efficacy of 3rd-G CAR-T cells in adults with r/r B-ALL. Methods and analysis This study is a phase I clinical trial for patients with r/r B-ALL to test the safety and preliminary efficacy of 3rd-G CAR-T cells. Before receiving lymphodepleting conditioning regimen, the peripheral blood mononuclear cells from eligible patients will be leukapheresed, and the T cells will be purified, activated, transduced and expanded ex vivo. On day 6 in the protocol, a single dose of 1 million CAR-T cells per kg will be administrated intravenously. The phenotypes of infused CAR-T cells, copy number of CAR transgene and plasma cytokines will be assayed for 2 years after CAR-T infusion using flow cytometry, real-time quantitative PCR and cytometric bead array, respectively. Moreover, several predictive plasma cytokines including interferon-γ, interleukin (IL)-6, IL-8, Soluble Interleukin (sIL)-2R-α, solubleglycoprotein (sgp)130, sIL-6R, Monocyte chemoattractant protein (MCP1), Macrophage inflammatory protein (MIP1)-α, MIP1-β and Granulocyte-macrophage colony-stimulating factor (GM-CSF), which are highly associated with severe cytokine release syndrome (CRS), will be used to forecast CRS to allow doing earlier intervention, and CRS will

  1. Inhibition of COX 1 and 2 prior to Renal Ischemia/Reperfusion Injury Decreases the Development of Fibrosis

    PubMed Central

    Feitoza, Carla Q; Gonçalves, Giselle M; Semedo, Patrícia; Cenedeze, Marcos A; Pinheiro, Hélady S; Beraldo, Felipe Caetano; dos Santos, Oscar Fernando Pavão; de Paula A Teixeira, Vicente; dos Reis, Marlene A; Mazzali, Marilda; Pacheco-Silva, Alvaro; Câmara, Niels O S

    2008-01-01

    Ischemia and reperfusion injury (IRI) contributes to the development of chronic interstitial fibrosis/tubular atrophy in renal allograft patients. Cyclooxygenase (COX) 1 and 2 actively participate in acute ischemic injury by activating endothelial cells and inducing oxidative stress. Furthermore, blockade of COX 1 and 2 has been associated with organ improvement after ischemic damage. The aim of this study was to evaluate the role of COX 1 and 2 in the development of fibrosis by performing a COX 1 and 2 blockade immediately before IRI. We subjected C57Bl/6 male mice to 60 min of unilateral renal pedicle occlusion. Prior to surgery mice were either treated with indomethacin (IMT) at days –1 and 0 or were untreated. Blood and kidney samples were collected 6 wks after IRI. Kidney samples were analyzed by real-time reverse transcription–polymerase chain reaction for expression of transforming growth factor β (TGF-β), monocyte chemoattractant protein 1 (MCP-1), osteopontin (OPN), tumor necrosis factor α (TNF-α), interleukin (IL)-1β, IL-10, heme oxygenase 1 (HO-1), vimentin, connective-tissue growth factor (CTGF), collagen I, and bone morphogenic protein 7 (BMP-7). To assess tissue fibrosis we performed morphometric analyses and Sirius red staining. We also performed immunohistochemical analysis of anti-actin smooth muscle. Renal function did not significantly differ between groups. Animals pretreated with IMT showed significantly less interstitial fibrosis than nontreated animals. Gene transcript analyses showed decreased expression of TGF-β, MCP-1, TNF-α, IL-1-β, vimentin, collagen I, CTGF, and IL-10 mRNA (all P < 0.05). Moreover, HO-1 mRNA was increased in animals pretreated with IMT (P < 0.05). Conversely, IMT treatment decreased osteopontin expression and enhanced BMP-7 expression, although these levels did not reach statistical significance when compared with control expression levels. The blockade of COX 1 and 2 resulted in less tissue fibrosis, which

  2. Quantitative Proteomics of Gut-Derived Th1 and Th1/Th17 Clones Reveal the Presence of CD28+ NKG2D- Th1 Cytotoxic CD4+ T cells*

    PubMed Central

    Riaz, Tahira; Sollid, Ludvig Magne; Olsen, Ingrid; de Souza, Gustavo Antonio

    2016-01-01

    T-helper cells are differentiated from CD4+ T cells and are traditionally characterized by inflammatory or immunosuppressive responses in contrast to cytotoxic CD8+ T cells. Mass-spectrometry studies on T-helper cells are rare. In this study, we aimed to identify the proteomes of human Th1 and Th1/Th17 clones derived from intestinal biopsies of Crohn's disease patients and to identify differentially expressed proteins between the two phenotypes. Crohn's disease is an inflammatory bowel disease, with predominantly Th1- and Th17-mediated response where cells of the “mixed” phenotype Th1/Th17 have also been commonly found. High-resolution mass spectrometry was used for protein identification and quantitation. In total, we identified 7401 proteins from Th1 and Th1/Th17 clones, where 334 proteins were differentially expressed. Major differences were observed in cytotoxic proteins that were overrepresented in the Th1 clones. The findings were validated by flow cytometry analyses using staining with anti-granzyme B and anti-perforin and by a degranulation assay, confirming higher cytotoxic features of Th1 compared with Th1/Th17 clones. By testing a larger panel of T-helper cell clones from seven different Crohn's disease patients, we concluded that only a subgroup of the Th1 cell clones had cytotoxic features, and these expressed the surface markers T-cell-specific surface glycoprotein CD28 and were negative for expression of natural killer group 2 member D. PMID:26637539

  3. Morphological abnormalities, impaired fetal development and decrease in myostatin expression following somatic cell nuclear transfer in dogs.

    PubMed

    Hong, Il-Hwa; Jeong, Yeon-Woo; Shin, Taeyoung; Hyun, Sang-Hwan; Park, Jin-Kyu; Ki, Mi-Ran; Han, Seon-Young; Park, Se-Il; Lee, Ji-Hyun; Lee, Eun-Mi; Kim, Ah-Young; You, Sang-Young; Hwang, Woo-Suk; Jeong, Kyu-Shik

    2011-05-01

    Several mammals, including dogs, have been successfully cloned using somatic cell nuclear transfer (SCNT), but the efficiency of generating normal, live offspring is relatively low. Although the high failure rate has been attributed to incomplete reprogramming of the somatic nuclei during the cloning process, the exact cause is not fully known. To elucidate the cause of death in cloned offspring, 12 deceased offspring cloned by SCNT were necropsied. The clones were either stillborn just prior to delivery or died with dyspnea shortly after birth. On gross examination, defects in the anterior abdominal wall and increased heart and liver sizes were found. Notably, a significant increase in muscle mass and macroglossia lesions were observed in deceased SCNT-cloned dogs. Interestingly, the expression of myostatin, a negative regulator of muscle growth during embryogenesis, was down-regulated at the mRNA level in tongues and skeletal muscles of SCNT-cloned dogs compared with a normal dog. Results of the present study suggest that decreased expression of myostatin in SCNT-cloned dogs may be involved in morphological abnormalities such as increased muscle mass and macroglossia, which may contribute to impaired fetal development and poor survival rates.

  4. Human progenitor cells isolated from the developing cortex undergo decreased neurogenesis and eventual senescence following expansion in vitro

    SciTech Connect

    Wright, Lynda S.; Prowse, Karen R.; Wallace, Kyle; Linskens, Maarten H.K.; Svendsen, Clive N. . E-mail: svendsen@waisman.wisc.edu

    2006-07-01

    Isolation of a true self-renewing stem cell from the human brain would be of great interest as a reliable source of neural tissue. Here, we report that human fetal cortical cells grown in epidermal growth factor expressed low levels of telomerase and telomeres in these cultures shortened over time leading to growth arrest after 30 weeks. Following leukemia inhibitory factor (LIF) supplementation, growth rates and telomerase expression increased. This was best demonstrated following cell cycle synchronization and staining for telomerase using immunocytochemistry. This increase in activity resulted in the maintenance of telomeres at approximately 7 kb for more than 60 weeks in vitro. However, all cultures displayed a lack of oligodendrotye production, decreases in neurogenesis over time and underwent replicative senescence associated with increased expression of p21 before 70 weeks in vitro. Thus, under our culture conditions, these cells are not stable, multipotent, telomerase expressing self-renewing stem cells. They may be more accurately described as human neural progenitor cells (hNPC) with limited lifespan and bi-potent potential (neurons/astrocytes). Interestingly, hNPC follow a course of proliferation, neuronal production and growth arrest similar to that seen during expansion and development of the human cortex, thus providing a possible model neural system. Furthermore, due to their high expansion potential and lack of tumorogenicity, these cells remain a unique and safe source of tissue for clinical transplantation.

  5. Rapid Copper Acquisition by Developing Murine Mesothelioma: Decreasing Bioavailable Copper Slows Tumor Growth, Normalizes Vessels and Promotes T Cell Infiltration

    PubMed Central

    Crowe, Andrew; Jackaman, Connie; Beddoes, Katie M.; Ricciardo, Belinda; Nelson, Delia J.

    2013-01-01

    Copper, an essential trace element acquired through nutrition, is an important co-factor for pro-angiogenic factors including vascular endothelial growth factor (VEGF). Decreasing bioavailable copper has been used as an anti-angiogenic and anti-cancer strategy with promising results. However, the role of copper and its potential as a therapy in mesothelioma is not yet well understood. Therefore, we monitored copper levels in progressing murine mesothelioma tumors and analyzed the effects of lowering bioavailable copper. Copper levels in tumors and organs were assayed using atomic absorption spectrophotometry. Mesothelioma tumors rapidly sequestered copper at early stages of development, the copper was then dispersed throughout growing tumor tissues. These data imply that copper uptake may play an important role in early tumor development. Lowering bioavailable copper using the copper chelators, penicillamine, trientine or tetrathiomolybdate, slowed in vivo mesothelioma growth but did not provide any cures similar to using cisplatin chemotherapy or anti-VEGF receptor antibody therapy. The impact of copper lowering on tumor blood vessels and tumor infiltrating T cells was measured using flow cytometry and confocal microscopy. Copper lowering was associated with reduced tumor vessel diameter, reduced endothelial cell proliferation (reduced Ki67 expression) and lower surface ICAM/CD54 expression implying reduced endothelial cell activation, in a process similar to endothelial normalization. Copper lowering was also associated with a CD4+ T cell infiltrate. In conclusion, these data suggest copper lowering is a potentially useful anti-mesothelioma treatment strategy that slows tumor growth to provide a window of opportunity for inclusion of other treatment modalities to improve patient outcomes. PMID:24013775

  6. Loss of neurons in rostral ventromedial medulla that express neurokinin-1 receptors decreases the development of hyperalgesia.

    PubMed

    Khasabov, S G; Simone, D A

    2013-10-10

    It is well known that neurons in the rostral ventromedial medulla (RVM) are involved in descending modulation of nociceptive transmission in the spinal cord. It has been shown that activation of neurokinin-1 receptors (NK-1Rs) in the RVM, which are presumably located on pain facilitating ON cells, produces hyperalgesia whereas blockade of NK-1Rs attenuates hyperalgesia. To obtain a better understanding of the functions of NK-1R expressing neurons in the RVM, we selectively ablated these neurons by injecting the stable analog of substance P (SP), Sar(9),Met(O2)(11)-Substance P, conjugated to the ribosomal toxin saporin (SSP-SAP) into the RVM. Rats received injections of SSP-SAP (1 μM) or an equal volume of 1 μM of saporin conjugated to artificial peptide (Blank-SAP). Stereological analysis of NK-1R- and NeuN-labeled neurons in the RVM was determined 21-24 days after treatment. Withdrawal responses to mechanical and heat stimuli applied to the plantar hindpaw were determined 5-28 days after treatment. Withdrawal responses were also determined before and after intraplantar injection of capsaicin (acute hyperalgesia) or complete Freund's adjuvant (CFA) (prolonged hyperalgesia). The proportion of NK-1R-labeled neurons in the RVM was 8.8 ± 1.3% in naïve rats and 8.1 ± 0.8% in rats treated with Blank-SAP. However, injection of SSP-SAP into the RVM resulted in a 90% decrease in NK-1R-labeled neurons. SSP-SAP did not alter withdrawal responses to mechanical or heat stimuli under normal conditions, and did not alter analgesia produced by morphine administered into the RVM. In contrast, the duration of nocifensive behaviors produced by capsaicin and mechanical and heat hyperalgesia produced by capsaicin and CFA were decreased in rats pretreated with SSP-SAP as compared to those that received Blank-SAP. These data support our earlier studies using NK-1R antagonists in the RVM and demonstrate that RVM neurons that possess the NK-1R do not play a significant role in

  7. Preliminary development of a diabetic foot ulcer database from a wound electronic medical record: A tool to decrease limb amputations

    PubMed Central

    Golinko, Michael S.; Margolis, David J.; Tal, Adit; Hoffstad, Ole; Boulton, Andrew J. M.; Brem, Harold

    2010-01-01

    Our objective was to create a practical standardized database of clinically relevant variables in the care of patients with diabetes and foot ulcers. Numerical clinical variables such as age, baseline laboratory values, and wound area were extracted from the wound electronic medical record (WEMR). A coding system was developed to translate narrative data, culture, and pathology reports into discrete, quantifiable variables. Using data extracted from the WEMR, a diabetic foot ulcer-specific database incorporated the following tables: (1) demographics, medical history, and baseline laboratory values; (2) vascular testing data; (3) radiology data; (4) wound characteristics; and (5) wound debridement data including pathology, culture results, and amputation data. The database contains variables that can be easily exported for analysis. Amputation was studied in 146 patients who had at least two visits (e.g., two entries in the database). Analysis revealed that 19 (13%) patients underwent 32 amputations (nine major and 23 minor) in 23 limbs. There was a decreased risk of amputation, 0.87 (0.78, 1.00), using a proportional hazards model, associated with an increased number of visits and entries in the WEMR. Further analysis revealed no significant difference in age, gender, HbA1c%, cholesterol, white blood cell count, or prealbumin at baseline, whereas hemoglobin and albumin were significantly lower in the amputee group (p < 0.05) than the nonamputee group. Fifty-nine percent of amputees had histological osteomyelitis based on operating room biopsy vs. 45% of non-amputees. In conclusion, tracking patients with a WEMR is a tool that could potentially increase patient safety and quality of care, allowing clinicians to more easily identify a nonhealing wound and intervene. This report describes a method of capturing data relevant to clinical care of a patient with a diabetic foot ulcer, and may enable clinicians to adapt such a system to their own patient population. PMID

  8. Anti-CD28 monoclonal antibody-stimulated cytokines released from blood suppress CYP1A2, CYP2B6, and CYP3A4 in human hepatocytes in vitro.

    PubMed

    Czerwiński, Maciej; Kazmi, Faraz; Parkinson, Andrew; Buckley, David B

    2015-01-01

    Like most infections and certain inflammatory diseases, some therapeutic proteins cause a cytokine-mediated suppression of hepatic drug-metabolizing enzymes, which may lead to pharmacokinetic interactions with small-molecule drugs. We propose a new in vitro method to evaluate the whole blood-mediated effects of therapeutic proteins on drug-metabolizing enzymes in human hepatocytes cocultured with Kupffer cells. The traditional method involves treating hepatocyte cocultures with the therapeutic protein, which detects hepatocyte- and macrophage-mediated suppression of cytochrome P450 (P450). The new method involves treating whole human blood with a therapeutic protein to stimulate the release of cytokines from peripheral blood mononuclear cells (PBMCs), after which plasma is prepared and added to the hepatocyte coculture to evaluate P450 enzyme expression. In this study, human blood was treated for 24 hours at 37°C with bacterial lipopolysaccharide (LPS) or ANC28.1, an antibody against human T-cell receptor CD28. Cytokines were measured in plasma by sandwich immunoassay with electrochemiluminescense detection. Treatment of human hepatocyte cocultures with LPS or with plasma from LPS-treated blood markedly reduced the expression of CYP1A2, CYP2B6, and CYP3A4. However, treatment of hepatocyte cocultures with ANC28.1 did not suppress P450 expression, but treatment with plasma from ANC28.1-treated blood suppressed CYP1A2, CYP2B6, and CYP3A4 activity and mRNA levels. The results demonstrated that applying plasma from human blood treated with a therapeutic protein to hepatocytes cocultured with Kupffer cells is a suitable method to identify those therapeutic proteins that suppress P450 expression by an indirect mechanism-namely, the release of cytokines from PBMCs.

  9. Decreasing spatial disorientation in care-home settings: How psychology can guide the development of dementia friendly design guidelines.

    PubMed

    O'Malley, Mary; Innes, Anthea; Wiener, Jan M

    2017-04-01

    Alzheimer's disease results in marked declines in navigation skills that are particularly pronounced in unfamiliar environments. However, many people with Alzheimer's disease eventually face the challenge of having to learn their way around unfamiliar environments when moving into assisted living or care-homes. People with Alzheimer's disease would have an easier transition moving to new residences if these larger, and often more institutional, environments were designed to compensate for decreasing orientation skills. However, few existing dementia friendly design guidelines specifically address orientation and wayfinding. Those that do are often based on custom, practice or intuition and not well integrated with psychological and neuroscientific knowledge or navigation research, therefore often remaining unspecific. This paper discusses current dementia friendly design guidelines, reports findings from psychological and neuropsychological experiments on navigation and evaluates their potential for informing design guidelines that decrease spatial disorientation for people with dementia.

  10. Development of methods for the decrease in instability of recycling water of conjugated closed-circuit cooling system of HPP

    NASA Astrophysics Data System (ADS)

    Chichirov, A. A.; Chichirova, N. D.; Vlasov, S. M.; Lyapin, A. I.; Misbakhov, R. Sh.; Silov, I. Yu.; Murtazin, A. I.

    2016-10-01

    On Russian HPPs, conjugated closed-circuit cooling systems, where purge water is used as initial for water-treatment facilities, are widespread. For this reason, it is impossible to use general methods for the stabilization treatment of recycling water in order to prevent scale formation in the units of a system, namely, turbine condensers and cooling towers. In this paper, the methods for the decrease in the instability of recycling water using the methods of chemical engineering, such as stabilization and synchronization of flows and organization of recycles, are suggested. The results of an industrial experiment on the implementation of stabilization treatment of recycling water by the organization of recycle are given. The experiment was carried out on Kazan CHPP-3. The flow scheme involved the recycle of chemically purified water (CPW) for the heat network make-up to the closed-circuit cooling system. The experiment was carried out at three stages with the gradual change of the consumption of the recycle, namely, 0, 50, and 100 t/h. According to the results of experiments, the reliable decrease in the rate of the sedimentation was recorded on the units of the system, namely, turbine condenser and chimney-type cooling tower. This is caused by two reasons. Firstly, this is periodic excessive concentration of recycling water due to the nonstationary character of inlet and outlet flows. Secondly, this is seasonal (particularly, in the summer period) exceeding of the evaporation coefficient. As a result of stabilization and synchronization of flows and organization of recycles, the quality of clarified and chemically purified water for the heat network make-up increases and the corrosion of iron- and copper-containing structural materials decreases. A natural decrease in temperature drop on the operating turbine condensers is mentioned.

  11. Increasing the ex vivo antigen-specific IFN-γ production in subpopulations of T cells and NKp46+ cells by anti-CD28, anti-CD49d and recombinant IL-12 costimulation in cattle vaccinated with recombinant proteins from Mycobacterium avium subspecies paratuberculosis.

    PubMed

    Thakur, Aneesh; Riber, Ulla; Davis, William C; Jungersen, Gregers

    2013-10-01

    T cells, which encounter specific antigen (Ag), require additional signals to mount a functional immune response. Here, we demonstrate activation of signal 2, by anti-CD28 mAb (aCD28) and other costimulatory molecules (aCD49d, aCD5), and signal 3, by recombinant IL-12, enhance Ag-specific IFN-γ secretion by CD4, CD8, γδ T cells and NK cells. Age matched male jersey calves, experimentally infected with Mycobacterium avium subsp. paratuberculosis (MAP), were vaccinated with a cocktail of recombinant MAP proteins or left unvaccinated. Vaccine induced ex vivo recall responses were measured through Ag-specific IFN-γ production by ELISA and flow cytometry. There was a significant increase in production of IFN-γ by T cell subsets or NKp46+ cells cultured in the presence of Ag and aCD28/aCD49d. The increase was accompanied by an increase in the integrated median fluorescence intensity (iMFI) of activated T cells. Addition of rIL-12 induced a significant additive effect leading to a maximum increase in responder frequency of Ag-specific T cell subsets or NKp46+ cells with a heavy bias toward IFN-γ production by CD4 T cells. We provide the first description of using aCD28/aCD49d costimulation to potentiate an Ag-specific increase in the production of IFN-γ in bovine immunology. The study also shows the degree of signaling in T cells is regulated by the costimulatory environment.

  12. Long-term treatment with finasteride 1 mg decreases the likelihood of developing further visible hair loss in men with androgenetic alopecia (male pattern hair loss).

    PubMed

    Kaufman, Keith D; Rotonda, Jennifer; Shah, Arvind K; Meehan, Alan G

    2008-01-01

    There are no reports on the effects of pharmacologic treatment on the likelihood of developing further visible hair loss in men with androgenetic alopecia (AGA). Our objectives were to examine whether finasteride 1 mg treatment decreases the likelihood of developing further visible hair loss in men with AGA. We conducted an analysis of global photographic assessment data from two Phase III trials in which 1553 men with AGA received finasteride 1 mg/day or placebo for up to 5 years. Finasteride 1 mg treatment led to a 93% decrease relative to placebo in the 5-year likelihood of developing further visible hair loss (95% CI: 89-97%; p < 0.001). We conclude that, in men with AGA, treatment with finasteride 1 mg/day over 5 years led to a marked and sustained decrease in the likelihood of developing further visible hair loss.

  13. CpG sites with continuously increasing or decreasing methylation from early to late human fetal brain development.

    PubMed

    Schneider, Eberhard; Dittrich, Marcus; Böck, Julia; Nanda, Indrajit; Müller, Tobias; Seidmann, Larissa; Tralau, Tim; Galetzka, Danuta; El Hajj, Nady; Haaf, Thomas

    2016-10-30

    Normal human brain development is dependent on highly dynamic epigenetic processes for spatial and temporal gene regulation. Recent work identified wide-spread changes in DNA methylation during fetal brain development. We profiled CpG methylation in frontal cortex of 27 fetuses from gestational weeks 12-42, using Illumina 450K methylation arrays. Sites showing genome-wide significant correlation with gestational age were compared to a publicly available data set from gestational weeks 3-26. Altogether, we identified 2016 matching developmentally regulated differentially methylated positions (m-dDMPs): 1767m-dDMPs were hypermethylated and 1149 hypomethylated during fetal development. M-dDMPs are underrepresented in CpG islands and gene promoters, and enriched in gene bodies. They appear to cluster in certain chromosome regions. M-dDMPs are significantly enriched in autism-associated genes and CpGs. Our results promote the idea that reduced methylation dynamics during fetal brain development may predispose to autism. In addition, m-dDMPs are enriched in genes with human-specific brain expression patterns and/or histone modifications. Collectively, we defined a subset of dDMPs exhibiting constant methylation changes from early to late pregnancy. The same epigenetic mechanisms involving methylation changes in cis-regulatory regions may have been adopted for human brain evolution and ontogeny.

  14. The role of ontogeny in physiological tolerance: decreasing hydrostatic pressure tolerance with development in the northern stone crab Lithodes maja

    PubMed Central

    Munro, Catriona; Morris, James P.; Brown, Alastair; Hauton, Chris; Thatje, Sven

    2015-01-01

    Extant deep-sea invertebrate fauna represent both ancient and recent invasions from shallow-water habitats. Hydrostatic pressure may present a significant physiological challenge to organisms seeking to colonize deeper waters or migrate ontogenetically. Pressure may be a key factor contributing to bottlenecks in the radiation of taxa and potentially drive speciation. Here, we assess shifts in the tolerance of hydrostatic pressure through early ontogeny of the northern stone crab Lithodes maja, which occupies a depth range of 4–790 m in the North Atlantic. The zoea I, megalopa and crab I stages were exposed to hydrostatic pressures up to 30.0 MPa (equivalent of 3000 m depth), and the relative fold change of genes putatively coding for the N-methyl-d-aspartate receptor-regulated protein 1 (narg gene), two heat-shock protein 70 kDa (HSP70) isoforms and mitochondrial Citrate Synthase (CS gene) were measured. This study finds a significant increase in the relative expression of the CS and hsp70a genes with increased hydrostatic pressure in the zoea I stage, and an increase in the relative expression of all genes with increased hydrostatic pressure in the megalopa and crab I stages. Transcriptional responses are corroborated by patterns in respiratory rates in response to hydrostatic pressure in all stages. These results suggest a decrease in the acute high-pressure tolerance limit as ontogeny advances, as reflected by a shift in the hydrostatic pressure at which significant differences are observed. PMID:26041343

  15. Marble waste and pig manure amendments decrease metal availability, increase soil quality and facilitate vegetation development in bare mine soils

    NASA Astrophysics Data System (ADS)

    Zornoza, Raúl; Faz, Ángel; Martínez-Martínez, Silvia; Acosta, José A.; Gómez, M. Dolores; Ángeles Muñoz, M.

    2013-04-01

    In order to bring out a functional and sustainable land use in a highly contaminated mine tailing, firstly environmental risks have to be reduced or eliminated by suitable reclamation activities. Tailing ponds pose environmental hazards, such as acidity and toxic metals reaching to waters through wind and water erosions and leaching. As a consequence, soils have no vegetation and low soil organic matter and nutrients. Various physicochemical and biochemical properties, together with exchangeable metals were measured before, 6 months and 12 months after the application of marble waste and pigs manure as reclamation strategy in a tailing pond from SE Spain to reduce hazards for environment and human health. Three months after the last addition of amendments, eight different native shrub species where planted for phytostabilization. Results showed the pH increased up to neutrality. Aggregates stability, organic carbon, total nitrogen, cation exchange capacity, bioavailable phosphorus and potassium, microbial biomass and microbial activity increased with the application of the amendments, while exchangeable metals drastically decreased (~90%). After one year of plantation, only 20% planted species died, with a high growth of survivals reaching flowering and fructification. This study confirms the high effectiveness of initial applications of marble wastes together with pig manure and plantation of shrub species to initialize the recovery of the ecosystem in bare mine soils under Mediterranean semiarid conditions. Key Words: pig manure, marble waste, heavy metals, mine soil. Acknowledgements This work has been funded by the European Union LIFE+ project MIPOLARE (LIFE09 ENV/ES/000439). J.A. Acosta acknowledges a "Saavedra Fajardo" contract from Comunidad Autónoma de Murcia (Spain)

  16. 5-azacytidine promotes microspore embryogenesis initiation by decreasing global DNA methylation, but prevents subsequent embryo development in rapeseed and barley

    PubMed Central

    Solís, María-Teresa; El-Tantawy, Ahmed-Abdalla; Cano, Vanesa; Risueño, María C.; Testillano, Pilar S.

    2015-01-01

    Microspores are reprogrammed by stress in vitro toward embryogenesis. This process is an important tool in breeding to obtain double-haploid plants. DNA methylation is a major epigenetic modification that changes in differentiation and proliferation. We have shown changes in global DNA methylation during microspore reprogramming. 5-Azacytidine (AzaC) cannot be methylated and leads to DNA hypomethylation. AzaC is a useful demethylating agent to study DNA dynamics, with a potential application in microspore embryogenesis. This work analyzes the effects of short and long AzaC treatments on microspore embryogenesis initiation and progression in two species, the dicot Brassica napus and the monocot Hordeum vulgare. This involved the quantitative analyses of proembryo and embryo production, the quantification of DNA methylation, 5-methyl-deoxy-cytidine (5mdC) immunofluorescence and confocal microscopy, and the analysis of chromatin organization (condensation/decondensation) by light and electron microscopy. Four days of AzaC treatments (2.5 μM) increased embryo induction, response associated with a decrease of DNA methylation, modified 5mdC, and heterochromatin patterns compared to untreated embryos. By contrast, longer AzaC treatments diminished embryo production. Similar effects were found in both species, indicating that DNA demethylation promotes microspore reprogramming, totipotency acquisition, and embryogenesis initiation, while embryo differentiation requires de novo DNA methylation and is prevented by AzaC. This suggests a role for DNA methylation in the repression of microspore reprogramming and possibly totipotency acquisition. Results provide new insights into the role of epigenetic modifications in microspore embryogenesis and suggest a potential benefit of inhibitors, such as AzaC, to improve the process efficiency in biotechnology and breeding programs. PMID:26161085

  17. Disrupting Hepatocyte Cyp51 from Cholesterol Synthesis Leads to Progressive Liver Injury in the Developing Mouse and Decreases RORC Signalling

    PubMed Central

    Urlep, Žiga; Lorbek, Gregor; Perše, Martina; Jeruc, Jera; Juvan, Peter; Matz-Soja, Madlen; Gebhardt, Rolf; Björkhem, Ingemar; Hall, Jason A.; Bonneau, Richard; Littman, Dan R.; Rozman, Damjana

    2017-01-01

    Development of mice with hepatocyte knockout of lanosterol 14α-demethylase (HCyp51−/−) from cholesterol synthesis is characterized by the progressive onset of liver injury with ductular reaction and fibrosis. These changes begin during puberty and are generally more aggravated in the knockout females. However, a subgroup of (pre)pubertal knockout mice (runts) exhibits a pronounced male prevalent liver dysfunction characterized by downregulated amino acid metabolism and elevated Casp12. RORC transcriptional activity is diminished in livers of all runt mice, in correlation with the depletion of potential RORC ligands subsequent to CYP51 disruption. Further evidence for this comes from the global analysis that identified a crucial overlap between hepatic Cyp51−/− and Rorc−/− expression profiles. Additionally, the reduction in RORA and RORC transcriptional activity was greater in adult HCyp51−/− females than males, which correlates well with their downregulated amino and fatty acid metabolism. Overall, we identify a global and sex-dependent transcriptional de-regulation due to the block in cholesterol synthesis during development of the Cyp51 knockout mice and provide in vivo evidence that sterol intermediates downstream of lanosterol may regulate the hepatic RORC activity. PMID:28098217

  18. Disrupting Hepatocyte Cyp51 from Cholesterol Synthesis Leads to Progressive Liver Injury in the Developing Mouse and Decreases RORC Signalling

    NASA Astrophysics Data System (ADS)

    Urlep, Žiga; Lorbek, Gregor; Perše, Martina; Jeruc, Jera; Juvan, Peter; Matz-Soja, Madlen; Gebhardt, Rolf; Björkhem, Ingemar; Hall, Jason A.; Bonneau, Richard; Littman, Dan R.; Rozman, Damjana

    2017-01-01

    Development of mice with hepatocyte knockout of lanosterol 14α-demethylase (HCyp51‑/‑) from cholesterol synthesis is characterized by the progressive onset of liver injury with ductular reaction and fibrosis. These changes begin during puberty and are generally more aggravated in the knockout females. However, a subgroup of (pre)pubertal knockout mice (runts) exhibits a pronounced male prevalent liver dysfunction characterized by downregulated amino acid metabolism and elevated Casp12. RORC transcriptional activity is diminished in livers of all runt mice, in correlation with the depletion of potential RORC ligands subsequent to CYP51 disruption. Further evidence for this comes from the global analysis that identified a crucial overlap between hepatic Cyp51‑/‑ and Rorc‑/‑ expression profiles. Additionally, the reduction in RORA and RORC transcriptional activity was greater in adult HCyp51‑/‑ females than males, which correlates well with their downregulated amino and fatty acid metabolism. Overall, we identify a global and sex-dependent transcriptional de-regulation due to the block in cholesterol synthesis during development of the Cyp51 knockout mice and provide in vivo evidence that sterol intermediates downstream of lanosterol may regulate the hepatic RORC activity.

  19. Rapid eye movement sleep deprivation decreases long-term potentiation stability and affects some glutamatergic signaling proteins during hippocampal development.

    PubMed

    Lopez, J; Roffwarg, H P; Dreher, A; Bissette, G; Karolewicz, B; Shaffery, J P

    2008-04-22

    Development of the mammalian CNS requires formation and stabilization of neuronal circuits and synaptic connections. Sensory stimulation provided by the environment orchestrates neuronal circuit formation in the waking state. Endogenous sources of activation are also implicated in these processes. Accordingly we hypothesized that sleep, especially rapid eye movement sleep (REMS), the stage characterized by high neuronal activity that is more prominent in development than adulthood, provides endogenous stimulation, which, like sensory input, helps to stabilize and refine neuronal circuits during CNS development. Young (Y: postnatal day (PN) 16) and adolescent (A: PN44) rats were rapid eye movement sleep-deprived (REMSD) by gentle cage-shaking for only 4 h on 3 consecutive days (total 12 h). The effect of REMS deprivation in Y and A rats was tested 3-7 days after the last deprivation session (Y, PN21-25; A, PN49-53) and was compared with younger (immature, I, PN9-12) untreated, age-matched, treated and normal control groups. REMS deprivation negatively affected the stability of long-term potentiation (LTP) in Y but not A animals. LTP instability in Y-REMSD animals was similar to the instability in even the more immature, untreated animals. Utilizing immunoblots, we identified changes in molecular components of glutamatergic synapses known to participate in mechanisms of synaptic refinement and plasticity. Overall, N-methyl-d-aspartate receptor subunit 2B (NR2B), N-methyl-d-aspartate receptor subunit 2A, AMPA receptor subunit 1 (GluR1), postsynaptic density protein 95 (PSD-95), and calcium/calmodulin kinase II tended to be lower in Y REMSD animals (NR2B, GluR1 and PSD-95 were significantly lower) compared with controls, an effect not present in the A animals. Taken together, these data indicate that early-life REMS deprivation reduces stability of hippocampal neuronal circuits, possibly by hindering expression of mature glutamatergic synaptic components. The findings

  20. Development of Advanced Surface Enhancement Technology for Decreasing Wear and Corrosion of Equipment Used for Mineral Processing

    SciTech Connect

    Daniel Tao; Craig A. Blue

    2006-07-20

    Equipment wear is a major concern in the mineral processing industry, which dramatically increases the maintenance cost and adversely affects plant operation efficiency. In this research, novel surface treatment technologies, High Density Infrared (HDI) and Laser Surface Engineering (LSE) surface coating processes were developed for the surface enhancement of selected mineral processing equipment. Microstructural and mechanical properties of the coated specimens were characterized. Laboratory-simulated wear tests were conducted to evaluate the tribological performance of the coated components. Test results indicate that the wear resistance of ASTM A36 (raw coal screen section) and can be significantly increased by applying HDI and LSE coating processes. Field testing has been performed using a LSE-treated screen panel and it showed a 2 times improvement of the service life.

  1. Development of Advanced Surface Enhancement Technology for Decreasing Wear and Corrosion of Equipment Used for Mineral Processing

    SciTech Connect

    Daniel Tao; R. Honaker; B. K. Parekh

    2007-09-20

    Equipment wear is a major concern in the mineral processing industry, which dramatically increases the maintenance cost and adversely affects plant operation efficiency. In this research, novel surface treatment technologies, High Density Infrared (HDI) and Laser Surface Engineering (LSE) surface coating processes were developed for the surface enhancement of selected mineral and coal processing equipment. Microstructural and mechanical properties of the coated specimens were characterized. Laboratory-simulated wear tests were conducted to evaluate the tribological performance of the coated components. Test results indicate that the wear resistance of ASTM A36 (raw coal screen section) and can be significantly increased by applying HDI and LSE coating processes. Field testing has been performed using a LSE-treated screen panel and it showed a significant improvement of the service life.

  2. Effects of decreased O2 and elevated CO2 on survival, development, and gene expression in cowpea bruchids.

    PubMed

    Cheng, Weining; Lei, Jiaxin; Ahn, Ji-Eun; Liu, Tong-Xian; Zhu-Salzman, Keyan

    2012-06-01

    Use of modified atmospheres with depleted O(2) and/or elevated CO(2) is an environmentally friendly alternative to currently used fumigants for control of stored grain insect pests. In the present study, we examined the impact of hypoxia and hypercapnia on cowpea bruchids (Callosobruchus maculatus), a storage pest of cowpea and other legumes. Two O(2)/CO(2) combinations were used; (i) 10% O(2)+10% CO(2), (ii) 2% O(2)+18% CO(2). In both cases, N(2) was maintained at 80%, equivalent to normal atmospheric concentration. In ambient atmosphere, the rate of O(2) consumption and CO(2) output at different stages (from low to high) was: eggs≈1st instar<2nd instar≈pupae≈adults<3rd instar<4th instar. When exposed to 10% O(2)+10% CO(2), eggs, larvae and pupae were able to complete development and successfully enter the next developmental stage, although developmental time and mortality varied at different stages. In contrast, more severe hypoxic/hypercapnic treatment, i.e. 2% O(2)+18% CO(2), led to cessation of development of all stages. Effects on eggs and adults were most dramatic as they could only withstand 2-3 days exposure. Further, eggs at early (4-6h old) and later stages (102-104 h old, black-headed) were more susceptible compared to those at intermediate stage (52-54 h old). The 3rd and 4th instar larvae were least sensitive and could survive up to 20 days treatment. To gain some insight into molecular mechanisms underpinning the hypoxic/hypercarpnic response, we performed qPCR reactions on selected metabolic genes involved in TCA cycle and in protein digestion, as well as genes encoding stress-responsive heat shock proteins. Patterns of gene expression and proteolysis suggest that cowpea bruchids suppress their metabolic activity and increase stress tolerance when challenged by O(2) deprivation. Transcript abundance as well as proteolytic activity recovered once normoxic conditions resumed. Taken together, cowpea bruchids were found able to cope with hypoxic

  3. Decrease social inequalities return-to-work: development and design of a randomised controlled trial among women with breast cancer

    PubMed Central

    2014-01-01

    Background Despite the improvement in the care management, women cancer patients who are still in employment find themselves for the most part obliged to stop working while they are having treatment. Their return-to-work probability is impacted by numerous psychosocial factors. The objective is to describe the development and the content of an intervention aimed to facilitate the return to work of female breast cancer patients and in particular the women in the most precarious situations through early active individualised psychosocial support (APAPI). Methods The intervention proposed is made up of 4 interviews with a psychologist at the hospital, distributed over the year according to the diagnosis and conducted on the same day as a conventional follow-up consultation, then a consultation with a specialist job retention physician. We expect, in the first instance, that this intervention will reduce the social inequalities of the return-to-work rate at 12 months. The EPICES score will enable the population to be broken down according to the level of social precariousness. The other expected results are the reduction of the social inequalities in the quality of the return to work at 18 and 24 months and the disparities between the individual and collective resources of the patients. This intervention is assessed in the context of a controlled and randomised multi-centre study. The patients eligible are women aged between 18 and 55 years with a unilateral breast cancer with local extension exclusively, having received surgery followed by adjuvant chemotherapy, in employment at the time of the diagnosis and dealt with by one of the 2 investigating centres. Discussion It is essential to assess this type of intervention before envisaging its generalisation. The study set in place will enable us to measure the impact of this intervention aiming to facilitate the return to work of breast cancer patients, in particular for those who suffer from social fragility

  4. MALFORMATIONS IN GUBERNACULAR LIGAMENT DEVELOPMENT INDUCED BY DEHP, DBP, AND BBP ARE ASSOCIATED WITH DECREASES IN INSL3 GENE EXPRESSION IN THE FETAL RAT TESTIS

    EPA Science Inventory

    Malformations in gubernacular ligament development induced by DEHP, DBP, and BBP are associated with decreases in insl3 gene expression in the fetal rat testis.
    Vickie S.Wilson, Christy Lambright, Johnathan Furr, Carmen Wood, Gary Held, L. Earl Gray Jr. U.S. EPA, ORD, NHEER...

  5. Decreased maternal and fetal cholesterol following maternal bococizumab (anti-PCSK9 monoclonal antibody) administration does not affect rat embryo-fetal development.

    PubMed

    Campion, Sarah N; Han, Bora; Cappon, Gregg D; Lewis, Elise M; Kraynov, Eugenia; Liang, Hong; Bowman, Christopher J

    2015-11-01

    Bococizumab is a humanized monoclonal IgG2Δa antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9) for the treatment of hyperlipidemia. The evaluation of potential effects on embryo-fetal development was conducted in the rat. In a pharmacokinetic/pharmacodynamic study bococizumab was administered intravenously to pregnant Sprague-Dawley (SD) rats (n = 8/group) at 0, 10, 30, and 100 mg/kg during organogenesis. Maternal and fetal bococizumab, total cholesterol and HDL concentrations were determined. Bococizumab was well tolerated and there were no effects on ovarian or uterine parameters. Maternal and fetal bococizumab exposure increased with increasing dose, with a corresponding dose-dependent decrease in fetal cholesterol levels. Maternal cholesterol levels were decreased significantly, with reductions that were of a similar magnitude regardless of dose. In the definitive embryo-fetal development study bococizumab was administered to pregnant SD rats (n = 20/group) at 0, 10, 30, and 100 mg/kg and no adverse maternal or developmental effects were observed up to 100 mg/kg. These studies have provided an appropriate and relevant safety assessment of bococizumab in pregnant rats to inform human risk assessment, demonstrating no adverse effects on embryo-fetal development at magnitudes greater than anticipated clinical exposure and in the presence of maximal reductions in maternal cholesterol and dose-dependent reductions in fetal cholesterol.

  6. Decreased T cell ERK pathway signaling may contribute to the development of lupus through effects on DNA methylation and gene expression.

    PubMed

    Oelke, Kurt; Richardson, Bruce

    2004-01-01

    T cells from patients with active lupus have multiple biochemical abnormalities. One of these is DNA hypomethylation, which in model systems alters gene expression and induces lupus-like autoimmunity. Recent reports indicate that DNA methylation is regulated in part by the ERK pathway, and that ERK pathway signaling is diminished in lupus T cells. This suggests a model in which defective T cell ERK pathway signaling contributes to the development of autoimmunity by decreasing DNA methyltransferase expression, modifying DNA methylation patterns and altering gene expression. This mechanism could contribute to idiopathic and drug-induced lupus.

  7. Deficient sucrose synthase activity in developing wood does not specifically affect cellulose biosynthesis, but causes an overall decrease in cell wall polymers.

    PubMed

    Gerber, Lorenz; Zhang, Bo; Roach, Melissa; Rende, Umut; Gorzsás, András; Kumar, Manoj; Burgert, Ingo; Niittylä, Totte; Sundberg, Björn

    2014-09-01

    The biosynthesis of wood in aspen (Populus) depends on the metabolism of sucrose, which is the main transported form of carbon from source tissues. The largest fraction of the wood biomass is cellulose, which is synthesized from UDP-glucose. Sucrose synthase (SUS) has been proposed previously to interact directly with cellulose synthase complexes and specifically supply UDP-glucose for cellulose biosynthesis. To investigate the role of SUS in wood biosynthesis, we characterized transgenic lines of hybrid aspen with strongly reduced SUS activity in developing wood. No dramatic growth phenotypes in glasshouse-grown trees were observed, but chemical fingerprinting with pyrolysis-GC/MS, together with micromechanical analysis, showed notable changes in chemistry and ultrastructure of the wood in the transgenic lines. Wet chemical analysis showed that the dry weight percentage composition of wood polymers was not changed significantly. However, a decrease in wood density was observed and, consequently, the content of lignin, hemicellulose and cellulose was decreased per wood volume. The decrease in density was explained by a looser structure of fibre cell walls as shown by increased wall shrinkage on drying. The results show that SUS is not essential for cellulose biosynthesis, but plays a role in defining the total carbon incorporation to wood cell walls.

  8. Quetiapine attenuates cognitive impairment and decreases seizure susceptibility possibly through promoting myelin development in a rat model of malformations of cortical development.

    PubMed

    Ma, Lei; Yang, Feng; Zhao, Rui; Li, Li; Kang, Xiaogang; Xiao, Lan; Jiang, Wen

    2015-10-05

    Developmental delay, cognitive impairment, and refractory epilepsy are the most frequent consequences found in patients suffering from malformations of cortical development (MCD). However, therapeutic options for these psychiatric and neurological comorbidities are currently limited. The development of white matter undergoes dramatic changes during postnatal brain maturation, thus myelination deficits resulting from MCD contribute to its comorbid diseases. Consequently, drugs specifically targeting white matter are a promising therapeutic option for the treatment of MCD. We have used an in utero irradiation rat model of MCD to investigate the effects of postnatal quetiapine treatment on brain myelination as well as neuropsychological and cognitive performances and seizure susceptibility. Fatally irradiated rats were treated with quetiapine (10mg/kg, i.p.) or saline once daily from postnatal day 0 (P0) to P30. We found that postnatal administration of quetiapine attenuated object recognition memory impairment and improved long-term spatial memory in the irradiated rats. Quetiapine treatment also reduced the susceptibility and severity of pentylenetetrazol-induced seizures. Importantly, quetiapine treatment resulted in an inhibition of irradiation-induced myelin breakdown in the cerebral cortex and corpus callosum. These findings suggest that quetiapine may have beneficial, postnatal effects in the irradiated rats, strongly suggesting that improving MCD-derived white matter pathology is a possible underlying mechanism. Collectively, these results indicate that brain myelination represents an encouraging pharmacological target to improve the prognosis of patients with MCD.

  9. Aberrant decrease of microRNA19b regulates TSLP expression and contributes to Th17 cells development in myasthenia gravis related thymomas.

    PubMed

    Wang, Zhongkui; Chen, Yuping; Xu, Shengjie; Yang, Yanhua; Wei, Dongning; Wang, Wei; Huang, Xusheng

    2015-11-15

    Myasthenia gravis (MG) is an organ-specific autoimmune disease. The imbalance of T helper type 17 cells (Th17) plays a key role in the pathogenesis of thymomatous MG. But the regulatory mechanism for Th17 cell development in MG-related thymoma remains undefined. Here we demonstrated that thymic stromal lymphopoietin (TSLP) is significantly decreased in thymomas. We also proved that TSLP was post-trancriptionally regulated by microRNA-19b. The expression of microRNA-19b was negatively correlated with the expression of TSLP mRNA and protein in thymomas. This study indicated that the elevation of microRNA-19b suppressed TSLP expression and then influenced T cell development in thymomatous MG.

  10. Transient Decrease in Circulatory Testosterone and Homocysteine Precedes the Development of Metabolic Syndrome Features in Fructose-Fed Sprague Dawley Rats

    PubMed Central

    Sakamuri, Anil; Pitla, Sujatha; Putcha, Uday Kumar; Jayapal, Sugeedha; Pothana, Sailaja; Vadakattu, Sai Santosh

    2016-01-01

    Background. Increased fructose consumption is linked to the development of metabolic syndrome (MS). Here we investigated the time course of development of MS features in high-fructose-fed Sprague Dawley rats along with circulatory testosterone and homocysteine levels. Methods. Rats were divided into control and experimental groups and fed with diets containing 54.5% starch and fructose, respectively, for 4, 12, and 24 weeks. Plasma testosterone and homocysteine levels were measured along with insulin, glucose, and lipids. Body composition, insulin resistance, and hepatic lipids were measured. Results. Increase in hepatic triglyceride content was first observed in metabolic disturbance followed by hypertriglyceridemia and systemic insulin resistance in fructose-fed rats. Hepatic lipids were increased in time-dependent manner by fructose-feeding starting from 4 weeks, but circulatory triglyceride levels were increased after 12 weeks. Fasting insulin and Homeostatis Model Assessment of Insulin Resistance (HOMA-IR) were increased after 12 weeks of fructose-feeding. Decreased visceral adiposity, circulatory testosterone, and homocysteine levels were observed after 4 weeks of fructose-feeding, which were normalized at 12 and 24 weeks. Conclusions. We conclude that transient decrease in circulatory testosterone and homocysteine levels and increased hepatic triglyceride content are the earliest metabolic disturbances that preceded hypertriglyceridemia and insulin resistance in fructose-fed SD rats. PMID:27818793

  11. Decreased expression of Fli-1 in bone marrow-derived haematopoietic cells significantly affects disease development in Murphy Roths Large/lymphoproliferation (MRL/lpr) mice

    PubMed Central

    Molano, I; Mathenia, J; Ruiz, P; Gilkeson, G S; Zhang, X K

    2010-01-01

    The transcription factor Fli-1 is implicated in the pathogenesis of both murine and human lupus. Decreased expression of Fli-1 in heterozygous (Fli-1+/−) Murphy Roths Large (MRL)/lpr mice resulted in significantly lower kidney pathological scores and markedly increased survival. In this study, bone marrow (BM) transplantation was used to investigate the role of decreased expression of Fli-1 in haematopoietic versus non-haematopoietic cell lineages in autoimmune disease development. Wild-type (WT) MRL/lpr that received BM from Fli-1+/− MRL/lpr mice had statistically significantly lower autoantibodies, less proteinuria, reduced renal disease and prolonged survival compared to WT MRL/lpr mice that received BM from WT MRL/lpr mice. Although not statistically significant, Fli-1+/− MRL/lpr mice that received BM from WT MRL/lpr mice also had lower autoantibodies and improved survival compared to WT MRL/lpr mice that received BM from WT MRL/lpr mice. Our data indicate that expression of Fli-1 in haematopoietic cell lineages has a significant effect on disease development in MRL/lpr mice. PMID:20015093

  12. Decreased expression of Fli-1 in bone marrow-derived haematopoietic cells significantly affects disease development in Murphy Roths Large/lymphoproliferation (MRL/lpr) mice.

    PubMed

    Molano, I; Mathenia, J; Ruiz, P; Gilkeson, G S; Zhang, X K

    2010-05-01

    The transcription factor Fli-1 is implicated in the pathogenesis of both murine and human lupus. Decreased expression of Fli-1 in heterozygous (Fli-1(+/-)) Murphy Roths Large (MRL)/lpr mice resulted in significantly lower kidney pathological scores and markedly increased survival. In this study, bone marrow (BM) transplantation was used to investigate the role of decreased expression of Fli-1 in haematopoietic versus non-haematopoietic cell lineages in autoimmune disease development. Wild-type (WT) MRL/lpr that received BM from Fli-1(+/-) MRL/lpr mice had statistically significantly lower autoantibodies, less proteinuria, reduced renal disease and prolonged survival compared to WT MRL/lpr mice that received BM from WT MRL/lpr mice. Although not statistically significant, Fli-1(+/-) MRL/lpr mice that received BM from WT MRL/lpr mice also had lower autoantibodies and improved survival compared to WT MRL/lpr mice that received BM from WT MRL/lpr mice. Our data indicate that expression of Fli-1 in haematopoietic cell lineages has a significant effect on disease development in MRL/lpr mice.

  13. Regulatory T cells generated during cytomegalovirus in vitro stimulation of mononuclear cells from HIV-infected individuals on HAART correlate with decreased lymphocyte proliferation

    SciTech Connect

    Jesser, Renee D.; Li, Shaobing; Weinberg, Adriana . E-mail: Adriana.Weinberg@uchsc.edu

    2006-09-01

    HIV-infected patients fail to fully recover cell-mediated immunity despite HAART. To identify regulatory factors, we studied the phenotype and function of in vitro cytomegalovirus (CMV)-stimulated T cells from HAART recipients. CFSE-measured proliferation showed CD4{sup +} and CD8{sup +} cells dividing in CMV-stimulated cultures. Compared with healthy controls, CMV-stimulated lymphocytes from HAART recipients had lower {sup 3}H-thymidine incorporation; lower IFN{gamma} and TNF{alpha} production; higher CD4{sup +}CD27{sup -}CD28{sup -} and CD8{sup +}CD27{sup -}CD28{sup -} frequencies; lower CD4{sup +}CD25{sup hi}; and higher FoxP3 expression in CD8{sup +}CD25{sup hi} cells. CMV-specific proliferation correlated with higher IFN{gamma}, TNF{alpha} and IL10 levels and higher CD4{sup +}perforin{sup +} and CD8{sup +}perforin{sup +} frequencies. Decreased proliferation correlated with higher CD4{sup +}CD27{sup -}CD28{sup -} frequencies and TGF{beta}1 production, which also correlated with each other. Anti-TGF{beta}1 neutralizing antibodies restored CMV-specific proliferation in a dose-dependent fashion. In HIV-infected subjects, decreased proliferation correlated with higher CMV-stimulated CD8{sup +}CD25{sup hi} frequencies and their FoxP3 expression. These data indicate that FoxP3- and TGF{beta}1-expressing regulatory T cells contribute to decreased immunity in HAART recipients.

  14. Decreased zinc in the development and progression of malignancy: an important common relationship and potential for prevention and treatment of carcinomas

    PubMed Central

    Costello, Leslie C.; Franklin, Renty B.

    2016-01-01

    Introduction Efficacious chemotherapy does not exist for treatment or prevention of prostate, liver, and pancreatic carcinomas, and some other cancers that exhibit decreased zinc in malignancy. Zinc treatment offers a potential solution; but its support has been deterred by adverse bias. Areas covered 1. The clinical and experimental evidence for the common ZIP transporter/Zn down regulation in these cancers. 2. The evidence for a zinc approach to prevent and/or treat these carcinomas. 3. The issues that introduce bias against support for the zinc approach. Expert opinion ZIP/Zn downregulation is a clinically established common event in prostate, hepatocellular and pancreatic cancers. 2. Compelling evidence supports the plausibility that a zinc treatment regimen will prevent development of malignancy and termination of progressing malignancy in these cancers; and likely other carcinomas that exhibit decreased zinc. 3. Scientifically-unfounded issues that oppose this ZIP/Zn relationship have introduced bias against support for research and funding of a zinc treatment approach. 4. The clinically-established and supporting experimental evidence provide the scientific credibility that should dictate the support for research and funding of a zinc approach for the treatment and possible prevention of these cancers. 5. This is in the best interest of the medical community and the public-at-large. PMID:27885880

  15. Decreased apoptosis and persistence of the common nephric duct during the development of an aberrant vesicoureteral junction in Dlg1 gene-targeted mice.

    PubMed

    Iizuka-Kogo, Akiko; Akiyama, Tetsu; Senda, Takao

    2013-12-01

    Congenital anomalies of the kidney and urinary tract occur at a frequency of 1 in 500 live births in humans. Mutant mice null for Dlg1 (Dlg1(-/-) mice), a membrane-associated guanylate kinase containing PDZ domains, exhibit various urogenital malformations, including hypoplasia of the kidney and ureter, megaureter, hydronephrosis, and aplasia of the seminal vesicle and the vagina. The common nephric duct (CND) is a distal part of the Wolffian duct between the ureteric branch and the opening to the urogenital sinus, and normally disappears by embryonic day (E) 12.5 by a downward shift of the ureteric branch. Although retardation of the disappearance of the CND is apparent during urogenital development in Dlg1(-/-) mice, its pathogenesis and prognosis are unclear. In the present study, we found a decrease in apoptotic cells in the CND epithelium in Dlg1(-/-) mice at E11.5. Cell proliferation did not change. Additionally, histological observation of the development of the ureteral orifice indicated that the CND remained at E15.5 and was widely open to the vesical lumen in Dlg1(-/-) mice, in contrast to the complete disappearance of the CND and a narrow ureteric orifice in control mice. The dilatation of the vesicoureteral junction remained at E18.5. Opening of the vesicoureteral junction is known to cause vesicoureteral reflux and subsequent megaureter and hydronephrosis. Therefore, our present observation demonstrates that lack of the Dlg1 gene induces a decrease in apoptotic epithelial cell death and the persistence of the CND, which result in a dysfunctional vesicoureteral junction and cause megaureter or hydronephrosis through vesicoureteral reflux.

  16. t10,c12-CLA decreases adiposity in peripubertal mice without dose-related detrimental effects on mammary development, inflammation status, and metabolism.

    PubMed

    Foote, M R; Giesy, S L; Bernal-Santos, G; Bauman, D E; Boisclair, Y R

    2010-12-01

    The trans 10, cis 12-conjugated linoleic acid (10,12-CLA) isomer reduces adiposity in several animal models. In the mouse, however, this effect is associated with adipose tissue inflammation, hyperinsulinemia and hepatic lipid accumulation. Moreover, 10,12-CLA was recently shown to promote mammary ductal hyperplasia and ErbB2/Her2-driven mammary cancer in the mouse. Reasons for detrimental effects of 10,12-CLA on the mouse mammary gland could relate to its effect on the mammary fat pad (MFP), which is essential for normal development. Accordingly, we hypothesized that mammary effects of 10,12-CLA were mediated through the MFP in a dose-dependent manner. Female FVB mice were fed 10,12-CLA at doses of 0%, 0.1%, 0.2%, or 0.5% of the diet from day 24 of age, and effects on mammary development and metabolism were measured on day 49. The 0.5% dose reduced ductal elongation and caused premature alveolar budding. These effects were associated with increased expression of inflammatory markers and genes shown to alter epithelial growth (IGF binding protein-5) and alveolar budding (TNF-α and receptor of activated NF-κB ligand). The 0.5% dose also caused hyperinsulinemia and hepatic lipid accumulation. In contrast, the 0.1% 10,12-CLA dose had no adverse effects on mammary development, metabolic events, and inflammatory responses, but remained effective in decreasing adipose weights and lipogenic gene expression. These results show that a low dose of 10,12-CLA reduces adiposity in the mouse without negative effects on mammary development, inflammation, and metabolism, and suggest that previously reported detrimental effects relate to the use of excessive doses.

  17. Tretinoin-loaded lipid-core nanocapsules decrease reactive oxygen species levels and improve bovine embryonic development during in vitro oocyte maturation.

    PubMed

    Lucas, Caroline Gomes; Remião, Mariana Härter; Komninou, Eliza Rossi; Domingues, William Borges; Haas, Cristina; Leon, Priscila Marques Moura de; Campos, Vinicius Farias; Ourique, Aline; Guterres, Silvia S; Pohlmann, Adriana R; Basso, Andrea Cristina; Seixas, Fabiana Kömmling; Beck, Ruy Carlos Ruver; Collares, Tiago

    2015-12-01

    In vitro oocyte maturation (IVM) protocols can be improved by adding chemical supplements to the culture media. Tretinoin is considered an important retinoid in embryonic development and its association with lipid-core nanocapsules (TTN-LNC) represents an innovative way of improving its solubility, and chemical stability, and reducing its toxicity. The effects of supplementing IVM medium with TTN-LNC was evaluated by analyzing production of reactive oxygen species (ROS), S36-phosphorilated-p66Shc levels and caspase activity in early embryonic development, and expression of apoptosis and pluripotency genes in blastocysts. The lowest concentration tested (0.25μM) of TTN-LNC generated higher blastocyst rate, lower ROS production and S36-p66Shc amount. Additionally, expression of BAX and SHC1 were lower in both non-encapsulated tretinoin (TTN) and TTN-LNC-treated groups. Nanoencapsulation allowed the use of smaller concentrations of tretinoin to supplement IVM medium thus reducing toxic effects related with its use, decreasing ROS levels and apoptose frequency, and improving the blastocyst rates.

  18. The Decreased apical dominance1/Petunia hybrida CAROTENOID CLEAVAGE DIOXYGENASE8 gene affects branch production and plays a role in leaf senescence, root growth, and flower development.

    PubMed

    Snowden, Kimberley C; Simkin, Andrew J; Janssen, Bart J; Templeton, Kerry R; Loucas, Holly M; Simons, Joanne L; Karunairetnam, Sakuntala; Gleave, Andrew P; Clark, David G; Klee, Harry J

    2005-03-01

    Carotenoids and carotenoid cleavage products play an important and integral role in plant development. The Decreased apical dominance1 (Dad1)/PhCCD8 gene of petunia (Petunia hybrida) encodes a hypothetical carotenoid cleavage dioxygenase (CCD) and ortholog of the MORE AXILLARY GROWTH4 (MAX4)/AtCCD8 gene. The dad1-1 mutant allele was inactivated by insertion of an unusual transposon (Dad-one transposon), and the dad1-3 allele is a revertant allele of dad1-1. Consistent with its role in producing a graft-transmissible compound that can alter branching, the Dad1/PhCCD8 gene is expressed in root and shoot tissue. This expression is upregulated in the stems of the dad1-1, dad2, and dad3 increased branching mutants, indicating feedback regulation of the gene in this tissue. However, this feedback regulation does not affect the root expression of Dad1/PhCCD8. Overexpression of Dad1/PhCCD8 in the dad1-1 mutant complemented the mutant phenotype, and RNA interference in the wild type resulted in an increased branching phenotype. Other differences in phenotype associated with the loss of Dad1/PhCCD8 function included altered timing of axillary meristem development, delayed leaf senescence, smaller flowers, reduced internode length, and reduced root growth. These data indicate that the substrate(s) and/or product(s) of the Dad1/PhCCD8 enzyme are mobile signal molecules with diverse roles in plant development.

  19. Decreasing maternal nutrient intake during the final third of pregnancy in previously overnourished adolescent sheep: effects on maternal nutrient partitioning and feto-placental development.

    PubMed

    Redmer, D A; Milne, J S; Aitken, R P; Johnson, M L; Borowicz, P P; Reynolds, L P; Caton, J S; Wallace, J M

    2012-02-01

    When pregnant adolescent sheep are overnourished during pregnancy normal nutrient partitioning priorities to the gravid uterus are altered, leading to impaired placental development and fetal growth restriction. We hypothesized that decreasing dietary intake in overnourished dams during the final third of gestation may reverse this inappropriate nutrient partitioning in favor of the fetus. Adolescent ewes were offered control (C; n = 12) or high (H; n = 20) dietary intakes to induce normal vs. compromised placental development. Ten ewes receiving the H intake were switched to a low intake at d90 of gestation (HL). Between d90 to 130, HL dams lost weight and adiposity, and metabolic hormones and glucose at d130 were less than H and similar to C. In spite of these maternal changes, at d130 fetal bodyweight was equivalent in HL and H groups and ∼20% less than in C. A greater degree of brain sparing was evident in HL fetuses and glucose and insulin concentrations were more perturbed than in H fetuses. Relative to C, placentome weight was reduced by 46 and 32% in H and HL and the fetal:placentome weight ratio was H > HL > C. Placental vascular morphology was largely unaffected by maternal diet during late gestation but mRNA expression of five angiogenic genes was up-regulated in the fetal cotyledon of HL pregnancies, commensurate with blood vessel remodeling. Nevertheless, overfeeding to promote maternal anabolic growth during adolescent pregnancy impairs feto-placental development that cannot be rescued by reducing maternal intake during the final third of gestation.

  20. The Decreased apical dominance1/Petunia hybrida CAROTENOID CLEAVAGE DIOXYGENASE8 Gene Affects Branch Production and Plays a Role in Leaf Senescence, Root Growth, and Flower Development

    PubMed Central

    Snowden, Kimberley C.; Simkin, Andrew J.; Janssen, Bart J.; Templeton, Kerry R.; Loucas, Holly M.; Simons, Joanne L.; Karunairetnam, Sakuntala; Gleave, Andrew P.; Clark, David G.; Klee, Harry J.

    2005-01-01

    Carotenoids and carotenoid cleavage products play an important and integral role in plant development. The Decreased apical dominance1 (Dad1)/PhCCD8 gene of petunia (Petunia hybrida) encodes a hypothetical carotenoid cleavage dioxygenase (CCD) and ortholog of the MORE AXILLARY GROWTH4 (MAX4)/AtCCD8 gene. The dad1-1 mutant allele was inactivated by insertion of an unusual transposon (Dad-one transposon), and the dad1-3 allele is a revertant allele of dad1-1. Consistent with its role in producing a graft-transmissible compound that can alter branching, the Dad1/PhCCD8 gene is expressed in root and shoot tissue. This expression is upregulated in the stems of the dad1-1, dad2, and dad3 increased branching mutants, indicating feedback regulation of the gene in this tissue. However, this feedback regulation does not affect the root expression of Dad1/PhCCD8. Overexpression of Dad1/PhCCD8 in the dad1-1 mutant complemented the mutant phenotype, and RNA interference in the wild type resulted in an increased branching phenotype. Other differences in phenotype associated with the loss of Dad1/PhCCD8 function included altered timing of axillary meristem development, delayed leaf senescence, smaller flowers, reduced internode length, and reduced root growth. These data indicate that the substrate(s) and/or product(s) of the Dad1/PhCCD8 enzyme are mobile signal molecules with diverse roles in plant development. PMID:15705953

  1. SGLT2 Expression is increased in Human Diabetic Nephropathy: SGLT2 Inhibition Decreases Renal Lipid Accumulation, Inflammation and the Development of Nephropathy in Diabetic Mice.

    PubMed

    Wang, Xiaoxin X; Levi, Jonathan; Luo, Yuhuan; Myakala, Komuraiah; Herman-Edelstein, Michal; Qiu, Liru; Wang, Dong; Peng, Yingqiong; Grenz, Almut; Lucia, Scott; Dobrinskikh, Evgenia; D'Agati, Vivette D; Koepsell, Hermann; Kopp, Jeffrey B; Rosenberg, Avi; Levi, Moshe

    2017-02-14

    There is very limited human renal sodium gradient dependent glucose transporter protein SGLT2 mRNA and protein expression data reported in the literature. Aim 1 of this study was to determine SGLT2 mRNA and protein levels in human and animal models of diabetic nephropathy. We have found that the expression of SGLT2 mRNA and protein is increased in renal biopsies from human subjects with diabetic nephropathy. This is in contrast to db-db mice which had no changes in renal SGLT-2 protein expression. Furthermore, the effect of SGLT2 inhibition on renal lipid content and inflammation is not known. Aim 2 of this study was to determine the potential mechanisms of beneficial effects of SGLT2 inhibition in progression of diabetic renal disease. We treated db/db mice with a selective SGLT2 inhibitor JNJ 39933673. We found that SGLT2 inhibition caused marked decreases in systolic blood pressure, kidney weight/body weight ratio, urinary albumin and urinary thiobarbituric acid-reacting substances (TBARS). SGLT2 inhibition prevented renal lipid accumulation via inhibition of ChREBP-β, LPK, SCD-1 and DGAT1, key transcriptional factors and enzymes that mediate fatty acid and triglyceride synthesis. SGLT2 inhibition also prevented inflammation via inhibition of CD68 macrophage accumulation, and expression of p65, TLR4, MCP-1 and OPN. These effects were associated with reduced mesangial expansion, accumulation of extracellular matrix proteins fibronectin and type IV collagen, and loss of podocyte markers WT1 and synaptopodin, as determined by immunofluorescence microscopy. In summary, our study showed that SGLT2 inhibition modulates renal lipid metabolism and inflammation and prevents the development of nephropathy in db/db mice.

  2. Changes in blood metabolic parameters during the development of Walker-256 tumour-induced cachexia in rats are not caused by decreased food intake.

    PubMed

    Cassolla, Priscila; Moreira, Carolina Campos Lima; Liboni, Thaís Fernanda; Zaia, Cássia Thaïs Bussamra Vieira; Borba-Murad, Glaucia Regina; Bazotte, Roberto Barbosa; de Souza, Helenir Medri

    2012-06-01

    Blood metabolic parameters of Walker-256 tumour-bearing rats, on days 5, 8, 11 and 14 after implantation of tumour, were compared with those of rats without tumour fed ad libitum (free-fed control) or with reduced feeding (pair-fed control), similar to the anorexic tumour-bearing rats. Cachexia parameters and tumour mass also were investigated. In general, especially on day 14 after implantation of tumour, there was reduction of body mass, gastrocnemius muscle mass, food intake and glycemia and increase of blood triacylglycerol, free fatty acids, lactate and urea, compared with free-fed controls rats. These changes did not occur in pair-fed control, except a slight reduction of glycemia. Pair-fed control showed no significant changes in blood cholesterol and glycerol in comparison with free-fed control, although there was reduction of cholesterol and increase of blood glycerol on day 14 after tumour implantation compared with pair-fed control. The results demonstrate that, besides the characteristic signs of the cachexia syndrome such as anorexia, weight loss and muscle catabolism, Walker-256 tumour-bearing rats show several blood metabolic alterations, some of which begin as early as day 5 after implantation of tumour, and are accentuated during the development of cachexia. Evidence that the alterations of blood metabolic parameters of tumour-bearing rats were not found in pair-fed control indicate that they were not caused by decreased food intake. These changes were probably mediated by factors produced by tumour or host tissue in response to the presence of tumour.

  3. Dietary strawberries increase proliferative response of CD3/CD28-activated CD8+ T cells and production of TNF-alpha in lipopolysaccharide-stimulated monocytes from obese human subjects

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Obesity increases the risk of developing bacterial and viral infections compared to normal weight. In a 7 wk double-blind, randomized, crossover trial, twenty obese volunteers (20-50 y old, BMI between 30-40 kg/m2) were fed freeze-dried strawberry powder or strawberry-flavored placebo preparations ...

  4. GnRH dose reduction decreases pituitary LH release and ovulatory response but does not affect corpus luteum (CL) development and function in llamas.

    PubMed

    Silva, M E; Colazo, M G; Ratto, M H

    2012-06-01

    time interaction affected (P > 0.05) CL diameter or plasma progesterone concentrations. In summary, reducing the dose of GnRH gradually decreased the magnitude of the preovulatory LH surge and ovulatory response; however, subsequent CL development and plasma progesterone concentrations were not affected.

  5. Decreased cyclin A2 and increased cyclin G1 levels coincide with loss of proliferative capacity in rat Leydig cells during pubertal development.

    PubMed

    Ge, R S; Hardy, M P

    1997-09-01

    Postnatal development of Leydig cells can be divided into three distinct stages of differentiation: initially they exist as mesenchymal-like progenitors (PLC) by day 21; subsequently, as immature Leydig cells (ILC) by day 35, they acquire steroidogenic organelle structure and enzyme activities but metabolize most of the testosterone they produce; finally, as adult Leydig cells (ALC) by day 90 they actively produce testosterone. The aims of the present study were to determine whether changes in proliferative capacity are associated with progressive differentiation of Leydig cells, and if the proliferative capacity of Leydig cells is controlled by known hormonal regulators of testosterone biosynthesis: LH, insulin-like growth factor I (IGF-I), androgen, and estradiol (E2). Isolated PLC, ILC, and ALC were cultured in DMEM/F-12 for 24 h followed by an additional 24 h in the presence of LH (1 ng/ml), IGF-I (70 ng/ml), 7alpha-methyl-19-nortestosterone (MENT, 50 nM), a synthetic androgen that is not metabolized by 5alpha-reductase, or E2 (50 nM). Proliferative capacity was measured by assaying [3H]thymidine incorporation and labeling index (LI). Messenger RNA (mRNA) and protein levels for cyclin A2 and G1, which are putative intracellular regulators of Leydig cell proliferation and differentiation, were measured by RT-PCR and immunoblotting, respectively. Thymidine incorporation was highest in PLC (9.24 +/- 0.21 cpm/10(3) cell, mean +/- SE), intermediate in ILC (1.74 +/- 0.07) and lowest in ALC (0.24 +/- 0.03). Similarly, LI was highest in PLC (13.42 +/- 0.30%, mean +/- SE), intermediate in ILC (1.95 +/- 0.08%), and undetectable in ALC. Cyclin A2 mRNA levels, normalized to ribosomal protein S16 (RPS16), were highest in PLC (2.76 +/- 0.21, mean +/- SE), intermediate in ILC (1.79 +/- 0.14), and lowest in ALC (0.40 +/- 0.06). In contrast, cyclin G1 mRNA levels were highest in ALC (1.32 +/- 0.16), intermediate in ILC (0.47 +/- 0.07), and lowest in PLC (0.12 +/- 0.02). The

  6. Schur monotone decreasing sequences

    NASA Astrophysics Data System (ADS)

    Ganikhodjaev, Rasul; Saburov, Mansoor; Saburov, Khikmat

    2013-09-01

    In this paper, we introduce Schur monotone decreasing sequences in an n-dimensional space by considering a majorization pre-order. By means of down arrow mappings, we study omega limiting points of bounded Schur monotone decreasing sequences. We provide convergence criteria for such kinds of sequences. We prove that a Cesaro mean (or an arithmetic mean) of any bounded Schur monotone decreasing sequences converges to a unique limiting point.

  7. Development of Knowledge, Awareness, Global Warming Decreasing Behavior and Critical Thinking of Grade 11 Students Using the Four Noble Truths Method with Meta-Cognitive Techniques

    ERIC Educational Resources Information Center

    Chattuchai, Sakkarin; Singseewo, Adisak; Suksringarm, Paitool

    2015-01-01

    This study aims to investigate the effects of learning environmental education on the knowledge, awareness, global warming decreasing behavior, and critical thinking of eighty grade 11 students from two classes. The Four Noble Truths method with metacognitive techniques and traditional teaching method were used for the investigation. The sample…

  8. Decrease in the ratio of high- to low-affinity isozymes of (Na+ +K+)-ATPase during the development of rat cardiac ventricles.

    PubMed

    Alves, C M; Silva, C L; Moura, G M; Noël, F

    1995-03-01

    The ratio of (Na+ +K+)-ATPase (EC 3.6.1.3.)isoforms with high and low affinity for cardiac glycosides was studied in heart preparations from neonatal, 3-month and 6-month old Wistar rats. Biphasic ouabain inhibition curves of (Na+ +K+)-ATPase activity indicated that the relative contribution of the high-affinity process decreased from 34% at 9 days to 23% at 3 months and to 10% at 6 months. Scatchard plots for [3H]ouabain binding were curvilinear and indicated that the relative contribution of the high-affinity sites (Kd = 0.1-0.25 microM) decreased by about one-half between 3 months (19-24%, N = 2) and 6 months (9-11%, N = 2).

  9. Stratospheric ozone is decreasing

    NASA Astrophysics Data System (ADS)

    Kerr, Richard A.

    1988-03-01

    The recent discovery that chlorofluorocarbons create the Antarctic ozone hole every October through reactions mediated by ice particles formed at the lowest temperatures of the stratosphere is discussed. A large-scale reanalysis of measurements reveals that protective stratospheric ozone has decreased during the past 17 yrs with some decreases greatly exceeding predictions. It is noted that standard models did not, and still do not, include the ice in their reaction schemes. A tendency toward larger losses at higher colder latitudes is seen.

  10. Decreasing strabismus surgery

    PubMed Central

    Arora, A; Williams, B; Arora, A K; McNamara, R; Yates, J; Fielder, A

    2005-01-01

    Aim: To determine whether there has been a consistent change across countries and healthcare systems in the frequency of strabismus surgery in children over the past decade. Methods: Retrospective analysis of data on all strabismus surgery performed in NHS hospitals in England and Wales, on children aged 0–16 years between 1989 and 2000, and between 1994 and 2000 in Ontario (Canada) hospitals. These were compared with published data for Scotland, 1989–2000. Results: Between 1989 and 1999–2000 the number of strabismus procedures performed on children, 0–16 years, in England decreased by 41.2% from 15 083 to 8869. Combined medial rectus recession with lateral rectus resection decreased from 5538 to 3013 (45.6%) in the same period. Bimedial recessions increased from 489 to 762, oblique tenotomies from 43 to 121, and the use of adjustable sutures from 29 to 44, in 2000. In Ontario, operations for squint decreased from 2280 to 1685 (26.1%) among 0–16 year olds between 1994 and 2000. Conclusion: The clinical impression of decrease in the frequency of paediatric strabismus surgery is confirmed. In the authors’ opinion this cannot be fully explained by a decrease in births or by the method of healthcare funding. Two factors that might have contributed are better conservative strabismus management and increased subspecialisation that has improved the quality of surgery and the need for re-operation. This finding has a significant impact upon surgical services and also on the training of ophthalmologists. PMID:15774914

  11. Knockdown of SPARC leads to decreased cell-cell adhesion and lens cataracts during post-gastrula development in Xenopus laevis.

    PubMed

    Huynh, My-Hang; Zhu, Shu Jun; Kollara, Alexandra; Brown, Theodore; Winklbauer, Rudolf; Ringuette, Maurice

    2011-03-01

    SPARC is a multifunctional matricellular glycoprotein with complex, transient tissue distribution during embryonic development. In Xenopus laevis embryos, zygotic activation of SPARC is first detected during late gastrulation, undergoing rapid changes in its spatiotemporal distribution throughout organogenesis. Injections of anti-sense Xenopus SPARC morpholinos (XSMOs) into 2- and 4-cell embryos led to a dose-dependent dissociation of embryos during neurula and tailbud stages of development. Animal cap explants derived from XSMO-injected embryos also dissociated, resulting in the formation of amorphous ciliated microspheres. At low doses of XSMOs, lens cataracts were formed, phenocopying that observed in Sparc-null mice. At XSMOs concentrations that did not result in a loss of axial tissue integrity, adhesion between myotomes at intersomitic borders was compromised with a reduction in SPARC concentration. The combined data suggest a critical requirement for SPARC during post-gastrula development in Xenopus embryos and that SPARC, directly or indirectly, promotes cell-cell adhesion in vivo.

  12. Decreased flight performance and sperm production in drones of the honey bee (Apis mellifera) slightly infested by Varroa destructor mites during pupal development.

    PubMed

    Duay, Pedro; De Jong, David; Engels, Wolf

    2002-09-30

    We developed a bioassay to measure the flying power of drone, in order to determine which drones could reach a drone congregation area. A wind tunnel was used to test unparasitized drones and drones slightly parasitized by one or two mites during pupal development, and counts were made of the number of spermatozoa that they produced. Drones parasitized with one mite flew as long as control drones (x= 6'55" and 6'48", respectively, P = 0.512); however, those that had been infested by two mites flew significantly less (x= 2'16", P<0.001). There was a significant positive correlation (P<0.01) between flight duration and the number of spermatozoa per drone in control group (r = 0.53), and in both the one mite (r = 0.43) and two mite (r = 0.54) groups. Drones infested during development with one or two mites produced 24 and 45% fewer sperm, respectively.

  13. Cloudy apple juice decreases DNA damage, hyperproliferation and aberrant crypt foci development in the distal colon of DMH-initiated rats.

    PubMed

    Barth, S W; Fähndrich, C; Bub, A; Dietrich, H; Watzl, B; Will, F; Briviba, K; Rechkemmer, G

    2005-08-01

    Clear (CleA) and cloudy (CloA) apple juices containing different amounts of analyzed procyanidins and pectin were investigated for preventive effects of colon cancer and underlying molecular mechanisms in F344 rats given intraperitoneal injections of 1,2-dimethylhydrazine (DMH; 20 mg/kg body wt) once a week for 4 weeks. Rats received either water (Cont), CleA or CloA (ad libitum) for 7 weeks starting 1 week before the first DMH injection. CloA inhibited DMH induced genotoxic damage in mucosa cells of the distal colon compared with Cont as investigated by single-cell microgel electrophoresis assay. The mean tail intensity in mucosa cells of DMH-treated controls (Cont/DMH: 6.1+/-0.9%) was significantly reduced by CloA (2.4+/-0.8%; P<0.01) but not by CleA intervention (4.1+/-1.2%; P>0.05). The crypt cell proliferation index induced by DMH (Cont/NaCl: 10.0+/-0.7%; Cont/DMH: 19.9+/-1.0%; P<0.001) was significantly decreased by CleA (15.7+/-0.7%; P<0.001) and CloA intervention (11.9+/-0.4%; P<0.001). CloA but not CleA significantly reduced the number of large aberrant crypt foci (ACF) consisting of more than four aberrant crypts (AC) (Cont/DMH: 37.4+/-5.4; CleA/DMH: 32.8+/-4.4, P>0.05; CloA/DMH: 18.8+/-2.5 ACF; P<0.05) and the overall mean ACF size in the distal colon (Cont/DMH: 2.31+/-0.09; CleA/DMH: 2.27+/-0.05; CloA/DMH: 2.04+/-0.03 AC/ACF; P<0.05). After treatment with DMH and/or apple juices there were no changes in transcript levels of colonic cyclooxygenase isoforms (COX-1, COX-2) or glutathione-associated enzymes (GST-M2, gamma-GCS, GST-P), the splenocyte natural killer cell activity and plasma antioxidant status. However, CloA but not CleA prevented the DMH-induced reduction of splenocyte CD4/CD8 (T-helper cells to cytotoxic lymphocytes) ratio. Since both formulations contained comparable concentrations and types of monomeric polyphenols, complex polyphenols or non-polyphenolic compounds, such as pectin might be responsible for the stronger cancer

  14. CO2 induced seawater acidification impacts sea urchin larval development I: elevated metabolic rates decrease scope for growth and induce developmental delay.

    PubMed

    Stumpp, M; Wren, J; Melzner, F; Thorndyke, M C; Dupont, S T

    2011-11-01

    Anthropogenic CO(2) emissions are acidifying the world's oceans. A growing body of evidence is showing that ocean acidification impacts growth and developmental rates of marine invertebrates. Here we test the impact of elevated seawater pCO(2) (129 Pa, 1271 μatm) on early development, larval metabolic and feeding rates in a marine model organism, the sea urchin Strongylocentrotus purpuratus. Growth and development was assessed by measuring total body length, body rod length, postoral rod length and posterolateral rod length. Comparing these parameters between treatments suggests that larvae suffer from a developmental delay (by ca. 8%) rather than from the previously postulated reductions in size at comparable developmental stages. Further, we found maximum increases in respiration rates of +100% under elevated pCO(2), while body length corrected feeding rates did not differ between larvae from both treatments. Calculating scope for growth illustrates that larvae raised under high pCO(2) spent an average of 39 to 45% of the available energy for somatic growth, while control larvae could allocate between 78 and 80% of the available energy into growth processes. Our results highlight the importance of defining a standard frame of reference when comparing a given parameter between treatments, as observed differences can be easily due to comparison of different larval ages with their specific set of biological characters.

  15. Solar-wind velocity decreases

    NASA Astrophysics Data System (ADS)

    Geranios, A.

    1980-08-01

    A model is developed to account for the solar wind electron and proton temperature decreases observed following the passage of an interplanetary shock wave and during the velocity decrease of a solar wind stream. The equations of mass and energy conservation are solved for a fully ionized, electrically neutral plasma expanding radially and spherically symmetrically, taking into account the heat flux from the solor corona to the plasma along the open magnetic field lines, and the electron thermal conductivity. An analytical relationship between the temperature and the velocity of the solar wind plasma is obtained which is found to be in agreement with experimental measurements made by the Vela 5 and 6 and IMP 6 satellites from August 1969-May 1974. It is thus proposed that the observed low plasma temperatures are due to the fact that the temperature decrease of the expanding plasma exceeds the heat gain due to thermal conduction from the corona.

  16. Development and characterization of K562 cell clones expressing BCL11A-XL: Decreased hemoglobin production with fetal hemoglobin inducers and its rescue with mithramycin

    PubMed Central

    Finotti, Alessia; Gasparello, Jessica; Breveglieri, Giulia; Cosenza, Lucia Carmela; Montagner, Giulia; Bresciani, Alberto; Altamura, Sergio; Bianchi, Nicoletta; Martini, Elisa; Gallerani, Eleonora; Borgatti, Monica; Gambari, Roberto

    2015-01-01

    Induction of fetal hemoglobin (HbF) is considered a promising strategy in the treatment of β-thalassemia, in which production of adult hemoglobin (HbA) is impaired by mutations affecting the β-globin gene. Recent results indicate that B-cell lymphoma/leukemia 11A (BCL11A) is a major repressor of γ-globin gene expression. Therefore, disrupting the binding of the BCL11A transcriptional repressor complex to the γ-globin gene promoter provides a novel approach for inducing expression of the γ-globin genes. To develop a cellular screening system for the identification of BCL11A inhibitors, we produced K562 cell clones with integrated copies of a BCL11A-XL expressing vector. We characterized 12 K562 clones expressing different levels of BCL11A-XL and found that a clear inverse relationship does exist between the levels of BCL11A-XL and the extent of hemoglobinization induced by a panel of HbF inducers. Using mithramycin as an inducer, we found that this molecule was the only HbF inducer efficient in rescuing the ability to differentiate along the erythroid program, even in K562 cell clones expressing high levels of BCL11A-XL, suggesting that BCL11A-XL activity is counteracted by mithramycin. PMID:26342260

  17. Profound bradycardia with decreased PEEP.

    PubMed

    Wilcox, Susan R; Kansagra, Ankit; Richards, Jeremy B

    2013-11-01

    An athletic 21-year-old male was admitted to the surgical ICU after sustaining 2 stab wounds to his torso. He had an episode of left lung collapse early in his course, managed with suctioning and increased PEEP, to 15 cm H2O. He was bradycardic (heart rates 50-60 beats/min) throughout his ICU stay, but when the PEEP was lowered to 5 cm H2O in preparation for extubation, he developed sinus pauses and his heart rate dropped to 20 beats/min. After a thorough evaluation, the drop in his heart rate was determined to be due to increased vagal tone from increased cardiac output with the decreased PEEP. After premedication with glycopyrrolate, he was successfully extubated the following day, while his heart rate remained at his baseline of 50 beats/min. We review the physiologic mechanisms of bradycardia due to the removal of mechanical ventilation.

  18. Preoperative levosimendan decreases mortality and the development of low cardiac output in high-risk patients with severe left ventricular dysfunction undergoing coronary artery bypass grafting with cardiopulmonary bypass

    PubMed Central

    Levin, Ricardo; Degrange, Marcela; Del Mazo, Carlos; Tanus, Eduardo; Porcile, Rafael

    2012-01-01

    BACKGROUND: The calcium sensitizer levosimendan has been used in cardiac surgery for the treatment of postoperative low cardiac output syndrome (LCOS) and difficult weaning from cardiopulmonary bypass (CPB). OBJECTIVES: To evaluate the effects of preoperative treatment with levosimendan on 30-day mortality, the risk of developing LCOS and the requirement for inotropes, vasopressors and intra-aortic balloon pumps in patients with severe left ventricular dysfunction. METHODS: Patient with severe left ventricular dysfunction and an ejection fraction <25% undergoing coronary artery bypass grafting with CPB were admitted 24 h before surgery and were randomly assigned to receive levosimendan (loading dose 10 μg/kg followed by a 23 h continuous infusion of 0.1μg/kg/min) or a placebo. RESULTS: From December 1, 2002 to June 1, 2008, a total of 252 patients were enrolled (127 in the levosimendan group and 125 in the control group). Individuals treated with levosimendan exhibited a lower incidence of complicated weaning from CPB (2.4% versus 9.6%; P<0.05), decreased mortality (3.9% versus 12.8%; P<0.05) and a lower incidence of LCOS (7.1% versus 20.8%; P<0.05) compared with the control group. The levosimendan group also had a lower requirement for inotropes (7.9% versus 58.4%; P<0.05), vasopressors (14.2% versus 45.6%; P<0.05) and intra-aortic balloon pumps (6.3% versus 30.4%; P<0.05). CONCLUSION: Patients with severe left ventricle dysfunction (ejection fraction <25%) undergoing coronary artery bypass grafting with CPB who were pretreated with levosimendan exhibited lower mortality, a decreased risk for developing LCOS and a reduced requirement for inotropes, vasopressors and intra-aortic balloon pumps. Studies with a larger number of patients are required to confirm whether these findings represent a new strategy to reduce the operative risk in this high-risk patient population. PMID:23620700

  19. Proline substitutions and threonine pseudophosphorylation of the SH3 ligand of 18.5-kDa myelin basic protein decrease its affinity for the Fyn-SH3 domain and alter process development and protein localization in oligodendrocytes.

    PubMed

    Smith, Graham S T; De Avila, Miguel; Paez, Pablo M; Spreuer, Vilma; Wills, Melanie K B; Jones, Nina; Boggs, Joan M; Harauz, George

    2012-01-01

    The developmentally regulated myelin basic proteins (MBPs), which arise from the golli (gene of oligodendrocyte lineage) complex, are highly positively charged, intrinsically disordered, multifunctional proteins having several alternatively spliced isoforms and posttranslational modifications, and they play key roles in myelin compaction. The classic 18.5-kDa MBP isoform has a proline-rich region comprising amino acids 92-99 (murine sequence -T(92)PRTPPPS(99)-) that contains a minimal SH3 ligand domain. We have previously shown that 18.5-kDa MBP binds to several SH3 domains, including that of Fyn, a member of the Src family of tyrosine kinases involved in a number of signaling pathways during CNS development. To determine the physiological role of this binding as well as the role of phosphorylation of Thr92 and Thr95, in the current study we have produced several MBP variants specifically targeting phosphorylation sites and key structural regions of MBP's SH3 ligand domain. Using isothermal titration calorimetry, we have demonstrated that, compared with the wild-type protein, these variants have lower affinity for the SH3 domain of Fyn. Moreover, overexpression of N-terminal-tagged GFP versions in immortalized oligodendroglial N19 and N20.1 cell cultures results in aberrant elongation of membrane processes and increased branching complexity and inhibits the ability of MBP to decrease Ca(2+) influx. Phosphorylation of Thr92 can also cause MBP to traffic to the nucleus, where it may participate in additional protein-protein interactions. Coexpression of MBP with a constitutively active form of Fyn kinase resulted in membrane process elaboration, a phenomenon that was abolished by point amino acid substitutions in MBP's SH3 ligand domain. These results suggest that MBP's SH3 ligand domain plays a key role in intracellular protein interactions in vivo and may be required for proper membrane elaboration of developing oligodendrocytes and, further, that phosphorylation

  20. Decreased bacteria density on nanostructured polyurethane.

    PubMed

    Yao, Chang; Webster, Thomas J; Hedrick, Matthew

    2014-06-01

    As is well known, medical device infections are a growing clinical problem with no clear solution due to previous failed attempts of using antibiotics to decrease bacteria functions for which bacteria quickly develop a resistance toward. Because of their altered surface energetics, the objective of the present in vitro study was to create nanoscale surface features on polyurethane (PU) by soaking PU films in HNO3 and to determine bacteria (specifically, S. epidermidis, E. coli, and P. mirabilis) colony forming units after 1 h. Such bacteria frequently infect numerous medical devices. Results provided the first evidence that without using antibiotics, S. epidermidis density decreased by 5 and 13 times, E. coli density decreased by 6 and 20 times, and P. mirabilis density decreased by 8 and 35 times compared to conventional PU and a tissue engineering control small intestine submucosa (SIS), respectively. Material characterization studies revealed significantly greater nanoscale roughness and hydrophobicity for the HNO3-treated nanostructured PU compared to conventional PU (albeit, still hydrophilic) which may provide a rationale for the observed decreased bacteria responses. In addition, significantly greater amounts of fibronectin adsorption from serum were measured on nanorough compared conventional PU which may explain the decreased bacteria growth. In summary, this study provides significant promise for the use of nanostructured PU to decrease bacteria functions without the use of antibiotics, clearly addressing the wide spread problem of increased medical device infections observed today.

  1. Calbindins decreased after space flight

    NASA Technical Reports Server (NTRS)

    Sergeev, I. N.; Rhoten, W. B.; Carney, M. D.

    1996-01-01

    Exposure of the body to microgravity during space flight causes a series of well-documented changes in Ca2+ metabolism, yet the cellular and molecular mechanisms leading to these changes are poorly understood. Calbindins, vitamin D-dependent Ca2+ binding proteins, are believed to have a significant role in maintaining cellular Ca2+ homeostasis. In this study, we used biochemical and immunocytochemical approaches to analyze the expression of calbindin-D28k and calbindin-D9k in kidneys, small intestine, and pancreas of rats flown for 9 d aboard the space shuttle. The effects of microgravity on calbindins in rats from space were compared with synchronous Animal Enclosure Module controls, modeled weightlessness animals (tail suspension), and their controls. Exposure to microgravity resulted in a significant and sustained decrease in calbindin-D28k content in the kidney and calbindin-D9k in the small intestine of flight animals, as measured by enzyme-linked immunosorbent assay (ELISA). Modeled weightlessness animals exhibited a similar decrease in calbindins by ELISA. Immunocytochemistry (ICC) in combination with quantitative computer image analysis was used to measure in situ the expression of calbindins in the kidney and the small intestine, and the expression of insulin in pancreas. There was a large decrease of immunoreactivity in renal distal tubular cell-associated calbindin-D28k and in intestinal absorptive cell-associated calbindin-D9k of space flight and modeled weightlessness animals compared with matched controls. No consistent difference in pancreatic insulin immunoreactivity between space flight, modeled weightlessness, and controls was observed. Regression analysis of results obtained by quantitative ICC and ELISA for space flight, modeled weightlessness animals, and their controls demonstrated a significant correlation. These findings after a short-term exposure to microgravity or modeled weightlessness suggest that a decreased expression of calbindins

  2. The transcriptional regulator PLZF induces the development of CD44 high memory phenotype T cells.

    PubMed

    Raberger, Julia; Schebesta, Alexandra; Sakaguchi, Shinya; Boucheron, Nicole; Blomberg, K Emelie M; Berglöf, Anna; Kolbe, Thomas; Smith, C I Edvard; Rülicke, Thomas; Ellmeier, Wilfried

    2008-11-18

    Transcriptional pathways controlling the development of CD44(hi) memory phenotype (MP) T cells with "innate-like" functions are not well understood. Here we show that the BTB (bric-a-brac, tramtrack, broad complex) domain-containing protein promyelocytic leukemia zinc finger (PLZF) is expressed in CD44(hi), but not in CD44(lo), CD4(+) T cells. Transgenic expression of PLZF during T cell development and in CD4(+) and CD8(+) T cells induced a T cell intrinsic program leading to an increase in peripheral CD44(hi) MP CD4(+) and CD8(+) T cells and a corresponding decrease of naïve CD44(lo) T cells. The MP CD4(+) and CD8(+) T cells produced IFNgamma upon PMA/ionomycin stimulation, thus showing innate-like function. Changes in the naïve versus memory-like subset distribution were already evident in single-positive thymocytes, indicating PLZF-induced T cell developmental alterations. In addition, CD1d-restricted natural killer T cells in PLZF transgenic mice showed impaired development and were severely reduced in the periphery. Finally, after anti-CD3/CD28 stimulation, CD4(+) transgenic T cells showed reduced IL-2 and IFNgamma production but increased IL-4 secretion as a result of enhanced IL-4 production of the CD44(hi)CD62L(+) subset. Our data indicate that PLZF is a novel regulator of the development of CD44(hi) MP T cells with a characteristic partial innate-like phenotype.

  3. Decreasing Fires in Mediterranean Europe.

    PubMed

    Turco, Marco; Bedia, Joaquín; Di Liberto, Fabrizio; Fiorucci, Paolo; von Hardenberg, Jost; Koutsias, Nikos; Llasat, Maria-Carmen; Xystrakis, Fotios; Provenzale, Antonello

    2016-01-01

    Forest fires are a serious environmental hazard in southern Europe. Quantitative assessment of recent trends in fire statistics is important for assessing the possible shifts induced by climate and other environmental/socioeconomic changes in this area. Here we analyse recent fire trends in Portugal, Spain, southern France, Italy and Greece, building on a homogenized fire database integrating official fire statistics provided by several national/EU agencies. During the period 1985-2011, the total annual burned area (BA) displayed a general decreasing trend, with the exception of Portugal, where a heterogeneous signal was found. Considering all countries globally, we found that BA decreased by about 3020 km2 over the 27-year-long study period (i.e. about -66% of the mean historical value). These results are consistent with those obtained on longer time scales when data were available, also yielding predominantly negative trends in Spain and France (1974-2011) and a mixed trend in Portugal (1980-2011). Similar overall results were found for the annual number of fires (NF), which globally decreased by about 12600 in the study period (about -59%), except for Spain where, excluding the provinces along the Mediterranean coast, an upward trend was found for the longer period. We argue that the negative trends can be explained, at least in part, by an increased effort in fire management and prevention after the big fires of the 1980's, while positive trends may be related to recent socioeconomic transformations leading to more hazardous landscape configurations, as well as to the observed warming of recent decades. We stress the importance of fire data homogenization prior to analysis, in order to alleviate spurious effects associated with non-stationarities in the data due to temporal variations in fire detection efforts.

  4. Decreasing Fires in Mediterranean Europe

    PubMed Central

    Turco, Marco; Bedia, Joaquín; Di Liberto, Fabrizio; Fiorucci, Paolo; von Hardenberg, Jost; Koutsias, Nikos; Llasat, Maria-Carmen; Xystrakis, Fotios; Provenzale, Antonello

    2016-01-01

    Forest fires are a serious environmental hazard in southern Europe. Quantitative assessment of recent trends in fire statistics is important for assessing the possible shifts induced by climate and other environmental/socioeconomic changes in this area. Here we analyse recent fire trends in Portugal, Spain, southern France, Italy and Greece, building on a homogenized fire database integrating official fire statistics provided by several national/EU agencies. During the period 1985-2011, the total annual burned area (BA) displayed a general decreasing trend, with the exception of Portugal, where a heterogeneous signal was found. Considering all countries globally, we found that BA decreased by about 3020 km2 over the 27-year-long study period (i.e. about -66% of the mean historical value). These results are consistent with those obtained on longer time scales when data were available, also yielding predominantly negative trends in Spain and France (1974-2011) and a mixed trend in Portugal (1980-2011). Similar overall results were found for the annual number of fires (NF), which globally decreased by about 12600 in the study period (about -59%), except for Spain where, excluding the provinces along the Mediterranean coast, an upward trend was found for the longer period. We argue that the negative trends can be explained, at least in part, by an increased effort in fire management and prevention after the big fires of the 1980’s, while positive trends may be related to recent socioeconomic transformations leading to more hazardous landscape configurations, as well as to the observed warming of recent decades. We stress the importance of fire data homogenization prior to analysis, in order to alleviate spurious effects associated with non-stationarities in the data due to temporal variations in fire detection efforts. PMID:26982584

  5. Thermoelectric device exhibiting decreased stress

    SciTech Connect

    Heath, D.L.; Chou, D.J.

    1985-02-05

    A thermoelectric device exhibiting both structural integrity and decreased stress across the device notwithstanding the application of thermally cycled temperature differentials thereacross includes, electrically interconnected thermoelectric elements and a rigidly affixed substrate. Thermal stress is relieved by using flexible conductors to interconnect the thermoelectric elements, and by the use of a flexile joint to attach a second substrate to the remainder of the device. Complete elimination of the second substrate may also be used to eliminate stress. Presence of the rigidly affixed substrate gives the device sufficient structural integrity to enable it to withstand rugged conditions.

  6. Technologies for Decreasing Mining Losses

    NASA Astrophysics Data System (ADS)

    Valgma, Ingo; Väizene, Vivika; Kolats, Margit; Saarnak, Martin

    2013-12-01

    In case of stratified deposits like oil shale deposit in Estonia, mining losses depend on mining technologies. Current research focuses on extraction and separation possibilities of mineral resources. Selective mining, selective crushing and separation tests have been performed, showing possibilities of decreasing mining losses. Rock crushing and screening process simulations were used for optimizing rock fractions. In addition mine backfilling, fine separation, and optimized drilling and blasting have been analyzed. All tested methods show potential and depend on mineral usage. Usage in addition depends on the utilization technology. The questions like stability of the material flow and influences of the quality fluctuations to the final yield are raised.

  7. Hyperhomocysteinemia decreases bone blood flow.

    PubMed

    Tyagi, Neetu; Vacek, Thomas P; Fleming, John T; Vacek, Jonathan C; Tyagi, Suresh C

    2011-01-25

    Elevated plasma levels of homocysteine (Hcy), known as hyperhomocysteinemia (HHcy), are associated with osteoporosis. A decrease in bone blood flow is a potential cause of compromised bone mechanical properties. Therefore, we hypothesized that HHcy decreases bone blood flow and biomechanical properties. To test this hypothesis, male Sprague-Dawley rats were treated with Hcy (0.67 g/L) in drinking water for 8 weeks. Age-matched rats served as controls. At the end of the treatment period, the rats were anesthetized. Blood samples were collected from experimental or control rats. Biochemical turnover markers (body weight, Hcy, vitamin B(12), and folate) were measured. Systolic blood pressure was measured from the right carotid artery. Tibia blood flow was measured by laser Doppler flow probe. The results indicated that Hcy levels were significantly higher in the Hcy-treated group than in control rats, whereas vitamin B(12) levels were lower in the Hcy-treated group compared with control rats. There was no significant difference in folate concentration and blood pressure in Hcy-treated versus control rats. The tibial blood flow index of the control group was significantly higher (0.78 ± 0.09 flow unit) compared with the Hcy-treated group (0.51 ± 0.09). The tibial mass was 1.1 ± 0.1 g in the control group and 0.9 ± 0.1 in the Hcy-treated group. The tibia bone density was unchanged in Hcy-treated rats. These results suggest that Hcy causes a reduction in bone blood flow, which contributes to compromised bone biomechanical properties.

  8. Methodology of decreasing software complexity using ontology

    NASA Astrophysics Data System (ADS)

    DÄ browska-Kubik, Katarzyna

    2015-09-01

    In this paper a model of web application`s source code, based on the OSD ontology (Ontology for Software Development), is proposed. This model is applied to implementation and maintenance phase of software development process through the DevOntoCreator tool [5]. The aim of this solution is decreasing software complexity of that source code, using many different maintenance techniques, like creation of documentation, elimination dead code, cloned code or bugs, which were known before [1][2]. Due to this approach saving on software maintenance costs of web applications will be possible.

  9. Are urban noise pollution levels decreasing?

    PubMed

    Arana, M

    2010-04-01

    The majority of acoustic impact studies developed over the last 50 years have used a similar acoustic parameter (L(eq), L(dn)) but the noise mapping methodology has been very uneven. The selection of the measurement points, the measurement periods, or the evaluation indices have not followed a unique criterion. Therefore, it is not possible to compare the sound pollution levels between different cities from those studies, at least in a rigorous sense. Even more, different studies carried out in the same city by different researchers during different years and using different methodologies are not conclusive whether the acoustic pollution increases or decreases. The present paper shows results, with statistical significance, about the evolution of the acoustic pollution obtained for two Spanish cities, Pamplona and Madrid. In both cases, it can be concluded that noise pollution decreases over time (P<0.01).

  10. Is the incidence of heart attack still decreasing in Australia? Developing reliable methods for monitoring trends in myocardial infarction and coronary heart disease (AUS-MOCHA): a study protocol

    PubMed Central

    Nedkoff, Lee; Knuiman, Matthew; Hobbs, Michael S T; Hung, Joseph; Mathur, Sushma; Beilby, John; Reynolds, Anna; Briffa, Tom G; Lopez, Derrick

    2016-01-01

    Introduction Accurate monitoring of acute coronary heart disease (CHD) is essential for understanding the effects of primary and secondary prevention and for planning of healthcare services. The ability to reliably monitor acute CHD has been affected by new diagnostic tests for myocardial infarction (MI) and changing clinical classifications and management of CHD. Our study will develop new and reliable methods for monitoring population trends in incidence, outcomes and health service usage for acute CHD and chest pain. Methods and analysis The study cohort of all CHD will be identified from the Western Australian Data Linkage System using state-wide data sets for emergency department presentation, hospitalisations and mortality data for 2002–2014. This core linked data set will be supplemented with data from hospital medical record reviews, pathology data and hospital pharmacy dispensing databases. The consistency over time of the coding of the different subgroups of CHD/chest pain (ST-elevation MI, non-ST elevation MI, unstable angina, stable angina, other CHD, non-CHD chest pain) in linked data will be assessed using these data sources, and an algorithm developed detailing groups in which temporal trends can be reliably measured. This algorithm will be used for measurement of trends in incidence and outcomes of acute CHD, and to develop further methods for monitoring acute CHD using unlinked and linked data with varying availability of hospitalisation history. Ethics and dissemination Ethics approval has been obtained from the Human Research Ethics Committees of the WA Department of Health (#2016/23) and The University of Western Australia (RA/4/1/7230). Findings will be disseminated via publication in peer-reviewed journals, and presentation at national and international conferences. There will also be a strong platform for dissemination of new monitoring methods via collaboration with the Australian Institute of Health and Welfare which will assist with

  11. Bone Marrow Stress Decreases Osteogenic Progenitors.

    PubMed

    Ng, Adeline H; Baht, Gurpreet S; Alman, Benjamin A; Grynpas, Marc D

    2015-11-01

    Age-related bone loss may be a result of declining levels of stem cells in the bone marrow. Using the Col2.3Δtk (DTK) transgenic mouse, osteoblast depletion was used as a source of marrow stress in order to investigate the effects of aging on osteogenic progenitors which reside in the marrow space. Five-month-old DTK mice were treated with one or two cycles of ganciclovir to conditionally ablate differentiated osteoblasts, whereas controls were saline-treated. Treatment cycles were two weeks in length followed by four weeks of recovery. All animals were sacrificed at 8 months of age; bone marrow stromal cells (BMSCs) were harvested for cell culture and whole bones were excised for bone quality assessment. Colony-forming unit (CFU) assays were conducted to investigate the osteogenic potential of BMSC in vitro, and RNA was extracted to assess the expression of osteoblastic genes. Bone quality assessments included bone histomorphometry, TRAP staining, microcomputed tomography, and biomechanical testing. Osteoblast depletion decreased CFU-F (fibroblast), CFU-ALP (alkaline phosphatase), and CFU-VK (von Kossa) counts and BMSC osteogenic capacity in cell culture. Ex vivo, there were no differences in bone mineral density of vertebrae or femurs between treatment groups. Histology showed a decrease in bone volume and bone connectivity with repeated osteoblast depletion; however, this was accompanied by an increase in bone formation rate. There were no notable differences in osteoclast parameters or observed bone marrow adiposity. We have developed a model that uses bone marrow stress to mimic age-related decrease in osteogenic progenitors. Our data suggest that the number of healthy BMSCs and their osteogenic potential decline with repeated osteoblast depletion. However, activity of the remaining osteoblasts increases to compensate for this loss in progenitor osteogenic potential.

  12. High-fat diet decreases energy expenditure and expression of genes controlling lipid metabolism, mitochondrial function and skeletal system development in the adipose tissue, along with increased expression of extracellular matrix remodelling- and inflammation-related genes.

    PubMed

    Choi, Myung-Sook; Kim, Young-Je; Kwon, Eun-Young; Ryoo, Jae Young; Kim, Sang Ryong; Jung, Un Ju

    2015-03-28

    The aim of the present study was to identify the genes differentially expressed in the visceral adipose tissue in a well-characterised mouse model of high-fat diet (HFD)-induced obesity. Male C57BL/6J mice (n 20) were fed either HFD (189 % of energy from fat) or low-fat diet (LFD, 42 % of energy from fat) for 16 weeks. HFD-fed mice exhibited obesity, insulin resistance, dyslipidaemia and adipose collagen accumulation, along with higher levels of plasma leptin, resistin and plasminogen activator inhibitor type 1, although there were no significant differences in plasma cytokine levels. Energy intake was similar in the two diet groups owing to lower food intake in the HFD group; however, energy expenditure was also lower in the HFD group than in the LFD group. Microarray analysis revealed that genes related to lipolysis, fatty acid metabolism, mitochondrial energy transduction, oxidation-reduction, insulin sensitivity and skeletal system development were down-regulated in HFD-fed mice, and genes associated with extracellular matrix (ECM) components, ECM remodelling and inflammation were up-regulated. The top ten up- or down-regulated genes include Acsm3, mt-Nd6, Fam13a, Cyp2e1, Rgs1 and Gpnmb, whose roles in the deterioration of obesity-associated adipose tissue are poorly understood. In conclusion, the genes identified here provide new therapeutic opportunities for prevention and treatment of diet-induced obesity.

  13. Can Diuretics Decrease Your Potassium Level?

    MedlinePlus

    ... High blood pressure (hypertension) Can diuretics decrease your potassium level? Answers from Sheldon G. Sheps, M.D. Yes, some diuretics — also called water pills — decrease potassium in the blood. Diuretics are commonly used to ...

  14. HHLA2 and TMIGD2: new immunotherapeutic targets of the B7 and CD28 families

    PubMed Central

    Janakiram, Murali; Chinai, Jordan M; Zhao, Aimin; Sparano, Joseph A; Zang, Xingxing

    2015-01-01

    We and others recently discovered HHLA2 as a new B7 family member and transmembrane and immunoglobulin domain containing 2 (TMIGD2) as one of its receptors. Based on a new study we propose that HHLA2 may represent a novel immunosuppressive mechanism within the tumor microenvironment and hence could be a target for cancer therapy. TMIGD2 may be another therapeutic target. PMID:26405587

  15. Development of thermosets for thermal nanoimprint lithography at decreased temperatures

    NASA Astrophysics Data System (ADS)

    Reuther, Freimut; Kubenz, Mike; Schuster, Christine; Fink, Marion; Vogler, Marko; Gruetzner, Gabi; Grimm, Juergen; Kaeppel, Andi

    2005-05-01

    Prepolymers formed from multifunctional allyl monomers can beneficially used in nanoimprint lithography (NIL), since they cure as a consequence of heating during the imprint process. Thus they have the potential to enable NIL at comparatively low temperatures while the imprinted patterns concurrently show high thermal stability, in contrast to thermoplastic polymers, where the thermal behaviour of the imprinted patterns is closely related to the glass transition temperature (Tg) of the polymers. The use of allyl prepolymers for NIL was previously described, but only very few experimental data are known. In recent investigations on the application of allyl prepolymers for NIL a displacement of the patterns on the wafer has been observed after cooling down the imprinted polymer in the press. This could be avoided by detaching the stamp at the imprint temperature, i.e. without cooling down the press, which requires the polymer to be crosslinked to a great extent in this stage. Since high temperatures are necessary (150 °C - 190 °C), and the imprint time is still long, allyl prepolymers to be reported here have been modified aiming at a reduction of imprint temperature and time. The admixture of free-radical initiators increases the polymerization rate and allows the polymerization to start at lower temperatures. A reduced imprint temperature (100 °C) and shorter imprint time (10 min) are achieved. Additional polymer modification by plasticizers improves the material flow during the imprint due to a lower Tg. Recipes for polymer modifications have been found out, which result in thermally stable imprints under the specified processing conditions.

  16. Amylose content decreases during tuber development in potato

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Potato starch is composed of amylopectin and amylose in an approximately three to one ratio. Amylose is considered to be nutritionally desirable, so there is interest in finding strategies to increase the amylose content of potatoes. There is also interest in marketing “baby” potatoes, which are har...

  17. Lifestyle decreases risk factors for cardiovascular diseases.

    PubMed

    Slavícek, Jaroslav; Kittnar, Otomar; Fraser, Gary E; Medová, Eva; Konecná, Jana; Zizka, Robert; Dohnalová, Alena; Novák, Vladimir

    2008-12-01

    The morbidity and mortality of cardiovascular diseases is high in the developed countries. The lifestyle changes are capable to decrease it by 50%. The aim of the present study was to measure the parameters of some risk factors before and after a one-week NEW START rehabilitative retreat. 1349 volunteers, 320 men, 1029 woman, mean age 51 +/- 14.5 (SD) years participated in 30 rehabilitative retreats from 1999-2006 in the Czech Republic, using a low-fat, low-energy, lacto-ovo-vegetarian diet and exercise, in a stress-free environment. Body weight, height, BMI, blood pressure, heart rate, serum cholesterol and blood glucose were measured. Body weight decreased in 1223 measured persons from 71.2 +/- 14.38 (SD) to 70.6 +/- 14.02 kg (p<0.0001), BMI (1,046 measured persons) from 25.1 +/- 4.60 (SD) to 24.8+4.49 (SD) kg/m2 (p<0.0001), systolic blood pressure (1,218 persons) from 129.8 +/- 23.02 (SD) to 123.8 +/- 21.52 (SD) mmHg (p<0.0001), diastolic blood pressure (1210 persons) from 79.8 +/- 12.7 (SD) to 77.5 +/- 11.6 (SD) mmHg (p<0.0001), serum cholesterol (998 persons) from 4.86 +/- 0.95 (SD) to 4.32 +/- 0.77 (SD) mmol (p<0.0001), blood glucose (544 persons) from 4.31 +/- 1.59 (SD) to 3.88 +/- 1.33 (SD) mmol (p<0.0001). Heart rate was not significantly decreased. The parameters were lower in lacto-ovo vegetarians and Seventh-day Adventists than in controls who never observed the diet and avail the lifestyle programs. The parameters were nonsignificantly changed one year after finishing the retreat in the sample of 68 persons showing the positive effect of retreats. Our results showed, that the intake of a low-fat, low-energy diet, over the course of one week in a stress-free environment, had positive impact on the risk factors of cardiovascular diseases.

  18. Differential effects of anti-B7-1 and anti-B7-2 monoclonal antibody treatment on the development of diabetes in the nonobese diabetic mouse

    PubMed Central

    1995-01-01

    Insulin-dependent diabetes mellitus (IDDM) is thought to be an immunologically mediated disease resulting in the complete destruction of the insulin-producing islets of Langerhans. It has become increasingly clear that autoreactive T cells play a major role in the development and progression of this disease. In this study, we examined the role of the CD28/B7 costimulation pathway in the development and progression of autoimmune diabetes in the nonobese diabetic (NOD) mouse model. Female NOD mice treated at the onset of insulitis (2-4 wk of age) with CTLA4Ig immunoglobulin (Ig) (a soluble CD28 antagonist) or a monoclonal antibody (mAb) specific for B7-2 (a CD28 ligand) did not develop diabetes. However, neither of these treatments altered the disease process when administered late, at > 10 wk of age. Histological examination of islets from the various treatment groups showed that while CTLA4Ig and anti-B7-2 mAb treatment blocked the development of diabetes, these reagents had little effect on the development or severity of insulitis. Together these results suggest that blockade of costimulatory signals by CTLA4Ig or anti-B7-2 acts early in disease development, after insulitis but before the onset of frank diabetes. NOD mice were also treated with mAbs to another CD28 ligand, B7-1. In contrast to the previous results, the anti-B7-1 treatment significantly accelerated the development of disease in female mice and, most interestingly, induced diabetes in normally resistant male mice. A combination of anti-B7-1 and anti-B7-2 mAbs also resulted in an accelerated onset of diabetes, similar to that observed with anti-B7-1 mAb treatment alone, suggesting that anti-B7-1 mAb's effect was dominant. Furthermore, treatment with anti-B7-1 mAbs resulted in a more rapid and severe infiltrate. Finally, T cells isolated from the pancreas of these anti-B7-1-treated animals exhibited a more activated phenotype than T cells isolated from any of the other treatment groups. These studies

  19. Red blood cell decreases of microgravity

    NASA Technical Reports Server (NTRS)

    Johnson, P. C.

    1985-01-01

    Postflight decreases in red blood cell mass (RBCM) have regularly been recorded after exposure to microgravity. These 5-25 percent decreases do not relate to the mission duration, workload, caloric intake or to the type of spacecraft used. The decrease is accompanied by normal red cell survivals, increased ferritin levels, normal radioactive iron studies, and increases in mean red blood cell volume. Comparable decreases in red blood cell mass are not found after bed rest, a commonly used simulation of the microgravity state. Inhibited bone marrow erythropoiesis has not been proven to date, although reticulocyte numbers in the peripheral circulation are decreased about 50 percent. To date, the cause of the microgravity induced decreases in RBCM is unknown. Increased splenic trapping of circulating red blood cells seem the most logical way to explain the results obtained.

  20. Daidzin decreases ethanol consumption in rats.

    PubMed

    Heyman, G M; Keung, W M; Vallee, B L

    1996-09-01

    In a previous study, daidzin, a constituent of an ancient Chinese herbal treatment for alcoholism, decreased home-cage ethanol consumption in laboratory Syrian golden hamsters. The present study tested the generality of daidzin's antidipsotropic effects. Rats served as subjects in a two-lever choice procedure. At one lever, responses earned 10% ethanol, flavored with saccharin. At the other lever, responses earned an isocaloric starch solution. Daidzin decreased both ethanol and starch consumption, but the decreases in ethanol intake were larger. Changes in consumption were dose dependent, and differences in ethanol and food consumption increased slightly (but significantly) as dose increased. Daidzin produced a similar pattern of decreases in lever pressing. In baseline, there was an approximately equal distribution of responses between the two levers; at the highest daidzin dose, the relative number of responses at the ethanol lever decreased to 30%. These results replicate and extend earlier findings, and they encourage further research on daidzin's capacity to decrease ethanol consumption.

  1. Development of a nascent galectin-1 chimeric molecule for studying the role of leukocyte galectin-1 ligands and immune disease modulation.

    PubMed

    Cedeno-Laurent, Filiberto; Barthel, Steven R; Opperman, Matthew J; Lee, David M; Clark, Rachael A; Dimitroff, Charles J

    2010-10-15

    Galectin-1 (Gal-1), a β-galactoside-binding lectin, plays a profound role in modulating adaptive immune responses by altering the phenotype and fate of T cells. Experimental data showing recombinant Gal-1 (rGal-1) efficacy on T cell viability and cytokine production, nevertheless, is controversial due to the necessity of using stabilizing chemicals to help retain Gal-1 structure and function. To address this drawback, we developed a mouse Gal-1 human Ig chimera (Gal-1hFc) that did not need chemical stabilization for Gal-1 ligand recognition, apoptosis induction, and cytokine modulation in a variety of leukocyte models. At high concentrations, Gal-1hFc induced apoptosis in Gal-1 ligand(+) Th1 and Th17 cells, leukemic cells, and granulocytes from synovial fluids of patients with rheumatoid arthritis. Importantly, at low, more physiologic concentrations, Gal-1hFc retained its homodimeric form without losing functionality. Not only did Gal-1hFc-binding trigger IL-10 and Th2 cytokine expression in activated T cells, but members of the CD28 family and several other immunomodulatory molecules were upregulated. In a mouse model of contact hypersensitivity, we found that a non-Fc receptor-binding isoform of Gal-1hFc, Gal-1hFc2, alleviated T cell-dependent inflammation by increasing IL-4(+), IL-10(+), TGF-β(+), and CD25(high)/FoxP3(+) T cells, and by decreasing IFN-γ(+) and IL-17(+) T cells. Moreover, in human skin-resident T cell cultures, Gal-1hFc diminished IL-17(+) T cells and increased IL-4(+) and IL-10(+) T cells. Gal-1hFc will not only be a useful new tool for investigating the role of Gal-1 ligands in leukocyte death and cytokine stimulation, but for studying how Gal-1-Gal-1 ligand binding shapes the intensity of immune responses.

  2. CD5 costimulation induces stable Th17 development by promoting IL-23R expression and sustained STAT3 activation.

    PubMed

    de Wit, Jelle; Souwer, Yuri; van Beelen, Astrid J; de Groot, Rosa; Muller, Femke J M; Klaasse Bos, Hanny; Jorritsma, Tineke; Kapsenberg, Martien L; de Jong, Esther C; van Ham, S Marieke

    2011-12-01

    IL-17-producing CD4(+) T helper (Th17) cells are important for immunity against extracellular pathogens and in autoimmune diseases. The factors that drive Th17 development in human remain a matter of debate. Here we show that, compared with classic CD28 costimulation, alternative costimulation via the CD5 or CD6 lymphocyte receptors forms a superior pathway for human Th17-priming. In the presence of the Th17-promoting cytokines IL-1β, IL-6, IL-23, and transforming growth factor-β (TGF-β), CD5 costimulation induces more Th17 cells that produce higher amounts of IL-17, which is preceded by prolonged activation of signal transducer and activator of transcription 3 (STAT3), a key regulator in Th17 differentiation, and enhanced levels of the IL-17-associated transcription factor retinoid-related orphan receptor-γt (ROR-γt). Strikingly, these Th17-promoting signals critically depend on CD5-induced elevation of IL-23 receptor (IL-23R) expression. The present data favor the novel concept that alternative costimulation via CD5, rather than classic costimulation via CD28, primes naive T cells for stable Th17 development through promoting the expression of IL-23R.

  3. Decreasing child mortality, spatial clustering and decreasing disparity in North-Western Burkina Faso.

    PubMed

    Becher, Heiko; Müller, Olaf; Dambach, Peter; Gabrysch, Sabine; Niamba, Louis; Sankoh, Osman; Simboro, Seraphin; Schoeps, Anja; Stieglbauer, Gabriele; Yé, Yazoume; Sié, Ali

    2016-04-01

    Within relatively small areas, there exist high spatial variations of mortality between villages. In rural Burkina Faso, with data from 1993 to 1998, clusters of particularly high child mortality were identified in the population of the Nouna Health and Demographic Surveillance System (HDSS), a member of the INDEPTH Network. In this paper, we report child mortality with respect to temporal trends, spatial clustering and disparity in this HDSS from 1993 to 2012. Poisson regression was used to describe village-specific child mortality rates and time trends in mortality. The spatial scan statistic was used to identify villages or village clusters with higher child mortality. Clustering of mortality in the area is still present, but not as strong as before. The disparity of child mortality between villages has decreased. The decrease occurred in the context of an overall halving of child mortality in the rural area of Nouna HDSS between 1993 and 2012. Extrapolated to the Millennium Development Goals target period 1990-2015, this yields an estimated reduction of 54%, which is not too far off the aim of a two-thirds reduction.

  4. Decrease in T Cell Activation and Calcium Flux during Clinorotation

    NASA Technical Reports Server (NTRS)

    Sams, Clarence; Holtzclaw, J. David

    2006-01-01

    We investigated the effect of altered gravitational environments on T cell activation. We isolated human, naive T cells (CD3+CD14-CD19-CD16-CD56-CD25-CD69-CD45RA-) following IRB approved protocols. These purified T cells were then incubated with 6 mm polystyrene beads coated with OKT3 (Ortho Biotech, Raritan, NJ) and antiCD28 (Becton Dickinson (BD), San Jose, CA) at 37 C for 24 hours. Antibodies were at a 1:1 ratio and the bead-to-cell ratio was 2:1. Four incubation conditions existed: 1) static or "1g"; 2) centrifugation at 10 relative centrifugal force (RCF) or "10g"; 3) clinorotation at 25 RPM (functional weightlessness or "0g"); and 4) clinorotation at 80 RPM ("1g" plus net shear force approx.30 dynes/sq cm). Following incubation, T cells were stained for CD25 expression (BD) and intracellular calcium (ratio of Fluo4 to Fura Red, Molecular Probes, Eugene, OR) and analyzed by flow cytometry (Coulter EPICS XL, Miami, FL). Results: Static or "1g" T cells had the highest level of CD25 expression and intracellular calcium. T cells centrifuged at 10 RCF ("10g") had lower CD25 expression and calcium levels compared to the static control. However, cells centrifuged at 10 RCF had higher CD25 expression and calcium levels than those exposed to 24 RPM clinorotation ("0g"). T cells exposed to 24 RPM clinorotation had lower CD25 expression, but the approximately the same calcium levels than T cells exposed to 80 RPM clinorotation. These data suggest that stress-activated calcium channel exist in T cells and may play a role during T cell activation.

  5. Distraction decreases prefrontal oxygenation: A NIRS study.

    PubMed

    Ozawa, Sachiyo; Hiraki, Kazuo

    2017-04-01

    When near-infrared spectroscopy (NIRS) is used to measure emotion-related cerebral blood flow (CBF) changes in the prefrontal cortex regions, the functional distinction of CBF changes is often difficult because NIRS is unable to measure neural activity in deeper brain regions that play major roles in emotional processing. The CBF changes could represent cognitive control of emotion and emotional responses to emotional materials. Supposing that emotion-related CBF changes in the prefrontal cortex regions during distraction are emotional responses, we examined whether oxygenated hemoglobin (oxyHb) decreases. Attention-demanding tasks cause blood flow decreases, and we thus compared the effects of visually paced tapping with different tempos, on distraction. The results showed that the oxyHb level induced by emotional stimulation decreased with fast-tempo tapping significantly more than slow-tempo tapping in ventral medial prefrontal cortex regions. Moreover, a Global-Local task following tapping showed significantly greater local-minus-global response time (RT) difference scores in the fast- and mid-tempo condition compared with those in the slow-tempo, suggesting an increased attentional focus, and decreased negative emotion. The overall findings indicate that oxyHb changes in a relatively long distraction task, as measured by NIRS, are associated with emotional responses, and oxyHb can be decreased by successfully performing attention-demanding distraction tasks.

  6. An electronic alert to decrease Kayexalate ordering

    PubMed Central

    Leaf, David E.; Cheng, Xingxing S.; Sanders, Jason L.; Mendu, Mallika; Schiff, Gordon D.; Mount, David B.; Bazari, Hasan

    2016-01-01

    Important safety concerns have recently emerged regarding the use of sodium polystyrene sulfonate (Kayexalate), a cation-exchange resin commonly used for the treatment of hyperkalemia. We implemented an electronic alert system at a tertiary care academic medical center to warn providers of the safety concerns of Kayexalate. We assessed the number of Kayexalate prescriptions per month, as well as the number of grams of Kayexalate ordered per month, one year before versus one year after implementing the alert. The mean (±SD) number of Kayexalate orders decreased from 123 (±12) to 76 (±14) orders/month (38% absolute reduction, p < 0.001) after implementing the alert. Additionally, the mean (±SD) amount of Kayexalate prescribed decreased from 3332 (±329) to 1885 (±358) g/month (43% absolute reduction, p < 0.001). We conclude that an electronic alert is an effective tool to decrease Kayexalate ordering. PMID:27183825

  7. Decreased group velocity in compositionally graded films.

    PubMed

    Gao, Lei

    2006-03-01

    A theoretical formalism is presented that describes the group velocity of electromagnetic signals in compositionally graded films. The theory is first based on effective medium approximation or the Maxwell-Garnett approximation to obtain the equivalent dielectric function in a z slice. Then the effective dielectric tensor of the graded film is directly determined, and the group velocities for ordinary and extraordinary waves in the film are derived. It is found that the group velocity is sensitively dependent on the graded profile. For a power-law graded profile f(x)=ax(m), increasing m results in the decreased extraordinary group velocity. Such a decreased tendency becomes significant when the incident angle increases. Therefore the group velocity in compositionally graded films can be effectively decreased by our suitable adjustment of the total volume fraction, the graded profile, and the incident angle. As a result, the compositionally graded films may serve as candidate material for realizing small group velocity.

  8. Aggregate Unemployment Decreases Individual Returns to Education

    ERIC Educational Resources Information Center

    Ammermueller, Andreas; Kuckulenz, Anja; Zwick, Thomas

    2009-01-01

    Aggregate unemployment may affect individual returns to education through qualification-specific responses in participation and wage bargaining. This paper shows that an increase in regional unemployment by 1% decreases returns to education by 0.005 percentage points. This implies that higher skilled employees are better sheltered from labour…

  9. Helical Gears Modified To Decrease Transmission Errors

    NASA Technical Reports Server (NTRS)

    Handschuh, R. F.; Coy, J. J.; Litvin, F. L.; Zhang, J.

    1993-01-01

    Tooth surfaces of helical gears modified, according to proposed design concept, to make gears more tolerant of misalignments and to improve distribution of contact stresses. Results in smaller transmission errors, with concomitant decreases in vibrations and noise and, possibly, increases in service lives.

  10. Temporal Decrease in Upper Atmospheric Chlorine

    NASA Technical Reports Server (NTRS)

    Froidevaux, L.; Livesey, N. J.; Read, W. G.; Salawitch, R. J.; Waters, J. W.; Drouin, B.; MacKenzie, I. A.; Pumphrey, H. C.; Bernath, P.; Boone, C.; Nassar, R.; Montzka, S.; Elkins, J.; Cunnold, D.; Waugh, D.

    2006-01-01

    We report a steady decrease in the upper stratospheric and lower mesospheric abundances of hydrogen chloride (HCl) from August 2004 through January 2006, as measured by the Microwave Limb Sounder (MLS) aboard the Aura satellite. For 60(deg)S to 60(deg)N zonal means, the average yearly change in the 0.7 to 0.1 hPa (approx.50 to 65 km) region is -27 +/- 3 pptv/year, or -0.78 +/- 0.08 percent/year. This is consistent with surface abundance decrease rates (about 6 to 7 years earlier) in chlorine source gases. The MLS data confirm that international agreements to reduce global emissions of ozone-depleting industrial gases are leading to global decreases in the total gaseous chlorine burden. Tracking stratospheric HCl variations on a seasonal basis is now possible with MLS data. Inferred stratospheric total chlorine (CITOT) has a value of 3.60 ppbv at the beginning of 2006, with a (2-sigma) accuracy estimate of 7%; the stratospheric chlorine loading has decreased by about 43 pptv in the 18-month period studied here. We discuss the MLS HCl measurements in the context of other satellite-based HCl data, as well as expectations from surface chlorine data. A mean age of air of approx. 5.5 years and an age spectrum width of 2 years or less provide a fairly good fit to the ensemble of measurements.

  11. Pyrazinoic acid decreases peritoneal transfer rates.

    PubMed

    Grzegorzewska, A E; Czyzewska, K; Szary, B

    1995-01-01

    It was shown elsewhere that in a peritoneally dialyzed woman with pulmonary tuberculosis, oral treatment with rifampicin and pyrazinamide (11 and 25 mg/kg/day, respectively) caused a decrease in the peritoneal transport of sodium, potassium, urea, uric acid, protein, and ultrafiltration rate by 48% to 75% compared to the pretreatment values. Pyrazinoic acid (PA), a metabolite of pyrazinamide, may account for these changes, because rifampicin was also previously used in this patient without peritoneal function impairment. Thus in the present study the influence of PA on the human peritoneum is examined using the modified Ussing-type chamber. PA (1 mg/dL) was introduced into the medium on the interstitial side of the membrane. After the introduction of PA, uric acid transfer from the interstitial to the mesothelial side decreased by about 50%. There were no significant changes in the urea and albumin transfer rates. In conclusion, PA induces changes in uric acid transfer acting directly on mesothelial cells, whereas a decrease in the peritoneal transfer of other solutes may be caused by a decrease in convective transfer rates due to impaired ultrafiltration.

  12. Decreasing trend of groundwater in Turkey

    NASA Astrophysics Data System (ADS)

    Sarachi, S.; Moghim, S.; Famiglietti, J. S.

    2010-12-01

    In these days the increasing demand for water has created problems for availability of its resources. Some recent issues like population growth, global warming and inefficient methods of water consumption, generated the need to find sources of water other than surface water such as ground water. Excess using of groundwater in most parts of the world causes depletion of ground water in those areas. Scientists are trying to find efficient means to quantify these trends. GRACE (Gravity Recovery and Climate Experiment) including two satellites launched in March 2002, is making measurements of the Earth's gravity field which is used to display the change of storage of the water on the Earth. GRACE makes it possible to find the trend of the change of storage all over the world.It can show specific areas in the world that have dramatic decreasing trend of water storage. One of these regions that have been considered in this study is Turkey in western Asia, as one of the countries deeply affected by global warming. Turkey is identified as one of the first places where desertification will start in Europe, according to estimates by the UN Environment Program (UNEP). Turkey has 25 underground water tables and they had a decrease in level of 27 meters in the past 25 years (Turkey water report 2009). In this paper the change of the ground water is evaluated by applying the GRACE storage anomalies and the mass conservation equation that concludes the reduction trend in groundwater. The results clarify that decreasing trend of groundwater is more noticeable during recent years, particularly since 2006. Our results show that in recent years the average decrease in ground water level is 2.5 cm per year and the maximum decrease occurred in May 2007 with the value of about 7.9 cm. KEY WORDS: water resources; Ground water; Turkey; GRACE

  13. Flowable composite resins: do they decrease microleakage and shrinkage stress?

    PubMed

    Conte, Nicholas R; Goodchild, Jason H

    2013-06-01

    All flowable composites shrink and undergo polymerization stress; however, new technologic developments have sought to minimize this, while streamlining dental techniques and producing better results. The new category of bulk-fill flowable composites promotes the effective use of 4-mm increments while decreasing shrinkage stresses generated during polymerization.

  14. Forbush Decrease Prediction Based on Remote Solar Observations

    NASA Astrophysics Data System (ADS)

    Dumbovic, Mateja; Vrsnak, Bojan; Calogovic, Jasa

    2016-04-01

    We study the relation between remote observations of coronal mass ejections (CMEs), their associated solar flares and short-term depressions in the galactic cosmic-ray flux (so called Forbush decreases). Statistical relations between Forbush decrease magnitude and several CME/flare parameters are examined. In general we find that Forbush decrease magnitude is larger for faster CMEs with larger apparent width, which is associated with stronger flares that originate close to the center of the solar disk and are (possibly) involved in a CME-CME interaction. The statistical relations are quantified and employed to forecast expected Forbush decrease magnitude range based on the selected remote solar observations of the CME and associated solar flare. Several verification measures are used to evaluate the forecast method. We find that the forecast is most reliable in predicting whether or not a CME will produce a Forbush decrease with a magnitude >3 %. The main advantage of the method is that it provides an early prediction, 1-4 days in advance. Based on the presented research, an online forecast tool was developed (Forbush Decrease Forecast Tool, FDFT) available at Hvar Observatory web page: http://oh.geof.unizg.hr/FDFT/fdft.php. We acknowledge the support of Croatian Science Foundation under the project 6212 „Solar and Stellar Variability" and of European social fond under the project "PoKRet".

  15. Construction noise decreases reproductive efficiency in mice.

    PubMed

    Rasmussen, Skye; Glickman, Gary; Norinsky, Rada; Quimby, Fred W; Tolwani, Ravi J

    2009-07-01

    Excessive noise is well known to impair rodent health. To better understand the effect of construction noise and to establish effective noise limits during a planned expansion of our vivarium, we analyzed the effects of construction noise on mouse gestation and neonatal growth. Our hypothesis was that high levels of construction noise would reduce the number of live births and retard neonatal growth. Female Swiss Webster mice were individually implanted with 15 B6CBAF1/J embryos and then exposed to 70- and 90-dBA concrete saw cutting noise samples at defined time points during gestation. In addition, groups of mice with litters were exposed to noise at 70, 80, or 90 dBA for 1 h daily during the first week after parturition. Litter size, birth weight, incidence of stillborn pups, and rate of neonatal weight gain were analyzed. Noise decreased reproductive efficiency by decreasing live birth rates and increasing the number of stillborn pups.

  16. Did liberalising bar hours decrease traffic accidents?

    PubMed

    Green, Colin P; Heywood, John S; Navarro, Maria

    2014-05-01

    Legal bar closing times in England and Wales have historically been early and uniform. Recent legislation liberalised closing times with the object of reducing social problems thought associated with drinking to "beat the clock." Indeed, using both difference in difference and synthetic control approaches we show that one consequence of this liberalisation was a decrease in traffic accidents. This decrease is heavily concentrated among younger drivers. Moreover, we provide evidence that the effect was most pronounced in the hours of the week directly affected by the liberalisation: late nights and early mornings on weekends. This evidence survives a series of robustness checks and suggests at least one socially positive consequence of extending bar hours.

  17. Decreasing Human Trafficking through Sex Work Decriminalization.

    PubMed

    Albright, Erin; D'Adamo, Kate

    2017-01-01

    In order to decrease human trafficking, health care workers should support the full decriminalization of prostitution. Similar to trafficking in other forms of labor, preventing trafficking in the sex trade requires addressing the different forms of marginalization that create vulnerable communities. By removing punitive laws that prevent reporting of exploitation and abuse, decriminalization allows sex workers to work more safely, thereby reducing marginalization and vulnerability. Decriminalization can also help destigmatize sex work and help resist political, social, and cultural marginalization of sex workers.

  18. Decreased fibrinolytic activity in juvenile chronic arthritis.

    PubMed

    Mussoni, L; Pintucci, G; Romano, G; De Benedetti, F; Massa, M; Martini, A

    1990-12-01

    The basal fibrinolytic activity in 17 children with active juvenile chronic arthritis (JCA) was investigated. It was found that patients with JCA, and particularly those with the systemic form, show decreased plasma fibrinolytic activity and a marked increase in plasminogen activator inhibitor. Additionally, it was found that patients with systemic JCA, but not those with the polyarticular or pauciarticular form, have increased circulating levels of tissue-type plasminogen activator, and endothelial cell protein, suggesting possible endothelial cell participation in systemic JCA.

  19. Decreasing luminescence lifetime of evaporating phosphorescent droplets

    NASA Astrophysics Data System (ADS)

    van der Voort, D. D.; Dam, N. J.; Sweep, A. M.; Kunnen, R. P. J.; van Heijst, G. J. F.; Clercx, H. J. H.; van de Water, W.

    2016-12-01

    Laser-induced phosphorescence has been used extensively to study spray dynamics. It is important to understand the influence of droplet evaporation in the interpretation of such measurements, as it increases luminescence quenching. By suspending a single evaporating n-heptane droplet in an acoustic levitator, the properties of lanthanide-complex europium-thenoyltrifluoroacetone-trioctylphosphine oxide (Eu-TTA-TOPO) phosphorescence are determined through high-speed imaging. A decrease was found in the measured phosphorescence decay coefficient (780 → 200 μs) with decreasing droplet volumes (10-9 → 10-11 m3) corresponding to increasing concentrations (10-4 → 10-2 M). This decrease continues up to the point of shell-formation at supersaturated concentrations. The diminished luminescence is shown not to be attributable to triplet-triplet annihilation, quenching between excited triplet-state molecules. Instead, the pure exponential decays found in the measurements show that a non-phosphorescent quencher, such as free TTA/TOPO, can be attributable to this decay. The concentration dependence of the phosphorescence lifetime can therefore be used as a diagnostic of evaporation in sprays.

  20. Decreasing sperm quality: a global problem?

    PubMed Central

    2010-01-01

    Background Carlsen and coworkers (1992) reviewed 61 heterogeneous observational studies on semen quality published between 1938 and 1990. This review indicates that mean sperm density decreased significantly between 1940 and 1990. An extended meta-analysis with 101 studies confirmed a decline in sperm density for the period from 1934 to 1996 (2000). The key message of the meta-analyses is that sperm counts have decreased globally by about 50% over the past decades. This assessment has been questioned. Discussion A major methodological problem of the meta-analysis is the use of data collected in different countries, at different times, on different populations and with different methods of semen analysis. Furthermore, the results of studies concerning semen analysis are frequently biased e.g. by selection criteria of volunteers. In most studies on human semen characteristics the populations under study are insufficiently defined and the study participants are not a representative population sample. The incidence of testicular cancer has increased in Caucasian men worldwide. The investigation of common risk factors for male reproductive disorders requires well designed epidemiological studies and the collection of individual data. Summary Former meta-analyses of sperm count data show a global downward trend. This conclusion should be interpreted with caution. The included studies are of great heterogeneity due to geographical and/or ethnical variation, different study designs and different methodological standards. Population-based prospective studies are needed to investigate secular trends in male reproductive disorders. PMID:20085639

  1. Resistance exercise decreases beta-endorphin immunoreactivity.

    PubMed Central

    Pierce, E F; Eastman, N W; McGowan, R W; Tripathi, H; Dewey, W L; Olson, K G

    1994-01-01

    Previous research investigating the response of plasma beta-endorphins (beta-EP) to resistance exercise has resulted in equivocal findings. To examine further the effects of resistance exercise on beta-EP immunoreactivity, 10 male and 10 female college-age students participated in a series of controlled isotonic resistance exercises. The session consisted of three sets of eight repetitions at 80% of one repetition maximum (1-RM) for each of the following exercises: (1) bench press; (2) lateral pull-downs; (3) seated arm curls; and (4) military press. Blood plasma was sampled both before and after the lifting routine and beta-endorphin levels were determined by radioimmunoassay. A Students t test for paired samples indicated that mean(s.e.) plasma beta-endorphin levels after exercise (10.5(1.3) pg beta-EP ml-1) were significantly decreased as compared with pre-exercise (control) levels (16.5(1.2), P < 0.05). While the mechanism(s) contributing to the decrease in immunoreactivity is unclear, it may be the result of the synergistic effect of beta-EP clearance during rest intervals and changes in psychological states between sampling. PMID:8000813

  2. Decreasing mitochondrial fission prevents cholestatic liver injury.

    PubMed

    Yu, Tianzheng; Wang, Li; Lee, Hakjoo; O'Brien, Dawn K; Bronk, Steven F; Gores, Gregory J; Yoon, Yisang

    2014-12-05

    Mitochondria frequently change their shape through fission and fusion in response to physiological stimuli as well as pathological insults. Disrupted mitochondrial morphology has been observed in cholestatic liver disease. However, the role of mitochondrial shape change in cholestasis is not defined. In this study, using in vitro and in vivo models of bile acid-induced liver injury, we investigated the contribution of mitochondrial morphology to the pathogenesis of cholestatic liver disease. We found that the toxic bile salt glycochenodeoxycholate (GCDC) rapidly fragmented mitochondria, both in primary mouse hepatocytes and in the bile transporter-expressing hepatic cell line McNtcp.24, leading to a significant increase in cell death. GCDC-induced mitochondrial fragmentation was associated with an increase in reactive oxygen species (ROS) levels. We found that preventing mitochondrial fragmentation in GCDC by inhibiting mitochondrial fission significantly decreased not only ROS levels but also cell death. We also induced cholestasis in mouse livers via common bile duct ligation. Using a transgenic mouse model inducibly expressing a dominant-negative fission mutant specifically in the liver, we demonstrated that decreasing mitochondrial fission substantially diminished ROS levels, liver injury, and fibrosis under cholestatic conditions. Taken together, our results provide new evidence that controlling mitochondrial fission is an effective strategy for ameliorating cholestatic liver injury.

  3. Dexmedetomidine decreases the oral mucosal blood flow.

    PubMed

    Kawaai, Hiroyoshi; Yoshida, Kenji; Tanaka, Eri; Togami, Kohei; Tada, Hitoshi; Ganzberg, Steven; Yamazaki, Shinya

    2013-12-01

    There is an abundance of blood vessels in the oral cavity, and intraoperative bleeding can disrupt operations. There have been some interesting reports about constriction of vessels in the oral cavity, one of which reported that gingival blood flow in cats is controlled by sympathetic α-adrenergic fibres that are involved with vasoconstriction. Dexmedetomidine is a sedative and analgesic agent that acts through the α-2 adrenoceptor, and is expected to have a vasoconstrictive action in the oral cavity. We have focused on the relation between the effects of α-adrenoceptors by dexmedetomidine and vasoconstriction in oral tissues, and assessed the oral mucosal blood flow during sedation with dexmedetomidine. The subjects comprised 13 healthy male volunteers, sedated with dexmedetomidine in a loading dose of 6 μg/kg/h for 10 min and a continuous infusion of 0.7 μg/kg/h for 32 min. The mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), stroke volume (SV), systemic vascular resistance (SVR), and palatal mucosal blood flow (PMBF) were measured at 0, 5, 10, 12, 22, and 32 min after the start of the infusion. The HR, CO, and PBMF decreased significantly during the infusion even though there were no differences in the SV. The SVR increased significantly but the PMBF decreased significantly. In conclusion, PMBF was reduced by the mediating effect of dexmedetomidine on α-2 adrenoceptors.

  4. Solarwind Transient flows and Associated Forbush Decrease

    NASA Astrophysics Data System (ADS)

    Kaushik, S. C.; Subhash Chandra Kaushik

    2011-12-01

    In this study we discuss the behavior of cosmic rays during the phase of highly intense or ultra intense geomagnetic storms, as shocks driven by energetic coronal mass ejections (CME's) and other interplanetary (IP) transients are mainly responsible for initiating large and intense geomagnetic storms. Observational results indicate that galactic cosmic rays (CR) coming from deep surface interact with these abnormal solar and IP conditions and suffer modulation effects. In this paper a systematic study has been performed to analyze the CRI variation during super storms i.e. very intense geomagnetic storms with Dst index ≥ -100 nT. The neutron monitor data of three stations Oulu (Rc = 0.77 GV), Climax (Rc = 2.97 GV) and Huancayo (Rc = 13.01 GV) well distributed over different latitudes and hourly values of IMF parameters derived from satellite observations near Earth IP medium from OMNI Data base is used for the period spanning over solar cycles 20, 21, 22 and 23. It is found that AP and AE indices show rise before the forward turnings of IMF, while the Dst index shows a classic storm time decrease. The analysis indicates that the magnitude of all the responses depends on BZ component of IMF being well correlated with solar maximum and minimum periods. Transient decrease in CRI with slow recovery is observed during the storm phase duration.

  5. Thalidomide decreases intrahepatic resistance in cirrhotic rats.

    PubMed

    Yang, Ying-Ying; Huang, Yi-Tsau; Lin, Han-Chieh; Lee, Fa-Yauh; Lee, Kuei-Chuan; Chau, Ga-Yang; Loong, Che-Chuan; Lai, Chiung-Ru; Lee, Shou-Dong

    2009-03-13

    Increased intrahepatic resistance (IHR) within cirrhotic liver is caused by increased endotoxemia, cytokines tumor necrosis factor-alpha (TNF-alpha), vasoconstrictor thromboxane A(2) (TXA(2)), and disrupted microvasculatures. We evaluated the effects of thalidomide-related inhibition of TNF-alpha upon the hepatic microcirculation of cirrhosis in rats. Portal venous pressure (PVP), hepatic TNF-alpha, expression of thromboxane synthase (TXS), and leukocyte common antigen (LCA) were measured in bile-duct-ligated (BDL) rats receiving 1 month of thalidomide (BDL-thalido rats). Portal perfusion pressure (PPP), IHR, and hepatic TXA(2) production were measured in the isolated liver perfusion system. Intravital microscopy was used to examine hepatic microvascular disruptions. In BDL-thalido rats, PVP, PPP, IHR, hepatic TXA(2) and TNF-alpha, hydroxyproline content, expression of TXS and LCA, and LPS-induced leukocyte recruitment were significantly decreased. Conversely, hepatic microvascular density and perfused sinusoids were significantly increased. Thalidomide decreased PVP and IHR by reducing hepatic TXA(2) and improving hepatic microvascular disruptions in rats with biliary cirrhosis.

  6. Adolescent impatience decreases with increased frontostriatal connectivity

    PubMed Central

    van den Bos, Wouter; Rodriguez, Christian A.; Schweitzer, Julie B.; McClure, Samuel M.

    2015-01-01

    Adolescence is a developmental period associated with an increase in impulsivity. Impulsivity is a multidimensional construct, and in this study we focus on one of the underlying components: impatience. Impatience can result from (i) disregard of future outcomes and/or (ii) oversensitivity to immediate rewards, but it is not known which of these evaluative processes underlie developmental changes. To distinguish between these two causes, we investigated developmental changes in the structural and functional connectivity of different frontostriatal tracts. We report that adolescents were more impatient on an intertemporal choice task and reported less future orientation, but not more present hedonism, than young adults. Developmental increases in structural connectivity strength in the right dorsolateral prefrontal tract were related to increased negative functional coupling with the striatum and an age-related decrease in discount rates. Our results suggest that mainly increased control, and the integration of future-oriented thought, drives the reduction in impatience across adolescence. PMID:26100897

  7. Decreased adult neurogenesis in hibernating Syrian hamster.

    PubMed

    León-Espinosa, Gonzalo; García, Esther; Gómez-Pinedo, Ulises; Hernández, Félix; DeFelipe, Javier; Ávila, Jesús

    2016-10-01

    Generation of new neurons from adult neural stem cells occurs in the dentate gyrus (DG) of the hippocampus and the lateral walls of the lateral ventricles. In this article, we study the neurogenesis that takes place during the hibernation of the Syrian hamster (Mesocricetus auratus). Using a variety of standard neurogenesis markers and 5-bromo-2-deoxyuridine (BrdU) incorporation, we describe a preferential decrease in the proliferation of newborn neurons in the subventricular zone (SVZ) of the hibernating hamsters (torpor) rather than in the hippocampus. Furthermore, we demonstrate that the proliferative capacity is recovered after 3-4days of torpor when arousal is triggered under natural conditions (i.e., not artificially provoked). In addition, we show that tau3R, a tau isoform with three microtubule-binding domains, is a suitable marker to study neurogenesis both in the SVZ and subgranular zone (SGZ) of the Syrian hamster brain.

  8. Wastewater temperature decrease in pressure sewers.

    PubMed

    Sallanko, Jarmo; Pekkala, Mari

    2008-12-01

    The centralization of wastewater treatment in large central treatment plants and the connection of sparsely populated areas to sewerage systems have increased the time wastewater is retained in sewers. These retention times lead to a decrease in wastewater temperature and affect wastewater treatment, especially the removal of nitrogen. In this study, temperature changes in long transfer sewers were examined. The temperature change was greatest at the end of winter and in the front part of the sewer. Temperature changes in the front parts of the sewers ranged from 0.16 to 0.27 degree C/km, and in the end parts from 0.02 to 0.10 degree C/km. When expressed in terms of the retention time for wastewater in the sewer, the temperature changes ranged from 0.12 to 0.17 degree C per retention hour.

  9. Periventricular leukomalacia is decreasing in Japan.

    PubMed

    Sugiura, Tokio; Goto, Tatenobu; Ueda, Hiroko; Ito, Koichi; Kakita, Hiroki; Nagasaki, Rika; Mizuno, Keisuke; Suzuki, Satoshi; Kato, Ineko; Togari, Hajime

    2012-07-01

    Periventricular leukomalacia is recognized as the leading cause of cerebral palsy in preterm infants. To clarify the prevalence of periventricular leukomalacia and cerebral palsy in Japan, a nationwide survey was performed. The prevalence of periventricular leukomalacia in the group of surviving preterm infants of gestational ages less than 33 weeks born in 2007 was 2.7% (78/2883) on ultrasound diagnosis, and 3.3% (92/2824) on magnetic resonance imaging. The prevalence of cerebral palsy was 4.3% (125/2883) on clinical diagnosis. In our previous study, the prevalences of periventricular leukomalacia in 1990-1991, 1993-1994, 1996, and 1999 were 4.8%, 4.9%, 4.9%, and 5.3% on ultrasound, and 7.9%, 7.7%, 6.9%, and 7.3% on magnetic resonance imaging, respectively. The prevalence of periventricular leukomalacia has decreased significantly in Japan.

  10. Incomplete and transitory decrease of glycolysis

    PubMed Central

    Schoors, Sandra; Cantelmo, Anna Rita; Georgiadou, Maria; Stapor, Peter; Wang, Xingwu; Quaegebeur, Annelies; Cauwenberghs, Sandra; Wong, Brian W; Bifari, Francesco; Decimo, Ilaria; Schoonjans, Luc; De Bock, Katrien; Dewerchin, Mieke; Carmeliet, Peter

    2014-01-01

    During vessel sprouting, a migratory endothelial tip cell guides the sprout, while proliferating stalk cells elongate the branch. Tip and stalk cell phenotypes are not genetically predetermined fates, but are dynamically interchangeable to ensure that the fittest endothelial cell (EC) leads the vessel sprout. ECs increase glycolysis when forming new blood vessels. Genetic deficiency of the glycolytic activator PFKFB3 in ECs reduces vascular sprouting by impairing migration of tip cells and proliferation of stalk cells. PFKFB3-driven glycolysis promotes the tip cell phenotype during vessel sprouting, since PFKFB3 overexpression overrules the pro-stalk activity of Notch signaling. Furthermore, PFKFB3-deficient ECs cannot compete with wild-type neighbors to form new blood vessels in chimeric mosaic mice. In addition, pharmacological PFKFB3 blockade reduces pathological angiogenesis with modest systemic effects, likely because it decreases glycolysis only partially and transiently. PMID:24335389

  11. Assortativity decreases the robustness of interdependent networks.

    PubMed

    Zhou, Di; Stanley, H Eugene; D'Agostino, Gregorio; Scala, Antonio

    2012-12-01

    It was recently recognized that interdependencies among different networks can play a crucial role in triggering cascading failures and, hence, systemwide disasters. A recent model shows how pairs of interdependent networks can exhibit an abrupt percolation transition as failures accumulate. We report on the effects of topology on failure propagation for a model system consisting of two interdependent networks. We find that the internal node correlations in each of the two interdependent networks significantly changes the critical density of failures that triggers the total disruption of the two-network system. Specifically, we find that the assortativity (i.e., the likelihood of nodes with similar degree to be connected) within a single network decreases the robustness of the entire system. The results of this study on the influence of assortativity may provide insights into ways of improving the robustness of network architecture and, thus, enhance the level of protection of critical infrastructures.

  12. Assortativity decreases the robustness of interdependent networks

    NASA Astrophysics Data System (ADS)

    Zhou, Di; Stanley, H. Eugene; D'Agostino, Gregorio; Scala, Antonio

    2012-12-01

    It was recently recognized that interdependencies among different networks can play a crucial role in triggering cascading failures and, hence, systemwide disasters. A recent model shows how pairs of interdependent networks can exhibit an abrupt percolation transition as failures accumulate. We report on the effects of topology on failure propagation for a model system consisting of two interdependent networks. We find that the internal node correlations in each of the two interdependent networks significantly changes the critical density of failures that triggers the total disruption of the two-network system. Specifically, we find that the assortativity (i.e., the likelihood of nodes with similar degree to be connected) within a single network decreases the robustness of the entire system. The results of this study on the influence of assortativity may provide insights into ways of improving the robustness of network architecture and, thus, enhance the level of protection of critical infrastructures.

  13. Cosmic ray decreases and magnetic clouds

    SciTech Connect

    Cane, H.V. )

    1993-03-01

    A study has been made of energetic particle data, obtained from IMP 8, in conjunction with solar wind field and plasma data at the times of reported magnetic clouds. It is shown that magnetic clouds can cause a depression of the cosmic ray flux but high fields are required. A depression of 3% in a neutron monitor requires a field of about 25 nT. Such high fields are found only in a subset of coronal ejecta. The principal cause for Forbush decreases associated with energetic shocks is probably turbulence in the postshock region, although some shocks will be followed by an ejecta with a high field. Each event is different. The lower-energy particles can help in identifying the dominant processes in individual events. 19 refs., 5 figs.

  14. Attending to music decreases inattentional blindness.

    PubMed

    Beanland, Vanessa; Allen, Rosemary A; Pammer, Kristen

    2011-12-01

    This article investigates how auditory attention affects inattentional blindness (IB), a failure of conscious awareness in which an observer does not notice an unexpected event because their attention is engaged elsewhere. Previous research using the attentional blink paradigm has indicated that listening to music can reduce failures of conscious awareness. It was proposed that listening to music would decrease IB by reducing observers' frequency of task-unrelated thoughts (TUTs). Observers completed an IB task that varied both visual and auditory demands. Listening to music was associated with significantly lower IB, but only when observers actively attended to the music. Follow-up experiments suggest this was due to the distracting qualities of the audio task. The results also suggest a complex relationship between IB and TUTs: during demanding tasks, as predicted, noticers of the unexpected stimulus reported fewer TUTs than non-noticers. During less demanding tasks, however, noticers reported more TUTs than non-noticers.

  15. New ipratropium formulation to decrease nebulization time.

    PubMed

    Majoral, Caroline; Vecellio, Laurent; Grimbert, Daniel; de Monte, Michèle; le Guellec, Chantal; Ingremeau, Valérie; Minois, Carole; Cordeau, Emeline; Paintaud, Gilles; Steinberg, Anouck; Diot, Patrice

    2007-02-01

    A new anticholinergic aerosol containing 0.5mg ipratropium bromide dissolved in 1mL of solution has been produced with the purpose of decreasing nebulization time for patients compared to the traditional formulation which is twice as voluminal (0.5mg/2mL, Boehringer-Ingelheim, France). The aim of this study was to compare aerosol characteristics (inhaled mass, particle size distribution and nebulization time) of these two formulations of ipratropium bromide, nebulized alone and with terbutaline (5mg/2mL, Astra Zeneca, Sweden), to determine whether the new formulation was equivalent to the old one. Four different jet nebulizers were used: PariLC+, Atomisor NL9M, Sidestream and Mistyneb. Statistical analysis of the results showed that for all types of nebulizer, the inhaled mass of ipratropium bromide 0.5mg/1mL was significantly lower than the inhaled mass of ipratropium bromide 0.5mg/2mL, and that there was no statistical difference between the inhaled mass of ipratropium bromide 0.5mg/1mL+terbutaline 5mg/2mL and the inhaled mass of ipratropium bromide 0.5mg/2mL+terbutaline 5mg/2mL. The study also showed that the new formulation of ipratropium bromide (0.5mg/1mL) mixed with terbutaline allowed a 26% decrease in nebulization time compared to the old formulation (0.5mg/2mL) mixed with terbutaline without changing aerosol characteristics (inhaled mass and particle size distribution). This leads to the conclusion that a 2mL minimum volume is required for nebulization, and that nebulization of ipratropium bromide 0.5mg/1mL alone must be avoided.

  16. 29 CFR 778.321 - Decrease in hours without decreasing pay-general.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... LABOR STATEMENTS OF GENERAL POLICY OR INTERPRETATION NOT DIRECTLY RELATED TO REGULATIONS OVERTIME COMPENSATION Special Problems Reduction in Workweek Schedule with No Change in Pay § 778.321 Decrease in...

  17. Decreasing seagrass density negatively influences associated fauna

    PubMed Central

    McCloskey, Rosemary M.

    2015-01-01

    Seagrass meadows globally are disappearing at a rapid rate with physical disturbances being one of the major drivers of this habitat loss. Disturbance of seagrass can lead to fragmentation, a reduction in shoot density, canopy height and coverage, and potentially permanent loss of habitat. Despite being such a widespread issue, knowledge of how such small scale change affects the spatial distribution and abundances of motile fauna remains limited. The present study investigated fish and macro faunal community response patterns to a range of habitat variables (shoot length, cover and density), including individual species habitat preferences within a disturbed and patchy intertidal seagrass meadow. Multivariate analysis showed a measurable effect of variable seagrass cover on the abundance and distribution of the fauna, with species specific preferences to both high and low seagrass cover seagrass. The faunal community composition varied significantly with increasing/decreasing cover. The faunal species composition of low cover seagrass was more similar to sandy control plots than to higher cover seagrass. Shannon Wiener Diversity (H′) and species richness was significantly higher in high cover seagrass than in low cover seagrass, indicating increasing habitat value as density increases. The results of this study underline how the impacts of small scale disturbances from factors such as anchor damage, boat moorings and intertidal vehicle use on seagrass meadows that reduce shoot density and cover can impact upon associated fauna. These impacts have negative consequences for the delivery of ecosystem services such as the provision of nursery habitat. PMID:26137432

  18. Decreasing effluent loads through bleaching modification.

    PubMed

    Tran, Ai Van

    2006-02-01

    Almost all of the kraft pulp bleach plants worldwide are now practicing elemental chlorine-free (ECF) process to comply with environmental regulations in different countries. Usually, these conventional ECF bleaching sequences contain one or two alkaline extraction stages of which the first one is often the principal source of color and chemical oxygen demand (COD) in the resulting effluent. However, the results of this study showed that the ECF sequences which did not include any alkaline extraction stage and contained solely chlorine dioxide decreased both the color and COD loads of the effluent. On the other hand, the ECF sequences containing both chlorine dioxide and hydrogen peroxide but excluding the alkaline extraction stage could lower only the color but not the COD load. It is suggested that the total kappa factor (the ratio of the total active chlorine to the kappa number) affected the COD load and that the content of hexeneuronic acid groups influenced the color of the bleach effluent. Compared to the reference pulp, the viscosity of the pulp from the exclusively chlorine-dioxide-based ECF sequence without the alkaline extraction stage was lower but the tear index and sheet density at a given tensile index were similar.

  19. Hyper-arousal decreases human visual thresholds.

    PubMed

    Woods, Adam J; Philbeck, John W; Wirtz, Philip

    2013-01-01

    Arousal has long been known to influence behavior and serves as an underlying component of cognition and consciousness. However, the consequences of hyper-arousal for visual perception remain unclear. The present study evaluates the impact of hyper-arousal on two aspects of visual sensitivity: visual stereoacuity and contrast thresholds. Sixty-eight participants participated in two experiments. Thirty-four participants were randomly divided into two groups in each experiment: Arousal Stimulation or Sham Control. The Arousal Stimulation group underwent a 50-second cold pressor stimulation (immersing the foot in 0-2° C water), a technique known to increase arousal. In contrast, the Sham Control group immersed their foot in room temperature water. Stereoacuity thresholds (Experiment 1) and contrast thresholds (Experiment 2) were measured before and after stimulation. The Arousal Stimulation groups demonstrated significantly lower stereoacuity and contrast thresholds following cold pressor stimulation, whereas the Sham Control groups showed no difference in thresholds. These results provide the first evidence that hyper-arousal from sensory stimulation can lower visual thresholds. Hyper-arousal's ability to decrease visual thresholds has important implications for survival, sports, and everyday life.

  20. Decreasing seagrass density negatively influences associated fauna.

    PubMed

    McCloskey, Rosemary M; Unsworth, Richard K F

    2015-01-01

    Seagrass meadows globally are disappearing at a rapid rate with physical disturbances being one of the major drivers of this habitat loss. Disturbance of seagrass can lead to fragmentation, a reduction in shoot density, canopy height and coverage, and potentially permanent loss of habitat. Despite being such a widespread issue, knowledge of how such small scale change affects the spatial distribution and abundances of motile fauna remains limited. The present study investigated fish and macro faunal community response patterns to a range of habitat variables (shoot length, cover and density), including individual species habitat preferences within a disturbed and patchy intertidal seagrass meadow. Multivariate analysis showed a measurable effect of variable seagrass cover on the abundance and distribution of the fauna, with species specific preferences to both high and low seagrass cover seagrass. The faunal community composition varied significantly with increasing/decreasing cover. The faunal species composition of low cover seagrass was more similar to sandy control plots than to higher cover seagrass. Shannon Wiener Diversity (H') and species richness was significantly higher in high cover seagrass than in low cover seagrass, indicating increasing habitat value as density increases. The results of this study underline how the impacts of small scale disturbances from factors such as anchor damage, boat moorings and intertidal vehicle use on seagrass meadows that reduce shoot density and cover can impact upon associated fauna. These impacts have negative consequences for the delivery of ecosystem services such as the provision of nursery habitat.

  1. Decreased chewing activity during mouth breathing.

    PubMed

    Hsu, H-Y; Yamaguchi, K

    2012-08-01

    This study examined the effect of mouth breathing on the strength and duration of vertical effect on the posterior teeth using related functional parameters during 3 min of gum chewing in 39 nasal breathers. A CO(2) sensor was placed over the mouth to detect expiratory airflow. When no airflow was detected from the mouth throughout the recording period, the subject was considered a nasal breather and enrolled in the study. Electromyographic (EMG) activity was recorded during 3 min of gum chewing. The protocol was repeated with the nostrils occluded. The strength of the vertical effect was obtained as integrated masseter muscle EMG activity, and the duration of vertical effect was also obtained as chewing stroke count, chewing cycle variation and EMG activity duration above baseline. Baseline activity was obtained from the isotonic EMG activity during jaw movement at 1.6 Hz without making tooth contact. The duration represented the percentage of the active period above baseline relative to the 3-min chewing period. Paired t-test and repeated analysis of variance were used to compare variables between nasal and mouth breathing. The integrated EMG activity and the duration of EMG activity above baseline, chewing stroke count and chewing cycle significantly decreased during mouth breathing compared with nasal breathing (P<0.05). Chewing cycle variance during mouth breathing was significantly greater than nasal breathing (P<0.05). Mouth breathing reduces the vertical effect on the posterior teeth, which can affect the vertical position of posterior teeth negatively, leading to malocclusion.

  2. Exogenous spatial attention decreases audiovisual integration.

    PubMed

    Van der Stoep, N; Van der Stigchel, S; Nijboer, T C W

    2015-02-01

    Multisensory integration (MSI) and spatial attention are both mechanisms through which the processing of sensory information can be facilitated. Studies on the interaction between spatial attention and MSI have mainly focused on the interaction between endogenous spatial attention and MSI. Most of these studies have shown that endogenously attending a multisensory target enhances MSI. It is currently unclear, however, whether and how exogenous spatial attention and MSI interact. In the current study, we investigated the interaction between these two important bottom-up processes in two experiments. In Experiment 1 the target location was task-relevant, and in Experiment 2 the target location was task-irrelevant. Valid or invalid exogenous auditory cues were presented before the onset of unimodal auditory, unimodal visual, and audiovisual targets. We observed reliable cueing effects and multisensory response enhancement in both experiments. To examine whether audiovisual integration was influenced by exogenous spatial attention, the amount of race model violation was compared between exogenously attended and unattended targets. In both Experiment 1 and Experiment 2, a decrease in MSI was observed when audiovisual targets were exogenously attended, compared to when they were not. The interaction between exogenous attention and MSI was less pronounced in Experiment 2. Therefore, our results indicate that exogenous attention diminishes MSI when spatial orienting is relevant. The results are discussed in terms of models of multisensory integration and attention.

  3. Perfluorochemical emulsions decrease Kupffer cell phagocytosis

    SciTech Connect

    Bottalico, L.A.; Betensky, H.T.; Min, Y.B.; Weinstock, S.B. )

    1991-07-01

    One drawback to using perfluorochemical emulsions as blood substitutes is that perfluorochemical particles are cleared from the blood by the reticuloendothelial system, primarily liver and spleen. The authors measured the impact of two perfluorochemical emulsions on clearance of colloidal carbon (less than 1 microns) and 51Cr-sheep red blood cells (about 8 microns) by the reticuloendothelial system in vivo and in the isolated perfused liver. Male rats were injected with 2 ml/100 gm body wt of Fluosol-DA or Oxypherol-ET for 4 consecutive days. Carbon (1 ml/100 gm body wt) or sheep red blood cells (0.05 ml of 5% vol/vol/100 gm body wt) were then injected intravenously (in vivo) or added to perfusate. Samples were taken at several time points for 1 hr. In the isolated perfused liver, carbon clearance was depressed by 25% 1 day after treatment. Rates returned to control levels by 12 days in Fluosol-DA-treated rats but remained depressed by 67% in Oxypherol-ET-treated rats. Sheep red blood cell (8 microns) clearance was two to five times slower than carbon clearance and depressed by 40% in livers from Fluosol-DA rats 1 day and 12 days after treatment. Added serum did not improve phagocytosis. In vivo carbon clearance remained normal in Fluosol-DA-treated rats but decreased by 74% in Oxypherol-ET-treated rats 1 day after treatment, returning to normal by 12 days. Clearance rates were similar in control rats in vivo and in the perfused liver. They conclude that the isolated perfused liver is a good model to measure liver clearance function. Although low doses of perfluorochemical emulsions may depress Kupffer cell phagocytosis, general reticuloendothelial system function is not significantly compromised.

  4. Do proton pump inhibitors decrease calcium absorption?

    PubMed

    Hansen, Karen E; Jones, Andrea N; Lindstrom, Mary J; Davis, Lisa A; Ziegler, Toni E; Penniston, Kristina L; Alvig, Amy L; Shafer, Martin M

    2010-12-01

    Proton pump inhibitors (PPIs) increase osteoporotic fracture risk presumably via hypochlorhydria and consequent reduced fractional calcium absorption (FCA). Existing studies provide conflicting information regarding the direct effects of PPIs on FCA. We evaluated the effect of PPI therapy on FCA. We recruited women at least 5 years past menopause who were not taking acid suppressants. Participants underwent three 24-hour inpatient FCA studies using the dual stable isotope method. Two FCA studies were performed 1 month apart to establish baseline calcium absorption. The third study occurred after taking omeprazole (40 mg/day) for 30 days. Each participant consumed the same foods during all FCA studies; study meals replicated subjects' dietary habits based on 7-day diet diaries. Twenty-one postmenopausal women ages 58 ± 7 years (mean ± SD) completed all study visits. Seventeen women were white, and 2 each were black and Hispanic. FCA (mean ± SD) was 20% ± 10% at visit 1, 18% ± 10% at visit 2, and 23% ± 10% following 30 ± 3 days of daily omeprazole (p = .07, ANOVA). Multiple linear regression revealed that age, gastric pH, serum omeprazole levels, adherence to omeprazole, and 25-hydroxyvitamin D levels were unrelated to changes in FCA between study visits 2 and 3. The 1,25-dihydroxyvitamin D(3) level at visit 2 was the only variable (p = .049) associated with the change in FCA between visits 2 and 3. PPI-associated hypochlorhydria does not decrease FCA following 30 days of continuous use. Future studies should focus on identifying mechanisms by which PPIs increase the risk of osteoporotic fracture.

  5. Does machine perfusion decrease ischemia reperfusion injury?

    PubMed

    Bon, D; Delpech, P-O; Chatauret, N; Hauet, T; Badet, L; Barrou, B

    2014-06-01

    In 1990's, use of machine perfusion for organ preservation has been abandoned because of improvement of preservation solutions, efficient without perfusion, easy to use and cheaper. Since the last 15 years, a renewed interest for machine perfusion emerged based on studies performed on preclinical model and seems to make consensus in case of expanded criteria donors or deceased after cardiac death donations. We present relevant studies highlighted the efficiency of preservation with hypothermic machine perfusion compared to static cold storage. Machines for organ preservation being in constant evolution, we also summarized recent developments included direct oxygenation of the perfusat. Machine perfusion technology also enables organ reconditioning during the last hours of preservation through a short period of perfusion on hypothermia, subnormothermia or normothermia. We present significant or low advantages for machine perfusion against ischemia reperfusion injuries regarding at least one primary parameter: risk of DFG, organ function or graft survival.

  6. Stop signals decrease choices for palatable foods through decreased food evaluation.

    PubMed

    Veling, Harm; Aarts, Henk; Stroebe, Wolfgang

    2013-01-01

    The present study explores whether presenting specific palatable foods in close temporal proximity of stop signals in a go/no-go task decreases subsequent evaluations of such foods among participants with a relatively high appetite. Furthermore, we tested whether any decreased evaluations could mediate subsequent food choice. Participants first received a go/no-go task in which palatable foods were consistently linked to go cues or no-go cues within participants. Next, evaluation of the palatable foods was measured as well as food choice. Replicating previous work, results show that among participants with a relatively high appetite palatable foods associated with no-go cues are less often chosen as snacks compared to when these foods are associated with go cues, whereas this manipulation did not affect participants with a relatively low appetite. Moreover, this effect was completely mediated by decreased evaluation of the palatable foods that had been associated with the no-go cues, whereas evaluation of the foods associated with go cues did not mediate this effect. Results further showed that the devaluation effect of foods associated with no-go cues was independent of the amount of pairings (4 vs. 12 vs. 24) with the no-go cues. The current findings suggest that decreased food evaluation is a mechanism that explains effects of stop signals on food choice.

  7. Aspiration prevention protocol: decreasing postoperative pneumonia in heart surgery patients.

    PubMed

    Starks, Bobbie; Harbert, Christy

    2011-10-01

    BACKGROUND Postoperative pneumonia contributes to morbidity and mortality in patients who have open heart surgery. OBJECTIVES To determine if measures to reduce aspiration in patients after cardiothoracic surgery would decrease the occurrence of postoperative pneumonia. METHODS All patients undergoing cardiothoracic surgery from April 2008 through October 2008 were prospectively enrolled in the study. An aspiration prevention protocol was developed and implemented in a 24-bed intensive care unit. The protocol incorporated a bedside swallowing evaluation by a speech therapist and progressive oral intake. RESULTS In the 6 months before development and implementation of the protocol, postoperative pneumonia developed in 11% of patients. After implementation of the protocol, no patients had postoperative pneumonia (P < .01). CONCLUSIONS Implementing an aspiration prevention protocol was effective in reducing the occurrence of postoperative pneumonia in patients who had cardiothoracic surgery.

  8. Footwear Decreases Gait Asymmetry during Running

    PubMed Central

    Hoerzer, Stefan; Federolf, Peter A.; Maurer, Christian; Baltich, Jennifer; Nigg, Benno M.

    2015-01-01

    Previous research on elderly people has suggested that footwear may improve neuromuscular control of motion. If footwear does in fact improve neuromuscular control, then such an influence might already be present in young, healthy adults. A feature that is often used to assess neuromuscular control of motion is the level of gait asymmetry. The objectives of the study were (a) to develop a comprehensive asymmetry index (CAI) that is capable of detecting gait asymmetry changes caused by external boundary conditions such as footwear, and (b) to use the CAI to investigate whether footwear influences gait asymmetry during running in a healthy, young cohort. Kinematic and kinetic data were collected for both legs of 15 subjects performing five barefoot and five shod over-ground running trials. Thirty continuous gait variables including ground reaction forces and variables of the hip, knee, and ankle joints were computed for each leg. For each individual, the differences between the variables for the right and left leg were calculated. Using this data, a principal component analysis was conducted to obtain the CAI. This study had two main outcomes. First, a sensitivity analysis suggested that the CAI had an improved sensitivity for detecting changes in gait asymmetry caused by external boundary conditions. The CAI may, therefore, have important clinical applications such as monitoring the progress of neuromuscular diseases (e.g. stroke or cerebral palsy). Second, the mean CAI for shod running (131.2 ± 48.5; mean ± standard deviation) was significantly lower (p = 0.041) than the CAI for barefoot running (155.7 ± 39.5). This finding suggests that in healthy, young adults gait asymmetry is reduced when running in shoes compared to running barefoot, which may be a result of improved neuromuscular control caused by changes in the afferent sensory feedback. PMID:26488484

  9. Footwear Decreases Gait Asymmetry during Running.

    PubMed

    Hoerzer, Stefan; Federolf, Peter A; Maurer, Christian; Baltich, Jennifer; Nigg, Benno M

    2015-01-01

    Previous research on elderly people has suggested that footwear may improve neuromuscular control of motion. If footwear does in fact improve neuromuscular control, then such an influence might already be present in young, healthy adults. A feature that is often used to assess neuromuscular control of motion is the level of gait asymmetry. The objectives of the study were (a) to develop a comprehensive asymmetry index (CAI) that is capable of detecting gait asymmetry changes caused by external boundary conditions such as footwear, and (b) to use the CAI to investigate whether footwear influences gait asymmetry during running in a healthy, young cohort. Kinematic and kinetic data were collected for both legs of 15 subjects performing five barefoot and five shod over-ground running trials. Thirty continuous gait variables including ground reaction forces and variables of the hip, knee, and ankle joints were computed for each leg. For each individual, the differences between the variables for the right and left leg were calculated. Using this data, a principal component analysis was conducted to obtain the CAI. This study had two main outcomes. First, a sensitivity analysis suggested that the CAI had an improved sensitivity for detecting changes in gait asymmetry caused by external boundary conditions. The CAI may, therefore, have important clinical applications such as monitoring the progress of neuromuscular diseases (e.g. stroke or cerebral palsy). Second, the mean CAI for shod running (131.2 ± 48.5; mean ± standard deviation) was significantly lower (p = 0.041) than the CAI for barefoot running (155.7 ± 39.5). This finding suggests that in healthy, young adults gait asymmetry is reduced when running in shoes compared to running barefoot, which may be a result of improved neuromuscular control caused by changes in the afferent sensory feedback.

  10. Development

    ERIC Educational Resources Information Center

    Childress, Dana C.; Raver, Sharon A.; Michalek, Anne M. P.; Wilson, Corinne L.

    2013-01-01

    All eligible infants and toddlers who receive early intervention services under Part C of Individuals with Disabilities Education Act are entitled to service coordination. To examine the effectiveness of one state's service coordination training and its impact on knowledge and skill development, a pretest--posttest design with follow-up survey was…

  11. The effect of decreased interletter spacing on orthographic processing.

    PubMed

    Montani, Veronica; Facoetti, Andrea; Zorzi, Marco

    2015-06-01

    There is growing interest in how perceptual factors such as the spacing between letters within words modulate performance in visual word recognition and reading aloud. Extra-large letter spacing can strongly improve the reading performance of dyslexic children, and a small increase with respect to the standard spacing seems beneficial even for skilled word recognition in adult readers. In the present study we examined the effect of decreased letter spacing on perceptual identification and lexical decision tasks. Identification in the decreased spacing condition was slower than identification of normally spaced strings, thereby confirming that the reciprocal interference among letters located in close proximity (crowding) poses critical constraints on visual word processing. Importantly, the effect of spacing was not modulated by string length, suggesting that the locus of the spacing effect is at the level of letter detectors. Moreover, the processing of crowded letters was facilitated by top-down support from orthographic lexical representation as indicated by the fact that decreased spacing affected pseudowords significantly more than words. Conversely, in the lexical decision task only word responses were affected by the spacing manipulation. Overall, our findings support the hypothesis that increased crowding is particularly harmful for phonological decoding, thereby adversely affecting reading development in dyslexic children.

  12. Respiratory Kinetics of Marine Bacteria Exposed to Decreasing Oxygen Concentrations

    PubMed Central

    Gong, Xianzhe; Garcia-Robledo, Emilio; Schramm, Andreas

    2015-01-01

    During aerobic respiration, microorganisms consume oxygen (O2) through the use of different types of terminal oxidases which have a wide range of affinities for O2. The Km values for O2 of these enzymes have been determined to be in the range of 3 to 200 nmol liter−1. In this study, we examined the time course of development of aerobic respiratory kinetics of four marine bacterial species (Dinoroseobacter shibae, Roseobacter denitrificans, Idiomarina loihiensis, and Marinobacter daepoensis) during exposure to decreasing O2 concentrations. The genomes of all four species have genes for both high-affinity and low-affinity terminal oxidases. The respiration rate of the bacteria was measured by the use of extremely sensitive optical trace O2 sensors (range, 1 to 1,000 nmol liter−1). Three of the four isolates exhibited apparent Km values of 30 to 60 nmol liter−1 when exposed to submicromolar O2 concentrations, but a decrease to values below 10 nmol liter−1 was observed when the respiration rate per cell was lowered and the cell size was decreased due to starvation. The fourth isolate did not reach a low respiration rate per cell during starvation and exhibited apparent Km values of about 20 nmol liter−1 throughout the experiment. The results clearly demonstrate not only that enzyme kinetics may limit O2 uptake but also that even individual cells may be diffusion limited and that this diffusion limitation is the most pronounced at high respiration rates. A decrease in cell size by starvation, due to limiting organic carbon, and thereby more efficient diffusion uptake may also contribute to lower apparent Km values. PMID:26682857

  13. Decreased energy levels can cause and sustain obesity.

    PubMed

    Wlodek, Danuta; Gonzales, Michael

    2003-11-07

    Obesity has reached epidemic proportions and has become one of the major health problems in developed countries. Current theories consider obesity a result of overeating and sedentary life style and most efforts to treat or prevent weight gain concentrate on exercise and food intake. This approach does not improve the situation as may be seen from the steep increase in the prevalence of obesity. This encouraged us to reanalyse existing information and look for biochemical basis of obesity. Our approach was to ignore current theories and concentrate on experimental data which are described in scientific journals and are available from several databases. We developed and applied a Knowledge Discovery in Databases procedure to analyse metabolic data. We began with the contradictory information: in obesity, more calories are consumed than used up, suggesting that obese people should have excess energy. On the other side, obese people experience fatigue and decreased physical endurance that indicates diminished energy supply in the body. The result of our work is a chain of metabolic events leading to obesity. The crucial event is the inhibition of the TCA cycle at the step of aconitase. It disturbs energy metabolism and results in ATP deficiency with simultaneous fat accumulation. Further steps in obesity development are the consequences of diminished energy supply: inhibition of beta-oxidation, leptin resistance, increase in appetite and food intake and a decrease in physical activity. Thus, our theory shows that obesity does not have to be caused by overeating and sedentary life-style but may be the result of the "obese" change in metabolism which is forcing people to overeat and save energy to sustain metabolic functions of cells. This "obese" change is caused by environmental factors that activate chronic low-grade inflammatory process in the body linking obesity with the environment of developed countries.

  14. Decreased anthocyanidin reductase expression strongly decreases silver birch (Betula pendula) growth and alters accumulation of phenolics.

    PubMed

    Kosonen, Minna; Lännenpää, Mika; Ratilainen, Milla; Kontunen-Soppela, Sari; Julkunen-Tiitto, Riitta

    2015-12-01

    Phenolics, formed via a complex phenylpropanoid pathway, are important defensive agents in plants and are strongly affected by nitrogen (N) fertilization. Proanthocyanidins (PAs) are one possible endpoint of the phenylpropanoid pathway, and anthocyanidin reductase (ANR) represents a key enzyme in PA biosynthesis. In this study, the expression of silver birch (Betula pendula) anthocyanidin reductase BpANR was inhibited using the RNA interference (RNAi) method, in three consequent BpANR RNAi (ANRi birches) lines. The growth, the metabolites of the phenylpropanoid pathway, and the number of resin glands of the ANRi birches were studied when grown at two N levels. ANRi birches showed decreased growth and reduction in PA content, while the accumulation of total phenolics in both stems and leaves increased. Moreover, ANRi birches produced more resin glands than did wild-type (WT) birches. The response of ANRi birches to N depletion varied compared with that of WT birches, and in particular, the concentrations of some phenolics in stems increased in WT birches and decreased in ANRi birches. Because the inhibition of PAs biosynthesis via ANR seriously affected birch growth and resulted in accumulation of the precursors, the native level of PAs in plant tissues is assumed to be the prerequisite for normal plant growth. This draws attention to the real plant developmental importance of PAs in plant tissues.

  15. Receptor-mediated control of regulatory volume decrease (RVD) and apoptotic volume decrease (AVD)

    PubMed Central

    Okada, Yasunobu; Maeno, Emi; Shimizu, Takahiro; Dezaki, Katsuya; Wang, Jun; Morishima, Shigeru

    2001-01-01

    A fundamental property of animal cells is the ability to regulate their own cell volume. Even under hypotonic stress imposed by either decreased extracellular or increased intracellular osmolarity, the cells can re-adjust their volume after transient osmotic swelling by a mechanism known as regulatory volume decrease (RVD). In most cell types, RVD is accomplished mainly by KCl efflux induced by parallel activation of K+ and Cl− channels. We have studied the molecular mechanism of RVD in a human epithelial cell line (Intestine 407). Osmotic swelling results in a significant increase in the cytosolic Ca2+ concentration and thereby activates intermediate-conductance Ca2+-dependent K+ (IK) channels. Osmotic swelling also induces ATP release from the cells to the extracellular compartment. Released ATP stimulates purinergic ATP (P2Y2) receptors, thereby inducing phospholipase C-mediated Ca2+ mobilization. Thus, RVD is facilitated by stimulation of P2Y2 receptors due to augmentation of IK channels. In contrast, stimulation of another G protein-coupled Ca2+-sensing receptor (CaR) enhances the activity of volume-sensitive outwardly rectifying Cl− channels, thereby facilitating RVD. Therefore, it is possible that Ca2+ efflux stimulated by swelling-induced and P2Y2 receptor-mediated intracellular Ca2+ mobilization activates the CaR, thereby secondarily upregulating the volume-regulatory Cl− conductance. On the other hand, the initial process towards apoptotic cell death is coupled to normotonic cell shrinkage, called apoptotic volume decrease (AVD). Stimulation of death receptors, such as TNFα receptor and Fas, induces AVD and thereafter biochemical apoptotic events in human lymphoid (U937), human epithelial (HeLa), mouse neuroblastoma × rat glioma hybrid (NG108-15) and rat phaeochromocytoma (PC12) cells. In those cells exhibiting AVD, facilitation of RVD is always observed. Both AVD induction and RVD facilitation as well as succeeding apoptotic events can be

  16. Resolvins Decrease Oxidative Stress Mediated Macrophage and Epithelial Cell Interaction through Decreased Cytokine Secretion

    PubMed Central

    Cox, Ruan; Phillips, Oluwakemi; Fukumoto, Jutaro; Fukumoto, Itsuko; Tamarapu Parthasarathy, Prasanna; Mandry, Maria; Cho, Young; Lockey, Richard; Kolliputi, Narasaiah

    2015-01-01

    Background Inflammation is a key hallmark of ALI and is mediated through ungoverned cytokine signaling. One such cytokine, interleukin-1beta (IL-1β) has been demonstrated to be the most bioactive cytokine in ALI patients. Macrophages are the key players responsible for IL-1β secretion into the alveolar space. Following the binding of IL-1β to its receptor, “activated” alveolar epithelial cells show enhanced barrier dysfunction, adhesion molecule expression, cytokine secretion, and leukocyte attachment. More importantly, it is an important communication molecule between the macrophage and alveolar epithelium. While the molecular determinants of this inflammatory event have been well documented, endogenous resolution processes that decrease IL-1β secretion and resolve alveolar epithelial cell activation and tissue inflammation have not been well characterized. Lipid mediator Aspirin-Triggered Resolvin D1 (AT-RvD1) has demonstrated potent pro-resolutionary effects in vivo models of lung injury; however, the contribution of the alveoli to the protective benefits of this molecule has not been well documented. In this study, we demonstrate that AT-RvD1 treatment lead to a significant decrease in oxidant induced macrophage IL-1β secretion and production, IL-1β-mediated cytokine secretion, adhesion molecule expression, leukocyte adhesion and inflammatory signaling. Methods THP-1 macrophages were treated with hydrogen peroxide and extracellular ATP in the presence or absence of AT-RvD1 (1000–0.1 nM). A549 alveolar-like epithelial cells were treated with IL-1β (10 ng/mL) in the presence or absence of AT-RvD1 (0.1 μM). Following treatment, cell lysate and cell culture supernatants were collected for Western blot, qPCR and ELISA analysis of pro-inflammatory molecules. Functional consequences of IL-1β induced alveolar epithelial cell and macrophage activation were also measured following treatment with IL-1β ± AT-RvD1. Results Results demonstrate that

  17. Chronic Stress Decreases Cerebrovascular Responses During Rat Hindlimb Electrical Stimulation

    PubMed Central

    Lee, Sohee; Kang, Bok-Man; Shin, Min-Kyoo; Min, Jiwoong; Heo, Chaejeong; Lee, Yubu; Baeg, Eunha; Suh, Minah

    2015-01-01

    Repeated stress is one of the major risk factors for cerebrovascular disease, including stroke, and vascular dementia. However, the functional alterations in the cerebral hemodynamic response induced by chronic stress have not been clarified. Here, we investigated the in vivo cerebral hemodynamic changes and accompanying cellular and molecular changes in chronically stressed rats. After 3 weeks of restraint stress, the elicitation of stress was verified by behavioral despair in the forced swimming test and by physical indicators of stress. The evoked changes in the cerebral blood volume and pial artery responses following hindpaw electrical stimulation were measured using optical intrinsic signal imaging. We observed that, compared to the control group, animals under chronic restraint stress exhibited a decreased hemodynamic response, with a smaller pial arterial dilation in the somatosensory cortex during hindpaw electrical stimulation. The effect of chronic restraint stress on vasomodulator enzymes, including neuronal nitric oxide synthase (nNOS) and heme oxygenase-2 (HO-2), was assessed in the somatosensory cortex. Chronic restraint stress downregulated nNOS and HO-2 compared to the control group. In addition, we examined the subtypes of cells that can explain the environmental changes due to the decreased vasomodulators. The expression of parvalbumin in GABAergic interneurons and glutamate receptor-1 in neurons were decreased, whereas the microglial activation was increased. Our results suggest that the chronic stress-induced alterations in cerebral vascular function and the modulations of the cellular expression in the neuro-vasomodulatory system may be crucial contributing factors in the development of various vascular-induced conditions in the brain. PMID:26778944

  18. Dark septate endophyte decreases stress on rice plants.

    PubMed

    Santos, Silvana Gomes Dos; Silva, Paula Renata Alves da; Garcia, Andres Calderin; Zilli, Jerri Édson; Berbara, Ricardo Luis Louro

    Abiotic stress is one of the major limiting factors for plant development and productivity, which makes it important to identify microorganisms capable of increasing plant tolerance to stress. Dark septate endophytes can be symbionts of plants. In the present study, we evaluated the ability of dark septate endophytes isolates to reduce the effects of water stress in the rice varieties Nipponbare and Piauí. The experiments were performed under gnotobiotic conditions, and the water stress was induced with PEG. Four dark septate endophytes were isolated from the roots of wild rice (Oryza glumaepatula) collected from the Brazilian Amazon. Plant height as well as shoot and root fresh and dry matter were measured. Leaf protein concentrations and antioxidant enzyme activity were also estimated. The dark septate endophytes were grown in vitro in Petri dishes containing culture medium; they exhibited different levels of tolerance to salinity and water stress. The two rice varieties tested responded differently to inoculation with dark septate endophytes. Endophytes promoted rice plant growth both in the presence and in the absence of a water deficit. Decreased oxidative stress in plants in response to inoculation was observed in nearly all inoculated treatments, as indicated by the decrease in antioxidant enzyme activity. Dark septate endophytes fungi were shown to increase the tolerance of rice plants to stress caused by water deficiency.

  19. Androgen decreases dopamine neurone survival in rat midbrain.

    PubMed

    Johnson, M L; Day, A E; Ho, C C; Walker, Q D; Francis, R; Kuhn, C M

    2010-04-01

    Clinical studies show that men are more likely to develop disorders affecting midbrain dopaminergic pathways, such as drug addiction and Parkinson's disease (PD). Although a great deal of focus has been given to the role of oestrogen in the maintenance of midbrain dopaminergic pathways, little is known about how testosterone influences these pathways. In the present study, we used stereological analysis of tyrosine hydroxylase-immunoreactive (TH-IR) cell bodies to determine how testosterone influences the dopaminergic cell bodies of the substantia nigra pars compacta (SNpc) and ventral tegmental area (VTA). Rats and mice were castrated at postnatal day (PN) 60, and these midbrain cell populations were counted on PN 90. One month after castration, TH-IR cell number had increased in the SNpc and VTA of rats and mice. Replacement with testosterone or the non-aromatisable analogue dihydrotestosterone (DHT) in castrated animals reduced TH-IR cell number in the SNpc and VTA in rats. In mice, the decrease of TH-IR cell number with testosterone or DHT replacement was observed only in the SNpc. The apparent increase in TH-IR neurone number after castration is not explained by an increase in TH expression because the number of nondopaminergic cells (TH-immunonegative, TH-IN) did not decrease proportionally after castration. TH-IN cell number did not change after castration or hormone replacement in rat or mouse SNpc or VTA. These findings suggest that testosterone may play a suppressive role in midbrain dopaminergic pathways.

  20. Decreased Self-Concept Clarity in People with Schizophrenia

    PubMed Central

    Cicero, David C.; Martin, Elizabeth A; Becker, Theresa M.; Kerns, John G.

    2015-01-01

    Disturbances in the perception of self are thought to be central to the development of psychosis. Self-concept clarity (SCC) is the extent to which one’s beliefs about oneself are internally consistent, stable, and clear. Participants with schizophrenia (N = 54) and healthy controls (N = 32) completed the Me Not-Me Decision Task (MNMDT), in which they decided whether 60 adjectives (30 pairs of antonyms), did or did not describe themselves. SCC is conceptualized as the number of consistent responses. Participants also completed the Self-Concept Clarity Scale (SCCS). Compared to healthy controls, participants with schizophrenia scored lower on the MNMDT and SCCS, and scores were negatively correlated with positive and negative symptoms. In a simultaneous regression, SCCS scores were uniquely associated with positive symptoms, while MNMDT scores were uniquely associated with negative symptoms. This suggests that people with schizophrenia have decreased self-concept claritythat is related to positive and negative symptoms. PMID:26669980

  1. Evaluation of zuclopenthixol acetate to decrease handling stress in wapiti.

    PubMed

    Read, M; Caulkett, N; McCallister, M

    2000-07-01

    Handling stress and capture myopathy are important consequences of intensively managing wildlife species. Over the last 15 yr, the use of long-acting neuroleptic (LAN) drugs in wildlife has increased, and these drugs have become a valuable tool for decreasing capture and handling stress in many species. At this time, reports on the use of these drugs in North American species are limited. The major objective of this study was to evaluate the use of the LAN, zuclopenthixol acetate (Clopixol-Acuphase), to decrease both quantifiable and subjective measurements of stress and activity in wild wapiti (Cervus elaphus, North American elk). This blinded, randomized study took place in February 1999 in Manitoba (Canada) and involved 11 animals receiving the drug and 12 animals acting as controls. At 24 hr after drug administration, there were measurable and significant decreases in the stress and activity of treated animals versus controls during handling. Treated animals had significantly lower mean body temperatures (39.0 versus 40.6 C), less hemoconcentration (mean packed cell volume 0.42 versus 0.49, mean hemoglobin 159.09 versus 181.75 g/L, mean total protein 65.0 versus 70.25 g/L), lower mean serum cortisol (97.91 versus 139.50 mmol/L), lower mean blood lactate (3.39 versus 5.98 mmol/L), and were less metabolically acidotic (mean pHv 7.45 versus 7.34, mean bicarbonate 29.36 versus 24.25 mmol/L, mean base excess 5.64 versus -0.83 mmol/L). Only control animals had evidence of muscle damage based on serum biochemistry (creatine phosphate values of two animals of 42,080 and 25,887 U/L). No animals developed clinical capture myopathy, and no animals died. Measurable effects of this drug were still apparent at 72 hr post-administration. The results of this study support the use of Clopixol-Acuphase in wapiti as a means to decrease handling stress and activity.

  2. Concurrent working memory task decreases the Stroop interference effect as indexed by the decreased theta oscillations.

    PubMed

    Zhao, Y; Tang, D; Hu, L; Zhang, L; Hitchman, G; Wang, L; Chen, A

    2014-03-14

    Working memory (WM) tasks may increase or decrease the interference effect of concurrently performed cognitive control tasks. However, the neural oscillatory correlates of this modulation effect of WM on the Stroop task are still largely unknown. In the present study, behavioral and electroencephalographic (EEG) data were recorded from 32 healthy participants during their performance of the single Stroop task and the same task with a concurrent WM task. We observed that the Stroop interference effect represented in both response times (RTs) and theta-band event-related spectral perturbation (ERSP) magnitude reduced under the dual-task condition compared with the single-task condition. The reduction of interference in theta-band ERSP was further positively correlated with interference reduction in RTs, and was mainly explained by the source in the left middle frontal gyrus. In conclusion, the present study suggests that the effect of concurrent WM tasks on the reduction of the Stroop interference effect can be indexed by EEG oscillations in theta-band rhythm in the centro-frontal regions and this modulation was mediated by the reduced cognitive control under the concurrent WM task.

  3. Poor Predictive Value of Cytomegalovirus (CMV)–Specific T Cell Assays for the Development of CMV Retinitis in Patients with AIDS

    PubMed Central

    Jacobson, Mark A.; Tan, Qi Xuan; Girling, Valerie; Poon, C.; Van Natta, Mark; Jabs, Douglas A.; Inokuma, Margaret; Maecker, Holden T.; Bredt, Barry; Sinclair, Elizabeth

    2009-01-01

    Background We examined the potential clinical utility of using a cytomegalovirus (CMV)–specific T cell immunoassay to determine the risk of developing new-onset CMV retinitis (CMVR) in patients with acquired immunodeficiency syndrome (AIDS). Methods CMV-specific T cell assays were performed by multiparameter flow cytometry using stored peripheral blood mononuclear cells that had been obtained in an observational study 2–6 months before new-onset CMVR was diagnosed in case patients (at a study visit during which a dilated ophthalmologic examination revealed no evidence of CMVR) and at the same study visit in control subjects (matched by absolute CD4+ T cell count at entry) who did not subsequently develop retinitis during 1–6 years of study follow-up. Results There were no significant differences in CMV-specific CD4+ or CD8+ T cell interferon-γ or interleukin-2 expression in peripheral blood mononuclear cells from case patients and control subjects. Although there were trends toward lower percentages and absolute numbers of CMV-specific, cytokine-expressing CD8+ T cells with a “late memory” phenotype (CD27−CD28−) as well as with an “early memory” phenotype (CD27+CD28+CD45RA+) in case patients than in control subjects, these differences were not statistically significant. Conclusions Many studies have reported that CMV-specific CD4+ and CD8+ T cell responses distinguish patients with active CMVR (i.e., who lack CMV-protective immunity) from those with inactive CMVR after immune restoration by antiretroviral treatment (i.e., who have CMV-protective immunity). However, the multiple CMV-specific immune responses we measured do not appear to have clinical utility for predicting the risk for patients with AIDS of developing new-onset CMVR with sufficient accuracy to be used in guiding therapeutic management. PMID:18173357

  4. Investigation of application possibility of quasi-softening for scale formation decrease

    NASA Astrophysics Data System (ADS)

    Ananeva, E. A.; Feklistov, D. Y.

    2016-09-01

    Methods of water treatment were developed using activators, which lead to decrease of scale formation due to the conversion of hardness salts into aragonite crystal form. The installation was created on the base of conducted research, which can be used in systems of circulating water supply and allows to provide the decrease of scale formation.

  5. 43 CFR 4110.4-2 - Decrease in land acreage.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 43 Public Lands: Interior 2 2011-10-01 2011-10-01 false Decrease in land acreage. 4110.4-2 Section 4110.4-2 Public Lands: Interior Regulations Relating to Public Lands (Continued) BUREAU OF LAND... Qualifications and Preference § 4110.4-2 Decrease in land acreage. (a) Where there is a decrease in public...

  6. Forbush decreases geomagnetic and atmospheric effects cosmogenic nuclides

    NASA Technical Reports Server (NTRS)

    Flueckiger, E. O.

    1986-01-01

    An overview and synthesis is given of recent developments that have occurred in the areas of Forbush decreases, geomagnetic and atmospheric effects, and cosmogenic nuclides. Experimental evidence has been found for substantial differences in the effects of the various types of interplanetary perturbations on cosmic rays, and for a dependence of these effects on the three-dimensional configuration of the interplanetary medium. In order to fully understand and to be able to simulate the solar cosmic ray particle access to the polar regions of the earth we need accurate models of the magnetospheric magnetic field. These models must include all major magnetospheric current systems (in particular the field aligned currents), and they should represent magnetically quiet time periods as well as different levels of geomagnetic activity. In the evolution of magnetospheric magnetic field models, cosmic ray and magnetospheric physicists should work closely together since cosmic ray measurements are a powerful additional tool in the study of the perturbed magnetosphere. In the field of cosmogenic nuclides, finally, exciting new results and developments follow in rapid succession. Thanks to new techniques and new isotopes the analysis of cosmic ray history has entered into a new dimension.

  7. The response of clouds and aerosols to cosmic ray decreases

    NASA Astrophysics Data System (ADS)

    Svensmark, J.; Enghoff, M. B.; Shaviv, N. J.; Svensmark, H.

    2016-09-01

    A method is developed to rank Forbush decreases (FDs) in the galactic cosmic ray radiation according to their expected impact on the ionization of the lower atmosphere. Then a Monte Carlo bootstrap-based statistical test is formulated to estimate the significance of the apparent response in physical and microphysical cloud parameters to FDs. The test is subsequently applied to one ground-based and three satellite-based data sets. Responses (>95%) to FDs are found in the following parameters of the analyzed data sets. AERONET: Ångström exponent (cloud condensation nuclei changes), SSM/I: liquid water content, International Satellite Cloud Climate Project (ISCCP): total, high, and middle, IR-detected clouds over the oceans, Moderate Resolution Imaging Spectroradiometer (MODIS): cloud effective emissivity, cloud optical thickness, liquid water, cloud fraction, liquid water path, and liquid cloud effective radius. Moreover, the responses in MODIS are found to correlate positively with the strength of the FDs, and the signs and magnitudes of the responses agree with model-based expectations. The effect is mainly seen in liquid clouds. An impact through changes in UV-driven photo chemistry is shown to be negligible and an impact via UV absorption in the stratosphere is found to have no effect on clouds. The total solar irradiance has a relative decrease in connection with FDs of the order of 10-3, which is too small to have a thermodynamic impact on timescales of a few days. The results demonstrate that there is a real influence of FDs on clouds probably through ions.

  8. Low social status decreases the neural salience of unfairness.

    PubMed

    Hu, Jie; Cao, Yuan; Blue, Philip R; Zhou, Xiaolin

    2014-01-01

    Social hierarchy exists in almost all social species and affects everything from resource allocation to the development of intelligence. Previous studies showed that status within a social hierarchy influences the perceived fairness of income allocation. However, the effect of one's social status on economic decisions is far from clear, as are the neural processes underlying these decisions. In this study, we dynamically manipulated participants' social status and analyzed their behavior as recipients in the ultimatum game (UG), during which event-related potentials (ERPs) were recorded. Behavioral results showed that acceptance rates for offers increased with the fairness level of offers. Importantly, participants were less likely to accept unfair offers when they were endowed with high status than with low status. In addition, cues indicating low status elicited a more positive P2 than cues indicating high status in an earlier time window (170-240 ms), and cues indicating high status elicited a more negative N400 than cues indicating low status in a later time window (350-520 ms). During the actual reception of offers, the late positivity potential (LPP, 400-700 ms) for unfair offers was more positive in the high status condition than in the low status condition, suggesting a decreased arousal for unfair offers during low status. These findings suggest a strong role of social status in modulating individual behavioral and neural responses to fairness.

  9. Low frequency electroacupuncture selectively decreases voluntarily ethanol intake in rats.

    PubMed

    Li, Jing; Zou, Yihuai; Ye, Jiang-Hong

    2011-11-25

    Although there is increasing clinical acceptance of acupuncture and electroacupuncture (EA) as a treatment of substance abuse-related disorders, our understanding of this treatment remains incomplete. Previous clinical and pre-clinical studies have shown that acupuncture and EA are effective in reducing ethanol consumption. Recent studies have shown that Sprague-Dawley (SD) rats under an intermittent-access two-bottle choice drinking procedure (IE procedure) voluntarily drank high amounts of ethanol. However, an effect of EA on ethanol consumption of the SD rats under this drinking procedure has not been demonstrated. In the present study, we demonstrated that SD rats escalated their ethanol intake and subsequently developed ethanol dependence under the IE procedure. A single low (2 Hz), but not high frequency (100 Hz) EA treatment applied at the bilateral acupoint Zusanli (ST36), but not at the tail reduced voluntary intake of, and preference for ethanol, but not sucrose. Furthermore, repeated EA treatments decreased the intake of and preference for ethanol, without resulting in a rebound increase in ethanol intake when the EA treatments were terminated. These observations indicate that EA may be a useful treatment for alcohol abuse.

  10. Decreased Prolidase Activity in Patients with Posttraumatic Stress Disorder

    PubMed Central

    Bulut, Mahmut; Atli, Abdullah; Kaplan, İbrahim; Kaya, Mehmet Cemal; Bez, Yasin; Özdemir, Pınar Güzel; Sır, Aytekin

    2016-01-01

    Objective Many neurochemical systems have been implicated in the development of Posttraumatic Stress Disorder (PTSD). The prolidase enzyme is a cytosolic exopeptidase that detaches proline or hydroxyproline from the carboxyl terminal position of dipeptides. Prolidase has important biological effects, and to date, its role in the etiology of PTSD has not been studied. In the present study, we aimed to evaluate prolidase activity in patients with PTSD. Methods The study group consisted of patients who were diagnosed with PTSD after the earthquake that occurred in the province of Van in Turkey in 2011 (n=25); the first control group consisted of patients who experienced the earthquake but did not show PTSD symptoms (n=26) and the second control group consisted of patients who have never been exposed to a traumatic event (n=25). Prolidase activities in the patients and the control groups were determined by the ELISA method using commercial kits. Results Prolidase activity in the patient group was significantly lower when compared to the control groups. Prolidase activity was also significantly lower in the traumatized healthy subjects compared to the other healthy group (p<0.01). Conclusion The findings of the present study suggest that the decrease in prolidase activity may have neuroprotective effects in patients with PTSD. PMID:27482243

  11. Decrease of fibrinolytic activity in human endothelial cells by arsenite.

    PubMed

    Jiang, Shinn-Jong; Lin, Tsun-Mei; Wu, Hua-Lin; Han, Huai-Song; Shi, Guey-Yueh

    2002-01-01

    Blackfoot disease (BFD) is an endemic peripheral vascular occlusive disease that occurred in the southwest coast of Taiwan. It is believed that arsenic in the drinking water from artesian wells plays an important role in the development of the disease. We have previously shown that BFD patients had significant lower tissue-type plasminogen activator (t-PA) antigen level and higher plasminogen activator inhibitor, Type 1 (PAI-1) antigen level than normal controls. The purpose of this study was to investigate the effects of arsenite on the fibrinolytic and anticoagulant activities of cultured macrovascular and microvascular endothelial cells. Incubation of human microvascular endothelial cells (HMEC-1), but not human umbilical vein endothelial cells (HUVECs), with arsenite caused a decrease of t-PA mRNA level, a rise of both PAI-1 mRNA level and PAI activity. Arsenite could also inhibit the thrombomodulin (TM) mRNA expression and reduce the TM antigen level in HMEC-1. In conclusion, arsenite had a greater effect on HMEC-1 as compared to HUVECs in lowering the fibrinolytic activity and may be responsible for the reduced capacity of fibrinolysis associated with BFD.

  12. Fibroblast growth factor receptor levels decrease during chick embryogenesis

    PubMed Central

    1990-01-01

    Two putative receptors for fibroblast growth factor (FGF) of approximately 150 and 200 kD were identified in membrane preparations from chick embryos. Specific binding (femtomoles/milligram) of 125I- aFGF to whole chick embryonic membranes was relatively constant from day 2 to 7, then decreased fivefold between days 7 and 13. Day-19 chick embryos retained 125I-aFGF binding at low levels to brain, eye, and liver tissues but not to skeletal muscle or cardiac tissues. The 200-kD FGF receptor began to decline between day 4.5 and 7 and was barely detectable by day 9, whereas the 150-kD FGF receptor began to decline by day 7 but was still detectable in day-9 embryonic membranes. It is not known whether the two FGF-binding proteins represent altered forms of one polypeptide, but it is clear that their levels undergo differential changes during development. Because endogenous chick FGF may remain bound to FGF receptor in membrane preparations, membranes were treated with acidic (pH 4.0) buffers to release bound FGF; such treatment did not affect 125I-aFGF binding and moderately increased the number of binding sites in day-7 and -19 embryos. Consequently, the observed loss of high affinity 125I-aFGF binding sites and FGF-binding polypeptides most likely represents a loss of FGF receptor protein. These experiments provide in vivo evidence to support the hypothesis that regulation of FGF receptor levels may function as a mechanism for controlling FGF-dependent processes during embryonic development. PMID:2153684

  13. The Continuing Incidence of Natural Decrease in American Counties

    ERIC Educational Resources Information Center

    Johnson, Kenneth M.

    2011-01-01

    In 2002, more American counties (985) experienced natural decrease than at any time in the nation's history. The incidence of natural decrease has diminished since then, but remains near record levels. It is most common in rural areas remote from metropolitan centers. Spatial concentrations exist in the Great Plains, Corn Belt, and East Texas,…

  14. Decreases in Human Semen Quality with Age Among Healthy Men

    SciTech Connect

    Eskenazi, B.; Wyrobek, A.J.; Kidd, S.A.; Moore, L.; Young, S.S.; Moore, D.

    2001-12-01

    The objective of this report is to characterize the associations between age and semen quality among healthy active men after controlling for identified covariates. Ninety-seven healthy, nonsmoking men between 22 and 80 years without known fertility problems who worked for or retired from a large research laboratory. There was a gradual decrease in all semen parameters from 22-80 years of age. After adjusting for covariates, volume decreased 0.03 ml per year (p = 0.001); sperm concentration decreased 2.5% per year (p = 0.005); total count decreased 3.6% per year of age (p < 0.001); motility decreased 0.7% per year (P < 0.001); progressive motility decreased 3.1% per year (p < 0.001); and total progressively motile sperm decreased 4.8% per year (p < 0.001). In a group of healthy active men, semen volume, sperm concentration, total sperm count, and sperm motility decrease continuously between 22-80 years of age, with no evidence of a threshold.

  15. Effect of decreased gravity on circulation in the rat

    NASA Technical Reports Server (NTRS)

    Popovic, Vojin P.

    1987-01-01

    It has been reported that hypokinesia and bed rest induce cardiovascular changes similar to those observed in space flights. Using an animal model that was developed in our laboratory and that was extensively studied and characterized in our laboratory and other laboratories in this country and abroad, we have studied circulatory mechanisms that occur during exposure to hypokinesia (with or without negative tilt) as well as during readaptation to control conditions (free activity). We believe that this study contributes to better understanding of mammalian circulatory mechanisms that operate under 1-g force and will serve to provide control data to be compared with cardiovascular data obtained in conditions of a Space lab. Because survey and anesthesia drastically decrease cardiac output and other circulatory parameters in rats, only unanesthetized rats were used in experiments. Aorta and right atrium of the animals were permanently cannulated fifteen to twenty days before experiments. Arterial and right ventricular blood pressures, cardiac output, cerebral and other regional blood flow, ECG, other cardiovascular parameters, and oxygen consumption were measured with techniques routinely used in our laboratory. Specifically, we undertook the following investigations during the period of three years: (1) A study of circulatory changes (right ventricular pressure, arterial blood pressure, heart rate, cardiac output) during exposure of rats to hypokinetic conditions. Used the head down tilted Holton-Musacchia system in order to compare the results with the results already obtained on unrestrained rats, (2) Humoral changes were investigated in animals exposed to hypokinesia; also, lymphocyte and neutrophil levels in hypokinetic animals (with or without tilt) were determined to ascertain the level of induced stress and possible changes observed in weightless animals, and (3) circulating blood volume was determined during and after hypokinesia.

  16. Toxoplasma gondii decreases the reproductive fitness in mice.

    PubMed

    Dvorakova-Hortova, Katerina; Sidlova, Adela; Ded, Lukas; Hladovcova, Denisa; Vieweg, Markus; Weidner, Wolfgang; Steger, Klaus; Stopka, Pavel; Paradowska-Dogan, Agnieszka

    2014-01-01

    Toxoplasma gondii is a common protozoan parasite that infects warm-blooded animals throughout the world, including mice and humans. During infection, both, the parasite and the host, utilize various mechanisms to maximize their own reproductive success. Mice and humans are both the intermediate hosts for Toxoplasma gondii, which forms specialized vacuoles containing reproductive cysts in the formers' tissue. As half of the human population is infected, developing a disease called toxoplasmosis, along with an ever-growing number of couples suffering with idiopathic infertility, it is therefore surprising that there is a lack of research on how Toxoplasma gondii can alter reproductive parameters. In this study, a detailed histometric screening of the testicular function along with the levels of the pituitary luteinizing hormone (LH) were analysed in infected mice. Data on relative testis and epididymis weight, and sperm count were also collected. Based on the results obtained, the level of LH in the urine of Toxoplasma gondii infected mice was lower compared to the control. In direct correlation with the hormone level, testicular function and sperm production was also significantly lower in Toxoplasma gondii positive group using sperm count and histometric analysis as a marker. Not only were the number of leptotene primary spermatocytes and spermatids lowered, but the number of Sertoli cells and the tubule diameter were elevated. In parallel, a pilot epigenetic study on global testicular methylation, and specific methylation of Crem, Creb1 and Hspa1genes essential for successfully ongoing spermatogenesis was performed. Global methylation was elevated in Toxoplasma infected mice, and differences in the DNA methylation of selected genes were detected between the Toxoplasma positive and control group. These findings demonstrate a direct relation between Toxoplasma gondii infection and the decrease of male reproductive fitness in mice, which may contribute to an increase

  17. Decreasing nonmarital births and strengthening marriage to reduce poverty.

    PubMed

    Amato, Paul R; Maynard, Rebecca A

    2007-01-01

    Since the 1970s, the share of U.S. children growing up in single-parent families has doubled, a trend that has disproportionately affected disadvantaged families. Paul Amato and Rebecca Maynard argue that reversing that trend would reduce poverty in the short-term and, perhaps more important, improve children's growth and development over the long term, thus reducing the likelihood that they would be poor when they grew up. The authors propose school and community programs to help prevent nonmarital births. They also propose to lower divorce rates by offering more educational programs to couples before and during marriage. Amato and Maynard recommend that all school systems offer health and sex education whose primary message is that parenthood is highly problematic for unmarried youth. They also recommend educating young people about methods to prevent unintended pregnancies. Ideally, the federal government would provide tested curriculum models that emphasize both abstinence and use of contraception. All youth should understand that unintended pregnancies are preventable and have enormous costs for the mother, the father, the child, and society. Strengthening marriage, argue the authors, is also potentially an effective strategy for fighting poverty. Researchers consistently find that premarital education improves marital quality and lowers the risk of divorce. About 40 percent of couples about to marry now participate in premarital education. Amato and Maynard recommend doubling that figure to 80 percent and making similar programs available for married couples. Increasing the number of couples receiving services could mean roughly 72,000 fewer divorces each year, or around 65,000 fewer children entering a single-parent family every year because of marital dissolution. After seven or eight years, half a million fewer children would have entered single-parent families through divorce. Efforts to decrease the share of children in single-parent households, say the

  18. Persistent Postconcussive Symptoms Are Accompanied by Decreased Functional Brain Oxygenation.

    PubMed

    Helmich, Ingo; Saluja, Rajeet S; Lausberg, Hedda; Kempe, Mathias; Furley, Philip; Berger, Alisa; Chen, Jen-Kai; Ptito, Alain

    2015-01-01

    Diagnostic methods are considered a major concern in the determination of mild traumatic brain injury. The authors examined brain oxygenation patterns in subjects with severe and minor persistent postconcussive difficulties and a healthy control group during working memory tasks in prefrontal brain regions using functional near-infrared spectroscopy. The results demonstrated decreased working memory performances among concussed subjects with severe postconcussive symptoms that were accompanied by decreased brain oxygenation patterns. An association appears to exist between decreased brain oxygenation, poor performance of working memory tasks, and increased symptom severity scores in subjects suffering from persistent postconcussive symptoms.

  19. Nitrate leaching concentrations in the Netherlands decreased more than expected

    NASA Astrophysics Data System (ADS)

    Boumans, Leo; Fraters, Dico; Wattel, Esther

    2014-05-01

    The implementation of EU environmental directives and national policies into measures has led to a decrease in nitrogen (N) surplus in agriculture, notably at dairy farms in the 1995-2002 period. In addition, N emissions to air from agricultural fields have been reduced, and atmospheric N deposition on nature areas subsequently lessened. The nitrate concentrations in root zone leaching at dairy farms and nature areas in the Sand region of the Netherlands also decreased. These decreases were larger than would be expected based on the decreases in net loads. We have formulated and tested hypotheses to explain these extra decreases at farms and in nature areas. Dairy farms cover about 60% of the area in the sandy region of the Netherlands. They have shown a nitrate leaching decrease of 100 mg/l during the 1992-2010 period (67%). The N-surplus at dairy farms decreased from about 340 to 180 kg/ha in this period (47%). Other farm management factors may have caused the additional decrease in root zone leaching concentration on farm level. The main potential factors are the ratio grassland - arable land, the grazing intensity and the ratio artificial fertilizer N - manure N. There are no indications that the ratio grassland - arable land or the ratio artificial fertilizer N - manure N significantly changed between 1992 and 2010. The mowing percentage, as an indicator for grazing intensity, increased from about 180 to 290% in the study period. About 80% (80 mg/l) of the decrease at dairy farms can be attributed to a lower N-surplus and about 20% (20 mg/l) is postulated to be caused by an increasing mowing percentage or less fodder grazing. Nature areas cover about 20% of the area in the Sand region. Nitrate concentrations in root zone leaching in nature areas showed a decrease of 55% in 2010 compared to 1990. Yet in rainwater, the concentration decrease is only 40%. Several factors may cause an additional decrease in nitrate concentration particularly an increase of plant

  20. Sensing Disaster: The Use of Wearable Sensor Technology to Decrease Firefighter Line-of-Duty Deaths

    DTIC Science & Technology

    2015-12-01

    THE USE OF WEARABLE SENSOR TECHNOLOGY TO DECREASE FIREFIGHTER LINE-OF-DUTY DEATHS by John A. Payne December 2015 Thesis Co-Advisors...REPORT TYPE AND DATES COVERED Master’s thesis 4. TITLE AND SUBTITLE “SENSING DISASTER”: THE USE OF WEARABLE SENSOR TECHNOLOGY TO DECREASE...cardiac complications while on the fire ground than anywhere else while on duty. The development of wearable sensor technology now allows for

  1. Ozone decreases spring root growth and root carbohydrate content in ponderosa pine the year following exposure

    SciTech Connect

    Andersen, C.P.; Hogsett, W.E.; Wessling, R.; Plocher, M.

    1991-01-01

    Storage carbohydrates are extremely important for new shoot and root development following dormancy or during periods of high stress. The hypothesis that ozone decreases carbohydrate storage and decreases new root growth during the year following exposure was investigated. The results suggest that (1) ponderosa pine seedlings exposed to 122 and 169 ppm hrs ozone for one season have significantly less root starch reserves available just prior to and during bud break the following year, and (2) spring root growth is decreased following ozone exposure. The carry-over effects of ozone stress may be important in long-lived perennial species which are annually subjected to ozone.

  2. Cantharidin decreases in vitro digestion of alfalfa and smooth bromegrass.

    PubMed

    Lenssen, A W; Blodgett, S L; Higgins, R A; Nagaraja, T G; Posler, G L; Broce, A B

    1990-10-01

    Blister beetles (Coleoptera:Meloidae) containing the toxin cantharidin can be incorporated with alfalfa (Medicago sativa L) during forage conservation. Cantharidin inadvertently ingested with animal feed may cause illness or death. Little information is available on the effects of cantharidin on ruminant microbial digestion. The objective of our study was to determine cantharidin effects on digestibility of alfalfa and smooth bromegrass (Bromus inermis Leyss) by measuring in vitro digestible dry matter (IVDDM) and cell wall digestion (CWD). Alfalfa dry matter digestibility, measured after IVDDM at 48 and 96 h fermentation periods, decreased as cantharidin concentration increased. Increasing cantharidin concentration also significantly reduced IVDDM of smooth bromegrass at 24 and 96 h digestion time. The CWD of alfalfa and smooth bromegrass decreased as cantharidin concentration increased. These results indicate that ingestion of cantharidin by ruminants may decrease microbial digestion of fibrous feeds and therefore may decrease the efficiency of feed utilization by ruminants.

  3. Sodium retention by insulin may depend on decreased plasma potassium.

    PubMed

    Friedberg, C E; Koomans, H A; Bijlsma, J A; Rabelink, T J; Dorhout Mees, E J

    1991-02-01

    Evidence is accumulating that insulin is a hypertensive factor in humans. The involved mechanism may be its sodium-retaining effect. We examined whether insulin causes sodium retention through a direct action on the kidney, as is generally assumed, or indirectly through hypokalemia. Insulin was infused (euglycemic clamp technique) with and without potassium infusion to prevent hypokalemia in six healthy subjects. Without potassium infusion, insulin caused a marked decrease in plasma potassium (-0.75 mmol/L), and decreased urinary sodium and potassium excretions by, approximately 38% and 65%, respectively. Simultaneous potassium infusion largely prevented the decrease in plasma potassium, as well as the decrease in urinary sodium and potassium excretions. These data suggest that the acute antinatriuretic effect of insulin may be largely mediated in an indirect way, ie, through hypokalemia.

  4. Punishment and Alternative Strategies for Decreasing a Behavior.

    ERIC Educational Resources Information Center

    Vought, James J.

    1984-01-01

    Provides an overview on the subject of punishment and alternative procedures to decelerate a behavior. Describes differential reinforcement, extinction, satiation, corrective feedback, using peers as models and rearranging the environment as positive and nonaversive procedures for decreasing a behavior. (LLL)

  5. Developmental Triclosan Exposure Decreases Maternal and Offspring Thyroxine in Rats*

    EPA Science Inventory

    Epidemiological and laboratory data have demonstrated that disruption of maternal thyroid hormones during fetal developmental may result in irreversible neurological consequences in offspring. In a short-term exposure paradigm, triclosan decreased systemic thyroxine (T4) concentr...

  6. NAD(+) administration decreases doxorubicin-induced liver damage of mice by enhancing antioxidation capacity and decreasing DNA damage.

    PubMed

    Wang, Ban; Ma, Yingxin; Kong, Xiaoni; Ding, Xianting; Gu, Hongchen; Chu, Tianqing; Ying, Weihai

    2014-04-05

    One of the major obstacles for cancer treatment is the toxic side effects of anti-cancer drugs. Doxorubicin (DOX) is one of the most widely used anti-cancer drugs, which produces significant toxic side effects on the heart and such organs as the liver. Because NAD(+) can decrease cellular or tissue damage under multiple conditions, we hypothesized that NAD(+) administration may decrease DOX-induced hepatotoxicity. In this study we tested this hypothesis by using a mouse model, showing that NAD(+) administration can significantly attenuate DOX-induced increase in serum glutamate oxaloacetate transaminase activity and decrease in liver weight. The NAD(+) administration also attenuated the DOX-induced increases in the levels of double-strand DNA (dsDNA) damage, TUNEL signals, and active caspase-3. Furthermore, our data has suggested that the NAD(+) administration could produce protective effects at least partially by restoring the antioxidation capacity of the liver, because NAD(+) administration can attenuate the decreases in both the GSH levels and the glutathione reductase activity of the DOX-treated liver, which could play a significant role in the DOX-induced hepatotoxicity. This finding has provided the first evidence indicating that NAD(+) is capable of increasing the antioxidation capacity of tissues. Collectively, our study has found that NAD(+) can significantly decrease DOX-induced liver damage at least partially by enhancing antioxidation capacity and decreasing dsDNA damage. Because it can also selectively decrease tumor cell survival, NAD(+) may have significant merits over antioxidants for applying jointly with DOX to decrease the toxic side effects of DOX.

  7. Decreased plasma isoleucine concentrations after upper gastrointestinal haemorrhage in humans.

    PubMed Central

    Dejong, C H; Meijerink, W J; van Berlo, C L; Deutz, N E; Soeters, P B

    1996-01-01

    BACKGROUND: A decrease in arterial isoleucine values after intragastric blood administration in pigs has been observed. This contrasted with increased values of most other amino acids, ammonia, and urea. After an isonitrogenous control meal in these pigs all amino acids including isoleucine increased, and urea increased to a lesser extent, suggesting a relation between the arterial isoleucine decrease and uraemia after gastrointestinal haemorrhage. METHODS: To extend these findings to humans, plasma amino acids were determined after gastrointestinal haemorrhage in patients with peptic ulcers (n = 9) or oesophageal varices induced by liver cirrhosis (n = 4) and compared with preoperative patients (n = 106). RESULTS: After gastrointestinal haemorrhage, isoleucine decreased in all patients by more than 60% and normalised within 48 hours. Most other amino acids increased and also normalised within 48 hours. Uraemia occurred in both groups, hyperammonaemia was seen in patients with liver cirrhosis. CONCLUSIONS: These results confirm previous findings in animals and healthy volunteers that plasma isoleucine decreases after simulated upper gastrointestinal haemorrhage. This supports the hypothesis that the absence of isoleucine in blood protein causes decreased plasma isoleucine values after gastrointestinal haemorrhage, and may be a contributory factor to uraemia and hyperammonaemia in patients with normal and impaired liver function, respectively. Intravenous isoleucine administration after gastrointestinal haemorrhage could be beneficial and will be the subject of further research. PMID:8881800

  8. Secular period decreasing of detached chromospherically active binaries

    NASA Astrophysics Data System (ADS)

    Luo, Chang Qing; Zhang, Xiao Bin; Deng, Li Cai; Luo, Yang Ping; Luo, Zhi Quan; Yang, Shu Zheng

    2010-05-01

    The long-term orbital period changes of a large sample of detached chromospherically active binaries (CABs) were studied. Eleven such systems were found to be undergoing secular period decreases with the rates of -6.3×10-9 to -1.1×10-6 days per year. The period decreasing rates are found to vary depending on the orbital period. The longer the orbital period is, the more rapidly the period decreases. Following Stepien (Mon. Not. R. Astron. Soc. 274:1019, 1995), the period decreasing rate predicted by angular momentum loss (AML) caused by magnetic wind is computed for each system. A comparison between the observed and calculated period decreasing rates shows that the former values are obviously larger than the latter by 1-3 orders of magnitude. It suggests that the magnetic wind is not likely the determinant mechanism driving the AML in these systems. Finally, the orbital angular momentum (AM) and the rate of AML, dot{J} , are computed for each system. It shows that the AM have a similar change with the orbital period like d P/d t does, but logdot{J}/J presents no strict changing with the kinematical ages.

  9. Social Branding to Decrease Smoking Among Young Adults in Bars

    PubMed Central

    Lee, Youn Ok; Hong, Juliette; Neilands, Torsten B.; Jordan, Jeffrey W.; Glantz, Stanton A.

    2014-01-01

    Objectives. We evaluated a Social Branding antitobacco intervention for “hipster” young adults that was implemented between 2008 and 2011 in San Diego, California. Methods. We conducted repeated cross-sectional surveys of random samples of young adults going to bars at baseline and over a 3-year follow-up. We used multinomial logistic regression to evaluate changes in daily smoking, nondaily smoking, and binge drinking, controlling for demographic characteristics, alcohol use, advertising receptivity, trend sensitivity, and tobacco-related attitudes. Results. During the intervention, current (past 30 day) smoking decreased from 57% (baseline) to 48% (at follow-up 3; P = .002), and daily smoking decreased from 22% to 15% (P < .001). There were significant interactions between hipster affiliation and alcohol use on smoking. Among hipster binge drinkers, the odds of daily smoking (odds ratio [OR] = 0.44; 95% confidence interval [CI] = 0.30, 0.63) and nondaily smoking (OR = 0.57; 95% CI = 0.42, 0.77) decreased significantly at follow-up 3. Binge drinking also decreased significantly at follow-up 3 (OR = 0.64; 95% CI = 0.53, 0.78). Conclusions. Social Branding campaigns are a promising strategy to decrease smoking in young adult bar patrons. PMID:24524502

  10. Decrease in serum potassium concentration during epidural anaesthesia.

    PubMed

    Hahn, R G

    1987-11-01

    A mean decrease in the arterial serum potassium concentration (S-K) of 0.40 mmol/l (range 0-1.0) was found in 45 elderly men who were studied before and after induction of epidural anaesthesia (using mepivacaine 2% with adrenaline). The decrease was similar in patients who received acetated Ringer solution or dextran 40 in normal saline as intravenous fluid supplementation. No difference in S-K change was found between patients with a normal (less than 115 mumol/l) or elevated serum creatinine concentration. The decrease in S-K prevailed at the end of surgery except in patients with an elevated serum creatinine. Corrections of S-K for changes in arterial blood pH and rectal temperature during induction of anaesthesia did not explain the decrease in S-K. Correlations of clinical parameters such as the extension of anaesthesia, amount of intravenous fluid given and blood pressure changes gave conflicting results. A smaller decrease or no change in S-K was usually seen in arterial (n = 7) and venous (n = 7) samples when no intravenous fluid was given, as well as in venous samples when acetated Ringer solution was given (n = 6).

  11. Decreasing auditory Simon effects across reaction time distributions.

    PubMed

    Xiong, Aiping; Proctor, Robert W

    2016-01-01

    The Simon effect for left-right visual stimuli previously has been shown to decrease across the reaction time (RT) distribution. This decrease has been attributed to automatic activation of the corresponding response, which then dissipates over time. In contrast, for left-right tone stimuli, the Simon effect has not been found to decrease across the RT distribution but instead tends to increase. It has been proposed that automatic activation occurs through visuomotor information transmission, whereas the auditory Simon effect reflects cognitive coding interference and not automatic activation. In 4 experiments, we examined distributions of the auditory Simon effect for RT, percentage error (PE), and an inverse efficiency score [IES = RT/(1 - PE)] as a function of tone frequency and duration to determine whether the activation-dissipation account is also applicable to auditory stimuli. Consistent decreasing functions were found for the RT Simon effect distribution with short-duration tones of low frequency and for the PE and IES Simon effect distributions for all durations and frequency sets. Together, these findings provide robust evidence that left and right auditory stimuli also produce decreasing Simon effect distribution functions suggestive of automatic activation and dissipation of the corresponding response.

  12. Secular period decreasing of 17 detached chromospherically active binaries

    NASA Astrophysics Data System (ADS)

    Luo, C. Q.; Luo, Y. P.; Zhang, X. B.; Deng, L. C.; Luo, Z. Q.; Yang, S. Z.

    2008-10-01

    The long-term orbital period changes of detached chromospheric active binaries were surveyed. 17 of such systems are found to be undergoing secular period decreasing with the rates (dP/dt) of -3.05 × 10-9 to -3.77 × 10-5 days per year. The longer the orbital period, the more rapidly the period decreases. Following Stepien (1995), the period decreasing rate due to the angular momentum loss (AML) caused by magnetic wind is computed for each system. A comparison shows that the observed dP/dt's are obviously higher than that of the theoretical predictions by 1-3 orders of magnitude. It suggests that the magnetic wind is not likely the determinant mechanism driving the AML in close binaries.

  13. Aspirin decreases platelet uptake on Dacron vascular grafts in baboons

    SciTech Connect

    Mackey, W.C.; Connolly, R.J.; Callow, A.D.; Keough, E.M.; Ramberg-Laskaris, K.; McCullough, J.L.; O'Donnell, T.F. Jr.; Melaragno, A.; Valeri, C.R.; Weiblen, B.

    1984-07-01

    The influence of a single dose of aspirin (5.4-7.4 mg/kg) on platelet uptake on 4-mm Dacron interposition grafts was studied in a baboon model using gamma camera scanning for 111-Indium labeled platelets. In vitro assessment of platelet function after aspirin administration revealed that in the baboon, as in the human, aspirin abolished arachidonic acid-induced platelet aggregation, prolonged the lag time between exposure to collagen and aggregation, and decreased plasma thromboxane B2 levels. Aspirin also prolonged the template bleeding time. Scans for 111-Indium labeled platelets revealed that pretreatment with a single dose of aspirin decreased platelet uptake on 4-mm Dacron carotid interposition grafts. This decrease in platelet uptake was associated with a significant improvement in 2-hour graft patency and with a trend toward improved 2-week patency.

  14. Recent decrease in typhoon destructive potential and global warming implications

    PubMed Central

    Lin, I-I; Chan, Johnny C.L.

    2015-01-01

    Typhoons (tropical cyclones) severely impact the half-billion population of the Asian Pacific. Intriguingly, during the recent decade, typhoon destructive potential (Power Dissipation Index, PDI) has decreased considerably (by ∼35%). This decrease, paradoxically, has occurred despite the increase in typhoon intensity and ocean warming. Using the method proposed by Emanuel (in 2007), we show that the stronger negative contributions from typhoon frequency and duration, decrease to cancel the positive contribution from the increasing intensity, controlling the PDI. Examining the typhoons' environmental conditions, we find that although the ocean condition became more favourable (warming) in the recent decade, the atmospheric condition ‘worsened' at the same time. The ‘worsened' atmospheric condition appears to effectively overpower the ‘better' ocean conditions to suppress PDI. This stronger negative contribution from reduced typhoon frequency over the increased intensity is also present under the global warming scenario, based on analysis of the simulated typhoon data from high-resolution modelling. PMID:25990561

  15. Decreased S100B expression in chronic liver diseases

    PubMed Central

    Baik, Su Jung; Kim, Tae Hun; Yoo, Kwon; Moon, Il Hwan; Choi, Ju Young; Chung, Kyu Won; Song, Dong Eun

    2017-01-01

    Background/Aims Hepatic innervation in liver diseases is not fully understood. We here evaluated S100B expression as a marker of hepatic nerves in patients with various chronic liver diseases, topographically and semi-quantitatively. Methods Liver specimens were obtained from 70 subjects (three controls, and 32 chronic hepatitis B, 14 chronic hepatitis C, 14 liver cirrhosis, and seven hepatocellular carcinoma patients). The hepatic nerve density was calculated based on immunohistochemical staining of S100B protein in the portal tracts and hepatic lobules. S100B mRNA levels were semi-quantitatively assessed as the S100B/glyceraldehyde 3-phosphate dehydrogenase (GAPDH) mRNA ratio. Results The densities of the hepatic nerves in portal tracts of chronic liver diseases were not significantly different from those of normal controls but the hepatic nerve densities in lobular areas of liver cirrhosis were significantly decreased (p = 0.025). Compared to the control, the S100B/GAPDH mRNA ratio was significantly decreased in chronic liver diseases (p = 0.006) and most decreased in chronic hepatitis C patients (p = 0.023). In chronic liver diseases, The S100B/GAPDH mRNA ratio tended to decrease as the fibrosis score > 0 (p = 0.453) but the overall correlation between the S100B/GAPDH mRNA ratio and fibrosis score was not statistically significant (r = 0.061, p = 0.657). Conclusions Hepatic innervation is decreased in cirrhotic regenerating nodules compared to the control group and seems to decrease in early stages of fibrosis progression. Further studies are needed to clarify the association between changes of hepatic innervation and chronic liver disease progression. PMID:27255110

  16. NASA Images Show Decreased Clarity in Lake Tahoe's Water

    NASA Technical Reports Server (NTRS)

    2002-01-01

    Images from the Advanced Spaceborne Thermal Emission and Reflection Radiometer aboard NASA's Terra satellite, launched in 1999, illustrate the state of gradually decreasing water clarity at Lake Tahoe, one of the clearest lakes in the world. The images are available at: http://asterweb.jpl.nasa.gov/default.htm.

    In the image on the left, acquired in November 2000, vegetation can be seen in red. The image on the right, acquired at the same time by a different spectral band of the instrument, is color-coded to show the bottom of the lake around the shoreline. Where the data are black, the bottom cannot be seen.

    Scientists monitoring the lake's water clarity from boat measurements obtained since 1965 have discovered that the lake along the California-Nevada border has lost more than one foot of visibility each year, according to the Lake Tahoe Watershed Assessment, a review of scientific information about the lake undertaken at the request of President Clinton and published in February 2000. The most likely causes are increases in algal growth, sediment washed in from surrounding areas and urban growth and development.

    By combining historical and current ground-based measurements with space measurements from new instruments like the Advanced Spaceborne Thermal Emission and Reflection Radiometer, scientists are now continuously monitoring and better understanding the circulation and changes in Lake Tahoe's water clarity. Images like these from satellites, which are able to capture entire views of the lake and its 63 contributing streams, can be used to determine and monitor spatial variations in the lake's clarity over time. These images complement 'point' measurements, made by boats from one spot in the lake. Rafts and buoys verify the satellite images, and help scientists develop and test circulation models.

    The Advanced Spaceborne Thermal Emission and Reflection Radiometer is one of five Earth-observing instruments on Terra, launched in 1999, and is its

  17. Mechanisms responsible for decreased glomerular filtration in hibernation and hypothermia

    NASA Technical Reports Server (NTRS)

    Tempel, G. E.; Musacchia, X. J.; Jones, S. B.

    1977-01-01

    Measurements of blood pressure, heart rate, red blood cell and plasma volumes, and relative distribution of cardiac output were made on hibernating and hypothermic adult male and female golden hamsters weighing 120-140 g to study the mechanisms underlying the elimination or marked depression of renal function in hibernation and hypothermia. The results suggest that the elimination or marked depression in renal function reported in hibernation and hypothermia may partly be explained by alterations in cardiovascular system function. Renal perfusion pressure which decreases nearly 60% in both hibernation and hypothermia and a decrease in plasma volume of roughly 35% in the hypothermic animal might both be expected to markedly alter glomerular function.

  18. Decreased respiratory sinus arrhythmia in individuals with deceptive intent.

    PubMed

    Aikins, Deane E; Martin, Daniel J; Morgan, C A

    2010-07-01

    In detecting deception, the Cognitive Load hypothesis states that lying requires more cognitive resources compared to truth telling. Further, increases in cognitive load are predicted to decrease respiratory sinus arrhythmia (RSA). We evaluated the impact of cognitive tasks and the intent to deceive on RSA in 40 male, native Arabic-speaking participants quasi-randomized into truthful (n=14) or deceptive (n=26) groups. Participants donned an ambulatory physiologic recording device and completed cognitive testing after receiving translated instructions about their role in an impending mock crime. The results show that a decrease in RSA recorded during the cognitive testing was greater in individuals who were about to commit a deceptive act.

  19. Effect of Electromagnetic Brake on Decreasing Unbalanced Flow in Mold

    NASA Astrophysics Data System (ADS)

    Miki, Yuji; Furumai, Kohei

    2015-06-01

    In order to clarify the mechanism of suppression of unbalanced flow in the mold under high throughput conditions in continuous casting, the effect of using an electromagnetic brake on decreasing molten steel momentum and suppressing unbalanced flow in the mold was investigated. (1) The measured value of the effect of the electromagnetic brake on decreasing molten steel momentum was consistent with the calculated value. Molten steel momentum could be reduced by more than 50% when the Stuart number was more than 3. 5. (2) Increased mold level fluctuations caused by unbalanced flow in the mold are suppressed by applying the optimum magnetic flux density with an electromagnetic brake, even under high throughput conditions.

  20. Ignition of wood subjected to the decreasing radiant energy flux

    NASA Astrophysics Data System (ADS)

    Kuznetsov, V. T.; Filkov, A. I.; Isaev, Yu N.; Guk, V. O.

    2015-04-01

    In this paper we analyze the ignition of wood samples subjected to the decreasing heat flow. The experimental setup was created on the base of the optical wave "Uran-1". The intensity of the heat flow was changed during the experiment by moving the test sample along the optical axis of the elliptic reflector in the setup. Pine wood was used as the test samples. We received the delay times for ignition of pine wood during heating by the decreasing heat flow. The received data were compared with the data for a static heat flow.

  1. Developmental traumatic brain injury decreased brain derived neurotrophic factor expression late after injury.

    PubMed

    Schober, Michelle Elena; Block, Benjamin; Requena, Daniela F; Hale, Merica A; Lane, Robert H

    2012-06-01

    Pediatric traumatic brain injury (TBI) is a major cause of acquired cognitive dysfunction in children. Hippocampal Brain Derived Neurotrophic Factor (BDNF) is important for normal cognition. Little is known about the effects of TBI on BDNF levels in the developing hippocampus. We used controlled cortical impact (CCI) in the 17 day old rat pup to test the hypothesis that CCI would first increase rat hippocampal BDNF mRNA/protein levels relative to SHAM and Naïve rats by post injury day (PID) 2 and then decrease BDNF mRNA/protein by PID14. Relative to SHAM, CCI did not change BDNF mRNA/protein levels in the injured hippocampus in the first 2 days after injury but did decrease BDNF protein at PID14. Surprisingly, BDNF mRNA decreased at PID 1, 3, 7 and 14, and BDNF protein decreased at PID 2, in SHAM and CCI hippocampi relative to Naïve. In conclusion, TBI decreased BDNF protein in the injured rat pup hippocampus 14 days after injury. BDNF mRNA levels decreased in both CCI and SHAM hippocampi relative to Naïve, suggesting that certain aspects of the experimental paradigm (such as craniotomy, anesthesia, and/or maternal separation) may decrease the expression of BDNF in the developing hippocampus. While BDNF is important for normal cognition, no inferences can be made regarding the cognitive impact of any of these factors. Such findings, however, suggest that meticulous attention to the experimental paradigm, and possible inclusion of a Naïve group, is warranted in studies of BDNF expression in the developing brain after TBI.

  2. Hydrocarbon Contamination Decreases Mating Success in a Marine Planktonic Copepod

    PubMed Central

    Seuront, Laurent

    2011-01-01

    The mating behavior and the mating success of copepods rely on chemoreception to locate and track a sexual partner. However, the potential impact of the water-soluble fraction of hydrocarbons on these aspects of copepod reproduction has never been tested despite the widely acknowledged acute chemosensory abilities of copepods. I examined whether three concentrations of the water-soluble fraction of diesel oil (0.01%, 0.1% and 1%) impacts (i) the swimming behavior of both adult males and females of the widespread calanoid copepod Temora longcornis, and (ii) the ability of males to locate, track and mate with females. The three concentrations of the water-soluble fraction of diesel oil (WSF) significantly and non-significantly affect female and male swimming velocities, respectively. In contrast, both the complexity of male and female swimming paths significantly decreased with increasing WSF concentrations, hence suggesting a sex-specific sensitivity to WSF contaminated seawater. In addition, the three WSF concentrations impacted both T. longicornis mating behavior and mating success. Specifically, the ability of males to detect female pheromone trails, to accurately follow trails and to successfully track a female significantly decreased with increasing WSF concentrations. This led to a significant decrease in contact and capture rates from control to WSF contaminated seawater. These results indicate that hydrocarbon contamination of seawater decreases the ability of male copepods to detect and track a female, hence suggest an overall impact on population fitness and dynamics. PMID:22053187

  3. Use of an Explicit Rule Decreases Procrastination in University Students

    ERIC Educational Resources Information Center

    Johnson, Paul E.; Perrin, Christopher J.; Salo, Allen; Deschaine, Elyssa; Johnson, Beth

    2016-01-01

    The procrastination behavior of students from a small rural university was decreased by presenting them with a rule indicating that a sooner final due date for a writing assignment would be contingent on procrastination during earlier phases of the paper. A counterbalanced AB BA design was used to measure the effects of the rule-based treatment…

  4. Gradual decrease in spermatogenesis caused by chronic stress.

    PubMed

    Juárez-Rojas, Lizbeth; Vigueras-Villaseñor, Rosa María; Casillas, Fahiel; Retana-Márquez, Socorro

    2017-02-21

    Chronic stress induces decreased sperm motility, viability and concentration in stressed males. Also, stress modifies oxidative status and causes apoptosis in testes, as well as a decrease in the epithelial area of seminiferous tubules. However, there are no studies that analyze the alterations caused by stress in testicular cells. Thus, in this study, alterations in the morphology of testicular germ cells caused by different days of chronic stress were assessed. Adult male rats were exposed to stress by immersion in cold water (ICW) daily for 3, 8, 20 or 50 consecutive days. Plasma testosterone and corticosterone were also assessed. Results showed that chronic stress causes loss of germ cells, and alteration of spermatogenesis. Seminiferous tubules from stressed males showed several degenerative signs, such as vacuoles in the basal epithelium, with picnotic indicia; moderate to severe exfoliation of degenerative germinal cells in the tubule lumen was also observed. These alterations were observed in all days of stress in a gradual way, from day 3-50. Testosterone levels were decreased at all those times, and corticosterone concentrations were increased on the same days. These results show that chronic stress causes severe damage to germ cells, which can account for infertility problems in males. These alterations are related to a decrease in testosterone as well as an increase in corticosterone caused by stress.

  5. Does Child Labor Decrease when Parental Incomes Rise?

    ERIC Educational Resources Information Center

    Rogers, Carol Ann; Swinnerton, Kenneth A.

    2004-01-01

    When parents and children care about each other's utility, increases in parental income need not always lead to decreases in child labor. Adults raised in poor families make altruistic transfers to their elderly parents, which the parents take as repayment for income lost when their children were young and spent some time in school instead of…

  6. Decreased interpretation of nonverbal cues in rape victims.

    PubMed

    Giannini, A J; Price, W A; Kniepple, J L

    The ability to receive nonverbal facial cues was tested in twelve female victims of multiple nonserial rapes and matched controls. Subjects attempted to interpret nonverbal messages transmitted by male and female senders who were covertly taped while involved in a gambling task. Rape victims had significantly decreased ability to interpret the nonverbal facial cues of both male and female senders.

  7. Decreasing Anxiety and Frustration in the Spanish Language Classroom.

    ERIC Educational Resources Information Center

    Haskin, Joanna; Smith, Maria de Lourdes Hernandez; Racine, Margaret

    This report describes instructional strategies to decrease anxiety and frustration in the Spanish classroom. Participants were five 7th grade Spanish classes in two suburban middle schools. Student interventions included a study skills guide; partner and group presentations, skits, and activities; and group oral reading. Teacher interventions…

  8. Does Early Reading Failure Decrease Children's Reading Motivation?

    ERIC Educational Resources Information Center

    Morgan, Paul L.; Fuchs, Douglas; Compton, Donald L.; Cordray, David S.; Fuchs, Lynn S.

    2008-01-01

    The authors used a pretest-posttest control group design with random assignment to evaluate whether early reading failure decreases children's motivation to practice reading. First, they investigated whether 60 first-grade children would report substantially different levels of interest in reading as a function of their relative success or failure…

  9. Dietary management to decrease methane emissions from beef feedlots

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Methane is a powerful greenhouse gas that can be produced within the digestive tract of domestic (cattle, sheep), and undomesticated (bison, deer, elk) ruminants. This publicatoin gives a brief review of research on dietary procedures that have been tested to decrease enteric methane emissions fro...

  10. Downsizing a database platform for increased performance and decreased costs

    SciTech Connect

    Miller, M.M.; Tolendino, L.F.

    1993-06-01

    Technological advances in the world of microcomputers have brought forth affordable systems and powerful software than can compete with the more traditional world of minicomputers. This paper describes an effort at Sandia National Laboratories to decrease operational and maintenance costs and increase performance by moving a database system from a minicomputer to a microcomputer.

  11. Pseudoephedrine legislation decreases methamphetamine laboratory-related burns.

    PubMed

    Burke, Bridget A; Lewis, Robert W; Latenser, Barbara A; Chung, Joseph Y; Willoughby, Clark

    2008-01-01

    Pseudoephedrine (PSE) is one of the main ingredients used to manufacture methamphetamine (MA); approximately 700 to 1000 PSE pills are necessary to "cook" a batch of MA. Steps have been taken to decrease the availability of ingredients needed to concoct MA. On May 21, 2005, the state of Iowa enacted a strict law, making PSE a Schedule V Controlled substance, restricting PSE availability, and sales. Using the same 6-month time frames in 2004 and 2005, we retrospectively compared epidemiological data on burn patients in the year before the new PSE law and again immediately after the law was enacted. Data collected between May 21 to December 31, 2004 and 2005 included sex, age, length of stay, body surface area burn, urine drug toxicity status, insurance status, and cost of hospital stay. Reports on statewide MA laboratory incidents were provided by the Office of Drug Control Policy. In 2004, Iowa ranked second in the nation for MA lab incidents, seizing an average of 120 labs per month. In 2006, Iowa ranked eighth in the nation for MA lab incidents, when only 20 labs per month were seized, an 83% decreased from the previous year. By limiting the availability of PSE, Iowa saw a marked decrease in MA laboratory-related incidents, leading to a drastic decrease in MA related burns statewide.

  12. Decrease of the Atmospheric Co-Rotation with Height

    ERIC Educational Resources Information Center

    Membrado, M.; Pacheco, A. F.

    2010-01-01

    Considering our atmosphere as a steady viscous gaseous envelope that co-rotates with the Earth, we obtain a solution for the form in which this induced rotational effect decreases as a function of the distances to the centre of the Earth and to the rotation axis. (Contains 1 figure.)

  13. Decreased femoral arterial flow during simulated microgravity in the rat

    NASA Technical Reports Server (NTRS)

    Roer, Robert D.; Dillaman, Richard M.

    1994-01-01

    To determine whether the blood supply to the hindlimbs of rats is altered by the tail-suspension model of weightlessness, rats were chronically instrumented for the measurement of femoral artery flow. Ultrasonic transit-time flow probes were implanted into 8-wk-old Wistar-Furth rats under ketamine-xylazine anesthesia, and, after 24 h of recovery, flow was measured in the normal ambulatory posture. Next, rats were suspended and flow was measured immediately and then daily over the next 4-7 days. Rats were subsequently returned to normal posture, and flow was monitored daily for 1-3 days. Mean arterial flow decreased immediately on the rats being suspensed and continued to decrease until a new steady state of approximately 60% of control values was attained at 5 days. On the rats returning to normal posture, flow increased to levels observed before suspension. Quantile-quantile plots of blood flow data revealed a decrease in flow during both systole and diastole. The observed decrease in hindlimb blood flow during suspension suggests a possible role in the etiology of muscular atrophy and bone loss in microgravity.

  14. 76 FR 8871 - Walnuts Grown in California; Decreased Assessment Rate

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-02-16

    ... From the Federal Register Online via the Government Publishing Office #0; #0;Rules and Regulations... Marketing Service 7 CFR Part 984 Walnuts Grown in California; Decreased Assessment Rate AGENCY: Agricultural Marketing Service, USDA. ACTION: Affirmation of interim rule as final rule. SUMMARY: The Department...

  15. 78 FR 24979 - Olives Grown in California; Decreased Assessment Rate

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-04-29

    ... Service 7 CFR Part 932 Olives Grown in California; Decreased Assessment Rate AGENCY: Agricultural... assessment rate established for the California Olive Committee (Committee) for the 2013 and subsequent fiscal years from $31.32 to $21.16 per ton of assessable olives handled. The Committee locally administers...

  16. 78 FR 45841 - Olives Grown in California; Decreased Assessment Rate

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-07-30

    ... Service 7 CFR Part 932 Olives Grown in California; Decreased Assessment Rate AGENCY: Agricultural... rate established for the California Olive Committee (Committee) for the 2013 and subsequent fiscal years from $31.32 to $21.16 per ton of assessable olives handled. The Committee locally administers...

  17. 76 FR 35957 - Olives Grown in California; Decreased Assessment Rate

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-06-21

    ... Agricultural Marketing Service 7 CFR Part 932 Olives Grown in California; Decreased Assessment Rate AGENCY... the assessment rate established for the California Olive Committee (Committee) for 2011 and subsequent fiscal years from $44.72 to $16.61 per ton of olives handled. The Committee locally administers...

  18. 76 FR 11937 - Olives Grown in California; Decreased Assessment Rate

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-03-04

    ... Service 7 CFR Part 932 Olives Grown in California; Decreased Assessment Rate AGENCY: Agricultural... assessment rate established for the California Olive Committee (Committee) for 2011 and subsequent fiscal years from $44.72 to $16.61 per ton of olives handled. The Committee locally administers the...

  19. Human placental lactogen decreases regional blood flow in anesthetized pigs.

    PubMed

    Grossini, E; Molinari, C; Battaglia, A; Mary, D A S G; Ribichini, F; Surico, N; Vacca, G

    2006-01-01

    In 22 pigs anesthetized with sodium pentobarbitone, changes in blood flow caused by infusion of human placental lactogen into the left renal, external iliac, and anterior descending coronary arteries were assessed using electromagnetic flowmeters. In 17 pigs, infusion of human placental lactogen whilst keeping the heart rate and arterial pressure constant decreased coronary, renal and iliac flow. In 5 additional pigs, increasing the dose of human placental lactogen produced a dose-related decrease in regional blood flow. The mechanisms of the above response were studied in 15 of the 17 pigs by repeating the experiment of infusion. The human placental lactogen-induced decrease in regional blood flow was not affected by blockade of cholinergic receptors (5 pigs) or of alpha-adrenergic receptors (5 pigs), but it was abolished by blockade of beta2-adrenergic receptors (5 pigs). The present study showed that intra-arterial infusion of human placental lactogen primarily decreased coronary, renal and iliac blood flow. The mechanism of this response was shown to be due to the inhibition of a vasodilatory beta2-adrenergic receptor-mediated effect.

  20. ASCORBIC ACID IS DECREASED IN INDUCED SPUTUM OF MILD ASTHMATICS

    EPA Science Inventory

    Asthma is primarily an airways inflammatory disease, and the bronchial airways have been shown to be particularly susceptible to oxidant-induced tissue damage. The antioxidant ascorbic acid (AA) plays an essential role in defending against oxidant attack in the airways. Decreased...

  1. 34 CFR 300.810 - Decrease in funds.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 34 Education 2 2010-07-01 2010-07-01 false Decrease in funds. 300.810 Section 300.810 Education Regulations of the Offices of the Department of Education (Continued) OFFICE OF SPECIAL EDUCATION AND REHABILITATIVE SERVICES, DEPARTMENT OF EDUCATION ASSISTANCE TO STATES FOR THE EDUCATION OF CHILDREN...

  2. Using habit reversal to decrease filled pauses in public speaking.

    PubMed

    Mancuso, Carolyn; Miltenberger, Raymond G

    2016-03-01

    This study evaluated the effectiveness of simplified habit reversal in reducing filled pauses that occur during public speaking. Filled pauses consist of "uh," "um," or "er"; clicking sounds; and misuse of the word "like." After baseline, participants received habit reversal training that consisted of awareness training and competing response training. During postintervention assessments, all 6 participants exhibited an immediate decrease in filled pauses.

  3. 78 FR 62959 - Kiwifruit Grown in California; Decreased Assessment Rate

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-10-23

    ... Service 7 CFR Part 920 Kiwifruit Grown in California; Decreased Assessment Rate AGENCY: Agricultural... assessment rate established for the Kiwifruit Administrative Committee (Committee) for the 2013-14 and subsequent fiscal periods from $0.035 to $0.025 per 9-kilo volume-fill container or equivalent of...

  4. 78 FR 28120 - Tomatoes Grown in Florida; Decreased Assessment Rate

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-05-14

    ... Agricultural Marketing Service 7 CFR Part 966 Tomatoes Grown in Florida; Decreased Assessment Rate AGENCY: Agricultural Marketing Service, USDA. ACTION: Affirmation of interim rule as final rule. SUMMARY: The... locally administers the marketing order which regulates the handling of tomatoes grown in Florida....

  5. Decreased reproductive rates in sheep fed a high selenium diet

    Technology Transfer Automated Retrieval System (TEKTRAN)

    High Se-containing forages grow on seleniferous soils in many parts of the United States and throughout the world. Selenium is an essential trace element that is required for many physiological processes but can also be either acutely or chronically toxic to livestock. Anecdotal reports of decrease...

  6. Selenium bond decreases ON resistance of light-activated switch

    NASA Technical Reports Server (NTRS)

    1965-01-01

    Vitrified amorphous selenium bond decreases the ON resistance of a gallium arsenide-silicon light-activated, low-level switch. The switch is used under a pulse condition to prolong switch life and minimize errors due to heating, devitrification, and overdrawing.

  7. Baroreflex Sensitivity Decreases During 90-Day Bed Rest

    NASA Technical Reports Server (NTRS)

    Stenger, M. B.; Arzeno, N. M.; Platts, S. H.

    2008-01-01

    Baroreflex sensitivity (BRS) decreases during spaceflight and simulated spaceflight (head down bed rest [BR]). However, previous studies have only examined BRS in response to a limited blood pressure (BP) range or to a single sudden change in BP. PURPOSE: The purpose of this study was to examine BRS during 90 days of 6deg head-down tilt BR over a broad range of BP perturbations. METHODS: Nineteen normal volunteers (12M, 7F) were tested one day before BR, and then near BR days 30, 60 and 90. BP was pharmacologically altered by continuous infusions of phenylephrine (PE) and sodium nitroprusside (SNP). Electrocardiogram and continuous BP were collected during 10 min of normal saline (NS), followed by increasing concentrations of PE (10 min each of 0.4, 0.8 and 1.6 micro-g/kg/min). After a 20 min break, NS was infused again for 10 min, followed by increasing concentrations of SNP (10 min each of 0.4, 0.8, 1.2 micro-g/kg/min). Baroreceptor sensitivity was measured as the slope of a sequence of 3 or more beats in which the systolic BP and following R-R interval (RR) both increased or decreased. Spectral heart rate variability (HRV) and mean RR were analyzed using data from only the NS infusions. Two-way repeated-measures analysis of variance was performed to examine the effects of BR and gender. RESULTS: RR decreased (p<0.001) from pre- BR across BR days. High frequency in normalized units, a measure of parasympathetic activity, decreased with BR (p=0.027) and was lower (p=0.046) in men (0.39+/-0.02, mean+/-SEM) than women (0.48+/-0.02). The spontaneous baroreflex slope, our measure of BRS, increased with PE and decreased with SNP across BR (p<0.001). The percentage decrease in BRS from pre- to post-BR appeared to be larger in women (43.6+/-7.0%) than in men (31.3+/-3.9%, p=0.06). CONCLUSION: Parasympathetic activity and baroreflex sensitivity decrease during 90 days of BR, and BRS tends to diminish more in women than in men.

  8. Perivascular fluid cuffs decrease lung compliance by increasing tissue resistance

    PubMed Central

    Lowe, Kevin; Alvarez, Diego F.; King, Judy A.; Stevens, Troy

    2010-01-01

    Objective Lung inflammation causes perivascular fluid cuffs to form around extra-alveolar blood vessels; however, the physiologic consequences of such cuffs remain poorly understood. Herein, we tested the hypothesis that perivascular fluid cuffs, without concomitant alveolar edema, are sufficient to decrease lung compliance. Design Prospective, randomized, controlled study. Setting Research laboratory. Subjects One hundred twenty male CD40 rats. Interventions To test this hypothesis, the plant alkaloid thapsigargin was used to activate store-operated calcium entry and increase cytosolic calcium in endothelium. Thapsigargin was infused into a central venous catheter of intact, sedated, and mechanically ventilated rats. Measurements Static and dynamic lung mechanics and hemodynamics were measured continuously. Main Results Thapsigargin produced perivascular fluid cuffs along extra-alveolar vessels but did not cause alveolar flooding or blood gas abnormalities. Lung compliance dose-dependently decreased after thapsigargin infusion, attributable to an increase in tissue resistance that was attributed to increased tissue damping and tissue elastance. Airway resistance was not changed. Neither central venous pressure nor left ventricular end diastolic pressure was altered by thapsigargin. Heart rate did not change, although thapsigargin decreased pressure over time sufficient to reduce cardiac output by 50%. Infusion of the type 4 phosphodiesterase inhibitor, rolipram, prevented thapsigargin from inducing perivascular cuffs and decreasing lung compliance. Rolipram also normalized pressure over time and corrected the deficit in cardiac output. Conclusions Our findings resolve for the first time that perivascular cuff formation negatively impacts mechanical coupling between the bronchovascular bundle and the lung parenchyma, decreasing lung compliance without impacting central venous pressure. PMID:20400904

  9. Decreased Expression of DREAM Promotes the Degeneration of Retinal Neurons

    PubMed Central

    Chintala, Shravan; Cheng, Mei; Zhang, Xiao

    2015-01-01

    The intrinsic mechanisms that promote the degeneration of retinal ganglion cells (RGCs) following the activation of N-Methyl-D-aspartic acid-type glutamate receptors (NMDARs) are unclear. In this study, we have investigated the role of downstream regulatory element antagonist modulator (DREAM) in NMDA-mediated degeneration of the retina. NMDA, phosphate-buffered saline (PBS), and MK801 were injected into the vitreous humor of C57BL/6 mice. At 12, 24, and 48 hours after injection, expression of DREAM in the retina was determined by immunohistochemistry, western blot analysis, and electrophoretic mobility-shift assay (EMSA). Apoptotic death of cells in the retina was determined by terminal deoxynucleotidyl transferace dUTP nick end labeling (TUNEL) assays. Degeneration of RGCs in cross sections and in whole mount retinas was determined by using antibodies against Tuj1 and Brn3a respectively. Degeneration of amacrine cells and bipolar cells was determined by using antibodies against calretinin and protein kinase C (PKC)-alpha respectively. DREAM was expressed constitutively in RGCs, amacrine cells, bipolar cells, as well as in the inner plexiform layer (IPL). NMDA promoted a progressive decrease in DREAM levels in all three cell types over time, and at 48 h after NMDA-treatment very low DREAM levels were evident in the IPL only. DREAM expression in retinal nuclear proteins was decreased progressively after NMDA-treatment, and correlated with its decreased binding to the c-fos-DRE oligonucleotides. A decrease in DREAM expression correlated significantly with apoptotic death of RGCs, amacrine cells and bipolar cells. Treatment of eyes with NMDA antagonist MK801, restored DREAM expression to almost normal levels in the retina, and significantly decreased NMDA-mediated apoptotic death of RGCs, amacrine cells, and bipolar cells. Results presented in this study show for the first time that down-regulation of DREAM promotes the degeneration of RGCs, amacrine cells, and

  10. Decreased Expression of DREAM Promotes the Degeneration of Retinal Neurons.

    PubMed

    Chintala, Shravan; Cheng, Mei; Zhang, Xiao

    2015-01-01

    The intrinsic mechanisms that promote the degeneration of retinal ganglion cells (RGCs) following the activation of N-Methyl-D-aspartic acid-type glutamate receptors (NMDARs) are unclear. In this study, we have investigated the role of downstream regulatory element antagonist modulator (DREAM) in NMDA-mediated degeneration of the retina. NMDA, phosphate-buffered saline (PBS), and MK801 were injected into the vitreous humor of C57BL/6 mice. At 12, 24, and 48 hours after injection, expression of DREAM in the retina was determined by immunohistochemistry, western blot analysis, and electrophoretic mobility-shift assay (EMSA). Apoptotic death of cells in the retina was determined by terminal deoxynucleotidyl transferace dUTP nick end labeling (TUNEL) assays. Degeneration of RGCs in cross sections and in whole mount retinas was determined by using antibodies against Tuj1 and Brn3a respectively. Degeneration of amacrine cells and bipolar cells was determined by using antibodies against calretinin and protein kinase C (PKC)-alpha respectively. DREAM was expressed constitutively in RGCs, amacrine cells, bipolar cells, as well as in the inner plexiform layer (IPL). NMDA promoted a progressive decrease in DREAM levels in all three cell types over time, and at 48 h after NMDA-treatment very low DREAM levels were evident in the IPL only. DREAM expression in retinal nuclear proteins was decreased progressively after NMDA-treatment, and correlated with its decreased binding to the c-fos-DRE oligonucleotides. A decrease in DREAM expression correlated significantly with apoptotic death of RGCs, amacrine cells and bipolar cells. Treatment of eyes with NMDA antagonist MK801, restored DREAM expression to almost normal levels in the retina, and significantly decreased NMDA-mediated apoptotic death of RGCs, amacrine cells, and bipolar cells. Results presented in this study show for the first time that down-regulation of DREAM promotes the degeneration of RGCs, amacrine cells, and

  11. Clopidogrel enhances periodontal repair in rats through decreased inflammation

    PubMed Central

    Coimbra, Leila S; Steffens, Joao Paulo; Rossa, Carlos; Graves, Dana T; Spolidorio, Luis C.

    2014-01-01

    Aim We hypothesized that platelet inactivation induced by drugs might interfere with periodontal repair in experimental periodontitis by suppressing the release of biological mediators from platelets at the site of injury. Material and Methods 60 rats were randomly assigned to 6 groups (n=10) and ligatures were placed around lower first molars of three groups. The other three groups were used as negative controls. Ligatures were removed after 10 days of periodontitis induction and all groups were submitted to treatment with aspirin (Asp) (30 mg/kg), clopidogrel (Clop) (75 mg/kg) or NaCl 0.9% intragastrically once daily for 3 days. Periodontal tissue was assessed by the measurement of CXCL12, CXCL4, CCL5 and PDGF by ELISA; histomorphometric analysis of PMN infiltration, attachment loss, bone loss and osteoclast numbers and quantification of blood vessels by imunnohistochemistry. Results During periodontal repair and treatment with NaCl 0.9%, CCL5 was decreased and CXCL12 increased when compared to negative control groups. Asp and Clop did not affect CCL5 expression, decreased CXCL12 but only Clop decreased CXCL4 and PDGF content compared to saline-treated animals. Clop increased blood vessel number, reduced PMN count, and decreased attachment and bone loss, also decreased osteoclast number in animals submitted or not to periodontal repair. Conclusion Systemic administration of Clop during 3 days improved the repair process associated with experimental periodontal disease, suggesting that it may have therapeutic value under situations where tissues undergo a transition from inflammation to repair. PMID:24433307

  12. Dichloroacetate increases glucose use and decreases lactate in developing rat brain

    SciTech Connect

    Miller, A.L.; Hatch, J.P.; Prihoda, T.J. )

    1990-12-01

    Dichloroacetate (DCA) activates pyruvate dehydrogenase (PDH) by inhibiting PDH kinase. Neutralized DCA (100 mg/kg) or saline was intravenously administered to 20 to 25-day-old rats (50-75g). Fifteen minutes later a mixture of {sup 6-14}C glucose and {sup 3}H fluorodeoxyglucose (FDG) was administered intravenously and the animals were sacrificed by microwave irradiation (2450 MHz, 8.0 kW, 0.6-0.8 sec) after 2 or 5 min. Brain regional rates of glucose use and metabolite levels were determined. DCA-treated rats had increased rates of glucose use in all regions studied (cortex, thalamus, striatum, and brain stem), with an average increase of 41%. Lactate levels were lower in all regions, by an average of 35%. There were no significant changes in levels of ATP, creatine phosphate, or glycogen in any brain region. Blood levels of lactate did not differ significantly between the DCA- and the saline-treated groups. Blood glucose levels were higher in the DCA group. In rats sacrificed by freeze-blowing, DCA treatment caused lower brain levels of both lactate and pyruvate. These results cannot be explained by any systemic effect of DCA. Rather, it appears that in the immature rat, DCA treatment results in activation of brain PDH, increased metabolism of brain pyruvate and lactate, and a resulting increase in brain glycolytic rate.

  13. Awareness that early cancer lump is painless could decrease breast cancer mortality in developing countries.

    PubMed

    Garg, Pankaj

    2016-06-10

    There are several factors which contribute to patients' reporting late to healthcare facility even after detecting the breast lump (patient delay). Amongst these, one of the important factors in low- and middle-income countries is lack of awareness that early cancer lump is painless (ECLIPs). Pain is often taken as a danger sign and absence of pain is often not taken seriously. The studies have shown that up to 98% of women in low-income countries are unaware that a painless lump could be a warning sign of early breast cancer. This fact is significant because this could be one of the prime reasons for the women having discovered a painless lump in the breast, accidentally or by breast self-examination, presume it to be harmless and don't report early to health care facility. Therefore, creating awareness about ECLIPs could be an effective strategy to reduce mortality due to breast cancer in low- and middle-income countries. Moreover, unlike modifying risk factors which requires long term behavior modification, creating awareness about ECLIPs is easy and cost effective.

  14. Increasing coffee berry borer (Hypothenemus hampei; Curculionidae: Scolytinae) female density in artificial diet decreases fecundity

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Three experiments were conducted to determine the influence of number of coffee berry borer females (1, 2, or 5) reared in artificial diet on fecundity and subsequent development of larvae, pupae and adults. When data for the three different experiments were analyzed, decreased fecundity was observe...

  15. Whole-Genome Sequences of Burkholderia pseudomallei Isolates Exhibiting Decreased Meropenem Susceptibility.

    PubMed

    Price, Erin P; Smith, Melissa Laird; Paxinos, Ellen E; Tallon, Luke J; Sadzewicz, Lisa; Sengamalay, Naomi; Baird, Robert W; Currie, Bart J; Sarovich, Derek S

    2017-04-06

    We report here paired isogenic Burkholderia pseudomallei genomes obtained from three patients receiving intravenous meropenem for melioidosis treatment, with post-meropenem isolates developing decreased susceptibility. Two genomes were finished, and four were drafted to improved high-quality standard. These genomes will be used to identify meropenem resistance mechanisms in B. pseudomallei.

  16. Whole-Genome Sequences of Burkholderia pseudomallei Isolates Exhibiting Decreased Meropenem Susceptibility

    PubMed Central

    Smith, Melissa Laird; Paxinos, Ellen E.; Tallon, Luke J.; Sadzewicz, Lisa; Sengamalay, Naomi; Baird, Robert W.; Currie, Bart J.

    2017-01-01

    ABSTRACT We report here paired isogenic Burkholderia pseudomallei genomes obtained from three patients receiving intravenous meropenem for melioidosis treatment, with post-meropenem isolates developing decreased susceptibility. Two genomes were finished, and four were drafted to improved high-quality standard. These genomes will be used to identify meropenem resistance mechanisms in B. pseudomallei. PMID:28385830

  17. Changing College Students' Conceptions of Autism: An Online Training to Increase Knowledge and Decrease Stigma

    ERIC Educational Resources Information Center

    Gillespie-Lynch, Kristen; Brooks, Patricia J.; Someki, Fumio; Obeid, Rita; Shane-Simpson, Christina; Kapp, Steven K.; Daou, Nidal; Smith, David Shane

    2015-01-01

    College students with autism may be negatively impacted by lack of understanding about autism on college campuses. Thus, we developed an online training to improve knowledge and decrease stigma associated with autism among college students. Participants (N = 365) completed a pre-test, online training, and post-test. Women reported lower stigma…

  18. Using Antecedent Exercise to Decrease Challenging Behavior in Boys with Developmental Disabilities and an Emotional Disorder

    ERIC Educational Resources Information Center

    Cannella-Malone, Helen I.; Tullis, Christopher A.; Kazee, Aline R.

    2011-01-01

    Some individuals with developmental disabilities and emotional disorders may engage in challenging behavior that can result in the use of aversive procedures and/or seclusion from typically developing peers. They may also engage in low levels of physical activity. One way to decrease challenging behaviors while increasing overall levels of…

  19. Indoleamine 2,3-dioxygenase attenuates inhibitor development in gene-therapy-treated hemophilia A mice.

    PubMed

    Liu, L; Liu, H; Mah, C; Fletcher, B S

    2009-06-01

    A serious impediment to gene and protein replacement therapy in hemophilia A is the development of inhibitors. Mechanisms responsible for inhibitor development include T-cell-dependent adaptive immune responses and the CD28-B7 signaling pathway that eventually leads to the formation of antibodies directed against factor VIII (FVIII). Indoleamine 2,3-dioxygenase (IDO) is a potent immunosuppressive enzyme that can inhibit T-cell responses and induce T-cell apoptosis by regulation of tryptophan metabolism. Kynurenine, one of the metabolites of tryptophan, has been implicated as an immune modulator. Here we hypothesize that co-delivery of the genes for FVIII and IDO can attenuate inhibitor formation. Using transposon-based gene delivery, we observed long-term therapeutic FVIII expression and significantly reduced inhibitor titers when the genes were co-delivered. Co-expression of FVIII and IDO in the liver was associated with increased plasma kynurenine levels, an inhibition of T-cell infiltration and increased apoptosis of T cells within the liver. These experiments suggest that modulation of tryptophan catabolism through IDO expression provides a novel strategy to reduce inhibitor development in hemophilia gene/protein therapy.

  20. Decreased serum vitamin D in idiopathic benign paroxysmal positional vertigo.

    PubMed

    Jeong, Seong-Hae; Kim, Ji-Soo; Shin, Jong Wook; Kim, Sungbo; Lee, Hajeong; Lee, Ae Young; Kim, Jae-Moon; Jo, Hyunjin; Song, Junghan; Ghim, Yuna

    2013-03-01

    Previous studies have demonstrated an association of osteopenia/osteoporosis with idiopathic benign paroxysmal positional vertigo (BPPV). Since vitamin D takes part in the regulation of calcium and phosphorus found in the body and plays an important role in maintaining proper bone structure, decreased bone mineral density in patients with BPPV may be related to decreased serum vitamin D. We measured the serum levels of 25-hydroxyvitamin D in 100 patients (63 women and 37 men, mean age ± SD = 61.8 ± 11.6) with idiopathic BPPV and compared the data with those of 192 controls (101 women and 91 men, mean age ± SD = 60.3 ± 11.3) who had lived in the same community without dizziness or imbalance during the preceding year. The selection of the controls and acquisition of clinical information were done using the data from the Fourth Korean National Health and Nutrition Examination Survey, 2008. The serum level of 25-hydroxyvitamin D was lower in the patients with BPPV than in the controls (mean ± SD = 14.4 ± 8.4 versus 19.1 ± 6.8 ng/ml, p = 0.001). Furthermore, patients with BPPV showed a higher prevalence of decreased serum vitamin D (<20 ng/ml, 80.0 vs. 60.1 %, p < 0.001) than the controls. Multiple logistic regression analyses adjusted for age, sex, body mass index, hypertension, diabetes, proteinuria, regular exercise and the existence of decreased bone mineral density demonstrated that vitamin D insufficiency (10-20 ng/ml) and deficiency (<10 ng/ml) were associated with BPPV with the odds ratios of 3.8 (95 % confidence interval = 1.51-9.38, p = 0.004) and 23.0 (95 % confidence interval = 6.88-77.05, p < 0.001). Our study demonstrated an association between idiopathic BPPV and decreased serum vitamin D. Decreased serum vitamin D may be a risk factor of BPPV.

  1. Mars Secular Obliquity Decrease and the Layered Terrain

    NASA Technical Reports Server (NTRS)

    Rubincam, D. P.

    2000-01-01

    Mars may have substantially decreased its average axial tilt over geologic time due to the waxing and waning of water ice caps through the phenomenon of climate friction (also called obliquity-oblateness feedback). Depending upon Mars' climate and internal structure, water caps of the order of 10(exp 17) - 10(exp 18) kg cycling with the obliquity oscillations could have either increased or decreased the average obliquity by possibly tens of degrees over the age of the solar system. Gravity and topography observations by the Mars Global Surveyor indicate that the south polar cap is mostly uncompensated, so that Mars may be largely rigid on the obliquity timescale. Further, Mars may be a water-rich planet, so that there is a large phase angle between insolation forcing and the size of the obliquity-driven water caps. A stiff, water-rich planet implies an obliquity decrease over the eons. Such a decrease might account for the apparent youthfulness of the polar layered terrain. The idea is that fewer volatiles were available to be cycled into and out of the terrain at high mean obliquity, because of the eveness of insolation between equator and pole, and because of small insolation variations as the obliquity oscillated; so that the movement of volatiles and dust produced thin layers or perhaps no layers at all. As the average obliquity decreased, the insolation contrast between high and low latitudes increased, plus the insolation variations over the obliquity cycle grew somewhat bigger, so that more volatiles and dust might have shuttled into and out of the polar regions, forming the observed thick layers late in Mars' history. It may also be that the average tilt has decreased to the point where the climate friction mechanism is starving itself: more and more water has gotten locked up in the polar regions, making less available for cycling with the oscillations. And the layer-forming mechanism may be starving too: not only less water, but also at low average

  2. Environmental Enrichment Decreases Asphyxia-Induced Neurobehavioral Developmental Delay in Neonatal Rats

    PubMed Central

    Kiss, Peter; Vadasz, Gyongyver; Kiss-Illes, Blanka; Horvath, Gabor; Tamas, Andrea; Reglodi, Dora; Koppan, Miklos

    2013-01-01

    Perinatal asphyxia during delivery produces long-term disability and represents a major problem in neonatal and pediatric care. Numerous neuroprotective approaches have been described to decrease the effects of perinatal asphyxia. Enriched environment is a popular strategy to counteract nervous system injuries. The aim of the present study was to investigate whether enriched environment is able to decrease the asphyxia-induced neurobehavioral developmental delay in neonatal rats. Asphyxia was induced in ready-to-deliver mothers by removing the pups by caesarian section after 15 min of asphyxia. Somatic and neurobehavioral development was tested daily and motor coordination weekly. Our results show that rats undergoing perinatal asphyxia had a marked developmental delay and worse performance in motor coordination tests. However, pups kept in enriched environment showed a decrease in the developmental delay observed in control asphyctic pups. Rats growing up in enriched environment did not show decrease in weight gain after the first week and the delay in reflex appearance was not as marked as in control rats. In addition, the development of motor coordination was not as strikingly delayed as in the control group. Short-term neurofunctional outcome are known to correlate with long-term deficits. Our results thus show that enriched environment could be a powerful strategy to decrease the deleterious developmental effects of perinatal asphyxia. PMID:24232451

  3. Lidocaine decreases the xylazine-evoked contractility in pregnant cows.

    PubMed

    Piccinno, M; Rizzo, A; Mutinati, M; D'Onghia, G; Sciorsci, R L

    2016-08-01

    The objective of this in vitro study was to evaluate and compare the effects of xylazine on basal uterine contractility of bovine pregnant uterine strips and that of lidocaine on xylazine-sensitized bovine pregnant uterine strips, at different stages of pregnancy. Basal contractility was evaluated in an isolated organ bath and the functionality of the strips throughout the experiment was evaluated using a dose of carbachol (10(-5)M). Uterine motility, expressed with amplitude, frequency of contractions as well as the area under the curve, was recorded in different stages of pregnancy and data were collected at 15-min intervals (5-min before and 5-min after xylazine administration and 5-min after lidocaine addition on the plateau contraction induced by xylazine). Uterine motility increased in all the stages of pregnancy after xylazine addition and gradually decreased after treatment with lidocaine. These data suggest that lidocaine might decrease the tonic effect induced by xylazine on bovine pregnant uteri.

  4. Recent divergences and size decreases of eastern gorilla populations.

    PubMed

    Roy, Justin; Arandjelovic, Mimi; Bradley, Brenda J; Guschanski, Katerina; Stephens, Colleen R; Bucknell, Dan; Cirhuza, Henry; Kusamba, Chifundera; Kyungu, Jean Claude; Smith, Vince; Robbins, Martha M; Vigilant, Linda

    2014-11-01

    Compared with other African apes, eastern gorillas (Gorilla beringei) have been little studied genetically. We used analysis of autosomal DNA genotypes obtained from non-invasively collected faecal samples to estimate the evolutionary histories of the two extant mountain gorilla populations and the closely related eastern lowland gorillas. Our results suggest that eastern lowland gorillas and mountain gorillas split beginning some 10 000 years ago, followed 5000 years ago by the split of the two mountain gorilla populations of Bwindi Impenetrable National Park and the Virungas Massif. All three populations have decreased in effective population size, with particularly substantial 10-fold decreases for the mountain gorillas. These dynamics probably reflect responses to habitat changes resulting from climate fluctuations over the past 20 000 years as well as increasing human influence in this densely populated region in the last several thousand years.

  5. Decrease of Pseudomonas aeruginosa biofilm formation by food waste materials.

    PubMed

    Maderova, Zdenka; Horska, Katerina; Kim, Sang-Ryoung; Lee, Chung-Hak; Pospiskova, Kristyna; Safarikova, Mirka; Safarik, Ivo

    2016-01-01

    The formation of bacterial biofilm on various surfaces has significant negative economic effects. The aim of this study was to find a simple procedure to decrease the Pseudomonas aeruginosa biofilm formation in a water environment by using different food waste biological materials as signal molecule adsorbents. The selected biomaterials did not reduce the cell growth but affected biofilm formation. Promising biomaterials were magnetically modified in order to simplify manipulation and facilitate their magnetic separation. The best biocomposite, magnetically modified spent grain, exhibited substantial adsorption of signal molecules and decreased the biofilm formation. These results suggest that selected food waste materials and their magnetically responsive derivatives could be applied to solve biofilm problems in water environment.

  6. Does early reading failure decrease children's reading motivation?

    PubMed

    Morgan, Paul L; Fuchs, Douglas; Compton, Donald L; Cordray, David S; Fuchs, Lynn S

    2008-01-01

    The authors used a pretest-posttest control group design with random assignment to evaluate whether early reading failure decreases children's motivation to practice reading. First, they investigated whether 60 first-grade children would report substantially different levels of interest in reading as a function of their relative success or failure in learning to read. Second, they evaluated whether increasing the word reading ability of 15 at-risk children would lead to gains in their motivation to read. Multivariate analyses of variance suggest marked differences in both motivation and reading practice between skilled and unskilled readers. However, bolstering at-risk children's word reading ability did not yield evidence of a causal relationship between early reading failure and decreased motivation to engage in reading activities. Instead, hierarchical regression analyses indicate a covarying relationship among early reading failure, poor motivation, and avoidance of reading.

  7. Decreasing Outer Hair Cell Membrane Cholesterol Increases Cochlear Electromechanics

    NASA Astrophysics Data System (ADS)

    Brownell, William E.; Jacob, Stefan; Hakizimana, Pierre; Ulfendahl, Mats; Fridberger, Anders

    2011-11-01

    The effect of decreasing membrane cholesterol on the mechanical response of the cochlea to acoustic and/or electrical stimulation was monitored using laser interferometry. In contrast to pharmacological interventions that typically decrease cochlear electromechanics, reducing membrane cholesterol increased the response. The electromechanical response in untreated preparations was asymmetric with greater displacements in response to positive currents and cholesterol depletion increased the asymmetry. The results confirm that outer hair cell electromotility is enhanced by low membrane cholesterol. The asymmetry of the response indicates the outer hair cell resting membrane potential is hyperpolarized relative to the voltage of maximum gain for the outer hair cell voltage-displacement function. The magnitude of the response increase suggests a non-uniform distribution of cholesterol along the lateral wall of normal adult outer hair cells.

  8. Complementary Gompertz survival models: decreasing alive versus increasing dead.

    PubMed

    Easton, Dexter M

    2009-05-01

    The survival patterns of many animals can be classified into one of two asymmetric sigmoid forms: One group can be predicted from the standard, classical Gompertz assumption that, with age, the number of individuals alive in the population decreases exponentially at an exponentially increasing rate. The other can be predicted from the alternative Gompertz assumption that, with age, the number of individuals that have died increases exponentially at an exponentially decreasing rate. The two models have similar mathematical forms, but the curves are not the same. In contrast to the standard, the alternative form has an early rapid fall and terminates in a gradual decay of the number of live individuals. It fits "non-Gompertzian" survival plots that are not predicted by the number-alive assumption. Analyses of published data show one or the other survival mode in various animal populations, depending on sex, genetic strain, nutrition, or activity.

  9. Time variation analysis of the daily Forbush decrease indices

    NASA Astrophysics Data System (ADS)

    Patra, Sankar Narayan; Ghosh, Koushik; Panja, Subhash Chandra

    2011-08-01

    In the present paper we have analyzed the daily Forbush decrease indices from January 1, 1967 to December 31, 2003. First filtering the time series by Simple Exponential Smoothing, we have applied Scargle Method of Periodogram on the processed time series in order to search for its time variation. Study exhibits periodicities around 174, 245, 261, 321, 452, 510, 571, 584, 662, 703, 735, 741, 767, 774, 820, 970, 1062, 1082, 1489, 1715, 2317, 2577, 2768, 3241 and 10630 days with confidence levels higher than 90%. Some of these periods are significantly similar to the observed periodicities of other solar activities, like solar filament activity, solar electron flare occurrence, solar-flare rate, solar proton events, solar neutrino flux, solar irradiance, cosmic ray intensity and flare, spectrum of the sunspot, solar wind, southern coronal hole area and solar cycle, which may suggest that the Forbush decrease behaves similarly to these solar activities and these activities may have a common origin.

  10. Playing prosocial video games increases empathy and decreases schadenfreude.

    PubMed

    Greitemeyer, Tobias; Osswald, Silvia; Brauer, Markus

    2010-12-01

    Past research provided abundant evidence that exposure to violent video games increases aggressive tendencies and decreases prosocial tendencies. In contrast, research on the effects of exposure to prosocial video games has been relatively sparse. The present research found support for the hypothesis that exposure to prosocial video games is positively related to prosocial affect and negatively related to antisocial affect. More specifically, two studies revealed that playing a prosocial (relative to a neutral) video game increased interpersonal empathy and decreased reported pleasure at another's misfortune (i.e., schadenfreude). These results lend further credence to the predictive validity of the General Learning Model (Buckley & Anderson, 2006) for the effects of media exposure on social tendencies.

  11. Decreased serum ceruloplasmin concentration in aluminum welders exposed to ozone.

    PubMed

    Pierre, F; Baruthio, F; Diebold, F; Wild, P; Goutet, M

    1988-01-01

    During an epidemiological survey on arc welders, serum copper and ceruloplasmin were determined in two groups of workers. One group consisted of aluminum welders who were divided into two groups: 13 welders working inside aluminum tanks (confined atmosphere) and 8 welders engaged in the production of vans for dump trucks (nonconfined atmosphere). The reference group consisted of 26 workers of the same plant who were not exposed to welding fumes. Ozone, the major pollutant in aluminum arc welding, was thought to be the principal factor in the significant decrease (P less than 0.01) of mean ceruloplasmin in confined welders. This decrease in the level of ceruloplasmin was still within the reference values and was not linked to age or to tobacco consumption. We found a linear relationship between ceruloplasmin concentration and the cumulated worktime along the week. This effect could be a sign in the serum of a lung reaction against oxidant activity in this type occupational exposure.

  12. Knots cascade detected by a monotonically decreasing sequence of values

    PubMed Central

    Liu, Xin; Ricca, Renzo L.

    2016-01-01

    Due to reconnection or recombination of neighboring strands superfluid vortex knots and DNA plasmid torus knots and links are found to undergo an almost identical cascade process, that tend to reduce topological complexity by stepwise unlinking. Here, by using the HOMFLYPT polynomial recently introduced for fluid knots, we prove that under the assumption that topological complexity decreases by stepwise unlinking this cascade process follows a path detected by a unique, monotonically decreasing sequence of numerical values. This result holds true for any sequence of standardly embedded torus knots T(2, 2n + 1) and torus links T(2, 2n). By this result we demonstrate that the computation of this adapted HOMFLYPT polynomial provides a powerful tool to measure topological complexity of various physical systems. PMID:27052386

  13. Decrease in selenium status in relation to coal dust exposure.

    PubMed

    Oryszczyn, M P; Godin, J; Frette, C; Hellier, G; Bertrand, J P; Pham, Q T; Kauffmann, F

    1996-09-01

    Selenium (Se) plasma levels were studied in 222 coal miners to assess whether selenium is decreased in relation to coal dust exposure, taking age, alcohol, and tobacco consumption into account. Selenium levels decreased significantly with age and current tobacco consumption, among miners aged 34-50. Long-term and current exposure to coal dust were studied. The lowest Se values were observed for those with both long-term and current exposure (60.2 ng/ml), the highest for those never or slightly exposed (64.1 ng/ml); those with long-term exposure not currently exposed fell in an intermediate position (61.3 ng/ml). No relation was observed with alcohol consumption. The association of coal dust with low selenium remained significant after adjustment for age and smoking.

  14. Incentive spirometry decreases respiratory complications following major abdominal surgery.

    PubMed

    Westwood, K; Griffin, M; Roberts, K; Williams, M; Yoong, K; Digger, T

    2007-12-01

    Pulmonary complications are the leading cause of morbidity and mortality following major abdominal surgery. Chest physiotherapy aims to decrease the likelihood of these complications and hasten recovery. Exercises aimed at maximising inspiratory effort are the most beneficial for the patients. The incentive spirometer is a handheld device that patients use to achieve effective inspiration. In a nonrandomised pilot study of 263 patients we have found that the addition of the incentive spirometer, as part of an intensive post-operative physiotherapy programme, decreased the occurrence of pulmonary complications (6 vs 17%, p = 0.01) and length of stay on the surgical high dependency unit (3.1 vs 4 days p = 0.03). The two groups were comparable when age, sex, smoking history, the need for emergency surgery and post-operative analgesia were compared.

  15. Exposure to common quaternary ammonium disinfectants decreases fertility in mice

    PubMed Central

    Melin, Vanessa E.; Potineni, Haritha; Hunt, Patricia; Griswold, Jodi; Siems, Bill; Werre, Stephen R.; Hrubec, Terry C.

    2014-01-01

    Quaternary ammonium compounds (QACs) are antimicrobial disinfectants commonly used in commercial and household settings. Extensive use of QACs results in ubiquitous human exposure, yet reproductive toxicity has not been evaluated. Decreased reproductive performance in laboratory mice coincided with the introduction of a disinfectant containing both alkyl dimethyl benzyl ammonium chloride (ADBAC) and didecyl dimethyl ammonium chloride (DDAC). QACs were detected in caging material over a period of several months following cessation of disinfectant use. Breeding pairs exposed for six months to a QAC disinfectant exhibited decreases in fertility and fecundity: increased time to first litter, longer pregnancy intervals, fewer pups per litter and fewer pregnancies. Significant morbidity in near term dams was also observed. In summary, exposure to a common QAC disinfectant mixture significantly impaired reproductive health in mice. This study illustrates the importance of assessing mixture toxicity of commonly used products whose components have only been evaluated individually. PMID:25483128

  16. Decreasing intestinal parasites in recent Northern California refugees.

    PubMed

    Chang, Alicia H; Perry, Sharon; Du, Jenny N T; Agunbiade, Abdulkareem; Polesky, Andrea; Parsonnet, Julie

    2013-01-01

    Beginning in 2005, the Centers for Disease Control and Prevention (CDC) expanded the overseas presumptive treatment of intestinal parasites with albendazole to include refugees from the Middle East. We surveyed the prevalence of helminths and protozoa in recent Middle Eastern refugees (2008-2010) in comparison with refugees from other geographical regions and from a previous survey (2001-2004) in Santa Clara County, California. Based on stool microscopy, helminth infections decreased, particularly in Middle Eastern refugees (0.1% versus 2.3% 2001-2004, P = 0.01). Among all refugees, Giardia intestinalis was the most common protozoan found. Protozoa infections also decreased somewhat in Middle Eastern refugees (7.2%, 2008-2010 versus 12.9%, 2001-2004, P = 0.08). Serology for Strongyloides stercoralis and Schistosoma spp. identified more infected individuals than stool exams. Helminth infections are increasingly rare in refugees to Northern California. Routine screening stool microscopy may be unnecessary in all refugees.

  17. Knots cascade detected by a monotonically decreasing sequence of values

    NASA Astrophysics Data System (ADS)

    Liu, Xin; Ricca, Renzo L.

    2016-04-01

    Due to reconnection or recombination of neighboring strands superfluid vortex knots and DNA plasmid torus knots and links are found to undergo an almost identical cascade process, that tend to reduce topological complexity by stepwise unlinking. Here, by using the HOMFLYPT polynomial recently introduced for fluid knots, we prove that under the assumption that topological complexity decreases by stepwise unlinking this cascade process follows a path detected by a unique, monotonically decreasing sequence of numerical values. This result holds true for any sequence of standardly embedded torus knots T(2, 2n + 1) and torus links T(2, 2n). By this result we demonstrate that the computation of this adapted HOMFLYPT polynomial provides a powerful tool to measure topological complexity of various physical systems.

  18. Hyperglycemia decreases mitochondrial function: The regulatory role of mitochondrial biogenesis

    SciTech Connect

    Palmeira, Carlos M. Rolo, Anabela P.; Berthiaume, Jessica; Bjork, James A.; Wallace, Kendall B.

    2007-12-01

    Increased generation of reactive oxygen species (ROS) is implicated in 'glucose toxicity' in diabetes. However, little is known about the action of glucose on the expression of transcription factors in hepatocytes, especially those involved in mitochondrial DNA (mtDNA) replication and transcription. Since mitochondrial functional capacity is dynamically regulated, we hypothesized that stressful conditions of hyperglycemia induce adaptations in the transcriptional control of cellular energy metabolism, including inhibition of mitochondrial biogenesis and oxidative metabolism. Cell viability, mitochondrial respiration, ROS generation and oxidized proteins were determined in HepG2 cells cultured in the presence of either 5.5 mM (control) or 30 mM glucose (high glucose) for 48 h, 96 h and 7 days. Additionally, mtDNA abundance, plasminogen activator inhibitor-1 (PAI-1), mitochondrial transcription factor A (TFAM) and nuclear respiratory factor-1 (NRF-1) transcripts were evaluated by real time PCR. High glucose induced a progressive increase in ROS generation and accumulation of oxidized proteins, with no changes in cell viability. Increased expression of PAI-1 was observed as early as 96 h of exposure to high glucose. After 7 days in hyperglycemia, HepG2 cells exhibited inhibited uncoupled respiration and decreased MitoTracker Red fluorescence associated with a 25% decrease in mtDNA and 16% decrease in TFAM transcripts. These results indicate that glucose may regulate mtDNA copy number by modulating the transcriptional activity of TFAM in response to hyperglycemia-induced ROS production. The decrease of mtDNA content and inhibition of mitochondrial function may be pathogenic hallmarks in the altered metabolic status associated with diabetes.

  19. Dehydration decreases saliva antimicrobial proteins important for mucosal immunity.

    PubMed

    Fortes, Matthew B; Diment, Bethany C; Di Felice, Umberto; Walsh, Neil P

    2012-10-01

    The aim of the study was to investigate the effect of exercise-induced dehydration and subsequent overnight fluid restriction on saliva antimicrobial proteins important for host defence (secretory IgA (SIgA), α-amylase, and lysozyme). On two randomized occasions, 13 participants exercised in the heat, either without fluid intake to evoke progressive body mass losses (BML) of 1%, 2%, and 3% with subsequent overnight fluid restriction until 0800 h in the following morning (DEH) or with fluids to offset losses (CON). Participants in the DEH trial rehydrated from 0800 h until 1100 h on day 2. BML, plasma osmolality (Posm), and urine specific gravity (USG) were assessed as hydration indices. Unstimulated saliva samples were assessed for flow rate (SFR), SIgA, α-amylase, and lysozyme concentrations. Posm and USG increased during dehydration and remained elevated after overnight fluid restriction (BML = 3.5% ± 0.3%, Posm = 297 ± 6 mosmol·kg⁻¹, and USG = 1.026 ± 0.002; P < 0.001). Dehydration decreased SFR (67% at 3% BML, 70% at 0800 h; P < 0.01) and increased SIgA concentration, with no effect on SIgA secretion rate. SFR and SIgA responses remained unchanged in the CON trial. Dehydration did not affect α-amylase or lysozyme concentration but decreased secretion rates of α-amylase (44% at 3% BML, 78% at 0800 h; P < 0.01) and lysozyme (46% at 3% BML, 61% at 0800 h; P < 0.01), which were lower than in CON at these time points (P < 0.05). Rehydration returned all saliva variables to baseline. In conclusion, modest dehydration (~3% BML) decreased SFR, α-amylase, and lysozyme secretion rates. Whether the observed magnitude of decrease in saliva AMPs during dehydration compromises host defence remains to be shown.

  20. Atropine-Induced Cutaneous Vasodilation Decreases Body Temperature during Exercise,

    DTIC Science & Technology

    1987-07-01

    during exercise in a cool environment after atropine treatment decreased body temperature and resulted in further suppression of eccrine sweating , thereby...block nsumber) FIEL GRUP SB-GOUP cholinergic blockage, skin blood flow, sweating , temperature regulation, vasodilation * 19. ABSTRACT (Contine on...revese sf neceury and Ilentify by block number) Jil ystemic atropine enhances forearm cutaneous blood flow (FBF) but depresses forearm sweating (Ia5) in

  1. Solar Radiation: An Anomalous Decrease of Direct Solar Radiation.

    PubMed

    Flowers, E C; Viebrock, H J

    1965-04-23

    Beginning in November 1963, measurements made at the South Pole of solar radiation at normal incidence indicate a decrease of from 5 to 78 percent of the normal intensity. Similar measurements made at Mauna Loa, Hawaii, show a similar though smaller reduction. The causal factor is believed to be a layer of atmospheric dust resulting from the eruption of Mt. Agung, Bali, in March 1963.

  2. Multiple medullary venous malformations decreasing cerebral blood flow: Case report

    SciTech Connect

    Tomura, N.; Inugami, A.; Uemura, K.; Hadeishi, H.; Yasui, N. )

    1991-02-01

    A rare case of multiple medullary venous malformations in the right cerebral hemisphere is reported. The literature review yielded only one case of multiple medullary venous malformations. Computed tomography scan showed multiple calcified lesions with linear contrast enhancement representing abnormal dilated vessels and mild atrophic change of the right cerebral hemisphere. Single-photon emission computed tomography using N-isopropyl-p-({sup 123}I) iodoamphetamine demonstrated decreased cerebral blood flow in the right cerebral hemisphere.

  3. Use of an explicit rule decreases procrastination in university students.

    PubMed

    Johnson, Paul E; Perrin, Christopher J; Salo, Allen; Deschaine, Elyssa; Johnson, Beth

    2016-06-01

    The procrastination behavior of students from a small rural university was decreased by presenting them with a rule indicating that a sooner final due date for a writing assignment would be contingent on procrastination during earlier phases of the paper. A counterbalanced AB BA design was used to measure the effects of the rule-based treatment across 2 introductory psychology classes (N = 33). Overall, participants engaged in less procrastination, missed fewer deadlines, and produced higher quality writing in the treatment condition.

  4. Surprising resistivity decrease in manganites with constant electronic density

    NASA Astrophysics Data System (ADS)

    Cortés-Gil, R.; Ruiz-González, M. L.; Alonso, J. M.; Martínez, J. L.; Hernando, A.; Vallet-Regí, M.; González-Calbet, J. M.

    2013-12-01

    A decrease of eight orders of magnitude in the resistance of (La0.5Ca0.5)zMnO3 has been detected when the electronic density is kept constant while the calcium content is modified by introducing cationic vacancies. This effect is related to the disappearance of the charge ordering state and the emergence of an antiferromagnetic-ferromagnetic transition. Moreover, high values of the colossal magnetoresistance above room temperature are attained. Dedicated to Professor J M Rojo.

  5. Decreased Circulating Levels of APRIL: Questioning Its Role in Diabetes

    PubMed Central

    Carvalho-Santos, Adriana; Ribeiro-Alves, Marcelo; Cardoso-Weide, Luciene Carvalho; Nunes, Joyce; Kuhnert, Lia Rafaella Ballard; Xavier, Analucia Rampazzo; Cunha, Samuel; Hahne, Michael; Villa-Verde, Déa Maria Serra; Carvalho-Pinto, Carla Eponina

    2015-01-01

    Diabetes mellitus is a chronic disease that affects over 382 million people worldwide. Type-1 Diabetes (T1D) is classified as an autoimmune disease that results from pancreatic β-cell destruction and insulin deficiency. Type-2 Diabetes (T2D) is characterized principally by insulin resistance in target tissues followed by decreased insulin production due to β-cell failure. It is challenging to identify immunological markers such as inflammatory molecules that are triggered in response to changes during the pathogenesis of diabetes. APRIL is an important member of the TNF family and has been linked to chronic inflammatory processes of various diseases since its discovery in 1998. Therefore, this study aimed to evaluate APRIL serum levels in T1D and T2D. For this, we used the ELISA assay to measure serum APRIL levels of 33 T1D and 30 T2D patients, and non-diabetic subjects as control group. Our data showed a decrease in serum APRIL levels in T1D patients when compared with healthy individuals. The same pattern was observed in the group of T2D patients when compared with the control. The decrease of serum APRIL levels in diabetic patients suggests that this cytokine has a role in T1D and T2D. Diabetes is already considered as an inflammatory condition with different cytokines being implicated in its physiopathology. Our data suggest that APRIL can be considered as a potential modulating cytokine in the inflammatory process of diabetes. PMID:26469782

  6. Decreased glomerular filtration rate in solderers exposed to cadmium.

    PubMed Central

    Järup, L; Persson, B; Elinder, C G

    1995-01-01

    OBJECTIVES--to evaluate the degree of cadmium induced glomerular impairment and to assess the dose-response relation between cadmium dose and the prevalence of glomerular dysfunction. METHODS--A comparison of glomerular filtration rates (GFR) assessed by Cr-EDTA clearance was made in 42 solderers previously exposed to cadmium for at least five years. Blood and urine data were collected at health examinations in 1984, 1989, and 1993. Individual doses of cadmium were estimated by analysing cadmium in blood. RESULTS--Glomerular lesions induced by cadmium are irreversible and the GFR decreases with the degree of tubular damage. The GFR also decreases with cadmium dose and there is a dose-response relation between blood cadmium and prevalence of glomerular damage with 3.4% prevalence at blood cadmium concentrations below 50 nmol/l, 33% at blood cadmium concentrations between 50 and 75 nmol/l and 100% prevalence of glomerular damage when cadmium in blood exceeds 75 nmol/l. CONCLUSIONS--The kidney lesions induced by cadmium are irreversible and the prevalence of those lesions are dose dependent. There is also evidence of a dose related decrease in GFR even a long time after the end of exposure. Exposure to cadmium should therefore be minimised and workers exposed to cadmium should be examined regularly for many years after the end of exposure. PMID:8563845

  7. Cellular memory: Neutrophil orientation reverses during temporally decreasing chemoattractant concentrations

    PubMed Central

    Albrecht, Eric; Petty, Howard R.

    1998-01-01

    Cell directional orientation or shape polarization is the first cellular step in neutrophil locomotion. To better understand how chemoattractants interact with cells, we studied neutrophil polarization (or shape changes) during exposure to a temporally decreasing chemoattractant signal of N-formyl-methionyl-leucyl-phenylalanine (FMLP) in the absence of a spatial concentration gradient. To accomplish this objective, we used a manifold of differing FMLP concentrations attached to a stopped-flow microscope chamber. Spatial gradients of a fluorescent chemotactic peptide could not be detected in the chamber by using microfluorometry. When FMLP was injected at continually increasing concentrations at 10-s intervals, the shape and relative direction of the neutrophil persisted. However, when temporally decreasing FMLP concentrations were injected, ≈80% of the cells changed their direction with 44% of the total cells swinging about to 180° ± 15°. Most of these directional changes involved dissolution of both the lamellipodium and uropod and reformation of these structures 180° from their original positions. This research suggests that neutrophils reverse their morphological polarity when exposed to temporally decreasing ligand concentrations by “remembering” their ligand exposure history and relative direction. PMID:9560224

  8. Home interventions are effective at decreasing indoor nitrogen dioxide concentrations

    PubMed Central

    Paulin, L. M.; Diette, G. B.; Scott, M.; McCormack, M. C.; Matsui, E. C.; Curtin-Brosnan, J.; Williams, D. L.; Kidd-Taylor, A.; Shea, M.; Breysse, P. N.; Hansel, N. N.

    2016-01-01

    Nitrogen dioxide (NO2), a by-product of combustion produced by indoor gas appliances such as cooking stoves, is associated with respiratory symptoms in those with obstructive airways disease. We conducted a three-armed randomized trial to evaluate the efficacy of interventions aimed at reducing indoor NO2 concentrations in homes with unvented gas stoves: (i) replacement of existing gas stove with electric stove; (ii) installation of ventilation hood over existing gas stove; and (iii) placement of air purifiers with high-efficiency particulate air (HEPA) and carbon filters. Home inspection and NO2 monitoring were conducted at 1 week pre-intervention and at 1 week and 3 months post-intervention. Stove replacement resulted in a 51% and 42% decrease in median NO2 concentration at 3 months of follow-up in the kitchen and bedroom, respectively (P = 0.01, P = 0.01); air purifier placement resulted in an immediate decrease in median NO2 concentration in the kitchen (27%, P < 0.01) and bedroom (22%, P = 0.02), but at 3 months, a significant reduction was seen only in the kitchen (20%, P = 0.05). NO2 concentrations in the kitchen and bedroom did not significantly change following ventilation hood installation. Replacing unvented gas stoves with electric stoves or placement of air purifiers with HEPA and carbon filters can decrease indoor NO2 concentrations in urban homes. PMID:24329966

  9. Strengthen flame stability during the furnace`s load decrease

    SciTech Connect

    Zhang Zhiguo; Sun Xuexin; Li Fujin; Qiu Jihua; Chen Gang

    1996-12-31

    This paper presents the result of the study of the coal combustion characteristic and flame stability during the load decrease of PCFF (corner burner arrangement). Considering the relation between flame stability and furnace load during the furnace load change, some method must be used to strengthen the pulverized coal ignition and combustion for the furnace to maintain the flame stability especially for the furnace which fires low rank anthracite. Experimental results show that when the furnace load decreased, the temperature distribution in furnace decreased and the flame stability in furnace had changed because of the load changing. This paper also introduces a new pulverized coal burner: Bluff-body with cavity burner. According to the result of application of this burner, this kind of pulverized coal burner can improve the coal ignition and combustion efficiency. Especially for low load operation of furnace the bluff-body with cavity burner has demonstrated its ability in strengthening coal ignition and improving the flame stability for furnace operation. Experimental results show that using bluff-body with cavity burner, the lowest load for furnace fired bituminous is 40% MCR and 50% MCr for low rank anthracite (V{sup r} < 12%, A{sup f} > 45%). This burner has simple structure and is very easy to set up for furnace.

  10. Oxidative stress decreases microtubule growth and stability in ventricular myocytes.

    PubMed

    Drum, Benjamin M L; Yuan, Can; Li, Lei; Liu, Qinghang; Wordeman, Linda; Santana, L Fernando

    2016-04-01

    Microtubules (MTs) have many roles in ventricular myocytes, including structural stability, morphological integrity, and protein trafficking. However, despite their functional importance, dynamic MTs had never been visualized in living adult myocytes. Using adeno-associated viral vectors expressing the MT-associated protein plus end binding protein 3 (EB3) tagged with EGFP, we were able to perform live imaging and thus capture and quantify MT dynamics in ventricular myocytes in real time under physiological conditions. Super-resolution nanoscopy revealed that EB1 associated in puncta along the length of MTs in ventricular myocytes. The vast (~80%) majority of MTs grew perpendicular to T-tubules at a rate of 0.06μm∗s(-1) and growth was preferentially (82%) confined to a single sarcomere. Microtubule catastrophe rate was lower near the Z-line than M-line. Hydrogen peroxide increased the rate of catastrophe of MTs ~7-fold, suggesting that oxidative stress destabilizes these structures in ventricular myocytes. We also quantified MT dynamics after myocardial infarction (MI), a pathological condition associated with increased production of reactive oxygen species (ROS). Our data indicate that the catastrophe rate of MTs increases following MI. This contributed to decreased transient outward K(+) currents by decreasing the surface expression of Kv4.2 and Kv4.3 channels after MI. On the basis of these data, we conclude that, under physiological conditions, MT growth is directionally biased and that increased ROS production during MI disrupts MT dynamics, decreasing K(+) channel trafficking.

  11. Leptin selectively decreases visceral adiposity and enhances insulin action.

    PubMed Central

    Barzilai, N; Wang, J; Massilon, D; Vuguin, P; Hawkins, M; Rossetti, L

    1997-01-01

    Intraabdominal adiposity and insulin resistance are risk factors for diabetes mellitus, dyslipidemia, arteriosclerosis, and mortality. Leptin, a fat-derived protein encoded by the ob gene, has been postulated to be a sensor of energy storage in adipose tissue capable of mediating a feedback signal to sites involved in the regulation of energy homeostasis. Here, we provide evidence for specific effects of leptin on fat distribution and in vivo insulin action. Leptin (LEP) or vehicle (CON) was administered by osmotic minipumps for 8 d to pair-fed adult rats. During the 8 d of the study, body weight and total fat mass decreased similarly in LEP and in CON. However, while moderate calorie restriction (CON) resulted in similar decreases in whole body (by 20%) and visceral (by 21%) fat, leptin administration led to a specific and marked decrease (by 62%) in visceral adiposity. During physiologic hyperinsulinemia (insulin clamp), leptin markedly enhanced insulin action on both inhibition of hepatic glucose production and stimulation of glucose uptake. Finally, leptin exerted complex effects on the hepatic gene expression of key metabolic enzymes and on the intrahepatic partitioning of metabolic fluxes, which are likely to represent a defense against excessive storage of energy in adipose depots. These studies demonstrate novel actions of circulating leptin in the regulation of fat distribution, insulin action, and hepatic gene expression and suggest that it may play a role in the pathophysiology of abdominal obesity and insulin resistance. PMID:9399957

  12. Prefrontal cortical dopamine transmission is decreased in alcoholism

    PubMed Central

    Narendran, Rajesh; Mason, Neale Scott; Paris, Jennifer; Himes, Michael L.; Douaihy, Antoine B.; Frankle, W. Gordon

    2014-01-01

    Objective Basic studies have demonstrated that optimal levels of prefrontal cortical dopamine are critical to various executive functions such working memory, attention, inhibitory control and risk/reward decisions--all of which are impaired in addictive disorders such as alcoholism. Based on this and imaging studies in alcoholics that have demonstrated less dopamine in the striatum, we hypothesized decreased dopamine transmission in the prefrontal cortex in alcoholism. To test this hypothesis, we used amphetamine and [11C]FLB 457 positron emission tomography (PET) to measure cortical dopamine transmission in a group of 21 recently abstinent alcoholics and matched healthy controls. Methods [11C]FLB 457 binding potential (BPND) was measured in subjects with kinetic analysis using the arterial input function both before and after 0.5 mg kg−1 of d-amphetamine. Results Amphetamine-induced displacement of [11C]FLB 457 binding potential (Δ BPND) was significantly smaller in the cortical regions in alcoholics compared to healthy controls. Cortical regions that demonstrated lower dopamine transmission in alcoholics included the dorsolateral prefrontal cortex, medial prefrontal cortex, orbital frontal cortex, temporal cortex and medial temporal lobe. Conclusions The results of this study for the first time unambiguously demonstrate decreased dopamine transmission in the cortex in alcoholism. Further research is necessary to understand the clinical relevance of decreased cortical dopamine as to whether it is related to impaired executive function, relapse, and outcome in alcoholism. PMID:24874293

  13. Decreased Dp71 expression is associated with gastric adenocarcinoma prognosis

    PubMed Central

    Tan, Sipin; Tan, Jin; Tan, Sichuang; Zhao, Shuai; Cao, Xiaoxia; Chen, Zhikang; Weng, Qiaocheng; Zhang, Huali; Wang, Kang kai; Zhou, Jiang; Xiao, Xianzhong

    2016-01-01

    For the first time, dramatically decreased Dp71 protein and mRNA was found in 34 pairs of resected primary gastric adenocarcinoma. Immunohistochemistry identified Dp71 expression suppressed in 72.2% of 104 gastric cancer patients. The decreased Dp71 expression was significantly correlated with cancer differentiation (P=0.001) and lymph vascular invasion (p=0.041). Decreased Dp71 expression was associated with a poor gastric adenocarcinoma prognosis (P=0.001). Significantly less Dp71 mRNA and protein were found in BGC823, SGC7901, AGS compared with GES-1. Via increasing lamin B1 mRNA and protein, enforced Dp71d and Dp71f expression resulted in SGC7901 proliferation inhibition. Co-IP proved interaction of Dp71 with lamin B1 in GES-1 cells. Further expression characterization showed reduced lamin B1 in gastric cancer tissue and cancer cells. Increasing lamin B1 expression results in the growth inhibition of SGC7901, which suggests that Dp71-lamin B1 protein complex plays an important role for the newly identified tumor suppressive function of Dp71. PMID:27449096

  14. Eye movements during recall of aversive memory decreases conditioned fear.

    PubMed

    Leer, Arne; Engelhard, Iris M; Altink, Annemarie; van den Hout, Marcel A

    2013-10-01

    Cognitive-behavioral therapy for anxiety disorders typically involves exposure to the conditioned stimulus (CS). Despite its status as an effective and primary treatment, many patients do not show clinical improvement or relapse. Contemporary learning theory suggests that treatment may be optimized by adding techniques that aim at revaluating the aversive consequence (US) of the feared stimulus. This study tested whether US devaluation via a dual task--imagining the US while making eye movements--decreases conditioned fear. Following fear acquisition one group recalled the US while making eye movements (EM) and one group merely recalled the US (RO). Next, during a test phase, all participants were re-presented the CSs. Dual tasking, relative to the control condition, decreased memory vividness and emotionality. Moreover, only in the dual task condition reductions were observed in self-reported fear, US expectancy, and CS unpleasantness, but not in skin conductance responses. Findings provide the first evidence that the dual task decreases conditioned fear and suggest it may be a valuable addition to exposure therapy.

  15. Elite synchronized swimmers display decreased energy availability during intensified training.

    PubMed

    Schaal, K; Tiollier, E; Le Meur, Y; Casazza, G; Hausswirth, C

    2016-07-01

    Elite synchronized swimmers follow high-volume training regimen that result in elevated rates of exercise energy expenditure (ExEE). While adequate energy intake (EI) is important to optimize recovery, a number of sport-specific constraints may lead to chronically low energy availability (EA = EI-ExEE). This study aimed to quantify changes in EA, endocrine markers of energy conservation, and perceived fatigue in synchronized swimmers, during a week of baseline training followed by 4 weeks of intensified training (IT). EI, ExEE, and body composition were measured in nine swimmers at Baseline, midpoint (ITWK2 ), and end of IT (ITWK4 ). Waking saliva samples were obtained to measure [leptin]s , [ghrelin]s , and [cortisol]s . Fatigue ratings were provided daily. ExEE increased by 27% during IT. Swimmers increased EI from Baseline to ITWK2 , but decreased it significantly from ITWK2 to ITWK4 . EA, fat mass, and [leptin]s decreased from Baseline to ITWK4 , while [ghrelin]s increased significantly. Fatigue at ITWK4 was inversely correlated with Baseline EI and EA. The significant decrease in EA was accompanied by endocrine signs of energy conservation in elite swimmers. As perceived fatigue was associated with low EA, particular attention should be paid to these athletes' energy intake during phases of heavy training.

  16. Decreased function of survival motor neuron protein impairs endocytic pathways

    PubMed Central

    Dimitriadi, Maria; Derdowski, Aaron; Kalloo, Geetika; Maginnis, Melissa S.; O’Hern, Patrick; Bliska, Bryn; Sorkaç, Altar; Nguyen, Ken C. Q.; Cook, Steven J.; Poulogiannis, George; Atwood, Walter J.; Hall, David H.; Hart, Anne C.

    2016-01-01

    Spinal muscular atrophy (SMA) is caused by depletion of the ubiquitously expressed survival motor neuron (SMN) protein, with 1 in 40 Caucasians being heterozygous for a disease allele. SMN is critical for the assembly of numerous ribonucleoprotein complexes, yet it is still unclear how reduced SMN levels affect motor neuron function. Here, we examined the impact of SMN depletion in Caenorhabditis elegans and found that decreased function of the SMN ortholog SMN-1 perturbed endocytic pathways at motor neuron synapses and in other tissues. Diminished SMN-1 levels caused defects in C. elegans neuromuscular function, and smn-1 genetic interactions were consistent with an endocytic defect. Changes were observed in synaptic endocytic proteins when SMN-1 levels decreased. At the ultrastructural level, defects were observed in endosomal compartments, including significantly fewer docked synaptic vesicles. Finally, endocytosis-dependent infection by JC polyomavirus (JCPyV) was reduced in human cells with decreased SMN levels. Collectively, these results demonstrate for the first time, to our knowledge, that SMN depletion causes defects in endosomal trafficking that impair synaptic function, even in the absence of motor neuron cell death. PMID:27402754

  17. Platelet peripheral benzodiazepine receptors are decreased in Parkinson's disease

    SciTech Connect

    Bonuccelli, U.; Nuti, A.; Del Dotto, P.; Piccini, P.; Martini, C.; Giannacccini, G.; Lucacchini, A.; Muratorio, A. )

    1991-01-01

    Peripheral benzodiazepine (BDZ) receptors are located in a variety of tissues, including platelets, in the nuclear and/or mitochondrial membranes. The authors studied the density of peripheral BDZ receptors in platelets of 10 de novo Parkinson's disease (PD) patients, 18 PD patients treated with a levodopa/carbidopa combination, and in 15 healthy subjects matched for sex and age. The binding assay was conducted using ({sup 3}H)PK 11195, a specific ligand for peripheral BDZ receptors. A significant decrease in the density of ({sup 3}H)PK 11195 binding sites has been observed in PD patients with respect to controls but not between de novo and treated PD patients. No correlation has been found between the decrease in density of ({sup 3}H)PK 11195 binding sites in platelets and either the duration or severity of PD. Peripheral BDZ receptors are implicated in the regulation of mitochondrial respiratory function. Thus, their decrease in PD might parallel the abnormalities in mitochondrial function recently found in this neurologic disease.

  18. Modafinil decreases anxiety-like behaviour in zebrafish

    PubMed Central

    Johnson, Adrian

    2017-01-01

    Modafinil (2-((diphenylmethyl)sulfinyl)acetamide), a selective dopamine and norepinephrine transporter inhibitor, is most commonly prescribed for narcolepsy but has gained recent interest for treating a variety of disorders. Zebrafish (Danio rerio) are becoming a model of choice for pharmacological and behavioural research. To investigate the behavioural effects of modafinil on anxiety, we administered doses of 0, 2, 20, and 200 mg/L for 30 minutes then tested zebrafish in the novel approach test. In this test, the fish was placed into a circular arena with a novel object in the center and motion-tracking software was used to quantify the time the fish spent in the outer area of the arena (thigmotaxis zone), middle third of the arena (transition zone) and center of the arena, as well as total distance traveled, immobility and meandering. Modafinil caused a decrease in time spent in the thigmotaxis zone and increased time spent in the transition zone across all doses. Modafinil did not significantly alter the time spent in the center zone (near the novel object), the distance moved, meandering, or the duration of time spent immobile. We also validated this test as a measure of anxiety with the administration of ethanol (1%) which decreased time spent in the thigmotaxis zone and increased time spent in the transition zone. These results suggest that modafinil decreases anxiety-like behaviour in zebrafish. PMID:28229024

  19. Ammonia causes decreased brain monoamines in fathead minnows (Pimephales promelas)

    USGS Publications Warehouse

    Ronan, Patrick J.; Gaikowski, Mark P.; Hamilton, Steven J.; Buhl, Kevin J.; Summers, Cliff H.

    2007-01-01

    Hyperammonemia, arising from variety of disorders, leads to severe neurological dysfunction. The mechanisms of ammonia toxicity in brain are not completely understood. This study investigated the effects of ammonia on monoaminergic systems in brains of fathead minnows (Pimephales promelas). Fish serve as a good model system to investigate hyperammonemic effects on brain function since no liver manipulations are necessary to increase endogenous ammonia concentrations. Using high performance liquid chromatography with electrochemical detection, monoamines and some associated metabolites were measured from whole brain homogenate. Adult males were exposed for 48 h to six different concentrations of ammonia (0.01–2.36 mg/l unionized) which bracketed the 96-h LC50 for this species. Ammonia concentration-dependent decreases were found for the catecholamines (norepinephrine and dopamine) and the indoleamine serotonin (5-HT). After an initial increase in the 5-HT precursor 5-hydroxytryptophan it too decreased with increasing ammonia concentrations. There were also significant increases in the 5-HIAA/5-HT and DOPAC/DA ratios, often used as measures of turnover. There were no changes in epinephrine (Epi) or monoamine catabolites (DOPAC, 5-HIAA) at any ammonia concentrations tested. Results suggest that ammonia causes decreased synthesis while also causing increased release and degradation. Increased release may underlie behavioral reactions to ammonia exposure in fish. This study adds weight to a growing body of evidence demonstrating that ammonia leads to dysfunctional monoaminergic systems in brain which may underlie neurological symptoms associated with human disorders such as hepatic encephalopathy.

  20. Decreasing particle number concentrations in a warming atmosphere and implications

    NASA Astrophysics Data System (ADS)

    Yu, F.; Luo, G.; Turco, R. P.; Ogren, J. A.; Yantosca, R. M.

    2011-10-01

    New particle formation contributes significantly to the number concentration of condensation nuclei (CN) as well as cloud CN (CCN), a key factor determining aerosol indirect radiative forcing of the climate system. Using a physics-based nucleation mechanism that is consistent with a range of field observations of aerosol formation, it is shown that projected increases in global temperatures could significantly inhibit new particle, and CCN, formation rates worldwide. An analysis of CN concentrations observed at four NOAA ESRL/GMD baseline stations since the 1970s and two other sites since 1990s reveals long-term decreasing trends consistent with these predictions. The analysis also suggests, owing to larger observed CN reductions at remote sites than can be explained by the basic nucleation mechanism, that dimethylsulphide (DMS) emissions may be decreasing worldwide with increasing global temperatures, implying a positive DMS-based cloud feedback forcing of the climate ("CLAW"). The combined effects of rising temperatures on aerosol nucleation rates, and possibly on DMS emissions, may imply substantial decreases in future tropospheric particle abundances associated with global warming, delineating a potentially significant feedback mechanism that increases Earth's climate sensitivity to greenhouse gas emissions. Further research is needed to quantify the magnitude of such a feedback process.

  1. Magnetically induced decrease in droplet contact angle on nanostructured surfaces.

    PubMed

    Zhou, Qian; Ristenpart, William D; Stroeve, Pieter

    2011-10-04

    We report a magnetic technique for altering the apparent contact angle of aqueous droplets deposited on a nanostructured surface. Polymeric tubes with embedded superparamagnetic magnetite (Fe(3)O(4)) nanoparticles were prepared via layer-by-layer deposition in the 800 nm diameter pores of polycarbonate track-etched (PCTE) membranes. Etching away the original membrane yields a superparamagnetic film composed of mostly vertical tubes attached to a rigid substrate. We demonstrate that the apparent contact angle of pure water droplets deposited on the nanostructured film is highly sensitive to the ante situm strength of an applied magnetic field, decreasing linearly from 117 ± 1.3° at no applied field to 105 ± 0.4° at an applied field of approximately 500 G. Importantly, this decrease in contact angle did not require an inordinately strong magnetic field: a 15° decrease in contact angle was observed even with a standard alnico bar magnet. We interpret the observed contact angle behavior in terms of magnetically induced conformation changes in the film nanostructure, and we discuss the implications for reversibly switching substrates from hydrophilic to hydrophobic via externally tunable magnetic fields.

  2. Repeated Habitat Disturbances by Fire Decrease Local Effective Population Size.

    PubMed

    Schrey, Aaron W; Ragsdale, Alexandria K; McCoy, Earl D; Mushinsky, Henry R

    2016-07-01

    Effective population size is a fundamental parameter in population genetics, and factors that alter effective population size will shape the genetic characteristics of populations. Habitat disturbance may have a large effect on genetic characteristics of populations by influencing immigration and gene flow, particularly in fragmented habitats. We used the Florida Sand Skink (Plestiodon reynoldsi) to investigate the effect of fire-based habitat disturbances on the effective population size in the highly threatened, severely fragmented, and fire dependent Florida scrub habitat. We screened 7 microsatellite loci in 604 individuals collected from 12 locations at Archbold Biological Station. Archbold Biological Station has an active fire management plan and detailed records of fires dating to 1967. Our objective was to determine how the timing, number, and intervals between fires affect effective population size, focusing on multiple fires in the same location. Effective population size was higher in areas that had not been burned for more than 10 years and decreased with number of fires and shorter time between fires. A similar pattern was observed in abundance: increasing abundance with time-since-fire and decreasing abundance with number of fires. The ratio of effective population size to census size was higher at sites with more recent fires and tended to decrease with time-since-last-fire. These results suggest that habitat disturbances, such as fire, may have a large effect in the genetic characteristics of local populations and that Florida Sand Skinks are well adapted to the natural fire dynamics required to maintain Florida scrub.

  3. Modafinil decreases anxiety-like behaviour in zebrafish.

    PubMed

    Johnson, Adrian; Hamilton, Trevor James

    2017-01-01

    Modafinil (2-((diphenylmethyl)sulfinyl)acetamide), a selective dopamine and norepinephrine transporter inhibitor, is most commonly prescribed for narcolepsy but has gained recent interest for treating a variety of disorders. Zebrafish (Danio rerio) are becoming a model of choice for pharmacological and behavioural research. To investigate the behavioural effects of modafinil on anxiety, we administered doses of 0, 2, 20, and 200 mg/L for 30 minutes then tested zebrafish in the novel approach test. In this test, the fish was placed into a circular arena with a novel object in the center and motion-tracking software was used to quantify the time the fish spent in the outer area of the arena (thigmotaxis zone), middle third of the arena (transition zone) and center of the arena, as well as total distance traveled, immobility and meandering. Modafinil caused a decrease in time spent in the thigmotaxis zone and increased time spent in the transition zone across all doses. Modafinil did not significantly alter the time spent in the center zone (near the novel object), the distance moved, meandering, or the duration of time spent immobile. We also validated this test as a measure of anxiety with the administration of ethanol (1%) which decreased time spent in the thigmotaxis zone and increased time spent in the transition zone. These results suggest that modafinil decreases anxiety-like behaviour in zebrafish.

  4. Bromelain treatment decreases neutrophil migration to sites of inflammation.

    PubMed

    Fitzhugh, David J; Shan, Siqing; Dewhirst, Mark W; Hale, Laura P

    2008-07-01

    Bromelain, a mixture of proteases derived from pineapple stem, has been reported to have therapeutic benefits in a variety of inflammatory diseases, including murine inflammatory bowel disease. The purpose of this work was to understand potential mechanisms for this anti-inflammatory activity. Exposure to bromelain in vitro has been shown to remove a number of cell surface molecules that are vital to leukocyte trafficking, including CD128a/CXCR1 and CD128b/CXCR2 that serve as receptors for the neutrophil chemoattractant IL-8 and its murine homologues. We hypothesized that specific proteolytic removal of CD128 molecules by bromelain would inhibit neutrophil migration to IL-8 and thus decrease acute responses to inflammatory stimuli. Using an in vitro chemotaxis assay, we demonstrated a 40% reduction in migration of bromelain- vs. sham-treated human neutrophils in response to rhIL-8. Migration to the bacterial peptide analog fMLP was unaffected, indicating that bromelain does not induce a global defect in leukocyte migration. In vivo bromelain treatment generated a 50-85% reduction in neutrophil migration in 3 different murine models of leukocyte migration into the inflamed peritoneal cavity. Intravital microscopy demonstrated that although in vivo bromelain treatment transiently decreased leukocyte rolling, its primary long-term effect was abrogation of firm adhesion of leukocytes to blood vessels at the site of inflammation. These changes in adhesion were correlated with rapid re-expression of the bromelain-sensitive CD62L/L-selectin molecules that mediate rolling following in vivo bromelain treatment and minimal re-expression of CD128 over the time period studied. Taken together, these studies demonstrate that bromelain can effectively decrease neutrophil migration to sites of acute inflammation and support the specific removal of the CD128 chemokine receptor as a potential mechanism of action.

  5. Decreased dopamine activity predicts relapse in methamphetamine abusers

    SciTech Connect

    Wang G. J.; Wang, G.-J.; Smith, L.; Volkow, N.D.; Telang, F.; Logan, J.; Tomasi, D.; Wong, C.T.; Hoffman, W.; Jayne, M.; Alia-Klein, N.; Thanos, P.; Fowler, J.S.

    2011-01-20

    Studies in methamphetamine (METH) abusers showed that the decreases in brain dopamine (DA) function might recover with protracted detoxification. However, the extent to which striatal DA function in METH predicts recovery has not been evaluated. Here we assessed whether striatal DA activity in METH abusers is associated with clinical outcomes. Brain DA D2 receptor (D2R) availability was measured with positron emission tomography and [{sup 11}C]raclopride in 16 METH abusers, both after placebo and after challenge with 60 mg oral methylphenidate (MPH) (to measure DA release) to assess whether it predicted clinical outcomes. For this purpose, METH abusers were tested within 6 months of last METH use and then followed up for 9 months of abstinence. In parallel, 15 healthy controls were tested. METH abusers had lower D2R availability in caudate than in controls. Both METH abusers and controls showed decreased striatal D2R availability after MPH and these decreases were smaller in METH than in controls in left putamen. The six METH abusers who relapsed during the follow-up period had lower D2R availability in dorsal striatum than in controls, and had no D2R changes after MPH challenge. The 10 METH abusers who completed detoxification did not differ from controls neither in striatal D2R availability nor in MPH-induced striatal DA changes. These results provide preliminary evidence that low striatal DA function in METH abusers is associated with a greater likelihood of relapse during treatment. Detection of the extent of DA dysfunction may be helpful in predicting therapeutic outcomes.

  6. Thresholds for significant decrease in hemodialysis access blood flow.

    PubMed

    Ram, Sunanda J; Nassar, Raja; Sharaf, Rashid; Magnasco, Alberto; Jones, Steven A; Paulson, William D

    2005-01-01

    During hemodialysis access surveillance, referral for evaluation and correction of stenosis is based upon determination that a significant decrease in blood flow (Q) has occurred. However, criteria for determining when a decrease is statistically significant have not yet been established. In this study we established such criteria by analyzing Q variation with the glucose pump test (GPT). We took nine Q measurements in each of 25 patients (18 grafts, 7 fistulas) during three dialysis sessions within a 2-week period (predialysis and during hours 1 and 3). We determined thresholds that define a significant percentage decrease in Q (deltaQ) for various p values. In order to confirm the general applicability of these thresholds, we computed the average within-patient Q variation during the three sessions (computed as a coefficient of variation and referred to as short-term variation). We then determined the relative influences of biological (true) variation and analytical error on short-term variation. We found that deltaQ must be > 33% to be significant at p < 0.05, whereas the threshold is > 17% for p < 0.20. Measuring Q at uniform versus different times during the sessions did not significantly reduce these thresholds. We also found that biological variation was nearly as large as short-term Q variation, whereas analytical error contributed minimally to short-term variation. In conclusion, this study defines thresholds for a significant deltaQ that have wide application in determining access referral for evaluation and correction of stenosis. Selection of a particular threshold should consider the relative importance of avoiding thrombosis versus avoiding unnecessary procedures. If avoiding unnecessary procedures is a priority, then we recommend a threshold of > 33%. These thresholds apply to other methods of measuring Q, provided analytical error is significantly less than biological variation.

  7. Bromelain Treatment Decreases Neutrophil Migration to Sites of Inflammation

    PubMed Central

    Fitzhugh, David J.; Shan, Siqing; Dewhirst, Mark W.; Hale, Laura P.

    2008-01-01

    Bromelain, a mixture of proteases derived from pineapple stem, has been reported to have therapeutic benefits in a variety of inflammatory diseases, including murine inflammatory bowel disease. The purpose of this work was to understand potential mechanisms for this anti-inflammatory activity. Exposure to bromelain in vitro has been shown to remove a number of cell surface molecules that are vital to leukocyte trafficking, including CD128a/CXCR1 and CD128b/CXCR2 that serve as receptors for the neutrophil chemoattractant IL-8 and its murine homologues. We hypothesized that specific proteolytic removal of CD128 molecules by bromelain would inhibit neutrophil migration to IL-8 and thus decrease acute responses to inflammatory stimuli. Using an in vitro chemotaxis assay, we demonstrated a 40% reduction in migration of bromelain- vs. sham-treated human neutrophils in response to rhIL-8. Migration to the bacterial peptide analog fMLP was unaffected, indicating that bromelain does not induce a global defect in leukocyte migration. In vivo bromelain treatment generated a 50 – 85% reduction in neutrophil migration in 3 different murine models of leukocyte migration into the inflamed peritoneal cavity. Intravital microscopy demonstrated that although in vivo bromelain treatment transiently decreased leukocyte rolling, its primary long-term effect was abrogation of firm adhesion of leukocytes to blood vessels at the site of inflammation. These changes in adhesion were correlated with rapid re-expression of the bromelain-sensitive CD62L/L-selectin molecules that mediate rolling following in vivo bromelain treatment and minimal re-expression of CD128 over the time period studied. Taken together, these studies demonstrate that bromelain can effectively decrease neutrophil migration to sites of acute inflammation and support the specific removal of the CD128 chemokine receptor as a potential mechanism of action. PMID:18482869

  8. Microbial Biofertilizer Decreases Nicotine Content by Improving Soil Nitrogen Supply.

    PubMed

    Shang, Cui; Chen, Anwei; Chen, Guiqiu; Li, Huanke; Guan, Song; He, Jianmin

    2017-01-01

    Biofertilizers have been widely used in many countries for their benefit to soil biological and physicochemical properties. A new microbial biofertilizer containing Phanerochaete chrysosporium and Bacillus thuringiensis was prepared to decrease nicotine content in tobacco leaves by regulating soil nitrogen supply. Soil NO3(-)-N, NH4(+)-N, nitrogen supply-related enzyme activities, and nitrogen accumulation in plant leaves throughout the growing period were investigated to explore the mechanism of nicotine reduction. The experimental results indicated that biofertilizer can reduce the nicotine content in tobacco leaves, with a maximum decrement of 16-18 % in mature upper leaves. In the meantime, the total nitrogen in mature lower and middle leaves increased with the application of biofertilizer, while an opposite result was observed in upper leaves. Protein concentration in leaves had similar fluctuation to that of total nitrogen in response to biofertilizer. NO3(-)-N content and nitrate reductase activity in biofertilizer-amended soil increased by 92.3 and 42.2 %, respectively, compared to those in the control, whereas the NH4(+)-N and urease activity decreased by 37.8 and 29.3 %, respectively. Nitrogen uptake was improved in the early growing stage, but this phenomenon was not observed during the late growth period. Nicotine decrease is attributing to the adjustment of biofertilizer in soil nitrogen supply and its uptake in tobacco, which result in changes of nitrogen content as well as its distribution in tobacco leaves. The application of biofertilizer containing P. chrysosporium and B. thuringiensis can reduce the nicotine content and improve tobacco quality, which may provide some useful information for tobacco cultivation.

  9. Cigarette smoke decreases mitochondrial porin expression and steroidogenesis

    SciTech Connect

    Bose, Mahuya; Whittal, Randy M.; Gairola, C. Gary; Bose, Himangshu S.

    2008-03-01

    Steroidogenic acute regulatory protein (StAR) facilitates the movement of cholesterol from the outer to inner mitochondrial membrane for steroidogenesis. Here, we investigated the effect of cigarette smoke (CS) on steroidogenesis using adrenal mitochondria isolated from mice chronically exposed to CS. Steroidogenesis was decreased approximately 78% in CS-exposed mitochondria, as measured by synthesis of the steroid hormone precursor pregnenolone. This effect was accompanied by decreased mitochondrial import of {sup 35}S-StAR. Further characterization of the imported {sup 35}S-StAR by native gradient PAGE revealed the presence of a high molecular weight complex in both control and CS-exposed groups. Following density gradient fractionation of {sup 35}S-StAR that had been extracted from control mitochondria, precursor StAR could be found in fractions 2-6 and smaller-sized StAR complexes in fractions 6-13. In the CS-exposed group, the appearance of precursor shifted from fraction 1-6 and the smaller complexes in fractions 6-9 disappeared. Mass spectrometric analysis revealed that the {sup 35}S-StAR-associated protein complex was composed of several resident matrix proteins as well as the OMM resident, VDAC. VDAC expression was greatly reduced by CS, and blockage of VDAC with Koenig's polyanion decreased pregnenolone synthesis in isolated mitochondria. Taken together, these results suggest that VDAC may participate in steroidogenesis by promoting StAR interaction with the OMM and that CS may inhibit steroidogenesis by reducing VDAC-StAR interactions.

  10. Sacroiliac joint manipulation decreases the H-reflex.

    PubMed

    Murphy, B A; Dawson, N J; Slack, J R

    1995-03-01

    Joint manipulation is widely utilized clinically to decrease pain and increase the range of motion of joints displaying limited mobility. Evidence of efficacy is based on subjective reports of symptom improvement as well as on the results of clinical trials. Experiments were designed to determine whether or not sacroiliac joint manipulation affects the amplitude of the Hoffman (H) reflex. Surface EMG recordings of the reflex response to electrical stimulation of the tibial nerve in the popliteal fossa were made from the soleus muscle. The averaged amplitudes of H-reflexes were compared on both legs before and after either sacroiliac joint manipulation or a sham procedure. H-reflex amplitude was significantly decreased (12.9%) in the ipsilateral leg (p < 0.001) following a sacroiliac joint manipulation while there was no significant alteration following the sham intervention. There was no significant alteration in reflex excitability in the contralateral leg to the sacroiliac joint manipulation. To further investigate the mechanism of these reflex alterations, the local anaesthetic cream EMLA (Astra Pharmaceuticals) was applied to the skin overlying the sacroiliac joint and the experiments were repeated on a different group of subjects. This was intended to determine if excitation of cutaneous afferents was responsible for the reflex excitability changes. There was still a significant decrease in reflex excitability (10.6%) following sacroiliac joint manipulation (p < 0.001). These findings indicate that joint manipulation exerts physiological effects on the central nervous system, probably at the segmental level. The fact that the changes persisted in the presence of cutaneous anaesthesia suggests that the reflex changes are likely to be mediated by joint and/or muscle afferents.

  11. Decreased Network Efficiency in Benign Epilepsy with Centrotemporal Spikes.

    PubMed

    Ji, Gong-Jun; Yu, Yang; Miao, Huan-Huan; Wang, Zhong-Jin; Tang, Ye-Lei; Liao, Wei

    2017-04-01

    Purpose To investigate the functional connectome alterations in benign epilepsy with centrotemporal spikes with respect to the occurrence of interictal epileptic discharges (IEDs) during functional magnetic resonance (MR) imaging. Materials and Methods This prospective study was approved by the local institutional review board and was HIPAA compliant. All participants were consecutively enrolled with written informed consent. Forty-three right-handed patients were classified into IED (n = 20, 13 girls and seven boys; mean age ± standard deviation, 9.00 years ± 1.95) and non-IED (n = 23, 11 girls and 12 boys; mean age, 10.22 years ± 2.13) groups on the basis of electroencephalographic data simultaneously recorded during resting-state functional MR imaging at 3.0 T. The functional connectome features (estimated with graph theoretical analysis) in patient groups and control subjects who were matched for sex, age, and education level (n = 28, all right-handed, 13 girls and 15 boys; mean age, 10.00 years ± 2.31) were compared by using one-way analysis of variance. Results Patients with IEDs and those without IEDs showed consistently abnormal global topology in their functional networks (ie, decreased global efficiency; P < .05) relative to that of control subjects, with no differences between the two patient groups (P > .05). Decreased regional efficiency and connectivity strength were observed in the patients with IEDs and those without (mainly in the perirolandic and frontal areas) relative to control subjects (P < .05). Moreover, the altered functional features significantly correlated with clinical characteristics (ie, disease duration and age at symptom onset, P < .05). Conclusion These findings suggest that decreased global and regional efficiency are prominent functional deficits in children with benign epilepsy with centrotemporal spikes and can be readily identified with resting-state functional MR imaging, irrespective of IEDs. (©) RSNA, 2016 Online

  12. Inflammatory granulocytes decrease subcutaneous growth of melanoma in mice.

    PubMed

    Costa, Madalena M; Aguas, Artur P

    2004-12-01

    Growing melanomas invade the subcutaneous tissues. We have compared the size of tumors implanted in the subcutaneous cavities of C57BL/6 mice where inflammatory reactions were induced before the injection of 5 x 10(5) melanoma cells (B16F10 cell line). Granulocytic inflammation of the subcutaneous cavities resulted in a significant decrease in the growth of the implanted melanomas, whereas monocytic inflammation had no effect on tumor growth. We conclude that granulocytes, but not monocytes/macrophages, have anti-tumor action on melanoma that invade the subcutaneous tissues.

  13. Causes of forbush decreases and other cosmic ray variations

    NASA Technical Reports Server (NTRS)

    Barouch, E.; Burlaga, L. F.

    1974-01-01

    The relationship between neutron monitor variations and the intensity variations of the interplanetary magnetic field is studied, using Deep River data and IMP-series satellite data. In over 80% of the cases studied, identifiable depressions of the cosmic ray intensity are associated with magnetic field enhancements of several hours duration and intensity above 10 gamma. Conversely, each magnetic field enhancement has an identifiable effect (though not necessarily a marked depression) on the cosmic ray intensity. Long lasting Forbush decreases are found to be the consequence of the successive action of several such features. An explanation is presented and discussed.

  14. Adjunctive aripiprazole decreased metabolic side effects of clozapine treatment.

    PubMed

    Masopust, Jirí; Tůma, Ivan; Libiger, Jan

    2008-08-01

    Clozapine is an atypical antipsychotic indicated for the treatment of refractory schizophrenia. Clozapine treatment is associated with the metabolic side effects. Weight gain, hyperlipidemia and hyperglycemia are the risk factors for onset of diabetes and cardiovascular disorders. We report a case vignette of a patient in whom the decrease in negative and general psychopathology after adjunctive aripiprazole appeared simultaneously with a reduction of clozapine-induced increase in weight and metabolic measures. Combined application of clozapine and aripiprazole is in accordance with a neurobiological rationale and appears to be a safe and well tolerated.

  15. Using awareness training to decrease nervous habits during public speaking.

    PubMed

    Spieler, Claire; Miltenberger, Raymond

    2017-01-01

    This study evaluated the effectiveness of awareness training for the reduction of three nervous habits that manifest during public speaking: filled pauses, tongue clicks, and inappropriate use of the word "like." Four university students delivered short speeches during baseline and assessment sessions. Awareness training resulted in meaningful reductions in target behaviors for all participants. Booster awareness training sessions were necessary for all participants to achieve further reductions in target behaviors. Generality probes conducted in front of a small audience indicated that treatment effects generally maintained. Social validity scores indicated that the treatment was acceptable, and participants indicated not only decreased use of verbal fillers, but also improved overall public speaking ability posttreatment.

  16. Decreased plasma arachidonic acid binding capacity in neonates.

    PubMed

    Sadowitz, P D; Walenga, R W; Clark, D; Stuart, M J

    1987-01-01

    Arachidonic acid (AA) metabolites have been implicated in neonatal pathologic states such as respiratory distress syndrome (RDS). Since free (nonprotein bound) AA is the substrate for synthesis of these compounds, a decreased capacity to bind AA in neonatal plasma could contribute to these disorders. AA binding was assayed by equilibrium dialysis in plasma samples from healthy adults and various infant groups. Plasma from these infant groups bound significantly less AA than adult plasma. Premature infants with RDS and premature infants receiving intralipid had the lowest capacity to bind AA. The increased availability of free AA may be important in neonatal pathophysiologic states involving arachidonate metabolites.

  17. Prenatal Protein Malnutrition Decreases KCNJ3 and 2DG Activity in Rat Prefrontal Cortex

    PubMed Central

    Amaral, A.C.; Jakovcevski, M.; McGaughy, J.A.; Calderwood, S.K.; Mokler, D.J.; Rushmore, R.J.; Galler, J.R.; Akbarian, S.A.; Rosene, D.L.

    2014-01-01

    Prenatal protein malnutrition (PPM) in rats causes enduring changes in brain and behavior including increased cognitive rigidity and decreased inhibitory control. A preliminary gene microarray screen of PPM rat prefrontal cortex (PFC) identified alterations in KCNJ3 (GIRK1/Kir3.1), a gene important for regulating neuronal excitability. Follow-up with polymerase chain reaction and Western blot showed decreased KCNJ3 expression in PFC, but not hippocampus or brainstem. To verify localization of the effect to the PFC, baseline regional brain activity was assessed with 14C-2-deoxyglucose. Results showed decreased activation in PFC but not hippocampus. Together these findings point to the unique vulnerability of the PFC to the nutritional insult during early brain development, with enduring effects in adulthood on KCNJ3 expression and baseline metabolic activity. PMID:25446346

  18. Prenatal protein malnutrition decreases KCNJ3 and 2DG activity in rat prefrontal cortex.

    PubMed

    Amaral, A C; Jakovcevski, M; McGaughy, J A; Calderwood, S K; Mokler, D J; Rushmore, R J; Galler, J R; Akbarian, S A; Rosene, D L

    2015-02-12

    Prenatal protein malnutrition (PPM) in rats causes enduring changes in brain and behavior including increased cognitive rigidity and decreased inhibitory control. A preliminary gene microarray screen of PPM rat prefrontal cortex (PFC) identified alterations in KCNJ3 (GIRK1/Kir3.1), a gene important for regulating neuronal excitability. Follow-up with polymerase chain reaction and Western blot showed decreased KCNJ3 expression in the PFC, but not hippocampus or brainstem. To verify localization of the effect to the PFC, baseline regional brain activity was assessed with (14)C-2-deoxyglucose. Results showed decreased activation in the PFC but not hippocampus. Together these findings point to the unique vulnerability of the PFC to the nutritional insult during early brain development, with enduring effects in adulthood on KCNJ3 expression and baseline metabolic activity.

  19. Effective flocculation of target microalgae with self-flocculating microalgae induced by pH decrease.

    PubMed

    Liu, Jiexia; Tao, Yujun; Wu, Jinheng; Zhu, Yi; Gao, Baoyan; Tang, Yu; Li, Aifen; Zhang, Chengwu; Zhang, Yuanming

    2014-09-01

    A flocculation method was developed to harvest target microalgae with self-flocculating microalgae induced by decreasing pH to just below isoelectric point. The flocculation efficiencies of target microalgae were much higher than those flocculated only via pH decrease. The mechanism could be that negatively charged self-flocculating microalgal cells became positively charged during pH decrease, subsequently attracted negatively charged target microalgae cells to form flocs and settled down due to gravity. Microalgal biomass concentration and released polysaccharide (RPS) from target microalgae influenced flocculation efficiencies, while multivalent metal ions in growth medium could not. Furthermore, neutralizing pH and then supplementing nutrients allowed flocculated medium to be recycled for cultivation. Finally, Spearman's Rank Correlation Coefficients (Rs) between flocculation efficiency and key factors were also investigated. These results suggest that this method is effective, simple to operate and allows the reuse of flocculated medium, thereby contributing to the economic production from microalgae to biodiesel.

  20. Basis of decreased risk of gastric cancer in severe atrophic gastritis with eradication of Helicobacter pylori.

    PubMed

    Tari, Akira; Kitadai, Yasuhiko; Sumii, Masaharu; Sasaki, Atsunori; Tani, Hiroshi; Tanaka, Sinji; Chayama, Kazuaki

    2007-01-01

    Helicobacter pylori infection induces chronic gastritis and lowers gastric juice ascorbic acid concentrations. We investigated how H. pylori eradication affected multiple variables that could prevent or delay development of new or occult gastric cancer in patients with early gastric cancer treated by endoscopic mucosal resection. Gastric juice pH, nitrite concentrations, and total vitamin C concentrations, serum concentrations of vitamin C and specific H. pylori antibody, and intensity of neutrophil infiltration in gastric mucosa were determined before and after successful H. pylori eradication. Successful eradication increased acid output and ascorbic acid secretion into gastric juice, accompanied by disappearance of polymorphonuclear infiltration from the surface epithelium and decreased gastric juice nitrite concentrations. Our data suggest that H. pylori eradication decreases the nitrosation rate as the ratio of vitamin C to nitrite increases. This decreases reactive oxygen species and nitric oxide, eliminating their damaging effect on DNA and reducing cell turnover.

  1. Decreased coherence and functional connectivity of electroencephalograph in Alzheimer's disease

    NASA Astrophysics Data System (ADS)

    Wang, Ruofan; Wang, Jiang; Yu, Haitao; Wei, Xile; Yang, Chen; Deng, Bin

    2014-09-01

    In this paper, we investigate the abnormalities of electroencephalograph (EEG) signals in the Alzheimer's disease (AD) by analyzing 16-scalp electrodes EEG signals and make a comparison with the normal controls. Coherence is introduced to measure the pair-wise normalized linear synchrony and functional correlations between two EEG signals in different frequency domains, and graph analysis is further used to investigate the influence of AD on the functional connectivity of human brain. Data analysis results show that, compared with the control group, the pair-wise coherence of AD group is significantly decreased, especially for the theta and alpha frequency bands in the frontal and parieto-occipital regions. Furthermore, functional connectivity among different brain regions is reconstructed based on EEG, which exhibit obvious small-world properties. Graph analysis demonstrates that the local functional connections between regions for AD decrease. In addition, it is found that small-world properties of AD networks are largely weakened, by calculating its average path lengths, clustering coefficients, global efficiency, local efficiency, and small-worldness. The obtained results show that both pair-wise coherence and functional network can be taken as effective measures to distinguish AD patients from the normal, which may benefit our understanding of the disease.

  2. Skeletal unloading decreases production of 1,25-dihydroxyvitamin D

    NASA Technical Reports Server (NTRS)

    Halloran, B. P.; Bikle, D. D.; Harris, J.; Foskett, H. C.; Morey-Holton, E.

    1993-01-01

    The plasma concentration of 1,25-dihydroxyvitamin D [1,25(OH)2D] decreases during skeletal unloading and increases when normal weight bearing is restored. To determine whether these changes in plasma 1,25(OH)2D reflect changes in production, metabolic clearance, or both we measured the kinetics of 1,25(OH)2D metabolism in rats whose skeletons were normally loaded, unloaded, or reloaded after a period of nonweight bearing. Skeletal unloading produced a transient but striking fall in the production (-73%) and plasma concentration (-72%) of 1,25(OH)2D without having a significant effect (< 20%) on metabolic clearance. Skeletal reloading returned production to normal. Bone formation predictably decreased during unloading and returned to normal after return to weight bearing. No consistent changes in blood ionized calcium, plasma immunoreactive parathyroid hormone (irPTH), or plasma phosphorus occurred. These data suggest that the changes in plasma 1,25-(OH)2D associated with changes in skeletal weight bearing primarily reflect changes in 1,25(OH)2D production. The data provide no evidence that the changes in 1,25(OH)2D production are a consequence of changes in blood ionized calcium, plasma irPTH, or phosphorus.

  3. Dramatically decreased magnetoresistance in non-stoichiometric WTe2 crystals

    NASA Astrophysics Data System (ADS)

    Lv, Yang-Yang; Zhang, Bin-Bin; Li, Xiao; Pang, Bin; Zhang, Fan; Lin, Da-Jun; Zhou, Jian; Yao, Shu-Hua; Chen, Y. B.; Zhang, Shan-Tao; Lu, Minghui; Liu, Zhongkai; Chen, Yulin; Chen, Yan-Feng

    2016-05-01

    Recently, the layered semimetal WTe2 has attracted renewed interest owing to the observation of a non-saturating and giant positive magnetoresistance (~105%), which can be useful for magnetic memory and spintronic devices. However, the underlying mechanisms of the giant magnetoresistance are still under hot debate. Herein, we grew the stoichiometric and non-stoichiometric WTe2 crystals to test the robustness of giant magnetoresistance. The stoichiometric WTe2 crystals have magnetoresistance as large as 3100% at 2 K and 9-Tesla magnetic field. However, only 71% and 13% magnetoresistance in the most non-stoichiometry (WTe1.80) and the highest Mo isovalent substitution samples (W0.7Mo0.3Te2) are observed, respectively. Analysis of the magnetic-field dependent magnetoresistance of non-stoichiometric WTe2 crystals substantiates that both the large electron-hole concentration asymmetry and decreased carrier mobility, induced by non-stoichiometry, synergistically lead to the decreased magnetoresistance. This work sheds more light on the origin of giant magnetoresistance observed in WTe2.

  4. Decreased segregation of brain systems across the healthy adult lifespan

    PubMed Central

    Chan, Micaela Y.; Park, Denise C.; Savalia, Neil K.; Petersen, Steven E.; Wig, Gagan S.

    2014-01-01

    Healthy aging has been associated with decreased specialization in brain function. This characterization has focused largely on describing age-accompanied differences in specialization at the level of neurons and brain areas. We expand this work to describe systems-level differences in specialization in a healthy adult lifespan sample (n = 210; 20–89 y). A graph-theoretic framework is used to guide analysis of functional MRI resting-state data and describe systems-level differences in connectivity of individual brain networks. Young adults’ brain systems exhibit a balance of within- and between-system correlations that is characteristic of segregated and specialized organization. Increasing age is accompanied by decreasing segregation of brain systems. Compared with systems involved in the processing of sensory input and motor output, systems mediating “associative” operations exhibit a distinct pattern of reductions in segregation across the adult lifespan. Of particular importance, the magnitude of association system segregation is predictive of long-term memory function, independent of an individual’s age. PMID:25368199

  5. Statin Decreases Helicobacter pylori Burden in Macrophages by Promoting Autophagy

    PubMed Central

    Liao, Wei-Chih; Huang, Mei-Zi; Wang, Michelle Lily; Lin, Chun-Jung; Lu, Tzu-Li; Lo, Horng-Ren; Pan, Yi-Jiun; Sun, Yu-Chen; Kao, Min-Chuan; Lim, Hui-Jing; Lai, Chih-Ho

    2017-01-01

    Statins, 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors, have been found to provide protective effects against several bacterial infectious diseases. Although the use of statins has been shown to enhance antimicrobial treated Helicobacter pylori eradication and reduce H. pylori-mediated inflammation, the mechanisms underlying these effects remain unclear. In this study, in vitro and ex vivo macrophage models were established to investigate the molecular pathways involved in statin-mediated inhibition of H. pylori-induced inflammation. Our study showed that statin treatment resulted in a dose-dependent decrease in intracellular H. pylori burden in both RAW264.7 macrophage cells and murine peritoneal exudate macrophages (PEMs). Furthermore, statin yielded enhanced early endosome maturation and subsequent activation of the autophagy pathway, which promotes lysosomal fusion resulting in degradation of sequestered bacteria, and in turn attenuates interleukin (IL)-1β production. These results indicate that statin not only reduces cellular cholesterol but also decreases the H. pylori burden in macrophages by promoting autophagy, consequently alleviating H. pylori-induced inflammation. PMID:28144585

  6. Evidence for decreasing quality of semen during past 50 years.

    PubMed Central

    Carlsen, E.; Giwercman, A.; Keiding, N.; Skakkebaek, N. E.

    1992-01-01

    OBJECTIVE--To investigate whether semen quality has changed during the past 50 years. DESIGN--Review of publications on semen quality in men without a history of infertility selected by means of Cumulated Index Medicus and Current List (1930-1965) and MEDLINE Silver Platter database (1966-August 1991). SUBJECTS--14,947 men included in a total of 61 papers published between 1938 and 1991. MAIN OUTCOME MEASURES--Mean sperm density and mean seminal volume. RESULTS--Linear regression of data weighted by number of men in each study showed a significant decrease in mean sperm count from 113 x 10(6)/ml in 1940 to 66 x 10(6)/ml in 1990 (p < 0.0001) and in seminal volume from 3.40 ml to 2.75 ml (p = 0.027), indicating an even more pronounced decrease in sperm production than expressed by the decline in sperm density. CONCLUSIONS--There has been a genuine decline in semen quality over the past 50 years. As male fertility is to some extent correlated with sperm count the results may reflect an overall reduction in male fertility. The biological significance of these changes is emphasised by a concomitant increase in the incidence of genitourinary abnormalities such as testicular cancer and possibly also cryptorchidism and hypospadias, suggesting a growing impact of factors with serious effects on male gonadal function. PMID:1393072

  7. Resilience in migraine brains: decrease of coherence after photic stimulation

    PubMed Central

    Mendonça-de-Souza, Mayara; Monteiro, Ubirakitan M.; Bezerra, Amana S.; Silva-de-Oliveira, Ana P.; Ventura-da-Silva, Belvânia R.; Barbosa, Marcelo S.; de Souza, Josiane A.; Criado, Elisângela C.; Ferrarezi, Maria C. M.; Alencar, Giselly de A.; Lins, Otávio G.; Coriolano, Maria das G. W. S.; Costa, Belmira L. S. A.; Rodrigues, Marcelo C. A.

    2012-01-01

    Background: During migraine attacks, patients generally have photophobia and phonophobia and seek for environments with less sensorial stimulation. Present work aimed to quantify cortical partial directed coherence (PDC) of electroencephalographic (EEG) recordings from migraine patients and controls in occipital, parietal, and frontal areas with or without photic stimulation. Our hypothesis is that migraine patients with visual aura might have neuronal networks with higher coherence than controls even in interictal periods due to a predisposition in sensory cortical processing. Methods: Eleven adult women with migraine with visual aura (at least 48 h without previous attacks) and seven healthy adult woman were submitted to EEG recording in basal state and during photic stimulation. Results: When compared to healthy volunteers, migraine patients show different coherence profiles. Migraine patients had greater coherence than controls during the basal period (without photic stimulation), showing predisposition for sensory processing in many frequency ranges. After photic stimulation, patients showed a decrease in cortical coherence while controls had an increase. Conclusions: When compared to healty subjects, migraineurs show increased cortical coherence before photic stimulation, but a decrease when stimulation starts. This may be the expression of a resilience mechanism that allows migraineurs the interictal period. The PDC analysis permits to address a patient coherence profile, or “coherence map,” that can be utilized for management of the headache disorder or following up treatments. PMID:22837743

  8. Central transthyretin acts to decrease food intake and body weight

    PubMed Central

    Zheng, Fenping; Kim, Yonwook J.; Moran, Timothy H.; Li, Hong; Bi, Sheng

    2016-01-01

    Transthyretin (TTR) is a blood and cerebrospinal fluid transporter of thyroxine and retinol. Gene expression profiling revealed an elevation of Ttr expression in the dorsomedial hypothalamus (DMH) of rats with exercise-induced anorexia, implying that central TTR may also play a functional role in modulating food intake and energy balance. To test this hypothesis, we have examined the effects of brain TTR on food intake and body weight and have further determined hypothalamic signaling that may underlie its feeding effect in rats. We found that intracerebroventricular (icv) administration of TTR in normal growing rats decreased food intake and body weight. This effect was not due to sickness as icv TTR did not cause a conditioned taste aversion. ICV TTR decreased neuropeptide Y (NPY) levels in the DMH and the paraventricular nucleus (P < 0.05). Chronic icv infusion of TTR in Otsuka Long-Evans Tokushima Fatty rats reversed hyperphagia and obesity and reduced DMH NPY levels. Overall, these results demonstrate a previously unknown anorectic action of central TTR in the control of energy balance, providing a potential novel target for treating obesity and its comorbidities. PMID:27053000

  9. Stabilization of miscible viscous fingering by chemical reaction decreasing viscosity

    NASA Astrophysics Data System (ADS)

    Arai, Shuntaro; Nagatsu, Yuichiro; Shukla, Priyanka; de Wit, Anne

    2016-11-01

    Viscous fingering (VF) occurs when a more viscous fluid is displaced by a less viscous one in porous media or Hele-Shaw cells. In this study, experiment on miscible VF with chemical reaction is conducted by using a Hele-Shaw cell. Here, the chemical reaction takes place between a polymer dissolved in the more viscous solution and hydrochloric acid (HCl) dissolved in the less viscous one in the miscible interface region. The reaction decreases the viscosity of the polymer solution. The experiment shows that the reaction stabilizes VF when the flow rate is small. In the present study, the corresponding numerical simulation is also conducted. The simulation is able to reproduce the experimental results mentioned above when different diffusion coefficients are considered meaning that HCl diffuses faster than the polymer. However, the stabilization cannot be found under conditions of the same diffusivity of the reactants. These numerical results show that the different diffusivity is responsible for the stabilization of miscible VF by the chemical reaction decreasing viscosity.

  10. Sodium alginate decreases the permeability of intestinal mucus.

    PubMed

    Mackie, Alan R; Macierzanka, Adam; Aarak, Kristi; Rigby, Neil M; Parker, Roger; Channell, Guy A; Harding, Stephen E; Bajka, Balazs H

    2016-01-01

    In the small intestine the nature of the environment leads to a highly heterogeneous mucus layer primarily composed of the MUC2 mucin. We set out to investigate whether the soluble dietary fibre sodium alginate could alter the permeability of the mucus layer. The alginate was shown to freely diffuse into the mucus and to have minimal effect on the bulk rheology when added at concentrations below 0.1%. Despite this lack of interaction between the mucin and alginate, the addition of alginate had a marked effect on the diffusion of 500 nm probe particles, which decreased as a function of increasing alginate concentration. Finally, we passed a protein stabilised emulsion through a simulation of oral, gastric and small intestinal digestion. We subsequently showed that the addition of 0.1% alginate to porcine intestinal mucus decreased the diffusion of fluorescently labelled lipid present in the emulsion digesta. This reduction may be sufficient to reduce problems associated with high rates of lipid absorption such as hyperlipidaemia.

  11. Sodium alginate decreases the permeability of intestinal mucus

    PubMed Central

    Mackie, Alan R.; Macierzanka, Adam; Aarak, Kristi; Rigby, Neil M.; Parker, Roger; Channell, Guy A.; Harding, Stephen E.; Bajka, Balazs H.

    2016-01-01

    In the small intestine the nature of the environment leads to a highly heterogeneous mucus layer primarily composed of the MUC2 mucin. We set out to investigate whether the soluble dietary fibre sodium alginate could alter the permeability of the mucus layer. The alginate was shown to freely diffuse into the mucus and to have minimal effect on the bulk rheology when added at concentrations below 0.1%. Despite this lack of interaction between the mucin and alginate, the addition of alginate had a marked effect on the diffusion of 500 nm probe particles, which decreased as a function of increasing alginate concentration. Finally, we passed a protein stabilised emulsion through a simulation of oral, gastric and small intestinal digestion. We subsequently showed that the addition of 0.1% alginate to porcine intestinal mucus decreased the diffusion of fluorescently labelled lipid present in the emulsion digesta. This reduction may be sufficient to reduce problems associated with high rates of lipid absorption such as hyperlipidaemia. PMID:26726279

  12. Malondialdehyde-acetaldehyde adducts decrease bronchial epithelial wound repair.

    PubMed

    Wyatt, Todd A; Kharbanda, Kusum K; Tuma, Dean J; Sisson, Joseph H; Spurzem, John R

    2005-05-01

    Most people who abuse alcohol are cigarette smokers. Previously, we have shown that malondialdehyde, an inflammation product of lipid peroxidation, and acetaldehyde, a component of both ethanol metabolism and cigarette smoke, form protein adducts that stimulate protein kinase C (PKC) activation in bronchial epithelial cells. We have also shown that PKC can regulate bronchial epithelial cell wound repair. We hypothesize that bovine serum albumin adducted with malondialdehyde and acetaldehyde (BSA-MAA) decreases bronchial epithelial cell wound repair via binding to scavenger receptors on bronchial epithelial cells. To test this, confluent monolayers of bovine bronchial epithelial cells were grown in serum-free media prior to wounding the cells. Bronchial epithelial cell wound closure was inhibited in a dose-dependent manner (up to 60%) in the presence of BSA-MAA than in media treated cells (Laboratory of Human Carcinogenesis [LHC]-9-Roswell Park Memorial Institute [RPMI]). The specific scavenger receptor ligand, fucoidan, also stimulated PKC activation and decreased wound repair. Pretreatment with fucoidan blocked malondialdehyde-acetaldehyde binding to bronchial epithelial cells. When bronchial epithelial cells were preincubated with a PKC alpha inhibitor, Gö 6976, the inhibition of wound closure by fucoidan and BSA-MAA was blocked. Western blot demonstrated the presence of several scavenger receptors on bronchial epithelial cell membranes, including SRA, SRBI, SRBII, and CD36. Scavenger receptor-mediated activation of PKC alpha may function to reduce wound healing under conditions of alcohol and cigarette smoke exposure where malondialdehyde-acetaldehyde adducts may be present.

  13. Can Delignification Decrease Cellulose Digestibility in Acid Pretreated Corn Stover?

    SciTech Connect

    Ishizawa, C. I.; Jeoh, T.; Adney, W. S.; Himmel, M. E.; Johnson, D. K.; Davis, M. F.

    2009-01-01

    It has previously been shown that the improved digestibility of dilute acid pretreated corn stover is at least partially due to the removal of xylan and the consequent increase in accessibility of the cellulose to cellobiohydrolase enzymes. We now report on the impact that lignin removal has on the accessibility and digestibility of dilute acid pretreated corn stover. Samples of corn stover were subjected to dilute sulfuric acid pretreatment with and without simultaneous (partial) lignin removal. In addition, some samples were completely delignified after the pretreatment step using acidified sodium chlorite. The accessibility and digestibility of the samples were tested using a fluorescence-labeled cellobiohydrolase (Trichoderma reesei Cel7A) purified from a commercial cellulase preparation. Partial delignification of corn stover during dilute acid pretreatment was shown to improve cellulose digestibility by T. reesei Cel7A; however, decreasing the lignin content below 5% (g g{sup -1}) by treatment with acidified sodium chlorite resulted in a dramatic reduction in cellulose digestibility. Importantly, this effect was found to be enhanced in samples with lower xylan contents suggesting that the near complete removal of xylan and lignin may cause aggregation of the cellulose microfibrils resulting in decreased cellulase accessibility.

  14. High monetary reward rates and caloric rewards decrease temporal persistence

    PubMed Central

    Bode, Stefan; Murawski, Carsten

    2017-01-01

    Temporal persistence refers to an individual's capacity to wait for future rewards, while forgoing possible alternatives. This requires a trade-off between the potential value of delayed rewards and opportunity costs, and is relevant to many real-world decisions, such as dieting. Theoretical models have previously suggested that high monetary reward rates, or positive energy balance, may result in decreased temporal persistence. In our study, 50 fasted participants engaged in a temporal persistence task, incentivised with monetary rewards. In alternating blocks of this task, rewards were delivered at delays drawn randomly from distributions with either a lower or higher maximum reward rate. During some blocks participants received either a caloric drink or water. We used survival analysis to estimate participants' probability of quitting conditional on the delay distribution and the consumed liquid. Participants had a higher probability of quitting in blocks with the higher reward rate. Furthermore, participants who consumed the caloric drink had a higher probability of quitting than those who consumed water. Our results support the predictions from the theoretical models, and importantly, suggest that both higher monetary reward rates and physiologically relevant rewards can decrease temporal persistence, which is a crucial determinant for survival in many species. PMID:28228517

  15. Berberine Suppresses Adipocyte Differentiation via Decreasing CREB Transcriptional Activity.

    PubMed

    Zhang, Juan; Tang, Hongju; Deng, Ruyuan; Wang, Ning; Zhang, Yuqing; Wang, Yao; Liu, Yun; Li, Fengying; Wang, Xiao; Zhou, Libin

    2015-01-01

    Berberine, one of the major constituents of Chinese herb Rhizoma coptidis, has been demonstrated to lower blood glucose, blood lipid, and body weight in patients with type 2 diabetes mellitus. The anti-obesity effect of berberine has been attributed to its anti-adipogenic activity. However, the underlying molecular mechanism remains largely unknown. In the present study, we found that berberine significantly suppressed the expressions of CCAAT/enhancer-binding protein (C/EBP)α, peroxisome proliferators-activated receptor γ2 (PPARγ2), and other adipogenic genes in the process of adipogenesis. Berberine decreased cAMP-response element-binding protein (CREB) phosphorylation and C/EBPβ expression at the early stage of 3T3-L1 preadipocyte differentiation. In addition, CREB phosphorylation and C/EBPβ expression induced by 3-isobutyl-1-methylxanthine (IBMX) and forskolin were also attenuated by berberine. The binding activities of cAMP responsive element (CRE) stimulated by IBMX and forskolin were inhibited by berberine. The binding of phosphorylated CREB to the promoter of C/EBPβ was abrogated by berberine after the induction of preadipocyte differentiation. These results suggest that berberine blocks adipogenesis mainly via suppressing CREB activity, which leads to a decrease in C/EBPβ-triggered transcriptional cascades.

  16. Intracerebroventricular injection of ghrelin decreases wheel running activity in rats.

    PubMed

    Miyatake, Yumiko; Shiuchi, Tetsuya; Mawatari, Kazuaki; Toda, Satomi; Taniguchi, Yasuko; Futami, Akari; Sato, Fukiko; Kuroda, Masashi; Sebe, Mayu; Tsutsumi, Rie; Harada, Nagakatsu; Minokoshi, Yasuhiko; Kitamura, Tadahiro; Gotoh, Koro; Ueno, Masaki; Nakaya, Yutaka; Sakaue, Hiroshi

    2017-01-01

    There is an increasing interest in elucidating the molecular mechanisms by which voluntary exercise is regulated. In this study, we examined how the central nervous system regulates exercise. We used SPORTS rats, which were established in our laboratory as a highly voluntary murine exercise model. SPORTS rats showed lower levels of serum ghrelin compared with those of the parental line of Wistar rats. Intracerebroventricular and intraperitoneal injection of ghrelin decreased wheel-running activity in SPORTS rats. In addition, daily injection of the ghrelin inhibitor JMV3002 into the lateral ventricles of Wistar rats increased wheel-running activity. Co-administration of obestatin inhibited ghrelin-induced increases in food intake but did not inhibit ghrelin-induced suppression of voluntary exercise in rats. Growth hormone secretagogue receptor (GHSR) in the hypothalamus and hippocampus of SPORTS rats was not difference that in control rats. We created an arcuate nucleus destruction model by administering monosodium glutamate (MSG) to neonatal SPORTS rats. Injection of ghrelin into MSG-treated rats decreased voluntary exercise but did not increase food intake, suggesting that wheel-running activity is not controlled by the arcuate nucleus neurons that regulate feeding. These results provide new insights into the mechanism by which ghrelin regulates voluntary activity independent of arcuate nucleus neurons.

  17. Methamphetamine Self-Administration Acutely Decreases Monoaminergic Transporter Function

    PubMed Central

    McFadden, Lisa M.; Stout, Kristen A.; Vieira-Brock, Paula L.; Allen, Scott C.; Nielsen, Shannon M.; Wilkins, Diana G.; Hanson, Glen R.; Fleckenstein, Annette E.

    2014-01-01

    Numerous pre-clinical studies have demonstrated that non-contingent methamphetamine (METH) administration rapidly decreases both dopamine (DA) transporter (DAT) and vesicular monoamine-2 transporter (VMAT-2) function. Because of the importance of transporter function to the abuse and neurotoxic liabilities of METH, and previous research indicating that the effects of non-contingent METH treatment do not necessarily predict effects of contingent exposure, the present study examined the acute impact of METH self-administration on these transporters. Results revealed that five days of METH self-administration (4 h/session; 0.06 mg/infusion) decreased DAT and VMAT-2 activity, as assessed in synaptosomes and vesicles, respectively, prepared from striatal tissue 1 h after the final self-administration session. METH self-administration increased core body temperatures as well. Brain METH and amphetamine (AMPH) levels, assessed 1 h after the final self-administration session, were approximately twice greater in high-pressing rats compared to low-pressing rats despite similar changes in DAT function. In conclusion, the present manuscript is the first to describe transporter function and METH/AMPH levels after self-administration in rodents. These data provide a foundation to investigate complex questions including how the response of dopaminergic systems to METH self-administration contributes to contingent-related processes such as dependence. PMID:22120988

  18. Intracoronary ghrelin infusion decreases coronary blood flow in anesthetized pigs.

    PubMed

    Grossini, Elena; Molinari, Claudio; Mary, David A S G; Ghigo, Ezio; Bona, Gianni; Vacca, Giovanni

    2007-02-01

    The peptide ghrelin has been linked to the atherosclerotic process and coronary artery disease. We planned to study, for the first time, the primary effects of ghrelin on the intact coronary circulation and determine the mechanisms involved. In 24 sodium pentobarbitone-anesthetized pigs, changes in anterior descending coronary blood flow caused by intracoronary infusion of ghrelin at constant heart rate and arterial pressure were assessed using electromagnetic flowmeters. In 20 pigs, intracoronary infusion of ghrelin decreased coronary blood flow without affecting left ventricular maximum rate of change of left ventricular systolic pressure (dP/dt(max)), filling pressures of the heart or plasma levels of GH. In four pigs, this decrease was graded by step increments of infused dose of the hormone. The mechanisms of the above response were studied in the 20 pigs by repeating the experiment after coronary flow had returned to the control values observed before infusion. The ghrelin-induced coronary vasoconstriction was not affected by iv atropine (five pigs) or phentolamine (five pigs). This response was abolished by iv butoxamine (five pigs) and intracoronary N(omega)-nitro-l-arginine methyl ester (five pigs), even after reversing the increase in arterial pressure and coronary vascular resistance caused by the two blocking agents with iv infusion of papaverine. The present study showed that intracoronary infusion of ghrelin primarily caused coronary vasoconstriction. The mechanisms of this response were shown to involve the inhibition of a vasodilatory beta(2)-adrenergic receptor-mediated effect related to the release of nitric oxide.

  19. Decreased proliferation kinetics of mouse myoblasts overexpressing FRG1.

    PubMed

    Chen, Steven C; Frett, Ellie; Marx, Joseph; Bosnakovski, Darko; Reed, Xylena; Kyba, Michael; Kennedy, Brian K

    2011-01-01

    Although recent publications have linked the molecular events driving facioscapulohumeral muscular dystrophy (FSHD) to expression of the double homeobox transcription factor DUX4, overexpression of FRG1 has been proposed as one alternative causal agent as mice overexpressing FRG1 present with muscular dystrophy. Here, we characterize proliferative defects in two independent myoblast lines overexpressing FRG1. Myoblasts isolated from thigh muscle of FRG1 transgenic mice, an affected dystrophic muscle, exhibit delayed proliferation as measured by decreased clone size, whereas myoblasts isolated from the unaffected diaphragm muscle proliferated normally. To confirm the observation that overexpression of FRG1 could impair myoblast proliferation, we examined C2C12 myoblasts with inducible overexpression of FRG1, finding increased doubling time and G1-phase cells in mass culture after induction of FRG1 and decreased levels of pRb phosphorylation. We propose that depressed myoblast proliferation may contribute to the pathology of mice overexpressing FRG1 and may play a part in FSHD.

  20. Bandwidths for the perception of head orientation decrease during childhood.

    PubMed

    Vida, Mark D; Wilson, Hugh R; Maurer, Daphne

    2014-05-01

    Adults use the orientation of people's heads as a cue to the focus of their attention. We examined developmental changes in mechanisms underlying sensitivity to head orientation during childhood. Eight-, 10-, 12-year-olds, and adults were adapted to a frontal face view or a 20° left or right side view before judging the orientation of a face at or near frontal. After frontal adaptation, there were no age differences in judgments of head orientation. However, after adaptation to a 20° left or right side view, aftereffects were larger and sensitivity to head orientation was lower in 8- and 10-year-olds than in adults, with no difference between 12-year-olds and adults. A computational model indicates that these results can be modeled as a consequence of decreasing neural tuning bandwidths and decreasing additive internal noise during childhood, and/or as a consequence of increasing inhibition during childhood. These results provide the first evidence that neural mechanisms underlying sensitivity to head orientation undergo considerable refinement during childhood.

  1. Methamphetamine self-administration acutely decreases monoaminergic transporter function.

    PubMed

    McFadden, Lisa M; Stout, Kristen A; Vieira-Brock, Paula L; Allen, Scott C; Nielsen, Shannon M; Wilkins, Diana G; Hanson, Glen R; Fleckenstein, Annette E

    2012-03-01

    Numerous preclinical studies have demonstrated that noncontingent methamphetamine (METH) administration rapidly decreases both dopamine (DA) transporter (DAT) and vesicular monoamine-2 transporter (VMAT-2) function. Because of the importance of transporter function to the abuse and neurotoxic liabilities of METH, and previous research indicating that the effects of noncontingent METH treatment do not necessarily predict effects of contingent exposure, the present study examined the acute impact of METH self-administration on these transporters. Results revealed that five days of METH self-administration (4 h/session; 0.06 mg/infusion) decreased DAT and VMAT-2 activity, as assessed in synaptosomes and vesicles, respectively, prepared from striatal tissue 1 h after the final self-administration session. METH self-administration increased core body temperatures as well. Brain METH and amphetamine (AMPH) levels, assessed 1 h after the final self-administration session, were approximately twice greater in high-pressing rats compared to low-pressing rats despite similar changes in DAT function. In conclusion, the present manuscript is the first to describe transporter function and METH/AMPH levels after self-administration in rodents. These data provide a foundation to investigate complex questions including how the response of dopaminergic systems to METH self-administration contributes to contingent-related processes such as dependence.

  2. Decreasing particle number concentrations in a warming atmosphere and implications

    NASA Astrophysics Data System (ADS)

    Yu, F.; Luo, G.; Turco, R. P.; Ogren, J. A.; Yantosca, R. M.

    2012-03-01

    New particle formation contributes significantly to the number concentration of condensation nuclei (CN) as well as cloud CN (CCN), a key factor determining aerosol indirect radiative forcing of the climate system. Using a physics-based nucleation mechanism that is consistent with a range of field observations of aerosol formation, it is shown that projected increases in global temperatures could significantly inhibit new particle, and CCN, formation rates worldwide. An analysis of CN concentrations observed at four NOAA ESRL/GMD baseline stations since the 1970s and two other sites since 1990s reveals long-term decreasing trends that are consistent in sign with, but are larger in magnitude than, the predicted temperature effects. The possible reasons for larger observed long-term CN reductions at remote sites are discussed. The combined effects of rising temperatures on aerosol nucleation rates and other chemical and microphysical processes may imply substantial decreases in future tropospheric particle abundances associated with global warming, delineating a potentially significant feedback mechanism that increases Earth's climate sensitivity to greenhouse gas emissions. Further research is needed to quantify the magnitude of such a feedback process.

  3. Fitness of RNA virus decreased by Muller's ratchet

    NASA Astrophysics Data System (ADS)

    Chao, Lin

    1990-11-01

    WHY sex exists remains an unsolved problem in biology1-3. If mutations are on the average deleterious, a high mutation rate can account for the evolution of sex4. One form of this mutational hypothesis is Muller's ratchet5,6. If the mutation rate is high, mutation-free individuals become rare and they can be lost by genetic drift in small populations. In asexual populations, as Muller5 noted, the loss is irreversible and the load of deleterious mutations increases in a ratchet-like manner with the successive loss of the least-mutated individuals. Sex can be advantageous because it increases the fitness of sexual populations by re-creating mutation-free individuals from mutated individuals and stops (or slows) Muller's ratchet. Although Muller's ratchet is an appealing hypothesis, it has been investigated and documented experimentally in only one group of organisms-ciliated protozoa2. I initiated a study to examine the role of Muller's ratchet on the evolution of sex in RNA viruses and report here a significant decrease in fitness due to Muller's ratchet in 20 lineages of the RNA bacteriophage Φ6. These results show that deleterious mutations are generated at a sufficiently high rate to advance Muller's ratchet in an RNA virus and that beneficial, backward and compensatory mutations cannot stop the ratchet in the observed range of fitness decrease.

  4. Decreasing net primary production due to drought and slight decreases in solar radiation in China from 2000 to 2012

    NASA Astrophysics Data System (ADS)

    Wang, J.; Dong, J.; Yi, Y.; Lu, G.; Oyler, J.; Smith, W. K.; Zhao, M.; Liu, J.; Running, S.

    2017-01-01

    Terrestrial ecosystems have continued to provide the critical service of slowing the atmospheric CO2 growth rate. Terrestrial net primary productivity (NPP) is thought to be a major contributing factor to this trend. Yet our ability to estimate NPP at the regional scale remains limited due to large uncertainties in the response of NPP to multiple interacting climate factors and uncertainties in the driver data sets needed to estimate NPP. In this study, we introduced an improved NPP algorithm that used local driver data sets and parameters in China. We found that bias decreased by 30% for gross primary production (GPP) and 17% for NPP compared with the widely used global GPP and NPP products, respectively. From 2000 to 2012, a pixel-level analysis of our improved NPP for the region of China showed an overall decreasing NPP trend of 4.65 Tg C a-1. Reductions in NPP were largest for the southern forests of China (-5.38 Tg C a-1), whereas minor increases in NPP were found for North China (0.65 Tg C a-1). Surprisingly, reductions in NPP were largely due to decreases in solar radiation (82%), rather than the more commonly expected effects of drought (18%). This was because for southern China, the interannual variability of NPP was more sensitive to solar radiation (R2 in 0.29-0.59) relative to precipitation (R2 < 0.13). These findings update our previous knowledge of carbon uptake responses to climate change in terrestrial ecosystems of China and highlight the importance of shortwave radiation in driving vegetation productivity for the region, especially for tropical forests.

  5. Iron Deficiency Decreases Suberization in Bean Roots through a Decrease in Suberin-Specific Peroxidase Activity 1

    PubMed Central

    Sijmons, Peter C.; Kolattukudy, P. E.; Bienfait, H. Frits

    1985-01-01

    The suberin content of young root parts of iron-deficient and iron-sufficient Phaseolus vulgaris L. cv Prélude was determined. The aliphatic components that could be released from suberin-enriched fractions by LiAID4 depolymerization were identified by gas chromatography-mass spectrometry. In the normal roots, the major aliphatic components were ω-hydroxy acids and dicarboxylic acids in which saturated C16 and monounsaturated C18 were the dominant homologues. Iron-deficient bean roots contained only 11% of the aliphatic components of suberin found in control roots although the relative composition of the constituents was not significantly affected by iron deficiency. Analysis of the aromatic components of the suberin polymer that could be released by alkaline nitrobenzene oxidation of bean root samples showed a 95% decrease in p-hydroxybenzaldehyde, vanillin, and syringaldehyde under iron-deficient conditions. The inhibition of suberin synthesis in bean roots was not due to a decrease in Fe-dependent ω-hydroxylase activity since normal ω-hydroxylation could be demonstrated, both in vitro with microsomal preparations and in situ by labeling of ω-hydroxy and dicarboxylic acids with [14C]acetate. The level of the isozyme of peroxidase that is specifically associated with suberization was suppressed by iron deficiency to 25% of that found in control roots. None of the other extracted isozymes of peroxidase was affected by the iron nutritional status. The activity of the suberin-associated peroxidase was restored within 3 to 4 days after application of iron to the growth medium. The results suggest that, in bean roots, iron deficiency causes inhibition of suberization by causing a decrease in the level of isoperoxidase activity which is required for polymerization of the aromatic domains of suberin, while the ability to synthesize the aliphatic components of the suberin polymer is not impaired. Images Fig. 2 PMID:16664183

  6. Inhibition of FAK and VEGFR-3 Binding Decreases Tumorigenicity in Neuroblastoma

    PubMed Central

    Stewart, Jerry E.; Ma, Xiaojie; Megison, Michael; Nabers, Hugh; Cance, William G.; Kurenova, Elena V.; Beierle, Elizabeth A.

    2015-01-01

    Neuroblastoma is the most common extracranial solid tumor of childhood and is responsible for over 15% of pediatric cancer deaths. Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase that is important in many facets of tumor development and progression. Vascular endothelial growth factor receptor-3 (VEGFR-3), another tyrosine kinase, has also been found to be important in the development of many human tumors including neuroblastoma. Recent reports have found that FAK and VEGFR-3 interact, and we have previously shown that both of these kinases interact in neuroblastoma. We have hypothesized that interruption of the FAK–VEGFR-3 interaction would lead to decreased neuroblastoma cell survival. In the current study, we examined the effects of a small molecule, chloropyramine hydrochloride (C4), designed to disrupt the FAK–VEGFR-3 interaction, upon cellular attachment, migration, and survival in two human neuroblastoma cell lines. We also utilized a murine xenograft model to study the impact of C4 upon tumor growth. In these studies, we showed that disruption of the FAK–VEGFR-3 interaction led to decreased cellular attachment, migration, and survival in vitro. In addition, treatment of murine xenografts with chloropyramine hydrochloride decreased neuroblastoma xenograft growth. Further, this molecule acted synergistically with standard chemotherapy to further decrease neuroblastoma xenograft growth. The findings from this current study help to further our understanding of the regulation of neuroblastoma tumorigenesis, and may provide novel therapeutic strategies and targets for neuroblastoma and other solid tumors of childhood. PMID:23868727

  7. Caffeine and nicotine decrease acetylcholine receptor clustering in C2C12 myotube culture.

    PubMed

    Kordosky-Herrera, Kaia; Grow, Wade A

    2009-02-01

    As motor neurons approach skeletal muscle during development, agrin is released and induces acetylcholine receptor (AChR) clustering. Our laboratory investigates the effect of environmental agents on skeletal muscle development by using C2C12 cell culture. For the current project, we investigated both short-term and long-term exposure to caffeine, nicotine, or both, at physiologically relevant concentrations. Short-term exposure was limited to the last 48 h of myotube formation, whereas a long-term exposure of 2 weeks allowed for several generations of myoblast proliferation followed by myotube formation. Both agrin-induced and spontaneous AChR clustering frequencies were assessed. For agrin-induced AChR clustering, agrin was added for the last 16 h of myotube formation. Caffeine, nicotine, or both significantly decreased agrin-induced AChR clustering during short-term and long-term exposure. Furthermore, caffeine, nicotine, or both significantly decreased spontaneous AChR clustering during long-term, but not short-term exposure. Surprisingly, caffeine and nicotine in combination did not decrease AChR clustering beyond the effect of either treatment alone. We conclude that physiologically relevant concentrations of caffeine or nicotine decrease AChR clustering. Moreover, we predict that fetuses exposed to caffeine or nicotine may be less likely to form appropriate neuromuscular synapses.

  8. Phenylephrine Decreases Vascular Tension in Goat Arteries in Specific Circumstances

    PubMed Central

    Raj, Renu R.

    2016-01-01

    Phenylephrine (PE) causes vasoconstriction through alpha adrenergic receptors. PE-induced vasodilatation has also been reported earlier in pre-constricted vessels. Here we demonstrate in spiral strips of goat arteries that addition of PE can decrease tone even from base-line levels (i.e. not pre-constricted) and show that this process requires nitric oxide (NO) and alpha adrenergic stimulation, but is cGMP-independent. Under control conditions, PE caused vasoconstriction, but under conditions where NO levels are higher, as with L-Arginine or sodium nitroprusside, PE decreased vessel tension. L-Arginine/PE combination was not able to decrease tension when alpha adrenoceptors were blocked with Phentolamine or endothelial nitric oxide synthase (eNOS) was blocked with Nω-Nitro-L-arginine (L-NNA). Propranolol, a beta blocker, was unable to prevent the reduction in tension by the L-Arginine/PE combination. Adrenaline and noradrenaline (and not isoproterenol) also reduced vessel tension in the presence of L-Arginine. Even when NO levels were not enhanced, relieving NO from having to stimulate the enzyme soluble guanylyl cyclase (sGC) (either by using sGC blockers, namely ODQ or methylene blue, or by enhancing cGMP levels (with sildenafil) which by negative feedback probably inhibits sGC) led to PE-induced reduction of vascular tension. PMA—phorbol myristate acetate—an agonist which stimulates Protein Kinase C was able to prevent the ability of PE to reduce vascular tension in a high NO environment. Our conclusion is that PE reduces vascular tension through alpha adrenoceptors if there is excess NO availability to activate a putative pathway. Though the reduction of vessel tone by PE is dependent on NO, it is independent of cGMP. Prior treatment with PMA or PE itself can prevent further PE-induced reduction of tension in a high NO environment. The results here suggest, counter-intuitively, that alpha blockers may be of help in the treatment of septic shock where

  9. Model Sensitivity Studies of the Decrease in Atmospheric Carbon Tetrachloride

    NASA Technical Reports Server (NTRS)

    Chipperfield, Martyn P.; Liang, Qing; Rigby, Matt; Hossaini, Ryan; Montzka, Stephen A.; Dhomse, Sandip; Feng, Wuhu; Prinn, Ronald G.; Weiss, Ray F.; Harth, Christina M.; Salameh, Peter K.; Muehle, Jens; O’Doherty, Simon; Young, Dickon; Simmonds, Peter G.; Krummel, Paul B.; Fraser, Paul J.; Steele, L. Paul; Happell, James D.; Rhew, Robert C.; Butler, James; Yvon-Lewis, Shari A.; Hall, Bradley; Nance, David; Moore, Fred; Miller, Ben R.; Elkins, James W.; Harrison, Jeremy J.; Boone, Chris D.; Atlas, Elliot L.; Mahieu, Emmanuel

    2016-01-01

    Carbon tetrachloride (CCl4) is an ozone-depleting substance, which is controlled by the Montreal Protocol and for which the atmospheric abundance is decreasing. However, the current observed rate of this decrease is known to be slower than expected based on reported CCl4 emissions and its estimated overall atmospheric lifetime. Here we use a three-dimensional (3-D) chemical transport model to investigate the impact on its predicted decay of uncertainties in the rates at which CCl4 is removed from the atmosphere by photolysis, by ocean uptake and by degradation in soils. The largest sink is atmospheric photolysis (74% of total), but a reported 10% uncertainty in its combined photolysis cross section and quantum yield has only a modest impact on the modelled rate of CCl4 decay. This is partly due to the limiting effect of the rate of transport of CCl4 from the main tropospheric reservoir to the stratosphere, where photolytic loss occurs. The model suggests large interannual variability in the magnitude of this stratospheric photolysis sink caused by variations in transport. The impact of uncertainty in the minor soil sink (9%of total) is also relatively small. In contrast, the model shows that uncertainty in ocean loss (17%of total) has the largest impact on modelled CCl4 decay due to its sizeable contribution to CCl4 loss and large lifetime uncertainty range (147 to 241 years). With an assumed CCl4 emission rate of 39 Gg year(exp -1), the reference simulation with the best estimate of loss processes still underestimates the observed CCl4 (overestimates the decay) over the past 2 decades but to a smaller extent than previous studies. Changes to the rate of CCl4 loss processes, in line with known uncertainties, could bring the model into agreement with in situ surface and remote-sensing measurements, as could an increase in emissions to around 47 Gg year(exp -1). Further progress in constraining the CCl4 budget is partly limited by systematic biases between

  10. Phenylephrine Decreases Vascular Tension in Goat Arteries in Specific Circumstances.

    PubMed

    Raj, Renu R; Subramani, Sathya

    2016-01-01

    Phenylephrine (PE) causes vasoconstriction through alpha adrenergic receptors. PE-induced vasodilatation has also been reported earlier in pre-constricted vessels. Here we demonstrate in spiral strips of goat arteries that addition of PE can decrease tone even from base-line levels (i.e. not pre-constricted) and show that this process requires nitric oxide (NO) and alpha adrenergic stimulation, but is cGMP-independent. Under control conditions, PE caused vasoconstriction, but under conditions where NO levels are higher, as with L-Arginine or sodium nitroprusside, PE decreased vessel tension. L-Arginine/PE combination was not able to decrease tension when alpha adrenoceptors were blocked with Phentolamine or endothelial nitric oxide synthase (eNOS) was blocked with Nω-Nitro-L-arginine (L-NNA). Propranolol, a beta blocker, was unable to prevent the reduction in tension by the L-Arginine/PE combination. Adrenaline and noradrenaline (and not isoproterenol) also reduced vessel tension in the presence of L-Arginine. Even when NO levels were not enhanced, relieving NO from having to stimulate the enzyme soluble guanylyl cyclase (sGC) (either by using sGC blockers, namely ODQ or methylene blue, or by enhancing cGMP levels (with sildenafil) which by negative feedback probably inhibits sGC) led to PE-induced reduction of vascular tension. PMA-phorbol myristate acetate-an agonist which stimulates Protein Kinase C was able to prevent the ability of PE to reduce vascular tension in a high NO environment. Our conclusion is that PE reduces vascular tension through alpha adrenoceptors if there is excess NO availability to activate a putative pathway. Though the reduction of vessel tone by PE is dependent on NO, it is independent of cGMP. Prior treatment with PMA or PE itself can prevent further PE-induced reduction of tension in a high NO environment. The results here suggest, counter-intuitively, that alpha blockers may be of help in the treatment of septic shock where nitric

  11. Model sensitivity studies of the decrease in atmospheric carbon tetrachloride

    NASA Astrophysics Data System (ADS)

    Chipperfield, Martyn P.; Liang, Qing; Rigby, Matthew; Hossaini, Ryan; Montzka, Stephen A.; Dhomse, Sandip; Feng, Wuhu; Prinn, Ronald G.; Weiss, Ray F.; Harth, Christina M.; Salameh, Peter K.; Mühle, Jens; O'Doherty, Simon; Young, Dickon; Simmonds, Peter G.; Krummel, Paul B.; Fraser, Paul J.; Steele, L. Paul; Happell, James D.; Rhew, Robert C.; Butler, James; Yvon-Lewis, Shari A.; Hall, Bradley; Nance, David; Moore, Fred; Miller, Ben R.; Elkins, James W.; Harrison, Jeremy J.; Boone, Chris D.; Atlas, Elliot L.; Mahieu, Emmanuel

    2016-12-01

    Carbon tetrachloride (CCl4) is an ozone-depleting substance, which is controlled by the Montreal Protocol and for which the atmospheric abundance is decreasing. However, the current observed rate of this decrease is known to be slower than expected based on reported CCl4 emissions and its estimated overall atmospheric lifetime. Here we use a three-dimensional (3-D) chemical transport model to investigate the impact on its predicted decay of uncertainties in the rates at which CCl4 is removed from the atmosphere by photolysis, by ocean uptake and by degradation in soils. The largest sink is atmospheric photolysis (74 % of total), but a reported 10 % uncertainty in its combined photolysis cross section and quantum yield has only a modest impact on the modelled rate of CCl4 decay. This is partly due to the limiting effect of the rate of transport of CCl4 from the main tropospheric reservoir to the stratosphere, where photolytic loss occurs. The model suggests large interannual variability in the magnitude of this stratospheric photolysis sink caused by variations in transport. The impact of uncertainty in the minor soil sink (9 % of total) is also relatively small. In contrast, the model shows that uncertainty in ocean loss (17 % of total) has the largest impact on modelled CCl4 decay due to its sizeable contribution to CCl4 loss and large lifetime uncertainty range (147 to 241 years). With an assumed CCl4 emission rate of 39 Gg year-1, the reference simulation with the best estimate of loss processes still underestimates the observed CCl4 (overestimates the decay) over the past 2 decades but to a smaller extent than previous studies. Changes to the rate of CCl4 loss processes, in line with known uncertainties, could bring the model into agreement with in situ surface and remote-sensing measurements, as could an increase in emissions to around 47 Gg year-1. Further progress in constraining the CCl4 budget is partly limited by systematic biases between observational

  12. Age-Dependent Decrease and Alternative Splicing of Methionine Synthase mRNA in Human Cerebral Cortex and an Accelerated Decrease in Autism

    PubMed Central

    Muratore, Christina R.; Hodgson, Nathaniel W.; Trivedi, Malav S.; Abdolmaleky, Hamid M.; Persico, Antonio M.; Lintas, Carla; De La Monte, Suzanne; Deth, Richard C.

    2013-01-01

    The folate and vitamin B12-dependent enzyme methionine synthase (MS) is highly sensitive to cellular oxidative status, and lower MS activity increases production of the antioxidant glutathione, while simultaneously decreasing more than 200 methylation reactions, broadly affecting metabolic activity. MS mRNA levels in postmortem human cortex from subjects across the lifespan were measured and a dramatic progressive biphasic decrease of more than 400-fold from 28 weeks of gestation to 84 years was observed. Further analysis revealed alternative splicing of MS mRNA, including deletion of folate-binding domain exons and age-dependent deletion of exons from the cap domain, which protects vitamin B12 (cobalamin) from oxidation. Although three species of MS were evident at the protein level, corresponding to full-length and alternatively spliced mRNA transcripts, decreasing mRNA levels across the lifespan were not associated with significant changes in MS protein or methionine levels. MS mRNA levels were significantly lower in autistic subjects, especially at younger ages, and this decrease was replicated in cultured human neuronal cells by treatment with TNF-α, whose CSF levels are elevated in autism. These novel findings suggest that rather than serving as a housekeeping enzyme, MS has a broad and dynamic role in coordinating metabolism in the brain during development and aging. Factors adversely affecting MS activity, such as oxidative stress, can be a source of risk for neurological disorders across the lifespan via their impact on methylation reactions, including epigenetic regulation of gene expression. PMID:23437274

  13. Increased anthropogenic pressure decreases species richness in tropical intertidal reefs.

    PubMed

    Portugal, Adriana Brizon; Carvalho, Fabrício Lopes; de Macedo Carneiro, Pedro Bastos; Rossi, Sergio; de Oliveira Soares, Marcelo

    2016-09-01

    Multiple human stressors affect tropical intertidal sandstone reefs, but little is known about their biodiversity and the environmental impacts of these stressors. In the present study, multiple anthropogenic pressures were integrated using the relative environmental pressure index (REPI) and related to benthic community structure across an intertidal gradient in five sandstone reefs in the tropical South Atlantic coast. Greater species richness and diversity were noted in the low intertidal zones. There was a negative relationship between REPI and species richness, suggesting that increasing anthropogenic pressure has decreased benthic richness. The factors associated with the loss of richness were jetties built to control erosion, urban areas, beachfront kiosks and restaurants, fish markets, and storm sewers with illegal sewage connections. Our results highlight the need for better infrastructure planning and rigorous monitoring of coastal urban areas, since the large influence of multiple human pressures in these reefs leads to biodiversity losses.

  14. 360 Degree Photography to Decrease Exposure, Increase Safety & Minimize Waste

    SciTech Connect

    LEBARON, G.J.

    2002-01-31

    High-resolution digital cameras, in conjunction with software techniques. make possible 360{sup o} photos that allow a person to look all around, up and dawn, and zoom in or out. The software provides the opportunity to attach other information to a 360{sup o} photo such as sound tiles, flat photos (providing additional detail about what is behind a panel or around a corner) and text (Information which can be used to show radiological conditions or identify other hazards not readily visible). The software also allows other 360{sup o} photos to be attached creating a virtual tour where the user can move from area to area, and stop, study and zoom in on areas of interest. A virtual tour of a building or room can be used for facility documentation, informing management and others, work planning and orientation, and training, thus minimizing the need to re-enter hazardous radioactive areas. Reducing entries decreases exposure, increases safety and minimizes waste.

  15. Localized compressional velocity decrease precursory to the kalapana, hawaii, earthquake.

    PubMed

    Johnston, A C

    1978-02-24

    A delay in the arrival times of compressional or P waves of 0.15 to 0.2 second from deep distant earthquakes has been detected at the closest seismograph station to the 20 November 1975 earthquake at Kalapana, Hawaii (surface-wave magnitude MS = 7.2). This delay appeared approximately 3.5 years prior to the quake, and travel times returned to normal several months before it. The P-wave arrival times at other nearby stations remained constant during this period, an indication that the decreased velocity implied by the delay in travel time was associated with this normal-faulting earthquake and was confined to distances less than 20 kilometers from the epicenter.

  16. Decrease of calorific value and particle size in coal stockpiles

    SciTech Connect

    Sensogut, C.; Ozdeniz, A.H.

    2008-07-01

    During storage of excess amount of coal, they lose both their economical value and cause environmental problems. In this work, two industrial-sized stockpiles were constituted at a coal stockyard of Western Lignite Corporation (WLC) in Tuncbilek, Turkey. The size of the stockpiles, formed as triangle prisms, was about 10 m x 5 m wide with a height of 3 m; each mass being approximately 120 tons of coal in total. Some of the parameters that were effective on the stockpiles were measured in a continuous manner during this experimental work. The calorific losses and the decreases that occurred in particle size due to atmospheric conditions were also examined and detailed as the result of this work.

  17. Exendin-4 Decreases Amphetamine-induced Locomotor Activity

    PubMed Central

    Erreger, Kevin; Davis, Adeola R.; Poe, Amanda M.; Greig, Nigel H.; Stanwood, Gregg D.; Galli, Aurelio

    2012-01-01

    Glucagon-like peptide-1 (GLP-1) is released in response to nutrient ingestion and is a regulator of energy metabolism and consummatory behaviors through both peripheral and central mechanisms. The GLP-1 receptor (GLP-1R) is widely distributed in the central nervous system, however little is known about how GLP-1Rs regulate ambulatory behavior. The abused psychostimulant amphetamine (AMPH) promotes behavioral locomotor activity primarily by inducing the release of the neurotransmitter dopamine. Here, we identify the GLP-1R agonist exendin-4 (Ex-4) as a modulator of behavioral activation by AMPH. We report that in rats a single acute administration of Ex-4 decreases both basal locomotor activity as well as AMPH-induced locomotor activity. Ex-4 did not induce behavioral responses reflecting anxiety or aversion. Our findings implicate GLP-1R signaling as a novel modulator of psychostimulant-induced behavior and therefore a potential therapeutic target for psychostimulant abuse. PMID:22465309

  18. Air radon concentration decrease in a waste water treatment plant.

    PubMed

    Juste, B; Ortiz, J; Verdú, G; Martorell, S

    2015-06-01

    (222)Rn is a naturally occurring gas created from the decay of (226)Ra. The long-term health risk of breathing radon is lung cancer. One particular place where indoor radon concentrations can exceed national guidelines is in wastewater treatment plants (WWTPs) where treatment processes may contribute to ambient airborne concentrations. The aim of this paper was to study the radon concentration decrease after the application of corrective measures in a Spanish WWTP. According to first measures, air radon concentration exceeded International Commission Radiologica1 Protection (ICRP) normative (recommends intervention between 400 and 1000 Bq m(-3)). Therefore, the WWTP improved mechanical forced ventilation to lower occupational exposure. This measure allowed to increase the administrative controls, since the limitation of workers access to the plant changed from 2 h d(-1) (considering a maximum permissible dose of 20 mSv y(-1) averaged over 5 y) to 7 h d(-1).

  19. Biophysical features of cereal endosperm that decrease starch digestibility.

    PubMed

    Roman, Laura; Gomez, Manuel; Li, Cheng; Hamaker, Bruce R; Martinez, Mario M

    2017-06-01

    The influence of the physical structure of cereal endosperm on the natural structural integrity (intact cells) and starch bioaccessibility of the resultant flours was studied using maize as example. Endosperm hardness, defined by its intracellular (protein matrix) and extracellular (cell walls) constituents, affected the granular and molecular damage of the starch of the resultant flours leading to higher digestibility of raw hard than soft endosperm flours, but comparatively lower digestibility after cooking. After milling, hard endosperm possessed more damaged starch (radial splitting of amylopectin clusters) in the periphery of the resultant particles that increased in vitro starch digestibility of raw flours. Conversely, the hard endosperm plant tissue matrix significantly limited water availability and heat transfer on starch gelatinisation, thereby decreasing the digestion rate after hydrothermal processing (in particle size flours >80μm). This study provides a unique mechanistic understanding to obtain cereal flours with slow digestion property for commercial utilisation.

  20. Altering the mechanical scenario to decrease the driving pressure.

    PubMed

    Borges, João Batista; Hedenstierna, Göran; Larsson, Anders; Suarez-Sipmann, Fernando

    2015-09-21

    Ventilator settings resulting in decreased driving pressure (ΔP) are positively associated with survival. How to further foster the potential beneficial mediator effect of a reduced ΔP? One possibility is promoting the active modification of the lung's "mechanical scenario" by means of lung recruitment and positive end-expiratory pressure selection. By taking into account the individual distribution of the threshold-opening airway pressures to achieve maximal recruitment, a redistribution of the tidal volume from overdistended to newly recruited lung occurs. The resulting more homogeneous distribution of transpulmonary pressures may induce a relief of overdistension in the upper regions. The gain in lung compliance after a successful recruitment rescales the size of the functional lung, potentially allowing for a further reduction in ΔP.

  1. Decreased susceptibility to nitroimidazoles among Bacteroides species in Brazil.

    PubMed

    B D Vieira, Jessica Manya; Boente, Renata F; Rodrigues Miranda, Karla; Avelar, Kátia E S; M C P Domingues, Regina; Candida de S Ferreira, Maria

    2006-01-01

    In this study, 197 strains of Bacteroides genus from different species and origins were evaluated with regard to their susceptibility to 5-nitroimidazoles (5-Ni)-such as tinidazole, ornidazole, and metronidazole-using the agar dilution method. The presence of nim genes was also investigated by polymerase chain reaction. It was found that 5.6% of Bacteroides strains among all origins showed decreased susceptibility (minimum inhibitory concentrations varying from 4 to 16 microg/ml) to at least one of the imidazoles studied without any known nim gene associate. Also, we detected one strain isolated from a polluted aquatic environment in which one nim gene was found and characterized as nim B using restriction fragment length polymorphism and sequencing. Hence, resistance to 5-Ni should be monitored closely because they constitute, among few drugs, the ones quite effective in treating Bacteroides infections.

  2. The nondiscriminating heart: lovingkindness meditation training decreases implicit intergroup bias.

    PubMed

    Kang, Yoona; Gray, Jeremy R; Dovidio, John F

    2014-06-01

    Although meditation is increasingly accepted as having personal benefits, less is known about the broader impact of meditation on social and intergroup relations. We tested the effect of lovingkindness meditation training on improving implicit attitudes toward members of 2 stigmatized social outgroups: Blacks and homeless people. Healthy non-Black, nonhomeless adults (N = 101) were randomly assigned to 1 of 3 conditions: 6-week lovingkindness practice, 6-week lovingkindness discussion (a closely matched active control), or waitlist control. Decreases in implicit bias against stigmatized outgroups (as measured by Implicit Association Test) were observed only in the lovingkindness practice condition. Reduced psychological stress mediated the effect of lovingkindness practice on implicit bias against homeless people, but it did not mediate the reduced bias against Black people. These results suggest that lovingkindness meditation can improve automatically activated, implicit attitudes toward stigmatized social groups and that this effect occurs through distinctive mechanisms for different stigmatized social groups.

  3. Decreased retinol in plasma of copper-deficient rats

    SciTech Connect

    Klevay, L.M. )

    1991-03-15

    There is increasing interest in oxidative effects in atherogenesis. Male, weanling rats of the Sprague-Dawley strain were matched by weight rats of the Sprague-Dawley strain were matched by weight into two groups of 10 and were fed a diet based on sucrose, egg white and corn oil deficient in copper and zinc and with vitamins A and E in excess of NRC recommendations. Retinol and {alpha}-tocopherol were measured in plasma by high performance liquid chromatography after hypercholesterolemia was detected. Retinol was decreased and {alpha}-tocopherol was increased by deficiency. Correction for cholestrolemia increased the effect on retinol and abolished the effect on retinol and abolished the effect on {alpha}-tocopherol. Epidemiologic association between mortality and vitamin A are not necessarily direct effects of low carotene intake; copper nutriture may be a hidden variable. The Western diet associated with high heart disease risk frequently is low in copper in comparison to putative requirements.

  4. Decreasing the length of residency training: a public policy perspective.

    PubMed

    Whitcomb, Michael E

    2013-12-01

    It is widely recognized that the United States is going to experience a serious shortage of physicians in the coming years unless the number of physicians completing residency training and entering practice is greatly increased. Members of the academic medicine community have approached this issue by calling on Congress to eliminate the cap that currently limits the number of residency positions that Medicare will support. Simply eliminating the cap, however, will not ensure an adequate supply of physicians. In this commentary the author argues that decreasing the length of training required in core clinical specialties will be required to effectively address the workforce shortage by allowing more residents to be trained in core specialties without greatly increasing the number of training programs and the aggregate amount that Medicare currently spends on graduate medical education.

  5. Neurokinin-1 receptors are decreased in major depressive disorder.

    PubMed

    Stockmeier, Craig A; Shi, Xiaochun; Konick, Lisa; Overholser, James C; Jurjus, George; Meltzer, Herbert Y; Friedman, Lee; Blier, Pierre; Rajkowska, Grazyna

    2002-07-02

    Treatment with an antagonist at the neurokinin-1 (NK-1) receptor may alleviate depression, however the brain region(s) in which the NK-1 receptor antagonist exerts its therapeutic effect is unknown. [125I]BH-Substance P was used to measure NK-1 receptors postmortem in cytoarchitectonically defined areas of rostral orbitofrontal cortex (Brodmann's area 47) of subjects with major depressive disorder (n = 12, six females) and psychiatrically normal subjects (n = 11, five females). Six subjects with depression died by suicide. Subjects with depression showed decreased binding to NK-1 receptors across all cortical layers (p = 0.024). The pathophysiology of depression, and the reported therapeutic benefit of NK-1 receptor antagonists, may thus involve NK-1 receptors in prefrontal cortex.

  6. Decreasing Brillouin and Raman scattering by alternating-polarization light

    NASA Astrophysics Data System (ADS)

    Liu, Z. J.; Zheng, C. Y.; Cao, L. H.; Li, B.; Xiang, J.; Hao, L.

    2017-03-01

    A new method to reduce the scattering levels of stimulated Raman scattering (SRS) and stimulated Brillouin (SBS) scattering is proposed using alternating-polarization light. The effect of the new technique is related to the alternating time. If the alternating time is smaller than the growth time, the scattering level of SRS or SBS can be decreased. The SBS process is simulated by the fluid method, and the SRS process is verified by the particle-in-cell method. This method is also compared with the spike trains of uneven duration and delay (STUD) technique. Combining STUD pulses with alternating-polarization light is also discussed. Under proper alternating-polarization parameters, the scattering level of SRS and SBS can be dramatically reduced by more than one order of magnitude.

  7. Alternative to decrease cholesterol in sheep milk cheeses.

    PubMed

    Gómez-Cortés, P; Viturro, E; Juárez, M; de la Fuente, M A

    2015-12-01

    The presence of cholesterol in foods is of nutritional interest because high levels of this molecule in human plasma are associated with an increasing risk of cardiovascular disease and nowadays consumers are demanding healthier products. The goal of this experiment was to diminish the cholesterol content of Manchego, the most popular Spanish cheese manufactured from ewes milk. For this purpose three bulk milks coming from dairy ewe fed with 0 (Control), 3 and 6% of linseed supplement on their diet were used. Nine cheeses (3 per bulk milk) were manufactured and ripened for 3 months. Cholesterol of ewes milk cheese from 6% to 12% linseed supplemented diets decreased by 9.6% and 16.1% respectively, therefore supplying a healthier profile. In a second experiment, different sources of unsaturated fatty acids (rich in oleic, linoleic and α-linolenic acids) were supplemented to dairy ewes and no significant differences were found on cheese cholesterol levels.

  8. Fluid flow plate for decreased density of fuel cell assembly

    DOEpatents

    Vitale, Nicholas G.

    1999-01-01

    A fluid flow plate includes first and second outward faces. Each of the outward faces has a flow channel thereon for carrying respective fluid. At least one of the fluids serves as reactant fluid for a fuel cell of a fuel cell assembly. One or more pockets are formed between the first and second outward faces for decreasing density of the fluid flow plate. A given flow channel can include one or more end sections and an intermediate section. An interposed member can be positioned between the outward faces at an interface between an intermediate section, of one of the outward faces, and an end section, of that outward face. The interposed member can serve to isolate the reactant fluid from the opposing outward face. The intermediate section(s) of flow channel(s) on an outward face are preferably formed as a folded expanse.

  9. Plant species loss decreases arthropod diversity and shifts trophic structure.

    PubMed

    Haddad, Nick M; Crutsinger, Gregory M; Gross, Kevin; Haarstad, John; Knops, Johannes M H; Tilman, David

    2009-10-01

    Plant diversity is predicted to be positively linked to the diversity of herbivores and predators in a foodweb. Yet, the relationship between plant and animal diversity is explained by a variety of competing hypotheses, with mixed empirical results for each hypothesis. We sampled arthropods for over a decade in an experiment that manipulated the number of grassland plant species. We found that herbivore and predator species richness were strongly, positively related to plant species richness, and that these relationships were caused by different mechanisms at herbivore and predator trophic levels. Even more dramatic was the threefold increase, from low- to high-plant species richness, in abundances of predatory and parasitoid arthropods relative to their herbivorous prey. Our results demonstrate that, over the long term, the loss of plant species propagates through food webs, greatly decreasing arthropod species richness, shifting a predator-dominated trophic structure to being herbivore dominated, and likely impacting ecosystem functioning and services.

  10. Are more North American species decreasing than increasing?

    USGS Publications Warehouse

    Droege, S.; Sauer, J.R.; Hagemeijer, E.J.M.; Verstrael, T.J.

    1994-01-01

    Population trends for North American species are calculated for 1966-'91 and 1982-'91 using Nonh American Breeding Bird Survey data. Species are grouped into 3 systems of guild classifications representing migration status, breeding habitat and nesting substrate. Trends for these groups are summarized by time period, bioregion and physiographic region. At the continental level, declines approximately equalled increases. There are slightly more declines during the last 10 years. Prairie populations declined more than expected, while western populations increased. Scrub and grassland nesting species declined significantly in several bioregions while woodland species increased. Most guilds did not depart significantly from a ratio of 50:50 increases to decreases or have opposing trends in different bioregions. Guild group changes are usually clustered geographically. Guild and other analyses that search for patterns among population trend estimates offer an excellent means of identifying critical conservation issues.

  11. Decreased Antitoxic Activities among Children with Clinical Episodes of Malaria

    PubMed Central

    Jakobsen, Palle Høy; McKay, Veronica; N’Jie, Ramou; Olaleye, Ben O.; D’Alessandro, Umberto; Zhang, Gui-Hang; Eggelte, Teunis A.; Koch, Claus; Greenwood, Brian M.

    1998-01-01

    Healthy Gambian children, children with clinical Plasmodium falciparum malaria, and children with asymptomatic P. falciparum infections were studied to investigate whether antitoxic activities may contribute to protection against malarial symptoms. Markers of inflammatory reactions, soluble tumor necrosis factor receptor I, and C-reactive protein were found in high concentrations in children with symptomatic P. falciparum malaria compared with levels in children with asymptomatic P. falciparum infections or in healthy children, indicating that inflammatory reactions are induced only in children with clinical symptoms. Concentrations of soluble tumor necrosis factor receptor I and C-reactive protein were associated with levels of parasitemia. We detected antitoxic activities in sera as measured by their capacity to block toxin-induced Limulus amoebocyte lysate (LAL) activation. Symptomatic children had decreased capacity to block induction of LAL activation by P. falciparum exoantigen. The decreased blocking activity was restored in the following dry season, when the children had no clinical malaria. Symptomatic children also had the highest immunoglobulin G (IgG) reactivities to conserved P. falciparum erythrocyte membrane protein 1 and “Pfalhesin” (band #3) peptides, indicating that such IgG antibodies are stimulated by acute disease but are lost rapidly after the disease episode. Half of the children with symptomatic infections had low levels of haptoglobin, suggesting that these children had chronic P. falciparum infections which may have caused symptoms previously. Only a few of the children with asymptomatic P. falciparum infections had high parasite counts, and antitoxic immunity in the absence of antiparasite immunity appears to be rare among children in this community. PMID:9529094

  12. Marine benthic ecological functioning over decreasing taxonomic richness

    NASA Astrophysics Data System (ADS)

    Törnroos, Anna; Bonsdorff, Erik; Bremner, Julie; Blomqvist, Mats; Josefson, Alf B.; Garcia, Clement; Warzocha, Jan

    2015-04-01

    Alterations to ecosystem function due to reductions in species richness are predicted to increase as humans continue to affect the marine environment, especially in coastal areas, which serve as the interface between land and sea. The potential functional consequences due to reductions in species diversity have attracted considerable attention recently but little is known about the consequence of such loss in natural communities. We examined how the potential for function is affected by natural reductions in taxon richness using empirical (non-simulated) coastal marine benthic macrofaunal data from the Skagerrak-Baltic Sea region (N. Europe), where taxon richness decreases 25-fold, from 151 to 6 taxa. To estimate functional changes we defined multiple traits (10 traits and 51 categories) on which trait category richness, functional diversity (FD) and number of taxa per trait category were calculated. Our results show that decrease in taxon richness leads to an overall reduction in function but functional richness remains comparatively high even at the lowest level of taxon richness. Although the taxonomic reduction was sharp, up to 96% of total taxon richness, we identified both potential thresholds in functioning and subtler changes where function was maintained along the gradient. The functional changes were not only caused by reductions in taxa per trait category, some categories were maintained or even increased. Primarily, the reduction in species richness altered trait categories related to feeding, living and movement and thus potentially could have an effect on various ecosystem processes. This highlights the importance of recognising ecosystem multifunctionality, especially at low taxonomic richness. We also found that in this system rare species (singletons) did not stand for the functional complexities and changes. Our findings were consistent with theoretical and experimental predictions and suggest that a large proportion of the information about

  13. Decreased thyroidal response to thyrotropin in diabetic mice

    SciTech Connect

    Bagchi, N.; Brown, T.R.; Shivers, B.; Lucas, S.; Mack, R.E.

    1981-11-01

    The effect of diabetes mellitus on the synthesis and secretion of thyroid hormone ws investigated in mice with streptozotocin-induced diabetes. Thyroid glands were labeled in vivo with 131I for 2 h. In control animals, TSH stimulated the synthesis of PB127I and 131I-labeled iodothyronines and simultaneously decreased the proportion of 131I-. These effects of TSH were not observed in diabetic animals but were demonstrable in diabetic animals treated with insulin. For studies of hormone secretion, labeled thyroid glands were cultured in vitro in medium containing 1 mM mononitrotyrosine. The rate of the hydrolysis of labeled thyroglobulin was measured as the proportion of 131I-labeled iodotyrosines and 131I-labeled iodothyronines recovered at the end of culture and was used as an index of thyroid secretion. TSH in vivo stimulated the rate of thyroglobulin hydrolysis for 6 h, with a peak occurring after 2 h. The diabetic mice had a diminished response to TSH, which improved on treatment with insulin. The addition of TSH and insulin to the culture medium significantly increased the rate of thyroglobulin hydrolysis in glands of diabetic mice over that resulting from the addition of dibutyryl cAMP alone. The generation of thyroidal cAMP in response to TSH was higher in diabetic mice than in controls. The rise in plasma T4 and T3 2 h after the administration of TSH was less in diabetic mice than in control mice or diabetic mice treated with insulin. Our studies, therefore, indicate that the thyroidal response to TSH is decreased in diabetes mellitus. The defect appears to be at a step beyond the generation of cAMP.

  14. Nicotine decreases the activity of glutamate transporter type 3.

    PubMed

    Yoon, Hea-Jo; Lim, Young-Jin; Zuo, Zhiyi; Hur, Wonseok; Do, Sang-Hwan

    2014-02-10

    Nicotine, the main ingredient of tobacco, elicits seizures in animal models and cigarette smoking is regarded as a behavioral risk factor associated with epilepsy or seizures. In the hippocampus, the origin of nicotine-induced seizures, most glutamate uptake could be performed primarily by excitatory amino acid transporter type 3 (EAAT3). An association between temporal lobe epilepsy and EAAT3 downregulation has been reported. Therefore, we hypothesized that nicotine may elicit seizures through the attenuation of EAAT3 activity. We investigated chronic nicotine exposure (72 h) cause reduction of the activity of EAAT3 in a Xenopus oocyte expression system using a two-electrode voltage clamp. The roles of protein kinase C (PKC) and phosphatidylinositol 3-kinase (PI3K) were also determined. Nicotine (0.001-1 μM) resulted in a time- and dose-dependent decrease in EAAT3 activity with maximal inhibition at nicotine concentrations of 0.03 μM or higher and at an exposure time of 72 h. Vmax on the glutamate response was significantly reduced in the nicotine group (0.03 μM for 72 h), but the Km value of EAAT3 for glutamate was not altered. When nicotine-exposed oocytes (0.03 μM for 72 h) were pretreated with phorbol-12-myristate-13-acetate (PMA, a PKC activator), the nicotine-induced reduction in EAAT3 activity was abolished. PKC inhibitors (staurosporine, chelerythrine, and calphostin C) significantly reduced basal EAAT3 activity, but there were no significant differences among the PKC inhibitors, nicotine, and PKC inhibitors+nicotine groups. Similar response patterns were observed among PI3K inhibitors (wortmannin and LY294002), nicotine, and PI3K inhibitors+nicotine. In conclusion, this study suggests that nicotine decreases EAAT3 activity, and that this inhibition seems to be dependent on PKC and PI3K. Our results may provide an additional mechanism for nicotine-induced seizure.

  15. Ego depletion decreases trust in economic decision making

    PubMed Central

    Ainsworth, Sarah E.; Baumeister, Roy F.; Vohs, Kathleen D.; Ariely, Dan

    2014-01-01

    Three experiments tested the effects of ego depletion on economic decision making. Participants completed a task either requiring self-control or not. Then participants learned about the trust game, in which senders are given an initial allocation of $10 to split between themselves and another person, the receiver. The receiver receives triple the amount given and can send any, all, or none of the tripled money back to the sender. Participants were assigned the role of the sender and decided how to split the initial allocation. Giving less money, and therefore not trusting the receiver, is the safe, less risky response. Participants who had exerted self-control and were depleted gave the receiver less money than those in the non-depletion condition (Experiment 1). This effect was replicated and moderated in two additional experiments. Depletion again led to lower amounts given (less trust), but primarily among participants who were told they would never meet the receiver (Experiment 2) or who were given no information about how similar they were to the receiver (Experiment 3). Amounts given did not differ for depleted and non-depleted participants who either expected to meet the receiver (Experiment 2) or were led to believe that they were very similar to the receiver (Experiment 3). Decreased trust among depleted participants was strongest among neurotics. These results imply that self-control facilitates behavioral trust, especially when no other cues signal decreased social risk in trusting, such as if an actual or possible relationship with the receiver were suggested. PMID:25013237

  16. Decrease of pairing strength with underdoping in cuprate superconductors

    NASA Astrophysics Data System (ADS)

    Chang, Johan

    2012-02-01

    The transition temperature Tc of cuprate superconductors decreases at low hole doping p, but it is still unclear whether the pairing strength decreases or increases. Different interpretations of the pseudogap lead to opposite conclusions. Different estimates of the upper critical field Hc2 are in sharp contradiction. In this talk, we resolve the latter contradiction by showing that superconducting fluctuations in the underdoped cuprate Eu-LSCO, measured via the Nernst effect, obey the theory of Gaussian fluctuations, as in conventional superconductors [1, 2]. The extracted critical field Hc2 is small, and it dips at p = 0.11, showing that pairing strength is weak where stripe order is strong. In the archetypal cuprate superconductor YBCO, Hc2 extracted from other measurements [3] has the same doping dependence, also with a minimum at p = 0.11, again where stripe order is present [4, 5]. We conclude that competing states such as stripe order weaken the pairing strength and this, rather than phase fluctuations, is the predominant cause for the low Tc of underdoped cuprates. Work done in collaboration with N. Doiron-Leyraud, E. Hassinger, J.-Ph. Reid, O. Cyr-Choinière, F. Lalibert'e, R. Daou, S. Pyon, T. Takayama, H. Takagi, and Louis Taillefer. [4pt] [1] M. N. Serbyn et al., Phys. Rev. Lett. 102, 067001 (2009). [0pt] [2] K. Michaeli and A. M. Finkel'stein, Europhys. Lett. 86, 27007 (2009).[0pt] [3] Y. Ando and K. Segawa, Phys. Rev. Lett. 88, 167005 (2002).[0pt] [4] F. Lalibert'e et al., Nature Comm. 2, 432 (2011).[0pt] [5] T. Wu et al., Nature 477, 191 (2011).

  17. Chronic cobalt treatment decreases hyperglycemia in streptozotocin-diabetic rats.

    PubMed

    Vasudevan, Harish; McNeill, John H

    2007-04-01

    Diabetes is a metabolic disorder characterized by elevated blood glucose levels. Although conventional treatments such as insulin and other drugs reduce blood glucose, there is still a therapeutic need for effective orally administered drugs. Trace elements like vanadium and tungstate have been successfully demonstrated to reduce blood glucose in experimental diabetes with minimal chronic complications. We investigated the anti-hyperglycemic effects of cobalt in streptozotocin-diabetic rats. Normal and diabetic rats were provided with drinking water containing 3.5 mM cobalt chloride for three weeks followed by 4 mM for four weeks. Body weights and fluid consumption were monitored on a daily basis, while food intake was recorded twice every week. Prior to termination, an oral glucose tolerance test was performed on the animals. Diabetic rats lost significant body weight (357 +/- 2 gm) compared to controls (482 +/- 3 gm). Body weight was further reduced by cobalt treatment (290 +/- 2 gm). Although it was difficult to establish a dosing regimen without weight loss, food and fluid consumption in cobalt-treated diabetic rats improved significantly compared to untreated diabetics. Plasma glucose levels were significantly reduced with reference to diabetic controls (29.3 +/- 0.9 mM) by the fourth week to a lower but still hyperglycemic level (13.6 +/- 3.4 mM). Cobalt-treated diabetic rats demonstrated an enhanced ability to clear a glucose load compared to untreated diabetics. Cobalt treatment neither affected the feeding and drinking patterns nor plasma glucose in normoglycemic animals although body weights decreased compared to untreated controls. We conclude that chronic cobalt treatment decreases plasma glucose levels in STZ-diabetic rats and improves tolerance to glucose.

  18. Vaccination of influenza a virus decreases transmission rates in pigs.

    PubMed

    Romagosa, Anna; Allerson, Matt; Gramer, Marie; Joo, Han Soo; Deen, John; Detmer, Susan; Torremorell, Montserrat

    2011-12-20

    Limited information is available on the transmission and spread of influenza virus in pig populations with differing immune statuses. In this study we assessed differences in transmission patterns and quantified the spread of a triple reassortant H1N1 influenza virus in naïve and vaccinated pig populations by estimating the reproduction ratio (R) of infection (i.e. the number of secondary infections caused by an infectious individual) using a deterministic Susceptible-Infectious-Recovered (SIR) model, fitted on experimental data. One hundred and ten pigs were distributed in ten isolated rooms as follows: (i) non-vaccinated (NV), (ii) vaccinated with a heterologous vaccine (HE), and (iii) vaccinated with a homologous inactivated vaccine (HO). The study was run with multiple replicates and for each replicate, an infected non-vaccinated pig was placed with 10 contact pigs for two weeks and transmission of influenza evaluated daily by analyzing individual nasal swabs by RT-PCR. A statistically significant difference between R estimates was observed between vaccinated and non-vaccinated pigs (p < 0.05). A statistically significant reduction in transmission was observed in the vaccinated groups where R (95%CI) was 1 (0.39-2.09) and 0 for the HE and the HO groups respectively, compared to an Ro value of 10.66 (6.57-16.46) in NV pigs (p < 0.05). Transmission in the HE group was delayed and variable when compared to the NV group and transmission could not be detected in the HO group. Results from this study indicate that influenza vaccines can be used to decrease susceptibility to influenza infection and decrease influenza transmission.

  19. Forearm muscle oxygenation decreases with low levels of voluntary contraction

    NASA Technical Reports Server (NTRS)

    Murthy, G.; Kahan, N. J.; Hargens, A. R.; Rempel, D. M.

    1997-01-01

    The purpose of our investigation was to determine if the near infrared spectroscopy technique was sensitive to changes in tissue oxygenation at low levels of isometric contraction in the extensor carpi radialis brevis muscle. Nine subjects were seated with the right arm abducted to 45 degrees, elbow flexed to 85 degrees, forearm pronated 45 degrees, and wrist and forearm supported on an armrest throughout the protocol. Altered tissue oxygenation was measured noninvasively with near infrared spectroscopy. The near infrared spectroscopy probe was placed over the extensor carpi radialis brevis of the subject's right forearm and secured with an elastic wrap. After 1 minute of baseline measurements taken with the muscle relaxed, four different loads were applied just proximal to the metacarpophalangeal joint such that the subjects isometrically contracted the extensor carpi radialis brevis at 5, 10, 15, and 50% of the maximum voluntary contraction for 1 minute each. A 3-minute recovery period followed each level of contraction. At the end of the protocol, with the probe still in place, a value for ischemic tissue oxygenation was obtained for each subject. This value was considered the physiological zero and hence 0% tissue oxygenation. Mean tissue oxygenation (+/-SE) decreased from resting baseline (100% tissue oxygenation) to 89 +/- 4, 81 +/- 8, 78 +/- 8, and 47 +/- 8% at 5, 10, 15, and 50% of the maximum voluntary contraction, respectively. Tissue oxygenation levels at 10, 15, and 50% of the maximum voluntary contraction were significantly lower (p < 0.05) than the baseline value. Our results indicate that tissue oxygenation significantly decreases during brief, low levels of static muscle contraction and that near infrared spectroscopy is a sensitive technique for detecting deoxygenation noninvasively at low levels of forearm muscle contraction. Our findings have important implications in occupational medicine because oxygen depletion induced by low levels of muscle

  20. Polyphenols decreased liver NADPH oxidase activity, increased muscle mitochondrial biogenesis and decreased gastrocnemius age-dependent autophagy in aged rats.

    PubMed

    Laurent, Caroline; Chabi, Beatrice; Fouret, Gilles; Py, Guillaume; Sairafi, Badie; Elong, Cecile; Gaillet, Sylvie; Cristol, Jean Paul; Coudray, Charles; Feillet-Coudray, Christine

    2012-09-01

    This study explored major systems of reactive oxygen species (ROS) production and their consequences on oxidative stress, mitochondriogenesis and muscle metabolism in aged rats, and evaluated the efficiency of 30-day oral supplementation with a moderate dose of a red grape polyphenol extract (RGPE) on these parameters. In the liver of aged rats, NADPH oxidase activity was increased and mitochondrial respiratory chain complex activities were altered, while xanthine oxidase activity remained unchanged. In muscles, only mitochondrial activity was modified with aging. The oral intake of RGPE decreased liver NADPH oxidase activity in the aged rats without affecting global oxidative stress, suggesting that NADPH oxidase was probably not the dominant detrimental source of production of O(2)·(-) in the liver. Interestingly, RGPE supplementation increased mitochondrial biogenesis and improved antioxidant status in the gastrocnemius of aged rats, while it had no significant effect in soleus. RGPE supplementation also decreased age-dependent autophagy in gastrocnemius of aged rats. These results extended existing findings on the beneficial effects of RGPE on mitochondriogenesis and muscle metabolism in aged rats.

  1. Increased radial glia quiescence, decreased reactivation upon injury and unaltered neuroblast behavior underlie decreased neurogenesis in the aging zebrafish telencephalon.

    PubMed

    Edelmann, Kathrin; Glashauser, Lena; Sprungala, Susanne; Hesl, Birgit; Fritschle, Maike; Ninkovic, Jovica; Godinho, Leanne; Chapouton, Prisca

    2013-09-01

    The zebrafish has recently become a source of new data on the mechanisms of neural stem cell (NSC) maintenance and ongoing neurogenesis in adult brains. In this vertebrate, neurogenesis occurs at high levels in all ventricular regions of the brain, and brain injuries recover successfully, owing to the recruitment of radial glia, which function as NSCs. This new vertebrate model of adult neurogenesis is thus advancing our knowledge of the molecular cues in use for the activation of NSCs and fate of their progeny. Because the regenerative potential of somatic stem cells generally weakens with increasing age, it is important to assess the extent to which zebrafish NSC potential decreases or remains unaltered with age. We found that neurogenesis in the ventricular zone, in the olfactory bulb, and in a newly identified parenchymal zone of the telencephalon indeed declines as the fish ages and that oligodendrogenesis also declines. In the ventricular zone, the radial glial cell population remains largely unaltered morphologically but enters less frequently into the cell cycle and hence produces fewer neuroblasts. The neuroblasts themselves do not change their behavior with age and produce the same number of postmitotic neurons. Thus, decreased neurogenesis in the physiologically aging zebrafish brain is correlated with an increasing quiescence of radial glia. After injuries, radial glia in aged brains are reactivated, and the percentage of cell cycle entry is increased in the radial glia population. However, this reaction is far less pronounced than in younger animals, pointing to irreversible changes in aging zebrafish radial glia.

  2. Lenalidomide enhances antigen-specific activity and decreases CD45RA expression of T cells from patients with multiple myeloma.

    PubMed

    Neuber, Brigitte; Herth, Isabelle; Tolliver, Claudia; Schoenland, Stefan; Hegenbart, Ute; Hose, Dirk; Witzens-Harig, Mathias; Ho, Anthony D; Goldschmidt, Hartmut; Klein, Bernard; Hundemer, Michael

    2011-07-15

    The aim of this study was to investigate whether the specific T cell response against the multiple myeloma Ag HM1.24 is enhanced by the immunomodulatory drug lenalidomide (Revlimid). Ag-specific CD3(+)CD8(+) T cells against the HM1.24 Ag were expanded in vitro by dendritic cells in 29 healthy donors and 26 patients with plasma cell dyscrasias. Ag-specific activation was analyzed by IFN-γ, granzyme B, and perforin secretion using ELISA, ELISPOT assay, and intracellular staining, and generation of Ag-specific T cells was analyzed by tetramer staining. Expression of T cell maturation markers (CD45RA, CD45R0, CCR7, and CD28) was investigated by flow cytometry. We found that activation of HM1.24-specific T cells from healthy donors and patients with plasma cell dyscrasias was enhanced significantly by lenalidomide and furthermore that the impact of lenalidomide on T cells depends on the duration of the exposure. Notably, lenalidomide supports the downregulation of CD45RA on T cells upon activation, observed in healthy donors and in patients in vitro and also in patients during lenalidomide therapy in vivo. We showed for the first time, to our knowledge, that lenalidomide enhances the Ag-specific activation of T cells and the subsequent downregulation of CD45RA expression of T cells in vitro and in vivo.

  3. A curriculum designed to decrease barriers related to scholarly writing by staff nurses.

    PubMed

    Shatzer, Melanie; Wolf, Gail A; Hravnak, Marilyn; Haugh, Amy; Kikutu, Julius; Hoffmann, Rosemary L

    2010-09-01

    Demonstrating professional development outcomes, such as scholarly publication, is critical as nurse leaders guide organizations seeking recognition as centers of excellence. However, personal and situational barriers often prevent staff nurses from achieving scholarly publication. This project tested a workshop and mentoring approach to decrease publication barriers with staff nurses in 2 community hospitals. Self-efficacy principles guided the curriculum that resulted in a statistically significant improvement in staff nurse perception of successful scholarly publication endeavors.

  4. Ozone decreases soybean productivity and water use efficiency

    NASA Astrophysics Data System (ADS)

    Betzelberger, A. M.; VanLoocke, A. D.; Ainsworth, E. A.; Bernacchi, C. J.

    2011-12-01

    The combination of population growth and climate change will increase pressure on agricultural and water resources throughout this century. An additional consequence of this growth is an increase in anthropogenic emissions that lead to the formation of tropospheric ozone (O3), which in concert with climate change, poses a significant threat to human health and nutrition. In addition to being an important greenhouse gas, O3 reduces plant productivity, an effect that has been particularly pronounced in soybean, which provides over half of the world's oilseed production. Plant productivity is linked to feedbacks in the climate system, indirectly through the carbon cycle, as well as directly through the partitioning of radiation into heat and moisture fluxes. Soybean, along with maize, comprises the largest ecosystem in the contiguous U.S. Therefore, changes in productivity and water use under increasing O3 could impact human nutrition as well as the regional climate. Soybean response to increasing O3 concentrations was tested under open-air agricultural conditions at the SoyFACE research site. During the 2009 growing season, eight 20 m diameter FACE plots were exposed to different O3 concentrations, ranging from 40 to 200 ppb. Canopy growth (leaf area index) and physiological measurements of leaf photosynthesis and stomatal conductance were taken regularly throughout the growing season. Canopy fluxes of heat and moisture were measured using the residual energy balance micrometeorological technique. Our results indicate that as O3 increased from 40 to 200 ppb, rates of photosynthesis and stomatal conductance decreased significantly. Further, the seed yield decreased by over 60%, while water use decreased by 30% and the water-use-efficiency (yield/water-use) declined by 50%. The growing season average canopy temperatures increased by 1°C and midday temperatures increased by 2°C compared to the control. Warmer and drier canopies may result in a positive feedback on O3

  5. ELF alternating magnetic field decreases reproduction by DNA damage induction.

    PubMed

    Panagopoulos, Dimitris J; Karabarbounis, Andreas; Lioliousis, Constantinos

    2013-11-01

    In the present experiments, the effect of 50-Hz alternating magnetic field on Drosophila melanogaster reproduction was studied. Newly eclosed insects were separated into identical groups of ten males and ten females and exposed to three different intensities of the ELF magnetic field (1, 11, and 21 G) continuously during the first 5 days of their adult lives. The reproductive capacity was assessed by the number of F1 pupae according to a well-defined protocol of ours. The magnetic field was found to decrease reproduction by up to 4.3%. The effect increased with increasing field intensities. The decline in reproductive capacity was found to be due to severe DNA damage (DNA fragmentation) and consequent cell death induction in the reproductive cells as determined by the TUNEL assay applied during early and mid-oogenesis (from germarium to stage 10) where physiological apoptosis does not occur. The increase in DNA damage was more significant than the corresponding decrease in reproductive capacity (up to ~7.5%). The TUNEL-positive signal denoting DNA fragmentation was observed exclusively at the two most sensitive developmental stages of oogenesis: the early and mid-oogenesis checkpoints (i.e. region 2a/2b of the germarium and stages 7-8 just before the onset of vitellogenesis)-in contrast to exposure to microwave radiation of earlier work of ours in which the DNA fragmentation was induced at all developmental stages of early and mid-oogenesis. Moreover, the TUNEL-positive signal was observed in all three types of egg chamber cells, mainly in the nurse and follicle cells and also in the oocyte, in agreement with the microwave exposure of our earlier works. According to previous reports, cell death induction in the oocyte was observed only in the case of microwave exposure and not after exposure to other stress factors as toxic chemicals or food deprivation. Now it is also observed for the first time after ELF magnetic field exposure. Finally, in contrast to microwave

  6. Large Wood Storage Does Not Decrease Downstream Through a Watershed

    NASA Astrophysics Data System (ADS)

    Vaughan, M.; Pasternack, G. B.; Senter, A. E.; Dahlke, H. E.

    2013-12-01

    The storage of large wood in streams at the watershed scale has long been characterized as decreasing downstream due to a transport limitation in headwater streams, and a supply limitation in larger rivers. The objective of this study was to test this hypothesis through a field study in the Upper Yuba River watershed in Northern California, USA. While most studies surveyed within the wetted channel at selected reaches of different sizes, this study measured overbank deposits of large wood in addition to those in-channel to reflect the total storage within the active river corridor, and used a stratified random sampling scheme to see if relations held at the watershed scale. The watershed is large (2,874 km2), mountainous, mostly forested, and has been dramatically altered by human activities primarily related to gold mining. One hundred fourteen field sites of varied drainage area sizes were visited, inventoried for large wood (length > 1 m, diameter > 10 cm) storage within the active river corridor, and the volume storage per river length was calculated. Inclusion of floodplains in field surveys illuminates the fact that the distribution of large wood changes within the active river corridor, while the total storage does not decrease downstream. Among many watershed-scale control variables, such as drainage area, stream order, and upslope distance, the local amount of shrub cover and bankfull channel width were the only significant predictors of large wood storage in a multiple linear regression model, both with positive coefficients. A critical literature review was also conducted to investigate the evidence for the common conceptual model. Findings were that (1) the observed downstream trend of large wood storage is largely a function of the methods employed by each study, (2) the use of storage per channel area has confounded the commonly held conceptual model, due to its correlation with channel width, and (3) there is little evidence to support the hypothesis

  7. Formaldehyde induces apoptosis through decreased Prx 2 via p38 MAPK in lung epithelial cells.

    PubMed

    Lim, Seul Ki; Kim, Jong Chun; Moon, Chang Jong; Kim, Gye Yeop; Han, Ho Jae; Park, Soo Hyun

    2010-05-27

    Formaldehyde (FA) is an important substance that induces sick house syndrome and diseases, such as asthma and allergies. Oxidative stress is involved in the development of respiratory disease, and diverse antioxidants may protect respiratory tract cells from apoptosis. Peroxiredoxin is a pivotal endogenous antioxidant. In the present study, FA induced death in A549 cells, a lung epithelial cell line, in a dose-dependent manner. FA also increased lipid peroxide formation (LPO) in A549 cells, suggesting a role for oxidative stress. Additionally, FA decreased peroxiredoxin 2 (Prx 2) protein levels after a 24 or 48h exposure to FA. We also examined whether the FA-induced decrease in Prx 2 was associated with apoptosis. Prx 2 overexpression protected against FA-induced cell apoptosis but not necrosis. Prx 2 overexpression blocked FA-induced increase in Bax, a pro-apoptotic molecule, and a decrease in Bcl-2, an anti-apoptotic molecule. Prx 2 overexpression also protected against FA-induced activation of some special apoptosis-associated proteins [caspase-3, caspase-9, and polypeptide poly (ADP-ribose) polymerase (PARP)]. Furthermore, we examined the signaling molecules involved in the FA-induced decrease in Prx 2 expression. The FA-induced decrease in Prx 2 and increase in cell apoptosis was restored by treatment with SB203580 [a p38 mitogen activated protein kinase (MAPK) inhibitor], but not by SP600125 [a c-jun-N-terminal kinase (JNK) inhibitor]. Also, FA-induced events were blocked by treatment with p38 siRNA, but not by scrambled siRNA. Indeed, FA increased p38 MAPK activation, suggesting a role for p38 MAPK in FA action. In conclusion, FA mediated apoptosis in lung epithelial cells by decreasing Prx 2 via p38 MAPK.

  8. Numerical simulation on dimension decrease for annular casing of one centrifugal boiler circulation pump

    NASA Astrophysics Data System (ADS)

    Fan, Y. Z.; Zuo, Z. G.; Liu, S. H.; Wu, Y. L.; Sha, Y. J.

    2012-11-01

    Primary formulation derivation indicates that the dimension of one existing centrifugal boiler circulation pump casing is too large. As great manufacture cost can be saved by dimension decrease, a numerical simulation research is developed in this paper on dimension decrease for annular casing of this pump with a specific speed equaling to 189, which aims at finding an appropriately smaller dimension of the casing while hydraulic performance and strength performance will hardly be changed according to the requirements of the cooperative company. The research object is one existing centrifugal pump with a diffuser and a semi-spherical annular casing, working as the boiler circulation pump for (ultra) supercritical units in power plants. Dimension decrease, the modification method, is achieved by decreasing the existing casing's internal radius (marked as "Ri0") while keeping the wall thickness. The research analysis is based on primary formulation derivation, CFD (Computational Fluid Dynamics) simulation and FEM (Finite Element Method) simulation. Primary formulation derivation estimates that a design casing's internal radius should be less than 0.75 Ri0. CFD analysis indicates that smaller casing with 0.75 Ri0 has a worse hydraulic performance when working at large flow rates and a better hydraulic performance when working at small flow rates. In consideration of hydraulic performance and dimension decrease, an appropriate casing's internal radius is determined, which equals to 0.875 Ri0. FEM analysis then confirms that modified pump casing has nearly the same strength performance as the existing pump casing. It is concluded that dimension decrease can be an economical method as well as a practical method for large pumps in engineering fields.

  9. Induction of hypothyroidism during early postnatal stages triggers a decrease in cognitive performance by decreasing hippocampal synaptic plasticity.

    PubMed

    Salazar, Paulina; Cisternas, Pedro; Codocedo, Juan Francisco; Inestrosa, Nibaldo C

    2017-04-01

    Thyroid hormones are vital in the control of multiple body functions, including the correct performance of the brain. Multiple diseases are associated with thyroid gland functioning, including hypothyroidism. To date, little is known regarding the effects of the establishment of this condition at a young age on brain function. Here, we evaluated the effect of hypothyroidism in an early postnatal stage in cognitive abilities with focus on the hippocampus. In our model, hypothyroidism was induced in young rats at 21days of age using 0.05% 6-propyl-2-thiouracil (PTU) for 4weeks reaching significantly lower levels of fT4 (control: 1.337ng/dL±0.115, PTU: 0.050ng/dL±0.001). Following the induction of hypothyroidism, several cognitive tasks were assessed to investigate the effects of hypothyroidism on cognition performance. We determined that hypothyroidism triggers a significant dysfunction in learning and memory processes observed in the Morris Water Maze were the latency times were higher in PTU rats (controls: 37s; PTU: 57s). The cognitive impairment was correlated with a reduction in hippocampal plasticity with respect to both long-term potentiation (LTP) (control: 1.45, PTU: 1.00) and depression (LTD) (control: 0.71, PTU: 1.01). Furthermore, a decrease in the rate of glucose utilization (control: 223nmol∗mg of protein, PTU:148nmol∗mg of protein) was observed, along with an increase in oxidative stress and a decrease in MAP2 marker in the hippocampus. Our findings suggest that the induction of hypothyroidism in a young rat model alters numerous functions at the level of the hippocampus.

  10. Do Ubiquitous Laptop Initiatives Decrease the High School Dropout Rate?

    ERIC Educational Resources Information Center

    Basham, Misty Dawn

    2012-01-01

    In 2007, Mooresville Graded School District developed a strategic plan to infuse twenty-first-century learning skills into the schools by providing staff and students in grades four through twelve with a laptop computer. In late fall of 2007, Mooresville High School deployed laptops to all certified staff and to the entire student body in the…

  11. Neutralizing antibodies decrease the envelope fluidity of HIV-1

    SciTech Connect

    Harada, Shinji Monde, Kazuaki; Tanaka, Yuetsu; Kimura, Tetsuya; Maeda, Yosuke; Yusa, Keisuke

    2008-01-05

    For successful penetration of HIV-1, the formation of a fusion pore may be required in order to accumulate critical numbers of fusion-activated gp41 with the help of fluidization of the plasma membrane and viral envelope. An increase in temperature to 40 {sup o}C after viral adsorption at 25 {sup o}C enhanced the infectivity by 1.4-fold. The enhanced infectivity was inhibited by an anti-CXCR4 peptide, T140, and anti-V3 monoclonal antibodies (0.5{beta} and 694/98-D) by post-attachment neutralization, but not by non-neutralizing antibodies (670-30D and 246-D) specific for the C5 of gp120 and cluster I of gp41, respectively. Anti-HLA-II and an anti-HTLV-I gp46 antibody, LAT27, neutralized the molecule-carrying HIV-1{sub C-2(MT-2)}. The anti-V3 antibodies suppressed the fluidity of the HIV-1{sub C-2} envelope, whereas the non-neutralizing antibodies did not. The anti-HLA-II antibody decreased the envelope fluidity of HIV-1{sub C-2(MT-2)}, but not that of HIV-1{sub C-2}. Therefore, fluidity suppression by these antibodies represents an important neutralization mechanism, in addition to inhibition of viral attachment.

  12. Decreases in thymopoiesis of astronauts returning from space flight

    PubMed Central

    Benjamin, Cara L.; Stowe, Raymond P.; St. John, Lisa; Sams, Cla