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Sample records for prevent pep inhibition

  1. The Ustilago maydis effector Pep1 suppresses plant immunity by inhibition of host peroxidase activity.

    Directory of Open Access Journals (Sweden)

    Christoph Hemetsberger

    Full Text Available The corn smut Ustilago maydis establishes a biotrophic interaction with its host plant maize. This interaction requires efficient suppression of plant immune responses, which is attributed to secreted effector proteins. Previously we identified Pep1 (Protein essential during penetration-1 as a secreted effector with an essential role for U. maydis virulence. pep1 deletion mutants induce strong defense responses leading to an early block in pathogenic development of the fungus. Using cytological and functional assays we show that Pep1 functions as an inhibitor of plant peroxidases. At sites of Δpep1 mutant penetrations, H₂O₂ strongly accumulated in the cell walls, coinciding with a transcriptional induction of the secreted maize peroxidase POX12. Pep1 protein effectively inhibited the peroxidase driven oxidative burst and thereby suppresses the early immune responses of maize. Moreover, Pep1 directly inhibits peroxidases in vitro in a concentration-dependent manner. Using fluorescence complementation assays, we observed a direct interaction of Pep1 and the maize peroxidase POX12 in vivo. Functional relevance of this interaction was demonstrated by partial complementation of the Δpep1 mutant defect by virus induced gene silencing of maize POX12. We conclude that Pep1 acts as a potent suppressor of early plant defenses by inhibition of peroxidase activity. Thus, it represents a novel strategy for establishing a biotrophic interaction.

  2. The Danish PEP Registry

    DEFF Research Database (Denmark)

    Lunding, Suzanne; Katzenstein, Terese L; Kronborg, Gitte

    2016-01-01

    BACKGROUND: The risk of occupational exposures to blood cannot be eliminated completely and access to post-exposure prophylaxis (PEP) to prevent HIV transmission is important. However, PEP administration has been associated with frequent adverse effects, low compliance and difficulties to ensure ...

  3. PEP-1-SIRT2 inhibits inflammatory response and oxidative stress-induced cell death via expression of antioxidant enzymes in murine macrophages.

    Science.gov (United States)

    Kim, Mi Jin; Kim, Dae Won; Park, Jung Hwan; Kim, Sang Jin; Lee, Chi Hern; Yong, Ji In; Ryu, Eun Ji; Cho, Su Bin; Yeo, Hyeon Ji; Hyeon, Jiye; Cho, Sung-Woo; Kim, Duk-Soo; Son, Ora; Park, Jinseu; Han, Kyu Hyung; Cho, Yoon Shin; Eum, Won Sik; Choi, Soo Young

    2013-10-01

    Sirtuin 2 (SIRT2), a member of the sirtuin family of proteins, plays an important role in cell survival. However, the biological function of SIRT2 protein is unclear with respect to inflammation and oxidative stress. In this study, we examined the protective effects of SIRT2 on inflammation and oxidative stress-induced cell damage using a cell permeative PEP-1-SIRT2 protein. Purified PEP-1-SIRT2 was transduced into RAW 264.7 cells in a time- and dose-dependent manner and protected against lipopolysaccharide- and hydrogen peroxide (H₂O₂)-induced cell death and cytotoxicity. Also, transduced PEP-1-SIRT2 significantly inhibited the expression of cytokines as well as the activation of NF-κB and mitogen-activated protein kinases (MAPKs). In addition, PEP-1-SIRT2 decreased cellular levels of reactive oxygen species (ROS) and of cleaved caspase-3, whereas it elevated the expression of antioxidant enzymes such as MnSOD, catalase, and glutathione peroxidase. Furthermore, topical application of PEP-1-SIRT2 to 12-O-tetradecanoylphorbol 13-acetate-treated mouse ears markedly inhibited expression levels of COX-2 and proinflammatory cytokines as well as the activation of NF-κB and MAPKs. These results demonstrate that PEP-1-SIRT2 inhibits inflammation and oxidative stress by reducing the levels of expression of cytokines and ROS, suggesting that PEP-1-SIRT2 may be a potential therapeutic agent for various disorders related to ROS, including skin inflammation. Copyright © 2013 Elsevier Inc. All rights reserved.

  4. PEP talk

    International Nuclear Information System (INIS)

    Anon.

    1980-01-01

    The newly operating PEP electron-positron storage ring, built by the Berkeley and Stanford Laboratories, was dedicated on 5 September. PEP comes on with some unusual handicaps. It is of course competing with PETRA at DESY. It is late and it will take all the ingenuity and imagination that this great Lab, with its great traditions, can muster to catch up and show the world that US physics is strong and that the large funds vested here are well spent

  5. PEP sextupoles

    International Nuclear Information System (INIS)

    Brunk, W.O.

    1976-10-01

    The sextupole requirements of PEP are such that they represent a much larger proportion of the ring magnet cost than they did in SPEAR. A study is given of various fabrication techniques all pointed toward cost reduction without an undue sacrifice of function quality. The point of debarkation is the sextupole design as described in the PEP Conceptual Design Report. There are three main areas of inquiry, namely, pole tip contour, coil material and fabrication and yoke size

  6. The Prevention Program for Externalizing Problem Behavior (PEP) Improves Child Behavior by Reducing Negative Parenting: Analysis of Mediating Processes in a Randomized Controlled Trial

    Science.gov (United States)

    Hanisch, Charlotte; Hautmann, Christopher; Plück, Julia; Eichelberger, Ilka; Döpfner, Manfred

    2014-01-01

    Background: Our indicated Prevention program for preschool children with Externalizing Problem behavior (PEP) demonstrated improved parenting and child problem behavior in a randomized controlled efficacy trial and in a study with an effectiveness design. The aim of the present analysis of data from the randomized controlled trial was to identify…

  7. Epidermal growth factor inhibits glycylsarcosine transport and hPepT1 expression in a human intestinal cell line

    DEFF Research Database (Denmark)

    Nielsen, C U; Amstrup, J; Steffansen, B

    2001-01-01

    (max) decreased from 2.61 +/- 0.4 to 1.06 +/- 0.1 nmol x cm(-2) x min(-1) (n = 3, P PepT1 mRNA (using glucose-6-phosphate dehydrogenase mRNA as control......) in cells treated with EGF. Western blotting indicated a decrease in hPepT1 protein in cell lysates. We conclude that EGF treatment decreases Gly-Sar transport in Caco-2 cells by decreasing the number of peptide transporter molecules in the apical membrane....

  8. Pep for PEP-II

    International Nuclear Information System (INIS)

    Anon.

    1995-01-01

    The major B-factory project at the Stanford Linear Accelerator Center have(SLAC) is well underway and moving along smartly, en route to commencement of operations in September 1998. Called PEP-II, the new facility is a joint venture of three California laboratories: Lawrence Berkeley Laboratory (LBL), Lawrence Livermore Laboratory (LLNL) and SLAC. Housed at SLAC in the tunnels and buildings built for the original PEP electron-positron collider in the late 1970s, it involves no conventional civil engineering. In fact, PEP-II is a recycling project in more ways than one: for example, most of the original PEP magnets have been renovated for reuse in the PEP-II high-energy ring. While some of them require substantial rework (to change their length, for instance), many of them merely require repainting and remeasuring. The work of building the hardware is divided up among the three laboratories. LBL is primarily responsible for the low-energy ring; LLNL is building most of the interaction region, the complicated part where the high and low energy rings come together; and SLAC is responsible for the rest. Proposed by President Clinton as a ''presidential initiative'' (December 1993, page 2), the project was given a four-year funding profile. The total cost of $177 million, excluding the BaBar detector (September, page 16), was planned by the US government to be entirely provided during the present administration, the last increment coming in the final quarter of 1997. Happily, the first two increments have been forthcoming as planned and the third is faring well in US Congress. The PEP-II design is based on two intersecting storage rings, one carrying 9 GeV electrons and the other 3.1 GeV positrons, operating with high beam currents (a few amperes) to produce a luminosity of 3 x 10 33 per sq cm per s. The asymmetry in the energies of the colliding particles means that the centre-ofmass of the electron-positron annihilation system moves rapidly in the

  9. Detecting effects of the indicated prevention Programme for Externalizing Problem behaviour (PEP) on child symptoms, parenting, and parental quality of life in a randomized controlled trial.

    Science.gov (United States)

    Hanisch, Charlotte; Freund-Braier, Inez; Hautmann, Christopher; Jänen, Nicola; Plück, Julia; Brix, Gabriele; Eichelberger, Ilka; Döpfner, Manfred

    2010-01-01

    Behavioural parent training is effective in improving child disruptive behavioural problems in preschool children by increasing parenting competence. The indicated Prevention Programme for Externalizing Problem behaviour (PEP) is a group training programme for parents and kindergarten teachers of children aged 3-6 years with externalizing behavioural problems. To evaluate the effects of PEP on child problem behaviour, parenting practices, parent-child interactions, and parental quality of life. Parents and kindergarten teachers of 155 children were randomly assigned to an intervention group (n = 91) and a nontreated control group (n = 64). They rated children's problem behaviour before and after PEP training; parents also reported on their parenting practices and quality of life. Standardized play situations were video-taped and rated for parent-child interactions, e.g. parental warmth. In the intention to treat analysis, mothers of the intervention group described less disruptive child behaviour and better parenting strategies, and showed more parental warmth during a standardized parent-child interaction. Dosage analyses confirmed these results for parents who attended at least five training sessions. Children were also rated to show less behaviour problems by their kindergarten teachers. Training effects were especially positive for parents who attended at least half of the training sessions. CBCL: Child Behaviour Checklist; CII: Coder Impressions Inventory; DASS: Depression anxiety Stress Scale; HSQ: Home-situation Questionnaire; LSS: Life Satisfaction Scale; OBDT: observed behaviour during the test; PCL: Problem Checklist; PEP: prevention programme for externalizing problem behaviour; PPC: Parent Problem Checklist; PPS: Parent Practices Scale; PS: Parenting Scale; PSBC: Problem Setting and Behaviour checklist; QJPS: Questionnaire on Judging Parental Strains; SEFS: Self-Efficacy Scale; SSC: Social Support Scale; TRF: Caregiver-Teacher Report Form.

  10. Therapeutical Administration of Peptide Pep19-2.5 and Ibuprofen Reduces Inflammation and Prevents Lethal Sepsis

    Science.gov (United States)

    Barcena Varela, Sergio; Ferrer-Espada, Raquel; Reiling, Norbert; Goldmann, Torsten; Gutsmann, Thomas; Mier, Walter; Schürholz, Tobias; Drömann, Daniel; Brandenburg, Klaus; Martinez de Tejada, Guillermo

    2015-01-01

    Sepsis is still a major cause of death and many efforts have been made to improve the physical condition of sepsis patients and to reduce the high mortality rate associated with this disease. While achievements were implemented in the intensive care treatment, all attempts within the field of novel therapeutics have failed. As a consequence new medications and improved patient stratification as well as a thoughtful management of the support therapies are urgently needed. In this study, we investigated the simultaneous administration of ibuprofen as a commonly used nonsteroidal anti-inflammatory drug (NSAID) and Pep19-2.5 (Aspidasept), a newly developed antimicrobial peptide. Here, we show a synergistic therapeutic effect of combined Pep19-2.5-ibuprofen treatment in an endotoxemia mouse model of sepsis. In vivo protection correlates with a reduction in plasma levels of both tumor necrosis factor α and prostaglandin E, as a likely consequence of Pep19-2.5 and ibuprofen-dependent blockade of TLR4 and COX pro-inflammatory cascades, respectively. This finding is further characterised and confirmed in a transcriptome analysis of LPS-stimulated human monocytes. The transcriptome analyses showed that Pep19-2.5 and ibuprofen exerted a synergistic global effect both on the number of regulated genes as well as on associated gene ontology and pathway expression. Overall, ibuprofen potentiated the anti-inflammatory activity of Pep19-2.5 both in vivo and in vitro, suggesting that NSAIDs could be useful to supplement future anti-sepsis therapies. PMID:26197109

  11. Post-Exposure Prophylaxis (PEP)

    Science.gov (United States)

    ... Child Transmission of HIV Post-Exposure Prophylaxis (PEP) Pre-Exposure Prophylaxis (PrEP) HIV Treatment HIV Treatment: The Basics Just ... to HIV frequently. Another HIV prevention method, called pre-exposure prophylaxis or PrEP, is when people at high risk ...

  12. Transduction of PEP-1-heme oxygenase-1 into insulin-producing INS-1 cells protects them against cytokine-induced cell death

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Su Jin; Kang, Hyung Kyung [Department of Physiology, College of Medicine, Hallym University, Chunchon 200-702 (Korea, Republic of); Song, Dong Keun [Department of Pharmacology, College of Medicine, Hallym University, Chunchon 200-702 (Korea, Republic of); Eum, Won Sik; Park, Jinseu [Department of Biomedical Science and Research Institute of Bioscience and Biotechnology, Hallym University, Chunchon 200-702 (Korea, Republic of); Choi, Soo Young, E-mail: sychoi@hallym.ac.kr [Department of Biomedical Science and Research Institute of Bioscience and Biotechnology, Hallym University, Chunchon 200-702 (Korea, Republic of); Kwon, Hyeok Yil, E-mail: hykwon@hallym.ac.kr [Department of Physiology, College of Medicine, Hallym University, Chunchon 200-702 (Korea, Republic of)

    2015-06-05

    Pro-inflammatory cytokines play a crucial role in the destruction of pancreatic β-cells, thereby triggering the development of autoimmune diabetes mellitus. We recently developed a cell-permeable fusion protein, PEP-1-heme oxygenase-1 (PEP-1-HO-1) and investigated the anti-inflammatory effects in macrophage cells. In this study, we transduced PEP-1-HO-1 into INS-1 insulinoma cells and examined its protective effect against cytokine-induced cell death. PEP-1-HO-1 was successfully delivered into INS-1 cells in time- and dose-dependent manner and was maintained within the cells for at least 48 h. Pre-treatment with PEP-1-HO-1 increased the survival of INS-1 cells exposed to cytokine mixture (IL-1β, IFN-γ, and TNF-α) in a dose-dependent manner. PEP-1-HO-1 markedly decreased cytokine-induced production of reactive oxygen species (ROS), nitric oxide (NO), and malondialdehyde (MDA). These protective effects of PEP-1-HO-1 against cytokines were correlated with the changes in the levels of signaling mediators of inflammation (iNOS and COX-2) and cell apoptosis/survival (Bcl-2, Bax, caspase-3, PARP, JNK, and Akt). These results showed that the transduced PEP-1-HO-1 efficiently prevented cytokine-induced cell death of INS-1 cells by alleviating oxidative/nitrosative stresses and inflammation. Further, these results suggested that PEP-1-mediated HO-1 transduction may be a potential therapeutic strategy to prevent β-cell destruction in patients with autoimmune diabetes mellitus. - Highlights: • We showed that PEP-1-HO-1 was efficiently delivered into INS-1 cells. • Transduced PEP-1-HO-1 exerted a protective effect against cytokine-induced cell death. • Transduced PEP-1-HO-1 inhibited cytokine-induced ROS and NO accumulation. • PEP-1-HO-1 suppressed cytokine-induced expression of iNOS, COX-2, and Bax. • PEP-1-HO-1 transduction may be an efficient tool to prevent β-cell destruction.

  13. Transduction of PEP-1-heme oxygenase-1 into insulin-producing INS-1 cells protects them against cytokine-induced cell death

    International Nuclear Information System (INIS)

    Lee, Su Jin; Kang, Hyung Kyung; Song, Dong Keun; Eum, Won Sik; Park, Jinseu; Choi, Soo Young; Kwon, Hyeok Yil

    2015-01-01

    Pro-inflammatory cytokines play a crucial role in the destruction of pancreatic β-cells, thereby triggering the development of autoimmune diabetes mellitus. We recently developed a cell-permeable fusion protein, PEP-1-heme oxygenase-1 (PEP-1-HO-1) and investigated the anti-inflammatory effects in macrophage cells. In this study, we transduced PEP-1-HO-1 into INS-1 insulinoma cells and examined its protective effect against cytokine-induced cell death. PEP-1-HO-1 was successfully delivered into INS-1 cells in time- and dose-dependent manner and was maintained within the cells for at least 48 h. Pre-treatment with PEP-1-HO-1 increased the survival of INS-1 cells exposed to cytokine mixture (IL-1β, IFN-γ, and TNF-α) in a dose-dependent manner. PEP-1-HO-1 markedly decreased cytokine-induced production of reactive oxygen species (ROS), nitric oxide (NO), and malondialdehyde (MDA). These protective effects of PEP-1-HO-1 against cytokines were correlated with the changes in the levels of signaling mediators of inflammation (iNOS and COX-2) and cell apoptosis/survival (Bcl-2, Bax, caspase-3, PARP, JNK, and Akt). These results showed that the transduced PEP-1-HO-1 efficiently prevented cytokine-induced cell death of INS-1 cells by alleviating oxidative/nitrosative stresses and inflammation. Further, these results suggested that PEP-1-mediated HO-1 transduction may be a potential therapeutic strategy to prevent β-cell destruction in patients with autoimmune diabetes mellitus. - Highlights: • We showed that PEP-1-HO-1 was efficiently delivered into INS-1 cells. • Transduced PEP-1-HO-1 exerted a protective effect against cytokine-induced cell death. • Transduced PEP-1-HO-1 inhibited cytokine-induced ROS and NO accumulation. • PEP-1-HO-1 suppressed cytokine-induced expression of iNOS, COX-2, and Bax. • PEP-1-HO-1 transduction may be an efficient tool to prevent β-cell destruction

  14. Transitioning to HIV Pre-Exposure Prophylaxis (PrEP) from Non-Occupational Post-Exposure Prophylaxis (nPEP) in a Comprehensive HIV Prevention Clinic: A Prospective Cohort Study.

    Science.gov (United States)

    Siemieniuk, Reed A C; Sivachandran, Nirojini; Murphy, Pauline; Sharp, Andrea; Walach, Christine; Placido, Tania; Bogoch, Isaac I

    2015-08-01

    The uptake of pre-exposure prophylaxis (PrEP) for HIV prevention remains low. We hypothesized that a high proportion of patients presenting for HIV non-occupational post-exposure prophylaxis (nPEP) would be candidates for PrEP based on current CDC guidelines. Outcomes from a comprehensive HIV Prevention Clinic are described. We evaluated all patients who attended the HIV Prevention Clinic for nPEP between January 1, 2013 and September 30, 2014. Each patient was evaluated for PrEP candidacy based on current CDC-guidelines and subjectively based on physician opinion. Patients were then evaluated for initiation of PrEP if they met guideline suggestions. Demographic, social, and behavioral factors were then analyzed with logistic regression for associations with PrEP candidacy and initiation. 99 individuals who attended the nPEP clinic were evaluated for PrEP. The average age was 32 years (range, 18-62), 83 (84%) were male, of whom 46 (55%) men who had have sex with men (MSM). 31 (31%) met CDC guidelines for PrEP initiation, which had very good agreement with physician recommendation (kappa=0.88, 0.78-0.98). Factors associated with PrEP candidacy included sexual exposure to HIV, prior nPEP use, and lack of drug insurance (p<0.05 for all comparisons). Combining nPEP and PrEP services in a dedicated clinic can lead to identification of PrEP candidates and may facilitate PrEP uptake. Strategies to ensure equitable access of PrEP should be explored such that those without drug coverage may also benefit from this effective HIV prevention modality.

  15. Transduced PEP-1-ribosomal protein S3 (rpS3) ameliorates 12-O-tetradecanoylphorbol-13-acetate-induced inflammation in mice

    International Nuclear Information System (INIS)

    Ahn, Eun Hee; Kim, Dae Won; Kang, Hye Won; Shin, Min Jae; Won, Moo Ho; Kim, Joon; Kim, Dong Joon; Kwon, Oh-Shin; Kang, Tae-Cheon; Han, Kyu Hyung; Park, Jinseu; Eum, Won Sik; Choi, Soo Young

    2010-01-01

    This study investigated the preventive effect of ribosomal protein S3 (rpS3) on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced ear edema in mice. A cell permeable expression vector PEP-1-rpS3 was constructed. Topical application of the vector markedly inhibited TPA-induced expression levels of cyclooxygenase-2 (COX-2) and pro-inflammatory cytokines. Application of PEP-1-rpS3 also resulted in a significant reduction in the activation of nuclear factor-kappa B (NF-kB) and mitogen-activated protein kinase (MAPK) in TPA-treated ears. These results indicate that PEP-1-rpS3 inhibits inflammatory response cytokines and enzymes by blocking NF-kB and MAPK, prompting the suggestion that PEP-1-rpS3 can be used as a therapeutic agent against skin inflammation.

  16. Luminosity monitor at PEP

    International Nuclear Information System (INIS)

    Fox, J.D.; Franklin, M.E.B.

    1981-02-01

    The luminosity monitor system utilized by the MKII Detector and by the PEP operators is described. This system processes information from 56 photomultipliers and calculates independent luminosities for each of the 3 colliding bunches in PEP. Design considerations, measurement techniques, and sources of error in the luminosity measurement are discussed

  17. PEP liquid level system

    International Nuclear Information System (INIS)

    Lauritzen, T.; Sah, R.C.

    1981-03-01

    A liquid level system has been installed in the accelerator housing of the PEP storage ring. This instrument spans the entire 2.2 km circumference of the PEP project, and over one hundred readouts provide reference elevations which are used for the accurate alignment of accelerator components. The liquid level has proven to be extremely precise (+-0.10 mm) and quick to use, and it has contributed to the accurate alignment of PEP before beam turn-on. Since the liquid level readouts are rigidly attached to the accelerator housing, the liquid level has been a convenient means to monitor the settling of the accelerator housing

  18. Perspectives on HIV Pre- and Post-Exposure Prophylaxes (PrEP and PEP) Among Female and Male Sex Workers in Mombasa, Kenya: Implications for Integrating Biomedical Prevention into Sexual Health Services.

    Science.gov (United States)

    Restar, Arjee J; Tocco, Jack Ume; Mantell, Joanne E; Lafort, Yves; Gichangi, Peter; Masvawure, Tsitsi B; Chabeda, Sophie Vusha; Sandfort, Theo G M

    2017-04-01

    Pre- and post-exposure prophylaxes (PrEP and PEP) can reduce the risk of HIV acquisition, yet often are inaccessible to and underutilized by most-vulnerable populations, including sex workers in sub-Saharan Africa. Based on in-depth interviews with 21 female and 23 male HIV-negative sex workers in Mombasa, Kenya, we found that awareness and knowledge of PrEP and PEP were low, although willingness to use both was high. Participants felt PrEP would be empowering and give added protection against infection, although some expressed concerns about side effects. Despite PEP's availability, few knew about it and even fewer had used it, but most who had would use it again. Sex workers valued confidentiality, privacy, trustworthiness, and convenient location in health services and wanted thorough HIV/STI assessments. These findings suggest the importance of situating PrEP and PEP within sex worker-friendly health services and conducting outreach to promote these biomedical prevention methods for Kenyan sex workers.

  19. PEP-II Alignment

    CERN Document Server

    Gaydosh, M

    2003-01-01

    The PEP-II Asymmetric B-factory consists of two independent storage rings, one located atop the other in the 2200m-circumference PEP tunnel. The high-energy ring, which stores a 9-GeV electron beam, is an upgrade of the existing PEP collider. It re-utilizes all of the PEP magnets and incorporates a state-of-the-art copper vacuum chamber and a new RF system capable of supporting a one-amp stored beam. The low-energy ring, which stores 3.1-GeV positrons, is new construction. Injection is achieved by extracting electrons and positrons at collision energies from the SLC and transporting them each in a dedicated bypass line. The low-emittance SLC beams will be used for the injection process.

  20. P.E.P

    International Nuclear Information System (INIS)

    Paterson, J.M.

    1980-07-01

    The design and construction of the PEP project is briefly reviewed. The initial testing of the storage ring system and its present performance is described. The short-range plans for continuing development are discussed

  1. Background sources at PEP

    International Nuclear Information System (INIS)

    Lynch, H.; Schwitters, R.F.; Toner, W.T.

    1988-01-01

    Important sources of background for PEP experiments are studied. Background particles originate from high-energy electrons and positrons which have been lost from stable orbits, γ-rays emitted by the primary beams through bremsstrahlung in the residual gas, and synchrotron radiation x-rays. The effect of these processes on the beam lifetime are calculated and estimates of background rates at the interaction region are given. Recommendations for the PEP design, aimed at minimizing background are presented. 7 figs., 4 tabs

  2. Targeted Inhibition of Pancreatic Acinar Cell Calcineurin Is a Novel Strategy to Prevent Post-ERCP PancreatitisSummary

    Directory of Open Access Journals (Sweden)

    Abrahim I. Orabi

    2017-01-01

    Full Text Available Background & Aims: There is a pressing need to develop effective preventative therapies for post–endoscopic retrograde cholangiopancreatography pancreatitis (PEP. We showed that early PEP events are induced through the calcium-activated phosphatase calcineurin and that global calcineurin deletion abolishes PEP in mice. A crucial question is whether acinar cell calcineurin controls the initiation of PEP in vivo. Methods: We used a mouse model of PEP and examined the effects of in vivo acinar cell-specific calcineurin deletion by either generating a conditional knockout line or infusing a novel adeno-associated virus–pancreatic elastase improved Cre (I–iCre into the pancreatic duct of a calcineurin floxed line. Results: We found that PEP is dependent on acinar cell calcineurin in vivo, and this led us to determine that calcineurin inhibitors, infused within the radiocontrast, largely can prevent PEP. Conclusions: These results provide the impetus for launching clinical trials to test the efficacy of intraductal calcineurin inhibitors to prevent PEP. Keywords: Adeno-Associated Virus, Calcineurin B1, FK506, Cyclosporine A, Intraductal Delivery

  3. PEP storage ring: current status

    International Nuclear Information System (INIS)

    Rees, J.R.

    1981-02-01

    This report comments on the performance of the subsystems of PEP, discusses the beam dynamical behavior of the machine and compares it with our expectations and, finally, describes plans for improving PEP

  4. Metalloproteinase inhibition prevents acute respiratory distress syndrome.

    Science.gov (United States)

    Carney, D E; McCann, U G; Schiller, H J; Gatto, L A; Steinberg, J; Picone, A L; Nieman, G F

    2001-08-01

    -3 prevented lung injury in our model of endotoxin-induced ARDS. The proposed mechanism of COL-3 is a synergistic inhibition of the terminal neutrophil effectors MMPs and NE. Similar to the universal practice of prophylaxis against gastric stress ulceration and deep venous thromboses in trauma patients, chemically modified tetracyclines may likewise be administered to prevent acute lung injury in critically injured patients at risk of developing ARDS. Copyright 2001 Academic Press.

  5. Muon shielding for PEP

    International Nuclear Information System (INIS)

    Jenkins, T.M.; Thomas, R.H.

    1974-01-01

    The first stage of construction of PEP will consist of electron and positron storage rings. At a later date a 200 GeV proton storage ring may be added. It is judicious therefore, to ensure that the first and second phases of construction are compatible with each other. One of several factors determining the elevation at which the storage rings will be constructed is the necessity to provide adequate radiation shielding. The overhead shielding of PEP is determined by the reproduction of neutrons in the hadron cascade generated by primary protons lost from the storage ring. The minimum overburden planned for PEP is 5.5 meters of earth (1100 gm cm/sup /minus/2/). To obtain a rough estimate of the magnitude of the muon radiation problem this note presents some preliminary calculations. Their purpose is intended merely to show that the presently proposed design for PEP will present no major shielding problems should the protons storage ring be installed. More detailed calculations will be made using muon yield computer codes developed at CERN and NAL and muon transport codes developed at SLAC, when details of the proton storage ring become settled. 9 refs., 4 figs

  6. Seepage into PEP tunnel

    International Nuclear Information System (INIS)

    Weidner, H.

    1990-01-01

    The current rate of seepage into the PEP tunnel in the vicinity of IR-10 is very low compared to previous years. Adequate means of handling this low flow are in place. It is not clear whether the reduction in the flow is temporary, perhaps due to three consecutive dry years, or permanent due to drainage of a perched water table. During PEP construction a large amount of effort was expended in attempts to seal the tunnel, with no immediate effect. The efforts to ''manage'' the water flow are deemed to be successful. By covering equipment to protect it from dripping water and channeling seepage into the drainage gutters, the seepage has been reduced to a tolerable nuisance. There is no sure, safe procedure for sealing a leaky shotcreted tunnel

  7. Preventive evidence into practice (PEP study: implementation of guidelines to prevent primary vascular disease in general practice protocol for a cluster randomised controlled trial

    Directory of Open Access Journals (Sweden)

    Harris Mark F

    2013-01-01

    Full Text Available Abstract Background There are significant gaps in the implementation and uptake of evidence-based guideline recommendations for cardiovascular disease (CVD and diabetes in Australian general practice. This study protocol describes the methodology for a cluster randomised trial to evaluate the effectiveness of a model that aims to improve the implementation of these guidelines in Australian general practice developed by a collaboration between researchers, non-government organisations, and the profession. Methods We hypothesise that the intervention will alter the behaviour of clinicians and patients resulting in improvements of recording of lifestyle and physiological risk factors (by 20% and increased adherence to guideline recommendations for: the management of CVD and diabetes risk factors (by 20%; and lifestyle and physiological risk factors of patients at risk (by 5%. Thirty-two general practices will be randomised in a 1:1 allocation to receive either the intervention or continue with usual care, after stratification by state. The intervention will be delivered through: small group education; audit of patient records to determine preventive care; and practice facilitation visits adapted to the needs of the practices. Outcome data will be extracted from electronic medical records and patient questionnaires, and qualitative evaluation from provider and patient interviews. Discussion We plan to disseminate study findings widely and directly inform implementation strategies by governments, professional bodies, and non-government organisations including the partner organisations.

  8. PEP Laser Surveying System

    International Nuclear Information System (INIS)

    Lauritzen, T.; Sah, R.C.

    1979-03-01

    A Laser Surveying System has been developed to survey the beam elements of the PEP storage ring. This system provides automatic data acquisition and analysis in order to increase survey speed and to minimize operator error. Two special instruments, the Automatic Readout Micrometer and the Small Automatic Micrometer, have been built for measuring the locations of fiducial points on beam elements with respect to the light beam from a laser. These instruments automatically encode offset distances and read them into the memory of an on-line computer. Distances along the beam line are automatically encoded with a third instrument, the Automatic Readout Tape Unit. When measurements of several beam elements have been taken, the on-line computer analyzes the measured data, compared them with desired parameters, and calculates the required adjustments to beam element support stands

  9. The PEP injection system

    International Nuclear Information System (INIS)

    Brown, K.L.; Avery, R.T.; Peterson, J.M.

    1988-01-01

    A system to transport 10-to-15-GeV electron and positron beams from the Stanford Linear Accelerator and to inject them into the PEP storage ring under a wide variety of lattice configurations has been designed. Optically, the transport line consists of three 360/degree/ phase-shift sections of FODO lattice, with bending magnets interspersed in such a way as to provide achromaticity, convenience in energy and emittance definition, and independent tuning of the various optical parameters for matching into the ring. The last 360/degree/ of phase shift has 88 milliradians of bend in a vertical plane and deposits the beam at the injection septum via a Lambertson magnet. Injection is accomplished by launching the beam with several centimeters of radial betatron amplitude in a fast bump provided by a triad of pulsed kicker magnets. Radiation damping reduces the collective amplitude quickly enough to allow injection at a high repetition rate

  10. Performance evaluation of PEP

    International Nuclear Information System (INIS)

    Zisman, M.S.

    1987-10-01

    An investigation of collective effects has been undertaken to assess the possibilities for using the low emittance operating mode of the PEP storage ring as a dedicated source of synchrotron radiation. Beam current limitations associated with longitudinal and transverse instabilities, and the expected emittance growth due to intrabeam scattering have been studied as a function of beam energy. Calculations of the beam lifetime due to Touschek and gas scattering are presented, and the growth times of coupled-bunch instabilities are estimated. In general, the results are encouraging, and no fundamental problems have been uncovered. It appears that beam currents up to about 10 mA per bunch should be achievable, and that the emittance growth is not a severe problem at an energy of about 8 GeV. A feedback system to deal with coupled-bunch instabilities is likely to be required. 7 refs., 13 figs

  11. Crystal Ball at PEP

    International Nuclear Information System (INIS)

    Bartel, W.; Bulos, F.; Luke, D.; Peck, C.; Strauch, K.

    1975-01-01

    The modifications to the SPEAR version of the Crystal Ball required by the higher energies at PEP are discussed. Since the hadron multiplicity is expected to rise as log s, their average energy must rise. On the other hand, if the hadrons are produced in jets, the low energy part of their spectrum is not heavily depleted. This implies that modifications for high energy particles should not deteriorate low energy performance. An external iron calorimeter for measuring the high energy hadrons, charged and neutral, is considered. To improve the angular resolution on γ's, an active internal converter has been studied, estimates have been made of its expected performance, and difficulties requiring further study have been outlined

  12. Pharmacologic inhibition of lactate production prevents myofibroblast differentiation.

    Science.gov (United States)

    Kottmann, Robert Matthew; Trawick, Emma; Judge, Jennifer L; Wahl, Lindsay A; Epa, Amali P; Owens, Kristina M; Thatcher, Thomas H; Phipps, Richard P; Sime, Patricia J

    2015-12-01

    Myofibroblasts are one of the primary cell types responsible for the accumulation of extracellular matrix in fibrosing diseases, and targeting myofibroblast differentiation is an important therapeutic strategy for the treatment of pulmonary fibrosis. Transforming growth factor-β (TGF-β) has been shown to be an important inducer of myofibroblast differentiation. We previously demonstrated that lactate dehydrogenase and its metabolic product lactic acid are important mediators of myofibroblast differentiation, via acid-induced activation of latent TGF-β. Here we explore whether pharmacologic inhibition of LDH activity can prevent TGF-β-induced myofibroblast differentiation. Primary human lung fibroblasts from healthy patients and those with pulmonary fibrosis were treated with TGF-β and or gossypol, an LDH inhibitor. Protein and RNA were analyzed for markers of myofibroblast differentiation and extracellular matrix generation. Gossypol inhibited TGF-β-induced expression of the myofibroblast marker α-smooth muscle actin (α-SMA) in a dose-dependent manner in both healthy and fibrotic human lung fibroblasts. Gossypol also inhibited expression of collagen 1, collagen 3, and fibronectin. Gossypol inhibited LDH activity, the generation of extracellular lactic acid, and the rate of extracellular acidification in a dose-dependent manner. Furthermore, gossypol inhibited TGF-β bioactivity in a dose-dependent manner. Concurrent treatment with an LDH siRNA increased the ability of gossypol to inhibit TGF-β-induced myofibroblast differentiation. Gossypol inhibits TGF-β-induced myofibroblast differentiation through inhibition of LDH, inhibition of extracellular accumulation of lactic acid, and inhibition of TGF-β bioactivity. These data support the hypothesis that pharmacologic inhibition of LDH may play an important role in the treatment of pulmonary fibrosis. Copyright © 2015 the American Physiological Society.

  13. PEP instrumentation and control system

    Energy Technology Data Exchange (ETDEWEB)

    Melen, R.

    1980-06-01

    This paper describes the operating characteristics of the primary components that form the PEP Instrumentation and Control System. Descriptions are provided for the computer control system, beam monitors, and other support systems.

  14. PEP instrumentation and control system

    International Nuclear Information System (INIS)

    Melen, R.

    1980-06-01

    This paper describes the operating characteristics of the primary components that form the PEP Instrumentation and Control System. Descriptions are provided for the computer control system, beam monitors, and other support systems

  15. New particle searches at PEP

    International Nuclear Information System (INIS)

    Berley, D.; Bulos, F.; Cheng, D.

    1988-01-01

    The new particles that could be produced at PEP are discussed in terms of their specific signatures and production rates. We find that a small number of general signatures characterize these particles. Backgrounds associated with the general signatures are considered and necessary rejection rates are calculated. We describe several typical detectors and tabulate the requirements they place on the PEP machine and the experimental areas. 10 figs., 2 tabs

  16. Skew quad compensation at PEP

    International Nuclear Information System (INIS)

    Murray, J.J.

    1977-10-01

    Rotational and focal effects of solenoids used in PEP detectors will cause severe perturbations of machine beam optics and must be corrected. Ordinarily this would be accomplished by the addition of compensating solenoids and adjustment of insertion quadrupole strengths. It has been found that an arbitrary cross plane coupling representing the effects of solenoids and/or skew quads in any combination can be synthesized (or compensated) exactly using a quartet of skew quads combined with other erect transport elements in a wide variety of configurations. Specific skew quad compensating systems for PEP have been designed and are under study by PEP staff. So far no fundamental flaws have been discovered. In view of that, PEP management has tentatively authorized the use of such a system in the PEP-4, PEP-9 experiments and proposes to leave the question open ''without prejudice'' for other experiments. Use of skew quad compensation involves an imponderable risk, of course, simply because the method is new and untested. But in addition to providing the only known method for dealing with skew quad perturbations, skew quad compensation, as an alternate to compensating solenoids, promises to be much cheaper, to require much less power and to occupy much less space in the IR's. The purpose of this note is to inform potential users of the foregoing situation and to explain skew quad compensation more fully. 2 refs., 1 fig., 1 tab

  17. PEP computer control system

    International Nuclear Information System (INIS)

    1979-03-01

    This paper describes the design and performance of the computer system that will be used to control and monitor the PEP storage ring. Since the design is essentially complete and much of the system is operational, the system is described as it is expected to 1979. Section 1 of the paper describes the system hardware which includes the computer network, the CAMAC data I/O system, and the operator control consoles. Section 2 describes a collection of routines that provide general services to applications programs. These services include a graphics package, data base and data I/O programs, and a director programm for use in operator communication. Section 3 describes a collection of automatic and semi-automatic control programs, known as SCORE, that contain mathematical models of the ring lattice and are used to determine in real-time stable paths for changing beam configuration and energy and for orbit correction. Section 4 describes a collection of programs, known as CALI, that are used for calibration of ring elements

  18. Background estimates for PEP

    International Nuclear Information System (INIS)

    Martin, F.

    1975-04-01

    The beam gas bremsstrahlung radiation for PEP has been studied in detail using the ray trace program TURTLE. With this program, an electron (positron) trajectory starting at an interaction region is traced through the storage ring until it radiates, then the radiated electron is traced until it stops in the beam pipe. The relative number of electrons stopping between the strong focusing quadrupoles is used to determine a rate at which electromagnetic showers will occur in the region of the experimental apparatus. It was found that 2.46% of the radiated electrons will stop in the interaction region. Assuming a uniform pressure of 2 x 10/sup /minus/9/ Torr in the vacuum pipe for a residual gas (X/sub o/ = 34.7 gm/cm 2 ), 2.5 x 10 5 electrons (positrons) will stop in the interaction region per beam (4 x 10 12 electrons at 15 GeV) per second. If the luminosity is 10 32 , this rate is equivalent to a cross section of 2.5 x 10/sup /minus/27/ cm 2 . 4 figs., 3 tabs

  19. PEP conceptual design report

    International Nuclear Information System (INIS)

    1976-02-01

    The accelerator system design, the physical plant, the experimental areas, cost estimates, and schedules for PEP are discussed. The main component of the proposed facility is a storage ring in which beams of positrons and electrons circulate in opposite directions in a vacuum chamber embedded in a magnetic guide field having six bending arcs and six long straight sections. The electrons and positrons to be stored in it are produced in the SLAC linac and are introduced into the storage ring via two beam transport paths emanating from the end of the two-mile accelerator. Beams of energies up to 18 GeV can be stored, and, at a future date, components could be added to permit energies as high as 22 GeV. Provisions are also made in the design of the ring housing so that a synchrotron-radiation research facility could be added in the future. The energy lost from the beams by synchrotron radiation is restored by a high-power radio frequency accelerating system which employs klystrons to drive the accelerating structures at a frequency of 353 MHz. The system is capable of delivering five megawatts of power to the beams. Low pressures will be sustained by means of long, narrow sputter-ion pumps located in the vacuum chamber in the bending magnets directly alongside the beams. The proposed storage ring is designed to generate a luminosity (reaction rate per unit reaction cross section) of more than 10 31 cm -2 sec -1 per interaction region at beam energies between 5 GeV and 18 GeV and a maximum luminosity of 10 32 cm -2 sec -1 per interaction region at a beam energy of 15 GeV

  20. Critical Role of PepT1 in Promoting Colitis-Associated Cancer and Therapeutic Benefits of the Anti-inflammatory PepT1-Mediated Tripeptide KPV in a Murine ModelSummary

    Directory of Open Access Journals (Sweden)

    Emilie Viennois

    2016-05-01

    Full Text Available Background & Aims: The human intestinal peptide transporter 1 (hPepT1, is expressed in the small intestine at low levels in the healthy colon and up-regulated during inflammatory bowel disease. hPepT1 plays a role in mouse colitis and human studies have shown that chronic intestinal inflammation leads to colorectal cancer (colitis-associated cancer; CAC. Hence, we assessed here the role of PepT1 in CAC. Methods: Mice with hPepT1 overexpression in intestinal epithelial cells (transgenic [TG] or PepT1 (PepT1-knockout [KO] deletion were used and CAC was induced by azoxymethane/dextran sodium sulfate. Results: TG mice had larger tumor sizes, increased tumor burdens, and increased intestinal inflammation compared with wild-type (WT mice. Conversely, tumor number and size and intestinal inflammation were decreased significantly in PepT1-KO mice. Proliferating crypt cells were increased in TG mice and decreased in PepT1-KO mice. Analysis of human colonic biopsy specimens showed increased expression of PepT1 in patients with colorectal cancer, suggesting that PepT1 might be targeted for the treatment of CAC. The use of an anti-inflammatory tripeptide Lys-Pro-Val (KPV transported by PepT1 was able to prevent carcinogenesis in WT mice. When administered to PepT1-KO mice, KPV did not trigger any of the inhibitory effect on tumorigenesis observed in WT mice. Conclusions: The observations that PepT1 was highly expressed in human colorectal tumor and that its overexpression and deletion in mice increased and decreased colitis-associated tumorigenesis, respectively, suggest that PepT1 is a potential therapeutic target for the treatment of colitis-associated tumorigenesis. Keywords: Colitis-Associated Cancer, Intestinal Inflammation, PepT1, KPV Peptide

  1. High-resolution spectrometer at PEP

    International Nuclear Information System (INIS)

    Weiss, J.M.; HRS Collaboration.

    1982-01-01

    A description is presented of the High Resolution Spectrometer experiment (PEP-12) now running at PEP. The advanced capabilities of the detector are demonstrated with first physics results expected in the coming months

  2. PEP magnet power supply systems

    International Nuclear Information System (INIS)

    Jackson, L.T.

    1977-01-01

    The dc electrical requirements of the PEP magnets fall mainly into two categories: (1) high power and current of single polarity and (2) low-power bi-polar. The first category will be thyristor-chopper controlled off common 600 V dc busses. The second group will utilize continuously controlled push-pull transistor actuators

  3. Positron--Electron Project (PEP)

    International Nuclear Information System (INIS)

    Rees, J.R.

    1977-01-01

    PEP, an 18-GeV electron-positron colliding-beam storage ring facility at SLAC, is being built by a team from LBL and SLAC. Construction is under way and completion is scheduled for Fall of 1979. A summary is given of the design of the facility, and the status of the project is reported

  4. Precision surveying system for PEP

    International Nuclear Information System (INIS)

    Gunn, J.; Lauritzen, T.; Sah, R.; Pellisier, P.F.

    1977-01-01

    A semi-automatic precision surveying system is being developed for PEP. Reference elevations for vertical alignment will be provided by a liquid level. The short range surveying will be accomplished using a Laser Surveying System featuring automatic data acquisition and analysis

  5. Effects of pergolide mesylate on transduction efficiency of PEP-1-catalase protein

    International Nuclear Information System (INIS)

    Sohn, Eun Jeong; Kim, Dae Won; Kim, Young Nam; Kim, So Mi; Lim, Soon Sung; Kang, Tae-Cheon; Kwon, Hyeok Yil; Kim, Duk-Soo; Cho, Sung-Woo; Han, Kyu Hyung; Park, Jinseu; Eum, Won Sik; Hwang, Hyun Sook; Choi, Soo Young

    2011-01-01

    Research highlights: → We studied effects of pergolide mesylate (PM) on in vitro and in vivo transduction of PEP-1-catalase. → PEP-1-catatase inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation. → PM enhanced the transduction of PEP-1-catalase into HaCaT cells and skin tissue. → PM increased anti-inflammatory activity of PEP-1-catalase. → PM stimulated therapeutic action of anti-oxidant enzyme catalase in oxidative-related diseases. -- Abstract: The low transduction efficiency of various proteins is an obstacle to their therapeutic application. However, protein transduction domains (PTDs) are well-known for a highly effective tool for exogenous protein delivery to cells. We examined the effects of pergolide mesylate (PM) on the transduction of PEP-1-catalase into HaCaT human keratinocytes and mice skin and on the anti-inflammatory activity of PEP-1-catatase against 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation using Western blot and histological analysis. PM enhanced the time- and dose-dependent transduction of PEP-1-catalase into HaCaT cells without affecting the cellular toxicity. In a mouse edema model, PEP-1-catalase inhibited the increased expressions of inflammatory mediators and cytokines such as cyclooxygenase-2, inducible nitric oxide synthase, interleukin-6 and -1β, and tumor necrosis factor-α induced by TPA. On the other hand, PM alone failed to exert any significant anti-inflammatory effects. However, the anti-inflammatory effect of co-treatment with PEP-1-catalase and PM was more potent than that of PEP-1-catalase alone. Our results indicate that PM may enhance the delivery of PTDs fusion therapeutic proteins to target cells and tissues and has potential to increase their therapeutic effects of such drugs against various diseases.

  6. Effects of pergolide mesylate on transduction efficiency of PEP-1-catalase protein

    Energy Technology Data Exchange (ETDEWEB)

    Sohn, Eun Jeong; Kim, Dae Won; Kim, Young Nam; Kim, So Mi [Department of Biomedical Science and Research Institute of Bioscience and Biotechnology, Hallym University, Chunchon 200-702 (Korea, Republic of); Lim, Soon Sung [Department of Food Science and Nutrition and RIC Center, Hallym University, Chunchon 200-702 (Korea, Republic of); Kang, Tae-Cheon [Department of Anatomy and Neurobiology, College of Medicine, Hallym University, Chunchon 200-702 (Korea, Republic of); Kwon, Hyeok Yil [Department of Physiology, College of Medicine, Hallym University, Chunchon 200-702 (Korea, Republic of); Kim, Duk-Soo [Department of Anatomy, College of Medicine, Soonchunhyang University, Cheonan-Si 330-090 (Korea, Republic of); Cho, Sung-Woo [Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul 138-736 (Korea, Republic of); Han, Kyu Hyung; Park, Jinseu; Eum, Won Sik [Department of Biomedical Science and Research Institute of Bioscience and Biotechnology, Hallym University, Chunchon 200-702 (Korea, Republic of); Hwang, Hyun Sook, E-mail: wazzup@hallym.ac.kr [Department of Biomedical Science and Research Institute of Bioscience and Biotechnology, Hallym University, Chunchon 200-702 (Korea, Republic of); Choi, Soo Young, E-mail: sychoi@hallym.ac.kr [Department of Biomedical Science and Research Institute of Bioscience and Biotechnology, Hallym University, Chunchon 200-702 (Korea, Republic of)

    2011-03-18

    Research highlights: {yields} We studied effects of pergolide mesylate (PM) on in vitro and in vivo transduction of PEP-1-catalase. {yields} PEP-1-catatase inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation. {yields} PM enhanced the transduction of PEP-1-catalase into HaCaT cells and skin tissue. {yields} PM increased anti-inflammatory activity of PEP-1-catalase. {yields} PM stimulated therapeutic action of anti-oxidant enzyme catalase in oxidative-related diseases. -- Abstract: The low transduction efficiency of various proteins is an obstacle to their therapeutic application. However, protein transduction domains (PTDs) are well-known for a highly effective tool for exogenous protein delivery to cells. We examined the effects of pergolide mesylate (PM) on the transduction of PEP-1-catalase into HaCaT human keratinocytes and mice skin and on the anti-inflammatory activity of PEP-1-catatase against 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation using Western blot and histological analysis. PM enhanced the time- and dose-dependent transduction of PEP-1-catalase into HaCaT cells without affecting the cellular toxicity. In a mouse edema model, PEP-1-catalase inhibited the increased expressions of inflammatory mediators and cytokines such as cyclooxygenase-2, inducible nitric oxide synthase, interleukin-6 and -1{beta}, and tumor necrosis factor-{alpha} induced by TPA. On the other hand, PM alone failed to exert any significant anti-inflammatory effects. However, the anti-inflammatory effect of co-treatment with PEP-1-catalase and PM was more potent than that of PEP-1-catalase alone. Our results indicate that PM may enhance the delivery of PTDs fusion therapeutic proteins to target cells and tissues and has potential to increase their therapeutic effects of such drugs against various diseases.

  7. Experiences of HIV postexposure prophylaxis (PEP) among highly exposed men who have sex with men (MSM).

    Science.gov (United States)

    Palich, Romain; Martin-Blondel, Guillaume; Cuzin, Lise; Le Talec, Jean-Yves; Boyer, Pierre; Massip, Patrice; Delobel, Pierre

    2017-11-01

    HIV postexposure prophylaxis (PEP) is indicated after sexual exposure with high risk of transmission. Men who have sex with men (MSM) are the main target of PEP. The aim of our study was to investigate the experience and shortcomings of PEP among people with a high risk of HIV exposure. Subjects with ongoing follow-up for HIV infection and PEP history were selected for the qualitative study. Semistructured interviews were conducted at the patients' homes. They were audio-recorded, transcribed and deidentified before data analysis, double coding and thematic analysis with an inductive approach. Twenty-three patients were eligible for the qualitative study. Thirteen interviews were carried out. All patients were 20-60-year-old MSM. The median time between PEP and HIV diagnosis was 3.3 years (interquartile range (IQR) 25-75 =0.9-4.9). Many participants reported negative PEP experiences: awkward access to the PEP clinic, uneasiness and shame in the hospital setting, unpleasant interaction and moral disapprobation from the medical staff, treatment intolerance and prevention messages that were 'inconsistent with real life' CONCLUSION: Our data highlight PEP management failures among its target population that may have compromised any subsequent attempts to seek out PEP. Practitioners should be more aware of MSM sexual contexts and practices. PEP consultations should provide the opportunity to discuss prevention strategies with highly exposed HIV-negative subjects, which may include pre-exposure prophylaxis. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  8. Effects of a school-based sexuality education program on peer educators: the Teen PEP model

    OpenAIRE

    Jennings, J. M.; Howard, S.; Perotte, C. L.

    2014-01-01

    This study evaluated the impact of the Teen Prevention Education Program (Teen PEP), a peer-led sexuality education program designed to prevent unintended pregnancy and sexually transmitted infections (STIs) including HIV among high school students. The study design was a quasi-experimental, nonrandomized design conducted from May 2007 to May 2008. The sample consisted of 96 intervention (i.e. Teen PEP peer educators) and 61 comparison students from five high schools in New Jersey. Baseline a...

  9. PEP-II prototype klystron

    International Nuclear Information System (INIS)

    Fowkes, W.R.; Caryotakis, G.; Lee, T.G.; Pearson, C.; Wright, E.L.

    1993-04-01

    A 540-kW continuous-wave (cw) klystron operating at 476 MHz was developed for use as a power source for testing PEP-II rf accelerating cavities and rf windows. It also serves as a prototype for a 1.2 MW cw klystron presently being developed as a potential rf source for asymmetric colliding ring use. The design incorporates the concepts and many of the parts used in the original 353 MHz PEP klystron developed sixteen years ago. The superior computer simulation codes available today result in improved performance with the cavity frequencies, drift lengths, and output circuit optimized for the higher frequency.The design and operating results of this tube are described with particular emphasis on the factors which affect efficiency and stability

  10. Optical beam diagnostics on PEP

    International Nuclear Information System (INIS)

    Sabersky, A.P.

    1981-02-01

    In designing the PEP optical diagnostics we have been able to build on the experience gained with SPEAR. Most of the problems at SPEAR could be traced to the optical diagnostic system being inside the tunnel. A machine shutdown is required for any maintenance or modification. This implies that in order to make such an instrument successful, a large engineering effort must be mounted to ensure 100% operation at startup. The functions that do not work at startup may never be made to work; this has happened at several machines. Experimental setups are likewise risky and time consuming. A point which has been borne out in both SPEAR and PEP is that the mechanical part of the instrument, the special vacuum chamber, the optical mounts, the alignment and adjustments, require approximately 60% of the effort and cost of the optical diagnostics. It is far better to economize on detectors and electronics than on mechanical and optical essentials

  11. Inhibition of the Unfolded Protein Response Mechanism Prevents Cardiac Fibrosis.

    Directory of Open Access Journals (Sweden)

    Jody Groenendyk

    Full Text Available Cardiac fibrosis attributed to excessive deposition of extracellular matrix proteins is a major cause of heart failure and death. Cardiac fibrosis is extremely difficult and challenging to treat in a clinical setting due to lack of understanding of molecular mechanisms leading to cardiac fibrosis and effective anti-fibrotic therapies. The objective in this study was to examine whether unfolded protein response (UPR pathway mediates cardiac fibrosis and whether a pharmacological intervention to modulate UPR can prevent cardiac fibrosis and preserve heart function.We demonstrate here that the mechanism leading to development of fibrosis in a mouse with increased expression of calreticulin, a model of heart failure, stems from impairment of endoplasmic reticulum (ER homeostasis, transient activation of the unfolded protein response (UPR pathway and stimulation of the TGFβ1/Smad2/3 signaling pathway. Remarkably, sustained pharmacologic inhibition of the UPR pathway by tauroursodeoxycholic acid (TUDCA is sufficient to prevent cardiac fibrosis, and improved exercise tolerance.We show that the mechanism leading to development of fibrosis in a mouse model of heart failure stems from transient activation of UPR pathway leading to persistent remodelling of cardiac tissue. Blocking the activation of the transiently activated UPR pathway by TUDCA prevented cardiac fibrosis, and improved prognosis. These findings offer a window for additional interventions that can preserve heart function.

  12. Inhibition of Cyclooxygenase-2 Prevents Chronic and Recurrent Cystitis

    Directory of Open Access Journals (Sweden)

    Thomas J. Hannan

    2014-11-01

    Full Text Available The spread of multidrug-resistant microorganisms globally has created an urgent need for novel therapeutic strategies to combat urinary tract infections (UTIs. Immunomodulatory therapy may provide benefit, as treatment of mice with dexamethasone during acute UTI improved outcome by reducing the development of chronic cystitis, which predisposes to recurrent infection. Here we discovered soluble biomarkers engaged in myeloid cell development and chemotaxis that were predictive of future UTI recurrence when elevated in the sera of young women with UTI. Translation of these findings revealed that temperance of the neutrophil response early during UTI, and specifically disruption of bladder epithelial transmigration of neutrophils by inhibition of cyclooxygenase-2, protected mice against chronic and recurrent cystitis. Further, proteomics identified bladder epithelial remodeling consequent to chronic infection that enhances sensitivity to neutrophil damage. Thus, cyclooxygenase-2 expression during acute UTI is a critical molecular trigger determining disease outcome and drugs targeting cyclooxygenase-2 could prevent recurrent UTI.

  13. Prevention of atrial fibrillation by Renin-Angiotensin system inhibition a meta-analysis

    DEFF Research Database (Denmark)

    Schneider, Markus; Hua, Tsushung A; Böhm, Michael

    2010-01-01

    The authors reviewed published clinical trial data on the effects of renin-angiotensin system (RAS) inhibition for the prevention of atrial fibrillation (AF), aiming to define when RAS inhibition is most effective.......The authors reviewed published clinical trial data on the effects of renin-angiotensin system (RAS) inhibition for the prevention of atrial fibrillation (AF), aiming to define when RAS inhibition is most effective....

  14. rf reference line for PEP

    International Nuclear Information System (INIS)

    Schwarz, H.D.; Weaver, J.N.

    1979-03-01

    A rf phase reference line in 6 segments around the 2200 meter circumference PEP storage ring is described. Each segment of the reference line is phase stabilized by its own independent feedback system, which uses an amplitude modulated reflection from the end of each line. The modulation is kept small and decoupled from the next segment to avoid crosstalk and significant modulation of the rf drive signal. An error evaluation of the system is made. The technical implementation and prototype performance are described. Prototype tests indicate that the phase error around the ring can be held below 1 degree with this relatively simple system

  15. rf reference line for PEP

    Energy Technology Data Exchange (ETDEWEB)

    Schwarz, H.D.; Weaver, J.N.

    1979-03-01

    A rf phase reference line in 6 segments around the 2200 meter circumference PEP storage ring is described. Each segment of the reference line is phase stabilized by its own independent feedback system, which uses an amplitude modulated reflection from the end of each line. The modulation is kept small and decoupled from the next segment to avoid crosstalk and significant modulation of the rf drive signal. An error evaluation of the system is made. The technical implementation and prototype performance are described. Prototype tests indicate that the phase error around the ring can be held below 1 degree with this relatively simple system.

  16. PEP-II status report

    International Nuclear Information System (INIS)

    Dorfan, J.M.

    1998-06-01

    The main design features of the PEP-II asymmetric two-ring electron-positron B Factory collider, built at the Stanford Linear Accelerator Center, are described. This facility will complete construction in June 1998. The high energy ring, completed in May 1997, has had 3 months of commissioning and successfully stored 0.75 A of electrons. The success of the high energy ring testing validates not only its ring components, but also the injection system, the RF system and the control system all of which are common to the two rings

  17. Perception of Arabidopsis AtPep peptides, but not bacterial elicitors, accelerates starvation-induced senescence

    Directory of Open Access Journals (Sweden)

    Kay eGully

    2015-01-01

    Full Text Available Members of the AtPep group of Arabidopsis endogenous peptides have frequently been reported to induce pattern-triggered immunity and to increase resistance to diverse pathogens by amplifying the innate immune response. Here, we made the surprising observation that dark-induced leaf senescence was accelerated by the presence of Peps. Adult leaves as well as leaf discs of Col-0 wild type plants showed a Pep-triggered early onset of chlorophyll breakdown and leaf yellowing whereas pepr1 pepr2 double mutant plants were insensitive. In addition, this response was dependent on ethylene signaling and inhibited by the addition of cytokinins. Notably, addition of the bacterial elicitors flg22 or elf18, both potent inducers of pattern-triggered immunity, did not provoke an early onset of leaf senescence.Continuous darkness leads to energy deprivation and starvation and therewith promotes leaf senescence. We found that continuous darkness also strongly induced PROPEP3 transcription. Moreover, Pep-perception led to a rapid induction of PAO, APG7 and APG8a, genes indispensable for chlorophyll degradation as well as autophagy, respectively, and all three hallmarks of starvation and senescence. Notably, addition of sucrose as a source of energy inhibited the Pep-triggered early onset of senescence. In conclusion, we report that Pep-perception accelerates dark/starvation-induced senescence via an early induction of chlorophyll degradation and autophagy. This represents a novel and unique characteristic of PEPR signaling, unrelated to pattern-triggered immunity.

  18. Influence of the metal ion on the enzyme activity and kinetics of PepA from Lactobacillus delbrueckii.

    Science.gov (United States)

    Ewert, Jacob; Glück, Claudia; Strasdeit, Henry; Fischer, Lutz; Stressler, Timo

    2018-03-01

    The aminopeptidase A (PepA; EC 3.4.11.7) belongs to the group of metallopeptidases with two bound metal ions per subunit (M1M2(PepA)) and is specific for the cleavage of N-terminal glutamic (Glu) and aspartic acid (Asp) and, in low amounts, serine (Ser) residues. Our group recently characterized the first PepA from a Lactobacillus strain. However, the characterization was performed using synthetic para-nitroaniline substrates and not original peptide substrates, as was done in the current study. Prior to the characterization using original peptide substrates, the PepA purified was converted to its inactive apo-form and eight different metal ions were tested to restore its activity. It was found that five of the metal ions were able to reactivate apo-PepA: Co 2+ , Cu 2+ , Mn 2+ , Ni 2+ and Zn 2+ . Interestingly, depending on the metal ion used for reactivation, the activity and the pH and temperature profile differed. Exemplarily, MnMn(PepA), NiNi(PepA) and ZnZn(PepA) had an activity optimum using MES buffer (50mM, pH 6.0) and 60°C, whereas the activity optimum changed to Na/K-phosphate-buffer (50mM, pH 7.0) and 55°C for CuCu(PepA). However, more important than the changes in optimum pH and temperature, the kinetic properties of PepA were affected by the metal ion used. While all PepA variants could release N-terminal Glu or Asp, only CoCo(PepA), NiNi(PepA) and CuCu(PepA) could release Ser from the particular peptide substrate. In addition, it was found that the enzyme efficiency (V max /K M ) and catalytic mechanism (positive cooperative binding (Hill coefficent; n), substrate inhibition (K IS )) were influenced by the metal ion. Exemplarily, a high cooperativity (n>2),K IS value >20mM and preference for N-terminal Glu were detected for CuCu(PepA). In summary, the results suggested that an exchange of the metal ion can be used for tailoring the properties of PepA for specific hydrolysis requirements. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Inhibition of Mutation: A Novel Approach to Preventing and Treating Cancer

    National Research Council Canada - National Science Library

    Romesberg, Floyd E

    2007-01-01

    .... Specific biochemical pathways are responsible for introducing mutation to the genome. Using drug(s) to inhibit one or more of these proteins and thereby prevent cancer is a novel and unique cancer prevention approach...

  20. Inhibition of fatty acid synthase prevents preadipocyte differentiation

    International Nuclear Information System (INIS)

    Schmid, Bernhard; Rippmann, Joerg F.; Tadayyon, Moh; Hamilton, Bradford S.

    2005-01-01

    Inhibition of fatty acid synthase (FAS) reduces food intake in rodents. As adipose tissue expresses FAS, we sought to investigate the effect of reduced FAS activity on adipocyte differentiation. FAS activity was suppressed either pharmacologically or by siRNA during differentiation of 3T3-L1 cells. Cerulenin (10 μM), triclosan (50 μM), and C75 (50 μM) reduced dramatically visible lipid droplet accumulation, while incorporation of [1- 14 C]acetate into lipids was reduced by 75%, 70%, and 90%, respectively. Additionally, the substances reduced FAS, CEBPα, and PPARγ mRNA by up to 85% compared to that of control differentiated cells. Transient transfection with FAS siRNA suppressed FAS mRNA and FAS activity, and this was accompanied by reduction of CEBPα and PPARγ mRNA levels, and complete prevention of lipid accumulation. CD36, a late marker of differentiation, was also reduced. Together, these results suggest that FAS generated signals may be essential to support preadipocyte differentiation

  1. A new lattice for PEP

    International Nuclear Information System (INIS)

    Rees, J.; Wiedemann, H.

    1976-01-01

    A new low-beta configuration has been proposed for PEP which has a reduced β/sub y/* and is capable of delivering design luminosity with lower circulating beam currents that those required in the standard configuration described in the Conceptual Design Report of February, 1976. A feasibility study has been carried out and it is reported in PTM-65, September 8, 1976, by Lee, Morton and Wiedemann. The beam-stay-clear region is specified in PTM-66, September 3, 1976 by H. Wiedemann. The principal advantages of the new lattice are that the lower beam currents lead to lower higher-order-mode power and permit reduction of the total rf power required which in turn reduces both capital cost and operating cost. Its disadvantages stem primarily from the relatively high maximum beta values which occur in the interaction-region quadrupoles. These produce high chromaticities which require a generally stronger sextupole system for their compensation. The advantages outweigh the disadvantages and the new 11-cm-beta configuration has been adopted as the design configuration for energies of 15-GeV and lower. In the remainder of this report we shall discuss the implications of this new configuration for the various systems of PEP. 1 fig., 3 tabs

  2. Status report of PEP-4

    International Nuclear Information System (INIS)

    Kamae, Tuneyoshi

    1982-01-01

    The present status of PEP-4 is reported. The cosmic ray test of a TPC without magnetic field was done in July, 1981, and tracks were observed on the first day of the test. The entire PEP-4 detector was tested with 3.9 kG magnetic field in November, 1981, and various trigger configurations were tested. The TPC performed well during the test, and a preliminary analysis gave an encouraging position resolution which is expected to be improved with the correction for various non-uniformity and by refining the fitting procedure. Furthermore, the detection efficiency of the muon chamber was about 99 %. In November and December, 1981, the cosmic ray test of the hexagonal calorimeter was carried out. The performance was just as expected. Noise did not pose any problem, and the peak of the Fourier coefficient gave a nice overall calibration of the calorimeter. There are some problems to be solved in future. With the TPC, the impurities in the gas, the electronic noise, the hooks and the magnetic coil should be improved. In addition, there are some problems with the inner drift chamber, the hexagonal calorimeter and the relativistic rise measured by the TPC. The very recent results with the first e + e - beam obtained in February, 1982, are briefly reported, although the events have not been fully analyzed. (Ito, K.)

  3. Status of PEP and TPC/2γ

    International Nuclear Information System (INIS)

    Zapalac, G.

    1989-06-01

    The TPC/2γ program at PEP has been upgraded by increasing the PEP luminosity and by the adding of a vertex chamber to the TPC detector. These improvements will allow a strong program in B and τ physics, and will contribute to ongoing studies in two-photon physics and hadronization. 10 refs., 3 figs

  4. PEP-II: An asymmetric B factory

    International Nuclear Information System (INIS)

    1993-06-01

    In this report, the authors have described an updated conceptual design for the high-luminosity Asymmetric B Factory (PEP-II) to be built in the PEP tunnel culmination of more than four years of effort aimed at the design and construction of an asymmetric e + e - collider capable of achieving a luminosity of L = 3 x 10 33 cm -2 s -1 . All aspects of the conceptual design were scrutinized in March 1991 by a DOE technical review committee chaired by Dr. L. Edward Temple. The design was deemed feasible and capable of achieving its physics goals. Furthermore, the cost estimate, schedule, and management plan for the project were fully endorsed by the committee. This updated conceptual design report captures the technical progress since the March 1991 review and reflects the lower cost estimate corresponding to the improved design. Although the PEP-II design has continued to evolve, no technical scope changes have been made that invalidate the conclusion of the DOE review. The configuration adopted utilizes two storage rings, an electron ring operating at 9 GeV and a positron ring at 3.1 GeV, each with a circumference of 2200 m. The high-energy ring is an upgrade of the PEP storage ring at SLAC; all PEP magnets and most power supplies will be reused. The upgrade consists primarily of replacing the PEP vacuum chamber and RF system with newly designed versions optimized for the high-current environment of PEP-II. The low-energy ring will be newly constructed and will be situated atop the high-energy ring in the PEP tunnel. Utilities already installed in the PEP tunnel are largely sufficient to operate the two PEP-II storage rings

  5. Virulent poxviruses inhibit DNA sensing by preventing STING activation.

    Science.gov (United States)

    Georgana, Iliana; Sumner, Rebecca P; Towers, Greg J; Maluquer de Motes, Carlos

    2018-02-28

    Cytosolic recognition of DNA has emerged as a critical cellular mechanism of host immune activation upon pathogen invasion. The central cytosolic DNA sensor cGAS activates STING, which is phosphorylated, dimerises and translocates from the ER to a perinuclear region to mediate IRF-3 activation. Poxviruses are dsDNA viruses replicating in the cytosol and hence likely to trigger cytosolic DNA sensing. Here we investigated the activation of innate immune signalling by 4 different strains of the prototypic poxvirus vaccinia virus (VACV) in a cell line proficient in DNA sensing. Infection with the attenuated VACV strain MVA activated IRF-3 via cGAS and STING, and accordingly STING dimerised and was phosphorylated during MVA infection. Conversely, VACV strains Copenhagen and Western Reserve inhibited STING dimerisation and phosphorylation during infection and in response to transfected DNA and cGAMP, thus efficiently suppressing DNA sensing and IRF-3 activation. A VACV deletion mutant lacking protein C16, thought to be the only viral DNA sensing inhibitor acting upstream of STING, retained the ability to block STING activation. Similar inhibition of DNA-induced STING activation was also observed for cowpox and ectromelia viruses. Our data demonstrate that virulent poxviruses possess mechanisms for targeting DNA sensing at the level of the cGAS-STING axis and that these mechanisms do not operate in replication-defective strains such as MVA. These findings shed light on the role of cellular DNA sensing in poxvirus-host interactions and will open new avenues to determine its impact on VACV immunogenicity and virulence. IMPORTANCE Poxviruses are dsDNA viruses infecting a wide range of vertebrates and include the causative agent of smallpox (variola virus) and its vaccine vaccinia virus (VACV). Despite smallpox eradication VACV remains of interest as a therapeutic. Attenuated strains are popular vaccine candidates, whereas replication-competent strains are emerging as

  6. PEP Run Report for Simulant Shakedown/Functional Testing

    Energy Technology Data Exchange (ETDEWEB)

    Josephson, Gary B.; Geeting, John GH; Bredt, Ofelia P.; Burns, Carolyn A.; Golovich, Elizabeth C.; Guzman-Leong, Consuelo E.; Kurath, Dean E.; Sevigny, Gary J.

    2009-12-29

    Pacific Northwest National Laboratory (PNNL) has been tasked by Bechtel National Inc. (BNI) on the River Protection Project-Waste Treatment Plant (RPP-WTP) project to perform research and development activities to resolve technical issues identified for the Pretreatment Facility (PTF). The Pretreatment Engineering Platform (PEP) was designed, constructed, and operated as part of a plan to respond to issue M12, "Undemonstrated Leaching Processes." The PEP is a 1/4.5-scale test platform designed to simulate the WTP pretreatment caustic leaching, oxidative leaching, ultrafiltration solids concentration, and slurry washing processes. The PEP replicates the WTP leaching processes using prototypic equipment and control strategies. The PEP also includes non-prototypic ancillary equipment to support the core processing. Two operating scenarios are currently being evaluated for the ultrafiltration process (UFP) and leaching operations. The first scenario has caustic leaching performed in the UFP-2 ultrafiltration feed vessels (i.e., vessel UFP-VSL-T02A in the PEP; and vessels UFP-VSL-00002A and B in the WTP PTF). The second scenario has caustic leaching conducted in the UFP-1 ultrafiltration feed preparation vessels (i.e., vessels UFP-VSL-T01A and B in the PEP; vessels UFP-VSL-00001A and B in the WTP PTF). In both scenarios, 19-M sodium hydroxide solution (NaOH, caustic) is added to the waste slurry in the vessels to leach solid aluminum compounds (e.g., gibbsite, boehmite). Caustic addition is followed by a heating step that uses direct injection of steam to accelerate the leach process. Following the caustic leach, the vessel contents are cooled using vessel cooling jackets and/or external heat exchangers. The main difference between the two scenarios is that for leaching in UFP-1, the 19-M NaOH is added to un-concentrated waste slurry (3-8 wt% solids), while for leaching in UFP-2, the slurry is concentrated to nominally 20 wt% solids using cross-flow ultrafiltration

  7. Collimation issues for the PEP-II B-factory

    International Nuclear Information System (INIS)

    Sullivan, M.

    1997-12-01

    This note describes how beam collimation affects detector backgrounds at the collision point for the PEP-II B-factory, a joint effort of three laboratories: LBNL, LLNL, and SLAC. Beam collimation controls the transverse size as well as the maximum allowed energy spread of the beam. The location of synchrotron radiation masks is determined by the transverse size of the beam in that the masks must prevent radiation generated by beam particles located at large transverse beam positions from directly striking the detector beam pipe. Collimation of the energy spread of the beam is important in the control of backgrounds produced by beam particles that strike a gas molecule (lost beam particles). The author describes some preliminary information from background studies during the first months of commissioning the high energy ring of the PEP-II B-factory and present some model predictions for synchrotron radiation backgrounds when collimators are not present

  8. PEP surveying procedures and equipment

    International Nuclear Information System (INIS)

    Linker, F.

    1982-06-01

    The PEP Survey and Alignment System, which employs both laser-based and optical survey methods, is described. The laser is operated in conjunction with the Tektronix 4051 computer and surveying instruments such as ARM and SAM, system which is designed to automate data input, reduction, and production of alignment instructions. The laser system is used when surveying ring quadrupoles, main bend magnets, sextupoles, and is optional when surveying RF cavities and insertion quadrupoles. Optical methods usually require that data be manually entered into the computer for alignment, but in some cases, an element can be aligned using nominal values of fiducial locations without use of the computer. Optical surveying is used in the alignment of NIT and SIT, low field bend magnets, wigglers, RF cavities, and insertion quadrupoles

  9. Status Report on PEP-II Performance

    International Nuclear Information System (INIS)

    Matter, Regina S.

    2002-01-01

    PEP-II [1-9] is an e+e- collider with asymmetric energies (3.1 and 9 GeV, respectively) in a 2200 m tunnel at the Stanford Linear Accelerator Center. The collider produces B mesons to study a particle physics effect called CP violation as well as other physics topics. PEP-II was completed in 1998 with the first luminosity generated in July of that year. The installation of the BaBar Detector was finished in May 1999. The overall layout of PEP-II is shown in Figure 1 and the interaction region of PEP-II in Figure 2. The accelerator parameters and achievements of the High Energy Ring (HER) are listed in Table 1 and those for the Low Energy Ring (LER) in Table 2. The two beams collide at a single point in the IR2 hall where the BaBar detector is located. Beam parameters at the best luminosity are shown in Table 3 and PEP-II milestones in Table 4. In August 1999 PEP-II passed the world's record for luminosity which was 8.1x10 32 /cm 2 /s. The present luminosity in PEP-II is 2.15x10 33 /cm 2 /s which is 72% of the design. In June 2000 PEP-II delivered an integrated luminosity of 150 pb -1 in one day, which is above the design integrated luminosity per day of 135 pb -1 . Over the past year PEP-II has delivered over 12 fb -1 to BaBar. BaBar has logged over 11 pb -1 . The present plan is collide until the end of October 2000 followed by a three month installation period

  10. Diagnosing the PEP-II Injection System

    Energy Technology Data Exchange (ETDEWEB)

    Decker, F.-J.; Donald, M.H.; Iverson, R.H.; Kulikov, A.; Pappas, G.C.; Weaver, M.; /SLAC

    2005-05-09

    The injection of beam into the PEP-II B-Factory, especially into the High Energy Ring (HER) has some challenges. A high background level in the BaBar detector has for a while inhibited us from trickling charge into the HER similar to the Low Energy Ring (LER). Analyzing the injection system has revealed many issues which could be improved. The injection bump between two kickers was not closed, mainly because the phase advance wasn't exactly 180{sup o} and the two kicker strengths were not balanced. Additionally we found reflections which kick the stored beam after the main kick and cause the average luminosity to drop about 3% for a 10 Hz injection rate. The strength of the overall kick is nearly twice as high as the design, indicating a much bigger effective septum thickness. Compared with single beam the background is worse when the HER beam is colliding with the LER beam. This hints that the beam-beam force and the observed vertical blow-up in the HER pushes the beam and especially the injected beam further out to the edge of the dynamic aperture or beyond.

  11. Diagnosing the PEP-II Injection System

    International Nuclear Information System (INIS)

    Decker, F.-J.; Donald, M.H.; Iverson, R.H.; Kulikov, A.; Pappas, G.C.; Weaver, M.; SLAC

    2005-01-01

    The injection of beam into the PEP-II B-Factory, especially into the High Energy Ring (HER) has some challenges. A high background level in the BaBar detector has for a while inhibited us from trickling charge into the HER similar to the Low Energy Ring (LER). Analyzing the injection system has revealed many issues which could be improved. The injection bump between two kickers was not closed, mainly because the phase advance wasn't exactly 180 o and the two kicker strengths were not balanced. Additionally we found reflections which kick the stored beam after the main kick and cause the average luminosity to drop about 3% for a 10 Hz injection rate. The strength of the overall kick is nearly twice as high as the design, indicating a much bigger effective septum thickness. Compared with single beam the background is worse when the HER beam is colliding with the LER beam. This hints that the beam-beam force and the observed vertical blow-up in the HER pushes the beam and especially the injected beam further out to the edge of the dynamic aperture or beyond

  12. Estimate of coherent tune shifts for PEP

    International Nuclear Information System (INIS)

    Yao, C.Y.; Chao, A.W.

    1981-02-01

    Transverse and longitudinal instabilities for a bunched PEP beam with a Gaussian distribution are treated using the standard technique in which instability problems are solved by looking for eigenvalues of the linearized Vlasov equation. The eigen solutions are conveniently expanded in terms of the Laquerre polynomials, and the eigenvalues are given by a symmetric matrix whose elements can be expressed in infinite series. The well-known formalism is used to obtain the matrix formula, and then applied numerically to the PEP ring to estimate the transverse coherent tune shifts. The impedance used is that estimated for the PEP RF cavities. The agreement with experimental data seems reasonable

  13. Event rates to be expected at PEP

    International Nuclear Information System (INIS)

    Richter, B.

    1988-01-01

    As a guide for planning experiments at PEP, some estimates are given of average luminosity, charged and neutral particle yields vs. momentum, QED test capabilities, and weak interaction effects. 2 figs

  14. Storage rings, internal targets and PEP

    International Nuclear Information System (INIS)

    Spencer, J.E.

    1986-11-01

    Storage rings with internal targets are described, using PEP as an example. The difference between electrons and heavier particles such as protons, antiprotons, and heavy ions is also discussed because it raises possibilities of bypass insertions for more exotic experiments. PEP is compared to other rings in various contexts to verify the assertion that it is an ideal ring for many fundamental and practical applications that can be carried on simultaneously

  15. Effects of a School-Based Sexuality Education Program on Peer Educators: The Teen PEP Model

    Science.gov (United States)

    Jennings, J. M.; Howard, S.; Perotte, C. L.

    2014-01-01

    This study evaluated the impact of the Teen Prevention Education Program (Teen PEP), a peer-led sexuality education program designed to prevent unintended pregnancy and sexually transmitted infections (STIs) including HIV among high school students. The study design was a quasi-experimental, nonrandomized design conducted from May 2007 to May…

  16. An asymmetric B factory based on PEP

    Energy Technology Data Exchange (ETDEWEB)

    1991-02-01

    In this report we describe a design for a high-luminosity Asymmetric B Factory to be built in the PEP tunnel on the SLAC site. This proposal, a collaborative effort SLAC, LBL, and LLNL, is the culmination of more than two years of effort aimed at the design and construction of an asymmetric e{sup +}e{sup {minus}} collider capable of achieving a luminosity of L = 3 {times} 10{sup 33} cm{sup {minus}2} s{sup {minus}1}. The configuration adopted utilizes two storage rings, and electron ring operating at 9 GeV and a positron ring at 3.1 GeV, each with a circumference of 2200 m. The high-energy ring is an upgrade of the PEP storage ring at SLAC; all PEP magnets and most power supplies will be reused. The upgrade consists primarily of replacing the PEP vacuum chamber and RF system with newly designed versions optimized for the high-current environment of the B Factory. The low-energy ring will be newly constructed and will be situated atop the high-energy ring in the PEP tunnel. Utilities already installed in the PEP tunnel are largely sufficient to operate the two B Factory storage rings.

  17. An asymmetric B factory based on PEP

    International Nuclear Information System (INIS)

    1991-02-01

    In this report we describe a design for a high-luminosity Asymmetric B Factory to be built in the PEP tunnel on the SLAC site. This proposal, a collaborative effort SLAC, LBL, and LLNL, is the culmination of more than two years of effort aimed at the design and construction of an asymmetric e + e - collider capable of achieving a luminosity of L = 3 x 10 33 cm -2 s -1 . The configuration adopted utilizes two storage rings, and electron ring operating at 9 GeV and a positron ring at 3.1 GeV, each with a circumference of 2200 m. The high-energy ring is an upgrade of the PEP storage ring at SLAC; all PEP magnets and most power supplies will be reused. The upgrade consists primarily of replacing the PEP vacuum chamber and RF system with newly designed versions optimized for the high-current environment of the B Factory. The low-energy ring will be newly constructed and will be situated atop the high-energy ring in the PEP tunnel. Utilities already installed in the PEP tunnel are largely sufficient to operate the two B Factory storage rings

  18. PEP quark search proportional chambers

    Energy Technology Data Exchange (ETDEWEB)

    Parker, S I; Harris, F; Karliner, I; Yount, D [Hawaii Univ., Honolulu (USA); Ely, R; Hamilton, R; Pun, T [California Univ., Berkeley (USA). Lawrence Berkeley Lab.; Guryn, W; Miller, D; Fries, R [Northwestern Univ., Evanston, IL (USA)

    1981-04-01

    Proportional chambers are used in the PEP Free Quark Search to identify and remove possible background sources such as particles traversing the edges of counters, to permit geometric corrections to the dE/dx and TOF information from the scintillator and Cerenkov counters, and to look for possible high cross section quarks. The present beam pipe has a thickness of 0.007 interaction lengths (lambdasub(i)) and is followed in both arms each with 45/sup 0/ <= theta <= 135/sup 0/, ..delta..phi=90/sup 0/ by 5 proportional chambers, each 0.0008 lambdasub(i) thick with 32 channels of pulse height readout, and by 3 thin scintillator planes, each 0.003 lambdasub(i) thick. Following this thin front end, each arm of the detector has 8 layers of scintillator (one with scintillating light pipes) interspersed with 4 proportional chambers and a layer of lucite Cerenkov counters. Both the calculated ion statistics and measurements using He-CH/sub 4/ gas in a test chamber indicate that the chamber efficiencies should be >98% for q=1/3. The Landau spread measured in the test was equal to that observed for normal q=1 traversals. One scintillator plane and thin chamber in each arm will have an extra set of ADC's with a wide gate bracketing the normal one so timing errors and tails of earlier pulses should not produce fake quarks.

  19. Donepezil prevents RANK-induced bone loss via inhibition of osteoclast differentiation by downregulating acetylcholinesterase

    Directory of Open Access Journals (Sweden)

    Tsuyoshi Sato

    2015-09-01

    Conclusions: AChE promotes osteoclast differentiation in vitro. Donepezil inhibits osteoclast function in vitro and prevents bone loss by suppressing bone resorption in vivo, suggesting the possibility that donepezil reduces fracture risk in patients with Alzheimer's disease.

  20. Community Screening for Preschool Child Inhibition to Offer the "Cool Little Kids" Anxiety Prevention Programme

    Science.gov (United States)

    Beatson, Ruth M.; Bayer, Jordana K.; Perry, Alexandra; Mathers, Megan; Hiscock, Harriet; Wake, Melissa; Beesley, Kate; Rapee, Ronald M.

    2014-01-01

    Temperamental inhibition has been identified as a key risk factor for childhood anxiety and internalizing problems. An efficacious early prevention programme for shy/inhibited children has been developed; however, accurate, efficient and acceptable screening is needed to support wider implementation. We explore community screening options in the…

  1. Prevention of 5-fluorouracil-caused growth inhibition in Sordaria fimicola.

    Science.gov (United States)

    Schoen, H F; Berech, J

    1977-02-01

    Growth (dry weight accumulation) of Sordaria fimicola in standing liquid culture (sucrose-nitrate-salts-vitamins) is inhibited by the presence of 5 muM 5-fluorouracil in the medium. This inhibition is completely prevented by uracil, deoxyuridine, and 5-bromouracil, partly prevented (40 to 90% of growth observed without 5-fluorouracil) by uridine, thymidine, and 5-bromodeoxyuridine, and slightly prevented by trifluorothymine, cytosine, cytidine, deoxycytidine, and 5-methylcytosine (all at 0.5 to 1 mM). Thymidine and thymine riboside were without any apparent effect. Growth is also inhibited by 0.2 mM 6-azauracil, and this inhibition was completely prevented by uracil and uridine, partly prevented by deoxyuridine, 5-bromouracil, cytidine, and 5-methylcytosine, and slightly prevented by thymine, thymidine, 5-bromodeoxyuridine, cytosine, and deoxycytidine. The data suggest that the observed inhibition of growth by 5-fluorouracil is due to inhibition of both ribonucleic acid and deoxyribonucleic acid synthesis. The data also allow inferences concerning pyrimidine interconversions in S. fimicola; i.e., thymine can be anabolized to thymidylic acid without first being demethylated, although demethylation appears to occur also.

  2. Inhibition of sortase A by chalcone prevents Listeria monocytogenes infection.

    Science.gov (United States)

    Li, Hongen; Chen, Yutao; Zhang, Bing; Niu, Xiaodi; Song, Meng; Luo, Zhaoqing; Lu, Gejin; Liu, Bowen; Zhao, Xiaoran; Wang, Jianfeng; Deng, Xuming

    2016-04-15

    The critical role of sortase A in gram-positive bacterial pathogenicity makes this protein a good potential target for antimicrobial therapy. In this study, we report for the first time the crystal structure of Listeria monocytogenes sortase A and identify the active sites that mediate its transpeptidase activity. We also used a sortase A (SrtA) enzyme activity inhibition assay, simulation, and isothermal titration calorimetry analysis to discover that chalcone, an agent with little anti-L. monocytogenes activity, could significantly inhibit sortase A activity with an IC50 of 28.41 ± 5.34 μM by occupying the active site of SrtA. The addition of chalcone to a co-culture of L. monocytogenes and Caco-2 cells significantly inhibited bacterial entry into the cells and L. monocytogenes-mediated cytotoxicity. Additionally, chalcone treatment decreased the mortality of infected mice, the bacterial burden in target organs, and the pathological damage to L. monocytogenes-infected mice. In conclusion, these findings suggest that chalcone is a promising candidate for the development of treatment against L. monocytogenes infection. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. PEP-II injection timing and controls

    International Nuclear Information System (INIS)

    Bharadwaj, V.; Browne, M.; Crane, M.; Gromme, T.; Himel, T.; Ross, M.; Stanek, M.; Ronan, M.

    1997-07-01

    Hardware has been built and software written and incorporated in the existing SLC accelerator control system to control injection of beam pulses from the accelerator into the PEP-II storage rings currently under construction. Hardware includes a CAMAC module to delay the machine timing fiducial in order that a beam pulse extracted from a damping ring will be injected into a selected group of four 476 MHz buckets in a PEP-II ring. Further timing control is accomplished by shifting the phase of the bunches stored in the damping rings before extraction while leaving the phase of the PEP-II stored beam unchanged. The software which drives timing devices on a pulse-to-pulse basis relies on a dedicated communication link on which one scheduling microprocessor broadcasts a 128-bit message to all distributed control microprocessors at 360 Hz. PEP-II injection will be driven by the scheduling microprocessor according to lists specifying bucket numbers in arbitrary order, and according to scheduling constraints maximizing the useful beam delivered to the SLC collider currently in operation. These lists will be generated by a microprocessor monitoring the current stored per bucket in each of the PEP-II rings

  4. Gain control through divisive inhibition prevents abrupt transition to chaos in a neural mass model

    Science.gov (United States)

    Papasavvas, Christoforos A.; Wang, Yujiang; Trevelyan, Andrew J.; Kaiser, Marcus

    2016-01-01

    Experimental results suggest that there are two distinct mechanisms of inhibition in cortical neuronal networks: subtractive and divisive inhibition. They modulate the input-output function of their target neurons either by increasing the input that is needed to reach maximum output or by reducing the gain and the value of maximum output itself, respectively. However, the role of these mechanisms on the dynamics of the network is poorly understood. We introduce a novel population model and numerically investigate the influence of divisive inhibition on network dynamics. Specifically, we focus on the transitions from a state of regular oscillations to a state of chaotic dynamics via period-doubling bifurcations. The model with divisive inhibition exhibits a universal transition rate to chaos (Feigenbaum behavior). In contrast, in an equivalent model without divisive inhibition, transition rates to chaos are not bounded by the universal constant (non-Feigenbaum behavior). This non-Feigenbaum behavior, when only subtractive inhibition is present, is linked to the interaction of bifurcation curves in the parameter space. Indeed, searching the parameter space showed that such interactions are impossible when divisive inhibition is included. Therefore, divisive inhibition prevents non-Feigenbaum behavior and, consequently, any abrupt transition to chaos. The results suggest that the divisive inhibition in neuronal networks could play a crucial role in keeping the states of order and chaos well separated and in preventing the onset of pathological neural dynamics. PMID:26465514

  5. Gain control through divisive inhibition prevents abrupt transition to chaos in a neural mass model.

    Science.gov (United States)

    Papasavvas, Christoforos A; Wang, Yujiang; Trevelyan, Andrew J; Kaiser, Marcus

    2015-09-01

    Experimental results suggest that there are two distinct mechanisms of inhibition in cortical neuronal networks: subtractive and divisive inhibition. They modulate the input-output function of their target neurons either by increasing the input that is needed to reach maximum output or by reducing the gain and the value of maximum output itself, respectively. However, the role of these mechanisms on the dynamics of the network is poorly understood. We introduce a novel population model and numerically investigate the influence of divisive inhibition on network dynamics. Specifically, we focus on the transitions from a state of regular oscillations to a state of chaotic dynamics via period-doubling bifurcations. The model with divisive inhibition exhibits a universal transition rate to chaos (Feigenbaum behavior). In contrast, in an equivalent model without divisive inhibition, transition rates to chaos are not bounded by the universal constant (non-Feigenbaum behavior). This non-Feigenbaum behavior, when only subtractive inhibition is present, is linked to the interaction of bifurcation curves in the parameter space. Indeed, searching the parameter space showed that such interactions are impossible when divisive inhibition is included. Therefore, divisive inhibition prevents non-Feigenbaum behavior and, consequently, any abrupt transition to chaos. The results suggest that the divisive inhibition in neuronal networks could play a crucial role in keeping the states of order and chaos well separated and in preventing the onset of pathological neural dynamics.

  6. Luminosity with more bunches in PEP

    International Nuclear Information System (INIS)

    Corbett, W.J.

    1990-12-01

    The near term accelerator physics program for PEP includes experiments in a collider mode with up to 9 bunches in each beam. In this memo, luminosity data from the 3 x 3 configuration is first used to calculate vertical beam size, emittance and tune shift as a function of current. The data is then used to extrapolate to the case with either 6 x 6 or 9 x 9 bunches colliding in PEP. Vertical emittance growth from the separated bunch optics and dispersion at the IP are included in the calculations. The conclusion is that given a 90 mA current drive limitation in PEP, operating with 6 x 6 bunches yields the maximum luminosity. 9 refs., 6 figs

  7. Single wavelength standard wiggler for PEP

    International Nuclear Information System (INIS)

    Brunk, W.; Fischer, G.; Spencer, J.

    1979-03-01

    A 1lambda planar wiggler has been designed that will be used for the initial operation of the 4 to 18 GeV storage ring PEP. Three of these wigglers will be installed symmetrically around the ring at 120 0 intervals in three of six available 5 m straight sections with the purpose of providing: (1) beam size control to obtain better luminosities below 15 GeV, and (2) decreased damping times to obtain better injection rates at lower energies. Design goals are discussed and a description of the final system including cost estimates is given. Expected results and usage in PEP are discussed. Some possibilities for production of synchrotron radiation and beam monitoring with shorter wavelength, multiple-period wigglers at PEP energies are also discussed. Comparison to a wiggler now operating in SPEAR is given

  8. Peptide drug stability: The anti-inflammatory drugs Pep19-2.5 and Pep19-4LF in cream formulation.

    Science.gov (United States)

    Kuhlmann, Nicole; Heinbockel, Lena; Correa, Wilmar; Gutsmann, Thomas; Goldmann, Torsten; Englisch, Uwe; Brandenburg, Klaus

    2018-03-30

    In previous years, we developed anti-infective drugs based on antimicrobial peptides (AMPs), which have been shown to effectively block severe infections and inflammation in vitro as well as in vivo. Besides systemic application, the occurrence of severe local infections necessitates a topical application for example in the case of severe skin and soft tissue infections (SSTI). Recent investigations show that the synthetic anti-lipopolysaccharide peptide (SALP) Pep19-2.5 (Aspidasept® I) and a variant called Pep19-4LF (Aspidasept® II) are able to supress inflammation reactions also in keratinocytes, Langerhans cells, and dendritic cells from the skin. For topical application, a possible formulation represents the drug dispersed into a pharmaceutical cream (DAC base cream). Here, we present investigations on the stability of the peptides using this formulation in dependence on time, which includes the evaluation of the extraction procedure, the quantitative analysis of the peptides after extraction, its sensitivity to protease degradation and its ability to maintain activity against LPS-induced inflammation in vitro. We have developed an extraction procedure for the peptides with an optimum yield and showed that Pep19-2.5 is present as a dimer after extraction from the cream, whereas Pep19-4LF retains its monomeric form. Both peptides show no degradation by chymotrypsin after extraction for at least 1 h, which is indicative for an attachment of constituents of the base cream, inhibiting the cutting into peptidic part structures. The extracted peptides and in particular the dimeric Pep19-2.5 are still able to inhibit the LPS-induced inflammation reaction in human mononuclear cells. Copyright © 2018 Elsevier B.V. All rights reserved.

  9. New results on flavor production at PEP

    International Nuclear Information System (INIS)

    Barbaro-Galtieri, A.

    1984-05-01

    This report includes results from five PEP detectors: DELCO, HRS, MAC, MARK II and TPC. All, except the TPC, are presently taking data at PEP. The TPC is being upgraded: a new superconducting coil is being installed and other improvements are being implemented. The results discussed here are either new or improved since the Cornell Conference. New results on Particle Searches and a limit on neutrino generations are discussed. New data are included on weak couplings of c and b quarks. Various new results on hadron production are reported. All data were obtained in e +- collisions with total energy √s=29 GeV. 54 references

  10. Anti-inflammatory effect of transduced PEP-1-heme oxygenase-1 in Raw 264.7 cells and a mouse edema model

    International Nuclear Information System (INIS)

    Kwon, Soon Won; Sohn, Eun Jeong; Kim, Dae Won; Jeong, Hoon Jae; Kim, Mi Jin; Ahn, Eun Hee; Kim, Young Nam; Dutta, Suman; Kim, Duk-Soo; Park, Jinseu; Eum, Won Sik; Hwang, Hyun Sook; Choi, Soo Young

    2011-01-01

    Highlights: → Recombinant PEP-1 heme oxygenase-1 expression vector was constructed and overexpressed. → We investigated transduction efficiency of PEP-1-HO-1 protein in Raw 264.7 cells. → PEP-1-HO-1 was efficiently transduced into Raw 264.7 cells in a dose and time dependent manner. → PEP-1-HO-1 exerted anti-inflammatory activity in Raw 264.7 cells and in a mice edema model. → PEP-1-HO-1 could be used as a therapeutic drug against inflammatory diseases. -- Abstract: Heme oxygenase-1 (HO-1), which catalyzes the degradation of free heme to biliverdin, carbon monoxide (CO), and free iron (Fe 2+ ), is up-regulated by several cellular stress and cell injuries, including inflammation, ischemia and hypoxia. In this study, we examined whether fusion of HO-1 with PEP-1, a protein transduction domain that is able to deliver exogenous molecules to living cells or tissues, would facilitate HO-1 delivery to target cells and tissues, and thereby effectively exert a therapeutically useful response against inflammation. Western blot analysis demonstrated that PEP-1-HO-1 fusion proteins were transduced into Raw 264.7 cells in time- and dose-dependent manners, and were stably maintained in the cells for about 60 h. In addition, fluorescence analysis revealed that only PEP-1-HO-1 fusion proteins were significantly transduced into the cytoplasm of cells, while HO-1 proteins failed to be transduced. In lipopolysaccharide (LPS)-stimulated Raw 264.7 cells and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse edema model, transduced PEP-1-HO-1 fusion proteins effectively inhibited the overexpression of pro-inflammatory mediators and cytokines. Also, histological analysis demonstrated that PEP-1-HO-1 remarkably suppressed ear edema. The results suggest that the PEP-1-HO-1 fusion protein can be used as a therapeutic molecule against reactive oxygen species-related inflammatory diseases.

  11. Recent improvements in luminosity at PEP

    International Nuclear Information System (INIS)

    Helm, R.; Allen, M.; Chao, A.

    1983-03-01

    We will describe improvements which have led to new records for peak and average luminosity at PEP. Comparison of recent results with several earlier lattice and optical modifications shows rather good correlation with the predictions of a beam-beam simulation program

  12. Genetic inhibition of PKA phosphorylation of RyR2 prevents dystrophic cardiomyopathy

    NARCIS (Netherlands)

    Sarma, Satyam; Li, Na; van Oort, Ralph J.; Reynolds, Corey; Skapura, Darlene G.; Wehrens, Xander H. T.

    2010-01-01

    Aberrant intracellular Ca(2+) regulation is believed to contribute to the development of cardiomyopathy in Duchenne muscular dystrophy. Here, we tested whether inhibition of protein kinase A (PKA) phosphorylation of ryanodine receptor type 2 (RyR2) prevents dystrophic cardiomyopathy by reducing SR

  13. KEKB and PEP-II B Factories

    International Nuclear Information System (INIS)

    Seeman, J.T.

    1997-01-01

    Two asymmetric B-Factories KEKB at KEK and PEP-II at SLAC are under construction, designed to study CP violation in the b-quark sector with a center of mass energy of 10.58 GeV. These two new accelerators are high luminosity two-ring two-energy e + e - colliders with one interaction point. There are many challenging accelerator physics and engineering issues associated with the high beam currents and high luminosities of these rings. The chosen solutions to these issues and the general parameters of the two rings are described in detail side-by-side. KEKB and PEP-II are well into the installation phase and are both scheduled to be completed in 1998. The particle physics programs are scheduled to start in 1999

  14. APS [Advanced Photon Source] interests in PEP

    International Nuclear Information System (INIS)

    Moncton, D.E.; Shenoy, G.K.; Mills, D.M.

    1987-11-01

    As one of the very few high-energy electron storage rings in the world, potentially available for synchrotron radiation studies, PEP represents an opportunity to accomplish certain preconstruction R and D tasks relevant to the successful construction and operation of dedicated user facilities such as the Advanced Photon Source (APS) at Argonne. Three topical areas are discussed: Accelerator R and D, Insertion Devices (ID) R and D, and Beam Line Instrumentation R and D

  15. Operation of PEP longitudinal feedback system

    International Nuclear Information System (INIS)

    Allen, M.A.; Karvonen, L.G.; McConnell, R.A.; Schwarz, H.

    1981-03-01

    In order to suppress longitudinal coupled-bunch oscillations which might limit the capabilities of PEP, the 18 GeV e + e - storage ring at SLAC, a longitudinal feedback system is utilized. A frequency domain feedback system was chosen with the frequency spectrum of the stored beam being sampled close to a symmetry point in the ring where the feedback cavity itself is also located. The symmetry point chosen is symmetry point 5 which lies half-way between interaction regions 4 and 6. The system has been installed in PEP and is now operational. However, at stored currents up to the maximum stored in PEP to date at 14.5 GeV (approximately 40 mA in 6 bunches), the ring has been stable to all modes of longitudinal coupled-bunch oscillations both barycentric and the other fundamental modes. By deliberately detuning the main accelerating cavities, small multibunch oscillations can be introduced which, in turn, can be damped by the feedback system. Under optimized beam conditions the feedback system could be adjusted to positive feedback and excite oscillations with relatively small power to the feedback cavity. This will be described along with other details of the system

  16. InverPep: A database of invertebrate antimicrobial peptides.

    Science.gov (United States)

    Gómez, Esteban A; Giraldo, Paula; Orduz, Sergio

    2017-03-01

    The aim of this work was to construct InverPep, a database specialised in experimentally validated antimicrobial peptides (AMPs) from invertebrates. AMP data contained in InverPep were manually curated from other databases and the scientific literature. MySQL was integrated with the development platform Laravel; this framework allows to integrate programming in PHP with HTML and was used to design the InverPep web page's interface. InverPep contains 18 separated fields, including InverPep code, phylum and species source, peptide name, sequence, peptide length, secondary structure, molar mass, charge, isoelectric point, hydrophobicity, Boman index, aliphatic index and percentage of hydrophobic amino acids. CALCAMPI, an algorithm to calculate the physicochemical properties of multiple peptides simultaneously, was programmed in PERL language. To date, InverPep contains 702 experimentally validated AMPs from invertebrate species. All of the peptides contain information associated with their source, physicochemical properties, secondary structure, biological activity and links to external literature. Most AMPs in InverPep have a length between 10 and 50 amino acids, a positive charge, a Boman index between 0 and 2 kcal/mol, and 30-50% hydrophobic amino acids. InverPep includes 33 AMPs not reported in other databases. Besides, CALCAMPI and statistical analysis of InverPep data is presented. The InverPep database is available in English and Spanish. InverPep is a useful database to study invertebrate AMPs and its information could be used for the design of new peptides. The user-friendly interface of InverPep and its information can be freely accessed via a web-based browser at http://ciencias.medellin.unal.edu.co/gruposdeinvestigacion/prospeccionydisenobiomoleculas/InverPep/public/home_en. Copyright © 2016 International Society for Chemotherapy of Infection and Cancer. Published by Elsevier Ltd. All rights reserved.

  17. Epigenetic Histone Deacetylation Inhibition Prevents the Development and Persistence of Temporal Lobe Epilepsy.

    Science.gov (United States)

    Reddy, Sandesh D; Clossen, Bryan L; Reddy, Doodipala Samba

    2018-01-01

    Epilepsy is a chronic brain disease characterized by repeated unprovoked seizures. Currently, no drug therapy exists for curing epilepsy or disease modification in people at risk. Despite several emerging mechanisms, there have been few studies of epigenetic signaling in epileptogenesis, the process whereby a normal brain becomes progressively epileptic because of precipitating factors. Here, we report a novel role of histone deacetylation as a critical epigenetic mechanism in epileptogenesis. Experiments were conducted using the histone deacetylase (HDAC) inhibitor sodium butyrate in the hippocampus kindling model of temporal lobe epilepsy (TLE), a classic model heavily used to approve drugs for treatment of epilepsy. Daily treatment with butyrate significantly inhibited HDAC activity and retarded the development of limbic epileptogenesis without affecting after-discharge signal. HDAC inhibition markedly impaired the persistence of seizure expression many weeks after epilepsy development. Moreover, subchronic HDAC inhibition for 2 weeks resulted in a striking retardation of epileptogenesis. HDAC inhibition, unexpectedly, also showed erasure of the epileptogenic state in epileptic animals. Finally, butyrate-treated animals exhibited a powerful reduction in mossy fiber sprouting, a morphologic index of epileptogenesis. Together these results underscore that HDAC inhibition prevents the development of TLE, indicating HDAC's critical signaling role in epileptogenesis. These findings, therefore, envisage a unique novel therapy for preventing or curing epilepsy by targeting the epigenetic HDAC pathway. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

  18. Peptidase-3 (Pep-3), dipeptidase variant in the rat homologous to mouse pep-3 (Dip-1) and human PEP-c.

    Science.gov (United States)

    Womack, J E; Cramer, D V

    1980-10-01

    Starch gel electrophoresis and histochemical staining with L-leucyl-L-tyrosine have revealed genetic variation for dipeptidase in Rattus norvegicus. The tissue distribution, substrate specificity, and heterozygous expression as a monmeric protein suggest homology of the variant peptidase to human PEP-C and mouse Pep-3 (Dip-1). We propose Peptidase-3 (Pep-3) as a name for this autosomal locus in the rat. The allele responsible for slower (less anodal) electrophoretic migration is designated Pep-3a and is characteristic of strain ACI/Pit. A faster (more anodal) electrophoretic mobility is the product of the Pep-3b allele in strain F344/Pit. Twenty-five additional inbred strains carry Pep-3a and 16 others carry Pep-3b. Wild rats trapped in Pittsburgh were polymorphic for this locus. Alleles at Pep-3 segregated independently of c (linkage group I), a (linkage group IV), RT2 and Es-1 (linkage group V), h (linkage group VI), and RTI (linkage group VIII).

  19. BERKELEY: Collaboration on PEP-II

    International Nuclear Information System (INIS)

    Anon.

    1995-01-01

    Since the announcement by President Clinton in October 1993 that the US Department of Energy would going ahead the PEPII Asymmetric B Factory project (a joint proposal of the Stanford Linear Accelerator Center - SLAC, the Lawrence Berkeley National Laboratory - LBNL, and the Lawrence Livermore National Laboratory - LLNL), LBNL has continued its strong support of the project (for a review, see October, page 9). LBNL accelerator physicists have been active in the design of PEP-II since 1988 - shortly after the original concept was suggested by LBNL Deputy Director Pier Oddone. Indeed, the original feasibility study for such a machine was a joint LBNLSLAC- Caltech effort led by Swapan Chattopadhyay, now head of LBNL's Center for Beam Physics (CBP) in the Accelerator & Fusion Research Division (AFRD). The effort grew to include about seven full-time LBNL accelerator physicists (along with about 15 SLAC and LLNL physicists) during the formal design phase, which began in late 1989. This effort encompassed three editions of the Conceptual Design Report, along with innumerable reviews, as is typical of today's accelerator projects. Taking advantage of an experienced engineering staff, fresh from the successful completion of the Advanced Light Source (ALS), LBNL has been assigned lead responsibility for the challenging Low Energy Ring (LER) of the PEP-II project, an entirely new storage ring to be added to the PEP tunnel. The LBNL design team is headed by CBP accelerator physicist Michael Zisman and senior engineers Ron Yourd (who served as the Project Manager for the ALS) and Hank Hsieh (a recent addition to the LBNL staff who was Project Engineer for the NSLS storage rings at BNL and most recently served as Project Engineer for the DAFNE project at Frascati). LBNL is also represented in the overall management of the PEP-II project by Tom Elioff, who serves as Deputy to the Project Director Jonathan Dorfan at SLAC. (Elioff served in the same role for the original

  20. Complement inhibition by hydroxychloroquine prevents placental and fetal brain abnormalities in antiphospholipid syndrome.

    Science.gov (United States)

    Bertolaccini, Maria Laura; Contento, Gregorio; Lennen, Ross; Sanna, Giovanni; Blower, Philip J; Ma, Michelle T; Sunassee, Kavitha; Girardi, Guillermina

    2016-12-01

    Placental ischemic disease and adverse pregnancy outcomes are frequently observed in patients with antiphospholipid syndrome (APS). Despite the administration of conventional antithrombotic treatment a significant number of women continue to experience adverse pregnancy outcomes, with uncertain prevention and management. Efforts to develop effective pharmacological strategies for refractory obstetric APS cases will be of significant clinical benefit for both mothers and fetuses. Although the antimalarial drug, hydroxychloroquine (HCQ) is increasingly used to treat pregnant women with APS, little is known about its efficacy and mechanism of action of HCQ. Because complement activation plays a crucial and causative role in placental ischemia and abnormal fetal brain development in APS we hypothesised that HCQ prevents these pregnancy complications through inhibition of complement activation. Using a mouse model of obstetric APS that closely resembles the clinical condition, we found that HCQ prevented fetal death and the placental metabolic changes -measured by proton magnetic resonance spectroscopy in APS-mice. Using 111 In labelled antiphospholipid antibodies (aPL) we identified the placenta and the fetal brain as the main organ targets in APS-mice. Using this same method, we found that HCQ does not inhibit aPL binding to tissues as was previously suggested from in vitro studies. While HCQ did not affect aPL binding to fetal brain it prevented fetal brain abnormal cortical development. HCQ prevented complement activation in vivo and in vitro. Complement C5a levels in serum samples from APS patients and APS-mice were lower after treatment with HCQ while the antibodies titres remained unchanged. HCQ prevented not only placental insufficiency but also abnormal fetal brain development in APS. By inhibiting complement activation, HCQ might also be an effective antithrombotic therapy. Copyright © 2016 Elsevier Ltd. All rights reserved.

  1. Arginase inhibition prevents the development of hypertension and improves insulin resistance in obese rats.

    Science.gov (United States)

    Peyton, Kelly J; Liu, Xiao-Ming; Shebib, Ahmad R; Johnson, Fruzsina K; Johnson, Robert A; Durante, William

    2018-04-27

    This study investigated the temporal activation of arginase in obese Zucker rats (ZR) and determined if arginase inhibition prevents the development of hypertension and improves insulin resistance in these animals. Arginase activity, plasma arginine and nitric oxide (NO) concentration, blood pressure, and insulin resistance were measured in lean and obese animals. There was a chronological increase in vascular and plasma arginase activity in obese ZR beginning at 8 weeks of age. The increase in arginase activity in obese animals was associated with a decrease in insulin sensitivity and circulating levels of arginine and NO. The rise in arginase activity also preceded the increase in blood pressure in obese ZR detected at 12 weeks of age. Chronic treatment of 8-week-old obese animals with an arginase inhibitor or L-arginine for 4 weeks prevented the development of hypertension and improved plasma concentrations of arginine and NO. Arginase inhibition also improved insulin sensitivity in obese ZR while L-arginine supplementation had no effect. In conclusion, arginase inhibition prevents the development of hypertension and improves insulin sensitivity while L-arginine administration only mitigates hypertension in obese animals. Arginase represents a promising therapeutic target in ameliorating obesity-associated vascular and metabolic dysfunction.

  2. Inhibition of aldose reductase prevents experimental allergic airway inflammation in mice.

    Directory of Open Access Journals (Sweden)

    Umesh C S Yadav

    2009-08-01

    Full Text Available The bronchial asthma, a clinical complication of persistent inflammation of the airway and subsequent airway hyper-responsiveness, is a leading cause of morbidity and mortality in critically ill patients. Several studies have shown that oxidative stress plays a key role in initiation as well as amplification of inflammation in airways. However, still there are no good anti-oxidant strategies available for therapeutic intervention in asthma pathogenesis. Most recent studies suggest that polyol pathway enzyme, aldose reductase (AR, contributes to the pathogenesis of oxidative stress-induced inflammation by affecting the NF-kappaB-dependent expression of cytokines and chemokines and therefore inhibitors of AR could be anti-inflammatory. Since inhibitors of AR have already gone through phase-III clinical studies for diabetic complications and found to be safe, our hypothesis is that AR inhibitors could be novel therapeutic drugs for the prevention and treatment of asthma. Hence, we investigated the efficacy of AR inhibition in the prevention of allergic responses to a common natural airborne allergen, ragweed pollen that leads to airway inflammation and hyper-responsiveness in a murine model of asthma.Primary Human Small Airway Epithelial Cells (SAEC were used to investigate the in vitro effects of AR inhibition on ragweed pollen extract (RWE-induced cytotoxic and inflammatory signals. Our results indicate that inhibition of AR prevents RWE -induced apoptotic cell death as measured by annexin-v staining, increase in the activation of NF-kappaB and expression of inflammatory markers such as inducible nitric oxide synthase (iNOS, cycloxygenase (COX-2, Prostaglandin (PG E(2, IL-6 and IL-8. Further, BALB/c mice were sensitized with endotoxin-free RWE in the absence and presence of AR inhibitor and followed by evaluation of perivascular and peribronchial inflammation, mucin production, eosinophils infiltration and airway hyperresponsiveness. Our results

  3. PEP-II IR-2 Alignment

    International Nuclear Information System (INIS)

    Seryi, A

    2004-01-01

    This paper describes the first results and preliminary analysis obtained with several alignment monitoring systems recently installed in the PEP-II interaction region. The hydrostatic level system, stretched wire system, and laser tracker have been installed in addition to the existing tiltmeters and LVDT sensors. These systems detected motion of the left raft, which correlated primarily with the low energy ring (LER) current. The motion is of the order of 120 micrometers. The cause was identified as synchrotron radiation heating the beampipe, causing its expansion which then results in its deformation and offset of the IR quadrupoles. We also discuss further plans on measurements, analysis and means to counteract this motion

  4. PEP-II RF feedback system simulation

    Energy Technology Data Exchange (ETDEWEB)

    Tighe, R [Stanford Linear Accelerator Center, Menlo Park, CA (United States)

    1996-08-01

    A model containing the fundamental impedance of the PEP-II cavity along with the longitudinal beam dynamics and RF feedback system components is in use. It is prepared in a format allowing time-domain as well as frequency-domain analysis and full graphics capability. Matlab and Simulink are control system design and analysis programs (widely available) with many built-in tools. The model allows the use of compiled C-code modules for compute intensive portions. We desire to represent as nearly as possible the components of the feedback system including all delays, sample rates and applicable nonlinearities. (author)

  5. Control electronics of the PEP RF system

    International Nuclear Information System (INIS)

    Pellegrin, J.L.; Schwarz, H.

    1981-01-01

    The operation of the major components used for controlling the phase and field level of the PEP RF cavities is described. The control electronics of one RF station is composed of several control loops: each cavity has a tuners' servo loop which maintains the frequency constant and also keeps the fields of each cavity balanced; the total gap voltage developed by a pair of cavities is regulated by a gap voltage controller; finally, the phase variation along the amplification chain, the klystron and the cavities are compensated by a phase lock loop. The design criteria of each loop are set forth and the circuit implementation and test results are presented

  6. Reliable 6 PEP LTPS device for AMOLED's

    Science.gov (United States)

    Chou, Cheng-Wei; Wang, Pei-Yun; Hu, Chin-Wei; Chang, York; Chuang, Ching-Sang; Lin, Yusin

    2013-09-01

    This study presents a TFT structure which has less photo process and higher cost competitiveness in AMOLED display markets. A novel LTPS based 6 masks TFT structure for bottom emission AMOLED display is demonstrated in this paper. High field effect mobility (PMOS < 80 cm2/Vs ) and high reliability (PBTS △Vth< 0.02V @ 50oC VG=15V 10ks) was accomplished without the high temperature and rapid thermal annealing (RTA) activation process. Furthermore, a 14-inch AMOLED TV was achieved on the proposed 6-pep TFT backplane using the Gen. 3.5 mass production factory.

  7. Search for heavy neutrino production at PEP

    International Nuclear Information System (INIS)

    Feldman, G.J.

    1985-10-01

    We report a search for long-lived heavy neutrinos produced by the neutral weak current in e + e - annihilation at 29 GeV at PEP. Data from the Mark II detector are examined for evidence of events with one or two separated vertices in the radial range of 2 mm to 10 cm. No events were found that were consistent with the hypothesis of heavy neutrino production, eliminating the possibility of heavy neutrinos with decay lengths of 1 to 20 cm in mass range 1 to 13 GeV/c 2

  8. Radiation and electrical safety systems for PEP

    International Nuclear Information System (INIS)

    Smith, H.; Constant, T.; Crook, K.; Fitch, J.; Taylor, T.

    1981-02-01

    At SLAC, the Personnel Protection System (PPS) protects people from radiation hazards. For PEP, the system has been expanded to include protection against electrical and RF hazards. This paper describes the overall system design, giving particular attention to the novel features not found in similar systems in other areas of SLAC. These include the Restricted Access Mode to allow limited occupancy in the ring while high voltage or RF may be present, the automatic badge reader system for improving the efficiency of entry logging and control, and the solid state lighting control system for switching large lighting loads with minimum electro-magetic interference

  9. Recent high precision surveys at PEP

    International Nuclear Information System (INIS)

    Sah, R.C.

    1980-12-01

    The task of surveying and aligning the components of PEP has provided an opportunity to develop new instruments and techniques for the purpose of high precision surveys. The new instruments are quick and easy to use, and they automatically encode survey data and read them into the memory of an on-line computer. When measurements of several beam elements have been taken, the on-line computer analyzes the measured data, compares them with desired parameters, and calculates the required adjustments to beam element support stands

  10. Searches for new particles at PEP

    International Nuclear Information System (INIS)

    Jonker, M.J.

    1986-05-01

    The status of searches for new particles at the PEP storage ring is reviewed. The result of the excited electron search by MARKII is presented and a limit on the coupling strength of the e*eγ vertex is given. The search for single photons in the ASP and MAC detectors is reported and the results are used to set limits on the number of light neutrino species and, in the context of supersymmetry (SUSY) theories, are interpreted as setting simultaneous limits on the masses of the selectron and photino

  11. Pep3p/Pep5p complex: a putative docking factor at multiple steps of vesicular transport to the vacuole of Saccharomyces cerevisiae.

    OpenAIRE

    Srivastava, A; Woolford, C A; Jones, E W

    2000-01-01

    Pep3p and Pep5p are known to be necessary for trafficking of hydrolase precursors to the vacuole and for vacuolar biogenesis. These proteins are present in a hetero-oligomeric complex that mediates transport at the vacuolar membrane. PEP5 interacts genetically with VPS8, implicating Pep5p in the earlier Golgi to endosome step and/or in recycling from the endosome to the Golgi. To understand further the cellular roles of Pep3p and Pep5p, we isolated and characterized a set of pep3 conditional ...

  12. Geotechnical investigations of the PEP site

    International Nuclear Information System (INIS)

    Gould, R.S.

    1976-02-01

    The purpose of this paper is to summarize the general nature of the geology and rock and soil formations of the PEP site as they relate to the design and construction of the project; to describe site investigation programs and to catalog the geotechnical information presently available about the site. The recently-completed investigation of subterranean conditions around the PEP ring when coupled with previous surveys gives us a good understanding of what to expect with regard to tunneling, undertaking larger underground excavations and constructing research halls are the interaction areas. It bears out the predictions made in Jacobs and Associates' report of 1973; i.e., that the ring housing construction is classified as soft-ground tunneling and that large underground openings, such as region 10 and the injection junction structures, will require great attention to support. A shield or shields will probably be required. On the positive side, the site affords very good conditions for soft-ground tunneling. Water will be a problem in some areas, but not an unsolvable one. The possibility of encountering lethal or explosive gases, almost always the case in tunneling in California's coastal formations, exists but has not been ascertained. Finally, no reasons to change current cost estimates or schedules have merged from the investigation. 13 refs., 1 fig

  13. Upgrades to PEP-II Tune Measurements

    Energy Technology Data Exchange (ETDEWEB)

    Fisher, Alan S.

    2002-07-30

    The tune monitors for the two-ring PEP-II collider convert signals from one set of four BPM-type pickup buttons per ring into horizontal and vertical differences, which are then downconverted from 952 MHz (twice the RF) to baseband. Two-channel 10-MHz FFT spectrum analyzers show spectra in X-window displays in the Control Room, to assist PEP operators. When operating with the original system near the beam-beam limit, collisions broadened and flattened the tune peaks, often bringing them near the noise floor. We recently installed new downconverters that increase the signal-to-noise ratio by about 5 dB. In addition, we went from one to two sets of pickups per ring, near focusing and defocusing quadrupoles, so that signals for both planes originate at locations with large amplitudes. We also have just installed a tune tracker, based on a digital lock-in amplifier (one per tune plane) that is controlled by an EPICS software feedback loop. The tracker monitors the phase of the beam's response to a sinusoidal excitation, and adjusts the drive frequency to track the middle of the 1 go-degree phase transition across the tune resonance. We plan next to test an outer loop controlling the tune quadrupoles based on this tune measurement.

  14. Upgrades to PEP-II Tune Measurements

    Energy Technology Data Exchange (ETDEWEB)

    Fisher, Alan S.

    2002-07-30

    The tune monitors for the two-ring PEP-II collider convert signals from one set of four BPM-type pickup buttons per ring into horizontal and vertical differences, which are then downconverted from 952 MHz (twice the RF) to baseband. Two-channel l0-MHz FFT spectrum analyzers show spectra in X-window displays in the Control Room, to assist PEP operators. When operating with the original system near the beam-beam limit, collisions broadened and flattened the tune peaks, often bringing them near the noise floor. We recently installed new downconverters that increase the signal-to-noise ratio by about 5 dB. In addition, we went from one to two sets of pickups per ring, near focusing and defocusing quadrupoles, so that signals for both planes originate at locations with large amplitudes. We also have just installed a tune tracker, based on a digital lock-in amplifier (one per tune plane) that is controlled by an EPICS software feedback loop. The tracker monitors the phase of the beam's response to a sinusoidal excitation, and adjusts the drive frequency to track the middle of the 180-degree phase transition across the tune resonance. We plan next to test an outer loop controlling the tune quadrupoles based on this tune measurement.

  15. Upgrades to PEP-II tune measurements

    International Nuclear Information System (INIS)

    Fisher, Alan S.; Petree, Mark; Wienands, Uli; Allison, Stephanie; Laznovsky, Michael; Seeman, Michael; Robin, Jolene

    2002-01-01

    The tune monitors for the two-ring PEP-II collider convert signals from one set of four BPM-type pickup buttons per ring into horizontal and vertical differences, which are then downconverted from 952 MHz (twice the RF) to baseband. Two-channel 10-MHz FFT spectrum analyzers show spectra in X-window displays in the Control Room, to assist PEP operators. When operating with the original system near the beam-beam limit, collisions broadened and flattened the tune peaks, often bringing them near the noise floor. We recently installed new downconverters that increase the signal-to-noise ratio by about 5 dB. In addition, we went from one to two sets of pickups per ring, near focusing and defocusing quadrupoles, so that signals for both planes originate at locations with large amplitudes. We also have just installed a tune tracker, based on a digital lock-in amplifier (one per tune plane) that is controlled by an EPICS software feedback loop. The tracker monitors the phase of the beam's response to a sinusoidal excitation, and adjusts the drive frequency to track the middle of the 180-degree phase transition across the tune resonance. We plan next to test an outer loop controlling the tune quadrupoles based on this tune measurement

  16. Knowledge, Attitude and Practice of Post-Exposure Prophylaxis (PEP)

    African Journals Online (AJOL)

    user

    Their levels of knowledge and indications for. PEP as well as ... uninfected patient and even re-infection of an already infected .... Surgical cuts/wounds. 7 ... Table 4: Knowledge of time of administration of PEP. Time .... respondents to be uncertain about the existence of such ... Surely, before the advent of this long awaited.

  17. cGMP-Phosphodiesterase Inhibition Prevents Hypoxia-Induced Cell Death Activation in Porcine Retinal Explants.

    Directory of Open Access Journals (Sweden)

    Lorena Olivares-González

    Full Text Available Retinal hypoxia and oxidative stress are involved in several retinal degenerations including diabetic retinopathy, glaucoma, central retinal artery occlusion, or retinopathy of prematurity. The second messenger cyclic guanosine monophosphate (cGMP has been reported to be protective for neuronal cells under several pathological conditions including ischemia/hypoxia. The purpose of this study was to evaluate whether the accumulation of cGMP through the pharmacological inhibition of phosphodiesterase (PDE with Zaprinast prevented retinal degeneration induced by mild hypoxia in cultures of porcine retina. Exposure to mild hypoxia (5% O2 for 24h reduced cGMP content and induced retinal degeneration by caspase dependent and independent (PARP activation mechanisms. Hypoxia also produced a redox imbalance reducing antioxidant response (superoxide dismutase and catalase activities and increasing superoxide free radical release. Zaprinast reduced mild hypoxia-induced cell death through inhibition of caspase-3 or PARP activation depending on the cell layer. PDE inhibition also ameliorated the effects of mild hypoxia on antioxidant response and the release of superoxide radical in the photoreceptor layer. The use of a PKG inhibitor, KT5823, suggested that cGMP-PKG pathway is involved in cell survival and antioxidant response. The inhibition of PDE, therefore, could be useful for reducing retinal degeneration under hypoxic/ischemic conditions.

  18. Theophylline prevents NAD+ depletion via PARP-1 inhibition in human pulmonary epithelial cells

    International Nuclear Information System (INIS)

    Moonen, Harald J.J.; Geraets, Liesbeth; Vaarhorst, Anika; Bast, Aalt; Wouters, Emiel F.M.; Hageman, Geja J.

    2005-01-01

    Oxidative DNA damage, as occurs during exacerbations in chronic obstructive pulmonary disease (COPD), highly activates the nuclear enzyme poly(ADP-ribose)polymerase-1 (PARP-1). This can lead to cellular depletion of its substrate NAD + , resulting in an energy crisis and ultimately in cell death. Inhibition of PARP-1 results in preservation of the intracellular NAD + pool, and of NAD + -dependent cellular processes. In this study, PARP-1 activation by hydrogen peroxide decreased intracellular NAD + levels in human pulmonary epithelial cells, which was found to be prevented in a dose-dependent manner by theophylline, a widely used compound in the treatment of COPD. This enzyme inhibition by theophylline was confirmed in an ELISA using purified human PARP-1 and was found to be competitive by nature. These findings provide new mechanistic insights into the therapeutic effect of theophylline in oxidative stress-induced lung pathologies

  19. PEP-II: An asymmetric B factory. Conceptual design report

    Energy Technology Data Exchange (ETDEWEB)

    1993-06-01

    In this report, the authors have described an updated conceptual design for the high-luminosity Asymmetric B Factory (PEP-II) to be built in the PEP tunnel culmination of more than four years of effort aimed at the design and construction of an asymmetric e{sub +}e{sub {minus}} collider capable of achieving a luminosity of L = 3 {times} 10{sup 33} cm{sup {minus}2} s{sup {minus}1}. All aspects of the conceptual design were scrutinized in March 1991 by a DOE technical review committee chaired by Dr. L. Edward Temple. The design was deemed feasible and capable of achieving its physics goals. Furthermore, the cost estimate, schedule, and management plan for the project were fully endorsed by the committee. This updated conceptual design report captures the technical progress since the March 1991 review and reflects the lower cost estimate corresponding to the improved design. Although the PEP-II design has continued to evolve, no technical scope changes have been made that invalidate the conclusion of the DOE review. The configuration adopted utilizes two storage rings, an electron ring operating at 9 GeV and a positron ring at 3.1 GeV, each with a circumference of 2200 m. The high-energy ring is an upgrade of the PEP storage ring at SLAC; all PEP magnets and most power supplies will be reused. The upgrade consists primarily of replacing the PEP vacuum chamber and RF system with newly designed versions optimized for the high-current environment of PEP-II. The low-energy ring will be newly constructed and will be situated atop the high-energy ring in the PEP tunnel. Utilities already installed in the PEP tunnel are largely sufficient to operate the two PEP-II storage rings.

  20. Atorvastatin prevents Aβ oligomer-induced neurotoxicity in cultured rat hippocampal neurons by inhibiting Tau cleavage

    Science.gov (United States)

    Sui, Hai-juan; Zhang, Ling-ling; Liu, Zhou; Jin, Ying

    2015-01-01

    Aim: The proteolytic cleavage of Tau is involved in Aβ-induced neuronal dysfunction and cell death. In this study, we investigated whether atorvastatin could prevent Tau cleavage and hence prevent Aβ1–42 oligomer (AβO)-induced neurotoxicity in cultured cortical neurons. Methods: Cultured rat hippocampal neurons were incubated in the presence of AβOs (1.25 μmol/L) with or without atorvastatin pretreatment. ATP content and LDH in the culture medium were measured to assess the neuronal viability. Caspase-3/7 and calpain protease activities were detected. The levels of phospho-Akt, phospho-Erk1/2, phospho-GSK3β, p35 and Tau proteins were measured using Western blotting. Results: Treatment of the neurons with AβO significantly decreased the neuronal viability, induced rapid activation of calpain and caspase-3/7 proteases, accompanied by Tau degradation and relatively stable fragments generated in the neurons. AβO also suppressed Akt and Erk1/2 kinase activity, while increased GSK3β and Cdk5 activity in the neurons. Pretreatment with atorvastatin (0.5, 1, 2.5 μmol/L) dose-dependently inhibited AβO-induced activation of calpain and caspase-3/7 proteases, and effectively diminished the generation of Tau fragments, attenuated synaptic damage and increased neuronal survival. Atorvastatin pretreatment also prevented AβO-induced decreases in Akt and Erk1/2 kinase activity and the increases in GSK3β and Cdk5 kinase activity. Conclusion: Atorvastatin prevents AβO-induced neurotoxicity in cultured rat hippocampal neurons by inhibiting calpain- and caspase-mediated Tau cleavage. PMID:25891085

  1. PEP-II Transverse Feedback Electronics Upgrade

    International Nuclear Information System (INIS)

    Weber, J.; Chin, M.; Doolittle, L.; Akre, R.

    2005-01-01

    The PEP-II B Factory at the Stanford Linear Accelerator Center (SLAC) requires an upgrade of the transverse feedback system electronics. The new electronics require 12-bit resolution and a minimum sampling rate of 238 Msps. A Field Programmable Gate Array (FPGA) is used to implement the feedback algorithm. The FPGA also contains an embedded PowerPC 405 (PPC-405) processor to run control system interface software for data retrieval, diagnostics, and system monitoring. The design of this system is based on the Xilinx(R) ML300 Development Platform, a circuit board set containing an FPGA with an embedded processor, a large memory bank, and other peripherals. This paper discusses the design of a digital feedback system based on an FPGA with an embedded processor. Discussion will include specifications, component selection, and integration with the ML300 design

  2. Search for scalar electrons at PEP

    International Nuclear Information System (INIS)

    Wilson, R.J.

    1983-08-01

    Experimental results from e + e - reactions at the Positron Electron Project (PEP) using the High Resolution Spectrometer (HRS) are presented. Events with two electrons, and no other charged particles, in the final state are studied. Limits are given for the production of scalar-electrons predicted by models based on supersymmetry. In particular the pair production of such particles through s-channel single photon annihilation and t-channel inelastic scattering is considered. The data are well described by quantum electrodynamics (QED) but we observe one event which is also consistent with a supersymmetric model. Using this single event we find that the mass, M/sub se/, of these scalar-electrons es excluded, to 95% CL, in the range 1.8 less than or equal to M/sub se/ less than or equal to 14.2 GeV/c 2 . A description of the HRS detector is given with particular emphasis on the electronic trigger system

  3. PEP-II Transverse Feedback Electronics Upgrade

    International Nuclear Information System (INIS)

    Weber, J.M.; Chin, M.J.; Doolittle, L.R.; Akre, R.

    2006-01-01

    The PEP-II B Factory at the Stanford Linear Accelerator Center (SLAC) requires an upgrade of the transverse feedback system electronics. The new electronics require 12-bit resolution and a minimum sampling rate of 238 Msps. A Field Programmable Gate Array (FPGA) is used to implement the feedback algorithm. The FPGA also contains an embedded PowerPC 405 (PPC-405) processor to run control system interface software for data retrieval, diagnostics, and system monitoring. The design of this system is based on the Xilinx(reg s ign) ML300 Development Platform, a circuit board set containing an FPGA with an embedded processor, a large memory bank, and other peripherals. This paper discusses the design of a digital feedback system based on an FPGA with an embedded processor. Discussion will include specifications, component selection, and integration with the ML300 design

  4. PEP-II Transverse Feedback Electronics Upgrade

    CERN Document Server

    Weber, Jonah; Chin, Michael; Doolittle, Lawrence

    2005-01-01

    The PEP-II B Factory at the Stanford Linear Accelerator Center (SLAC) requires an upgrade of the transverse feedback system electronics. The new electronics require 12-bit resolution and a minimum sampling rate of 238 Msps. A Field Programmable Gate Array (FPGA) is used to implement the feedback algorithm. The FPGA also contains an embedded PowerPC 405 (PPC-405) processor to run control system interface software for data retrieval, diagnostics, and system monitoring. The design of this system is based on the Xilinx® ML300 Development Platform, a circuit board set containing an FPGA with an embedded processor, a large memory bank, and other peripherals. This paper discusses the design of a digital feedback system based on an FPGA with an embedded processor. Discussion will include specifications, component selection, and integration with the ML300 design.

  5. PEP-II RF cavity revisited

    International Nuclear Information System (INIS)

    Rimmer, R.A.; Koehler, G.; Li, D.; Hartman, N.; Folwell, N.; Hodgson, J.; Ko, K.; McCandless, B.

    1999-01-01

    This report describes the results of numerical simulations of the PEP-II RF cavity performed after the completion of the construction phase of the project and comparisons are made to previous calculations and measured results. These analyses were performed to evaluate new calculation techniques for the HOM distribution and RF surface heating that were not available at the time of the original design. These include the use of a high frequency electromagnetic element in ANSYS and the new Omega 3P code to study wall losses, and the development of broadband time domain simulation methods in MAFIA for the HOM loading. The computed HOM spectrum is compared with cavity measurements and observed beam-induced signals. The cavity fabrication method is reviewed, with the benefit of hindsight, and simplifications are discussed

  6. Operation of the PEP transverse beam feedback

    International Nuclear Information System (INIS)

    Olson, C.W.; Paterson, J.M.; Pellegrin, J.L.; Rees, J.R.

    1981-02-01

    The PEP Storage Ring has been equipped with a wide band beam feedback system capable of damping the vertical and horizontal motion of six bunches. The oscillation detection is done at a symmetry point on the Storage Ring and feedback is applied at the same location one orbital period later. The signal is synchronously gated and the system appears as twelve independent feedback loops, operating on the two coordinates of each of the six bunches. Two beam deflection electrodes are driven each by a low-Q push-pull amplifier which is tuned at the 72nd harmonic of the revolution frequency and suppressed-carrier modulation is generated by a sequence of the detected bunch oscillations. The design parameters are reviewed as well as the salient features of the hardware, and the impact of this system on the machine operation is evaluated in the light of experimental results

  7. PEP725 Pan European Phenological Database

    Science.gov (United States)

    Koch, E.; Adler, S.; Lipa, W.; Ungersböck, M.; Zach-Hermann, S.

    2010-09-01

    Europe is in the fortunate situation that it has a long tradition in phenological networking: the history of collecting phenological data and using them in climatology has its starting point in 1751 when Carl von Linné outlined in his work Philosophia Botanica methods for compiling annual plant calendars of leaf opening, flowering, fruiting and leaf fall together with climatological observations "so as to show how areas differ". Recently in most European countries, phenological observations have been carried out routinely for more than 50 years by different governmental and non governmental organisations and following different observation guidelines, the data stored at different places in different formats. This has been really hampering pan European studies as one has to address many network operators to get access to the data before one can start to bring them in a uniform style. From 2004 to 2009 the COST-action 725 established a European wide data set of phenological observations. But the deliverables of this COST action was not only the common phenological database and common observation guidelines - COST725 helped to trigger a revival of some old networks and to establish new ones as for instance in Sweden. At the end of 2009 the COST action the database comprised about 8 million data in total from 15 European countries plus the data from the International Phenological Gardens IPG. In January 2010 PEP725 began its work as follow up project with funding from EUMETNET the network of European meteorological services and of ZAMG the Austrian national meteorological service. PEP725 not only will take over the part of maintaining, updating the COST725 database, but also to bring in phenological data from the time before 1951, developing better quality checking procedures and ensuring an open access to the database. An attractive webpage will make phenology and climate impacts on vegetation more visible in the public enabling a monitoring of vegetation development.

  8. The Woods Hole Partnership Education Program (PEP) (Invited)

    Science.gov (United States)

    Jearld, A.; Liles, G.; Gutierrez, B.

    2013-12-01

    In March 2009, the Woods Hole Diversity Initiative (WHDI) launched the Partnership Education Program (PEP), a multi-institutional effort to increase diversity in the student population (and ultimately the work force) in the Woods Hole science community. PEP, a summer research internship program, is open to students of all backgrounds but is designed especially to provide opportunities for individuals from populations under-represented in science, technology, engineering, and mathematics (STEM) and who otherwise would not have had the opportunity to come to Woods Hole to study or do research. A month-long course, 'Ocean and Environmental Sciences: Global Climate Change,' sets the stage for their summer research projects. The PEP model is emerging as an effective and sustainable approach to bringing students into the STEM research community. PEP is carefully structured to provide critical support for students as they complete their undergraduate experience and prepare for careers and/or graduate school. In its first five years, PEP has brought to the Woods Hole science community more than 75 students from over 50 colleges and universities, including many that do not typically send talent into marine and/or ecological research. PEP is unusual (perhaps even unique) in that it is a collaborative initiative involving seven partner institutions. Working together, the PEP collaborative has established a critical mass of under-represented students who are now in graduate school and/or working in STEM areas.

  9. The Cellular Prion Protein Prevents Copper-Induced Inhibition of P2X4 Receptors

    Directory of Open Access Journals (Sweden)

    Ramón A. Lorca

    2011-01-01

    Full Text Available Although the physiological function of the cellular prion protein (PrPC remains unknown, several evidences support the notion of its role in copper homeostasis. PrPC binds Cu2+ through a domain composed by four to five repeats of eight amino acids. Previously, we have shown that the perfusion of this domain prevents and reverses the inhibition by Cu2+ of the adenosine triphosphate (ATP-evoked currents in the P2X4 receptor subtype, highlighting a modulatory role for PrPC in synaptic transmission through regulation of Cu2+ levels. Here, we study the effect of full-length PrPC in Cu2+ inhibition of P2X4 receptor when both are coexpressed. PrPC expression does not significantly change the ATP concentration-response curve in oocytes expressing P2X4 receptors. However, the presence of PrPC reduces the inhibition by Cu2+ of the ATP-elicited currents in these oocytes, confirming our previous observations with the Cu2+ binding domain. Thus, our observations suggest a role for PrPC in modulating synaptic activity through binding of extracellular Cu2+.

  10. Extracellular cystatin SN and cathepsin B prevent cellular senescence by inhibiting abnormal glycogen accumulation.

    Science.gov (United States)

    Oh, Sang-Seok; Park, Soojong; Lee, Ki-Won; Madhi, Hamadi; Park, Sae Gwang; Lee, Hee Gu; Cho, Yong-Yeon; Yoo, Jiyun; Dong Kim, Kwang

    2017-04-06

    Cystatin SN (CST1), a known inhibitor of cathepsin B (CatB), has important roles in tumor development. Paradoxically, CatB is a member of the cysteine cathepsin family that acts in cellular processes, such as tumor development and invasion. However, the relationship between CST1 and CatB, and their roles in tumor development are poorly understood. In this study, we observed that the knockdown of CST1 induced the activity of senescence-associated β-galactosidase, a marker of cellular senescence, and expression of senescence-associated secretory phenotype genes, including interleukin-6 and chemokine (C-C motif) ligand 20, in MDA-MB-231 and SW480 cancer cells. Furthermore, CST1 knockdown decreased extracellular CatB activity, and direct CatB inhibition, using specific inhibitors or shCatB, induced cellular senescence. Reconstitution of CST1 restored CatB activity and inhibited cellular senescence in CST1 knockdown cells. CST1 knockdown or CatB inhibition increased glycogen synthase (GS) kinase 3β phosphorylation at serine 9, resulting in the activation of GS and the induction of glycogen accumulation associated with cellular senescence. Importantly, CST1 knockdown suppressed cancer cell proliferation, soft agar colony growth and tumor growth in a xenograft model. These results indicate that CST1-mediated extracellular CatB activity enhances tumor development by preventing cellular senescence. Our findings suggest that antagonists of CST1 or inhibitors of CatB are potential anticancer agents.

  11. Syringic Acid Extracted from Herba dendrobii Prevents Diabetic Cataract Pathogenesis by Inhibiting Aldose Reductase Activity

    Directory of Open Access Journals (Sweden)

    Xiaoyong Wei

    2012-01-01

    Full Text Available Objective. Effects of Syringic acid (SA extracted from dendrobii on diabetic cataract (DC pathogenesis were explored. Methods. Both in vitro and in vivo DC lens models were established using D-gal, and proliferation of HLEC exposed to SA was determined by MMT assay. After 60-day treatment with SA, rat lens transparency was observed by anatomical microscopy using a slit lamp. SA protein targets were extracted and isolated using 2-DE and MALDI TOF/TOF. AR gene expression was investigated using qRT-PCR. Interaction sites and binding characteristics were determined by molecule-docking techniques and dynamic models. Results. Targeting AR, SA provided protection from D-gal-induced damage by consistently maintaining lens transparency and delaying lens turbidity development. Inhibition of AR gene expression by SA was confirmed by qRT-PCR. IC50 of SA for inhibition of AR activity was 213.17 μg/mL. AR-SA binding sites were Trp111, His110, Tyr48, Trp20, Trp79, Leu300, and Phe122. The main binding modes involved hydrophobic interactions and hydrogen bonding. The stoichiometric ratio of non-covalent bonding between SA and AR was 1.0 to 13.3. Conclusion. SA acts to prevent DC in rat lenses by inhibiting AR activity and gene expression, which has potential to be developed into a novel drug for therapeutic management of DC.

  12. Vacuum system for the Stanford-LBL storage ring (PEP)

    International Nuclear Information System (INIS)

    Bostic, D.; Cummings, U.; Dean, N.; Jeong, B.; Jurow, J.

    1975-03-01

    The vacuum system for PEP will be similar in design, construction and operation to the system currently in operation at SPEAR. There will, of course, be quantitative differences since the closed path of PEP will be 10 times longer than the SPEAR path. Some qualitative differences will also arise since the radiated synchrotron power for PEP will be about 13 times greater than for SPEAR giving rise to an increased linear power density incident on the chamber wall. Other differences arise from the higher energy spectrum of the synchrotron radiation. The SPEAR vacuum system has been in operation since April 1972 and has proven satisfactory in design, construction and operation. The chamber has been subject to synchrotron radiation for approximately 300 ampere-hours and beam lifetimes are now more than several hours. The details of the PEP design and the SPEAR operating experience will be further discussed in this paper. 1 ref., 4 figs

  13. Configuring the SLC linac for injection into PEP

    International Nuclear Information System (INIS)

    Bane, K.L.F.

    1989-01-01

    From time to time the normal SLC physics program is to be interrupted so that beam can be delivered to PEP. In order that the switch to PEP injection (and the switch back again) can be accomplished quickly and easily, the gun, the damping rings, the linac phase ramp, the energy profile of the linac klystrons for the scavenger bunch, and the entire positron production system are to be kept the same as in the SLC configuration. What mainly remains to be changed is the linac klystron profile for the leading two bunches - those going to PEP. The new klystron profile must be such that it leaves these two beams (1) with final energies that match that of the storage ring and (2) with final energy spectra that fit within the energy aperture of the PEP transfer line. The conditions that need to be met in order to achieve these two goals are discussed in this note. 1 ref., 2 figs

  14. DIDS prevents ischemic membrane degradation in cultured hippocampal neurons by inhibiting matrix metalloproteinase release.

    Directory of Open Access Journals (Sweden)

    Matthew E Pamenter

    prevented stimulus-evoked release of von Willebrand Factor from human umbilical vein endothelial cells. We conclude that DIDS inhibits MMP exocytosis and through this mechanism preserves neuronal membrane integrity during pathological stress.

  15. PEP radiation shielding tests in SLAC A Beam

    International Nuclear Information System (INIS)

    Ash, W.; DeStaebler, H.; Harris, J.; Jenkins, T.; Murray, J.

    1977-09-01

    Radiation shielding tests designed to simulate possible conditions in and around the PEP experimental halls were conducted. The SLAC A Beam was targeted in the block tunnel at a point about midway between End Station A and Beam Dump East. At that site it was relatively easy to rearrange the concrete block structure to simulate the various shielding configurations under consideration for PEP. Extensive surveys of neutron and ionizing radiation were made. Complete results of the shielding tests are given

  16. PEP-II design update and R ampersand D results

    International Nuclear Information System (INIS)

    Zisman, M.S.

    1993-01-01

    We describe the present status of the PEP-II asymmetric β factory design undertaken by SLAC, LBL, and LLNL. Design optimization during the past year and changes from the original CDR design are described. R ampersand D activities have focused primarily on the key technology areas of vacuum, RF, and feedback system design. Recent progress in these areas is described. The R ampersand D results have verified our design assumptions and provide further confidence in the design of PEP-II

  17. Mactosylceramide Prevents Glial Cell Overgrowth by Inhibiting Insulin and Fibroblast Growth Factor Receptor Signaling

    DEFF Research Database (Denmark)

    Gerdøe-Kristensen, Stine; Lund, Viktor K; Wandall, Hans H

    2017-01-01

    , in which the mannosyltransferase Egghead controls conversion of glucosylceramide (GlcCer) to mactosylceramide (MacCer). Lack of elongated GSL in egghead (egh) mutants causes overgrowth of subperineurial glia (SPG), largely due to aberrant activation of phosphatidylinositol 3-kinase (PI3K). However, to what...... of the Drosophila Insulin Receptor (InR) and the FGFR homolog Heartless (Htl) in wild type SPG, and is suppressed by inhibiting Htl and InR activity in egh. Knockdown of GlcCer synthase in the SPG fails to suppress glial overgrowth in egh nerves, and slightly promotes overgrowth in wild type, suggesting that RTK...... hyperactivation is caused by absence of MacCer and not by GlcCer accumulation. We conclude that an early product in GSL biosynthesis, MacCer, prevents inappropriate activation of Insulin and Fibroblast Growth Factor Receptors in Drosophila glia. This article is protected by copyright. All rights reserved....

  18. Lithium prevents early cytosolic calcium increase and secondary injurious calcium overload in glycolytically inhibited endothelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Bosche, Bert, E-mail: bert.bosche@uk-essen.de [Department of Neurology, University of Duisburg-Essen (Germany); Max Planck Institute for Neurological Research with Klaus-Joachim-Zülch Laboratories of the Max Planck Society and the Medical Faculty of the University of Cologne (Germany); Schäfer, Matthias, E-mail: matthias.schaefer@sanofi.com [Institute of Physiology, Justus-Liebig-University Giessen (Germany); Graf, Rudolf, E-mail: rudolf.graf@nf.mpg.de [Max Planck Institute for Neurological Research with Klaus-Joachim-Zülch Laboratories of the Max Planck Society and the Medical Faculty of the University of Cologne (Germany); Härtel, Frauke V., E-mail: frauke.haertel@tu-dresden.de [Institute of Physiology, Medical Faculty Carl Gustav Carus, Technical University Dresden (Germany); Schäfer, Ute, E-mail: ute.schaefer@medunigraz.at [Research Unit for Experimental Neurotraumatology, Medical University of Graz (Austria); Noll, Thomas, E-mail: thomas.noll@tu-dresden.de [Institute of Physiology, Medical Faculty Carl Gustav Carus, Technical University Dresden (Germany)

    2013-05-03

    Highlights: •We investigate free calcium as a central signalling element in endothelial cells. •Inhibition of glycolysis with 2-deoxy-D-glucose reduces cellular ATP. •This manoeuvre leads to a biphasic increase and overload of free calcium. •Pre-treatment with lithium for 24 h abolishes both phases of the calcium increase. •This provides a new strategy to protect endothelial calcium homeostasis and barrier function. -- Abstract: Cytosolic free calcium concentration ([Ca{sup 2+}]{sub i}) is a central signalling element for the maintenance of endothelial barrier function. Under physiological conditions, it is controlled within narrow limits. Metabolic inhibition during ischemia/reperfusion, however, induces [Ca{sup 2+}]{sub i} overload, which results in barrier failure. In a model of cultured porcine aortic endothelial monolayers (EC), we addressed the question of whether [Ca{sup 2+}]{sub i} overload can be prevented by lithium treatment. [Ca{sup 2+}]{sub i} and ATP were analysed using Fura-2 and HPLC, respectively. The combined inhibition of glycolytic and mitochondrial ATP synthesis by 2-desoxy-D-glucose (5 mM; 2-DG) plus sodium cyanide (5 mM; NaCN) caused a significant decrease in cellular ATP content (14 ± 1 nmol/mg protein vs. 18 ± 1 nmol/mg protein in the control, n = 6 culture dishes, P < 0.05), an increase in [Ca{sup 2+}]{sub i} (278 ± 24 nM vs. 71 ± 2 nM in the control, n = 60 cells, P < 0.05), and the formation of gaps between adjacent EC. These observations indicate that there is impaired barrier function at an early state of metabolic inhibition. Glycolytic inhibition alone by 10 mM 2-DG led to a similar decrease in ATP content (14 ± 2 nmol/mg vs. 18 ± 1 nmol/mg in the control, P < 0.05) with a delay of 5 min. The [Ca{sup 2+}]{sub i} response of EC was biphasic with a peak after 1 min (183 ± 6 nM vs. 71 ± 1 nM, n = 60 cells, P < 0.05) followed by a sustained increase in [Ca{sup 2+}]{sub i}. A 24-h pre-treatment with 10 mM of lithium

  19. Inhibition of fatty acid biosynthesis prevents adipocyte lipotoxicity on human osteoblasts in vitro

    Science.gov (United States)

    Elbaz, Alexandre; Wu, Xiying; Rivas, Daniel; Gimble, Jeffrey M; Duque, Gustavo

    2010-01-01

    Abstract Although increased bone marrow fat in age-related bone loss has been associated with lower trabecular mass, the underlying mechanism responsible remains unknown. We hypothesized that marrow adipocytes exert a lipotoxic effect on osteoblast function and survival through the reversible biosynthesis of fatty acids (FA) into the bone marrow microenvironment. We have used a two-chamber system to co-culture normal human osteoblasts (NHOst) with differentiating pre-adipocytes in the absence or presence of an inhibitor of FA synthase (cerulenin) and separated by an insert that allowed unidirectional trafficking of soluble factors only and prevented direct cell–cell contact. Supernatants were assayed for the presence of FA using mass spectophotometry. After 3 weeks in co-culture, NHOst showed significantly lower levels of differentiation and function based on lower mineralization and expression of alkaline phosphatase, osterix, osteocalcin and Runx2. In addition, NHOst survival was affected by the presence of adipocytes as determined by MTS-formazan and TUNEL assays as well as higher activation of caspases 3/7. These toxic effects were inhibited by addition of cerulenin. Furthermore, culture of NHOst with either adipocyte-conditioned media alone in the absence of adipocytes themselves or with the addition of the most predominant FA (stearate or palmitate) produced similar toxic results. Finally, Runx2 nuclear binding was affected by addition of either adipocyte conditioned media or FA into the osteogenic media. We conclude that the presence of FA within the marrow milieu can contribute to the age-related changes in bone mass and can be prevented by the inhibition of FA synthase. PMID:19382912

  20. Acacetin inhibits glutamate release and prevents kainic acid-induced neurotoxicity in rats.

    Directory of Open Access Journals (Sweden)

    Tzu-Yu Lin

    Full Text Available An excessive release of glutamate is considered to be a molecular mechanism associated with several neurological diseases that causes neuronal damage. Therefore, searching for compounds that reduce glutamate neurotoxicity is necessary. In this study, the possibility that the natural flavone acacetin derived from the traditional Chinese medicine Clerodendrum inerme (L. Gaertn is a neuroprotective agent was investigated. The effect of acacetin on endogenous glutamate release in rat hippocampal nerve terminals (synaptosomes was also investigated. The results indicated that acacetin inhibited depolarization-evoked glutamate release and cytosolic free Ca(2+ concentration ([Ca(2+]C in the hippocampal nerve terminals. However, acacetin did not alter synaptosomal membrane potential. Furthermore, the inhibitory effect of acacetin on evoked glutamate release was prevented by the Cav2.2 (N-type and Cav2.1 (P/Q-type channel blocker known as ω-conotoxin MVIIC. In a kainic acid (KA rat model, an animal model used for excitotoxic neurodegeneration experiments, acacetin (10 or 50 mg/kg was administrated intraperitoneally to the rats 30 min before the KA (15 mg/kg intraperitoneal injection, and subsequently induced the attenuation of KA-induced neuronal cell death and microglia activation in the CA3 region of the hippocampus. The present study demonstrates that the natural compound, acacetin, inhibits glutamate release from hippocampal synaptosomes by attenuating voltage-dependent Ca(2+ entry and effectively prevents KA-induced in vivo excitotoxicity. Collectively, these data suggest that acacetin has the therapeutic potential for treating neurological diseases associated with excitotoxicity.

  1. Inhibition of FoxO transcriptional activity prevents muscle fiber atrophy during cachexia and induces hypertrophy

    Science.gov (United States)

    Reed, Sarah A.; Sandesara, Pooja B.; Senf, Sarah M.; Judge, Andrew R.

    2012-01-01

    Cachexia is characterized by inexorable muscle wasting that significantly affects patient prognosis and increases mortality. Therefore, understanding the molecular basis of this muscle wasting is of significant importance. Recent work showed that components of the forkhead box O (FoxO) pathway are increased in skeletal muscle during cachexia. In the current study, we tested the physiological significance of FoxO activation in the progression of muscle atrophy associated with cachexia. FoxO-DNA binding dependent transcription was blocked in the muscles of mice through injection of a dominant negative (DN) FoxO expression plasmid prior to inoculation with Lewis lung carcinoma cells or the induction of sepsis. Expression of DN FoxO inhibited the increased mRNA levels of atrogin-1, MuRF1, cathepsin L, and/or Bnip3 and inhibited muscle fiber atrophy during cancer cachexia and sepsis. Interestingly, during control conditions, expression of DN FoxO decreased myostatin expression, increased MyoD expression and satellite cell proliferation, and induced fiber hypertrophy, which required de novo protein synthesis. Collectively, these data show that FoxO-DNA binding-dependent transcription is necessary for normal muscle fiber atrophy during cancer cachexia and sepsis, and further suggest that basal levels of FoxO play an important role during normal conditions to depress satellite cell activation and limit muscle growth.—Reed, S. A., Sandesara, P. B., Senf, S. F., Judge, A. R. Inhibition of FoxO transcriptional activity prevents muscle fiber atrophy during cachexia and induces hypertrophy. PMID:22102632

  2. The Danish PEP registry: experience with the use of postexposure prophylaxis (PEP) following sexual exposure to HIV from 1998 to 2006

    DEFF Research Database (Denmark)

    Lunding, Suzanne; Katzenstein, Terese L; Kronborg, Gitte

    2010-01-01

    BACKGROUND: Studies indicate that antiretroviral postexposure prophylaxis (PEP) after sexual exposure to HIV reduce the risk of infection considerably. Since 1998 PEP after sexual HIV exposure within the preceding 24 hours, has been available in Denmark. PEP can only be prescribed at clinical...... centers with specialists experienced in HIV treatment. The objective of this study is to describe the use of PEP after sexual exposure from 1998 to 2006. METHODS: The Danish PEP registry collects data from all cases of PEP use in Denmark after exposure to HIV through a structured questionnaire. RESULTS......: There were 374 cases of PEP use after sexual exposure. The incidence increased from 5 cases in 1997 to 87 in 2006. PEP was used by heterosexuals (40%) as well as men who have sex with men (57%). The HIV-status of the source was unknown in 41% of the cases of which 90% involved a source belonging to a high...

  3. A failure of matrix metalloproteinase inhibition in the prevention of rat intracranial aneurysm formation

    International Nuclear Information System (INIS)

    Kaufmann, T.J.; Kallmes, D.F.; Marx, W.F.

    2006-01-01

    We tested the hypothesis that nonspecific matrix metalloproteinase (MMP) inhibition with doxycycline would decrease the incidence of intracranial aneurysm formation in a rat aneurysm model. We performed common carotid artery ligation on 96 Long-Evans rats. A treatment group of 48 animals was chosen at random to receive oral doxycycline (3 mg/kg) in addition to standard rat chow, and the control group of 48 animals received standard rat chow only. The major circle of Willis arteries was dissected at 1 year following carotid ligation, and the proportions of animals with aneurysms were compared between groups using Fisher's exact test. Four animals given oral doxycycline and ten control animals expired before 1 year. Of the examined animals, eight saccular intracranial aneurysms were found in 8 of 45 animals which had received doxycycline (17.8%) and seven saccular intracranial aneurysms were found in 7 of 37 control animals (18.9%). There was no significant difference in aneurysm formation between the doxycycline-treated and control groups (P=0.894). Nonspecific MMP inhibition with doxycycline is not effective in preventing intracranial aneurysm formation in a rat model. (orig.)

  4. Polysaccharides from Wolfberry Prevents Corticosterone-Induced Inhibition of Sexual Behavior and Increases Neurogenesis

    Science.gov (United States)

    Lau, Benson Wui-Man; Lee, Jada Chia-Di; Li, Yue; Fung, Sophia Man-Yuk; Sang, Yan-Hua; Shen, Jiangang; Chang, Raymond Chuen-Chung; So, Kwok-Fai

    2012-01-01

    Lycium barbarum, commonly known as wolfberry, has been used as a traditional Chinese medicine for the treatment of infertility and sexual dysfunction. However, there is still a scarcity of experimental evidence to support the pro-sexual effect of wolfberry. The aim of this study is to determine the effect of Lycium barbarum polysaccharides (LBP) on male sexual behavior of rats. Here we report that oral feeding of LBP for 21 days significantly improved the male copulatory performance including increase of copulatory efficiency, increase of ejaculation frequency and shortening of ejaculation latency. Furthermore, sexual inhibition caused by chronic corticosterone was prevented by LBP. Simultaneously, corticosterone suppressed neurogenesis in subventricular zone and hippocampus in adult rats, which could be reversed by LBP. The neurogenic effect of LBP was also shown in vitro. Significant correlation was found between neurogenesis and sexual performance, suggesting that the newborn neurons are associated with reproductive successfulness. Blocking neurogenesis in male rats abolished the pro-sexual effect of LBP. Taken together, these results demonstrate the pro-sexual effect of LBP on normal and sexually-inhibited rats, and LBP may modulate sexual behavior by regulating neurogenesis. PMID:22523540

  5. Cepharanthine Prevents Estrogen Deficiency-Induced Bone Loss by Inhibiting Bone Resorption

    Directory of Open Access Journals (Sweden)

    Chen-he Zhou

    2018-03-01

    Full Text Available Osteoporosis is a common health problem worldwide caused by an imbalance of bone formation vs. bone resorption. However, current therapeutic approaches aimed at enhancing bone formation or suppressing bone resorption still have some limitations. In this study, we demonstrated for the first time that cepharanthine (CEP, derived from Stephania cepharantha Hayata exerted a protective effect on estrogen deficiency-induced bone loss. This protective effect was confirmed to be achieved through inhibition of bone resorption in vivo, rather than through enhancement of bone formation in vivo. Furthermore, the in vitro study revealed that CEP attenuated receptor activator of nuclear factor κB ligand (RANKL-induced osteoclast formation, and suppressed bone resorption by impairing the c-Jun N-terminal kinase (JNK and phosphatidylinositol 3-kinase (PI3K-AKT signaling pathways. The inhibitory effect of CEP could be partly reversed by treatment with anisomycin (a JNK and p38 agonist and/or SC79 (an AKT agonist in vitro. Our results thus indicated that CEP could prevent estrogen deficiency-induced bone loss by inhibiting osteoclastogenesis. Hence, CEP might be a novel therapeutic agent for anti-osteoporosis therapy.

  6. The PEP-II abort kicker system

    International Nuclear Information System (INIS)

    Lamare, J de; Donaldson, A.; Kulikov, A. Lipari, J.

    1997-07-01

    The PEP-II project has two storage rings. The HER (High Energy Ring) has up to 1.48 A of electron beam at 9 GeV, and the LER (Low Energy Ring) has up to 2.14 A of positron beam at 3.1 GeV. To protect the HER and LER beam lines in the event of a ring component failure, each ring has an abort kicker system which directs the beam into a dump when a failure is detected. Due to the high current of the beams, the beam kick is tapered from 100% to 80% in 7.33 uS (the beam transit time around the time). This taper distributes the energy evenly across the window which separates the ring from the beam dump such that the window is not damaged. The abort kicker trigger is synchronized with the ion clearing gap of the beam allowing for the kicker field to rise from 0-80% in 370 nS. This report discusses the design of the system controls, interlocks, power supplies, and modulator

  7. Coherent x-rays from PEP

    International Nuclear Information System (INIS)

    Baird, S.; Nuhn, H.-D.; Tatchyn, R.; Winick, H.; Fisher, A.S.; Gallardo, J.C.; Pellegrini, C.

    1991-01-01

    This paper explores the use of a large-circumference, high-energy, electron-positron collider such as PEP to drive a free-electron laser (FEL), producing high levels of coherent power at short wavelengths. The author consider Self-Amplified Spontaneous Emission (SASE), in which electron bunches with low emittance, high peak current and small energy spread radiate coherently in a single passthrough a long undulator. As the electron beam passes down the undulator, its interaction with the increasingly intense spontaneous radiation causes a bunch density modulation at the optical wavelength, resulting in stimulated emissional growth of coherent power in a single pass. The need for optical-cavity mirrors, which place a lower limit on the wavelength of a conventional FEL oscillator, is avoided. The authors explore various combinations of electron-beam and undulator parameters, as well as special undulator designs and optical klystrons (OK), to reach high average or peak coherent power at wavelengths around 40 angstrom by achieving significant exponential gain or full saturation. Examples are presented for devices that achieve high peak coherent power (up to about 400 MW) with lower average coherent power (about 20 mW) and other devices which produce a few watts of average coherent power

  8. Implications of shorter cells in PEP

    International Nuclear Information System (INIS)

    Wiedemann, H.

    1975-01-01

    Further studies on the beam-stay-clear requirements in PEP led to the conclusion that the vertical aperture needed to be enlarged. There are two main reasons for that: Observations at SPEAR indicate that the aperture should be large enough for a fully coupled beam. Full coupling of the horizontal and vertical betatron oscillations occurs not only occasionally when the energy, tune or betatron function at the interaction point is changed but also due to the beam/endash/beam effect of two strong colliding beams. The second reason for an increased aperture requirement is the nonlinear perturbation of the particle trajectories by the sextupoles. This perturbation increases a fully coupled beam by another 50% to 80%. Both effects together with a +-5 mm allowance for closed orbit perturbation result in a vertical beam-stay-clear in the bending magnets of +-4.8 to +-5.6 cm, compared to the present +-2.0 cm. This beam-stay-clear, together with additional space for vacuum chamber, etc., leads to very costly bending magnets. In this note, a shorter cell length is proposed which would reduce considerably the vertical beam-stay-clear requirements in the bending magnets. 7 figs

  9. The PEP electron-positron ring

    International Nuclear Information System (INIS)

    Rees, J.R.

    1988-01-01

    The first stage of the positron-electron-proton (PEP) colliding-beam system which has been under joint study by a Lawrence Berkeley Laboratory-Stanford Linear Accelerator Center team for the past two years, will be the electron-positron storage ring. The physics justification for the e + e/sup minus/ ring is summarized briefly and the proposed facility is described. The ring will have six arcs having gross radii of about 220 m and six interaction regions located at the centers of straight sections about 130 m long. The longitudinal distance left free for experimental apparatus at the intersection regions will be 20 m. The range of operating beam energies will be from 5 GeV to 15 GeV. The design luminosity at 15 GeV will be 10 32 cm/sup minus 2/s/sup minus 1/, and the luminosity will vary approximately as the square of the beam energy. Alternative methods under consideration for adjusting the beam cross-section are discussed. The designs of the storage ring subsystems and of the conventional facilities including the experimental halls at the interaction regions are described

  10. cAMP prevents TNF-induced apoptosis through inhibiting DISC complex formation in rat hepatocytes

    International Nuclear Information System (INIS)

    Bhattacharjee, Rajesh; Xiang, Wenpei; Wang, Yinna; Zhang, Xiaoying; Billiar, Timothy R.

    2012-01-01

    complex upon the binding of TNF to TNFR1. In conclusion, our study shows that cAMP prevents TNF + ActD-induced apoptosis in rat hepatocytes by inhibiting DISC complex formation.

  11. cAMP prevents TNF-induced apoptosis through inhibiting DISC complex formation in rat hepatocytes

    Energy Technology Data Exchange (ETDEWEB)

    Bhattacharjee, Rajesh [Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213 (United States); Xiang, Wenpei [Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213 (United States); Family Planning Research Institute, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People' s Republic of China (China); Wang, Yinna [Vascular Medicine Institute, University of Pittsburgh School of Medicine, 10051-5A BST 3, 3501 Fifth Avenue, Pittsburgh, PA 15261 (United States); Zhang, Xiaoying [Department of Medicine/Endocrinology Division, University of Pittsburgh Medical Center, 200 Lothrop St., Pittsburgh, PA 15213 (United States); Billiar, Timothy R., E-mail: billiartr@upmc.edu [Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213 (United States)

    2012-06-22

    that cAMP exerts its affect at the proximal level of TNF signaling by inhibiting the formation of the DISC complex upon the binding of TNF to TNFR1. In conclusion, our study shows that cAMP prevents TNF + ActD-induced apoptosis in rat hepatocytes by inhibiting DISC complex formation.

  12. Inhibition of Matrix Metalloproteinase Activity Prevents Increases in Myocardial Tumor Necrosis Factor-α

    Science.gov (United States)

    Murray, David B.; Levick, Scott P; Brower, Gregory L.; Janicki, Joseph S.

    2010-01-01

    Aim TNF-α is known to cause adverse myocardial remodeling. While we have previously shown a role for cardiac mast cells in mediating myocardial TNF-α, matrix metalloproteinases (MMP) activation of TNF-α may also be contributory. We sought to determine the relative roles of MMPs and cardiac mast cells in the activation of TNF-α in the hearts of rats subjected to chronic volume overload. Methods Interventions with the broad spectrum MMP inhibitor, GM6001, or the mast cell stabilizer, nedocromil, were performed in the rat aortocaval fistula (ACF) model of volume overload. Results Myocardial TNF-α levels were significantly increased in the ACF. This increase was prevented by MMP inhibition with GM6001 (p ≤ 0.001 vs. ACF). Conversely, myocardial TNF-α levels were increased in the ACF + nedocromil treated fistula groups (p ≤ 0.001 vs. sham). The degradation of interstitial collagen volume fraction seen in the untreated ACF group was prevented in both the GM6001 and nedocromil treated hearts. Significant increases in LV myocardial ET-1 levels also occurred in the ACF group at 3 days post-fistula. Whereas administration of GM6001 significantly attenuated this increase, mast cell stabilization with nedocromil markedly exacerbated the increase, producing ET-1 levels 6.5 fold and 2 fold greater than that in the sham-operated control and ACF group, respectively. Conclusion The efficacy of the MMP inhibitor, GM6001, to prevent increased levels of myocardial TNF-α is indicative of MMP-mediated cleavage of latent extracellular membrane bound TNF-α protein as the primary source of bioactive TNF-α in the myocardium of the volume-overload heart. PMID:20403361

  13. Safflower bud inhibits RANKL-induced osteoclast differentiation and prevents bone loss in ovariectomized mice.

    Science.gov (United States)

    Choi, Joo-Hee; Lim, Seul-Ki; Kim, Dong-Il; Park, Min-Jung; Kim, Young-Kuk; Lee, An-Chul; Kim, Young-Min; Yang, Soo-Jin; Park, Jong-Hwan

    2017-10-15

    The powder and extract of safflower seeds are known to be effective in the prevention of bone loss in ovariectomized animals. However, the inhibitory effect and molecular mechanisms of safflower bud (SB), the germinated safflower, on bone destruction is unclear. The present study was designed to investigate the inhibitory effect and molecular mechanism of SB on osteoclastic differentiation and on bone loss in ovarietomized (OVX) mice. Osteoclastogenesis was determined by TRAP staining, F-actin ring formation, and bone resorption assay. NF-κB and MAPKs activation was analyzed by transfection assay and Western blot, respectively. Real-time PCR was performed to examine the expression of osteoclastogenesis-related genes. Histological changes, increases in TRAP-positive cells, and cathepsin K expression were examined in the metaphysis of OVX mice. Density of bone marrow was evaluated by µCT. SB inhibited the RANKL-induced differentiation of BMDMs into osteoclasts in a dose-dependent manner. F-actin ring formation and bone resorption were also reduced by SB in RANKL-treated BMDMs. In addition, SB decreased the activation of NF-κB and MAPKs and the expression of osteoclastogenesis-related genes in BMDMs treated with RANKL. Feeding of SB-included diet prevented bone loss in OVX mice. The number of TRAP-positive cells and level of protein expression of cathepsin K was reduced and bone mineral density was increased in the metaphysis of mice fed SB compared with OVX mice. These findings suggest that SB can be a preventive and therapeutic candidate for destructive bone diseases. Copyright © 2017. Published by Elsevier GmbH.

  14. Chloride channel inhibition by a red wine extract and a synthetic small molecule prevents rotaviral secretory diarrhoea in neonatal mice

    Science.gov (United States)

    Ko, Eun-A; Jin, Byung-Ju; Namkung, Wan; Ma, Tonghui; Thiagarajah, Jay R.; Verkman, A. S.

    2014-01-01

    Background Rotavirus is the most common cause of severe secretory diarrhoea in infants and young children globally. The rotaviral enterotoxin, NSP4, has been proposed to stimulate calcium-activated chloride channels (CaCC) on the apical plasma membrane of intestinal epithelial cells. We previously identified red wine and small molecule CaCC inhibitors. Objective To investigate the efficacy of a red wine extract and a synthetic small molecule, CaCCinh-A01, in inhibiting intestinal CaCCs and rotaviral diarrhoea. Design Inhibition of CaCC-dependent current was measured in T84 cells and mouse ileum. The effectiveness of an orally administered wine extract and CaCCinh-A01 in inhibiting diarrhoea in vivo was determined in a neonatal mouse model of rotaviral infection. Results Screening of ~150 red wines revealed a Cabernet Sauvignon that inhibited CaCC current in T84 cells with IC50 at a ~1:200 dilution, and higher concentrations producing 100% inhibition. A >1 kdalton wine extract prepared by dialysis, which retained full inhibition activity, blocked CaCC current in T84 cells and mouse intestine. In rotavirus-inoculated mice, oral administration of the wine extract prevented diarrhoea by inhibition of intestinal fluid secretion without affecting rotaviral infection. The wine extract did not inhibit the cystic fibrosis chloride channel (CFTR) in cell cultures, nor did it prevent watery stools in neonatal mice administered cholera toxin, which activates CFTR-dependent fluid secretion. CaCCinh-A01 also inhibited rotaviral diarrhoea. Conclusions Our results support a pathogenic role for enterocyte CaCCs in rotaviral diarrhoea and demonstrate the antidiarrhoeal action of CaCC inhibition by an alcohol-free, red wine extract and by a synthetic small molecule. PMID:24052273

  15. Transduced human copper chaperone for Cu,Zn-SOD (PEP-1-CCS) protects against neuronal cell death.

    Science.gov (United States)

    Choi, Soo Hyun; Kim, Dae Won; Kim, So Young; An, Jae Jin; Lee, Sun Hwa; Choi, Hee Soon; Sohn, Eun Jung; Hwang, Seok-Il; Won, Moo Ho; Kang, Tae-Cheon; Kwon, Hyung Joo; Kang, Jung Hoon; Cho, Sung-Woo; Park, Jinseu; Eum, Won Sik; Choi, Soo Young

    2005-12-31

    Reactive oxygen species (ROS) contribute to the development of various human diseases. Cu,Zn-superoxide dismutase (SOD) is one of the major means by which cells counteract the deleterious effects of ROS. SOD activity is dependent upon bound copper ions supplied by its partner metallochaperone protein, copper chaperone for SOD (CCS). In the present study, we investigated the protective effects of PEP-1-CCS against neuronal cell death and ischemic insults. When PEP-1-CCS was added to the culture medium of neuronal cells, it rapidly entered the cells and protected them against paraquat-induced cell death. Moreover, transduced PEP-1-CCS markedly increased endogenous SOD activity in the cells. Immunohistochemical analysis revealed that it prevented neuronal cell death in the hippocampus in response to transient forebrain ischemia. These results suggest that CCS is essential to activate SOD, and that transduction of PEP-1-CCS provides a potential strategy for therapeutic delivery in various human diseases including stroke related to SOD or ROS.

  16. The PEP II injection kicker system

    International Nuclear Information System (INIS)

    Pappas, G.C.; Donaldson, A.R.; Williams, D.

    1997-07-01

    PEP II or the B Factory consists of two asymmetric storage rings. The injection energy for electrons is 9 GeV, while that for positrons is 3.1 GeV. The bend angle into the high energy ring (HER) is 0.35 m-rad, and the angle into the low energy ring (LER) is 0.575 m-rad. The magnetic length for the HER kicker is 0.85 m, and 0.55 m for the LER kicker. The field produced by the magnet is therefore 123.5 G for the HER, and 132 G for the LER. Each ring has a kicker magnet upstream of the injection line which is used to distort the orbit of the stored beam. An identical magnet downstream of the injection line is used to restore the orbit of the stored beam and inject the incoming beam. The two magnets are driven in parallel by the modulator. The apeture of the magnets is 3.86x3.46 cm (HxV). Therefore the current required to drive the HER is 863 A, while for the LER it is 756 A. The inductance of the magnet is approximately 1.4 uH/m. The current pulse is a critically damped sinusoid with a rise time of less than 300 ns. A kicker system has been designed which can be used for injection of both beams by varying the charge of voltage. The modulator uses a conjugate circuit to match the impedance of the magnet, and coupling to the beam chamber

  17. AtPep3 is a hormone-like peptide that plays a role in the salinity stress tolerance of plants.

    Science.gov (United States)

    Nakaminami, Kentaro; Okamoto, Masanori; Higuchi-Takeuchi, Mieko; Yoshizumi, Takeshi; Yamaguchi, Yube; Fukao, Yoichiro; Shimizu, Minami; Ohashi, Chihiro; Tanaka, Maho; Matsui, Minami; Shinozaki, Kazuo; Seki, Motoaki; Hanada, Kousuke

    2018-05-29

    Peptides encoded by small coding genes play an important role in plant development, acting in a similar manner as phytohormones. Few hormone-like peptides, however, have been shown to play a role in abiotic stress tolerance. In the current study, 17 Arabidopsis genes coding for small peptides were found to be up-regulated in response to salinity stress. To identify peptides leading salinity stress tolerance, we generated transgenic Arabidopsis plants overexpressing these small coding genes and assessed survivability and root growth under salinity stress conditions. Results indicated that 4 of the 17 overexpressed genes increased salinity stress tolerance. Further studies focused on AtPROPEP3 , which was the most highly up-regulated gene under salinity stress. Treatment of plants with synthetic peptides encoded by AtPROPEP3 revealed that a C-terminal peptide fragment (AtPep3) inhibited the salt-induced bleaching of chlorophyll in seedlings. Conversely, knockdown AtPROPEP3 transgenic plants exhibited a hypersensitive phenotype under salinity stress, which was complemented by the AtPep3 peptide. This functional AtPep3 peptide region overlaps with an AtPep3 elicitor peptide that is related to the immune response of plants. Functional analyses with a receptor mutant of AtPep3 revealed that AtPep3 was recognized by the PEPR1 receptor and that it functions to increase salinity stress tolerance in plants. Collectively, these data indicate that AtPep3 plays a significant role in both salinity stress tolerance and immune response in Arabidopsis .

  18. C-peptide prevents SMAD3 binding to alpha promoters to inhibit collagen type IV synthesis.

    Science.gov (United States)

    Li, Yanning; Zhong, Yan; Gong, Wenjian; Gao, Xuehan; Qi, Huanli; Liu, Kun; Qi, Jinsheng

    2018-07-01

    Activation of transforming growth factor β1 (TGFB1)/SMAD3 signaling may lead to additional synthesis of collagen type IV (COL4), which is a major contributor to extracellular matrix (ECM) accumulation in diabetic nephropathy (DN). C-peptide can attenuate fibrosis to have unique beneficial effects in DN. However, whether and how C-peptide affects TGFB1/SMAD3-activated COL4 synthesis is unclear. In this study, pathological changes, expression of COL4 a1-a5 chains ( Col4a1-a5 ), COL4 distribution and protein and TGFB1 and SMAD3 protein were first assessed in a rat model of diabetes. Then, rat mesangial cells were treated with high glucose (HG) and/or C-peptide to investigate the underlying mechanism. Col4a1-a5 expression, COL4 protein and secretion, TGFB1 protein, SMAD3 nuclear translocation and binding of SMAD3 to its cognate sites in the promoters of Col4a1a2 , Col4a3a4 and Col4a5 were measured. It was found that C-peptide attenuated glomerular pathological changes and suppressed renal Col4a1 -a5 mRNA expression, COL4 protein content and TGFB1 protein content. C-peptide had a dose-dependent effect to inhibit Col4a1-a5 mRNA expression, COL4 protein content and secretion, in HG-stimulated mesangial cells. In addition, the HG-induced increase in TGFB1 protein content was significantly reduced by C-peptide. Although not apparently affecting SMAD3 nuclear translocation, C-peptide prevented SMAD3 from binding to its sites in the Col4a1a2 , Col4a3a4 and Col4a5 promoters in HG-stimulated mesangial cells. In conclusion, C-peptide could prevent SMAD3 from binding to its sites in the Col4a1a2 , Col4a3a4 and Col4a5 promoters, to inhibit COL4 generation. These results may provide a mechanism for the alleviation of fibrosis in DN by C-peptide. © 2018 Society for Endocrinology.

  19. Mind magic: a pilot study of preventive mind-body-based stress reduction in behaviorally inhibited and activated children

    NARCIS (Netherlands)

    Jellesma, F.C.; Cornelis, J.

    2012-01-01

    Purpose of study: The aim of this pilot study was to examine a mind-body-based preventive intervention program and to determine relationships between children's behavioral inhibition system (BIS) and behavioral activation system, stress, and stress reduction after the program. Design of study:

  20. StraPep: a structure database of bioactive peptides

    Science.gov (United States)

    Wang, Jian; Yin, Tailang; Xiao, Xuwen; He, Dan; Xue, Zhidong; Jiang, Xinnong; Wang, Yan

    2018-01-01

    Abstract Bioactive peptides, with a variety of biological activities and wide distribution in nature, have attracted great research interest in biological and medical fields, especially in pharmaceutical industry. The structural information of bioactive peptide is important for the development of peptide-based drugs. Many databases have been developed cataloguing bioactive peptides. However, to our knowledge, database dedicated to collect all the bioactive peptides with known structure is not available yet. Thus, we developed StraPep, a structure database of bioactive peptides. StraPep holds 3791 bioactive peptide structures, which belong to 1312 unique bioactive peptide sequences. About 905 out of 1312 (68%) bioactive peptides in StraPep contain disulfide bonds, which is significantly higher than that (21%) of PDB. Interestingly, 150 out of 616 (24%) bioactive peptides with three or more disulfide bonds form a structural motif known as cystine knot, which confers considerable structural stability on proteins and is an attractive scaffold for drug design. Detailed information of each peptide, including the experimental structure, the location of disulfide bonds, secondary structure, classification, post-translational modification and so on, has been provided. A wide range of user-friendly tools, such as browsing, sequence and structure-based searching and so on, has been incorporated into StraPep. We hope that this database will be helpful for the research community. Database URL: http://isyslab.info/StraPep PMID:29688386

  1. 5-Hydroxytryptamine 1A/7 and 4alpha receptors differentially prevent opioid-induced inhibition of brain stem cardiorespiratory function.

    Science.gov (United States)

    Wang, Xin; Dergacheva, Olga; Kamendi, Harriet; Gorini, Christopher; Mendelowitz, David

    2007-08-01

    Opioids evoke respiratory depression, bradycardia, and reduced respiratory sinus arrhythmia, whereas serotonin (5-HT) agonists stimulate respiration and cardiorespiratory interactions. This study tested whether serotonin agonists can prevent the inhibitory effects of opioids on cardiorespiratory function. Spontaneous and rhythmic inspiratory-related activity and gamma-aminobutyric acid (GABA) neurotransmission to premotor parasympathetic cardioinhibitory neurons in the nucleus ambiguus were recorded simultaneously in an in vitro thick slice preparation. The mu-opioid agonist fentanyl inhibited respiratory frequency. The 5-hydroxytryptamine 1A/7 receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin increased respiratory frequency by itself and also prevented the fentanyl-induced respiratory depression. The 5-hydroxytryptamine 4alpha agonist BIMU-8 did not by itself change inspiratory activity but prevented the mu-opioid-mediated respiratory depression. Both spontaneous and inspiratory-evoked GABAergic neurotransmission to cardiac vagal neurons were inhibited by fentanyl. 8-Hydroxy-2-(di-n-propylamino)tetralin inhibited spontaneous but not inspiratory-evoked GABAergic activity to parasympathetic cardiac neurons. However, 8-hydroxy-2-(di-n-propylamino)tetralin differentially altered the opioid-mediated depression of inspiratory-evoked GABAergic activity but did not change the opioid-induced reduction in spontaneous GABAergic neurotransmission. In contrast, BIMU-8 did not alter GABAergic neurotransmission to cardiac vagal neurons by itself but prevented the fentanyl depression of both spontaneous and inspiratory-elicited GABAergic neurotransmission to cardiac vagal neurons. In the presence of tetrodotoxin, the inhibition of GABAergic inhibitory postsynaptic currents with fentanyl is prevented by coapplication of BIMU-8, indicating that BIMU-8 acts at presynaptic GABAergic terminals to prevent fentanyl-induced depression. These results suggest that activation of 5

  2. Osteoprotegerin inhibits bone resorption and prevents tumor development in a xenogenic model of Ewing's sarcoma by inhibiting RANKL

    Science.gov (United States)

    Picarda, Gaëlle; Matous, Etienne; Amiaud, Jérôme; Charrier, Céline; Lamoureux, François; Heymann, Marie-Françoise; Tirode, Franck; Pitard, Bruno; Trichet, Valérie; Heymann, Dominique; Redini, Françoise

    2013-01-01

    Ewing's sarcoma (ES) associated with high osyeolytic lesions typically arises in the bones of children and adolescents. The development of multi-disciplinary therapy has increased current long-term survival rates to greater than 50% but only 20% for high risk group patients (relapse, metastases, etc.). Among new therapeutic approaches, osteoprotegerin (OPG), an anti-bone resorption molecule may represent a promising candidate to inhibit RANKL-mediated osteolytic component of ES and consequently to limit the tumor development. Xenogenic orthotopic models of Ewing's sarcoma were induced by intra-osseous injection of human TC-71 ES cells. OPG was administered in vivo by non-viral gene transfer using an amphiphilic non ionic block copolymer. ES bearing mice were assigned to controls (no treatment, synthetic vector alone or F68/empty pcDNA3.1 plasmid) and hOPG treated groups. A substantial but not significant inhibition of tumor development was observed in the hOPG group as compared to control groups. Marked bone lesions were revealed by micro-computed tomography analyses in control groups whereas a normal bone micro-architecture was preserved in the hOPG treated group. RANKL over-expressed in ES animal model was expressed by tumor cells rather than by host cells. However, TRAIL present in the tumor microenvironment may interfere with OPG effect on tumor development and bone remodeling via RANKL inhibition. In conclusion, the use of a xenogenic model of Ewing's sarcoma allowed discriminating between the tumor and host cells responsible for the elevation of RANKL production observed in this tumor and demonstrated the relevance of blocking RANKL by OPG as a promising therapy in ES. PMID:26909278

  3. PEP-II RF System Operation and Performance

    International Nuclear Information System (INIS)

    McIntosh, P.

    2005-01-01

    The Low Energy Ring (LER) and High Energy Ring (HER) RF systems have operated now on PEP-II since July 1998 and have assisted in breaking all design luminosity records back in June 2001. Luminosity on PEP-II has steadily increased since then as a consequence of larger e+ and e- beam currents being accumulated. This has meant that the RF systems have inevitably been driven harder, not only to achieve these higher stored beam currents, but also to reliably keep the beams circulating whilst at the same time minimizing the number of aborts due to RF system faults. This paper details the current PEP-II RF system configurations for both rings, as well as future upgrade plans spanning the next 3-5 years. Limitations of the current RF system configurations are presented, highlighting improvement projects which will target specific areas within the RF systems to ensure that adequate operating overheads are maintained and reliable operation is assured. The Low Energy Ring (LER) and High Energy Ring (HER) RF systems have operated now on PEP-II since July 1998 and have assisted in breaking all design luminosity records back in June 2001. Luminosity on PEP-II has steadily increased since then as a consequence of larger e+ and e- beam currents being accumulated. This has meant that the RF systems have inevitably been driven harder, not only to achieve these higher stored beam currents, but also to reliably keep the beams circulating whilst at the same time minimizing the number of aborts due to RF system faults. This paper details the current PEP-II RF system configurations for both rings, as well as future upgrade plans spanning the next 3-5 years. Limitations of the current RF system configurations are presented, highlighting improvement projects which will target specific areas within the RF systems to ensure that adequate operating overheads are maintained and reliable operation is assured

  4. Nuclear physics at PEP: First test and future plans

    International Nuclear Information System (INIS)

    Van Bibber, K.; Dietrich, F.S.; Melnikoff, S.O.

    1986-09-01

    A test run of internal target nuclear physics at the PEP storage ring is described. The Time Projection Chamber (TPC-2γ detector) was used to detect the inelastically scattered electron and complete hadronic final state in the interaction of 14.5 GeV electrons with D 2 , Ar and Xe gas targets. The data comprise mostly low-x low-Q 2 events, but some deep inelastic scattering as well. The future possibilities of a dedicated nuclear physics program at PEP are outlined. 15 refs., 25 figs

  5. An asymmetric Β-factory based on PEP

    International Nuclear Information System (INIS)

    Oddone, P.

    1989-01-01

    This paper reviews the motivation for building asymmetric B-factories based on storage rings and describes the current LBL/SLAC study to develop such a factory by modifying the PEP storage ring and adding a new low energy (2.5-3 GeV) storage ring. Collisions between the beam of the modified high energy PEP ring and the low energy ring lead to a luminosity of 2 x 10 33 cm- 2 sec - 1 at E cm = Y(4s) with currents of 0.8A in each beam. Further increases in current can lead to luminosities close to 10 34 cm - 2 sec - 1

  6. Plans for PEP survey and alignment: Status report

    International Nuclear Information System (INIS)

    Gunn, J.; Sah, R.

    1975-01-01

    This note discusses the current state of survey and alignment plans for PEP Stage I. Several surveying techniques are described; one is described in considerable detail. The survey and alignment task for PEP consists of positioning approximately 700 ring magnets, 100 injection line magnets, and 100 miscellaneous components. The alignment tolerances are tight and they are set by the requirement that closed orbit distortions must be small for proper storage ring operation. The alignment problem is aggravated by the circumstance that the storage ring components are placed in tunnels which span a large area (over 700 meters across) and which do not permit long lines of sight. 6 ref., 1 fig

  7. Curcumin Prevents Aflatoxin B1 Hepatoxicity by Inhibition of Cytochrome P450 Isozymes in Chick Liver

    Directory of Open Access Journals (Sweden)

    Ni-Ya Zhang

    2016-11-01

    Full Text Available This study was designed to establish if Curcumin (CM alleviates Aflatoxin B1 (AFB1-induced hepatotoxic effects and to determine whether alteration of the expression of cytochrome P450 (CYP450 isozymes is involved in the regulation of these effects in chick liver. One-day-old male broilers (n = 120 were divided into four groups and used in a two by two factorial trial in which the main factors included supplementing AFB1 (< 5 vs. 100 μg/kg and CM (0 vs. 150 mg/kg in a corn/soybean-based diet. Administration of AFB1 induced liver injury, significantly decreasing albumin and total protein concentrations and increasing alanine aminotransferase and aspartate aminotransferase activities in serum, and induced hepatic histological lesions at week 2. AFB1 also significantly decreased hepatic glutathione peroxidase, catalase, and glutathione levels, while increasing malondialdehyde, 8-hydroxydeoxyguanosine, and exo-AFB1-8,9-epoxide (AFBO-DNA concentrations. In addition, the mRNA and/or activity of enzymes responsible for the bioactivation of AFB1 into AFBO—including CYP1A1, CYP1A2, CYP2A6, and CYP3A4—were significantly induced in liver microsomes after 2-week exposure to AFB1. These alterations induced by AFB1 were prevented by CM supplementation. Conclusively, dietary CM protected chicks from AFB1-induced liver injury, potentially through the synergistic actions of increased antioxidant capacities and inhibition of the pivotal CYP450 isozyme-mediated activation of AFB1 to toxic AFBO.

  8. Mixed tocopherols prevent mammary tumorigenesis by inhibiting estrogen action and activating PPAR-γ

    Science.gov (United States)

    Lee, Hong Jin; Ju, Jihyeung; Paul, Shiby; So, Jae-Young; DeCastro, Andrew; Smolarek, Amanda; Lee, Mao-Jung; Yang, Chung S.; Newmark, Harold L.; Suh, Nanjoo

    2009-01-01

    Purpose Tocopherols are lipophilic antioxidants present in vegetable oils. Although the antioxidant and anticancer activities of α-tocopherol (vitamin E) have been studied for decades, recent intervention studies with α-tocopherol have been negative for protection from cancer in humans. The tocopherols consist of 4 isoforms, α, β, γ, and δ variants, and recent attention is being made to other isoforms. In the present study, we investigated the inhibitory effect of a tocopherol mixture rich in γ- and δ-tocopherols against mammary tumorigenesis. Experimental Design Female Sprague Dawley rats were treated with N-methyl-N-nitrosourea (NMU), and then fed diets containing 0.1%, 0.3%, or 0.5% mixed tocopherols rich in γ- and δ-tocopherols for 9 weeks. Tumor burden and multiplicity were determined, and the levels of markers of inflammation, proliferation and apoptosis were evaluated in the serum and in mammary tumors. The regulation of nuclear receptor signaling by tocopherols was studied in mammary tumors and in breast cancer cells. Results Dietary administration of 0.1%, 0.3%, or 0.5% mixed tocopherols suppressed mammary tumor growth by 38%, 50%, or 80%, respectively. Tumor multiplicity was also significantly reduced in all three mixed tocopherol groups. Mixed tocopherols increased the expression of p21, p27, caspase-3 and peroxisome proliferator activated receptor-γ (PPAR-γ), and inhibited AKT and estrogen signaling in mammary tumors. Our mechanistic study found that γ- and δ-tocopherols, but not α-tocopherol, activated PPAR-γ and antagonized estrogen action in breast cancer. Conclusion The results suggest that γ- and δ-tocopherols may be effective agents for the prevention of breast cancer. PMID:19509159

  9. Routine post-weaning handling of rats prevents isolation rearing-induced deficit in prepulse inhibition

    Directory of Open Access Journals (Sweden)

    M.L.N.M. Rosa

    2005-11-01

    Full Text Available Rats reared under isolation conditions from weaning present a number of behavioral changes compared to animals reared under social conditions (group housing. These changes include deficits in prepulse inhibition (PPI of the startle reflex to a loud sound. PPI refers to the reduction of the magnitude of the startle reflex when a relatively weak stimulus (the prepulse precedes by an appropriate time interval the intense startle-elicing stimulus (the pulse. PPI is useful for studying sensorimotor integration. The present study evaluated the effect of handling on the impairment of PPI induced by isolation-rearing. Male Wistar rats (N = 11-15/group were housed in groups (5 per cage and handled three times a week or isolated (housed individually since weaning (21 days for 10 weeks when they reach approximately 150 g. The isolated rats were divided into "minimally handled" animals (handled once a week for cleaning purposes only or "handled" animals (handled three times a week. This handling consisted of grasping the rat by the tail and moving it to a clean cage (approximately 5 s. A statistically significant reduction (52% in the PPI test was found only in the isolated group with minimal handling while no difference was seen between grouped animals and isolated handled animals. These results indicate that isolation rearing causes disruption in the PPI at adult age, which serves as an index of attention deficit. This change in the sensory processing of information induced by post-weaning isolation can be prevented by handling during the development of the animal.

  10. Routine post-weaning handling of rats prevents isolation rearing-induced deficit in prepulse inhibition.

    Science.gov (United States)

    Rosa, M L N M; Silva, R C B; Moura-de-Carvalho, F T; Brandão, M L; Guimarães, F S; Del Bel, E A

    2005-11-01

    Rats reared under isolation conditions from weaning present a number of behavioral changes compared to animals reared under social conditions (group housing). These changes include deficits in prepulse inhibition (PPI) of the startle reflex to a loud sound. PPI refers to the reduction of the magnitude of the startle reflex when a relatively weak stimulus (the prepulse) precedes by an appropriate time interval the intense startle-elicing stimulus (the pulse). PPI is useful for studying sensorimotor integration. The present study evaluated the effect of handling on the impairment of PPI induced by isolation-rearing. Male Wistar rats (N = 11-15/group) were housed in groups (5 per cage and handled three times a week) or isolated (housed individually) since weaning (21 days) for 10 weeks when they reach approximately 150 g. The isolated rats were divided into "minimally handled" animals (handled once a week for cleaning purposes only) or "handled" animals (handled three times a week). This handling consisted of grasping the rat by the tail and moving it to a clean cage (approximately 5 s). A statistically significant reduction (52%) in the PPI test was found only in the isolated group with minimal handling while no difference was seen between grouped animals and isolated handled animals. These results indicate that isolation rearing causes disruption in the PPI at adult age, which serves as an index of attention deficit. This change in the sensory processing of information induced by post-weaning isolation can be prevented by handling during the development of the animal.

  11. Morphological alterations of exogenous surfactant inhibited by meconium can be prevented by dextran

    Directory of Open Access Journals (Sweden)

    Stichtenoth Guido

    2006-06-01

    Full Text Available Abstract Background Surfactant dysfunction due to inhibition is involved in the pathophysiology of meconium aspiration syndrome. Dextran addition has been shown to reverse exogenous surfactant inactivation by meconium, but the precise mechanisms and the morphological correlate of this effect are yet unknown. Morphological surfactant analysis by transmission electron microscopy (TEM and stereology allows the differentiation of active (large aggregates = LA and inactive (small aggregates = SA subtypes. Methods To determine the in vitro effects of meconium and dextran addition on the morphology of a modified porcine natural surfactant (Curosurf, Curosurf samples were either incubated alone or together with meconium or with meconium and dextran, fixed and processed for TEM. Volume fractions of surfactant subtypes [lamellar body-like forms (LBL, multilamellar vesicles (MV, unilamellar vesicles (UV] were determined stereologically. Results All preparations contained LBL and MV (corresponding to LA as well as UV (corresponding to SA. The volume fraction of UV increased with addition of meconium and decreased with further addition of dextran. Correspondingly, the UV/(LBL+MV ratio (resembling the SA/LA ratio increased when meconium was added and decreased when dextran was added to the surfactant-meconium mixture. Conclusion Meconium causes alterations in the ultrastructural composition of Curosurf that can be visualized and analyzed by TEM and stereology. These alterations resemble an increase in the SA/LA ratio and are paralleled by an increase in minimum surface tension. Dextran prevents these effects and may therefore be a useful additive to exogenous surfactant preparations to preserve their structural and functional integrity, thereby improving their resistance to inactivation.

  12. Preschool Children's Performance on Profiling Elements of Prosody in Speech-Communication (PEPS-C)

    Science.gov (United States)

    Gibbon, Fiona E.; Smyth, Heather

    2013-01-01

    Profiling Elements of Prosody in Speech-Communication (PEPS-C) has not been used widely to assess prosodic abilities of preschool children. This study was therefore aimed at investigating typically developing 4-year-olds' performance on PEPS-C. PEPS-C was presented to 30 typically developing 4-year-olds recruited in southern Ireland. Children were…

  13. Review of e+e- physics at PEP - 1982

    International Nuclear Information System (INIS)

    Hollebeek, R.

    1982-10-01

    Results obtained at PEP by the MARK II, MAC and DELCO collaborations in the past year are reviewed. They include QED tests, measurements of tau lepton properties, charm and bottom fragmentation functions, scaling violations, energy correlations and the total hadronic cross section

  14. On setting magnets in the PEP beam-transport line

    International Nuclear Information System (INIS)

    Peterson, J.M.

    1979-01-01

    This paper discusses magnets in the PEP beam-transport line. Topics discussed are: conditioning, direction of excitation, rate of excitation; determination of the excitation current for the principal bend magnets; steering mechanisms; bump magnets; and determination of excitation currents of the quadrupole magnets

  15. Measuring, calculating and estimating PEP's parasitic mode loss parameters

    International Nuclear Information System (INIS)

    Weaver, J.N.

    1981-01-01

    This note discusses various ways the parasitic mode losses from a bunched beam to a vacuum chamber can be measured, calculated or estimated. A listing of the parameter, k, for the various PEP ring components is included. A number of formulas for calculating multiple and single pass losses are discussed and evaluated for several cases. 25 refs., 1 fig., 1 tab

  16. A missing-bending-magnet scheme for PEP

    International Nuclear Information System (INIS)

    Liu, R.Z.; Winick, H.

    1988-01-01

    This article presents a missing-bending-magnet scheme for PEP as a modification that could be considered if PEP were available as a fully dedicated synchrotron radiation source. The scheme can be applied to one or more PEP sextants without changing the rest. By removing some bending magnets, rearranging the remaining magnets, and adding two quadrupoles, ten additional straight sections per sextant can be created, each 5 m or more in length, for insertion devices. Beam lines therefrom, plus possible beam lines from bending magnets would enter a continuous experimental hall instead of individual tunnels and halls for each beam line. This should result in construction cost savings and increased operations efficiency. The ideal beam orbit is unchanged at the two ends and the middle of the sextant. At the end of the curved part of the sextant the lattice functions match those of the long interaction region straight section in the low emittance configuration of PEP. The electron beam characteristics in the newly created straight sections are described, including the enlargement of the horizontal beam size due to the nonzero dispersion. Some disadvantages of the scheme are increased operations complexity due to the need for nine new quadrupole families, increased beam emittance (by 14.5% is one sextant is modified), and reduced dynamic aperture. However, the dynamic aperture is still about as large as the physical aperture and should be adequate for good beam lifetime and injection. (orig.)

  17. e sup + e sup - Factories: PEP-II, KEKB, DAPHINE

    CERN Document Server

    Guiducci, S

    2001-01-01

    In 1999 two B-factories, PEP-II and KEK, and a PHI-factory, DAPHINE, started their physics experiments. A status report of the three factories is presented. A description of the interaction regions, strongly influenced by the detector requirements, and of the machine background in the detectors is presented.

  18. Transverse instability excited by rf deflecting modes for PEP

    International Nuclear Information System (INIS)

    Chao, A.W.; Yao, C.Y.

    1979-11-01

    We have looked at the possible transverse instability effects which are caused by the deflecting modes of the rf cavities in PEP. The results are obtained by applying the expression of the instability damping rate. We have assumed that there equal bunches equally spaced in PEP. We have worked out the equivalent for a single bunch beam. The effect of chromaticity ξ is included as a frequency shift in the bunch mode spectra. We rewrite this result in terms of the transverse wake field instead of the impedance. We include an application of the Sacherer formalism to the case of resistive wall. The resulting expression of the damping rate contains two terms. The first term corresponds to the effect of the short wake fields; it agrees with the result of the head-tail instability as derived by Sands. A numerical estimate of this resistive-wall head tail case for PEP is given. It re-confirms that the resistive wall instability is not a serious problem for PEP. The second term gives the effect of long wake fields and it agrees with the result of Courant and Sessler. 10 refs., 2 figs

  19. Preliminary design considerations for the stage 1 PEP lattice

    International Nuclear Information System (INIS)

    Helm, R.H.; Lee, M.J.

    1974-07-01

    A general description of the proposed PEP e + e - storage ring is discussed in the paper. We discuss the lattice and its operating characteristics in more detail, show how the design luminosity operative regions may be met and outline the limits of the operative regions of the beam parameters in several modes of operation. 18 refs., 16 figs., 1 tab

  20. Topology in quantum states. PEPS formalism and beyond

    Energy Technology Data Exchange (ETDEWEB)

    Aguado, M [Max-Planck-Institut fuer Quantenoptik. Hans-Kopfermann-Str. 1. D-85748 Garching (Germany); Cirac, J I [Max-Planck-Institut fuer Quantenoptik. Hans-Kopfermann-Str. 1. D-85748 Garching (Germany); Vidal, G [School of Physical Sciences. University of Queensland, Brisbane, QLD, 4072 (Australia)

    2007-11-15

    Topology has been proposed as a tool to protect quantum information encoding and processes. Work concerning the meaning of topology in quantum states as well as its characterisation in the projected entangled pair state (PEPS) formalism and related schemes is reviewed.

  1. Interleukin-1β inhibits insulin signaling and prevents insulin-stimulated system A amino acid transport in primary human trophoblasts.

    Science.gov (United States)

    Aye, Irving L M H; Jansson, Thomas; Powell, Theresa L

    2013-12-05

    Interleukin-1β (IL-1β) promotes insulin resistance in tissues such as liver and skeletal muscle; however the influence of IL-1β on placental insulin signaling is unknown. We recently reported increased IL-1β protein expression in placentas of obese mothers, which could contribute to insulin resistance. In this study, we tested the hypothesis that IL-1β inhibits insulin signaling and prevents insulin-stimulated amino acid transport in cultured primary human trophoblast (PHT) cells. Cultured trophoblasts isolated from term placentas were treated with physiological concentrations of IL-1β (10pg/ml) for 24h. IL-1β increased the phosphorylation of insulin receptor substrate-1 (IRS-1) at Ser307 (inhibitory) and decreased total IRS-1 protein abundance but did not affect insulin receptor β expression. Furthermore, IL-1β inhibited insulin-stimulated phosphorylation of IRS-1 (Tyr612, activation site) and Akt (Thr308) and prevented insulin-stimulated increase in PI3K/p85 and Grb2 protein expression. IL-1β alone stimulated cRaf (Ser338), MEK (Ser221) and Erk1/2 (Thr202/Tyr204) phosphorylation. The inflammatory pathways nuclear factor kappa B and c-Jun N-terminal kinase, which are involved in insulin resistance, were also activated by IL-1β treatment. Moreover, IL-1β inhibited insulin-stimulated System A, but not System L amino acid uptake, indicating functional impairment of insulin signaling. In conclusion, IL-1β inhibited the insulin signaling pathway by inhibiting IRS-1 signaling and prevented insulin-stimulated System A transport, thereby promoting insulin resistance in cultured PHT cells. These findings indicate that conditions which lead to increased systemic maternal or placental IL-1β levels may attenuate the effects of maternal insulin on placental function and consequently fetal growth. Published by Elsevier Ireland Ltd.

  2. PEP Integrated Test D Run Report Caustic and Oxidative Leaching in UFP-VSL-T02A

    Energy Technology Data Exchange (ETDEWEB)

    Sevigny, Gary J.; Bredt, Ofelia P.; Burns, Carolyn A.; Kurath, Dean E.; Geeting, John GH; Golovich, Elizabeth C.; Guzman-Leong, Consuelo E.; Josephson, Gary B.

    2009-12-11

    Pacific Northwest National Laboratory (PNNL) has been tasked by Bechtel National Inc. (BNI) on the River Protection Project-Hanford Tank Waste Treatment and Immobilization Plant (RPP-WTP) project to perform research and development activities to resolve technical issues identified for the Pretreatment Facility (PTF). The Pretreatment Engineering Platform (PEP) was designed, constructed and operated as part of a plan to respond to issue M12, "Undemonstrated Leaching Processes" of the External Flowsheet Review Team (EFRT) issue response plan. The PEP is a 1/4.5-scale test platform designed to simulate the WTP pretreatment caustic leaching, oxidative leaching, ultrafiltration solids concentration, and slurry washing processes. The PEP replicates the WTP leaching processes using prototypic equipment and control strategies. The PEP also includes non-prototypic ancillary equipment to support the core processing. Two operating scenarios are currently being evaluated for the ultrafiltration process (UFP) and leaching operations. The first scenario (Test B and D) has caustic leaching performed in the UFP-2 ultrafiltration feed vessels (i.e., vessel UFP-VSL-T02A in the PEP and vessels UFP-VSL-00002A and B in the WTP PTF). The second scenario (Test A) has caustic leaching conducted in the UFP-1 ultrafiltration feed preparation vessels (i.e., vessels UFP-VSL-T01A and B in the PEP and vessels UFP VSL-00001A and B in the WTP PTF). In Test D, 19M sodium hydroxide (NaOH, caustic) was added to the waste slurry in the UFP VSL T02 vessel after the solids were concentrated to ~20% undissolved solids. The NaOH was added to leach solid aluminum compounds (e.g., gibbsite, boehmite). Caustic addition is followed by heating to 85°C using direct injection of steam to accelerate the leach process. The main difference of Test D compared to Test B is that the leach temperature is 85°C for 24 hrs as compared to 100°C for 12 hours. The other difference is the Test D simulant had Cr in the

  3. Magnesium prevents vascular calcification in vitro by inhibition of hydroxyapatite crystal formation.

    NARCIS (Netherlands)

    Braake, A.D. ter; Tinnemans, P.T.; Shanahan, C.M.; Hoenderop, J.G.J.; Baaij, J.H.F. de

    2018-01-01

    Magnesium has been shown to effectively prevent vascular calcification associated with chronic kidney disease. Magnesium has been hypothesized to prevent the upregulation of osteoblastic genes that potentially drives calcification. However, extracellular effects of magnesium on hydroxyapatite

  4. Progress of the PEP-II B-factory

    International Nuclear Information System (INIS)

    Seeman, J.; Browne, M.; Cai, Y.; Colocho, W.; Decker, F.-J.; Donald, M.; Ecklund, S.; Erickson, R.; Fisher, A.; Fox, J.; Heifets, S.; Iverson, R.; Kozanecki, W.; Krejcik, P.; Kulikov, A.; Novokhatski, A.; Schuh, P.; Schwarz, H.; Stanek, M.; Sullivan, M.; Teytelman, D.; Turner, J.; Wienands, U.; Yan, Y.; Yocky, J.; Biagini, M.; Zisman, M.

    2003-01-01

    PEP-II is an e + e - B-Factory Collider located at SLAC operating at the Upsilon 4S resonance. PEP-II has delivered, over the past five years, an integrated luminosity to the BaBar detector of over 139 fb -1 and has reached a luminosity of 6.58 x 10 36 /cm 2 /s. Steady progress is being made in reaching higher luminosity. The goal over the next several years is to reach a luminosity of at least 2 x 10 34 /cm 2 /s. The accelerator physics issues being addressed in PEP-II to reach this goal include the electron cloud instability, beam-beam effects, parasitic beam-beam effects, high RF beam loading, shorter bunches, lower beta y*, interaction region operation, and coupling control. A view of the PEP-II tunnel is shown in Figure 1. The present parameters of the PEP-II B-Factory are shown in Table 1 compared to the design. The present peak luminosity is 219% of design and the best integrated luminosity per month is 7.4 fb -1 that is 225% of design. The best luminosity per month is shown in Figure 2. The integrated luminosity over a month is shown in Figure 3 and the total integrated luminosity in shown in Figure 4. The progress in luminosity has come from correcting the orbits, adding specific orbit bumps to correct coupling and dispersion issues, lowering the beta y* in the LER, and moving the fractional horizontal tunes in both rings to just above the half integer (<0.52)

  5. The PEP [positron-electron-proton] electron-positron ring: PEP Stage I

    International Nuclear Information System (INIS)

    Rees, J.R.

    1974-01-01

    The first stage of the positron-electron-proton (PEP) colliding-beam system which has been under joint study by a Lawrence Berkeley Laboratory-Stanford Linear Accelerator Center team for the past two years, will be the electron-positron storage ring. The physics justification for the e/sup /plus//e/sup /minus// ring is summarized briefly and the proposed facility is described. The ring will have six arcs having gross radii of about 220 m and six interaction regions located at the centers of straight sections about 130 m long. The longitudinal distance left free for experimental apparatus around the interaction regions will be 20 m. The range of operating beam energies will be from 5 GeV to 15 GeV. The design luminosity at 15 GeV will be 10 32 cm/sup /minus/2/s/sup/minus/1/, and the luminosity will vary approximately as the square of the beam energy. Alternative methods under consideration for adjusting the beam cross-section are discussed. The designs of the storage ring subsystems and of the conventional facilities including the experimental halls at the interaction regions are described. 7 refs., 8 figs., 3 tabs

  6. Isolation and characterization of PEP3, a gene required for vacuolar biogenesis in Saccharomyces cerevisiae.

    OpenAIRE

    Preston, R A; Manolson, M F; Becherer, K; Weidenhammer, E; Kirkpatrick, D; Wright, R; Jones, E W

    1991-01-01

    The Saccharomyces cerevisiae PEP3 gene was cloned from a wild-type genomic library by complementation of the carboxypeptidase Y deficiency in a pep3-12 strain. Subclone complementation results localized the PEP3 gene to a 3.8-kb DNA fragment. The DNA sequence of the fragment was determined; a 2,754-bp open reading frame predicts that the PEP3 gene product is a hydrophilic, 107-kDa protein that has no significant similarity to any known protein. The PEP3 predicted protein has a zinc finger (CX...

  7. Beam Aborts in PEP-II Rings and Lingering Drift Chamber Currents

    International Nuclear Information System (INIS)

    Meshkat, N.

    2004-01-01

    The BABAR detector at SLAC was designed to study CP-violation in B-meson decays from electron-positron collisions in the PEP-II electron-positron storage rings. Background radiation in the High Energy Ring (HER) and Low Energy Ring (LER) of PEP-II has the potential to damage the sensitive equipment in the BABAR detector. As a result, the beams in the HER and LER can be aborted to prevent such damage. In the span of a few microseconds, the HER and LER currents drop from, for example, 1450 micro Amps and 2300 micro Amps, respectively, to zero. At this time the voltage in the Drift Chamber is rapidly ramped down from a potential of 1930 V to a safe potential of 800 V, thus we would expect the currents in the Drift Chamber to quickly go to zero once the beams are aborted. However, we observe an average 15 second delay in the measured time it takes for all current in the Drift Chamber to fall below 1 micro Amp. This delay has been hypothesized as an instrumentation issue and not as a physical phenomenon. The specific sources of this error are still not completely known, but analysis suggests that it results from the interplay of the CAEN High Voltage supplies and the EPICS system and/or limitations within those systems

  8. Hydrogen sulphide-releasing diclofenac derivatives inhibit breast cancer-induced osteoclastogenesis in vitro and prevent osteolysis ex vivo.

    Science.gov (United States)

    Frantzias, J; Logan, J G; Mollat, P; Sparatore, A; Del Soldato, P; Ralston, S H; Idris, A I

    2012-03-01

    Hydrogen sulphide (H(2)S) and prostaglandins are both involved in inflammation, cancer and bone turnover, and non-steroidal anti-inflammatory drugs (NSAIDs) and H(2)S donors exhibit anti-inflammatory and anti-tumour properties. H(2)S-releasing diclofenac (S-DCF) derivatives are a novel class of NSAIDs combining the properties of a H(2)S donor with those of a conventional NSAID. We studied the effects of the S-DCF derivatives ACS15 and ACS32 on osteoclast and osteoblast differentiation and activity in vitro, human and mouse breast cancer cells support for osteoclast formation and signalling in vitro, and osteolysis ex vivo. The S-diclofenac derivatives ACS15 and ACS32 inhibited the increase in osteoclast formation induced by human MDA-MB-231 and MCF-7 and mouse 4T1 breast cancer cells without affecting breast cancer cell viability. Conditioned media from human MDA-MB-231 cells enhanced IκB phosphorylation and osteoclast formation and these effects were significantly inhibited following treatment by ACS15 and ACS32, whereas the parent compound diclofenac had no effects. ACS15 and ACS32 inhibited receptor activator of NFκB ligand-induced osteoclast formation and resorption, and caused caspase-3 activation and apoptosis in mature osteoclasts via a mechanism dependent on IKK/NFκB inhibition. In calvaria organ culture, human MDA-MB-231 cells caused osteolysis, and this effect was completely prevented following treatment with ACS15 and ACS32. S-diclofenac derivatives inhibit osteoclast formation and activity, suppress breast cancer cell support for osteoclastogenesis and prevent osteolysis. This suggests that H(2)S-releasing diclofenac derivatives exhibit anti-resorptive properties, which might be of clinical value in the treatment of osteolytic bone disease. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

  9. Soluble FGFR4 extracellular domain inhibits FGF19-induced activation of FGFR4 signaling and prevents nonalcoholic fatty liver disease

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Qiang [State Key Laboratory of Stress Cell Biology, School of Life Sciences, Xiamen University, Xiamen (China); The First Affiliated Hospital of Xiamen University, Xiamen (China); Jiang, Yuan; An, Yuan; Zhao, Na; Zhao, Yang [State Key Laboratory of Stress Cell Biology, School of Life Sciences, Xiamen University, Xiamen (China); Yu, Chundong, E-mail: cdyu@xmu.edu.cn [State Key Laboratory of Stress Cell Biology, School of Life Sciences, Xiamen University, Xiamen (China)

    2011-06-17

    Highlights: {yields} Soluble FGFR4 extracellular domain (FGFR4-ECD) was effectively expressed. {yields} FGFR4-ECD inhibited FGF19-induced activation of FGFR4 signaling. {yields} FGFR4-ECD reduced palmitic acid-induced steatosis of HepG2 cells. {yields} FGFR4-ECD reduced tetracycline-induced fatty liver in mice. {yields} FGFR4-ECD partially restored tetracycline-repressed PPAR{alpha} expression. -- Abstract: Fibroblast growth factor receptor 4 (FGFR4) is a transmembrane tyrosine kinase receptor that plays a crucial role in the regulation of hepatic bile acid and lipid metabolism. FGFR4 underlies high-fat diet-induced hepatic steatosis, suggesting that inhibition of FGFR4 activation may be an effective way to prevent or treat nonalcoholic fatty liver disease (NAFLD). To determine whether neutralization of FGFR4 ligands by soluble FGFR4 extracellular domain (FGFR4-ECD) can inhibit the activation of FGFR4, we constructed FGFR4-ECD expression vector and showed that FGFR4-ECD was effectively expressed in cells and secreted into culture medium. FGFR4-ECD inhibited FGF19-induced activation of FGFR4 signaling and reduced steatosis of HepG2 induced by palmitic acid in vitro. Furthermore, in a tetracycline-induced fatty liver model, expression of FGFR4-ECD in mouse liver reduced the accumulation of hepatic lipids and partially restored the expression of peroxisome proliferator-activated receptor {alpha} (PPAR{alpha}), which promotes the mitochondrial fatty acid beta-oxidation but is repressed by tetracycline. Taken together, these results demonstrate that FGFR4-ECD can block FGFR4 signaling and prevent hepatic steatosis, highlighting the potential value of inhibition of FGFR4 signaling as a method for therapeutic intervention against NAFLD.

  10. Soluble FGFR4 extracellular domain inhibits FGF19-induced activation of FGFR4 signaling and prevents nonalcoholic fatty liver disease

    International Nuclear Information System (INIS)

    Chen, Qiang; Jiang, Yuan; An, Yuan; Zhao, Na; Zhao, Yang; Yu, Chundong

    2011-01-01

    Highlights: → Soluble FGFR4 extracellular domain (FGFR4-ECD) was effectively expressed. → FGFR4-ECD inhibited FGF19-induced activation of FGFR4 signaling. → FGFR4-ECD reduced palmitic acid-induced steatosis of HepG2 cells. → FGFR4-ECD reduced tetracycline-induced fatty liver in mice. → FGFR4-ECD partially restored tetracycline-repressed PPARα expression. -- Abstract: Fibroblast growth factor receptor 4 (FGFR4) is a transmembrane tyrosine kinase receptor that plays a crucial role in the regulation of hepatic bile acid and lipid metabolism. FGFR4 underlies high-fat diet-induced hepatic steatosis, suggesting that inhibition of FGFR4 activation may be an effective way to prevent or treat nonalcoholic fatty liver disease (NAFLD). To determine whether neutralization of FGFR4 ligands by soluble FGFR4 extracellular domain (FGFR4-ECD) can inhibit the activation of FGFR4, we constructed FGFR4-ECD expression vector and showed that FGFR4-ECD was effectively expressed in cells and secreted into culture medium. FGFR4-ECD inhibited FGF19-induced activation of FGFR4 signaling and reduced steatosis of HepG2 induced by palmitic acid in vitro. Furthermore, in a tetracycline-induced fatty liver model, expression of FGFR4-ECD in mouse liver reduced the accumulation of hepatic lipids and partially restored the expression of peroxisome proliferator-activated receptor α (PPARα), which promotes the mitochondrial fatty acid beta-oxidation but is repressed by tetracycline. Taken together, these results demonstrate that FGFR4-ECD can block FGFR4 signaling and prevent hepatic steatosis, highlighting the potential value of inhibition of FGFR4 signaling as a method for therapeutic intervention against NAFLD.

  11. Butyrate transcriptionally enhances peptide transporter PepT1 expression and activity.

    Directory of Open Access Journals (Sweden)

    Guillaume Dalmasso

    Full Text Available BACKGROUND: PepT1, an intestinal epithelial apical di/tripeptide transporter, is normally expressed in the small intestine and induced in colon during chronic inflammation. This study aimed at investigating PepT1 regulation by butyrate, a short-chain fatty acid produced by commensal bacteria and accumulated inside inflamed colonocyte. RESULTS: We found that butyrate treatment of human intestinal epithelial Caco2-BBE cells increased human PepT1 (hPepT1 promoter activity in a dose- and time-dependent manner, with maximal activity observed in cells treated with 5 mM butyrate for 24 h. Under this condition, hPepT1 promoter activity, mRNA and protein expression levels were increased as assessed by luciferase assay, real-time RT-PCR and Western blot, respectively. hPepT1 transport activity was accordingly increased by approximately 2.5-fold. Butyrate did not alter hPepT1 mRNA half-life indicating that butyrate acts at the transcriptional level. Molecular analyses revealed that Cdx2 is the most important transcription factor for butyrate-induced increase of hPepT1 expression and activity in Caco2-BBE cells. Butyrate-activated Cdx2 binding to hPepT1 promoter was confirmed by gel shift and chromatin immunoprecipitation. Moreover, Caco2-BBE cells overexpressing Cdx2 exhibited greater hPepT1 expression level than wild-type cells. Finally, treatment of mice with 5 mM butyrate added to drinking water for 24 h increased colonic PepT1 mRNA and protein expression levels, as well as enhanced PepT1 transport activity in colonic apical membranes vesicles. CONCLUSIONS: Collectively, our results demonstrate that butyrate increases PepT1 expression and activity in colonic epithelial cells, which provides a new understanding of PepT1 regulation during chronic inflammation.

  12. IKKβ inhibition prevents fat-induced beta cell dysfunction in vitro and in vivo in rodents.

    Science.gov (United States)

    Ivovic, Aleksandar; Oprescu, Andrei I; Koulajian, Khajag; Mori, Yusaku; Eversley, Judith A; Zhang, Liling; Nino-Fong, Rodolfo; Lewis, Gary F; Donath, Marc Y; Karin, Michael; Wheeler, Michael B; Ehses, Jan; Volchuk, Allen; Chan, Catherine B; Giacca, Adria

    2017-10-01

    inhibition of IKKβ also prevented fat-induced beta-cell dysfunction ex vivo ([in pmol insulin islet -1  h -1 ] control saline: 0.16 ± 0.02; control oleate: 0.10 ± 0.02; knockout oleate: 0.17 ± 0.04; p < 0.05 control saline vs. control oleate) and in vivo (DI: control saline: 3.86 ± 0.40; control oleate: 1.95 ± 0.29; knockout oleate: 2.96 ± 0.24; p < 0.01 control saline vs control oleate). Our results demonstrate a causal role for IKKβ in fat-induced beta cell dysfunction in vitro, ex vivo and in vivo.

  13. Rottlerin Inhibits ROS Formation and Prevents NFκB Activation in MCF-7 and HT-29 Cells

    Directory of Open Access Journals (Sweden)

    Emanuela Maioli

    2009-01-01

    Full Text Available Rottlerin, a polyphenol isolated from Mallotus Philippinensis, has been recently used as a selective inhibitor of PKC δ, although it can inhibit many kinases and has several biological effects. Among them, we recently found that Rottlerin inhibits the Nuclear Factor κB (NFκB, activated by either phorbol esters or H2O2. Because of the redox sensitivity of NFκB and on the basis of Rottlerin antioxidant property, we hypothesized that Rottlerin could prevent NFκB activation acting as a free radicals scavenger, as other natural polyphenols. The current study confirms the antioxidant property of Rottlerin against the 2,2-diphenyl-1-picrylhydrazyl radical (DPPH in vitro and against oxidative stress induced by H2O2 and by menadione in culture cells. We also demonstrate that Rottlerin prevents TNFα-dependent NFκB activation in MCF-7 cells and in HT-29 cells transfected with the NFκB-driven plasmid pBIIX-LUC, suggesting that Rottlerin can inhibit NFκB via several pathways and in several cell types.

  14. Hazard Analysis for the Pretreatment Engineering Platform (PEP)

    Energy Technology Data Exchange (ETDEWEB)

    Sullivan, Robin S.; Geeting, John GH; Lawrence, Wesley E.; Young, Jonathan

    2008-07-10

    The Pretreatment Engineering Platform (PEP) is designed to perform a demonstration on an engineering scale to confirm the Hanford Waste Treatment Plant Pretreatment Facility (PTF) leaching and filtration process equipment design and sludge treatment process. The system will use scaled prototypic equipment to demonstrate sludge water wash, caustic leaching, oxidative leaching, and filtration. Unit operations to be tested include pumping, solids washing, chemical reagent addition and blending, heating, cooling, leaching, filtration, and filter cleaning. In addition, the PEP will evaluate potential design changes to the ultrafiltration process system equipment to potentially enhance leaching and filtration performance as well as overall pretreatment throughput. The skid-mounted system will be installed and operated in the Processing Development Laboratory-West at Pacific Northwest National Laboratory (PNNL) in Richland, Washington.

  15. The Optical Design of the PEP-II Injection Beamlines

    CERN Document Server

    Fieguth, T

    1996-01-01

    The optical design of the PEP-II electron and positron Injection Beamlines is described. Use of the existing high power, low emittance beams available from the SLC damping rings require that pulsed extraction of 9.0 GeV electrons and 3.1 GeV positrons for injection into the PEP-II rings occur in the early sectors of the accelerator. More than 5 kilometers of new beam transport lines have been designed and are being constructed to bring these beams to their respective rings. The optical design maximizes the tolerance to errors especially to those contributing to beam size and position jitter. Secondly, the design minimizes costs by utilizing existing components or component designs and minimizing the number required. Here we discuss important attributes including choice of lattice, specification of error tolerances, including errors in construction, alignment, field errors, power supply stability, and orbit correction.

  16. Design and performance of PEP dc-power systems

    International Nuclear Information System (INIS)

    Jackson, T.

    1981-03-01

    The PEP Magnet Power Supply System represents a significant departure from previous technology with the goal of improved performance at lower cost. In nineteen of the magnet families around the ring, Chopper power supplies are used. The many choppers are powered from two 2 MW dc supplies, and control the average power to the various magnet loads by pulse-width modulation at a 2 kilohertz repetition rate. Each chopper utilizes SCR's for switching, and stores sufficient capacitive energy for turn-off on command. Most of the energy is recirculated, resulting in high-efficiency. The two kilohertz chopping rate allows a one kilohertz unity-gain bandwidth in the current-regulator loop, and this wide bandwidth, coupled with low drift components in the error-detection system, provides a high-performance system. The PEP system has also shown that the chopper system is economical compared to standard multi-pulse controlled-rectifier

  17. The PEP-II project-wide database

    International Nuclear Information System (INIS)

    Chan, A.; Calish, S.; Crane, G.; MacGregor, I.; Meyer, S.; Wong, J.

    1995-05-01

    The PEP-II Project Database is a tool for monitoring the technical and documentation aspects of this accelerator construction. It holds the PEP-II design specifications, fabrication and installation data in one integrated system. Key pieces of the database include the machine parameter list, magnet and vacuum fabrication data. CAD drawings, publications and documentation, survey and alignment data and property control. The database can be extended to contain information required for the operations phase of the accelerator and detector. Features such as viewing CAD drawing graphics from the database will be implemented in the future. This central Oracle database on a UNIX server is built using ORACLE Case tools. Users at the three collaborating laboratories (SLAC, LBL, LLNL) can access the data remotely, using various desktop computer platforms and graphical interfaces

  18. The Optical Design of the PEP-II Injection Beamlines

    Energy Technology Data Exchange (ETDEWEB)

    Fieguth, Ted

    2003-05-23

    The optical design of the PEP-II electron and positron Injection Beamlines is described. Use of the existing high power, low emittance beams available from the SLC damping rings require that pulsed extraction of 9.0 GeV electrons and 3.1 GeV positrons for injection into the PEP-II rings occur in the early sectors of the accelerator. More than 5 kilometers of new beam transport lines have been designed and are being constructed to bring these beams to their respective rings. The optical design maximizes the tolerance to errors especially to those contributing to beam size and position jitter. Secondly, the design minimizes costs by utilizing existing components or component designs and minimizing the number required. Here we discuss important attributes including choice of lattice, specification of error tolerances, including errors in construction, alignment, field errors, power supply stability, and orbit correction.

  19. Sirtuin 6 prevents matrix degradation through inhibition of the NF-κB pathway in intervertebral disc degeneration

    International Nuclear Information System (INIS)

    Kang, Liang; Hu, Jia; Weng, Yuxiong; Jia, Jie; Zhang, Yukun

    2017-01-01

    Intervertebral disc degeneration (IDD) is marked by imbalanced metabolism of the extracellular matrix (ECM) in the nucleus pulposus (NP) of intervertebral discs. This study aimed to determine whether sirtuin 6 (SIRT6), a member of the sirtuin family of nicotinamide adenine dinucleotide-dependent deacetylases, protects the NP from ECM degradation in IDD. Our study showed that expression of SIRT6 markedly decreased during IDD progression. Overexpression of wild-type SIRT6, but not a catalytically inactive mutant, prevented IL-1β-induced NP ECM degradation. SIRT6 depletion by RNA interference in NP cells caused ECM degradation. Moreover, SIRT6 physically interacted with nuclear factor-κB (NF-κB) catalytic subunit p65, transcriptional activity of which was significantly suppressed by SIRT6 overexpression. These results suggest that SIRT6 prevented NP ECM degradation in vitro via inhibiting NF-κB-dependent transcriptional activity and that this effect depended on its deacetylase activity. - Highlights: • SIRT6 expression is decreased in degenerative nucleus pulposus (NP) tissues. • SIRT6 overexpression lowers IL-1β-induced matrix degradation of NP. • SIRT6 inhibition induces matrix degradation of NP. • SIRT6 prevents matrix degradation of NP via the NF-κB signaling pathway.

  20. Sirtuin 6 prevents matrix degradation through inhibition of the NF-κB pathway in intervertebral disc degeneration

    Energy Technology Data Exchange (ETDEWEB)

    Kang, Liang [Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022 (China); Hu, Jia [Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022 (China); Weng, Yuxiong [Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022 (China); Jia, Jie [Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022 (China); Zhang, Yukun, E-mail: zhangyukuncom@126.com [Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022 (China)

    2017-03-15

    Intervertebral disc degeneration (IDD) is marked by imbalanced metabolism of the extracellular matrix (ECM) in the nucleus pulposus (NP) of intervertebral discs. This study aimed to determine whether sirtuin 6 (SIRT6), a member of the sirtuin family of nicotinamide adenine dinucleotide-dependent deacetylases, protects the NP from ECM degradation in IDD. Our study showed that expression of SIRT6 markedly decreased during IDD progression. Overexpression of wild-type SIRT6, but not a catalytically inactive mutant, prevented IL-1β-induced NP ECM degradation. SIRT6 depletion by RNA interference in NP cells caused ECM degradation. Moreover, SIRT6 physically interacted with nuclear factor-κB (NF-κB) catalytic subunit p65, transcriptional activity of which was significantly suppressed by SIRT6 overexpression. These results suggest that SIRT6 prevented NP ECM degradation in vitro via inhibiting NF-κB-dependent transcriptional activity and that this effect depended on its deacetylase activity. - Highlights: • SIRT6 expression is decreased in degenerative nucleus pulposus (NP) tissues. • SIRT6 overexpression lowers IL-1β-induced matrix degradation of NP. • SIRT6 inhibition induces matrix degradation of NP. • SIRT6 prevents matrix degradation of NP via the NF-κB signaling pathway.

  1. Inhibition of macrophage oxidative stress prevents the reduction of ABCA-1 transporter induced by advanced glycated albumin.

    Science.gov (United States)

    de Souza Pinto, Raphael; Castilho, Gabriela; Paim, Bruno Alves; Machado-Lima, Adriana; Inada, Natalia M; Nakandakare, Edna Regina; Vercesi, Aníbal Eugênio; Passarelli, Marisa

    2012-05-01

    We investigated the role of aminoguanidine and benfotiamine on the inhibition of reactive oxygen species (ROS) generation in macrophages induced by advanced glycated albumin (AGE-albumin) and its relationship with cell cholesterol homeostasis, emphasizing the expression of the ATP binding cassette transporter A-1 (ABCA-1). AGE-albumin was made by incubating fatty acid-free albumin with 10 mM glycolaldehyde. ROS production and ABCA-1 protein level were determined by flow cytometry in J774 macrophages treated along time with control (C) or AGE-albumin alone or in the presence of aminoguanidine or benfotiamine. Mitochondrial function was evaluated by oxygraphy. Compared to C-albumin, AGE-albumin increased ROS production in macrophages, which was ascribed to the activities of NADPH oxidase and of the mitochondrial system. Mitochondrial respiratory chain activity was reduced in cells incubated with AGE-albumin. ROS generation along time was associated with the reduction in macrophage ABCA-1 protein level. Aminoguanidine prevented ROS elevation and restored the ABCA-1 content in macrophages; on the other hand, benfotiamine that promoted a lesser reduction in ROS generation was not able to restore ABCA-1 levels. Inhibition of oxidative stress induced by AGE-albumin prevents disturbances in reverse cholesterol transport by curbing the reduction of ABCA-1 elicited by advanced glycation in macrophages and therefore may contribute to the prevention of atherosclerosis in diabetes mellitus.

  2. Cigarette Smoke-Induced Emphysema and Pulmonary Hypertension Can Be Prevented by Phosphodiesterase 4 and 5 Inhibition in Mice

    Science.gov (United States)

    Pichl, Alexandra; Bednorz, Mariola; Ghofrani, Hossein Ardeschir; Schermuly, Ralph Theo; Seeger, Werner; Grimminger, Friedrich; Weissmann, Norbert

    2015-01-01

    Rationale Chronic obstructive pulmonary disease (COPD) is a widespread disease, with no curative therapies available. Recent findings suggest a key role of NO and sGC-cGMP signaling for the pathogenesis of the disease. Previous data suggest a downregulation/inactivation of the cGMP producing soluble guanylate cyclase, and sGC stimulation prevented cigarette smoke-induced emphysema and pulmonary hypertension (PH) in mice. We thus aimed to investigate if the inhibition of the cGMP degrading phosphodiesterase (PDE)5 has similar effects. Results were compared to the effects of a PDE 4 inhibitor (cAMP elevating) and a combination of both. Methods C57BL6/J mice were chronically exposed to cigarette smoke and in parallel either treated with Tadalafil (PDE5 inhibitor), Piclamilast (PDE4 inhibitor) or both. Functional measurements (lung compliance, hemodynamics) and structural investigations (alveolar and vascular morphometry) as well as the heart ratio were determined after 6 months of tobacco smoke exposure. In addition, the number of alveolar macrophages in the respective lungs was counted. Results Preventive treatment with Tadalafil, Piclamilast or a combination of both almost completely prevented the development of emphysema, the increase in lung compliance, tidal volume, structural remodeling of the lung vasculature, right ventricular systolic pressure, and right ventricular hypertrophy induced by cigarette smoke exposure. Single, but not combination treatment prevented or reduced smoke-induced increase in alveolar macrophages. Conclusion Cigarette smoke-induced emphysema and PH could be prevented by inhibition of the phosphodiesterases 4 and 5 in mice. PMID:26058042

  3. Regulatory T-Cell Augmentation or Interleukin-17 Inhibition Prevents Calcineurin Inhibitor-Induced Hypertension in Mice.

    Science.gov (United States)

    Chiasson, Valorie L; Pakanati, Abhinandan R; Hernandez, Marcos; Young, Kristina J; Bounds, Kelsey R; Mitchell, Brett M

    2017-07-01

    The immunosuppressive calcineurin inhibitors cyclosporine A and tacrolimus alter T-cell subsets and can cause hypertension, vascular dysfunction, and renal toxicity. We and others have reported that cyclosporine A and tacrolimus decrease anti-inflammatory regulatory T cells and increase proinflammatory interleukin-17-producing T cells; therefore, we hypothesized that inhibition of these effects using noncellular therapies would prevent the hypertension, endothelial dysfunction, and renal glomerular injury induced by calcineurin inhibitor therapy. Daily treatment of mice with cyclosporine A or tacrolimus for 1 week significantly decreased CD4 + /FoxP3 + regulatory T cells in the spleen and lymph nodes, as well as induced hypertension, vascular injury and dysfunction, and glomerular mesangial expansion in mice. Daily cotreatment with all-trans retinoic acid reported to increase regulatory T cells and decrease interleukin-17-producing T cells, prevented all of the detrimental effects of cyclosporine A and tacrolimus. All-trans retinoic acid also increased regulatory T cells and prevented the hypertension, endothelial dysfunction, and glomerular injury in genetically modified mice that phenocopy calcineurin inhibitor-treated mice (FKBP12-Tie2 knockout). Treatment with an interleukin-17-neutralizing antibody also increased regulatory T-cell levels and prevented the hypertension, endothelial dysfunction, and glomerular injury in cyclosporine A-treated and tacrolimus-treated mice and FKBP12-Tie2 knockout mice, whereas an isotype control had no effect. Augmenting regulatory T cells and inhibiting interleukin-17 signaling using noncellular therapies prevents the cardiovascular and renal toxicity of calcineurin inhibitors in mice. © 2017 American Heart Association, Inc.

  4. RF system design for the PEP-II B Factory

    International Nuclear Information System (INIS)

    Schwarz, H.; Rimmer, R.

    1994-06-01

    The paper presents an overview of the design of the RF system for the PEP-II B Factory. An RF station consists of either two or four single-cell cavities driven by a 1.2 MW klystron through a waveguide distribution network. A variety of feedback loops stabilize the RF and its interaction with the beam. System parameters and all the relevant parameters of klystron and cavities are given

  5. Beam-beam depolarization in SPEAR and PEP

    International Nuclear Information System (INIS)

    Montague, B.W.

    1977-01-01

    In this note some approximate estimates are made of depolarization due to beam-beam forces in SPEAR and PEP, using the results of a calculation by Kondratenko. The model assumes head-on collisions between bunches of Gaussian distribution in the transverse directions; the force on the weak-beam particle is taken to be a δ-function at the interaction point. 1 ref

  6. An asymmetric B-meson factory at PEP

    International Nuclear Information System (INIS)

    Garren, A.; Chattopadhyay, S.; Chin, Y.; Oddone, P.; Zisman, M.S.; Donald, M.; Feldman, G.; Paterson, J.M.; Rees, J.

    1989-03-01

    A preliminary design for a B-factory has been made using asymmetric collisions between positrons in the PEP storage ring and electrons in a new, log-energy ring. The design utilizes small-aperture, permanent-magnet quadrupoles close to the interaction point (IP). Optimization of optical and beam parameters at the IP will be discussed, as well as the lattice design of the interaction region and of the rings. 7 refs., 3 figs., 2 tabs

  7. A first look at a polarimeter for EPIC or PEP

    International Nuclear Information System (INIS)

    Toner, W.T.

    1988-01-01

    A derivation of the resolution function is given in terms of machine parameters and detector resolution. A preliminary design is outlined for a pair spectrometer to detect high energy backscattered laser photons. A more careful examination is needed of the asymmetry as a function of resolution, of laser geometry and rates, and of problems associated with installing and using the system at PEP. 2 figs., 1 tab

  8. Status of the PEP-II asymmetric B-Factory

    International Nuclear Information System (INIS)

    Mattison, T.S.

    1994-11-01

    The PEP-II project is an e + e - storage ring complex with unequal energy beams to study CP violation in the B meson system. High luminosity requires a large number of bunches and a low value of beta at the collision point. The high beam current requires advances in vacuum chambers, damped RF cavities, and feedback systems. Machine elements inside the detector are required to achieve low beta values and magnetic separation

  9. PEP-II vacuum system pressure profile modeling using EXCEL

    International Nuclear Information System (INIS)

    Nordby, M.; Perkins, C.

    1994-06-01

    A generic, adaptable Microsoft EXCEL program to simulate molecular flow in beam line vacuum systems is introduced. Modeling using finite-element approximation of the governing differential equation is discussed, as well as error estimation and program capabilities. The ease of use and flexibility of the spreadsheet-based program is demonstrated. PEP-II vacuum system models are reviewed and compared with analytical models

  10. RF feedback simulation results for PEP-II

    International Nuclear Information System (INIS)

    Tighe, R.; Corredoura, P.

    1995-06-01

    A model of the RF feedback system for PEP-II has been developed to provide time-domain simulation and frequency-domain analysis of the complete system. The model includes the longitudinal beam dynamics, cavity fundamental resonance, feedback loops, and the nonlinear klystron operating near saturation. Transients from an ion clearing gap and a reference phase modulation from the longitudinal feedback system are also studied. Growth rates are predicted and overall system stability examined

  11. RF feedback simulation for the PEP-II B Factory

    International Nuclear Information System (INIS)

    Tighe, R.

    1994-06-01

    A model, of the beam and RF system for PEP-11 has been developed to allow both time-domain simulation and frequency-domain analysis of the complete system. The model includes the full set of feedback loops and nonlinear elements such as the beam and klystron. The model may be used to predict beam and feedback stability in the presence of nonlinearities through time-domain simulation as well as system frequency response about a given operating point

  12. Bunch-by-bunch feedback for PEP II

    International Nuclear Information System (INIS)

    Oxoby, G.; Claus, R.; Eisen, N.; Fox, J.; Hindi, H.; Hoeflich, J.; Olsen, J.; Sapozhnikov, L.; Linscott, I.

    1993-01-01

    The proposed PEP II B factory at SLAC requires a feedback to damp out longitudinal synchrotron oscillations. A time domain, downsampled, bunch-by-bunch feedback system in which each bunch is treated as an oscillator being driven by disturbances from other bunches is presented as we review the evolution of the system design. Results from a synchrotron oscillation damping experiment conducted at the SLAC/SSRL/SPEAR ring are also presented in this paper

  13. Inhibition of leukocyte-type 12-lipoxygenase by guava tea leaves prevents development of atherosclerosis.

    Science.gov (United States)

    Takahashi, Yoshitaka; Otsuki, Akemi; Mori, Yoshiko; Kawakami, Yuki; Ito, Hideyuki

    2015-11-01

    Oxidation of low-density lipoprotein (LDL) is one of the crucial steps for atherosclerosis development, and an essential role of leukocyte-type 12-lipoxygenase expressed in macrophages in this process has been demonstrated. The biochemical mechanism of the oxidation of circulating LDL by leukocyte-type 12-lipoxygenase in macrophages has been proposed. The major ingredients in guava tea leaves which inhibited the catalytic activity of leukocyte-type 12-lipoxygenase were quercetin and ethyl gallate. Administration of extracts from guava tea leaves to apoE-deficient mice significantly attenuated atherogenic lesions in the aorta and aortic sinus. We recently showed that Qing Shan Lu Shui inhibited the catalytic activity of leukocyte-type 12-lipoxygenase. The major components inhibiting the enzyme contained in Qing Shan Lu Shui were identified to be novel monoterpene glycosides. The anti-atherogenic effect of the tea leaves might be attributed to the inhibition of leukocyte-type 12-lipoxygenase by these components. Copyright © 2015 Elsevier Ltd. All rights reserved.

  14. Prevention of secretory diarrhea by ethanol extract of Bistortae rhizoma through inhibition of chloride channel

    Directory of Open Access Journals (Sweden)

    Bo Yu

    2015-08-01

    Full Text Available Inhibition of cystic fibrosis transmembrane conductance regulator (CFTR and Ca2+-activated Cl- channel (CaCC represents an attractive approach for the treatment of secretory diarrhea. The aim of the study is to investigate the molecular basis of the anti-diarrheal effect of traditional Chinese herbal anti-diarrheal medicine Bistortae rhizoma. Fluorescence quenching assay indicated that the 40% methanol /water fraction (D5 dose-dependently inhibited both CFTR and CaCC function in transfected Fischer rat thyroid (FRT cells. Ex vivo studies indicated that D5 inhibited both forskolin (FSK-activated CFTR current and CCh-induced CaCC current in rat colonic mucosa. In the mouse closed-loop model, intraluminal application of D5 (200 µg/mL significantly reduced cholera toxin-stimulated fluid secretion. In the intestinal motility model, D5 significantly delayed intestinal peristalsis in mice. Our research suggests that CFTR and CaCC-mediated intestinal epithelial Cl- secretion inhibiting and gastrointestinal motility delaying may account for the anti-diarrheal activity of B. rhizoma.

  15. Aldose reductase inhibition prevents allergic airway remodeling through PI3K/AKT/GSK3β pathway in mice.

    Directory of Open Access Journals (Sweden)

    Umesh C S Yadav

    Full Text Available Long-term and unresolved airway inflammation and airway remodeling, characteristic features of chronic asthma, if not treated could lead to permanent structural changes in the airways. Aldose reductase (AR, an aldo-sugar and lipid aldehyde metabolizing enzyme, mediates allergen-induced airway inflammation in mice, but its role in the airway remodeling is not known. In the present study, we have examined the role of AR on airway remodeling using ovalbumin (OVA-induced chronic asthma mouse model and cultured human primary airway epithelial cells (SAECs and mouse lung fibroblasts (mLFs.Airway remodeling in chronic asthma model was established in mice sensitized and challenged twice a week with OVA for 6 weeks. AR inhibitor, fidarestat, was administered orally in drinking water after first challenge. Inflammatory cells infiltration in the lungs and goblet cell metaplasia, airway thickening, collagen deposition and airway hyper-responsiveness (AHR in response to increasing doses of methacholine were assessed. The TGFβ1-induced epithelial-mesenchymal transition (EMT in SAECs and changes in mLFs were examined to investigate AR-mediated molecular mechanism(s of airway remodeling.In the OVA-exposed mice for 6 wks inflammatory cells infiltration, levels of inflammatory cytokines and chemokines, goblet cell metaplasia, collagen deposition and AHR were significantly decreased by treatment with AR inhibitor, fidarestat. Further, inhibition of AR prevented TGFβ1-induced altered expression of E-cadherin, Vimentin, Occludin, and MMP-2 in SAECs, and alpha-smooth muscle actin and fibronectin in mLFs. Further, in SAECs, AR inhibition prevented TGFβ1- induced activation of PI3K/AKT/GSK3β pathway but not the phosphorylation of Smad2/3.Our results demonstrate that allergen-induced airway remodeling is mediated by AR and its inhibition blocks the progression of remodeling via inhibiting TGFβ1-induced Smad-independent and PI3K/AKT/GSK3β-dependent pathway.

  16. Nicorandil prevents right ventricular remodeling by inhibiting apoptosis and lowering pressure overload in rats with pulmonary arterial hypertension.

    Directory of Open Access Journals (Sweden)

    Xiang-Rong Zuo

    Full Text Available BACKGROUND: Most of the deaths among patients with severe pulmonary arterial hypertension (PAH are caused by progressive right ventricular (RV pathological remodeling, dysfunction, and failure. Nicorandil can inhibit the development of PAH by reducing pulmonary artery pressure and RV hypertrophy. However, whether nicorandil can inhibit apoptosis in RV cardiomyocytes and prevent RV remodeling has been unclear. METHODOLOGY/PRINCIPAL FINDINGS: RV remodeling was induced in rats by intraperitoneal injection of monocrotaline (MCT. RV systolic pressure (RVSP was measured at the end of each week after MCT injection. Blood samples were drawn for brain natriuretic peptide (BNP ELISA analysis. The hearts were excised for histopathological, ultrastructural, immunohistochemical, and Western blotting analyses. The MCT-injected rats exhibited greater mortality and less weight gain and showed significantly increased RVSP and RV hypertrophy during the second week. These worsened during the third week. MCT injection for three weeks caused pathological RV remodeling, characterized by hypertrophy, fibrosis, dysfunction, and RV mitochondrial impairment, as indicated by increased levels of apoptosis. Nicorandil improved survival, weight gain, and RV function, ameliorated RV pressure overload, and prevented maladaptive RV remodeling in PAH rats. Nicorandil also reduced the number of apoptotic cardiomyocytes, with a concomitant increase in Bcl-2/Bax ratio. 5-hydroxydecanoate (5-HD reversed these beneficial effects of nicorandil in MCT-injected rats. CONCLUSIONS/SIGNIFICANCE: Nicorandil inhibits PAH-induced RV remodeling in rats not only by reducing RV pressure overload but also by inhibiting apoptosis in cardiomyocytes through the activation of mitochondrial ATP-sensitive K(+ (mitoK(ATP channels. The use of a mitoK(ATP channel opener such as nicorandil for PAH-associated RV remodeling and dysfunction may represent a new therapeutic strategy for the amelioration of RV

  17. Fluoxetine Prevents Oligodendrocyte Cell Death by Inhibiting Microglia Activation after Spinal Cord Injury

    Science.gov (United States)

    Lee, Jee Y.; Kang, So R.

    2015-01-01

    Abstract Oligodendrocyte cell death and axon demyelination after spinal cord injury (SCI) are known to be important secondary injuries contributing to permanent neurological disability. Thus, blocking oligodendrocyte cell death should be considered for therapeutic intervention after SCI. Here, we demonstrated that fluoxetine, an antidepressant drug, alleviates oligodendrocyte cell death by inhibiting microglia activation after SCI. After injury at the T9 level with a Precision Systems and Instrumentation (Lexington, KY) device, fluoxetine (10 mg/kg, intraperitoneal) was administered once a day for the indicated time points. Immunostaining with CD11b (OX-42) antibody and quantification analysis showed that microglia activation was significantly inhibited by fluoxetine at 5 days after injury. Fluoxetine also significantly inhibited activation of p38 mitogen-activated protein kinase (p38-MAPK) and expression of pro-nerve growth factor (pro-NGF), which is known to mediate oligodendrocyte cell death through the p75 neurotrophin receptor after SCI. In addition, fluoxetine attenuated activation of Ras homolog gene family member A and decreased the level of phosphorylated c-Jun and, ultimately, alleviated caspase-3 activation and significantly reduced cell death of oligodendrocytes at 5 days after SCI. Further, the decrease of myelin basic protein, myelin loss, and axon loss in white matter was also significantly blocked by fluoxetine, as compared to vehicle control. These results suggest that fluoxetine inhibits oligodendrocyte cell death by inhibiting microglia activation and p38-MAPK activation, followed by pro-NGF production after SCI, and provide a potential usage of fluoxetine for a therapeutic agent after acute SCI in humans. PMID:25366938

  18. Ebselen inhibits hepatitis C virus NS3 helicase binding to nucleic acid and prevents viral replication.

    Science.gov (United States)

    Mukherjee, Sourav; Weiner, Warren S; Schroeder, Chad E; Simpson, Denise S; Hanson, Alicia M; Sweeney, Noreena L; Marvin, Rachel K; Ndjomou, Jean; Kolli, Rajesh; Isailovic, Dragan; Schoenen, Frank J; Frick, David N

    2014-10-17

    The hepatitis C virus (HCV) nonstructural protein 3 (NS3) is both a protease, which cleaves viral and host proteins, and a helicase that separates nucleic acid strands, using ATP hydrolysis to fuel the reaction. Many antiviral drugs, and compounds in clinical trials, target the NS3 protease, but few helicase inhibitors that function as antivirals have been reported. This study focuses on the analysis of the mechanism by which ebselen (2-phenyl-1,2-benzisoselenazol-3-one), a compound previously shown to be a HCV antiviral agent, inhibits the NS3 helicase. Ebselen inhibited the abilities of NS3 to unwind nucleic acids, to bind nucleic acids, and to hydrolyze ATP, and about 1 μM ebselen was sufficient to inhibit each of these activities by 50%. However, ebselen had no effect on the activity of the NS3 protease, even at 100 times higher ebselen concentrations. At concentrations below 10 μM, the ability of ebselen to inhibit HCV helicase was reversible, but prolonged incubation of HCV helicase with higher ebselen concentrations led to irreversible inhibition and the formation of covalent adducts between ebselen and all 14 cysteines present in HCV helicase. Ebselen analogues with sulfur replacing the selenium were just as potent HCV helicase inhibitors as ebselen, but the length of the linker between the phenyl and benzisoselenazol rings was critical. Modifications of the phenyl ring also affected compound potency over 30-fold, and ebselen was a far more potent helicase inhibitor than other, structurally unrelated, thiol-modifying agents. Ebselen analogues were also more effective antiviral agents, and they were less toxic to hepatocytes than ebselen. Although the above structure-activity relationship studies suggest that ebselen targets a specific site on NS3, we were unable to confirm binding to either the NS3 ATP binding site or nucleic acid binding cleft by examining the effects of ebselen on NS3 proteins lacking key cysteines.

  19. Luminosity upgrade possibilities for the PEP-II B-Factory

    CERN Document Server

    Sullivan, M

    2003-01-01

    PEP-II is an asymmetric e sup + e sup - collider being constructed in the SLAC PEP tunnel by SLAC, LBNL, and LLNL. The two beams have energies of 3.1 GeV and 9.0 GeV and are made to collide at a single interaction point. PEP-II has a 2200 m circumference. The nominal parameters for PEP-II are listed in Table 1. The High Energy Ring (HER) of PEP-II started commissioning in 1997. The Low Energy Ring (LER) will be commissioned in the summer of 1998. The BaBar detector is to be installed starting January 1999. Studies for increasing the luminosity in PEP-II beyond the design are underway. A brief summary of the possibilities are presented here. Improvements to the integrated luminosity will be implemented gradually. Major luminosity improvements will likely come in two phased upgrades. Several of these possibilities are summarized in Table 1.

  20. LUMINOSITY UPGRADE POSSIBILITIES FOR THE PEP-II B-FACTORY

    International Nuclear Information System (INIS)

    Sullivan, Michael K

    2003-01-01

    PEP-II is an asymmetric e + e - collider being constructed in the SLAC PEP tunnel by SLAC, LBNL, and LLNL. The two beams have energies of 3.1 GeV and 9.0 GeV and are made to collide at a single interaction point. PEP-II has a 2200 m circumference. The nominal parameters for PEP-II are listed in Table 1. The High Energy Ring (HER) of PEP-II started commissioning in 1997. The Low Energy Ring (LER) will be commissioned in the summer of 1998. The BaBar detector is to be installed starting January 1999. Studies for increasing the luminosity in PEP-II beyond the design are underway. A brief summary of the possibilities are presented here. Improvements to the integrated luminosity will be implemented gradually. Major luminosity improvements will likely come in two phased upgrades. Several of these possibilities are summarized in Table 1

  1. Curcumin prevents the oxidation and lipid modification of LDL and its inhibition of prostacyclin generation by endothelial cells in culture.

    Science.gov (United States)

    Mahfouz, Mohamedain M; Zhou, Sherry Q; Kummerow, Fred A

    2009-11-01

    Low-density lipoprotein (LDL) was isolated from human plasma and oxidized by 5microM copper sulfate for 4h at 37 degrees C in the absence and presence of 1, 3, 5, 10, or 20microM of curcumin. LDL oxidized in the absence of curcumin (oxLDL) showed an increased levels of conjugated dienes, lipid peroxides (TBARS) and lysolecithin (lysoPC) and a significant loss of polyunsaturated fatty acids (PUFA). LDL oxidized with 5microM copper sulfate in the presence of curcumin caused a significant decrease of conjugated diene, lipid peroxides, lysoPC and significant increase of PUFA compared to oxLDL. These changes were dose dependent and reached a maximum at 5microM curcumin. Incubation of human endothelial cells (EC) with 200microg protein/ml of oxLDL caused a significant decrease of prostacyclin (PGI(2)) generation. LDL oxidized in presence of 5microM curcumin did not show any inhibition of PGI(2) generation compared to the control cells. These results indicate that curcumin is an effective chain-breaking antioxidant which prevents oxidation and lipid modification of LDL. The inhibition of oxLDL on PGI(2) is considered a contributing factor in the pathogenesis of thrombosis and atherosclerosis. Curcumin supplementation could be an effective strategy in preventing LDL oxidation and its impact on atherosclerosis and lesion formation.

  2. Inhibition of WNT signaling in the bone marrow niche prevents the development of MDS in the Apcdel/+ MDS mouse model.

    Science.gov (United States)

    Stoddart, Angela; Wang, Jianghong; Hu, Chunmei; Fernald, Anthony A; Davis, Elizabeth M; Cheng, Jason X; Le Beau, Michelle M

    2017-06-01

    There is accumulating evidence that functional alteration(s) of the bone marrow (BM) microenvironment contribute to the development of some myeloid disorders, such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). In addition to a cell-intrinsic role of WNT activation in leukemia stem cells, WNT activation in the BM niche is also thought to contribute to the pathogenesis of MDS and AML. We previously showed that the Apc -haploinsufficient mice ( Apc del/+ ) model MDS induced by an aberrant BM microenvironment. We sought to determine whether Apc, a multifunctional protein and key negative regulator of the canonical β-catenin (Ctnnb1)/WNT-signaling pathway, mediates this disease through modulating WNT signaling, and whether inhibition of WNT signaling prevents the development of MDS in Apc del/+ mice. Here, we demonstrate that loss of 1 copy of Ctnnb1 is sufficient to prevent the development of MDS in Apc del/+ mice and that altered canonical WNT signaling in the microenvironment is responsible for the disease. Furthermore, the US Food and Drug Administration (FDA)-approved drug pyrvinium delays and/or inhibits disease in Apc del /+ mice, even when it is administered after the presentation of anemia. Other groups have observed increased nuclear CTNNB1 in stromal cells from a high frequency of MDS/AML patients, a finding that together with our results highlights a potential new strategy for treating some myeloid disorders. © 2017 by The American Society of Hematology.

  3. Inhibition of Klebsiella pneumoniae growth by selected Australian plants: natural approaches for the prevention and management of ankylosing spondylitis.

    Science.gov (United States)

    Winnett, V; Sirdaarta, J; White, A; Clarke, F M; Cock, I E

    2017-04-01

    A wide variety of herbal remedies are used in traditional Australian medicine to treat inflammatory disorders, including autoimmune inflammatory diseases. One hundred and six extracts from 40 native Australian plant species traditionally used for the treatment of inflammation and/or to inhibit bacterial growth were investigated for their ability to inhibit the growth of a microbial trigger for ankylosing spondylitis (K. pneumoniae). Eighty-six of the extracts (81.1%) inhibited the growth of K. pneumoniae. The D. leichardtii, Eucalyptus spp., K. flavescens, Leptospermum spp., M. quinquenervia, Petalostigma spp., P. angustifolium, S. spinescens, S. australe, S. forte and Tasmannia spp. extracts were effective K. pneumoniae growth inhibitors, with MIC values generally <1000 µg/mL. The T. lanceolata peppercorn extracts were the most potent growth inhibitors, with MIC values as low as 16 µg/mL. These extracts were examined by non-biased GC-MS headspace analysis and comparison with a compound database. A notable feature was the high relative abundance of the sesquiterpenoids polygodial, guaiol and caryophyllene oxide, and the monoterpenoids linalool, cineole and α-terpineol in the T. lanceolata peppercorn methanolic and aqueous extracts. The extracts with the most potent K. pneumoniae inhibitory activity (including the T. lanceolata peppercorn extracts) were nontoxic in the Artemia nauplii bioassay. The lack of toxicity and the growth inhibitory activity of these extracts against K. pneumoniae indicate their potential for both preventing the onset of ankylosing spondylitis and minimising its symptoms once the disease is established.

  4. The biflavonoid amentoflavone inhibits neovascularization preventing the activity of proangiogenic vascular endothelial growth factors

    DEFF Research Database (Denmark)

    Tarallo, Valeria; Lepore, Laura; Marcellini, Marcella

    2011-01-01

    collections consisting of >100 plant extracts. Here, we report the isolation and identification from an extract of the Malian plant Chrozophora senegalensis of the biflavonoid amentoflavone as an antiangiogenic bioactive molecule. Amentoflavone can to bind VEGFs preventing the interaction and phosphorylation...

  5. [Lactobacillus rhamnosus GG conditioned medium prevents E. coli meningitis by inhibiting nuclear factor-κB pathway].

    Science.gov (United States)

    Zeng, Qing; He, Xiao-Long; Xiao, Han-Sheng; DU, Lei; Li, Yu-Jing; Chen, Le-Cheng; Tian, Hui-Wen; Huang, Sheng-He; Cao, Hong

    2017-01-20

    To investigate whether Lactobacillus rhamnosus GG conditioned medium(LGG-CM)has preventive effect against E. coli K1-induced neuropathogenicity in vitro by inhibiting nuclear factor-κB (NF-κB) signaling pathway. An in vitro blood-brain barrier (BBB) model was constructed using human brain microvascular endothelial cells (HBMECs). The effect of LGG-CM on E. coli-actived NF-κB signaling pathway was assayed using Western blotting. Invasion assay and polymorphonuclear leukocyte (PMN) transmigration assay were performed to explore whether LGG-CM could inhibit E. coli invasion and PMN transmigration across the BBB in vitro. The expressions of ZO-1 and CD44 were detected using Western blotting and immunofluorescence. The changes of trans-epithelial electric resistance (TEER) and bacterial translocation were determined to evaluate the BBB permeability. Pre-treament with LGG-CM inhibited E. coli-activated NF-κB signaling pathway in HBMECs and decreased the invasion of E. coli K1 and transmigration of PMN. Western blotting showed that LGG-CM could alleviate E. coli-induced up-regulation of CD44 and down-regulation of ZO-1 expressions in HBMECs. In addition, pre-treatment with LGG-CM alleviated E. coli K1-induced reduction of TEER and suppressed bacterial translocation across the BBB in vitro. LGG-CM can block E. coli-induced activation of NF-κB signaling pathway and thereby prevents E. coli K1-induced neuropathogenicity by decreasing E. coli K1 invasion rates and PMN transmigration.

  6. The Danish PEP registry: experience with the use of postexposure prophylaxis (PEP) following sexual exposure to HIV from 1998 to 2006

    DEFF Research Database (Denmark)

    Lunding, Suzanne; Katzenstein, Terese L; Kronborg, Gitte

    2010-01-01

    centers with specialists experienced in HIV treatment. The objective of this study is to describe the use of PEP after sexual exposure from 1998 to 2006. METHODS: The Danish PEP registry collects data from all cases of PEP use in Denmark after exposure to HIV through a structured questionnaire. RESULTS......: There were 374 cases of PEP use after sexual exposure. The incidence increased from 5 cases in 1997 to 87 in 2006. PEP was used by heterosexuals (40%) as well as men who have sex with men (57%). The HIV-status of the source was unknown in 41% of the cases of which 90% involved a source belonging to a high...... risk group, and 63% involved exposure by receptive anal intercourse. PEP was administered within 24 hours in 95% of the cases and the median time to initiation (N = 225) was 11.0 hours (range 0.5-60.0). PEP was completed by 65%. CONCLUSIONS: This nationwide study showed a steady but moderate increase...

  7. Inhibition of phosphatidylcholine-specific phospholipase C prevents bone marrow stromal cell senescence in vitro.

    Science.gov (United States)

    Sun, Chunhui; Wang, Nan; Huang, Jie; Xin, Jie; Peng, Fen; Ren, Yinshi; Zhang, Shangli; Miao, Junying

    2009-10-01

    Bone marrow stromal cells (BMSCs) can proliferate in vitro and can be transplanted for treating many kinds of diseases. However, BMSCs become senescent with long-term culture, which inhibits their application. To understand the mechanism underlying the senescence, we investigated the activity of phosphatidylcholine-specific phospholipase C (PC-PLC) and levels of integrin beta4, caveolin-1 and ROS with BMSC senescence. The activity of PC-PLC and levels of integrin beta4, caveolin-1 and ROS increased greatly during cell senescence. Selective inhibition of increased PC-PLC activity with D609 significantly decreased the number of senescence-associated beta galactosidase positive cells in BMSCs. Furthermore, D609 restored proliferation of BMSCs and their differentiation into adipocytes. Moreover, D609 suppressed the elevated levels of integrin beta4, caveolin-1 and ROS. The data suggest that PC-PLC is involved in senescence of BMSCs, and its function is associated with integrin beta4, caveolin-1 and ROS. (c) 2009 Wiley-Liss, Inc.

  8. Inhibition of the Rho/ROCK pathway prevents neuronal degeneration in vitro and in vivo following methylmercury exposure

    International Nuclear Information System (INIS)

    Fujimura, Masatake; Usuki, Fusako; Kawamura, Miwako; Izumo, Shuji

    2011-01-01

    Methylmercury (MeHg) is an environmental neurotoxicant which induces neuropathological changes in both the central nervous and peripheral sensory nervous systems. Our recent study demonstrated that down-regulation of Ras-related C3 botulinum toxin substrate 1 (Rac1), which is known to promote neuritic extension, preceded MeHg-induced damage in cultured cortical neurons, suggesting that MeHg-mediated axonal degeneration is due to the disturbance of neuritic extension. Therefore we hypothesized that MeHg-induced axonal degeneration might be caused by neuritic extension/retraction incoordination. This idea brought our attention to the Ras homolog gene (Rho)/Rho-associated coiled coil-forming protein kinase (ROCK) pathway because it has been known to be associated with the development of axon and apoptotic neuronal cell death. Here we show that inhibition of the Rho/ROCK pathway prevents MeHg-intoxication both in vitro and in vivo. A Rho inhibitor, C3 toxin, and 2 ROCK inhibitors, Fasudil and Y-27632, significantly protected against MeHg-induced axonal degeneration and apoptotic neuronal cell death in cultured cortical neuronal cells exposed to 100 nM MeHg for 3 days. Furthermore, Fasudil partially prevented the loss of large pale neurons in dorsal root ganglia, axonal degeneration in dorsal spinal root nerves, and vacuolar degeneration in the dorsal columns of the spinal cord in MeHg-intoxicated model rats (20 ppm MeHg in drinking water for 28 days). Hind limb crossing sign, a characteristic MeHg-intoxicated sign, was significantly suppressed in this model. The results suggest that inhibition of the Rho/ROCK pathway rescues MeHg-mediated neuritic extension/retraction incoordination and is effective for the prevention of MeHg-induced axonal degeneration and apoptotic neuronal cell death.

  9. NecroX-7 prevents oxidative stress-induced cardiomyopathy by inhibition of NADPH oxidase activity in rats

    Energy Technology Data Exchange (ETDEWEB)

    Park, Joonghoon; Park, Eok; Ahn, Bong-Hyun; Kim, Hyoung Jin [LG Life Sciences Ltd., R and D Park, Daejeon, 305-380 (Korea, Republic of); Park, Ji-hoon [Department of Biochemistry, School of Medicine, Chungnam National University, Daejeon, 301-747 (Korea, Republic of); Koo, Sun Young; Kwak, Hyo-Shin; Park, Heui Sul; Kim, Dong Wook; Song, Myoungsub; Yim, Hyeon Joo; Seo, Dong Ook [LG Life Sciences Ltd., R and D Park, Daejeon, 305-380 (Korea, Republic of); Kim, Soon Ha, E-mail: shakim@lgls.com [LG Life Sciences Ltd., R and D Park, Daejeon, 305-380 (Korea, Republic of)

    2012-08-15

    Oxidative stress is one of the causes of cardiomyopathy. In the present study, NecroXs, novel class of mitochondrial ROS/RNS scavengers, were evaluated for cardioprotection in in vitro and in vivo model, and the putative mechanism of the cardioprotection of NecroX-7 was investigated by global gene expression profiling and subsequent biochemical analysis. NecroX-7 prevented tert-butyl hydroperoxide (tBHP)-induced death of H9C2 rat cardiomyocytes at EC{sub 50} = 0.057 μM. In doxorubicin (DOX)-induced cardiomyopathy in rats, NecroX-7 significantly reduced the plasma levels of creatine kinase (CK-MB) and lactate dehydrogenase (LDH) which were increased by DOX treatment (p < 0.05). Microarray analysis revealed that 21 genes differentially expressed in tBHP-treated H9C2 cells were involved in ‘Production of reactive oxygen species’ (p = 0.022), and they were resolved by concurrent NecroX-7 treatment. Gene-to-gene networking also identified that NecroX-7 relieved cell death through Ncf1/p47phox and Rac2 modulation. In subsequent biochemical analysis, NecroX-7 inhibited NADPH oxidase (NOX) activity by 53.3% (p < 0.001). These findings demonstrate that NecroX-7, in part, provides substantial protection of cardiomyopathy induced by tBHP or DOX via NOX-mediated cell death. -- Highlights: ► NecroX-7 prevented tert-butyl hydroperoxide-induced in vitro cardiac cell death. ► NecroX-7 ameliorated doxorubicin-induced in vivo cardiomyopathy. ► NecroX-7 prevented oxidative stress and necrosis-enriched transcriptional changes. ► NecroX-7 effectively inhibited NADPH oxidase activation. ► Cardioprotection of Necro-7 was brought on by modulation of NADPH oxidase activity.

  10. Bilirubin prevents acute DSS-induced colitis by inhibiting leukocyte infiltration and suppressing upregulation of inducible nitric oxide synthase.

    Science.gov (United States)

    Zucker, Stephen D; Vogel, Megan E; Kindel, Tammy L; Smith, Darcey L H; Idelman, Gila; Avissar, Uri; Kakarlapudi, Ganesh; Masnovi, Michelle E

    2015-11-15

    Bilirubin is thought to exert anti-inflammatory effects by inhibiting vascular cell adhesion molecule-1 (VCAM-1)-dependent leukocyte migration and by suppressing the expression of inducible nitric oxide synthase (iNOS). As VCAM-1 and iNOS are important mediators of tissue injury in the dextran sodium sulfate (DSS) murine model of inflammatory colitis, we examined whether bilirubin prevents colonic injury in DSS-treated mice. Male C57BL/6 mice were administered 2.5% DSS in the drinking water for 7 days, while simultaneously receiving intraperitoneal injections of bilirubin (30 mg/kg) or potassium phosphate vehicle. Disease activity was monitored, peripheral blood counts and serum nitrate levels were determined, and intestinal specimens were analyzed for histological injury, leukocyte infiltration, and iNOS expression. The effect of bilirubin on IL-5 production by HSB-2 cells and on Jurkat cell transendothelial migration also was determined. DSS-treated mice that simultaneously received bilirubin lost less body weight, had lower serum nitrate levels, and exhibited reduced disease severity than vehicle-treated animals. Concordantly, histopathological analyses revealed that bilirubin-treated mice manifested significantly less colonic injury, including reduced infiltration of eosinophils, lymphocytes, and monocytes, and diminished iNOS expression. Bilirubin administration also was associated with decreased eosinophil and monocyte infiltration into the small intestine, with a corresponding increase in peripheral blood eosinophilia. Bilirubin prevented Jurkat migration but did not alter IL-5 production. In conclusion, bilirubin prevents DSS-induced colitis by inhibiting the migration of leukocytes across the vascular endothelium and by suppressing iNOS expression. Copyright © 2015 the American Physiological Society.

  11. Inhibition of oxygen scavengers realized by peritoneal macrophages: an adhesion prevention target?

    Directory of Open Access Journals (Sweden)

    Mynbaev OA

    2014-11-01

    Full Text Available Ospan A Mynbaev,1–4 Marina Yu Eliseeva,1,2 Oktay T Kadayifci,1,5 Tahar Benhidjeb,1,6 Michael Stark1,41The International Translational Medicine and Biomodeling Research team, MIPT center for human physiology studies, Laboratory of Cellular and Molecular Technologies, The Department of Applied Mathematics, Moscow Institute of Physics and Technology (State University, Moscow Region, Russia; 2The Department of Obstetrics, Gynecology and Reproductive Medicine, Peoples’ Friendship University of Russia, Moscow, Russia; 3Laboratory of Pilot Projects, Moscow State University of Medicine and Dentistry, Moscow, Russia; 4The New European Surgical Academy, Berlin, Germany; 5Onkim Stem Cell Technologies Inc., Istanbul, Turkey; 6Department of Surgery, Burjeel Hospital, Abu Dhabi, United Arab EmiratesOur team, general surgeons and gynecologists look constantly for ways to prevent postsurgical adhesions, and hence, we appreciate the platform you have established through multiple publications.1–3 This is especially because postsurgical adhesions may result in several complications such as the small bowel obstruction, secondary infertility, dyspareunia, chronic abdominal/pelvic pain and many others.Prevention of postsurgical adhesions is still an unsolved problem in spite of the suggested modifications of current surgical methods and application of various barriers, sprays, and use of other antiadhesive medications. We have already pointed out that a design of ideal nanoparticles should become a target of personalized adhesion prevention strategy in the future4,5 and therefore, we read with great interest the article by Shin et al that was recently published in your journal.6 This article explores the potential of postoperative adhesion prevention by nanofibers of poly(lactic-co-glycolic acid (PLGA loaded with epigallocatechin-3-O-gallate (EGCG, which is the most bioactive polyphenolic compound extracted from green tea.Read the original article by Shin and

  12. LRRK2 kinase inhibition prevents pathological microglial phagocytosis in response to HIV-1 Tat protein

    Directory of Open Access Journals (Sweden)

    Marker Daniel F

    2012-11-01

    Full Text Available Abstract Background Human Immunodeficiency Virus-1 (HIV-1 associated neurocognitive disorders (HANDs are accompanied by significant morbidity, which persists despite the use of combined antiretroviral therapy (cART. While activated microglia play a role in pathogenesis, changes in their immune effector functions, including phagocytosis and proinflammatory signaling pathways, are not well understood. We have identified leucine-rich repeat kinase 2 (LRRK2 as a novel regulator of microglial phagocytosis and activation in an in vitro model of HANDs, and hypothesize that LRRK2 kinase inhibition will attenuate microglial activation during HANDs. Methods We treated BV-2 immortalized mouse microglia cells with the HIV-1 trans activator of transcription (Tat protein in the absence or presence of LRRK2 kinase inhibitor (LRRK2i. We used Western blot, qRT-PCR, immunocytochemistry and latex bead engulfment assays to analyze LRRK2 protein levels, proinflammatory cytokine and phagocytosis receptor expression, LRRK2 cellular distribution and phagocytosis, respectively. Finally, we utilized ex vivo microfluidic chambers containing primary hippocampal neurons and BV-2 microglia cells to investigate microglial phagocytosis of neuronal axons. Results We found that Tat-treatment of BV-2 cells induced kinase activity associated phosphorylation of serine 935 on LRRK2 and caused the formation of cytoplasmic LRRK2 inclusions. LRRK2i decreased Tat-induced phosphorylation of serine 935 on LRRK2 and inhibited the formation of Tat-induced cytoplasmic LRRK2 inclusions. LRRK2i also decreased Tat-induced process extension in BV-2 cells. Furthermore, LRRK2i attenuated Tat-induced cytokine expression and latex bead engulfment. We examined relevant cellular targets in microfluidic chambers and found that Tat-treated BV-2 microglia cells cleared axonal arbor and engulfed neuronal elements, whereas saline treated controls did not. LRRK2i was found to protect axons in the presence

  13. Resveratrol inhibits myeloma cell growth, prevents osteoclast formation, and promotes osteoblast differentiation

    DEFF Research Database (Denmark)

    Boissy, Patrice; Andersen, Thomas L; Abdallah, Basem M

    2005-01-01

    , a challenge for treating multiple myeloma is discovering drugs targeting not only myeloma cells but also osteoclasts and osteoblasts. Because resveratrol (trans-3,4',5-trihydroxystilbene) is reported to display antitumor activities on a variety of human cancer cells, we investigated the effects...... of this natural compound on myeloma and bone cells. We found that resveratrol reduces dose-dependently the growth of myeloma cell lines (RPMI 8226 and OPM-2) by a mechanism involving cell apoptosis. In cultures of human primary monocytes, resveratrol inhibits dose-dependently receptor activator of nuclear factor......RNA and cell surface protein levels and a decrease of NFATc1 stimulation and NF-kappaB nuclear translocation, whereas the gene expression of c-fms, CD14, and CD11a is up-regulated. Finally, resveratrol promotes dose-dependently the expression of osteoblast markers like osteocalcin and osteopontin in human bone...

  14. Inhibition of platelet-derived growth factor signaling prevents muscle fiber growth during skeletal muscle hypertrophy.

    Science.gov (United States)

    Sugg, Kristoffer B; Korn, Michael A; Sarver, Dylan C; Markworth, James F; Mendias, Christopher L

    2017-03-01

    The platelet-derived growth factor receptors alpha and beta (PDGFRα and PDGFRβ) mark fibroadipogenic progenitor cells/fibroblasts and pericytes in skeletal muscle, respectively. While the role that these cells play in muscle growth and development has been evaluated, it was not known whether the PDGF receptors activate signaling pathways that control transcriptional and functional changes during skeletal muscle hypertrophy. To evaluate this, we inhibited PDGFR signaling in mice subjected to a synergist ablation muscle growth procedure, and performed analyses 3 and 10 days after induction of hypertrophy. The results from this study indicate that PDGF signaling is required for fiber hypertrophy, extracellular matrix production, and angiogenesis that occur during muscle growth. © 2017 Federation of European Biochemical Societies.

  15. Kalanchoe pinnata inhibits mast cell activation and prevents allergic airway disease.

    Science.gov (United States)

    Cruz, E A; Reuter, S; Martin, H; Dehzad, N; Muzitano, M F; Costa, S S; Rossi-Bergmann, B; Buhl, R; Stassen, M; Taube, C

    2012-01-15

    Aqueous extract of Kalanchoe pinnata (Kp) have been found effective in models to reduce acute anaphylactic reactions. In the present study, we investigate the effect of Kp and the flavonoid quercetin (QE) and quercitrin (QI) on mast cell activation in vitro and in a model of allergic airway disease in vivo. Treatment with Kp and QE in vitro inhibited degranulation and cytokine production of bone marrow-derived mast cells following IgE/FcɛRI crosslinking, whereas treatment with QI had no effect. Similarly, in vivo treatment with Kp and QE decreased development of airway hyperresponsiveness, airway inflammation, goblet cell metaplasia and production of IL-5, IL-13 and TNF. In contrast, treatment with QI had no effect on these parameters. These findings demonstrate that treatment with Kp or QE is effective in treatment of allergic airway disease, providing new insights to the immunomodulatory functions of this plant. Copyright © 2011 Elsevier GmbH. All rights reserved.

  16. Fabrication process for the PEP II RF cavities

    Energy Technology Data Exchange (ETDEWEB)

    Franks, R.M.; Rimmer, R.A. [Lawrence Berkeley National Lab., CA (United States); Schwarz, H. [Stanford Linear Accelerator Center, Menlo Park, CA (United States)

    1997-06-05

    This paper presents the major steps used in the fabrication of the 26 RF Cavities required for the PEP-II B-factory. Several unique applications of conventional processes have been developed and successfully implemented: electron beam welding (EBW), with minimal porosity, of .75 inch (19 mm) copper cross-sections; extensive 5-axis milling of water channels; electroplating of .37 inch (10 mm) thick OFE copper; tuning of the cavity by profiling beam noses prior to final joining with the cavity body; and machining of the cavity interior, are described here.

  17. RF feedback development for the PEP-II B Factory

    Energy Technology Data Exchange (ETDEWEB)

    Corredoura, P.; Sapozhnikov, L.; Tighe, R.

    1994-06-01

    In PEP-II heavy beam loading along with a relatively long revolution period combine to strongly drive lower coupled-bunch modes through interaction with the fundamental cavity mode. Feedback techniques can be applied to reduce the cavity impedance seen by the beam. Several RF feedback loops are planned to reduce the growth rates down to a level which can be damped by the relatively low power bunch-by-bunch longitudinal feedback system. This paper describes the RF feedback loops as well as hardware tests using a 500 kW klystron, analog and digital feedback loops, and a low power test cavity.

  18. Numerical simulation of the PEP-II beam position monitor

    Energy Technology Data Exchange (ETDEWEB)

    Kurita, N; Martin, D; Ng, C -K; Smith, S [Stanford Linear Accelerator Center, Menlo Park, CA (United States); Weiland, T

    1996-08-01

    We use MAFIA to analyze the PEP-II button-type beam position monitor (BPM). Employing proper termination of the BPM into a coaxial cable, the output signal at the BPM is determined. Thus the issues of signal sensitivity and power output can be addressed quantitatively, including all transient effects and wakefields. Besides this first quantitative analysis of a true BPM 3D structure, we find that internal resonant modes are a major source of high value narrow-band impedances. The effects of these resonances on coupled-bunch instabilities are discussed. An estimate of the power dissipation in the ceramic vacuum seal under high current operation is given. (author)

  19. Impedance of the PEP-II DIP screen

    Energy Technology Data Exchange (ETDEWEB)

    Ng, C -K [Stanford Linear Accelerator Center, Menlo Park, CA (United States); Weiland, T

    1996-08-01

    The vacuum chamber of a storage ring normally consists of periodically spaced pumping slots. The longitudinal impedance of slots are analyzed in this paper. It is found that although the broad-band impedance is tolerable, the narrow-band impedance, as a consequence of the periodicity of the slots, may exceed the stability limit given by natural damping with no feedback system on. Based on this analysis, the PEP-II distributed-ion-pump (DIP) screen uses long grooves with hidden holes cut halfway to reduce both the broad-band and narrow-band impedances. (author)

  20. A proposed orbit and vertical dispersion correction system for PEP

    International Nuclear Information System (INIS)

    Close, E.; Cornacchia, M.; King, A.S.; Lee, M.J.

    1978-07-01

    The proposed arrangement of position monitors and dipole magnets for the closed orbit correction system in PEP is described. The computer code ALIGN, which simulates and corrects closed orbit displacements, has been used to study the most effective layout of monitors and correctors. The vertical dispersion function has been computed before and after closed orbit correction. The results indicate that the residual vertical dispersion after the orbit is corrected could exceed the tolerable values. A correction procedure for the vertical dispersion has been studied with the compute code CO-OP and this scheme of correction has been verified experimentally in SPEAR. 9 refs., 8 figs., 2 tabs

  1. Numerical simulation of the PEP-II beam position monitor

    International Nuclear Information System (INIS)

    Kurita, N.; Martin, D.; Ng, C.K.; Smith, S.; Weiland, T.

    1995-09-01

    The authors use MAFIA to analyze the PEP-II button-type beam position monitor (BPM). Employing proper termination of the BPM into a coaxial cable, the output signal at the BPM is determined. Thus the issues of signal sensitivity and power output can be addressed quantitatively, including all transient effects and wakefields. Besides this first quantitative analysis of a true BPM 3D structure, they find that internal resonant modes are a major-source of high value narrow-band impedances. The effects of these resonances on coupled-bunch instabilities are discussed. An estimate of the power dissipation in the ceramic vacuum seal under high current operation is given

  2. Impedance of the PEP-II DIP screen

    International Nuclear Information System (INIS)

    Ng, C.K.; Weiland, T.

    1995-09-01

    The vacuum chamber of a storage ring normally consists of periodically spaced pumping slots. The longitudinal impedance of slots are analyzed in this paper. It is found that although the broad-band impedance is tolerable, the narrow-band impedance, as a consequence of the periodicity of the slots, may exceed the stability limit given by natural damping with no feedback system on. Based on this analysis, the PEP-II distributed-ion-pump (DIP) screen uses long grooves with hidden holes cut halfway to reduce both the broad-band and narrow-band impedances

  3. Study of Beam-Beam Effects at PEP-II

    International Nuclear Information System (INIS)

    Narsky, I

    2004-01-01

    Using a self-consistent three-dimensional simulation running on parallel supercomputers, we have modeled the beam-beam interaction at the PEP-II asymmetric e + e - collider. To provide guidance for luminosity improvement, we scanned the tunes and currents in both rings and computed their impact on the luminosity and transverse beam sizes. We also studied the effects of colliding the beams with a small crossing angle. Where possible, the code was benchmarked against experimental measurements of luminosity and beam sizes, yielding an acceptable agreement

  4. RF feedback development for the PEP-II B Factory

    International Nuclear Information System (INIS)

    Corredoura, P.; Sapozhnikov, L.; Tighe, R.

    1994-06-01

    In PEP-II heavy beam loading along with a relatively long revolution period combine to strongly drive lower coupled-bunch modes through interaction with the fundamental cavity mode. Feedback techniques can be applied to reduce the cavity impedance seen by the beam. Several RF feedback loops are planned to reduce the growth rates down to a level which can be damped by the relatively low power bunch-by-bunch longitudinal feedback system. This paper describes the RF feedback loops as well as hardware tests using a 500 kW klystron, analog and digital feedback loops, and a low power test cavity

  5. Swimming Exercise Prevents Fibrogenesis in Chronic Kidney Disease by Inhibiting the Myofibroblast Transdifferentiation

    Science.gov (United States)

    Peng, Chiung-Chi; Chen, Kuan-Chou; Hsieh, Chiu-Lan; Peng, Robert Y.

    2012-01-01

    Background The renal function of chronic kidney disease (CKD) patients may be improved by a number of rehabilitative mechanisms. Swimming exercise training was supposed to be beneficial to its recovery. Methodology/Principal Findings Doxorubicin-induced CKD (DRCKD) rat model was performed. Swimming training was programmed three days per week, 30 or 60 min per day for a total period of 11 weeks. Serum biochemical and pathological parameters were examined. In DRCKD, hyperlipidemia was observed. Active mesangial cell activation was evidenced by overexpression of PDGFR, P-PDGFR, MMP-2, MMP-9, α-SMA, and CD34 with a huge amount collagen deposition. Apparent myofibroblast transdifferentiation implicating fibrogenesis in the glomerular mesangium, glomerulonephritis and glomeruloscelorosis was observed with highly elevated proteinuria and urinary BUN excretion. The 60-min swimming exercise but not the 30 min equivalent rescued most of the symptoms. To quantify the effectiveness of exercise training, a physical parameter, i.e. “the strenuosity coefficient” or “the myokine releasing coefficient”, was estimated to be 7.154×10−3 pg/mL-J. Conclusions The 60-min swimming exercise may ameliorate DRCKD by inhibiting the transdifferentiation of myofibroblasts in the glomerular mesangium. Moreover, rehabilitative exercise training to rescue CKD is a personalized remedy. Benefits depend on the duration and strength of exercise, and more importantly, on the individual physiological condition. PMID:22761655

  6. Sperm calcineurin inhibition prevents mouse fertility with implications for male contraceptive.

    Science.gov (United States)

    Miyata, Haruhiko; Satouh, Yuhkoh; Mashiko, Daisuke; Muto, Masanaga; Nozawa, Kaori; Shiba, Kogiku; Fujihara, Yoshitaka; Isotani, Ayako; Inaba, Kazuo; Ikawa, Masahito

    2015-10-23

    Calcineurin inhibitors, such as cyclosporine A and FK506, are used as immunosuppressant drugs, but their adverse effects on male reproductive function remain unclear. The testis expresses somatic calcineurin and a sperm-specific isoform that contains a catalytic subunit (PPP3CC) and a regulatory subunit (PPP3R2). We demonstrate herein that male mice lacking Ppp3cc or Ppp3r2 genes (knockout mice) are infertile, with reduced sperm motility owing to an inflexible midpiece. Treatment of mice with cyclosporine A or FK506 creates phenocopies of the sperm motility and morphological defects. These defects appear within 4 to 5 days of treatment, which indicates that sperm-specific calcineurin confers midpiece flexibility during epididymal transit. Male mouse fertility recovered a week after we discontinued treatment. Because human spermatozoa contain PPP3CC and PPP3R2 as a form of calcineurin, inhibition of this sperm-specific calcineurin may lead to the development of a reversible male contraceptive that would target spermatozoa in the epididymis. Copyright © 2015, American Association for the Advancement of Science.

  7. Kynurenine–3–monooxygenase inhibition prevents multiple organ failure in rodent models of acute pancreatitis

    Science.gov (United States)

    Mole, Damian J; Webster, Scott P; Uings, Iain; Zheng, Xiaozhong; Binnie, Margaret; Wilson, Kris; Hutchinson, Jonathan P; Mirguet, Olivier; Walker, Ann; Beaufils, Benjamin; Ancellin, Nicolas; Trottet, Lionel; Bénéton, Véronique; Mowat, Christopher G; Wilkinson, Martin; Rowland, Paul; Haslam, Carl; McBride, Andrew; Homer, Natalie ZM; Baily, James E; Sharp, Matthew GF; Garden, O James; Hughes, Jeremy; Howie, Sarah EM; Holmes, Duncan S; Liddle, John; Iredale, John P

    2015-01-01

    Acute pancreatitis (AP) is a common and devastating inflammatory condition of the pancreas that is considered to be a paradigm of sterile inflammation leading to systemic multiple organ dysfunction syndrome (MODS) and death1,2 Acute mortality from AP-MODS exceeds 20%3 and for those who survive the initial episode, their lifespan is typically shorter than the general population4. There are no specific therapies available that protect individuals against AP-MODS. Here, we show that kynurenine-3-monooxygenase (KMO), a key enzyme of tryptophan metabolism5, is central to the pathogenesis of AP-MODS. We created a mouse strain deficient for Kmo with a robust biochemical phenotype that protected against extrapancreatic tissue injury to lung, kidney and liver in experimental AP-MODS. A medicinal chemistry strategy based on modifications of the kynurenine substrate led to the discovery of GSK180 as a potent and specific inhibitor of KMO. The binding mode of the inhibitor in the active site was confirmed by X-ray co-crystallography at 3.2 Å resolution. Treatment with GSK180 resulted in rapid changes in levels of kynurenine pathway metabolites in vivo and afforded therapeutic protection against AP-MODS in a rat model of AP. Our findings establish KMO inhibition as a novel therapeutic strategy in the treatment of AP-MODS and open up a new area for drug discovery in critical illness. PMID:26752518

  8. Kynurenine-3-monooxygenase inhibition prevents multiple organ failure in rodent models of acute pancreatitis.

    Science.gov (United States)

    Mole, Damian J; Webster, Scott P; Uings, Iain; Zheng, Xiaozhong; Binnie, Margaret; Wilson, Kris; Hutchinson, Jonathan P; Mirguet, Olivier; Walker, Ann; Beaufils, Benjamin; Ancellin, Nicolas; Trottet, Lionel; Bénéton, Véronique; Mowat, Christopher G; Wilkinson, Martin; Rowland, Paul; Haslam, Carl; McBride, Andrew; Homer, Natalie Z M; Baily, James E; Sharp, Matthew G F; Garden, O James; Hughes, Jeremy; Howie, Sarah E M; Holmes, Duncan S; Liddle, John; Iredale, John P

    2016-02-01

    Acute pancreatitis (AP) is a common and devastating inflammatory condition of the pancreas that is considered to be a paradigm of sterile inflammation leading to systemic multiple organ dysfunction syndrome (MODS) and death. Acute mortality from AP-MODS exceeds 20% (ref. 3), and the lifespans of those who survive the initial episode are typically shorter than those of the general population. There are no specific therapies available to protect individuals from AP-MODS. Here we show that kynurenine-3-monooxygenase (KMO), a key enzyme of tryptophan metabolism, is central to the pathogenesis of AP-MODS. We created a mouse strain that is deficient for Kmo (encoding KMO) and that has a robust biochemical phenotype that protects against extrapancreatic tissue injury to the lung, kidney and liver in experimental AP-MODS. A medicinal chemistry strategy based on modifications of the kynurenine substrate led to the discovery of the oxazolidinone GSK180 as a potent and specific inhibitor of KMO. The binding mode of the inhibitor in the active site was confirmed by X-ray co-crystallography at 3.2 Å resolution. Treatment with GSK180 resulted in rapid changes in the levels of kynurenine pathway metabolites in vivo, and it afforded therapeutic protection against MODS in a rat model of AP. Our findings establish KMO inhibition as a novel therapeutic strategy in the treatment of AP-MODS, and they open up a new area for drug discovery in critical illness.

  9. CSF1R inhibition prevents radiation pulmonary fibrosis by depletion of interstitial macrophages.

    Science.gov (United States)

    Meziani, Lydia; Mondini, Michele; Petit, Benoît; Boissonnas, Alexandre; Thomas de Montpreville, Vincent; Mercier, Olaf; Vozenin, Marie-Catherine; Deutsch, Eric

    2018-03-01

    Radiation-induced lung fibrosis (RIF) is a delayed side-effect of chest radiotherapy, frequently associated with macrophage infiltration.We aimed to characterise the role of pulmonary macrophages in RIF using human lung biopsies from patients receiving radiotherapy for thorax malignancies and a RIF model developed in C57BL/6 mice after 16-Gy thorax irradiation.High numbers of macrophages (both interstitial and alveolar) were detected in clinical and preclinical RIF. In the preclinical model, upregulation of T-helper (Th)2 cytokines was measured, whereas Th1 cytokines were downregulated in RIF tissue lysate. Bronchoalveolar lavage demonstrated upregulation of both types of cytokines. At steady state, tissue-infiltrating macrophages (IMs) expressed 10-fold more arginase (Arg)-1 than alveolar macrophages (AMs), and a 40-fold upregulation of Arg-1 was found in IMs isolated from RIF. IMs, but not AMs, were able to induce myofibroblast activation in vitro In addition, whereas depletion of AMs using Clodrosome didn't affect RIF score, depletion of IMs using a clinically available colony-stimulating factor receptor-1 (CSF1R) neutralising antibody was antifibrotic.These findings suggest differential contributions of alveolar versus interstitial macrophages in RIF, highlighting the fibrogenic role of IMs. The CSF1/CSF1R pathway was identified as a new therapeutic target to inhibit RIF. Copyright ©ERS 2018.

  10. Rca1 inhibits APC-Cdh1(Fzr) and is required to prevent cyclin degradation in G2.

    Science.gov (United States)

    Grosskortenhaus, Ruth; Sprenger, Frank

    2002-01-01

    We demonstrate that Rca1 is an essential inhibitor of the anaphase-promoting complex/cyclosome (APC) in Drosophila. APC activity is restricted to mitotic stages and G1 by its activators Cdc20-Fizzy (Cdc20(Fzy)) and Cdh1-Fizzy-related (Cdh1(Fzr)), respectively. In rca1 mutants, cyclins are degraded prematurely in G2 by APC-Cdh1(Fzr)-dependent proteolysis, and cells fail to execute mitosis. Overexpression of Cdh1(Fzr) mimics the rca1 phenotype, and coexpression of Rca1 blocks this Cdh1(Fzr) function. We show that Rca1 and Cdh1(Fzr) are in a complex that also includes the APC component Cdc27. Previous studies have shown that phosphorylation of Cdh1 prevents its interaction with the APC. Our data reveal a different mode of APC regulation by Rca1 at the G2 stage, when low Cdk activity is unable to inhibit Cdh1(Fzr) interaction.

  11. Mind magic: a pilot study of preventive mind-body-based stress reduction in behaviorally inhibited and activated children.

    Science.gov (United States)

    Jellesma, Francine C; Cornelis, Janine

    2012-03-01

    The aim of this pilot study was to examine a mind-body-based preventive intervention program and to determine relationships between children's behavioral inhibition system (BIS) and behavioral activation system, stress, and stress reduction after the program. Children participated in the program (n=30) or in a control condition (n=24). They filled out questionnaires before and after the program and reported their levels of stress before and after each of the five sessions. The program consisted of weekly sessions. Each session incorporated yoga postures, visualization, and social exercises. Breathing techniques were integrated. Stress reductions were only seen in the intervention group and mainly in children with high BIS--irrespective of their behavioral activation system. The results demonstrate that children with high BIS may benefit from a mind-body-based stress reduction program.

  12. Inhibition of a Descending Prefrontal Circuit Prevents Ketamine-Induced Stress Resilience in Females

    DEFF Research Database (Denmark)

    Dolzani, S. D.; Baratta, M. V.; Moss, J. M.

    2018-01-01

    . The NMDA receptor antagonist ketamine has recently emerged as a prophylactic capable of preventing neurochemical and behavioral outcomes of a future stressor. Despite promising results of preclinical studies performed in male rats, the effects of proactive ketamine in female rats remains unknown....... This is alarming given that stress-related disorders affect females at nearly twice the rate of males. Here we explore the prophylactic effects of ketamine on stress-induced anxiety-like behavior and the neural circuit-level processes that mediate these effects in female rats. Ketamine given one week prior...... to an uncontrollable stressor (inescapable tailshock; IS) reduced typical stress-induced activation of the serotonergic (5-HT) dorsal raphe nucleus (DRN) and eliminated DRN-dependent juvenile social exploration (JSE) deficits 24 h after the stressor. Proactive ketamine altered prelimbic cortex (PL) neural ensembles so...

  13. Inhibition of xanthine oxidase by allopurinol prevents skeletal muscle atrophy: role of p38 MAPKinase and E3 ubiquitin ligases.

    Directory of Open Access Journals (Sweden)

    Frederic Derbre

    Full Text Available Alterations in muscle play an important role in common diseases and conditions. Reactive oxygen species (ROS are generated during hindlimb unloading due, at least in part, to the activation of xanthine oxidase (XO. The major aim of this study was to determine the mechanism by which XO activation causes unloading-induced muscle atrophy in rats, and its possible prevention by allopurinol, a well-known inhibitor of this enzyme. For this purpose we studied one of the main redox sensitive signalling cascades involved in skeletal muscle atrophy i.e. p38 MAPKinase, and the expression of two well known muscle specific E3 ubiquitin ligases involved in proteolysis, the Muscle atrophy F-Box (MAFbx; also known as atrogin-1 and Muscle RING (Really Interesting New Gene Finger-1 (MuRF-1. We found that hindlimb unloading induced a significant increase in XO activity and in the protein expression of the antioxidant enzymes CuZnSOD and Catalase in skeletal muscle. The most relevant new fact reported in this paper is that inhibition of XO with allopurinol, a drug widely used in clinical practice, prevents soleus muscle atrophy by ~20% after hindlimb unloading. This was associated with the inhibition of the p38 MAPK-MAFbx pathway. Our data suggest that XO was involved in the loss of muscle mass via the activation of the p38MAPK-MAFbx pathway in unloaded muscle atrophy. Thus, allopurinol may have clinical benefits to combat skeletal muscle atrophy in bedridden, astronauts, sarcopenic, and cachexic patients.

  14. The Association between Endometriomas and Ovarian Cancer: Preventive Effect of Inhibiting Ovulation and Menstruation during Reproductive Life.

    Science.gov (United States)

    Grandi, Giovanni; Toss, Angela; Cortesi, Laura; Botticelli, Laura; Volpe, Annibale; Cagnacci, Angelo

    2015-01-01

    Although endometriosis frequently involves multiple sites in the pelvis, malignancies associated with this disease are mostly confined to the ovaries, evolving from an endometrioma. Endometriomas present a 2-3-fold increased risk of transformation in clear-cell, endometrioid, and possibly low-grade serous ovarian cancers, but not in mucinous ovarian cancers. These last cancers are, in some aspects, different from the other epithelial ovarian cancers, as they do not appear to be decreased by the inhibition of ovulation and menstruation. The step by step process of transformation from typical endometrioma, through atypical endometrioma, finally to ovarian cancer seems mainly related to oxidative stress, inflammation, hyperestrogenism, and specific molecular alterations. Particularly, activation of oncogenic KRAS and PI3K pathways and inactivation of tumor suppressor genes PTEN and ARID1A are suggested as major pathogenic mechanisms for endometriosis associated clear-cell and endometrioid ovarian cancer. Both the risk for endometriomas and their associated ovarian cancers seems to be highly and similarly decreased by the inhibition of ovulation and retrograde menstruation, suggesting a common pathogenetic mechanism and common possible preventive strategies during reproductive life.

  15. Power Extension Package (PEP) system definition extension, orbital service module systems analysis study. Volume 9: PEP design, development and test plans

    Science.gov (United States)

    1979-01-01

    A plan for the production of two PEP flight systems is defined. The task's milestones are described. Provisions for the development and assembly of new ground support equipment required for both testing and launch operations are included.

  16. Progress on PEP-II magnet power conversion system

    International Nuclear Information System (INIS)

    Bellomo, P.; Genova, L.; Jackson, T.; Shimer, D.

    1996-01-01

    The various power systems for supplying the PEP-II DC magnets rely exclusively on switchmode conversion, utilizing a variety of means depending on the requirements. All of the larger power supplies, ranging from 10 to 200 kW, are powered from DC sources utilizing rectified 480 V AC. Choppers can be used for the series connected strings, but for smaller groups and individual magnets, inverters driving high-frequency transformers with rectifiers comprise the best approach. All of the various systems use a ''building block'' approach of multiple standard-size units connected in series or parallel to most cost-effectively deal with a great range of voltage and current requirements. Utilization of existing infrastructure from PEP-I has been a cost-effective determinant. Equipment is being purchased either off-the-shelf, through performance specification, or by hardware purchase based on design-through-prototype. The corrector magnet power system, utilizing inexpensive, off-the-shelf, four-quadrant switching motor-controllers, has already proven very reliable: 120 of the total of 900 units have been running on the injection system for four months with no failures

  17. PEP-II Beta Beat Fixes with MIA

    International Nuclear Information System (INIS)

    Yan, Y

    2004-01-01

    We first find a virtual accelerator for the HER or the LER through determination of all quadrupole strengths and sextupole feed-downs as well as all BPM gains and BPM cross-plane couplings by an SVD-enhanced Least-squares fitting of the quantities derivable from a complete set of orbits. These quantities are the phase advances, the Green's functions, and the tilt angles and axis ratios of the coupling eigen ellipses. They are obtained by analyzing turn-by-turn Beam Position Monitor (BPM) data with a high-resolution model-independent analysis (MIA). Once the virtual accelerator is found, we select a limited number of key quadrupoles, for example, the linear trombone quadrupoles and the global skews, for Least-square fitting of their strengths to minimize the beta beat while keeping other optics characters unchanged if not improved. We then dial in these limited number of quadrupole strength changes to the real accelerator (HER or LER) to achieve a better-performance PEP-II. Noticeable achievement by this MIA technique has been that MIA has helped PEP-II achieve its breaking record peak luminosity of 6.5 x 10 33 cm -2 s -1 in 2003 by bringing the LER working tune to near half integer and simultaneously fixing the beta beat, which would, otherwise, be difficult without MIA because of the strong LER coupling effect

  18. Progress on PEP-II magnet power conversion system

    Energy Technology Data Exchange (ETDEWEB)

    Bellomo, P.; Genova, L. [Stanford Linear Accelerator Center, Menlo Park, CA (United States); Jackson, T. [Lawrence Berkeley National Lab., CA (United States); Shimer, D. [Lawrence Livermore National Lab., CA (United States)

    1996-06-04

    The various power systems for supplying the PEP-II DC magnets rely exclusively on switchmode conversion, utilizing a variety of means depending on the requirements. All of the larger power supplies, ranging from 10 to 200 kW, are powered from DC sources utilizing rectified 480 V AC. Choppers can be used for the series connected strings, but for smaller groups and individual magnets, inverters driving high-frequency transformers with rectifiers comprise the best approach. All of the various systems use a ``building block`` approach of multiple standard-size units connected in series or parallel to most cost-effectively deal with a great range of voltage and current requirements. Utilization of existing infrastructure from PEP-I has been a cost-effective determinant. Equipment is being purchased either off-the-shelf, through performance specification, or by hardware purchase based on design-through-prototype. The corrector magnet power system, utilizing inexpensive, off-the-shelf, four-quadrant switching motor-controllers, has already proven very reliable: 120 of the total of 900 units have been running on the injection system for four months with no failures.

  19. Background sources and masks for Mark II detector at PEP

    International Nuclear Information System (INIS)

    Kadyk, J.

    1981-06-01

    The shielding masks currently at use in several of the current experiments at PEP are the result of an early organized effort to understand the sources of particle background expected at PEP, followed by the evolution of the conceptual designs into actual hardware. The degree and kind of background particle loading which could be tolerated was expected to differ significantly among the different experiments, and several designs emerged from the common study. Qualitatively, the types of radiations studied were, Synchrotron Radiation (SR), Beam Gas Bremsstrahlung (BGB), and, to a limited extent others, e.g., Electroproduction (EP). Calculations will be given of predicted occupancies in the pipe counter and other sensitive elements at small radius, since these will be most susceptible to the SR and BGB backgrounds. The calculations presented in this note are specific to the Mark II detector. Some general statements will be made first about the character of each of the various types of backgrounds considered, then some detailed calculations made for application to the Mark II detector

  20. Optimization of Dynamic Aperture of PEP-X Baseline Design

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Min-Huey; /SLAC; Cai, Yunhai; /SLAC; Nosochkov, Yuri; /SLAC

    2010-08-23

    SLAC is developing a long-range plan to transfer the evolving scientific programs at SSRL from the SPEAR3 light source to a much higher performing photon source. Storage ring design is one of the possibilities that would be housed in the 2.2-km PEP-II tunnel. The design goal of PEPX storage ring is to approach an optimal light source design with horizontal emittance less than 100 pm and vertical emittance of 8 pm to reach the diffraction limit of 1-{angstrom} x-ray. The low emittance design requires a lattice with strong focusing leading to high natural chromaticity and therefore to strong sextupoles. The latter caused reduction of dynamic aperture. The dynamic aperture requirement for horizontal injection at injection point is about 10 mm. In order to achieve the desired dynamic aperture the transverse non-linearity of PEP-X is studied. The program LEGO is used to simulate the particle motion. The technique of frequency map is used to analyze the nonlinear behavior. The effect of the non-linearity is tried to minimize at the given constrains of limited space. The details and results of dynamic aperture optimization are discussed in this paper.

  1. Optimization of Dynamic Aperture of PEP-X Baseline Design

    International Nuclear Information System (INIS)

    Wang, Min-Huey

    2010-01-01

    SLAC is developing a long-range plan to transfer the evolving scientific programs at SSRL from the SPEAR3 light source to a much higher performing photon source. Storage ring design is one of the possibilities that would be housed in the 2.2-km PEP-II tunnel. The design goal of PEPX storage ring is to approach an optimal light source design with horizontal emittance less than 100 pm and vertical emittance of 8 pm to reach the diffraction limit of 1-(angstrom) x-ray. The low emittance design requires a lattice with strong focusing leading to high natural chromaticity and therefore to strong sextupoles. The latter caused reduction of dynamic aperture. The dynamic aperture requirement for horizontal injection at injection point is about 10 mm. In order to achieve the desired dynamic aperture the transverse non-linearity of PEP-X is studied. The program LEGO is used to simulate the particle motion. The technique of frequency map is used to analyze the nonlinear behavior. The effect of the non-linearity is tried to minimize at the given constrains of limited space. The details and results of dynamic aperture optimization are discussed in this paper.

  2. An Orbit And Dispersion Correction Scheme for the PEP II

    International Nuclear Information System (INIS)

    Cai, Y.; Donald, M.; Shoaee, H.; White, G.; Yasukawa, L.A.

    2011-01-01

    To achieve optimum luminosity in a storage ring it is vital to control the residual vertical dispersion. In the original PEP storage ring, a scheme to control the residual dispersion function was implemented using the ring orbit as the controlling element. The 'best' orbit not necessarily giving the lowest vertical dispersion. A similar scheme has been implemented in both the on-line control code and in the simulation code LEGO. The method involves finding the response matrices (sensitivity of orbit/dispersion at each Beam-Position-Monitor (BPM) to each orbit corrector) and solving in a least squares sense for minimum orbit, dispersion function or both. The optimum solution is usually a subset of the full least squares solution. A scheme of simultaneously correcting the orbits and dispersion has been implemented in the simulation code and on-line control system for PEP-II. The scheme is based on the eigenvector decomposition method. An important ingredient of the scheme is to choose the optimum eigenvectors that minimize the orbit, dispersion and corrector strength. Simulations indicate this to be a very effective way to control the vertical residual dispersion.

  3. Optimizing the injection straight of PEP II asymmetric B Factory at SLAC

    International Nuclear Information System (INIS)

    Bulos, F.; Bloom, E.; Davies-White, W.; Donald, M.; Fairfield, K.; Fieguth, T.; Godfrey, G.; Holtzapple, R.; Hutton, A.; Loew, G.; Miller, R.; Sukiennicki, B.; Wen, H.; Ronan, M.

    1992-04-01

    The asymmetric energy PEP II B Factory proposed as an upgrade of PEP at the Stanford Linear Accelerator Center requires both a powerful low emittance source of e - e + and a very reliable and efficient injection system. The SLC linac fulfills the source requirement very well. We describe here the optimization of the optics of the injection straight to insure reliable and efficient injection

  4. PEP cooling water systems and underground piped utilities design criteria report

    International Nuclear Information System (INIS)

    Hall, F.; Robbins, D.

    1975-10-01

    This paper discusses the cooling systems required by the PEP Storage Ring. Particular topics discussed are: Cooling tower systems, RF cavity and vacuum chamber LCW cooling systems, klystron and ring magnet LLW cooling systems, Injection magnet LCW Cooling Systems; PEP interaction area detector LCW Cooling Systems; and underground piped utilities. 1 ref., 20 figs

  5. Problems in obtaining polarized e+ and e- beams and perspectives for PEP

    International Nuclear Information System (INIS)

    Chao, A.W.

    1980-09-01

    A matrix formalism for polarization calculation, as well as its comparison with other methods, is briefly discussed. The prediction for SPEAR is compared with experimental measurements. An estimate is offered for the transverse polarization for PEP. Various schemes for obtaining the longitudinal polarization in PEP are studied

  6. Optimizing the injection straight of PEP II asymmetric B factory at SLAC

    International Nuclear Information System (INIS)

    Bulos, F.; Bloom, E.; Davies-White, W.; Donald, M.; Fairfield, K.; Fieguth, T.; Godfrey, G.; Holtzapple, R.; Hutton, A.; Loew, G.; Miller, R.; Sukiennicki, B.; Wen, H.

    1992-01-01

    The asymmetric energy PEP II B Factory proposed as an upgrade of PEP at the Stanford Linear Accelerator Center requires both a powerful low emittance source of e - e + and a very reliable and efficient injection system. The SLC linac fulfills the source requirement very well. We describe here the optimization of the optics of the injection straight to insure reliable and efficient injection

  7. Evolutionary divergence of the plant elicitor peptides (Peps) and their receptors: interfamily incompatibility of perception but compatibility of downstream signalling

    KAUST Repository

    Lori, M.; van Verk, M. C.; Hander, T.; Schatowitz, H.; Klauser, D.; Flury, P.; Gehring, Christoph A; Boller, T.; Bartels, S.

    2015-01-01

    Plant elicitor peptides (Peps) are potent inducers of pattern-triggered immunity and amplify the immune response against diverse pathogens. Peps have been discovered and studied extensively in Arabidopsis and only recently orthologs in maize were

  8. mTOR pathway inhibition prevents neuroinflammation and neuronal death in a mouse model of cerebral palsy.

    Science.gov (United States)

    Srivastava, Isha N; Shperdheja, Jona; Baybis, Marianna; Ferguson, Tanya; Crino, Peter B

    2016-01-01

    Mammalian target of rapamycin (mTOR) pathway signaling governs cellular responses to hypoxia and inflammation including induction of autophagy and cell survival. Cerebral palsy (CP) is a neurodevelopmental disorder linked to hypoxic and inflammatory brain injury however, a role for mTOR modulation in CP has not been investigated. We hypothesized that mTOR pathway inhibition would diminish inflammation and prevent neuronal death in a mouse model of CP. Mouse pups (P6) were subjected to hypoxia-ischemia and lipopolysaccharide-induced inflammation (HIL), a model of CP causing neuronal injury within the hippocampus, periventricular white matter, and neocortex. mTOR pathway inhibition was achieved with rapamycin (an mTOR inhibitor; 5mg/kg) or PF-4708671 (an inhibitor of the downstream p70S6kinase, S6K, 75 mg/kg) immediately following HIL, and then for 3 subsequent days. Phospho-activation of the mTOR effectors p70S6kinase and ribosomal S6 protein and expression of hypoxia inducible factor 1 (HIF-1α) were assayed. Neuronal cell death was defined with Fluoro-Jade C (FJC) and autophagy was measured using Beclin-1 and LC3II expression. Iba-1 labeled, activated microglia were quantified. Neuronal death, enhanced HIF-1α expression, and numerous Iba-1 labeled, activated microglia were evident at 24 and 48 h following HIL. Basal mTOR signaling, as evidenced by phosphorylated-S6 and -S6K levels, was unchanged by HIL. Rapamycin or PF-4,708,671 treatment significantly reduced mTOR signaling, neuronal death, HIF-1α expression, and microglial activation, coincident with enhanced expression of Beclin-1 and LC3II, markers of autophagy induction. mTOR pathway inhibition prevented neuronal death and diminished neuroinflammation in this model of CP. Persistent mTOR signaling following HIL suggests a failure of autophagy induction, which may contribute to neuronal death in CP. These results suggest that mTOR signaling may be a novel therapeutic target to reduce neuronal cell death in

  9. Grape Seed Proanthocyanidin Extract Prevents Ovarian Aging by Inhibiting Oxidative Stress in the Hens

    Directory of Open Access Journals (Sweden)

    Xingting Liu

    2018-01-01

    Full Text Available Oxidative stress is an important inducement in ovarian aging which results in fecundity decline in human and diverse animals. As a potent antioxidant, grape seed proanthocyanidin extract (GSPE was investigated to ameliorate chicken ovarian aging in this study. Firstly, ovarian antioxidant capacity of hens at different ages (90, 150, 280, and 580 days old was compared to elucidate its age-related changes. Subsequently, a D-gal-induced (2.5 mg/mL aging ovarian model was established and the cultured ovarian tissues were treated with GSPE at 5 μg/mL for 72 h to evaluate the putative attenuating effects of GSPE on ovarian aging. Meanwhile, ovaries of D280 (young and D580 (old were treated with GSPE for 72 h in culture to verify the protective effects of GSPE on natural aging ovary. The results showed that GSPE could rescue the antioxidant capacity decline by increasing the antioxidase activities and their gene expression in either D-gal-induced or natural aging ovaries. Moreover, GSPE could maintain the homeostasis between cell proliferation and apoptosis in the D-gal-induced and natural aging ovaries, as well as alleviate D-gal-induced nucleus chromatin condensation in the ovarian granulosa cells. In conclusion, GSPE treatment can effectively prevent the ovarian aging process in hens by reducing oxidative stress.

  10. Andrographolide Sodium Bisulfate Prevents UV-Induced Skin Photoaging through Inhibiting Oxidative Stress and Inflammation

    Directory of Open Access Journals (Sweden)

    Janis Ya-Xian Zhan

    2016-01-01

    Full Text Available Andrographolide sodium bisulfate (ASB, a water-soluble form made from andrographolide through sulfonating reaction, is an antioxidant and anti-inflammatory drug; however, the antiphotoaging effect of ASB has still not been revealed. Oxidative stress and inflammation are known to be responsible for ultraviolet (UV irradiation induced skin damage and consequently premature aging. In this study, we aimed at examining the effect of ASB on UV-induced skin photoaging of mice by physiological and histological analysis of skin and examination of skin antioxidant enzymes and immunity analyses. Results showed that topical administration of ASB suppressed the UV-induced skin thickness, elasticity, wrinkles, and water content, while ASB, especially at dose of 3.6 mg/mouse, increased the skin collagen content by about 53.17%, decreased the epidermal thickness by about 41.38%, and prevented the UV-induced disruption of collagen fibers and elastic fibers. Furthermore, ASB decreased MDA level by about 40.21% and upregulated the activities of SOD and CAT and downregulated the production of IL-1β, IL-6, IL-10, and TNF-α in UV-irradiated mice. Our study confirmed the protective effect of ASB against UV-induced photoaging and initially indicated that this effect can be attributed to its antioxidant and anti-inflammatory activities in vivo, suggesting that ASB may be a potential antiphotoaging agent.

  11. Andrographolide Sodium Bisulfate Prevents UV-Induced Skin Photoaging through Inhibiting Oxidative Stress and Inflammation

    Science.gov (United States)

    Zhan, Janis Ya-Xian; Wang, Xiu-Fen; Liu, Yu-Hong; Zhang, Zhen-Biao; Wang, Lan; Chen, Jian-Nan; Huang, Song; Zeng, Hui-Fang; Lai, Xiao-Ping

    2016-01-01

    Andrographolide sodium bisulfate (ASB), a water-soluble form made from andrographolide through sulfonating reaction, is an antioxidant and anti-inflammatory drug; however, the antiphotoaging effect of ASB has still not been revealed. Oxidative stress and inflammation are known to be responsible for ultraviolet (UV) irradiation induced skin damage and consequently premature aging. In this study, we aimed at examining the effect of ASB on UV-induced skin photoaging of mice by physiological and histological analysis of skin and examination of skin antioxidant enzymes and immunity analyses. Results showed that topical administration of ASB suppressed the UV-induced skin thickness, elasticity, wrinkles, and water content, while ASB, especially at dose of 3.6 mg/mouse, increased the skin collagen content by about 53.17%, decreased the epidermal thickness by about 41.38%, and prevented the UV-induced disruption of collagen fibers and elastic fibers. Furthermore, ASB decreased MDA level by about 40.21% and upregulated the activities of SOD and CAT and downregulated the production of IL-1β, IL-6, IL-10, and TNF-α in UV-irradiated mice. Our study confirmed the protective effect of ASB against UV-induced photoaging and initially indicated that this effect can be attributed to its antioxidant and anti-inflammatory activities in vivo, suggesting that ASB may be a potential antiphotoaging agent. PMID:26903706

  12. Muscle wasting and impaired myogenesis in tumor bearing mice are prevented by ERK inhibition.

    Directory of Open Access Journals (Sweden)

    Fabio Penna

    Full Text Available BACKGROUND: The onset of cachexia is a frequent feature in cancer patients. Prominent characteristic of this syndrome is the loss of body and muscle weight, this latter being mainly supported by increased protein breakdown rates. While the signaling pathways dependent on IGF-1 or myostatin were causally involved in muscle atrophy, the role of the Mitogen-Activated-Protein-Kinases is still largely debated. The present study investigated this point on mice bearing the C26 colon adenocarcinoma. METHODOLOGY/PRINCIPAL FINDINGS: C26-bearing mice display a marked loss of body weight and muscle mass, this latter associated with increased phosphorylated (p-ERK. Administration of the ERK inhibitor PD98059 to tumor bearers attenuates muscle depletion and weakness, while restoring normal atrogin-1 expression. In C26 hosts, muscle wasting is also associated with increased Pax7 expression and reduced myogenin levels. Such pattern, suggestive of impaired myogenesis, is reversed by PD98059. Increased p-ERK and reduced myosin heavy chain content can be observed in TNFα-treated C2C12 myotubes, while decreased myogenin and MyoD levels occur in differentiating myoblasts exposed to the cytokine. All these changes are prevented by PD98059. CONCLUSIONS/SIGNIFICANCE: These results demonstrate that ERK is involved in the pathogenesis of muscle wasting in cancer cachexia and could thus be proposed as a therapeutic target.

  13. Reversible p53 inhibition prevents cisplatin ototoxicity without blocking chemotherapeutic efficacy.

    Science.gov (United States)

    Benkafadar, Nesrine; Menardo, Julien; Bourien, Jérôme; Nouvian, Régis; François, Florence; Decaudin, Didier; Maiorano, Domenico; Puel, Jean-Luc; Wang, Jing

    2017-01-01

    Cisplatin is a widely used chemotherapy drug, despite its significant ototoxic side effects. To date, the mechanism of cisplatin-induced ototoxicity remains unclear, and hearing preservation during cisplatin-based chemotherapy in patients is lacking. We found activation of the ATM-Chk2-p53 pathway to be a major determinant of cisplatin ototoxicity. However, prevention of cisplatin-induced ototoxicity is hampered by opposite effects of ATM activation upon sensory hair cells: promoting both outer hair cell death and inner hair cell survival. Encouragingly, however, genetic or pharmacological ablation of p53 substantially attenuated cochlear cell apoptosis, thus preserving hearing. Importantly, systemic administration of a p53 inhibitor in mice bearing patient-derived triple-negative breast cancer protected auditory function, without compromising the anti-tumor efficacy of cisplatin. Altogether, these findings highlight a novel and effective strategy for hearing protection in cisplatin-based chemotherapy. © 2016 The Authors. Published under the terms of the CC BY 4.0 license.

  14. Wasabia japonica is a potential functional food to prevent colitis via inhibiting the NF-κB signaling pathway.

    Science.gov (United States)

    Kang, Ju-Hee; Choi, Seungho; Jang, Jeong-Eun; Ramalingam, Prakash; Ko, Young Tag; Kim, Sun Yeou; Oh, Seung Hyun

    2017-08-01

    Inflammatory bowel diseases (IBDs), including Crohn's disease (CD) and ulcerative colitis (UC), are prevalent and debilitating health problems worldwide. Many types of drugs are used to treat IBDs, but they exhibit adverse effects such as vomiting, nausea, abdominal pain, diarrhea, etc. In order to overcome the limitations of current therapeutic drugs, scientists have searched for functional foods from natural resources. In this study, we investigated the anti-colitic effects of Wasabia japonica extract in a DSS-induced colitis model. Wasabi japonica is a plant of the Brassicaceae family that has recently been reported to exhibit properties of detoxification, anti-inflammation, and induction of apoptosis in cancer cells. In this study, we generated wasabi ethanol extract (WK) and assessed its anti-colitic effect. In addition, in order to improve delivery of the extract to the colon, WK was coated with 5% Eudragit S100 (WKE), after which the anti-colitic effects of WKE were assessed. In conclusion, WK prevented development of colitis through inhibition of the NF-kB signaling pathway and recovery of epithelial tight junctions. In addition, the anti-colitic effect of WK was enhanced by improving its delivery to the colon by coating the WK with Eudragit S100. Therefore, we suggest that wasabi can be used as a new functional food to prevent IBDs due to its anti-colitic effect.

  15. Effect of Chemical Prevention Drugs-based MicroRNAs and Their Target Genes 
on Tumor Inhibition

    Directory of Open Access Journals (Sweden)

    Yanhui JIANG

    2015-04-01

    Full Text Available Chemopreventive drugs including natural chemopreventive drugs and synthetic chemopreventive drugs, it not only can prevent cancer, can also play a role in tumor treatment. MicroRNAs (miRNAs is a kind of short chains of non-coding RNA, regulating the expression of many genes through the way of degradation of mRNA or inhibitting mRNA translation. In recent years, more and more studies have shown that chemopreventive drugs through influence the expression of miRNAs and their target genes play a role in the prevention and treatment in a variety of tumors, and chemopreventive drugs on the experimental study of miRNAs and their target genes in tumor have demonstrated a good safety and efficacy. Effect on chemopreventive drugs-based microRNAs and their target genes into cancer cells will be expected as a new starting point for cancer research. The thesis expounds and analyzes between the natural chemopreventive drugs and synthetic chemopreventive drugs and miRNAs and their target genes in tumor research progress.

  16. miR-378 Activates the Pyruvate-PEP Futile Cycle and Enhances Lipolysis to Ameliorate Obesity in Mice

    Directory of Open Access Journals (Sweden)

    Yong Zhang

    2016-03-01

    Full Text Available Obesity has been linked to many health problems, such as diabetes. However, there is no drug that effectively treats obesity. Here, we reveal that miR-378 transgenic mice display reduced fat mass, enhanced lipolysis, and increased energy expenditure. Notably, administering AgomiR-378 prevents and ameliorates obesity in mice. We also found that the energy deficiency seen in miR-378 transgenic mice was due to impaired glucose metabolism. This impairment was caused by an activated pyruvate-PEP futile cycle via the miR-378-Akt1-FoxO1-PEPCK pathway in skeletal muscle and enhanced lipolysis in adipose tissues mediated by miR-378-SCD1. Our findings demonstrate that activating the pyruvate-PEP futile cycle in skeletal muscle is the primary cause of elevated lipolysis in adipose tissues of miR-378 transgenic mice, and it helps orchestrate the crosstalk between muscle and fat to control energy homeostasis in mice. Thus, miR-378 may serve as a promising agent for preventing and treating obesity in humans.

  17. L-arginine prevents xanthoma development and inhibits atherosclerosis in LDL receptor knockout mice.

    Science.gov (United States)

    Aji, W; Ravalli, S; Szabolcs, M; Jiang, X C; Sciacca, R R; Michler, R E; Cannon, P J

    1997-01-21

    The potential antiatherosclerotic actions of NO were investigated in four groups of mice (n = 10 per group) lacking functional LDL receptor genes, an animal model of familial hypercholesterolemia. Group 1 was fed a regular chow diet. Groups 2 through 4 were fed a 1.25% high-cholesterol diet. In addition, group 3 received supplemental L-arginine and group 4 received L-arginine and N omega-nitro-L-arginine (L-NA), an inhibitor of NO synthase (NOS). Animals were killed at 6 months; aortas were stained with oil red O for planimetry and with antibodies against constitutive and inducible NOSs. Plasma cholesterol was markedly increased in the animals receiving the high-cholesterol diet. Xanthomas appeared in all mice fed the high-cholesterol diet alone but not in those receiving L-arginine. Aortic atherosclerosis was present in all mice on the high-cholesterol diet. The mean atherosclerotic lesion area was reduced significantly (P < .01) in the cholesterol-fed mice given L-arginine compared with those receiving the high-cholesterol diet alone. The mean atherosclerotic lesion area was significantly larger (P < .01) in cholesterol-fed mice receiving L-arginine + L-NA than in those on the high-cholesterol diet alone. Within the atherosclerotic plaques, endothelial cells immunoreacted for endothelial cell NOS; macrophages, foam cells, and smooth muscle cells immunostained strongly for inducible NOS and nitrotyrosine residues. The data indicate that L-arginine prevents xanthoma formation and reduces atherosclerosis in LDL receptor knockout mice fed a high-cholesterol diet. The abrogation of the beneficial effects of L-arginine by L-NA suggests that the antiatherosclerotic actions of L-arginine are mediated by NOS. The data suggest that L-arginine may be beneficial in familial hypercholesterolemia.

  18. Evolutionary divergence of the plant elicitor peptides (Peps) and their receptors: interfamily incompatibility of perception but compatibility of downstream signalling

    KAUST Repository

    Lori, M.

    2015-05-22

    Plant elicitor peptides (Peps) are potent inducers of pattern-triggered immunity and amplify the immune response against diverse pathogens. Peps have been discovered and studied extensively in Arabidopsis and only recently orthologs in maize were also identified and characterized in more detail. Here, the presence of PROPEPs, the Pep precursors, and PEPRs, the Pep receptors, was investigated within the plant kingdom. PROPEPs and PEPRs were identified in most sequenced species of the angiosperms. The conservation and compatibility of the Pep-PEPR-system was analysed by using plants of two distantly related dicot families, Brassicaceae and Solanaceae, and a representative family of monocot plants, the Poaceae. All three plant families contain important crop plants, including maize, rice, tomato, potato, and canola. Peps were not recognized by species outside of their plant family of origin, apparently because of a divergence of the Pep sequences. Three family-specific Pep motifs were defined and the integration of such a motif into the Pep sequence of an unrelated Pep enabled its perception. Transient transformation of Nicotiana benthamiana with the coding sequences of the AtPEPR1 and ZmPEPR1a led to the recognition of Pep peptides of Brassicaceae or Poaceae origin, respectively, and to the proper activation of downstream signalling. It was concluded that signalling machinery downstream of the PEPRs is highly conserved whereas the leucine-rich repeat domains of the PEPRs co-evolved with the Peps, leading to distinct motifs and, with it, interfamily incompatibility.

  19. TGF-β prevents phosphate-induced osteogenesis through inhibition of BMP and Wnt/β-catenin pathways.

    Directory of Open Access Journals (Sweden)

    Fátima Guerrero

    Full Text Available BACKGROUND: Transforming growth factor-β (TGF-β is a key cytokine during differentiation of mesenchymal stem cells (MSC into vascular smooth muscle cells (VSMC. High phosphate induces a phenotypic transformation of vascular smooth muscle cells (VSMC into osteogenic-like cells. This study was aimed to evaluate signaling pathways involved during VSMC differentiation of MSC in presence or not of high phosphate. RESULTS: Our results showed that TGF-β induced nuclear translocation of Smad3 as well as the expression of vascular smooth muscle markers, such as smooth muscle alpha actin, SM22α, myocardin, and smooth muscle-myosin heavy chain. The addition of high phosphate to MSC promoted nuclear translocation of Smad1/5/8 and the activation of canonical Wnt/β-catenin in addition to an increase in BMP-2 expression, calcium deposition and alkaline phosphatase activity. The administration of TGF-β to MSC treated with high phosphate abolished all these effects by inhibiting canonical Wnt, BMP and TGF-β pathways. A similar outcome was observed in high phosphate-treated cells after the inhibition of canonical Wnt signaling with Dkk-1. Conversely, addition of both Wnt/β-catenin activators CHIR98014 and lithium chloride enhanced the effect of high phosphate on BMP-2, calcium deposition and alkaline phosphatase activity. CONCLUSIONS: Full VSMC differentiation induced by TGF-β may not be achieved when extracellular phosphate levels are high. Moreover, TGF-β prevents high phosphate-induced osteogenesis by decreasing the nuclear translocation of Smad 1/5/8 and avoiding the activation of Wnt/β-catenin pathway.

  20. Melatonin prevents secondary intra-abdominal hypertension in rats possibly through inhibition of the p38 MAPK pathway.

    Science.gov (United States)

    Chang, Mingtao; Li, Yang; Liu, Dong; Zhang, Lianyang; Zhang, Hongguang; Tang, Hao; Zhang, Huayu

    2016-08-01

    Exogenous administration of melatonin has been demonstrated to down-regulate inflammatory responses and attenuate organ damage in various models. However, the salutary effect of melatonin against secondary intra-abdominal hypertension (IAH) remains unclear. This study sought to test the influence of melatonin on secondary IAH in a pathophysiological rat model and the underlying mechanisms involved. Before resuscitation, male rats underwent a combination of induced portal hypertension, applying an abdominal restraint device, and hemorrhaging to mean arterial pressure (MAP) of 40mmHg for 2h. After blood reinfusion, the rats were treated with lactated Ringer solution (LR) (30mL/h), melatonin (50mg/kg) +LR, and SB-203580 (10μmol/kg)+LR. LR was continuously infused for 6h. MAP, the inferior vena cava pressure and urine output were monitored. Histopathological examination, immunofluorescence of tight junction proteins, and transmission electron microscopy were administered. Intestinal permeability, myeloperoxidase activity, malondialdehyde, glutathione peroxidase, and levels of TNF-a, IL-2, and IL-6, were assessed. The expression of extracellular signal-regulated kinase, p38, c-Jun NH2-terminal kinase, translocation of nuclear factor kappa B subunit, signal transducers and activators of transcription and tight junction proteins were detected by Western blot. We found that melatonin inhibited the inflammatory responses, decreased expression of p38 MAPK, attenuated intestinal injury, and prevented secondary IAH. Moreover, administration of SB203580 abolished the increase in p38 MAPK and also attenuated intestinal injury. These data indicate that melatonin exerts a protective effect in intestine in secondary IAH primarily by attenuating the inflammatory responses which are in part attributable to p38 MAPK inhibition. Copyright © 2016 Elsevier Inc. All rights reserved.

  1. Inhibition of E. coli P-enolpyruvate carboxylase by P-enol-3-bromopyruvate

    International Nuclear Information System (INIS)

    Asem, K.; Smith, T.E.

    1986-01-01

    The generality of the mechanism based inhibition of P-enolpyruvate carboxylases (PEPCase) by P-enol-3-bromopyruvate (BrPEP) was tested by measuring its effects on the allosterically regulated enzyme from E. coli. In the presence of 1mM Mn 2+ , BrPEP appears to be a competitive inhibitor (K/sub i/ = 0.0087mM) of PEPCase. Incubation of 0.005mM PEPCase with 0.5mM (or 1.0mM)BrPEP along with H 14 CO 3 - and Mn 2+ , yielded, upon reduction with NaBH 4 , a protein containing radioactivity in an amount approximately proportional to that expected from the loss of catalytic activity. At both a 25- and a 50-fold excess (0.5mM and 1.0mM, respectively) of BrPEP to PEPCase subunits, first order loss of activity occurred with k values of 5.24 x 10 -3 min -1 and 1.03 x 10 -2 min -1 , respectively. At the lower concentration of BrPEP the inactivation process appeared to be reversible after 40 min with no further inhibition occurring even up to two hours of incubation. At the higher concentration of BrPEP, the rate of inhibition slowed dramatically after 50 min and appeared insignificant over the next hour. These data suggest that BrPEP irreversibly inactivates the E. coli PEP carboxylase, but that there may be considerable dissociation of the product, Br-oxaloacetate, before irreversible binding occurs, and that the reduced rate of inactivation may be due to depletion of BrPEP

  2. PEP-II RF Cavity Revisited (LCC-0032)

    Energy Technology Data Exchange (ETDEWEB)

    Rimmer, R.

    2004-03-23

    This report describes the results of numerical simulations of the PEP-II RF cavity performed after the completion of the construction phase of the project and comparisons are made to previous calculations and measured results. These analyses were performed to evaluate new calculation techniques for the HOM distribution and RF surface heating that were not available at the time of the original design. These include the use of a high frequency electromagnetic element in ANSYS and the new Omega 3P code to study wall losses, and the development of broadband time domain simulation methods in MAFIA for the HOM loading. The computed HOM spectrum is compared with cavity measurements and observed beam-induced signals. The cavity fabrication method is reviewed, with the benefit of hindsight, and simplifications are discussed.

  3. Impedance analysis of the PEP-II vacuum chamber

    International Nuclear Information System (INIS)

    Ng, C.K.; Weiland, T.

    1995-05-01

    The PEP-II high energy ring (HER) vacuum chamber consists of a copper tube with periodically spaced pumping slots. The impedance of the vacuum chamber due to the slots is analyzed. Both narrow-band and broadband impedances are considered as well as longitudinal and transverse components thereof. It is found that although the broad-band impedance is tolerable, the narrow-band impedance may exceed the instability limit given by the natural damping with no feedback system on. Traveling wave modes in the chamber are the major source of this high value narrow-band impedance. We also study the dependences of the impedance on the slot length and the geometrical cross section

  4. Simulation of PEP-II Accelerator Backgrounds Using TURTLE

    CERN Document Server

    Barlow, Roger J; Kozanecki, Witold; Majewski, Stephanie; Roudeau, Patrick; Stocchi, Achille

    2005-01-01

    We present studies of accelerator-induced backgrounds in the BaBar detector at the SLAC B-Factory, carried out using a modified version ofthe DECAY TURTLE simulation package. Lost-particle backgrounds in PEP-II are dominated by a combination of beam-gas bremstrahlung, beam-gas Coulomb scattering, radiative-Bhabha events and beam-beam blow-up. The radiation damage and detector occupancy caused by the associated electromagnetic shower debris can limit the usable luminosity. In order to understand and mitigate such backgrounds, we have performed a full programme of beam-gas and luminosity-background simulations, that include the effects of the detector solenoidal field, detailed modelling of limiting apertures in both collider rings, and optimization of the betatron collimation scheme in the presence of large transverse tails.

  5. Local chromatic correction scheme for LER of PEP-II

    International Nuclear Information System (INIS)

    Forest, E.; Robin, D.; Zholents, A.; Donald, M.; Helm, R.; Irwin, J.; Sullivan, M.K.

    1993-01-01

    The correction of the chromaticity of low-beta insertions in storage rings is usually made with sextupole lenses in the ring arcs. When decreasing the beta functions at the interaction point (IP), this technique becomes fairly ineffective, since it fails to properly correct the higher-order chromatic aberrations. Here we consider the approach for ampersand PEP-II B Factory low energy ring (LER) where the chromatic effects of the quadrupole lenses generating low beta functions at the IP are corrected locally with two families of sextupoles, one family for each plane. For the IP straight section the lattice is designed in such a way that the chromatic aberrations are made small and sextupole-like aberrations are eliminated. The results of dimensional tracking simulations are presented

  6. Dual Power Supplies for PEP-II Injection Kickers

    CERN Document Server

    Olszewski, Joseph; Iverson, Richard; Kulikov, Artem; Pappas, Chris

    2005-01-01

    Originally the PEP-II injection kickers where powered by one power supply. Since the kicker magnets where not perfectly matched, the stored beam got excited by about 7% of the maximum kicker amplitude. This led to luminosity losses which were especially obvious for trickle injection when the detector is on for data taking. Therefore two independant power supplies with thyratrons in the tunnel next to the kicker magnet were installed. This also reduces the necessary power by about a factor of five since there are no long cables that have to be charged. The kickers are now independantly adjustable to eliminate any non-closure of the kicker system and therefore excitation of the stored beam. Setup, commissioning and fine tuning of this system are discussed.

  7. Dual Power Supplies for PEP-II Injection Kickers

    Energy Technology Data Exchange (ETDEWEB)

    Olszewski, J; Decker, F.-J.; Iverson, R.H.; Kulikov, A.; Pappas, C.; /SLAC

    2005-05-25

    Originally the PEP-II injection kickers were powered by one power supply. Since the kicker magnets where not perfectly matched, the stored beam got excited by about 7% of the maximum kicker amplitude. This led to luminosity losses which were especially obvious for trickle injection when the detector is on for data taking. Therefore two independent power supplies with thyratrons in the tunnel next to the kicker magnet were installed. This also reduces the necessary power by about a factor of four since there are no long cables that have to be charged. The kickers are now independently adjustable to eliminate any non-closure of the kicker system and therefore excitation of the stored beam. Setup, commissioning and fine tuning of this system are discussed.

  8. Dual Power Supplies for PEP-II Injection Kickers

    International Nuclear Information System (INIS)

    Olszewski, J; Decker, F.-J.; Iverson, R.H.; Kulikov, A.; Pappas, C.; SLAC

    2005-01-01

    Originally the PEP-II injection kickers were powered by one power supply. Since the kicker magnets where not perfectly matched, the stored beam got excited by about 7% of the maximum kicker amplitude. This led to luminosity losses which were especially obvious for trickle injection when the detector is on for data taking. Therefore two independent power supplies with thyratrons in the tunnel next to the kicker magnet were installed. This also reduces the necessary power by about a factor of four since there are no long cables that have to be charged. The kickers are now independently adjustable to eliminate any non-closure of the kicker system and therefore excitation of the stored beam. Setup, commissioning and fine tuning of this system are discussed

  9. The PEP-II Lower Pressure HER Vacuum Chamber

    International Nuclear Information System (INIS)

    DeBarger, S.; Metcalfe, S.; Seeman, J.; Sullivan, M.; Wienands, U.; Wright, D.

    2006-01-01

    This new vacuum chamber has been installed from 12 to 21 meters upstream of the BaBar detector in the PEP-II High Energy Ring (HER) to reduce lost particle backgrounds. The backgrounds from HER now dominate the backgrounds in the BaBar detector and the present vacuum pressure is 1 x 10 -9 Torr. The new chamber will increase the pumping significantly by adding 18 x 2000 l/s titanium sublimation pumps to the existing 5 x 440 l/s ion pumps, and is expected to reduce the pressure by about a factor of five. Features of the chamber include improved water cooling, improved vacuum conductance through copper RF screens featuring over 15,000 small square holes and the ability to sublimate titanium while the beam is still on

  10. Beam Commissioning of the PEP-II High Energy Ring

    International Nuclear Information System (INIS)

    Wienands, U.; Anderson, S.; Assmann, R.; Bharadwaj, V.; Cai, Y.; Clendenin, J.; Corredoura, P.; Decker, F.J.; Donald, M.; Ecklund, S.; Emma, P.; Erickson, R.; Fox, J.; Fieguth, T.; Fisher, A.; Heifets, S.; Hill, A.; Himel, T.; Iverson, R.; Johnson, R.; Judkins, J.; Krejcik, P.; Kulikov, A.; Lee, M.; Mattison, T.; Minty, M.; Nosochkov, Y.; Phinney, N.; Placidi, M.; Prabhakar, S.; Ross, M.; Smith, S.; Schwarz, H.; Stanek, M.; Teytelman, D.; Traller, R.; Turner, J.; Zimmermann, F.; Barry, W.; Chattopadhyay, S.; Corlett, J.; Decking, W.; Furman, M.; Nishimura, H.; Portmann, G.; Rimmer, R.; Zholents, A.; Zisman, M.; Kozanecki, W.; Hofmann, A.; Zotter, B.; Steier, C.; Bialowons, W.; Lomperski, M.; Lumpkin, A.; Reichel, I.; Safranek, J.; Smith, V.; Tighe, R.; Sullivan, M.; Byrd, J.; Li, D.

    1998-01-01

    The PEP-II High Energy Ring (HER), a 9 GeV electron storage ring, has been in commissioning since spring 1997. Initial beam commissioning activities focused on systems checkout and commissioning and on determining the behavior of the machine systems at high beam currents. This phase culminated with the accumulation of 0.75 A of stored beam-sufficient to achieve design luminosity--in January 1998 after 3.5 months of beam time. Collisions with the 3 GeV positron beam of the Low Energy Ring (LER) were achieved in Summer of 1998. At high beam currents, collective instabilities have been seen. Since then, commissioning activities for the HER have shifted in focus towards characterization of the machine and a rigorous program to understand the machine and the beam dynamics is presently underway

  11. Commissioning experience from PEP-II HER longitudinal feedback

    International Nuclear Information System (INIS)

    Prabhakar, S.; Teytelman, D.; Fox, J.; Young, A.; Corredoura, P.; Tighe, R.

    1998-06-01

    The DSP-based bunch-by-bunch feedback system installed in the PEP-II HER has been used to damp HOM-induced instabilities at beam currents up to 6-5 mA during commissioning. Beam pseudospectra calcualted from feedback system data indicate the presence of coupled bunch modes that oincide with the 0-M-2 cavity HOM. Bunch current and synchronous phase measurements are also extracted from the data. These measurements reveal the impedance seen by the beam at revolution harmonics. The impedance peak at 3*frev indicates incorrect parking of the idle cavities, and explains the observed instability of mode 3. Bunch synchrotron tunes are calculated from lorentzian fits to the data. Bunch-to-bunch time variation due to the cavity transient is shown to be large enough to result in Landau damping of coupled bunch modes

  12. PEP II: RF and feedback R ampersand D

    International Nuclear Information System (INIS)

    Hindi, H.: Fox, J.; Eisen, N.; Linscott, I.; Oxoby, G.; Pendleton, R.; Sapozhnikov, L.; Schwarz, H.D.; Rimmer, R.; Lambertson, A.; Voelker, F.; Serio, M.

    1992-11-01

    The key elements of the PEP 11 approach to dealing with the problem of coupled-bunch instabilities are presented. The approach involves using warm copper RF cavities with damping waveguides (above the cutoff of the fundamental) attached to the cavity walls. These couple out the troublesome higher-order modes (HOMs) into absorbing loads, while the fundamental mode remains in the cavity. The Q of the worst HOM is reduced to below 70. Instabilities due to residual coupling are damped using a bunch-by-bunch feedback system, which is implemented using digital signal processors. A prototype cavity has been built and the concept of HOM damping has been verified. A prototype feedback system has been built and tested at SPEAR. Results to date indicate that the combination of damped cavities and bunch-by-bunch feedback provide a very effective means of dealing with the problem

  13. Identifying Lattice, Orbit, And BPM Errors in PEP-II

    International Nuclear Information System (INIS)

    Decker, F.-J.; SLAC

    2005-01-01

    The PEP-II B-Factory is delivering peak luminosities of up to 9.2 · 10 33 1/cm 2 · l/s. This is very impressive especially considering our poor understanding of the lattice, absolute orbit and beam position monitor system (BPM). A few simple MATLAB programs were written to get lattice information, like betatron functions in a coupled machine (four all together) and the two dispersions, from the current machine and compare it the design. Big orbit deviations in the Low Energy Ring (LER) could be explained not by bad BPMs (only 3), but by many strong correctors (one corrector to fix four BPMs on average). Additionally these programs helped to uncover a sign error in the third order correction of the BPM system. Further analysis of the current information of the BPMs (sum of all buttons) indicates that there might be still more problematic BPMs

  14. Development of HyPEP, A Hydrogen Production Plant Efficiency Calculation Program

    International Nuclear Information System (INIS)

    Lee, Young Jin; Park, Ji Won; Lee, Won Jae; Shin, Young Joon; Kim, Jong Ho; Hong, Sung Deok; Lee, Seung Wook; Hwang, Moon Kyu

    2007-12-01

    Development of HyPEP program for assessing the steady-state hydrogen production efficiency of the nuclear hydrogen production facilities was carried out. The main developmental aims of the HyPEP program are the extensive application of the GUI for enhanced user friendliness and the fast numerical solution scheme. These features are suitable for such calculations as the optimisation calculations. HyPEP was developed with the object-oriented programming techniques. The components of the facility was modelled as objects in a hierarchical structure where the inheritance property of the object oriented program were extensively applied. The Delphi program language which is based on the Object Pascal was used for the HyPEP development. The conservation equations for the thermal hydraulic flow network were setup and the numerical solution scheme was developed and implemented into HyPEP beta version. HyPEP beta version has been developed with working GUI and the numerical solution scheme implementation. Due to the premature end of this project the fully working version of HyPEP was not produced

  15. IFNγ inhibits G-CSF induced neutrophil expansion and invasion of the CNS to prevent viral encephalitis.

    Science.gov (United States)

    Ramakrishna, Chandran; Cantin, Edouard M

    2018-01-01

    Emergency hematopoiesis facilitates the rapid expansion of inflammatory immune cells in response to infections by pathogens, a process that must be carefully regulated to prevent potentially life threatening inflammatory responses. Here, we describe a novel regulatory role for the cytokine IFNγ that is critical for preventing fatal encephalitis after viral infection. HSV1 encephalitis (HSE) is triggered by the invasion of the brainstem by inflammatory monocytes and neutrophils. In mice lacking IFNγ (GKO), we observed unrestrained increases in G-CSF levels but not in GM-CSF or IL-17. This resulted in uncontrolled expansion and infiltration of apoptosis-resistant, degranulating neutrophils into the brainstem, causing fatal HSE in GKO but not WT mice. Excessive G-CSF in GKO mice also induced granulocyte derived suppressor cells, which inhibited T-cell proliferation and function, including production of the anti-inflammatory cytokine IL-10. Unexpectedly, we found that IFNγ suppressed G-CSF signaling by increasing SOCS3 expression in neutrophils, resulting in apoptosis. Depletion of G-CSF, but not GM-CSF, in GKO mice induced neutrophil apoptosis and reinstated IL-10 secretion by T cells, which restored their ability to limit innate inflammatory responses resulting in protection from HSE. Our studies reveals a novel, complex interplay among IFNγ, G-CSF and IL-10, which highlights the opposing roles of G-CSF and IFNγ in regulation of innate inflammatory responses in a murine viral encephalitis model and reveals G-CSF as a potential therapeutic target. Thus, the antagonistic G-CSF-IFNγ interactions emerge as a key regulatory node in control of CNS inflammatory responses to virus infection.

  16. Inhibition of NAPDH Oxidase 2 (NOX2 Prevents Oxidative Stress and Mitochondrial Abnormalities Caused by Saturated Fat in Cardiomyocytes.

    Directory of Open Access Journals (Sweden)

    Leroy C Joseph

    Full Text Available Obesity and high saturated fat intake increase the risk of heart failure and arrhythmias. The molecular mechanisms are poorly understood. We hypothesized that physiologic levels of saturated fat could increase mitochondrial reactive oxygen species (ROS in cardiomyocytes, leading to abnormalities of calcium homeostasis and mitochondrial function. We investigated the effect of saturated fat on mitochondrial function and calcium homeostasis in isolated ventricular myocytes. The saturated fatty acid palmitate causes a decrease in mitochondrial respiration in cardiomyocytes. Palmitate, but not the monounsaturated fatty acid oleate, causes an increase in both total cellular ROS and mitochondrial ROS. Palmitate depolarizes the mitochondrial inner membrane and causes mitochondrial calcium overload by increasing sarcoplasmic reticulum calcium leak. Inhibitors of PKC or NOX2 prevent mitochondrial dysfunction and the increase in ROS, demonstrating that PKC-NOX2 activation is also required for amplification of palmitate induced-ROS. Cardiomyocytes from mice with genetic deletion of NOX2 do not have palmitate-induced ROS or mitochondrial dysfunction. We conclude that palmitate induces mitochondrial ROS that is amplified by NOX2, causing greater mitochondrial ROS generation and partial depolarization of the mitochondrial inner membrane. The abnormal sarcoplasmic reticulum calcium leak caused by palmitate could promote arrhythmia and heart failure. NOX2 inhibition is a potential therapy for heart disease caused by diabetes or obesity.

  17. Adverse cardiac effects of exogenous angiotensin 1-7 in rats with subtotal nephrectomy are prevented by ACE inhibition.

    Directory of Open Access Journals (Sweden)

    Louise M Burrell

    Full Text Available We previously reported that exogenous angiotensin (Ang 1-7 has adverse cardiac effects in experimental kidney failure due to its action to increase cardiac angiotensin converting enzyme (ACE activity. This study investigated if the addition of an ACE inhibitor (ACEi to Ang 1-7 infusion would unmask any beneficial effects of Ang 1-7 on the heart in experimental kidney failure. Male Sprague-Dawley rats underwent subtotal nephrectomy (STNx and were treated with vehicle, the ACEi ramipril (oral 1mg/kg/day, Ang 1-7 (subcutaneous 24 μg/kg/h or dual therapy (all groups, n = 12. A control group (n = 10 of sham-operated rats were also studied. STNx led to hypertension, renal impairment, cardiac hypertrophy and fibrosis, and increased both left ventricular ACE2 activity and ACE binding. STNx was not associated with changes in plasma levels of ACE, ACE2 or angiotensin peptides. Ramipril reduced blood pressure, improved cardiac hypertrophy and fibrosis and inhibited cardiac ACE. Ang 1-7 infusion increased blood pressure, cardiac interstitial fibrosis and cardiac ACE binding compared to untreated STNx rats. Although in STNx rats, the addition of ACEi to Ang 1-7 prevented any deleterious cardiac effects of Ang 1-7, a limitation of the study is that the large increase in plasma Ang 1-7 with ramipril may have masked any effect of infused Ang 1-7.

  18. Proline iminopeptidase PepI overexpressing Lactobacillus casei as an adjunct starter in Edam cheese

    Science.gov (United States)

    Navidghasemizad, Sahar; Takala, Timo M; Alatossava, Tapani; Saris, Per EJ

    2013-01-01

    In this study the growth of genetically modified Lactobacillus casei LAB6, overexpressing proline iminopeptidase PepI and its capacity to increase free proline was investigated during ripening of Edam cheese. The strain successfully survived 12 weeks of ripening period in cheese. The food-grade plasmid pLEB604, carrying the pepI gene, was stable, and PepI enzyme was active in LAB6 cells isolated at different stages of the ripening process. However, HPLC analyses indicated that Lb. casei LAB6 could not increase the amount of free proline in ripened cheese. PMID:23851577

  19. Prevention of formation of acid drainage from high-sulfur coal refuse by inhibition of iron- and sulfur-oxidizing microorganisms. II. Inhibition in run of mine refuse under simulated field conditions

    Energy Technology Data Exchange (ETDEWEB)

    Dugan, P.R.

    1987-01-01

    The combination of sodium lauryl sulfate and benzoic acid effectively inhibits iron- and sulfur-oxidizing bacteria in coal refuse and prevents the conversion of iron pyrite to sulfate, ferric iron, and sulfuric acid, thereby significantly reducing the formation of acidic drainage from coal refuse. The inhibitors were effective in a concentration of 1.1. mg/kg refuse, and data indicate that the SLS was in excess of the concentration required. The treatment was compatible with the use of lime for neutralization of acid present prior to inhibition of its formation.

  20. A Chimeric Peptide Composed of a Dermaseptin Derivative and an RNA III-Inhibiting Peptide Prevents Graft-Associated Infections by Antibiotic-Resistant Staphylococci

    Science.gov (United States)

    Balaban, Naomi; Gov, Yael; Giacometti, Andrea; Cirioni, Oscar; Ghiselli, Roberto; Mocchegiani, Federico; Orlando, Fiorenza; D'Amato, Giuseppina; Saba, Vittorio; Scalise, Giorgio; Bernes, Sabina; Mor, Amram

    2004-01-01

    Staphylococcal bacteria are a prevalent cause of infections associated with foreign bodies and indwelling medical devices. Bacteria are capable of escaping antibiotic treatment through encapsulation into biofilms. RNA III-inhibiting peptide (RIP) is a heptapeptide that inhibits staphylococcal biofilm formation by obstructing quorum-sensing mechanisms. K4-S4(1-13)a is a 13-residue dermaseptin derivative (DD13) believed to kill bacteria via membrane disruption. We tested each of these peptides as well as a hybrid construct, DD13-RIP, for their ability to inhibit bacterial proliferation and suppress quorum sensing in vitro and for their efficacy in preventing staphylococcal infection in a rat graft infection model with methicillin-resistant Staphylococcus aureus (MRSA) or S. epidermidis (MRSE). In vitro, proliferation assays demonstrated that RIP had no inhibitory effect, while DD13-RIP and DD13 were equally effective, and that the chimeric peptide but not DD13 was slightly more effective than RIP in inhibiting RNA III synthesis, a regulatory RNA molecule important for staphylococcal pathogenesis. In vivo, the three peptides reduced graft-associated bacterial load in a dose-dependent manner, but the hybrid peptide was most potent in totally preventing staphylococcal infections at the lowest dose. In addition, each of the peptides acted synergistically with antibiotics. The data indicate that RIP and DD13 act in synergy by attacking bacteria simultaneously by two different mechanisms. Such a chimeric peptide may be useful for coating medical devices to prevent drug-resistant staphylococcal infections. PMID:15215107

  1. EFRT M-12 Issue Resolution: Comparison of PEP and Bench-Scale Oxidative Leaching Results

    International Nuclear Information System (INIS)

    Rapko, Brian M.; Schonewill, Philip P.; Brown, Christopher F.; Eslinger, Paul W.; Fountain, Matthew S.; Hausmann, Tom S.; Huckaby, James L.; Hanson, Brady D.; Kurath, Dean E.; Minette, Michael J.

    2010-01-01

    Pacific Northwest National Laboratory (PNNL) has been tasked by Bechtel National Inc. (BNI) on the River Protection Project-Hanford Tank Waste Treatment and Immobilization Plant (RPP-WTP) project to perform research and development activities to resolve technical issues identified for the Pretreatment Facility (PTF). The Pretreatment Engineering Platform (PEP) was designed, constructed, and operated as part of a plan to respond to issue M12, 'Undemonstrated Leaching Processes' of the External Flowsheet Review Team (EFRT) issue response plan. The PEP is a 1/4.5-scale test platform designed to simulate the WTP pretreatment caustic leaching, oxidative leaching, ultrafiltration solids concentration, and slurry washing processes. The PEP replicates the WTP leaching processes using prototypic equipment and control strategies. The PEP also includes non-prototypic ancillary equipment to support the core processing.

  2. EFRT M-12 Issue Resolution: Comparison of Filter Performance at PEP and CUF Scale

    International Nuclear Information System (INIS)

    Daniel, Richard C.; Billing, Justin M.; Bontha, Jagannadha R.; Brown, Christopher F.; Eslinger, Paul W.; Hanson, Brady D.; Huckaby, James L.; Karri, Naveen K.; Kimura, Marcia L.; Kurath, Dean E.; Minette, Michael J.

    2010-01-01

    Pacific Northwest National Laboratory (PNNL) has been tasked by Bechtel National Inc. (BNI) on the River Protection Project-Hanford Tank Waste Treatment and Immobilization Plant (RPP-WTP) project to perform research and development activities to resolve technical issues identified for the Pretreatment Facility (PTF). The Pretreatment Engineering Platform (PEP) was designed, constructed, and operated as part of a plan to respond to issue M12, 'Undemonstrated Leaching Processes' of the External Flowsheet Review Team (EFRT) issue response plan.(a) The PEP is a 1/4.5-scale test platform designed to simulate the WTP pretreatment caustic leaching, oxidative leaching, ultrafiltration solids concentration, and slurry washing processes. The PEP replicates the WTP leaching processes using prototypic equipment and control strategies. The PEP also includes non-prototypic ancillary equipment to support the core processing.

  3. EFRT M-12 Issue Resolution: Comparison of Filter Performance at PEP and CUF Scale

    Energy Technology Data Exchange (ETDEWEB)

    Daniel, Richard C.; Billing, Justin M.; Bontha, Jagannadha R.; Brown, Christopher F.; Eslinger, Paul W.; Hanson, Brady D.; Huckaby, James L.; Karri, Naveen K.; Kimura, Marcia L.; Kurath, Dean E.; Minette, Michael J.

    2010-01-22

    Pacific Northwest National Laboratory (PNNL) has been tasked by Bechtel National Inc. (BNI) on the River Protection Project-Hanford Tank Waste Treatment and Immobilization Plant (RPP-WTP) project to perform research and development activities to resolve technical issues identified for the Pretreatment Facility (PTF). The Pretreatment Engineering Platform (PEP) was designed, constructed, and operated as part of a plan to respond to issue M12, “Undemonstrated Leaching Processes” of the External Flowsheet Review Team (EFRT) issue response plan.(a) The PEP is a 1/4.5-scale test platform designed to simulate the WTP pretreatment caustic leaching, oxidative leaching, ultrafiltration solids concentration, and slurry washing processes. The PEP replicates the WTP leaching processes using prototypic equipment and control strategies. The PEP also includes non-prototypic ancillary equipment to support the core processing.

  4. EFRT M-12 Issue Resolution: Comparison of PEP and Bench-Scale Oxidative Leaching Results

    Energy Technology Data Exchange (ETDEWEB)

    Rapko, Brian M.; Schonewill, Philip P.; Brown, Christopher F.; Eslinger, Paul W.; Fountain, Matthew S.; Hausmann, Tom S.; Huckaby, James L.; Hanson, Brady D.; Kurath, Dean E.; Minette, Michael J.

    2010-01-01

    Pacific Northwest National Laboratory (PNNL) has been tasked by Bechtel National Inc. (BNI) on the River Protection Project-Hanford Tank Waste Treatment and Immobilization Plant (RPP-WTP) project to perform research and development activities to resolve technical issues identified for the Pretreatment Facility (PTF). The Pretreatment Engineering Platform (PEP) was designed, constructed, and operated as part of a plan to respond to issue M12, “Undemonstrated Leaching Processes” of the External Flowsheet Review Team (EFRT) issue response plan.( ) The PEP is a 1/4.5-scale test platform designed to simulate the WTP pretreatment caustic leaching, oxidative leaching, ultrafiltration solids concentration, and slurry washing processes. The PEP replicates the WTP leaching processes using prototypic equipment and control strategies. The PEP also includes non-prototypic ancillary equipment to support the core processing.

  5. Responses of mRNA expression of PepT1 in small intestine to ...

    African Journals Online (AJOL)

    STORAGESEVER

    2009-05-04

    May 4, 2009 ... 2National Key Laboratory of Animal Nutrition, Beijing, 100193, China. 3College ... porters are present in tissues of sheep, cows, pigs and .... PepT1; Peptide transporter, GAPDH; Glyceraldehyde-3-phosphate dehydrogenase.

  6. δ-Tocotrienol, a natural form of vitamin E, inhibits pancreatic cancer stem-like cells and prevents pancreatic cancer metastasis.

    Science.gov (United States)

    Husain, Kazim; Centeno, Barbara A; Coppola, Domenico; Trevino, Jose; Sebti, Said M; Malafa, Mokenge P

    2017-05-09

    The growth, metastasis, and chemotherapy resistance of pancreatic ductal adenocarcinoma (PDAC) is characterized by the activation and growth of tumor-initiating cells in distant organs that have stem-like properties. Thus, inhibiting growth of these cells may prevent PDAC growth and metastases. We have demonstrated that δ-tocotrienol, a natural form of vitamin E (VEDT), is bioactive against cancer, delays progression, and prevents metastases in transgenic mouse models of PDAC. In this report, we provide the first evidence that VEDT selectively inhibits PDAC stem-like cells. VEDT inhibited the viability, survival, self-renewal, and expression of Oct4 and Sox2 transcription factors in 3 models of PDAC stem-like cells. In addition, VEDT inhibited the migration, invasion, and several biomarkers of epithelial-to-mesenchymal transition and angiogenesis in PDAC cells and tumors. These processes are critical for tumor metastases. Furthermore, in the L3.6pl orthotopic model of PDAC metastases, VEDT significantly inhibited growth and metastases of these cells. Finally, in an orthotopic xenograft model of human PDAC stem-like cells, we showed that VEDT significantly retarded the growth and metastases of gemcitabine-resistant PDAC human stem-like cells. Because VEDT has been shown to be safe and to reach bioactive levels in humans, this work supports investigating VEDT for chemoprevention of PDAC metastases.

  7. Ca 2+ signaling by plant Arabidopsis thaliana Pep peptides depends on AtPepR1, a receptor with guanylyl cyclase activity, and cGMP-activated Ca 2+ channels

    KAUST Repository

    Qia, Zhi

    2010-11-18

    A family of peptide signaling molecules (AtPeps) and their plasma membrane receptor AtPepR1 are known to act in pathogendefense signaling cascades in plants. Little is currently known about the molecular mechanisms that link these signaling peptides and their receptor, a leucine-rich repeat receptor-like kinase, to downstream pathogen-defense responses. We identify some cellular activities of these molecules that provide the context for a model for their action in signaling cascades. AtPeps activate plasma membrane inwardly conducting Ca 2+ permeable channels in mesophyll cells, resulting in cytosolic Ca 2+ elevation. This activity is dependent on their receptor as well as a cyclic nucleotide-gated channel (CNGC2). We also show that the leucine-rich repeat receptor- like kinase receptor AtPepR1 has guanylyl cyclase activity, generating cGMP from GTP, and that cGMP can activate CNGC2- dependent cytosolic Ca 2+ elevation. AtPep-dependent expression of pathogen-defense genes (PDF1.2, MPK3, and WRKY33) is mediated by the Ca 2+ signaling pathway associated with AtPep peptides and their receptor. The work presented here indicates that extracellular AtPeps, which can act as danger-associated molecular patterns, signal by interaction with their receptor, AtPepR1, a plasma membrane protein that can generate cGMP. Downstream from AtPep and AtPepR1 in a signaling cascade, the cGMP-activated channel CNGC2 is involved in AtPep- and AtPepR1-dependent inward Ca 2+ conductance and resulting cytosolic Ca 2+ elevation. The signaling cascade initiated by AtPeps leads to expression of pathogen- defense genes in a Ca 2+-dependent manner.

  8. DomPep--a general method for predicting modular domain-mediated protein-protein interactions.

    Directory of Open Access Journals (Sweden)

    Lei Li

    Full Text Available Protein-protein interactions (PPIs are frequently mediated by the binding of a modular domain in one protein to a short, linear peptide motif in its partner. The advent of proteomic methods such as peptide and protein arrays has led to the accumulation of a wealth of interaction data for modular interaction domains. Although several computational programs have been developed to predict modular domain-mediated PPI events, they are often restricted to a given domain type. We describe DomPep, a method that can potentially be used to predict PPIs mediated by any modular domains. DomPep combines proteomic data with sequence information to achieve high accuracy and high coverage in PPI prediction. Proteomic binding data were employed to determine a simple yet novel parameter Ligand-Binding Similarity which, in turn, is used to calibrate Domain Sequence Identity and Position-Weighted-Matrix distance, two parameters that are used in constructing prediction models. Moreover, DomPep can be used to predict PPIs for both domains with experimental binding data and those without. Using the PDZ and SH2 domain families as test cases, we show that DomPep can predict PPIs with accuracies superior to existing methods. To evaluate DomPep as a discovery tool, we deployed DomPep to identify interactions mediated by three human PDZ domains. Subsequent in-solution binding assays validated the high accuracy of DomPep in predicting authentic PPIs at the proteome scale. Because DomPep makes use of only interaction data and the primary sequence of a domain, it can be readily expanded to include other types of modular domains.

  9. The Woods Hole Partnership Education Program (PEP): Broadening Participation in the Geosciences

    Science.gov (United States)

    Scott, O.; Jearld, A., Jr.; Liles, G.; Gutierrez, B.

    2015-12-01

    In March 2009, the Woods Hole Diversity Initiative launched the Partnership Education Program (PEP), a multi-institutional effort to increase diversity in the student population (and ultimately the work force) in the Woods Hole science community. PEP, a summer research internship program, is open to students of all backgrounds but is designed especially to provide opportunities for URM in science, technology, engineering, and mathematics (STEM). PEP is a 10-week program which provides intensive mentored research, a credit-bearing course and supplemental career and professional development activities. Students have opportunities to work in various research areas of geosciences. PEP is emerging as an effective and sustainable approach to bringing students into the STEM research community. PEP is carefully structured to provide critical support for students as they complete their undergraduate experience and prepare for geosciences careers and/or graduate school. The PEP experience is intended to provide students with an entry into the Woods Hole science community, one of the most vibrant marine and environmental research communities in the world. The program aims to provide a first-hand introduction to emerging issues and real-world training in the research skills that students need to advance in science, either as graduate students or bachelors-level working scientists. This is a long-recognized need and efforts are being made to ensure that the students begin to acquire skills and aptitudes that position them to take advantage of a wide range of opportunities. Of note is that the PEP is transitioning into a two year program where students are participating in a second year as a research intern or employee. Since 2013, at least four partner institutions have invited PEP alumni to participate in their respective programs as research assistants and/or full-time technicians.

  10. In roots of Arabidopsis thaliana, the damage-associated molecular pattern AtPep1 is a stronger elicitor of immune signalling than flg22 or the chitin heptamer.

    Directory of Open Access Journals (Sweden)

    Lorenzo Poncini

    Full Text Available Plants interpret their immediate environment through perception of small molecules. Microbe-associated molecular patterns (MAMPs such as flagellin and chitin are likely to be more abundant in the rhizosphere than plant-derived damage-associated molecular patterns (DAMPs. We investigated how the Arabidopsis thaliana root interprets MAMPs and DAMPs as danger signals. We monitored root development during exposure to increasing concentrations of the MAMPs flg22 and the chitin heptamer as well as of the DAMP AtPep1. The tissue-specific expression of defence-related genes in roots was analysed using a toolkit of promoter::YFPN lines reporting jasmonic acid (JA-, salicylic acid (SA-, ethylene (ET- and reactive oxygen species (ROS- dependent signalling. Finally, marker responses were analysed during invasion by the root pathogen Fusarium oxysporum. The DAMP AtPep1 triggered a stronger activation of the defence markers compared to flg22 and the chitin heptamer. In contrast to the tested MAMPs, AtPep1 induced SA- and JA-signalling markers in the root and caused a severe inhibition of root growth. Fungal attack resulted in a strong activation of defence genes in tissues close to the invading fungal hyphae. The results collectively suggest that AtPep1 presents a stronger danger signal to the Arabidopsis root than the MAMPs flg22 and chitin heptamer.

  11. The pepATTRACT web server for blind, large-scale peptide-protein docking.

    Science.gov (United States)

    de Vries, Sjoerd J; Rey, Julien; Schindler, Christina E M; Zacharias, Martin; Tuffery, Pierre

    2017-07-03

    Peptide-protein interactions are ubiquitous in the cell and form an important part of the interactome. Computational docking methods can complement experimental characterization of these complexes, but current protocols are not applicable on the proteome scale. pepATTRACT is a novel docking protocol that is fully blind, i.e. it does not require any information about the binding site. In various stages of its development, pepATTRACT has participated in CAPRI, making successful predictions for five out of seven protein-peptide targets. Its performance is similar or better than state-of-the-art local docking protocols that do require binding site information. Here we present a novel web server that carries out the rigid-body stage of pepATTRACT. On the peptiDB benchmark, the web server generates a correct model in the top 50 in 34% of the cases. Compared to the full pepATTRACT protocol, this leads to some loss of performance, but the computation time is reduced from ∼18 h to ∼10 min. Combined with the fact that it is fully blind, this makes the web server well-suited for large-scale in silico protein-peptide docking experiments. The rigid-body pepATTRACT server is freely available at http://bioserv.rpbs.univ-paris-diderot.fr/services/pepATTRACT. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

  12. Pan European Phenological database (PEP725): a single point of access for European data

    Science.gov (United States)

    Templ, Barbara; Koch, Elisabeth; Bolmgren, Kjell; Ungersböck, Markus; Paul, Anita; Scheifinger, Helfried; Rutishauser, This; Busto, Montserrat; Chmielewski, Frank-M.; Hájková, Lenka; Hodzić, Sabina; Kaspar, Frank; Pietragalla, Barbara; Romero-Fresneda, Ramiro; Tolvanen, Anne; Vučetič, Višnja; Zimmermann, Kirsten; Zust, Ana

    2018-02-01

    The Pan European Phenology (PEP) project is a European infrastructure to promote and facilitate phenological research, education, and environmental monitoring. The main objective is to maintain and develop a Pan European Phenological database (PEP725) with an open, unrestricted data access for science and education. PEP725 is the successor of the database developed through the COST action 725 "Establishing a European phenological data platform for climatological applications" working as a single access point for European-wide plant phenological data. So far, 32 European meteorological services and project partners from across Europe have joined and supplied data collected by volunteers from 1868 to the present for the PEP725 database. Most of the partners actively provide data on a regular basis. The database presently holds almost 12 million records, about 46 growing stages and 265 plant species (including cultivars), and can be accessed via http://www.pep725.eu/. Users of the PEP725 database have studied a diversity of topics ranging from climate change impact, plant physiological question, phenological modeling, and remote sensing of vegetation to ecosystem productivity.

  13. Factors Associated With Forensic Nurses Offering HIV nPEP Status Post Sexual Assault.

    Science.gov (United States)

    Draughon, Jessica E; Hauda, William E; Price, Bonnie; Rotolo, Sue; Austin, Kim Wieczorek; Sheridan, Daniel J

    2015-09-01

    Nonoccupational, postexposure prophylaxis (nPEP) for human immunodeficiency virus (HIV) is offered inconsistently to patients who have been sexually assaulted. This may be due to Forensic Nurse Examiner (FNE) programs utilizing diverse nPEP protocols and HIV risk assessment algorithms. This study examines factors associated with FNEs offering nPEP to patients following sexual assault at two FNE programs in urban settings. Offering nPEP is mostly driven by site-specific protocol. At Site 1, in addition to open anal or open genital wounds, the presence of injury to the head or face was associated with FNEs offering nPEP (adjusted odds ratio [AOR] 64.15, 95% confidence interval [CI] = [2.12, 1942.37]). At Site 2, patients assaulted by someone of Other race/ethnicity (non-White, non-African American) were 86% less likely to be offered nPEP (AOR 0.14, 95% CI = [.03, .72]) than patients assaulted by Whites. In addition to following site-specific protocols, future research should further explore the mechanisms influencing clinician decision making. © The Author(s) 2014.

  14. Pan European Phenological database (PEP725): a single point of access for European data

    Science.gov (United States)

    Templ, Barbara; Koch, Elisabeth; Bolmgren, Kjell; Ungersböck, Markus; Paul, Anita; Scheifinger, Helfried; Rutishauser, This; Busto, Montserrat; Chmielewski, Frank-M.; Hájková, Lenka; Hodzić, Sabina; Kaspar, Frank; Pietragalla, Barbara; Romero-Fresneda, Ramiro; Tolvanen, Anne; Vučetič, Višnja; Zimmermann, Kirsten; Zust, Ana

    2018-06-01

    The Pan European Phenology (PEP) project is a European infrastructure to promote and facilitate phenological research, education, and environmental monitoring. The main objective is to maintain and develop a Pan European Phenological database (PEP725) with an open, unrestricted data access for science and education. PEP725 is the successor of the database developed through the COST action 725 "Establishing a European phenological data platform for climatological applications" working as a single access point for European-wide plant phenological data. So far, 32 European meteorological services and project partners from across Europe have joined and supplied data collected by volunteers from 1868 to the present for the PEP725 database. Most of the partners actively provide data on a regular basis. The database presently holds almost 12 million records, about 46 growing stages and 265 plant species (including cultivars), and can be accessed via http://www.pep725.eu/ . Users of the PEP725 database have studied a diversity of topics ranging from climate change impact, plant physiological question, phenological modeling, and remote sensing of vegetation to ecosystem productivity.

  15. Is there an optimal level of positive expiratory pressure (PEP) to improve walking tolerance in patients with severe COPD?

    Science.gov (United States)

    Russo, Davide; Simonelli, Carla; Paneroni, Mara; Saleri, Manuela; Piroddi, Ines Maria Grazia; Cardinale, Francesco; Vitacca, Michele; Nicolini, Antonello

    2016-07-01

    The application of positive expiratory pressure (PEP) devices during exercise had been proposed in order to counteract the pulmonary hyperinflation, reduce the dyspnea and thus increase the exercise tolerance in patients with severe chronic obstructive pulmonary disease (COPD). This randomized controlled crossover trial investigated the effect of two different levels of PEP (1 cmH2O and 10 cmH2O) on distance covered at 6minute walk test (6MWT) in patients with severe COPD. Secondary outcomes were the evaluation of PEP effects on physiological and pulmonary function variables. Seventy-two severe COPD patients, referred to our hospitals as in and out patients, were recruited. A basal 6MWT without devices was performed on the first day, and then repeated with PEP 1 cmH2O (PEP1) and 10 cmH2O (PEP10), with a randomized crossover design. Slow and forced spirometries, including the inspiratory capacity measure, were repeated before and after each 6MWT. 50 patients (average age 69,92 year, mean FEV1 41,42% of predicted) concluded the trial. The 6MWT improved significantly among both PEP levels and baseline (323,8 mt at baseline vs. 337,8 PEP1 and 341,8 PEP10; p<.002 and p<.018, respectively). The difference between PEP10 and PEP1 did not reach the significance. No improvements were found in pulmonary function, symptoms and physiological variables after the 6MWT. In patients with severe COPD, the application of 1 cmH2O of PEP seems to improve the exercise tolerance as 10 cmH2O, with similar dyspnea. Further studies should investigate the effects of low levels of PEP on aerobic training programs. Copyright © 2016 SEPAR. Published by Elsevier Espana. All rights reserved.

  16. Progress on PEP-II injection R ampersand D

    International Nuclear Information System (INIS)

    Bloom, E.; Bulos, F.; Fieguth, T.; Godfrey, G.; Loew, G.; Miller, R.

    1993-06-01

    The R ampersand D program described in this paper focuses on an improvement of the SLAC linac designed to extract and study a 9 GeV electron beam under stringent control of energy, energy spread, emittance, optical parameters, and timing. The extraction system begins with an on-axis pulsed magnet, followed by a magnetic lattice and diagnostic equipment required for the measurement and optimization of the above beam qualities. Design, construction, and installation of this system is the first step in the development of the overall PEP-II e ± injection system. This system is required to fill 1658 bunches of 9 GeV electrons (0.99A stored) and 3.1 GeV positrons (2.14A stored) in two separate rings in a total of about 6 minutes from zero ring current (i.e., full-fill mode, 0 to 100%) or in about 3 minutes from 80% ring current (i.e., topping-off mode, 80 to 100%). This unprecedented rate of filling can be met by a judicious use of the SLC linac, damping rings, and positron source

  17. Design of the PEP-II Interaction Region Septum Quadrupole

    Science.gov (United States)

    Osborn, J.; Tanabe, J.; Yee, D.; Younger, F.

    1997-05-01

    The PEP-II QF2 magnet is one of the final focus quadrupoles for the Low-Energy Ring (LER) and utilizes a septum aperture to accommodate the adjacent High-Energy Ring (HER) beamline. The LER lattice design specification calls for an extremely high field quality for this magnet. A conventional water-cooled copper coil and laminated steel core design was selected to allow adjustment in the excitation. The close proximity between the LER and HER beamlines and the required integrated quadrupole strength result in a moderately high current density septum design. The QF2 magnets are imbedded in a confined region at each end of the BaBar detector, thus requiring a small magnet core cross section. Pole face windings are included in the QF2 design to buck the skew octupole term induced by the solenoidal fringe field that leaks out of the detector. Back-leg windings are included to buck a small dipole component induced by the lack of perfect quadrupole symmetry in this septum design. 2D pole contour optimization and 3D end chamfers are used to minimize harmonic errors; a separate permanent-magnet Harmonic Corrector Ring compensates for remaining field errors. The design methods and approach, 2D and 3D analyses, and the resulting expected magnet performance are described in this paper.

  18. Secondary Electron Emission Yields from PEP-II Accelerator Materials

    International Nuclear Information System (INIS)

    Kirby, Robert E.

    2000-01-01

    The PEP-II B-Factory at SLAC operates with aluminum alloy and copper vacuum chambers, having design positron and electron beam currents of 2 and 1 A, respectively. Titanium nitride coating of the aluminum vacuum chamber in the arcs of the positron ring is needed in order to reduce undesirable electron-cloud effects. The total secondary electron emission yield of TiN-coated aluminum alloy has been measured after samples of beam chamber material were exposed to air and again after electron-beam bombardment, as a function of incident electron beam angle and energy. The results may be used to simulate and better understand electron-cloud effects under actual operating conditions. We also present yield measurements for other accelerator materials because new surface effects are expected to arise as beam currents increase. Copper, in particular, is growing in popularity for its good thermal conductivity and self-radiation-shielding properties. The effect of electron bombardment, ''conditioning'', on the yield of TiN and copper is shown

  19. PEP-II Large Power Supplies Rebuild Program at SLAC

    CERN Document Server

    de Lira, Antonio C; Lipari, James J; da Silva Rafael, Fernando

    2005-01-01

    At PEP-II, seven large power supplies (LGPS) are used to power quad magnets in the electron-positron collider region. The LGPS ratings range from 72kW to 270kW, and were installed in 1997. They are unipolar off-line switch mode supplies, with a 6 pulse bridge rectifying 480VAC, 3-phase input power to yield 650VDC unregulated. This unregulated 650VDC is then input into one (or two) IGBT H-bridges, which convert the DC into PWM 16 kHz square wave AC. This high frequency AC drives the primary side of a step-down transformer followed by rectifiers and low pass filters. Over the years, these LGPS have presented many problems mainly in their control circuits, making it difficult to troubleshoot and affecting the overall accelerator availability. A redesign/rebuilding program for these power supplies was established under the coordination of the Power Conversion Department at SLAC. During the 2004 accelerator summer shutdown all the control circuits in these supplies were redesigned and replaced. A new PWM control b...

  20. Sensitivity of the PEP beam transport line to perturbations

    International Nuclear Information System (INIS)

    Peterson, J.M.; Brown, K.L.

    1979-03-01

    The sensitivity of a beam-transport line to various perturbations determines the extent to which one can simplify component design and relax tolerances. For the PEP injection lines, effects of various fabrication errors, magnet misalignments, and residual gas scattering were studied. Using the TURTLE ray-tracing program, it is found that magnetic-field errors corresponding to a relative sextupole strength in the dipoles of 0.5% and/or a relative sextupole or octupole strength in the quadrupoles of 5% are permissible. This allows relatively loose tolerances in magnet fabrication. Transverse misalignment of a quadrupole by a distance x causes the beam centroid to be displaced downstream by as much as 5x. This requires a quadrupole alignment accuracy of +- 0.5 mm or better. No compensation for the earth's field is necessary because an integral number of optical wavelengths and a short wavelength were used for the design. Analysis shows that beam broadening from multiple coulomb scattering is insignificant for pressures of less than 1/10 torr

  1. Progress on PEP-II injection R ampersand D

    International Nuclear Information System (INIS)

    Bloom, E.; Bulos, F.; Fieguth, T.; Godfrey, G.; Loew, G.; Miller, R.

    1993-01-01

    The R ampersand D program described in this paper focuses on an improvement of the SLAC linac designed to extract and study a 9 GeV electron beam under stringent control of energy, energy spread, emittance, optical parameters, and timing. The extraction system begins with an on-axis pulsed magnet, followed by a magnetic lattice and diagnostic equipment required for the measurement and optimization of the above beam qualities. Design, construction, and installation of this system is the first step in the development of the overall PEP-II e ± injection system. This system is required to fill 1658 bunches of 9 GeV electrons (0.99A stored) and 3.1 GeV positrons (2.14A stored) in two separate rings in a total of about 6 minutes from zero ring current (i.e., full-fill mode, 0 to 100%) or in about 3 minutes from 80% ring current (i.e., topping-off mode, 80 to 100%). This unprecedented rate of filling can be met by a judicious use of the SLC linac, damping rings, and positron source

  2. Lattice Effects Due to High Currents in PEP-II

    International Nuclear Information System (INIS)

    Decker, F.-J.; Smith, H.; Turner, J.L.; SLAC

    2005-01-01

    The very high beam currents in the PEP-II B-Factory have caused many expected and unexpected effects: Synchrotron light fans move the beam pipe and cause dispersion; higher order modes cause excessive heating, e-clouds around the positron beam blow up its beam size. Here we describe an effect where the measured dispersion of the beam in the Low Energy Ring (LER) is different at high and at low beam currents. The dispersion was iteratively lowered by making anti-symmetric orbit bumps in many sextupole duplets, checking each time with a dispersion measurement where a dispersive kick is generated. This can be done parasitically during collisions. It was a surprise when checking the low current characterization data that there is a change. Subsequent high and low current measurements confirmed the effect. One source was believed to be located far away from any synchrotron radiation in the middle of a straight (PR12), away from sextupoles and skew quadrupoles and created a dispersion wave of about 70 mm at high current while at low current it is negligible

  3. Prevention

    DEFF Research Database (Denmark)

    Halken, S; Høst, A

    2001-01-01

    , breastfeeding should be encouraged for 4-6 months. In high-risk infants a documented extensively hydrolysed formula is recommended if exclusive breastfeeding is not possible for the first 4 months of life. There is no evidence for preventive dietary intervention neither during pregnancy nor lactation...... populations. These theories remain to be documented in proper, controlled and prospective studies. Breastfeeding and the late introduction of solid foods (>4 months) is associated with a reduced risk of food allergy, atopic dermatitis, and recurrent wheezing and asthma in early childhood. In all infants....... Preventive dietary restrictions after the age of 4-6 months are not scientifically documented....

  4. Pregnenolone co-treatment partially restores steroidogenesis, but does not prevent growth inhibition and increased atresia in mouse ovarian antral follicles treated with mono-hydroxy methoxychlor

    Energy Technology Data Exchange (ETDEWEB)

    Craig, Zelieann R., E-mail: zelieann@illinois.edu; Hannon, Patrick R., E-mail: phannon2@illinois.edu; Flaws, Jodi A., E-mail: jflaws@illinois.edu

    2013-11-01

    Mono-hydroxy methoxychlor (mono-OH MXC) is a metabolite of the pesticide, methoxychlor (MXC). Although MXC is known to decrease antral follicle numbers, and increase follicle death in rodents, not much is known about the ovarian effects of mono-OH MXC. Previous studies indicate that mono-OH MXC inhibits mouse antral follicle growth, increases follicle death, and inhibits steroidogenesis in vitro. Further, previous studies indicate that CYP11A1 expression and production of progesterone (P{sub 4}) may be the early targets of mono-OH MXC in the steroidogenic pathway. Thus, this study tested whether supplementing pregnenolone, the precursor of progesterone and the substrate for HSD3B, would prevent decreased steroidogenesis, inhibited follicle growth, and increased follicle atresia in mono-OH MXC-treated follicles. Mouse antral follicles were exposed to vehicle (dimethylsulfoxide), mono-OH MXC (10 μg/mL), pregnenolone (1 μg/mL), or mono-OH MXC and pregnenolone together for 96 h. Levels of P{sub 4}, androstenedione (A), testosterone (T), estrone (E{sub 1}), and 17β-estradiol (E{sub 2}) in media were determined, and follicles were processed for histological evaluation of atresia. Pregnenolone treatment alone stimulated production of all steroid hormones except E{sub 2}. Mono-OH MXC-treated follicles had decreased sex steroids, but when given pregnenolone, produced levels of P{sub 4}, A, T, and E{sub 1} that were comparable to those in vehicle-treated follicles. Pregnenolone treatment did not prevent growth inhibition and increased atresia in mono-OH MXC-treated follicles. Collectively, these data support the idea that the most upstream effect of mono-OH MXC on steroidogenesis is by reducing the availability of pregnenolone, and that adding pregnenolone may not be sufficient to prevent inhibited follicle growth and survival. - Highlights: • Mono-OH MXC inhibited antral follicle steroidogenesis, growth, and survival. • Pregnenolone partially restored steroidogenesis

  5. Pregnenolone co-treatment partially restores steroidogenesis, but does not prevent growth inhibition and increased atresia in mouse ovarian antral follicles treated with mono-hydroxy methoxychlor

    International Nuclear Information System (INIS)

    Craig, Zelieann R.; Hannon, Patrick R.; Flaws, Jodi A.

    2013-01-01

    Mono-hydroxy methoxychlor (mono-OH MXC) is a metabolite of the pesticide, methoxychlor (MXC). Although MXC is known to decrease antral follicle numbers, and increase follicle death in rodents, not much is known about the ovarian effects of mono-OH MXC. Previous studies indicate that mono-OH MXC inhibits mouse antral follicle growth, increases follicle death, and inhibits steroidogenesis in vitro. Further, previous studies indicate that CYP11A1 expression and production of progesterone (P 4 ) may be the early targets of mono-OH MXC in the steroidogenic pathway. Thus, this study tested whether supplementing pregnenolone, the precursor of progesterone and the substrate for HSD3B, would prevent decreased steroidogenesis, inhibited follicle growth, and increased follicle atresia in mono-OH MXC-treated follicles. Mouse antral follicles were exposed to vehicle (dimethylsulfoxide), mono-OH MXC (10 μg/mL), pregnenolone (1 μg/mL), or mono-OH MXC and pregnenolone together for 96 h. Levels of P 4 , androstenedione (A), testosterone (T), estrone (E 1 ), and 17β-estradiol (E 2 ) in media were determined, and follicles were processed for histological evaluation of atresia. Pregnenolone treatment alone stimulated production of all steroid hormones except E 2 . Mono-OH MXC-treated follicles had decreased sex steroids, but when given pregnenolone, produced levels of P 4 , A, T, and E 1 that were comparable to those in vehicle-treated follicles. Pregnenolone treatment did not prevent growth inhibition and increased atresia in mono-OH MXC-treated follicles. Collectively, these data support the idea that the most upstream effect of mono-OH MXC on steroidogenesis is by reducing the availability of pregnenolone, and that adding pregnenolone may not be sufficient to prevent inhibited follicle growth and survival. - Highlights: • Mono-OH MXC inhibited antral follicle steroidogenesis, growth, and survival. • Pregnenolone partially restored steroidogenesis in mono-OH MXC

  6. CopA3 Peptide Prevents Ultraviolet-Induced Inhibition of Type-I Procollagen and Induction of Matrix Metalloproteinase-1 in Human Skin Fibroblasts

    Directory of Open Access Journals (Sweden)

    Dong-Hee Kim

    2014-05-01

    Full Text Available Ultraviolet (UV exposure is well-known to induce premature aging, which is mediated by matrix metalloproteinase-1 (MMP-1 activity. A 9-mer peptide, CopA3 (CopA3 was synthesized from a natural peptide, coprisin, which is isolated from the dung beetle Copris tripartitus. As part of our continuing search for novel bioactive natural products, CopA3 was investigated for its in vitro anti-skin photoaging activity. UV-induced inhibition of type-I procollagen and induction of MMP-1 were partially prevented in human skin fibroblasts by CopA3 peptide in a dose-dependent manner. At a concentration of 25 μM, CopA3 nearly completely inhibited MMP-1 expression. These results suggest that CopA3, an insect peptide, is a potential candidate for the prevention and treatment of skin aging.

  7. Ketogenic Diet Improves Brain Ischemic Tolerance and Inhibits NLRP3 Inflammasome Activation by Preventing Drp1-Mediated Mitochondrial Fission and Endoplasmic Reticulum Stress

    Directory of Open Access Journals (Sweden)

    Min Guo

    2018-03-01

    Full Text Available Background: Neuroprotective effects of ketogenic diets (KD have been reported in stroke models, and nucleotide-binding domain (NOD-like receptor protein 3 (NLRP3 inflammasome has also been implicated in the pathogenesis of stroke. This study aimed to investigate the effects of KD on NLRP3 inflammasome and explore the potential molecular mechanisms.Methods: In in vivo study, mice were fed with KD for 3 weeks and then subjected to middle cerebral artery occlusion/reperfusion (MCAO/R-injury. In in vitro study, SH-SY-5Y cells were treated with β-hydroxybutyrate (BHB followed by oxygen–glucose deprivation/reoxygenation (OGD/R. NLRP3 inflammasome activation and related regulatory mechanisms were evaluated.Results: Mice fed with KD had increased tolerance to MCAO/R. KD inhibited endoplasmic reticulum (ER stress and suppressed TXNIP/NLRP3 inflammasome activation in the brain. The in vitro study showed BHB (10 mM prevented the mitochondrial translocation of dynamin-related protein 1 (Drp1 to inhibit mitochondrial fission. Furthermore, BHB decreased reactive oxygen species (ROS generation, inhibited ROS-NLRP3 pathway in OGD/R-treated cells, and suppressed ER stress-induced NLRP3 inflammasome activation.Conclusions: KD may suppress ER stress and protect mitochondrial integrity by suppressing the mitochondrial translocation of Drp1 to inhibit NLRP3 inflammasome activation, thus exerting neuroprotective effects. Our findings provide evidence for the potential application of KD in the prevention of ischemic stroke.

  8. Can PEP-3 Provide a Cognitive Profile in Children with ASD? A Comparison between the Developmental Ages of PEP-3 and IQ of Leiter-R

    Science.gov (United States)

    De Giacomo, Andrea; Craig, Francesco; Cristella, Arcangelo; Terenzio, Vanessa; Buttiglione, Maura; Margari, Lucia

    2016-01-01

    Background: The assessment of the intelligence quotient (IQ) in children with autism spectrum disorder (ASD) is important to plan a detailed therapeutic-educative programme. The aim of the study was to evaluate the usefulness of the Psychoeducational Profile-third edition (PEP-3) to estimate the general cognitive development of children with ASD.…

  9. Inhibition of the CXCL12/CXCR4-axis as preventive therapy for radiation-induced pulmonary fibrosis.

    Directory of Open Access Journals (Sweden)

    Hui-Kuo G Shu

    Full Text Available A devastating late injury caused by radiation is pulmonary fibrosis. This risk may limit the volume of irradiation and compromise potentially curative therapy. Therefore, development of a therapy to prevent this toxicity can be of great benefit for this patient population. Activation of the chemokine receptor CXCR4 by its ligand stromal cell-derived factor 1 (SDF-1/CXCL12 may be important in the development of radiation-induced pulmonary fibrosis. Here, we tested whether MSX-122, a novel small molecule and partial CXCR4 antagonist, can block development of this fibrotic process.The radiation-induced lung fibrosis model used was C57BL/6 mice irradiated to the entire thorax or right hemithorax to 20 Gy. Our parabiotic model involved joining a transgenic C57BL/6 mouse expressing GFP with a wild-type mouse that was subsequently irradiated to assess for migration of GFP+ bone marrow-derived progenitor cells to the irradiated lung. CXCL12 levels in the bronchoalveolar lavage fluid (BALF and serum after irradiation were determined by ELISA. CXCR4 and CXCL12 mRNA in the irradiated lung was determined by RNase protection assay. Irradiated mice were treated daily with AMD3100, an established CXCR4 antagonist; MSX-122; and their corresponding vehicles to determine impact of drug treatment on fibrosis development. Fibrosis was assessed by serial CTs and histology. After irradiation, CXCL12 levels increased in BALF and serum with a corresponding rise in CXCR4 mRNA within irradiated lungs consistent with recruitment of a CXCR4+ cell population. Using our parabiotic model, we demonstrated recruitment of CXCR4+ bone marrow-derived mesenchymal stem cells, identified based on marker expression, to irradiated lungs. Finally, irradiated mice that received MSX-122 had significant reductions in development of pulmonary fibrosis while AMD3100 did not significantly suppress this fibrotic process.CXCR4 inhibition by drugs such as MSX-122 may alleviate potential

  10. Inhibition of the CXCL12/CXCR4-axis as preventive therapy for radiation-induced pulmonary fibrosis.

    Science.gov (United States)

    Shu, Hui-Kuo G; Yoon, Younghyoun; Hong, Samuel; Xu, Kaiming; Gao, Huiying; Hao, Chunhai; Torres-Gonzalez, Edilson; Nayra, Cardenes; Rojas, Mauricio; Shim, Hyunsuk

    2013-01-01

    A devastating late injury caused by radiation is pulmonary fibrosis. This risk may limit the volume of irradiation and compromise potentially curative therapy. Therefore, development of a therapy to prevent this toxicity can be of great benefit for this patient population. Activation of the chemokine receptor CXCR4 by its ligand stromal cell-derived factor 1 (SDF-1/CXCL12) may be important in the development of radiation-induced pulmonary fibrosis. Here, we tested whether MSX-122, a novel small molecule and partial CXCR4 antagonist, can block development of this fibrotic process. The radiation-induced lung fibrosis model used was C57BL/6 mice irradiated to the entire thorax or right hemithorax to 20 Gy. Our parabiotic model involved joining a transgenic C57BL/6 mouse expressing GFP with a wild-type mouse that was subsequently irradiated to assess for migration of GFP+ bone marrow-derived progenitor cells to the irradiated lung. CXCL12 levels in the bronchoalveolar lavage fluid (BALF) and serum after irradiation were determined by ELISA. CXCR4 and CXCL12 mRNA in the irradiated lung was determined by RNase protection assay. Irradiated mice were treated daily with AMD3100, an established CXCR4 antagonist; MSX-122; and their corresponding vehicles to determine impact of drug treatment on fibrosis development. Fibrosis was assessed by serial CTs and histology. After irradiation, CXCL12 levels increased in BALF and serum with a corresponding rise in CXCR4 mRNA within irradiated lungs consistent with recruitment of a CXCR4+ cell population. Using our parabiotic model, we demonstrated recruitment of CXCR4+ bone marrow-derived mesenchymal stem cells, identified based on marker expression, to irradiated lungs. Finally, irradiated mice that received MSX-122 had significant reductions in development of pulmonary fibrosis while AMD3100 did not significantly suppress this fibrotic process. CXCR4 inhibition by drugs such as MSX-122 may alleviate potential radiation-induced lung

  11. A novel arctigenin-containing latex glove prevents latex allergy by inhibiting type I/IV allergic reactions.

    Science.gov (United States)

    Wang, Yong-Xin; Xue, Dan-Ting; Liu, Meng; Zhou, Zheng-Min; Shang, Jing

    2016-03-01

    The present study aimed at developing a natural compound with anti-allergic effect and stability under latex glove manufacturing conditions and investigating whether its anti-allergic effect is maintained after its addition into the latex. The effects of nine natural compounds on growth of the RBL-2H3 cells and mouse primary spleen lymphocytes were determined using MTT assay. The compounds included glycyrrhizin, osthole, tetrandrine, tea polyphenol, catechin, arctigenin, oleanolic acid, baicalin and oxymatrine. An ELISA assay was used for the in vitro anti-type I/IV allergy screening; in this process β-hexosaminidase, histamine, and IL-4 released from RBL-2H3 cell lines and IFN-γ and IL-2 released from mouse primary spleen lymphocytes were taken as screening indices. The physical stability of eight natural compounds and the dissolubility of arctigenin, selected based on the in vitro pharnacodynamaic screening and the stability evaluation, were detected by HPLC. The in vivo pharmacodynamic confirmation of arctigenin and final latex product was evaluated with a passive cutaneous anaphylaxis (PCA) model and an allergen-specific skin response model. Nine natural compounds showed minor growth inhibition on RBL-2H3 cells and mouse primary spleen lymphocytes. Baicalin and arctigenin had the best anti-type I and IV allergic effects among the natural compounds based on the in vitro pharmacodynamic screening. Arctigenin and catechin had the best physical stability under different manufacturing conditions. Arctigenin was the selected for further evaluation and proven to have anti-type I and IV allergic effects in vivo in a dose-dependent manner. The final product of the arctigenin-containing latex glove had anti-type I and IV allergic effects in vivo which were mainly attributed to arctigenin as proved from the dissolubility results. Arctigenin showed anti-type I and IV allergic effects in vitro and in vivo, with a good stability under latex glove manufacturing conditions

  12. Control of beam size and polarization time in PEP

    International Nuclear Information System (INIS)

    Paterson, J.M.; Rees, J.R.; Wiedemann, H.

    1975-07-01

    In this report we describe a method of controlling beam size in which the focusing functions are not altered with beam energy but the curvature function is drastically altered in a few locations which comprise only a very small fraction of the circumference. As will be described in the following paper we are proposing to control the quantum excitation and radiation damping of the particles by means of special excitation magnets or /open quotes/wigglers/close quotes/. Since the mean square energy deviation and radial beam emittance are proportional approximately to E/sup 2//l angle/G/sup 3//r angle//l angle/G/sup 2//r angle//sup /minus/1 while the damping times are proportional to (E/sup 3//l angle/G/sup 2//r angle/)/sup /minus/1/, it is possible to achieve constant beam size in a constant focusing configuration while the damping times vary roughly as E/sup /minus/2/. In addition, it is possible to reduce the beam polarization time with these devices. A scheme for beam-size and damping control based on the same principle was described by M. Bassetti about a year ago, in which all of the storage-ring bending magnets were involved as wigglers, and a substantial increase in magnet cost resulted. The consequences for polarization times were not explored. The design formulae are derived and two specific applications to the PEP design in which the wigglers are installed in three of the six 5-m straight sections are described with attention given to practical magnet design, synchrotron radiation handling and other matters. 5 refs., 4 figs., 1 tab

  13. Estimate of spin polarization for PEP using generalized transformation matrices

    International Nuclear Information System (INIS)

    Chao, A.W.

    1978-04-01

    The spin polarization for PEP has been estimated before by using simplified models. The main difficulty in the previous estimates is that the strength of depolarization effects caused by various electromagnetic field errors could not be specified accurately. To overcome this difficulty, a matrix formalism for depolarization calculation was developed recently. One basic ingredient of this theory is to represent an electron by an 8-dimensional state vector, X = (x,x',y,y',z,δ,α,β) where the first six coordinates are the usual transverse and longitudinal canonical coordinates, while α and β are the two components of the electron's spin vector perpendicular to the equilibrium direction of polarization /cflx n/. The degree of depolarization is specified by 1/2(α 2 + β 2 ). The state vector X will be transformed by an 8 x 8 matrix as the electron passes through a beam-line element such as a bending magnet or an rf cavity. From any position s, one multiplies successively the 8 x 8 matrices around one revolution of the storage ring to obtain the total transformation T(s). Any impulse perturbation ΔX to the electron's state vector occurring at s will be transformed repeatedly by T(s) as the electron circulates around the storage ring. Another basic ingredient is to decompose ΔX into 8 eigenstate components with eigenvectors determined from T(s). Six of these eigenstate components corresponding to the space states will be damped out by the usual radiation damping. The projections of ΔX onto the remaining two spin eigenstates are directly related to the loss of polarization due to the impulse perturbation ΔX. Depolarization effects can thus be calculated directly once all perturbations are specified. 7 refs., 4 figs

  14. Supramolecular structure of enterobacterial wild-type lipopolysaccharides (LPS), fractions thereof, and their neutralization by Pep19-2.5.

    Science.gov (United States)

    Brandenburg, Klaus; Heinbockel, Lena; Correa, Wilmar; Fukuoka, Satoshi; Gutsmann, Thomas; Zähringer, Ulrich; Koch, Michel H J

    2016-04-01

    Lipopolysaccharides (LPS) belong to the strongest immune-modulating compounds known in nature, and are often described as pathogen-associated molecular patterns (PAMPs). In particular, at higher concentrations they are responsible for sepsis and the septic shock syndrome associated with high lethality. Since most data are indicative that LPS aggregates are the bioactive units, their supramolecular structures are considered to be of outmost relevance for deciphering the molecular mechanisms of its bioactivity. So far, however, most of the data available addressing this issue, were published only for the lipid part (lipid A) and the core-oligosaccharide containing rough LPS, representing the bioactive unit. By contrast, it is well known that most of the LPS specimen identified in natural habitats contain the smooth-form (S-form) LPS, which carry additionally a high-molecular polysaccharide (O-chain). To fill this lacuna and going into a more natural system, here various wild-type (smooth form) LPS including also some LPS fractions were investigated by small-angle X-ray scattering with synchrotron radiation to analyze their aggregate structure. Furthermore, the influence of a recently designed synthetic anti-LPS peptide (SALP) Pep19-2.5 on the aggregate structure, on the binding thermodynamics, and on the cytokine-inducing activity of LPS were characterized, showing defined aggregate changes, high affinity binding and inhibition of cytokine secretion. The data obtained are suitable to refine our view on the preferences of LPS for non-lamellar structures, representing the highest bioactive forms which can be significantly influenced by the binding with neutralizing peptides such as Pep19-2.5. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. Delphinidin prevents high glucose-induced cell proliferation and collagen synthesis by inhibition of NOX-1 and mitochondrial superoxide in mesangial cells

    Directory of Open Access Journals (Sweden)

    Seung Eun Song

    2016-04-01

    Full Text Available This study examined the effect of delphinidin on high glucose-induced cell proliferation and collagen synthesis in mesangial cells. Glucose dose-dependently (5.6–25 mM increased cell proliferation and collagen I and IV mRNA levels, whereas pretreatment with delphinidin (50 μM prevented cell proliferation and the increased collagen mRNA levels induced by high glucose (25 mM. High glucose increased reactive oxygen species (ROS generation, and this was suppressed by pretreating delphinidin or the antioxidant N-acetyl cysteine. NADPH oxidase (NOX 1 was upregulated by high glucose, but pretreatment with delphinidin abrogated this upregulation. Increased mitochondrial superoxide by 25 mM glucose was also suppressed by delphinidin. The NOX inhibitor apocynin and mitochondria-targeted antioxidant Mito TEMPO inhibited ROS generation and cell proliferation induced by high glucose. Phosphorylation of extracellular signal regulated kinase (ERK1/2 was increased by high glucose, which was suppressed by delphinidin, apocynin or Mito TEMPO. Furthermore, PD98059 (an ERK1/2 inhibitor prevented the high glucose-induced cell proliferation and increased collagen mRNA levels. Transforming growth factor (TGF-β protein levels were elevated by high glucose, and pretreatment with delphinidin or PD98059 prevented this augmentation. These results suggest that delphinidin prevents high glucose-induced cell proliferation and collagen synthesis by inhibition of NOX-1 and mitochondrial superoxide in mesangial cells.

  16. Robust Control of PEP Formation Rate in the Carbon Fixation Pathway of C4 Plants by a Bi-functional Enzyme

    Directory of Open Access Journals (Sweden)

    Hart Yuval

    2011-10-01

    Full Text Available Abstract Background C4 plants such as corn and sugarcane assimilate atmospheric CO2 into biomass by means of the C4 carbon fixation pathway. We asked how PEP formation rate, a key step in the carbon fixation pathway, might work at a precise rate, regulated by light, despite fluctuations in substrate and enzyme levels constituting and regulating this process. Results We present a putative mechanism for robustness in C4 carbon fixation, involving a key enzyme in the pathway, pyruvate orthophosphate dikinase (PPDK, which is regulated by a bifunctional enzyme, Regulatory Protein (RP. The robust mechanism is based on avidity of the bifunctional enzyme RP to its multimeric substrate PPDK, and on a product-inhibition feedback loop that couples the system output to the activity of the bifunctional regulator. The model provides an explanation for several unusual biochemical characteristics of the system and predicts that the system's output, phosphoenolpyruvate (PEP formation rate, is insensitive to fluctuations in enzyme levels (PPDK and RP, substrate levels (ATP and pyruvate and the catalytic rate of PPDK, while remaining sensitive to the system's input (light levels. Conclusions The presented PPDK mechanism is a new way to achieve robustness using product inhibition as a feedback loop on a bifunctional regulatory enzyme. This mechanism exhibits robustness to protein and metabolite levels as well as to catalytic rate changes. At the same time, the output of the system remains tuned to input levels.

  17. PepMapper: a collaborative web tool for mapping epitopes from affinity-selected peptides.

    Directory of Open Access Journals (Sweden)

    Wenhan Chen

    Full Text Available Epitope mapping from affinity-selected peptides has become popular in epitope prediction, and correspondingly many Web-based tools have been developed in recent years. However, the performance of these tools varies in different circumstances. To address this problem, we employed an ensemble approach to incorporate two popular Web tools, MimoPro and Pep-3D-Search, together for taking advantages offered by both methods so as to give users more options for their specific purposes of epitope-peptide mapping. The combined operation of Union finds as many associated peptides as possible from both methods, which increases sensitivity in finding potential epitopic regions on a given antigen surface. The combined operation of Intersection achieves to some extent the mutual verification by the two methods and hence increases the likelihood of locating the genuine epitopic region on a given antigen in relation to the interacting peptides. The Consistency between Intersection and Union is an indirect sufficient condition to assess the likelihood of successful peptide-epitope mapping. On average from 27 tests, the combined operations of PepMapper outperformed either MimoPro or Pep-3D-Search alone. Therefore, PepMapper is another multipurpose mapping tool for epitope prediction from affinity-selected peptides. The Web server can be freely accessed at: http://informatics.nenu.edu.cn/PepMapper/

  18. Performance of the PEP-II B-Factory Collider at SLAC

    International Nuclear Information System (INIS)

    Seeman, J.; Browne, M.; Cai, Y.; Colocho, W.; Decker, F.J.; Donald, M.H.; Ecklund, S.; Erickson, R.A.; Fisher, A.S.; Fox, J.D.; Heifets, S.A.; Iverson, R.H.; Kulikov, A.; Li, N.; Novokhatski, A.; Ross, M.C.; Schuh, P.; Smith, T.J.; Sonnad, K.G.; Stanek, M.; Sullivan, M.K.

    2006-01-01

    PEP-II is an e + e - asymmetric B-Factory Collider located at SLAC operating at the Upsilon 4S resonance (3.1 GeV x 9 GeV). It has reached a luminosity of 9.21 x 10 33 /cm 2 /s and has delivered an integrated luminosity of 710 pb -1 in one day. PEP-II has delivered, over the past six years, an integrated luminosity to the BaBar detector of over 262 fb -1 . PEP-II operates in continuous injection mode for both beams boosting the integrated luminosity. The peak positron current has reached 2.45 A in 1588 bunches. Steady progress is being made in reaching higher luminosity. The goal over the next several years is to reach a luminosity of 2.1 x 10 34 /cm 2 /s. The accelerator physics issues being addressed in PEP-II to reach this goal include the electron cloud instability, beam-beam effects, parasitic beam-beam effects, high RF beam loading, shorter bunches, lower β* y interaction region operation, and coupling control. Figure 1 shows the PEP-II tunnel

  19. Search for highly interacting fractionally charged particles at PEP

    International Nuclear Information System (INIS)

    Wlodzimierz, G.

    1982-01-01

    Fractionally charged, highly interacting particles produced in e + e - annihilation at 20 GeV c.m. energy have been search for. The experiment was performed at the positron electron storage ring (PEP) at the Stanford Linear Accelerator Center (SLAC). The search used in the innermost part of the two-arm Free Quark Search (FQS) detector. This part was called the Thin Front End (TFE) and it covered 1/3 of the full solid angle. Each of its arms consisted of five multiwire proportional chambers (MWPC's), used for tracking and dE/dx measurement, and three hodoscopes of 0.16 cm thick Pilot F scintillator. The total thickness of the five MWPC's and the beam pipe was 0.007 hadronic collision lengths (lambda/sub c/). No candidates for fractionally charged particles were found. Upper limits on R/sub q anti q/ = sigma(e + e - →q anti q)/sigma(e + e - →μμ) are between: (1) 0.7% to 7% for quark interaction lengths (lambda/sub q/) equal to lambda/sub c/ and between 3% and 33% for lambda/sub q/ = 100lambda/sub c/ for Q = 1/3e quark charge and for quark masses up to 13 GeV/c 2 ; (2) 2% to 38% for lambda/sub q/ - lambda/sub c/ and from 7% to 160% for lambda/sub q/ = 100lambda/sub c/ for Q = 2/3e quark charge and for masses up to 8 GeV/c 2 . In the inclusive production channel the upper limits on R/sub q/ = sigma(e + e - →qqX)/sigma(e + e - →μμ) are for charge 1/3e only. R/sub q/ varies from 2% to 11% for lambda/sub q/ = lambda/sub c/ and from 3% to 16% for lambda/sub q/ = 100lambda/sub c/ and for quark masses up to 6.5 GeV/c 2 . These are the first limits on the production of fractionally charged particles with lambda/sub q/ = 100lambda/sub c/

  20. Ca 2+ signaling by plant Arabidopsis thaliana Pep peptides depends on AtPepR1, a receptor with guanylyl cyclase activity, and cGMP-activated Ca 2+ channels

    KAUST Repository

    Qia, Zhi; Verma, Rajeev K.; Gehring, Christoph A; Yamaguchi, Yube; Zhao, Yichen; Ryan, Clarence A.; Berkowitz, Gerald A.

    2010-01-01

    receptor- like kinase receptor AtPepR1 has guanylyl cyclase activity, generating cGMP from GTP, and that cGMP can activate CNGC2- dependent cytosolic Ca 2+ elevation. AtPep-dependent expression of pathogen-defense genes (PDF1.2, MPK3, and WRKY33

  1. First Evidence of pep Solar Neutrinos by Direct Detection in Borexino

    Science.gov (United States)

    Bellini, G.; Benziger, J.; Bick, D.; Bonetti, S.; Bonfini, G.; Bravo, D.; Buizza Avanzini, M.; Caccianiga, B.; Cadonati, L.; Calaprice, F.; Carraro, C.; Cavalcante, P.; Chavarria, A.; Chepurnov, A.; D'Angelo, D.; Davini, S.; Derbin, A.; Etenko, A.; Fomenko, K.; Franco, D.; Galbiati, C.; Gazzana, S.; Ghiano, C.; Giammarchi, M.; Goeger-Neff, M.; Goretti, A.; Grandi, L.; Guardincerri, E.; Hardy, S.; Ianni, Aldo; Ianni, Andrea; Korablev, D.; Korga, G.; Koshio, Y.; Kryn, D.; Laubenstein, M.; Lewke, T.; Litvinovich, E.; Loer, B.; Lombardi, F.; Lombardi, P.; Ludhova, L.; Machulin, I.; Manecki, S.; Maneschg, W.; Manuzio, G.; Meindl, Q.; Meroni, E.; Miramonti, L.; Misiaszek, M.; Montanari, D.; Mosteiro, P.; Muratova, V.; Oberauer, L.; Obolensky, M.; Ortica, F.; Otis, K.; Pallavicini, M.; Papp, L.; Perasso, L.; Perasso, S.; Pocar, A.; Quirk, J.; Raghavan, R. S.; Ranucci, G.; Razeto, A.; Re, A.; Romani, A.; Sabelnikov, A.; Saldanha, R.; Salvo, C.; Schönert, S.; Simgen, H.; Skorokhvatov, M.; Smirnov, O.; Sotnikov, A.; Sukhotin, S.; Suvorov, Y.; Tartaglia, R.; Testera, G.; Vignaud, D.; Vogelaar, R. B.; von Feilitzsch, F.; Winter, J.; Wojcik, M.; Wright, A.; Wurm, M.; Xu, J.; Zaimidoroga, O.; Zavatarelli, S.; Zuzel, G.

    2012-02-01

    We observed, for the first time, solar neutrinos in the 1.0-1.5 MeV energy range. We determined the rate of pep solar neutrino interactions in Borexino to be 3.1±0.6stat±0.3systcounts/(day·100ton). Assuming the pep neutrino flux predicted by the standard solar model, we obtained a constraint on the CNO solar neutrino interaction rate of Mikheyev-Smirnov-Wolfenstein large mixing angle solution to solar neutrino oscillations, these values correspond to solar neutrino fluxes of (1.6±0.3)×108cm-2s-1 and <7.7×108cm-2s-1 (95% C.L.), respectively, in agreement with both the high and low metallicity standard solar models. These results represent the first direct evidence of the pep neutrino signal and the strongest constraint of the CNO solar neutrino flux to date.

  2. Evaluation of the BEAM--BEAM effect in PEP using Myer's simulation program

    International Nuclear Information System (INIS)

    Hutton, A.

    1982-09-01

    The program BEAM BEAM written by Steve Myers for the LEP machine at CERN has given encouraging results in the simulation of the beam-beam effect in electron-positron storage rings. It therefore seemed worthwhile to apply the program to PEP with two main intentions. Firstly, to confirm the validity of the program by comparison with experimental data from previous PEP runs and secondly, to search for an improvement in the operating conditions of PEP. Clearly a successful prediction would also enhance the credibility of the program. The program itself has been extensively described in the literature and will not be repeated here, except for some comments of direct relevance to the present simulation. 14 refs., 15 figs., 4 tabs

  3. BioPepDB: an integrated data platform for food-derived bioactive peptides.

    Science.gov (United States)

    Li, Qilin; Zhang, Chao; Chen, Hongjun; Xue, Jitong; Guo, Xiaolei; Liang, Ming; Chen, Ming

    2018-03-12

    Food-derived bioactive peptides play critical roles in regulating most biological processes and have considerable biological, medical and industrial importance. However, a large number of active peptides data, including sequence, function, source, commercial product information, references and other information are poorly integrated. BioPepDB is a searchable database of food-derived bioactive peptides and their related articles, including more than four thousand bioactive peptide entries. Moreover, BioPepDB provides modules of prediction and hydrolysis-simulation for discovering novel peptides. It can serve as a reference database to investigate the function of different bioactive peptides. BioPepDB is available at http://bis.zju.edu.cn/biopepdbr/ . The web page utilises Apache, PHP5 and MySQL to provide the user interface for accessing the database and predict novel peptides. The database itself is operated on a specialised server.

  4. Prevention of wear particle-induced osteolysis by a novel V-ATPase inhibitor saliphenylhalamide through inhibition of osteoclast bone resorption.

    Directory of Open Access Journals (Sweden)

    An Qin

    Full Text Available Wear particle-induced peri-implant loosening (Aseptic prosthetic loosening is one of the most common causes of total joint arthroplasty. It is well established that extensive bone destruction (osteolysis by osteoclasts is responsible for wear particle-induced peri-implant loosening. Thus, inhibition of osteoclastic bone resorption should prevent wear particle induced osteolysis and may serve as a potential therapeutic avenue for prosthetic loosening. Here, we demonstrate for the first time that saliphenylhalamide, a new V-ATPase inhibitor attenuates wear particle-induced osteolysis in a mouse calvarial model. In vitro biochemical and morphological assays revealed that the inhibition of osteolysis is partially attributed to a disruption in osteoclast acidification and polarization, both a prerequisite for osteoclast bone resorption. Interestingly, the V-ATPase inhibitor also impaired osteoclast differentiation via the inhibition of RANKL-induced NF-κB and ERK signaling pathways. In conclusion, we showed that saliphenylhalamide affected multiple physiological processes including osteoclast differentiation, acidification and polarization, leading to inhibition of osteoclast bone resorption in vitro and wear particle-induced osteolysis in vivo. The results of the study provide proof that the new generation V-ATPase inhibitors, such as saliphenylhalamide, are potential anti-resorptive agents for treatment of peri-implant osteolysis.

  5. Inhibition of Mitochondrial Cytochrome c Release and Suppression of Caspases by Gamma-Tocotrienol Prevent Apoptosis and Delay Aging in Stress-Induced Premature Senescence of Skin Fibroblasts

    Directory of Open Access Journals (Sweden)

    Suzana Makpol

    2012-01-01

    Full Text Available In this study, we determined the molecular mechanism of γ-tocotrienol (GTT in preventing cellular aging by focusing on its anti-apoptotic effect in stress-induced premature senescence (SIPS model of human diploid fibroblasts (HDFs. Results obtained showed that SIPS exhibited senescent-phenotypic characteristic, increased expression of senescence-associated β-galactosidase (SA β-gal and promoted G0/G1 cell cycle arrest accompanied by shortening of telomere length with decreased telomerase activity. Both SIPS and senescent HDFs shared similar apoptotic changes such as increased Annexin V-FITC positive cells, increased cytochrome c release and increased activation of caspase-9 and caspase-3 (P<0.05. GTT treatment resulted in a significant reduction of Annexin V-FITC positive cells, inhibited cytochrome c release and decreased activation of caspase-9 and caspase-3 (P<0.05. Gene expression analysis showed that GTT treatment down regulated BAX mRNA, up-regulated BCL2A1 mRNA and decreased the ratio of Bax/Bcl-2 protein expression (P<0.05 in SIPS. These findings suggested that GTT inhibits apoptosis by modulating the upstream apoptosis cascade, causing the inhibition of cytochrome c release from the mitochondria with concomitant suppression of caspase-9 and caspase-3 activation. In conclusion, GTT delays cellular senescence of human diploid fibroblasts through the inhibition of intrinsic mitochondria-mediated pathway which involved the regulation of pro- and anti-apoptotic genes and proteins.

  6. Anaplasma phagocytophilum inhibits human neutrophil apoptosis via upregulation of bfl-1, maintenance of mitochondrial membrane potential and prevention of caspase 3 activation.

    Science.gov (United States)

    Ge, Yan; Yoshiie, Kiyotaka; Kuribayashi, Futoshi; Lin, Mingqun; Rikihisa, Yasuko

    2005-01-01

    The inhibition of neutrophil apoptosis plays a central role in human granulocytic anaplasmosis. Intracellular signalling pathways through which the obligatory intracellular bacterium Anaplasma phagocytophilum inhibits the spontaneous apoptosis of human peripheral blood neutrophils were investigated. bfl-1 mRNA levels in uninfected neutrophils after 12 h in culture were reduced to approximately 5-25% of 0 h levels, but remained high in infected neutrophils. The eukaryotic RNA synthesis inhibitor, actinomycin D, prevented the maintenance of bfl-1 mRNA levels by A. phagocytophilum. Differences in mcl-1, bax, bcl-w, bad or bak mRNA levels in infected versus uninfected neutrophils were not remarkable. By using mitochondrial fluorescent dyes, Mitotracker Red and JC-1, it was found that most uninfected neutrophils lost mitochondrial membrane potential after 10-12 h incubation, whereas A. phagocytophilum-infected neutrophils maintained high membrane potential. Caspase 3 activity and the degree of apoptosis were lower in dose-dependent manner in A. phagocytophilum-infected neutrophils at 16 h post infection, as compared to uninfected neutrophils. Anti-active caspase 3 antibody labelling showed less positively stained population in infected neutrophils compared to those in uninfected neutrophils after 12 h incubation. These results suggest that A. phagocytophilum inhibits human neutrophil apoptosis via transcriptional upregulation of bfl-1 and inhibition of mitochondria-mediated activation of caspase 3.

  7. Multifunctional amaranth cystatin inhibits endogenous and digestive insect cysteine endopeptidases: A potential tool to prevent proteolysis and for the control of insect pests.

    Science.gov (United States)

    Valdés-Rodríguez, Silvia; Galván-Ramírez, Juan Pablo; Guerrero-Rangel, Armando; Cedro-Tanda, Alberto

    2015-01-01

    In a previous study, the amaranth cystatin was characterized. This cystatin is believed to provide protection from abiotic stress because its transcription is induced in response to heat, drought, and salinity. It has also been shown that recombinant amaranth cystatin inhibits bromelain, ficin, and cysteine endopeptidases from fungal sources and also inhibits the growth of phytopathogenic fungi. In the present study, evidence is presented regarding the potential function of amaranth cystatin as a regulator of endogenous proteinases and insect digestive proteinases. During amaranth germination and seedling growth, different proteolytic profiles were observed at different pH levels in gelatin-containing SDS-PAGE. Most of the proteolytic enzymes detected at pH 4.5 were mainly inhibited by trans-epoxysuccinyl-leucyl amido(4-guanidino)butane (E-64) and the purified recombinant amaranth cystatin. Furthermore, the recombinant amaranth cystatin was active against insect proteinases. In particular, the E-64-sensitive proteolytic digestive enzymes from Callosobruchus maculatus, Zabrotes subfasciatus, and Acanthoscelides obtectus were inhibited by the amaranth cystatin. Taken together, these results suggest multiple roles for cystatin in amaranth, specifically during germination and seedling growth and in the protection of A. hypochondriacus against insect predation. Amaranth cystatin represents a promising tool for diverse applications in the control of insect pest and for preventing undesirable proteolytic activity. © 2014 International Union of Biochemistry and Molecular Biology, Inc.

  8. Prevalence of cardiovascular disease risk factors in migrants participating in the PEP family heart study, Nuremberg

    Directory of Open Access Journals (Sweden)

    Gerda-Maria Haas

    2010-01-01

    Full Text Available Objectives: The aim of this study was to assess the prevalence of cardiovascular risk factors in adults and their children from the 3 major groups of migrants participating in the PEP Family Heart Study [11] and to compare the cardio-metabolic risk profiles between migrants and German participants. Methods: In this community-based cross-sectional study, anthropometric data, blood pressure and lipid profiles of migrants (480 children, 363 adults from Turkey (TUR, Eastern Europe (EEU and German immigrants from the former Soviet Union (GFSU were compared with age and gender adjusted German (GER resi-dents (3253 children, 2491 adults. Results: The profile of risk factors differed considerably regarding specificity and frequency. The prevalence of ≥3 risk factors was as follows: in GFSU men 62%, women 36%, boys 19% and girls 17%; in TUR men 57%, women 30%, 15% boys and 6% girls; in GER men 48%, women 19%, boys 4% and girls 6%; for EEU men 38%, women 25% and 0% in children. No risk factor was present in GFSU men 13%, women 25%, boys 38% and girls 42%; TUR men 13%, women 28%, boys 27% and girls 22 %; GER men16%, women 45%, boys 46% and girls 41%; EEU men 17%, women 42 %, boys 29% and girls 27%. About 50% of the adults from Turkey and Eastern Europe were current smokers and one third of women and half of men from these two countries were over-weight. Conclusions: The implementation of primary care measures for the prevention of cardiovascular disease in migrants is necessary, and it should consider the ethnic differences and the heterogene-ous risk profiles.

  9. PEP activity and expression of photosynthesis genes required for embryo and seed development in Arabidopsis

    Directory of Open Access Journals (Sweden)

    Dmitry eKremnev

    2014-08-01

    Full Text Available Chloroplast biogenesis and function is essential for proper plant embryo and seed development but the molecular mechanisms underlying the role of plastids during embryogenesis are poorly understood. Expression of plastid encoded genes is dependent on two different transcription machineries; a plastid-encoded bacterial-type RNA polymerase (PEP and a nuclear-encoded phage-type RNA polymerase (NEP, which recognize distinct types of promoters. However, the division of labor between PEP and NEP during plastid development and in mature chloroplasts is unclear. We show here that PRIN2 and CSP41b, two proteins identified in plastid nucleoid preparations, are essential for proper plant embryo development. Using Co-IP assays and native PAGE we have shown a direct physical interaction between PRIN2 and CSP41b. Moreover, PRIN2 and CSP41b form a distinct protein complex in vitro that binds DNA. The prin2.2 and csp41b-2 single mutants displayed pale phenotypes, abnormal chloroplasts with reduced transcript levels of photosynthesis genes and defects in embryo development. The respective csp41b-2prin2.2 homo/heterozygote double mutants produced abnormal white colored ovules and shrunken seeds. Thus, the csp41b-2prin2.2 double mutant is embryo lethal. In silico analysis of available array data showed that a large number of genes traditionally classified as PEP dependent genes are transcribed during early embryo development from the pre-globular stage to the mature-green-stage. Taken together, our results suggest that PEP activity and consequently the switch from NEP to PEP activity, is essential during embryo development and that the PRIN2-CSP41b DNA binding protein complex possibly is important for full PEP activity during this process.

  10. An Angiotensin II Type 1 Receptor Blocker Prevents Renal Injury via Inhibition of the Notch Pathway in Ins2 Akita Diabetic Mice

    Directory of Open Access Journals (Sweden)

    Masaya Koshizaka

    2012-01-01

    Full Text Available Recently, it has been reported that the Notch pathway is involved in the pathogenesis of diabetic nephropathy. In this study, we investigated the activation of the Notch pathway in Ins2 Akita diabetic mouse (Akita mouse and the effects of telmisartan, an angiotensin II type1 receptor blocker, on the Notch pathway. The intracellular domain of Notch1 (ICN1 is proteolytically cleaved from the cell plasma membrane in the course of Notch activation. The expression of ICN1 and its ligand, Jagged1, were increased in the glomeruli of Akita mice, especially in the podocytes. Administration of telmisartan significantly ameliorated the expression of ICN1 and Jagged1. Telmisartan inhibited the angiotensin II-induced increased expression of transforming growth factor β and vascular endothelial growth factor A which could directly activate the Notch signaling pathway in cultured podocytes. Our results indicate that the telmisartan prevents diabetic nephropathy through the inhibition of the Notch pathway.

  11. Does glyceryl nitrate prevent post-ERCP pancreatitis? A prospective, randomized, double-blind, placebo-controlled multicenter trial

    DEFF Research Database (Denmark)

    Nøjgaard, Camilla; Hornum, Mads; Elkjaer, Margarita

    2009-01-01

    OBJECTIVE: Acute pancreatitis is the most dreaded complication of ERCP. Two studies have shown a significant effect of glyceryl nitrate (GN) in preventing post-ERCP pancreatitis (PEP). We wanted to evaluate this promising effect in a larger study with a realistically precalculated incidence of PEP...... (PL) was an identical-looking patch applied before ERCP. A total of 401 patients received GN; 405 received PL. RESULTS: Forty-seven patients had PEP (5.8%), 18 (4.5%) in the GN group and 29 (7.1%) in the PL group. The relative risk reduction of PEP in the GN group of 36% (95% CI, 11%-65%) compared...... (P = .006) were more common in the GN group. Significant variables predictive of PEP were not having biliary stones extracted; hypotension after ERCP; morphine, propofol, glucagon, and general anesthesia during the procedure; or no sufentanil during the procedure. CONCLUSIONS: The trial showed...

  12. Inhibition of cerebrovascular raf activation attenuates cerebral blood flow and prevents upregulation of contractile receptors after subarachnoid hemorrhage

    DEFF Research Database (Denmark)

    Ansar, Saema; Maddahi, Aida; Edvinsson, Lars

    2011-01-01

    of mitogen-activated protein kinase (MAPK) of the extracellular signal-regulated kinase (ERK)1/2 signal pathway. We hypothesize that SAH initiates cerebrovascular ERK1/2 activation, resulting in receptor upregulation. The raf inhibitor will inhibit the molecular events upstream ERK1/2 and may provide...

  13. The First Year of the BABAR Experiment at PEP-II

    Energy Technology Data Exchange (ETDEWEB)

    Barrera, Barbara

    2000-12-18

    The BABAR detector, situated at the SLAC PEP-II asymmetric e{sup +}e{sup -} collider, has been recording data at energies on and around the {Upsilon}(4S) resonance since May 1999. In this paper, we briefly describe the PEP-II B Factory and the BABAR detector. The performance presently achieved by the experiment in the areas of tracking, vertexing, calorimetry and particle identification is reviewed. Analysis concepts that are used in the various papers submitted to this conference are also discussed.

  14. Micellization of symmetric PEP-PEO block copolymers in water molecular weight dependence

    CERN Document Server

    Kaya, H; Allgaier, J; Stellbrink, J; Richter, D

    2002-01-01

    The micellar behaviour of the amphiphilic block copolymer poly-(ethylene-propylene)-poly-(ethylene oxide) (PEP-PEO) in aqueous solution has been studied with small-angle neutron scattering. The polymer was studied over a wide range of molecular weights, always keeping the volume of the blocks equal. The scattering behaviour of the solutions showed that a morphological transition takes place upon lowering the molecular weight. The high molecular weight block copolymers all build spherical, monodisperse micelles with large aggregation numbers. At low molecular weights, however, cylindrical micelles are formed. An interesting intermediate case is represented by the PEP2-PEO2 system, in which a morphological transition occurs upon dilution. (orig.)

  15. Locality at the boundary implies gap in the bulk for 2D PEPS

    DEFF Research Database (Denmark)

    Kastoryano, Michael J.; Lucia, Angelo; Perez-Garcia, David

    2018-01-01

    Proving that the parent Hamiltonian of a Projected Entangled Pair State (PEPS) is gapped remains an important open problem. We take a step forward in solving this problem by showing that if the boundary state of any rectangular subregion is a quasi-local Gibbs state of the virtual indices, then t...... boundary theories and dynamical properties in an interacting many body system. We show that the proof can be extended to MPO-injective PEPS, and speculate that the assumption on the locality of the boundary Hamiltonian follows from exponential decay of correlations in the bulk....

  16. Vacuum system design for the PEP-II B Factory High-Energy Ring

    International Nuclear Information System (INIS)

    Perkins, C.; Bostic, D.; Daly, E.

    1994-06-01

    The design of the vacuum system for the PEP-II B Factory High-Energy Ring is reviewed. The thermal design and vacuum requirements are particularly challenging in PEP-II due to high stored beam currents up to 3.0 amps in 1658 bunches. The vacuum chambers for the HER arcs are fabricated by electron beam welding extruded copper sections up to 6 m long. Design of these chambers and the vacuum PumPing configuration is described with results from vacuum and thermal analyses

  17. Design features and operational characteristics of the PEP beam-transport and injection system

    International Nuclear Information System (INIS)

    Peterson, J.M.; Brown, K.L.; Truher, J.B.

    1981-03-01

    The PEP beam-transport system was designed to transmit 4-to-15 GeV electron and positron beams from the SLAC linac within a +- 0.8% momentum band, to have flexible tuning of the betatron and off-momentum functions for matching into the PEP storage ring, and to have convenient operating characteristics. The transport lines were brought into operation quickly and have operated well. Electron injection has been consistent and efficient and relatively easy to accomplish. Positron injection also has been satisfactory but is variable and more sensitive to ring conditions

  18. τ physics using the TPC/2γ facility at HiLum PEP

    International Nuclear Information System (INIS)

    Bloom, E.D.

    1991-01-01

    Plans for a TPC/2γ facility program using HiLum PEP for τ physics are presented. The detector and its performance are described in some detail. The possibilities for a τ physics program with an integrated luminosity of 1 fb -1 are discussed. The physics issues are reviewed, particularly the τ'1-prong' problem, and preliminary results on τ → ν τ K +- X + X - + ≥ 0 Neutrals are shown. The performance of HiLum PEP is also presented, and expectations for the future are discussed. (R.P.) 15 refs., 14 figs., 3 tabs

  19. Development of a high-power RF cavity for the PEP-II B factory

    International Nuclear Information System (INIS)

    Rimmer, R.A.; Allen, M.A.; Saba, J.; Schwarz, H.

    1995-03-01

    The authors describe the development and fabrication of the first high-power RF cavity for PEP-II. Design choices and fabrication technologies for the first cavity and subsequent production cavities are described. Conditioning and high-power testing of the first and subsequent cavities are discussed, as well as integration of the cavity into modular RF systems for both high-energy and low-energy rings. Plans for installation of the cavity raft assemblies in the RF sections of the PEP tunnel are also considered

  20. Inhibition of miR-155, a therapeutic target for breast cancer, prevented in cancer stem cell formation.

    Science.gov (United States)

    Zuo, Jiangcheng; Yu, Yalan; Zhu, Man; Jing, Wei; Yu, Mingxia; Chai, Hongyan; Liang, Chunzi; Tu, Jiancheng

    2018-02-06

    Breast cancer is a common cancer in women of worldwide. Cancer cells with stem-like properties played important roles in breast cancer, such as relapse, metastasis and treatment resistance. Micro-RNA-155 (miR-155) is a well-known oncogenic miRNA overexpressed in many human cancers. The expression levels of miR-155 in 38 pairs of cancer tissues and adjacent normal tissues from breast cancer patients were detected using quantitative real-time PCR. The invasive cell line MDA-MB-231 was used to quantify the expression of miR-155 by tumor-sphere forming experiment. Soft agar colony formation assay and tumor xenografts was used to explore whether the inhibition of miR-155 could reduce proliferation of cancer cells in vivo and vitro. In the study, we found miR-155 was upregulated in BC. Soft agar colony formation assay and tumor xenografts showed inhibition of miR-155 could significantly reduce proliferation of cancer cells in vivo and vitro, which confirmed that miR-155 is an effective therapeutic target of breast cancer. Sphere-forming experiment showed that overexpression of miR-155 significantly correlated with stem-like properties. Expressions of ABCG2, CD44 and CD90 were repressed by inhibition of miR-155, but CD24 was promoted. Interestingly, inhibition of miR-155 rendered MDA-MB-231 cells more sensitive to Doxorubicinol, which resulted in an increase of inhibition rate from 20.23% to 68.72%. Expression of miR-155 not only was a therapeutic target but also was associated with cancer stem cell formation and Doxorubicinol sensitivity. Our results underscore the importance of miR-155 as a therapeutic target and combination of Doxorubicinol and miR-155-silencing would be a potential way to cure breast cancer.

  1. Enrofloxacin and Probiotic Lactobacilli Influence PepT1 and LEAP-2 mRNA Expression in Poultry

    NARCIS (Netherlands)

    Pavlova, Ivelina; Milanova, Aneliya; Danova, Svetla; Fink-Gremmels, Johanna

    2016-01-01

    Expression of peptide transporter 1 (PepT1) and liver-expressed antimicrobial peptide 2 (LEAP-2) in chickens can be influenced by food deprivation, pathological conditions and drug administration. Effect of three putative probiotic Lactobacillus strains and enrofloxacin on the expression of PepT1

  2. Evolutionary divergence of the plant elicitor peptides (Peps) and their receptors : interfamily incompatibility of perception but compatibility of downstream signalling

    NARCIS (Netherlands)

    Lori, Martina; van Verk, Marcel C; Hander, Tim; Schatowitz, Hendrik; Klauser, Dominik; Flury, Pascale; Gehring, Christoph A; Boller, Thomas; Bartels, Sebastian

    2015-01-01

    Plant elicitor peptides (Peps) are potent inducers of pattern-triggered immunity and amplify the immune response against diverse pathogens. Peps have been discovered and studied extensively in Arabidopsis and only recently orthologs in maize were also identified and characterized in more detail.

  3. Taurine Pretreatment Prevents Isoflurane-Induced Cognitive Impairment by Inhibiting ER Stress-Mediated Activation of Apoptosis Pathways in the Hippocampus in Aged Rats.

    Science.gov (United States)

    Zhang, Yanan; Li, Dongliang; Li, Haiou; Hou, Dailiang; Hou, Jingdong

    2016-10-01

    Isoflurane, a commonly used inhalation anesthetic, may induce neurocognitive deficits, especially in elderly patients after surgery. Recent study demonstrated that isoflurane caused endoplasmic reticulum (ER) stress and subsequent neuronal apoptosis in the brain, contributing to cognitive deficits. Taurine, a major intracellular free amino acid, has been shown to inhibit ER stress and neuronal apoptosis in several neurological disorders. Here, we examined whether taurine can prevent isoflurane-induced ER stress and cognitive impairment in aged rats. Thirty minutes prior to a 4-h 1.3 % isoflurane exposure, aged rats were treated with vehicle or taurine at low, middle and high doses. Aged rats without any treatment served as control. The brains were harvested 6 h after isoflurane exposure for molecular measurements, and behavioral study was performed 2 weeks later. Compared with control, isoflurane increased expression of hippocampal ER stress biomarkers including glucose-regulated protein 78, phosphorylated (P-) inositol-requiring enzyme 1, P-eukaryotic initiation factor 2-α (EIF2α), activating transcription factor 4 (ATF-4), cleaved ATF-6 and C/EBP homologous protein, along with activation of apoptosis pathways as indicated by decreased B cell lymphoma 2 (BCL-2)/BCL2-associated X protein, increased expressions of cytochrome-c and cleaved caspase-3. Taurine pretreatment dose-dependently inhibited isoflurane-induced increase in expression of ER stress biomarkers except for P-EIF2α and ATF-4, and reversed isoflurane-induced changes in apoptosis-related proteins. Moreover, isoflurane caused spatial working memory deficits in aged rats, which were prevented by taurine pretreatment. The results indicate that taurine pretreatment prevents anesthetic isoflurane-induced cognitive impairment by inhibiting ER stress-mediated activation of apoptosis pathways in the hippocampus in aged rats.

  4. Glyceryl trinitrate for prevention of post-ERCP pancreatitis and improve the rate of cannulation: a meta-analysis of prospective, randomized, controlled trials.

    Directory of Open Access Journals (Sweden)

    Jiexia Ding

    Full Text Available BACKGROUND: Acute pancreatitis is the most common complication of diagnostic and therapeutic endoscopic retrograde cholangiopancreatography (ERCP. Several clinical trials used glyceryl trinitrate (GTN to prevent the incidence of post-ERCP pancreatitis (PEP. However, the results were still controversial. OBJECTIVE: To conduct a meta-analysis of published, full-length, randomized controlled trials evaluating the effect of prophylactic GTN on the prevention of PEP, improve the rate of cannulation and the prevention of hyperamylasemia. METHODS: Literature searches were conducted using PubMed, EMBASE, The Cochrane Library and Web of Knowledge databases, using keywords "post-ERCP" and "pancreatitis" and limited in randomized controlled trials. RESULTS: Twelve RCTs involving 2649 patients were included. Eleven RCTs compared GTN with placebo for PEP prevention. Meta-analysis showed the overall incidence of PEP was significantly reduced by GTN treatment (RR 0.67; 95% CI, 0.52-0.87. Nevertheless, GTN administration did not decrease the incidence of moderate to severe PEP (RR 0.70; 95% CI, 0.42-1.15. Subgroup analyses revealed that GTN administered by sublingual was more effective than transdermal and topical in reducing the incidence of PEP. Besides, the prophylactic effect of GTN was far more obvious in the group of high PEP incidence than in the group of low PEP incidence. Additionally, the incidence of hyperamylasemia was significantly reduced by GTN treatment (RR 0.69; 95% CI, 0.54-0.90. No differences of the successful cannulation rate of bile ducts (RR 1.03; 95% CI, 0.99-1.06 attributable to GTN were observed. CONCLUSION: Prophylactic use of GTN reduced the overall incidence of PEP and hyperamylasemia. However, GTN was not helpful for the severity of PEP and the rate of cannulation.

  5. Putative skin-protective formulations in preventing and/or inhibiting experimentally-produced irritant and allergic contact dermatitis.

    Science.gov (United States)

    Zhai, H; Willard, P; Maibach, H I

    1999-10-01

    The effectiveness of skin protective formulations was evaluated in a previously-described in vivo human model. All formulations failed to inhibit ammonium hydroxide and urea irritation. Only paraffin wax in cetyl alcohol statistically (plauryl sulfate irritation. Paraffin wax in cetyl alcohol was quantitatively the most effective formulation. These results suggest that some formulations may provide protective effects against certain, but not all, irritants or allergens.

  6. Inhibition of H3K27me3 Histone Demethylase Activity Prevents the Proliferative Regeneration of Zebrafish Lateral Line Neuromasts

    Science.gov (United States)

    Bao, Beier; He, Yingzi; Tang, Dongmei; Li, Wenyan; Li, Huawei

    2017-01-01

    The H3K27 demethylases are involved in a variety of biological processes, including cell differentiation, proliferation, and cell death by regulating transcriptional activity. However, the function of H3K27 demethylation in the field of hearing research is poorly understood. Here, we investigated the role of H3K27me3 histone demethylase activity in hair cell regeneration using an in vivo animal model. Our data showed that pharmacologic inhibition of H3K27 demethylase activity with the specific small-molecule inhibitor GSK-J4 decreased the number of regenerated hair cells in response to neomycin damage. Furthermore, inhibition of H3K27me3 histone demethylase activity dramatically suppressed cell proliferation and activated caspase-3 levels in the regenerating neuromasts of the zebrafish lateral line. GSK-J4 administration also increased the expression of p21 and p27 in neuromast cells and inhibited the ERK signaling pathway. Collectively, our findings indicate that H3K27me3 demethylation is a key epigenetic regulator in the process of hair cell regeneration in zebrafish and suggest that H3K27me3 histone demethylase activity might be a novel therapeutic target for the treatment of hearing loss. PMID:28348517

  7. The Extract of Aster Koraiensis Prevents Retinal Pericyte Apoptosis in Diabetic Rats and Its Active Compound, Chlorogenic Acid Inhibits AGE Formation and AGE/RAGE Interaction

    Directory of Open Access Journals (Sweden)

    Junghyun Kim

    2016-09-01

    Full Text Available Retinal capillary cell loss is a hallmark of early diabetic retinal changes. Advanced glycation end products (AGEs are believed to contribute to retinal microvascular cell loss in diabetic retinopathy. In this study, the protective effects of Aster koraiensis extract (AKE against damage to retinal vascular cells were investigated in streptozotocin (STZ-induced diabetic rats. To examine this issue further, AGE accumulation, nuclear factor-kappaB (NF-κB and inducible nitric oxide synthase (iNOS were investigated using retinal trypsin digests from streptozotocin-induced diabetic rats. In the diabetic rats, TUNEL (Terminal deoxynucleotidyl transferase mediated dUTP Nick End Labeling-positive retinal microvascular cells were markedly increased. Immunohistochemical studies revealed that AGEs were accumulated within the retinal microvascular cells, and this accumulation paralleled the activation of NF-κB and the expression of iNOS in the diabetic rats. However, AKE prevented retinal microvascular cell apoptosis through the inhibition of AGE accumulation and NF-κB activation. Moreover, to determine the active compounds of AKE, two major compounds, chlorogenic acid and 3,5-di-O-caffeoylquinic acid, were tested in an in vitro assay. Among these compounds, chlorogenic acid significantly reduced AGE formation as well as AGE/RAGE (receptor for AGEs binding activity. These results suggest that AKE, particularly chlorogenic acid, is useful in inhibiting AGE accumulation in retinal vessels and exerts a preventive effect against the injuries of diabetic retinal vascular cells.

  8. Alfalfa dwarf cytorhabdovirus P protein is a local and systemic RNA silencing supressor which inhibits programmed RISC activity and prevents transitive amplification of RNA silencing.

    Science.gov (United States)

    Bejerman, Nicolás; Mann, Krin S; Dietzgen, Ralf G

    2016-09-15

    Plants employ RNA silencing as an innate defense mechanism against viruses. As a counter-defense, plant viruses have evolved to express RNA silencing suppressor proteins (RSS), which target one or more steps of the silencing pathway. In this study, we show that the phosphoprotein (P) encoded by the negative-sense RNA virus alfalfa dwarf virus (ADV), a species of the genus Cytorhabdovirus, family Rhabdoviridae, is a suppressor of RNA silencing. ADV P has a relatively weak local RSS activity, and does not prevent siRNA accumulation. On the other hand, ADV P strongly suppresses systemic RNA silencing, but does not interfere with the short-distance spread of silencing, which is consistent with its lack of inhibition of siRNA accumulation. The mechanism of suppression appears to involve ADV P binding to RNA-induced silencing complex proteins AGO1 and AGO4 as shown in protein-protein interaction assays when ectopically expressed. In planta, we demonstrate that ADV P likely functions by inhibiting miRNA-guided AGO1 cleavage and prevents transitive amplification by repressing the production of secondary siRNAs. As recently described for lettuce necrotic yellows cytorhabdovirus P, but in contrast to other viral RSS known to disrupt AGO activity, ADV P sequence does not contain any recognizable GW/WG or F-box motifs, which suggests that cytorhabdovirus P proteins may use alternative motifs to bind to AGO proteins. Crown Copyright © 2016. Published by Elsevier B.V. All rights reserved.

  9. Downregulation of COX-2 and CYP 4A signaling by isoliquiritigenin inhibits human breast cancer metastasis through preventing anoikis resistance, migration and invasion

    Energy Technology Data Exchange (ETDEWEB)

    Zheng, Hao; Li, Ying [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China); Wang, Yuzhong [Key Laboratory for Oral Biomedical Engineering of Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan 430079 (China); Zhao, Haixia [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China); Zhang, Jing [Animal Experimental Center of Wuhan University, Wuhan 430071 (China); Chai, Hongyan [Center for Gene Diagnosis, Zhongnan Hospital, Wuhan University, Wuhan 430071 (China); Tang, Tian [Department of Oncology, Renmin Hospital of Wuhan University, Wuhan 430060 (China); Yue, Jiang [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China); Guo, Austin M., E-mail: Austin_Guo@nymc.edu [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China); Department of Pharmacology, New York Medical College, Valhalla, NY 10595 (United States); Yang, Jing, E-mail: yangjingliu2013@163.com [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China)

    2014-10-01

    Flavonoids exert extensive in vitro anti-invasive and in vivo anti-metastatic activities. Anoikis resistance occurs at multiple key stages of the metastatic cascade. Here, we demonstrate that isoliquiritigenin (ISL), a flavonoid from Glycyrrhiza glabra, inhibits human breast cancer metastasis by preventing anoikis resistance, migration and invasion through downregulating cyclooxygenase (COX)-2 and cytochrome P450 (CYP) 4A signaling. ISL induced anoikis in MDA-MB-231 and BT-549 human breast cancer cells as evidenced by flow cytometry and the detection of caspase cleavage. Moreover, ISL inhibited the mRNA expression of phospholipase A2, COX-2 and CYP 4A and decreased the secretion of prostaglandin E{sub 2} (PGE{sub 2}) and 20-hydroxyeicosatetraenoic acid (20-HETE) in detached MDA-MB-231 cells. In addition, it decreased the levels of phospho-PI3K (Tyr{sup 458}), phospho-PDK (Ser{sup 241}) and phospho-Akt (Thr{sup 308}). Conversely, the exogenous addition of PGE{sub 2}, WIT003 (a 20-HETE analog) and an EP4 agonist (CAY10580) or overexpression of constitutively active Akt reversed ISL-induced anoikis. ISL exerted the in vitro anti-migratory and anti-invasive activities, whereas the addition of PGE{sub 2}, WIT003 and CAY10580 or overexpression of constitutively active Akt reversed the in vitro anti-migratory and anti-invasive activities of ISL in MDA-MB-231 cells. Notably, ISL inhibited the in vivo lung metastasis of MDA-MB-231 cells, together with decreased intratumoral levels of PGE{sub 2}, 20-HETE and phospho-Akt (Thr{sup 308}). In conclusion, ISL inhibits breast cancer metastasis by preventing anoikis resistance, migration and invasion via downregulating COX-2 and CYP 4A signaling. It suggests that ISL could be a promising multi-target agent for preventing breast cancer metastasis, and anoikis could represent a novel mechanism through which flavonoids may exert the anti-metastatic activities. - Highlights: • Isoliquiritigenin induces anoikis and suppresses

  10. SAR405, a PIK3C3/Vps34 inhibitor that prevents autophagy and synergizes with MTOR inhibition in tumor cells.

    Science.gov (United States)

    Pasquier, Benoit

    2015-04-03

    Autophagy plays an important role in cancer and it has been suggested that it functions not only as a tumor suppressor pathway to prevent tumor initiation, but also as a prosurvival pathway that helps tumor cells endure metabolic stress and resist death triggered by chemotherapeutic agents. We recently described the discovery of inhibitors of PIK3C3/Vps34 (phosphatidylinositol 3-kinase, catalytic subunit type 3), the lipid kinase component of the class III phosphatidylinositol 3-kinase (PtdIns3K). This PtdIns3K isoform has attracted significant attention in recent years because of its role in autophagy. Following chemical optimization we identified SAR405, a low molecular mass kinase inhibitor of PIK3C3, highly potent and selective with regard to other lipid and protein kinases. We demonstrated that inhibiting the catalytic activity of PIK3C3 disrupts vesicle trafficking from late endosomes to lysosomes. SAR405 treatment also inhibits autophagy induced either by starvation or by MTOR (mechanistic target of rapamycin) inhibition. Finally our results show that combining SAR405 with everolimus, the FDA-approved MTOR inhibitor, results in a significant synergy on the reduction of cell proliferation using renal tumor cells. This result indicates a potential therapeutic application for PIK3C3 inhibitors in cancer.

  11. Alzheimer's Disease Brain-Derived Amyloid-{beta}-Mediated Inhibition of LTP In Vivo Is Prevented by Immunotargeting Cellular Prion Protein.

    LENUS (Irish Health Repository)

    Barry, Andrew E

    2011-05-18

    Synthetic amyloid-β protein (Aβ) oligomers bind with high affinity to cellular prion protein (PrP(C)), but the role of this interaction in mediating the disruption of synaptic plasticity by such soluble Aβ in vitro is controversial. Here we report that intracerebroventricular injection of Aβ-containing aqueous extracts of Alzheimer\\'s disease (AD) brain robustly inhibits long-term potentiation (LTP) without significantly affecting baseline excitatory synaptic transmission in the rat hippocampus in vivo. Moreover, the disruption of LTP was abrogated by immunodepletion of Aβ. Importantly, intracerebroventricular administration of antigen-binding antibody fragment D13, directed to a putative Aβ-binding site on PrP(C), prevented the inhibition of LTP by AD brain-derived Aβ. In contrast, R1, a Fab directed to the C terminus of PrP(C), a region not implicated in binding of Aβ, did not significantly affect the Aβ-mediated inhibition of LTP. These data support the pathophysiological significance of SDS-stable Aβ dimer and the role of PrP(C) in mediating synaptic plasticity disruption by soluble Aβ.

  12. A novel mechanism of RNase L inhibition: Theiler's virus L* protein prevents 2-5A from binding to RNase L

    Science.gov (United States)

    Drappier, Melissa; Elliott, Ruth; Zhang, Rong; Weiss, Susan R.; Silverman, Robert H.

    2018-01-01

    The OAS/RNase L pathway is one of the best-characterized effector pathways of the IFN antiviral response. It inhibits the replication of many viruses and ultimately promotes apoptosis of infected cells, contributing to the control of virus spread. However, viruses have evolved a range of escape strategies that act against different steps in the pathway. Here we unraveled a novel escape strategy involving Theiler’s murine encephalomyelitis virus (TMEV) L* protein. Previously we found that L* was the first viral protein binding directly RNase L. Our current data show that L* binds the ankyrin repeats R1 and R2 of RNase L and inhibits 2’-5’ oligoadenylates (2-5A) binding to RNase L. Thereby, L* prevents dimerization and oligomerization of RNase L in response to 2-5A. Using chimeric mouse hepatitis virus (MHV) expressing TMEV L*, we showed that L* efficiently inhibits RNase L in vivo. Interestingly, those data show that L* can functionally substitute for the MHV-encoded phosphodiesterase ns2, which acts upstream of L* in the OAS/RNase L pathway, by degrading 2-5A. PMID:29652922

  13. BABAR - the detector for the PEP II B Factory at SLAC

    International Nuclear Information System (INIS)

    Lueth, V.

    1994-09-01

    BABAR refers to the detector that is being designed for the PEP II B-Factory at SLAC to perform a comprehensive study of CP violation in B meson decays. The design requirements and the principal detector components are briefly described. A summary of the expected physics performance is presented

  14. An Over-damped Cavity Longitudinal Kicker for the PEP-II LER

    CERN Document Server

    McIntosh, P

    2003-01-01

    Both rings of PEP-II use drift tube kickers in the longitudinal bunch-by-bunch feedback system. Efforts are now underway to increase the stored beam currents and luminosity of PEP-II, and beam-induced heating of these structures, particularly in the Low Energy Ring (LER) is of concern. An alternative kicker design based on the over-damped cavity kicker, first developed by INFN-Frascati is being built for PEP-II. This low loaded Q (or wide bandwidth) structure is fed by a network of ridged waveguides coupled to a simple pill-box cavity. Beam induced RF power is also coupled out of the cavity to external loads, so that the higher order modes (HOMs) excited in the structure are well-damped. This paper details the kicker design for PEP-II and discusses some of the design trade-offs between shunt impedance and bandwidth, as well as the influence of the feedthroughs on the kicker parameters. Estimates of the expected power deposition in the cavity are also provided.

  15. Responses of mRNA expression of PepT1 in small intestine to ...

    African Journals Online (AJOL)

    To study the effect of circulation small peptides concentration on mRNA expression in small intestine, graded amount of soybean small peptides (SSP) were infused into lactating goats through duodenal fistulas. Peptide-bound amino acid (PBAA) concentration in arterial plasma and the mRNA expression of PepT1 was ...

  16. Search for Ne in e−μ+ events at petra and pep energies

    Directory of Open Access Journals (Sweden)

    K. Yamanashi

    1978-03-01

    Full Text Available We propose a way to check the possible existence of an electron-type neutral heavy lepton Ne which decays into e−μ+νμ. In the region of cosθcoll < 0 eμ signals due to Ne are expected to exceed those due to τ± at PETRA and PEP energies.

  17. Mesomorphic phase behaviour of low molar mass PEP-PDMS diblock copolymers synthesized by anionic polymerization

    International Nuclear Information System (INIS)

    Vigild, M.E.

    1997-10-01

    The phase behaviour of low molar mass poly(ethylene-alt-propylene) -poly(dimethylsiloxane) (PEP-PDMS) is investigated in this thesis by the combination of dynamical mechanical spectroscopy (rheology) to measure phase transition temperatures, and small-angle x-ray scattering to identify the morphology of encountered phases. Samples of PEP-PDMS in the range of 0.2-0.7 in volume fraction of PEP are studied. This diblock copolymer system exhibits the three classical phases of lamellar sandwich structure (LAM), hexagonally packed cylinders (HEX), and spheres arranged on a body centered cubic lattice (BCC). Furthermore the gyroid phase (Ia3d symmetry) of two interpenetrating networks was also identified as a stable phase of the PEP-PDMS system. Time resolved measurements of small-angle neutron scattering in tandem with simultaneous in-situ rheological measurements are performed on samples showing transitions between different ordered phases. The identification of especially the BCC and gyroid phases from scattering experiments is treated. By performing mesoscopic crystallographic measurements using a custom built goniometer it was unambiguously shown that the application of shear to an unoriented powder-like sample introduces uniaxial orientation of the gyroid phase. The orientation of the ordered phase is otherwise random, causing a two-dimensional powder. Finally this dissertation presents a discussion of relevant parameters for the description of diblock copolymer phase behaviour together with descriptions of anionic polymerization for the synthesis of copolymers, and various experimental techniques for the characterization of diblocks. (au)

  18. Tests of μ-e universality for weak neutral currents at PEP

    International Nuclear Information System (INIS)

    Cline, D.B.; Resvanis, L.K.

    1988-01-01

    Two techniques are proposed to test the universality of the μ/minus/e weak neutral current interaction of large Q 2 . Both techniques require large statistics and some degree of longitudinal e + ,e/sup minus/ polarization but are otherwise feasible at PEP

  19. Pep-up: A review of the Umgeni Valley Project evaulation process ...

    African Journals Online (AJOL)

    Pep-up: A review of the Umgeni Valley Project evaulation process. Tim Wright. Abstract. No Abstract. Full Text: EMAIL FREE FULL TEXT EMAIL FREE FULL TEXT · DOWNLOAD FULL TEXT DOWNLOAD FULL TEXT · Creative Commons License This work is licensed under a Creative Commons Attribution 3.0 License.

  20. Particle searches in e+e- experiments at PEP and PETRA

    International Nuclear Information System (INIS)

    Lau, K.H.

    1982-10-01

    This talk reviews recent results in new particle searches performed by experiments at the high energy e + e - storage rings PEP and PETRA. It concentrates on recent searches for: hadrons with a new quark flavor, spin-1/2 charged heavy leptons, spin-0 charged leptons, spin-0 point-like scalars or pseudoscalars, and neutral heavy leptons

  1. Trigger drift chamber for the upgraded mark II detector at PEP

    Science.gov (United States)

    Ford, W. T.; Smith, J. G.; Wagner, S. R.; Weber, P.; White, S. L.; Alvarez, M.; Calviño, F.; Fernandez, E.

    1987-04-01

    A small cylindrical track detector was built as an array of single-wire drift cells with aluminized mylar cathode tubes. Point measurement resolution of ˜ 90 μm was achieved with a drift gas of 50% argon-50% ethane at atmospheric pressure. The chamber construction, electronics, and calibration are discussed. Performance results from PEP colliding-beam data are presented.

  2. Trigger drift chamber for the upgraded Mark II detector at PEP

    International Nuclear Information System (INIS)

    Ford, W.T.; Smith, J.G.; Wagner, S.R.; Weber, P.; White, S.L.; Alvarez, M.; Calvino, F.; Fernandez, E.; Universidad Autonoma de Barcelona

    1987-01-01

    A small cylindrical track detector was built as an array of single-wire drift cells with aluminized mylar cathode tubes. Point measurement resolution of ∝90 μm was achieved with a drift gas of 50% argon-50% ethane at atmospheric pressure. The chamber construction, electronics, and calibration are discussed. Performance results from PEP colliding-beam data are presented. (orig.)

  3. The key determinants of perceived external prestige (PEP – Qualitative research approach

    Directory of Open Access Journals (Sweden)

    Tamara Sušanj Šulentić

    2017-01-01

    Full Text Available Perceived external prestige (PEP is a well-known concept oriented towards describing the way members of a certain organization interpret and assess their organisational reputation. Such perception can significantly affect employees’ identification and loyalty to the organisation as well as their job satisfaction and work performance. According to the social identification theory, people define themselves and others with respect to their belonging to a particular group or organization, and their basic motive is a personal need for self-respect and a sense of pride. Employees’ perception of being members of an important, reputable and significant organisation contributes to the feeling of self-respect, which increases their individual social value and status. According to literature, there are only few objections to the concept of PEP, mainly those related to the determination of its structure and, with it, to its management. Although there is a growing literature on PEP, it is still not clear whether PEP is a one-dimensional or a multidimensional construct. If PEP is a multidimensional concept, it is important to specify its key components, in order to enhance the management of favourable organizational prestige in a real work environment. The purpose of this paper was to determine the structure of PEP and important sources of information, based on which, employees value the prestige of their organisation. Qualitative research was conducted, comprising nine semi-structured interviews with communication experts working for a multinational organisation operating in several European countries. The results of this paper indicate that PEP is a multidimensional construct, with several components, important for its creation and management. Those components can be grouped into three main categories: track record of success and the position of the organisation on the market, social impact of the organisation on the immediate environment and the

  4. IL-6 Inhibition With MEDI5117 Decreases The Fraction of Head and Neck Cancer Stem Cells and Prevents Tumor Recurrence

    Directory of Open Access Journals (Sweden)

    Kelsey A. Finkel

    2016-05-01

    Full Text Available Head and neck squamous cell carcinomas (HNSCC exhibit a small population of uniquely tumorigenic cancer stem cells (CSC endowed with self-renewal and multipotency. We have recently shown that IL-6 enhances the survival and tumorigenic potential of head and neck cancer stem cells (i.e. ALDHhighCD44high cells. Here, we characterized the effect of therapeutic inhibition of IL-6 with a novel humanized anti-IL-6 antibody (MEDI5117 using three low-passage patient-derived xenograft (PDX models of HNSCC. We observed that single agent MEDI5117 inhibited the growth of PDX-SCC-M1 tumors (P < .05. This PDX model was generated from a previously untreated HNSCC. In contrast, MEDI5117 was not effective at reducing overall tumor volume for PDX models representing resistant disease (PDX-SCC-M0, PDX-SCC-M11. Low dose MEDI5117 (3 mg/kg consistently decreased the fraction of cancer stem cells in PDX models of HNSCC when compared to IgG-treated controls, as follows: PDX-SCC-M0 (P < .001, PDX-SCC-M1 (P < .001, PDX-SCC-M11 (P = .04. Interestingly, high dose MEDI5117 (30 mg/kg decreased the CSC fraction in the PDX-SCC-M11 model (P = .002, but not in PDX-SCC-M0 and PDX-SCC-M1. MEDI5117 mediated a dose-dependent decrease in the number of orospheres generated by ALDHhighCD44high cells cultured in ultra-low attachment plates (P < .05, supporting an inhibitory effect on head and neck cancer stem cells. Notably, single agent MEDI5117 reduced the overall recurrence rate of PDX-SCC-M0, a PDX generated from the local recurrence of human HNSCC. Collectively, these data demonstrate that therapeutic inhibition of IL-6 with low-dose MEDI5117 decreases the fraction of cancer stem cells, and that adjuvant MEDI5117 inhibits recurrence in preclinical models of HNSCC.

  5. Evidence that the rabbit proton-peptide co-transporter PepT1 is a multimer when expressed in Xenopus laevis oocytes.

    Science.gov (United States)

    Panitsas, Konstantinos-E; Boyd, C A R; Meredith, David

    2006-04-01

    To test whether the rabbit proton-coupled peptide transporter PepT1 is a multimer, we have employed a combination of transport assays, luminometry and site-directed mutagenesis. A functional epitope-tagged PepT1 construct (PepT1-FLAG) was co-expressed in Xenopus laevis oocytes with a non-functional but normally trafficked mutant form of the same transporter (W294F-PepT1). The amount of PepT1-FLAG cRNA injected into the oocytes was kept constant, while the amount of W294F-PepT1 cRNA was increased over the mole fraction range of 0 to 1. The uptake of [(3)H]-D: -Phe-L: -Gln into the oocytes was measured at pH(out) 5.5, and the surface expression of PepT1-FLAG was quantified by luminometry. As the mole fraction of injected W294F-PepT1 increased, the uptake of D: -Phe-L: -Gln decreased. This occurred despite the surface expression of PepT1-FLAG remaining constant, and so we can conclude that PepT1 must be a multimer. Assuming that PepT1 acts as a homomultimer, the best fit for the modelling suggests that PepT1 could be a tetramer, with a minimum requirement of two functional subunits in each protein complex. Western blotting also showed the presence of higher-order complexes of PepT1-FLAG in oocyte membranes. It should be noted that we cannot formally exclude the possibility that PepT1 interacts with unidentified Xenopus protein(s). The finding that PepT1 is a multimer has important implications for the molecular modelling of this protein.

  6. Detecting β-thalassaemia mutations from a single cell by PEP and RDB

    Institute of Scientific and Technical Information of China (English)

    YI Ping; LI Li; YAO Hong; ZHOU Yuan-guo; DENG Bing; CHEN Zhu-qin

    2006-01-01

    Objective:To evaluate the possibility of the technology involving PEP and RDB for detecting β-thalassaemia multipoint mutations from a single cell simultaneously. Methods: A set of allele specific oligonucleotide (ASO) probes used for detecting 8 familiar β-thalassaemia mutations (CD41-42, IVS- Ⅱ -654, CD17, TATA box nt-28, CD71-72, TATA box nt-29, CD26, IVS- Ⅰ -5) were immobilized on a strip of nylon membrane. The genome of a individual cell was amplified by primer extension preamplification (PEP) with the mixture of15-base random oligonucleotides. The aliquots from PEP were used to amplify the objective gene fractions of β-thalassaemia gene by nested or semi-nested PCR. The membrane was hybridized with the final amplified products and then treated with Streptavidin-HRP and color development.Results :Totally 30 lymphocytes were picked up from blood samples of 1 healthy female and 4 patients with known β-thalassaemia mutations respectively. Each single lymphocyte was lysed in the proteinase K buffer. The amplification efficacy was 94.0% and alle drop-out(ADO) rate was 8.0%. Revert dot blot (RDB) was applied to the final amplified products from the 5 participants. The results of diagnosis were the same to the expected, and their genotypes were N/N, CD17 (A→T)/N, IVS- Ⅱ -654(C→T)/CD17(A → T), CD41-42 (-CTTT)/N and TATA box nt-28 (A→G)/N, respectively. Conclusion: The technology involving PEP and RDB could detectmultiple β-thalassaemia mutations from a single cell simultaneously,and the research provides experimental evidences for the feasibility of applying PEP and DNA array technology to screening multiple genetic mutations from a single cell, and will be applied to preimplantation genetic diagnosis and non-invasive prenatal diagnosis for β-thalassaemia.

  7. Neurogenesis Inhibition Prevents Enriched Environment to Prolong and Strengthen Social Recognition Memory, But Not to Increase BDNF Expression.

    Science.gov (United States)

    Pereira-Caixeta, Ana Raquel; Guarnieri, Leonardo O; Pena, Roberta R; Dias, Thomáz L; Pereira, Grace Schenatto

    2017-07-01

    Hippocampus-dependent memories, such as social recognition (SRM), are modulated by neurogenesis. However, the precise role of newborn neurons in social memory processing is still unknown. We showed previously that 1 week of enriched environment (EE) is sufficient to increase neurogenesis in the hippocampus (HIP) and the olfactory bulb (OB) of mice. Here, we tested the hypothesis that 1 week of EE would enhance SRM persistence and strength. In addition, as brain-derived neurotrophic factor (BDNF) may mediate some of the neurogenesis effects on memory, we also tested if 1 week of EE would increase BDNF expression in the HIP and OB. We also predicted that neurogenesis inhibition would block the gain of function caused by EE on both SRM and BDNF expression. We found that EE increased BDNF expression in the HIP and OB of mice; at the same time, it allowed SRM to last longer. In addition, mice on EE had their SRM unaffected by memory consolidation interferences. As we predicted, treatment with the anti-mitotic drug AraC blocked EE effects on SRM. Surprisingly, neurogenesis inhibition did not affect the BDNF expression, increased by EE. Together, our results suggest that newborn neurons improve SRM persistence through a BDNF-independent mechanism. Interestingly, this study on social memory uncovered an unexpected dissociation between the effect of adult neurogenesis and BDNF expression on memory persistence, reassuring the idea that not all neurogenesis effects on memory are BDNF-dependent.

  8. Recombinant Marburg viruses containing mutations in the IID region of VP35 prevent inhibition of Host immune responses.

    Science.gov (United States)

    Albariño, César G; Wiggleton Guerrero, Lisa; Spengler, Jessica R; Uebelhoer, Luke S; Chakrabarti, Ayan K; Nichol, Stuart T; Towner, Jonathan S

    2015-02-01

    Previous in vitro studies have demonstrated that Ebola and Marburg virus (EBOV and MARV) VP35 antagonize the host cell immune response. Moreover, specific mutations in the IFN inhibitory domain (IID) of EBOV and MARV VP35 that abrogate their interaction with virus-derived dsRNA, lack the ability to inhibit the host immune response. To investigate the role of MARV VP35 in the context of infectious virus, we used our reverse genetics system to generate two recombinant MARVs carrying specific mutations in the IID region of VP35. Our data show that wild-type and mutant viruses grow to similar titers in interferon deficient cells, but exhibit attenuated growth in interferon-competent cells. Furthermore, in contrast to wild-type virus, both MARV mutants were unable to inhibit expression of various antiviral genes. The MARV VP35 mutants exhibit similar phenotypes to those previously described for EBOV, suggesting the existence of a shared immune-modulatory strategy between filoviruses. Published by Elsevier Inc.

  9. Pharmacological hypothesis: Nitric oxide-induced inhibition of ADAM-17 activity as well as vesicle release can in turn prevent the production of soluble endothelin-converting enzyme.

    Science.gov (United States)

    Kuruppu, Sanjaya; Rajapakse, Niwanthi W; Parkington, Helena C; Smith, Ian

    2017-10-01

    Endothelin-1 (ET-1) and nitric oxide (NO) are two highly potent vasoactive molecules with opposing effects on the vasculature. Endothelin-converting enzyme (ECE) and nitric oxide synthase (NOS) catalyse the production of ET-1 and NO, respectively. It is well established that these molecules play a crucial role in the initiation and progression of cardiovascular diseases and have therefore become targets of therapy. Many studies have examined the mechanism(s) by which NO regulates ET-1 production. Expression and localization of ECE-1 is a key factor that determines the rate of ET-1 production. ECE-1 can either be membrane bound or be released from the cell surface to produce a soluble form. NO has been shown to reduce the expression of both membrane-bound and soluble ECE-1. Several studies have examined the mechanism(s) behind NO-mediated inhibition of ECE expression on the cell membrane. However, the precise mechanism(s) behind NO-mediated inhibition of soluble ECE production are unknown. We hypothesize that both exogenous and endogenous NO, inhibits the production of soluble ECE-1 by preventing its release via extracellular vesicles (e.g., exosomes), and/or by inhibiting the activity of A Disintegrin and Metalloprotease-17 (ADAM17). If this hypothesis is proven correct in future studies, these pathways represent targets for the therapeutic manipulation of soluble ECE-1 production. © 2017 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.

  10. Tryptamine-gallic acid hybrid prevents non-steroidal anti-inflammatory drug-induced gastropathy: correction of mitochondrial dysfunction and inhibition of apoptosis in gastric mucosal cells.

    Science.gov (United States)

    Pal, Chinmay; Bindu, Samik; Dey, Sumanta; Alam, Athar; Goyal, Manish; Iqbal, Mohd Shameel; Sarkar, Souvik; Kumar, Rahul; Halder, Kamal Krishna; Debnath, Mita Chatterjee; Adhikari, Susanta; Bandyopadhyay, Uday

    2012-01-27

    We have investigated the gastroprotective effect of SEGA (3a), a newly synthesized tryptamine-gallic acid hybrid molecule against non-steroidal anti-inflammatory drug (NSAID)-induced gastropathy with mechanistic details. SEGA (3a) prevents indomethacin (NSAID)-induced mitochondrial oxidative stress (MOS) and dysfunctions in gastric mucosal cells, which play a pathogenic role in inducing gastropathy. SEGA (3a) offers this mitoprotective effect by scavenging of mitochondrial superoxide anion (O(2)(·-)) and intramitochondrial free iron released as a result of MOS. SEGA (3a) in vivo blocks indomethacin-mediated MOS, as is evident from the inhibition of indomethacin-induced mitochondrial protein carbonyl formation, lipid peroxidation, and thiol depletion. SEGA (3a) corrects indomethacin-mediated mitochondrial dysfunction in vivo by restoring defective electron transport chain function, collapse of transmembrane potential, and loss of dehydrogenase activity. SEGA (3a) not only corrects mitochondrial dysfunction but also inhibits the activation of the mitochondrial pathway of apoptosis by indomethacin. SEGA (3a) inhibits indomethacin-induced down-regulation of bcl-2 and up-regulation of bax genes in gastric mucosa. SEGA (3a) also inhibits indometacin-induced activation of caspase-9 and caspase-3 in gastric mucosa. Besides the gastroprotective effect against NSAID, SEGA (3a) also expedites the healing of already damaged gastric mucosa. Radiolabeled ((99m)Tc-labeled SEGA (3a)) tracer studies confirm that SEGA (3a) enters into mitochondria of gastric mucosal cell in vivo, and it is quite stable in serum. Thus, SEGA (3a) bears an immense potential to be a novel gastroprotective agent against NSAID-induced gastropathy.

  11. Use of Candida-specific chicken egg yolk antibodies to inhibit the adhering of Candida to denture base materials: prevention of denture stomatitis.

    Science.gov (United States)

    Kamikawa, Yoshiaki; Fujisaki, Junichi; Nagayama, Tomohiro; Kawasaki, Kiyotsugu; Hirabayashi, Daisuke; Hamada, Tomofumi; Sakamoto, Ryoich; Mukai, Hiroshi; Sugihara, Kazumasa

    2016-09-01

    Polyclonal anti-Candida chicken egg yolk antibodies (anti-IgY) were used to investigate the prevention of adherence of Candida species to denture base material in vitro. Candida is a potential virulence factor that can cause systemic infection and even death in immunocompromised individuals. Because long-term antifungal treatment may lead to the emergence of drug-resistant strains, it is necessary to develop novel preventive measures and treatments for candidiasis. Three types of chicken egg yolk antibodies were used in this study: non-specific antibody (control IgY), Candida albicans-specific antibody (anti-C.a.IgY) and Candida glabrata-specific antibody (anti-C.g.IgY). A mixture of different dilutions of each antibody with a suspension of Candida species and denture base material was incubated for 3 h, and then the colony-forming units of Candida on the denture base material were counted. Compared with control IgY, anti-C.a.IgY and anti-C.g.IgY significantly inhibited the adherence of C. albicans, but anti-C.a.IgY tended to be more potent than anti-C.g.IgY. The adherence of C. glabrata was also inhibited significantly by anti-C.a.IgY and anti-C.g.IgY with almost equivalent potency, indicating that their actions against C. glabrata were comparable. This study revealed the inhibitory effects of anti-C.a.IgY and anti-C.g.IgY against the adherence of C. albicans and C. glabrata to denture base material. This finding indicates the possibility of a beneficial effect of IgYs for the prevention of denture stomatitis and candidiasis in clinical settings. © 2014 John Wiley & Sons A/S and The Gerodontology Association. Published by John Wiley & Sons Ltd.

  12. IGF-1 prevents ANG II-induced skeletal muscle atrophy via Akt- and Foxo-dependent inhibition of the ubiquitin ligase atrogin-1 expression

    Science.gov (United States)

    Yoshida, Tadashi; Semprun-Prieto, Laura; Sukhanov, Sergiy

    2010-01-01

    Congestive heart failure is associated with activation of the renin-angiotensin system and skeletal muscle wasting. Angiotensin II (ANG II) has been shown to increase muscle proteolysis and decrease circulating and skeletal muscle IGF-1. We have shown previously that skeletal muscle-specific overexpression of IGF-1 prevents proteolysis and apoptosis induced by ANG II. These findings indicated that downregulation of IGF-1 signaling in skeletal muscle played an important role in the wasting effect of ANG II. However, the signaling pathways and mechanisms whereby IGF-1 prevents ANG II-induced skeletal muscle atrophy are unknown. Here we show ANG II-induced transcriptional regulation of two ubiquitin ligases atrogin-1 and muscle ring finger-1 (MuRF-1) that precedes the reduction of skeletal muscle IGF-1 expression, suggesting that activation of atrogin-1 and MuRF-1 is an initial mechanism leading to skeletal muscle atrophy in response to ANG II. IGF-1 overexpression in skeletal muscle prevented ANG II-induced skeletal muscle wasting and the expression of atrogin-1, but not MuRF-1. Dominant-negative Akt and constitutively active Foxo-1 blocked the ability of IGF-1 to prevent ANG II-mediated upregulation of atrogin-1 and skeletal muscle wasting. Our findings demonstrate that the ability of IGF-1 to prevent ANG II-induced skeletal muscle wasting is mediated via an Akt- and Foxo-1-dependent signaling pathway that results in inhibition of atrogin-1 but not MuRF-1 expression. These data suggest strongly that atrogin-1 plays a critical role in mechanisms of ANG II-induced wasting in vivo. PMID:20228261

  13. Five-year cost-effectiveness of the Patient Empowerment Programme (PEP) for type 2 diabetes mellitus in primary care.

    Science.gov (United States)

    Lian, Jinxiao; McGhee, Sarah M; So, Ching; Chau, June; Wong, Carlos K H; Wong, William C W; Lam, Cindy L K

    2017-09-01

    This study evaluated the short-term cost-effectiveness of the Patient Empowerment Programme (PEP) for diabetes mellitus (DM) in Hong Kong. Propensity score matching was used to select a matched group of PEP and non-PEP subjects. A societal perspective was adopted to estimate the cost of PEP. Outcome measures were the cumulative incidence of all-cause mortality and diabetic complication over a 5-year follow-up period and the number needed to treat (NNT) to avoid 1 event. The incremental cost-effectiveness ratio (ICER) of cost per event avoided was calculated using the PEP cost per subject multiplied by the NNT. The PEP cost per subject from the societal perspective was US$247. There was a significantly lower cumulative incidence of all-cause mortality (2.9% vs 4.6%, P US$14 465, US$19 617 and US$30 796, respectively. The extra amount allocated to managing PEP was small and it appears cost-effective in the short-term as an addition to RAMP. © 2017 John Wiley & Sons Ltd.

  14. Indirubin-3-Oxime Prevents H2O2-Induced Neuronal Apoptosis via Concurrently Inhibiting GSK3β and the ERK Pathway.

    Science.gov (United States)

    Yu, Jie; Zheng, Jiacheng; Lin, Jiajia; Jin, Linlu; Yu, Rui; Mak, Shinghung; Hu, Shengquan; Sun, Hongya; Wu, Xiang; Zhang, Zaijun; Lee, Mingyuen; Tsim, Wahkeung; Su, Wei; Zhou, Wenhua; Cui, Wei; Han, Yifan; Wang, Qinwen

    2017-05-01

    Oxidative stress-induced neuronal apoptosis plays an important role in many neurodegenerative disorders. In this study, we have shown that indirubin-3-oxime, a derivative of indirubin originally designed for leukemia therapy, could prevent hydrogen peroxide (H 2 O 2 )-induced apoptosis in both SH-SY5Y cells and primary cerebellar granule neurons. H 2 O 2 exposure led to the increased activities of glycogen synthase kinase 3β (GSK3β) and extracellular signal-regulated kinase (ERK) in SH-SY5Y cells. Indirubin-3-oxime treatment significantly reversed the altered activity of both the PI3-K/Akt/GSK3β cascade and the ERK pathway induced by H 2 O 2 . In addition, both GSK3β and mitogen-activated protein kinase inhibitors significantly prevented H 2 O 2 -induced neuronal apoptosis. Moreover, specific inhibitors of the phosphoinositide 3-kinase (PI3-K) abolished the neuroprotective effects of indirubin-3-oxime against H 2 O 2 -induced neuronal apoptosis. These results strongly suggest that indirubin-3-oxime prevents H 2 O 2 -induced apoptosis via concurrent inhibiting GSK3β and the ERK pathway in SH-SY5Y cells, providing support for the use of indirubin-3-oxime to treat neurodegenerative disorders caused or exacerbated by oxidative stress.

  15. A milk-based wolfberry preparation prevents prenatal stress-induced cognitive impairment of offspring rats, and inhibits oxidative damage and mitochondrial dysfunction in vitro.

    Science.gov (United States)

    Feng, Zhihui; Jia, Haiqun; Li, Xuesen; Bai, Zhuanli; Liu, Zhongbo; Sun, Lijuan; Zhu, Zhongliang; Bucheli, Peter; Ballèvre, Olivier; Wang, Junkuan; Liu, Jiankang

    2010-05-01

    Lycium barbarum (Fructus Lycii, Wolfberry, or Gouqi) belongs to the Solanaceae. The red-colored fruits of L. barbarum have been used for a long time as an ingredient in Chinese cuisine and brewing, and also in traditional Chinese herbal medicine for improving health. However, its effects on cognitive function have not been well studied. In the present study, prevention of a milk-based wolfberry preparation (WP) on cognitive dysfunction was tested in a prenatal stress model with rats and the antioxidant mechanism was tested by in vitro experiments. We found that prenatal stress caused a significant decrease in cognitive function (Morris water maze test) in female offspring. Pretreatment of the mother rats with WP significantly prevented the prenatal stress-induced cognitive dysfunction. In vitro studies showed that WP dose-dependently scavenged hydroxyl and superoxide radicals (determined by an electron spin resonance spectrometric assay), and inhibited FeCl(2)/ascorbic acid-induced dysfunction in brain tissue and tissue mitochondria, including increases in reactive oxygen species and lipid peroxidation and decreases in the activities of complex I, complex II, and glutamate cysteine ligase. These results suggest that dietary supplementation with WP may be an effective strategy for preventing the brain oxidative mitochondrial damage and cognitive dysfunction associated with prenatal stress.

  16. A novel imidazopyridine derivative, X22, prevents the retinal ischemia-reperfusion injury via inhibition of MAPKs.

    Science.gov (United States)

    Bian, Yang; Ren, Luqing; Wang, Lei; Xu, Shanmei; Tao, Jianjian; Zhang, Xiuhua; Huang, Yi; Qian, Yuanyuan; Zhang, Xin; Song, Zongming; Wu, Wencan; Wang, Yi; Liang, Guang

    2015-06-01

    Inflammation is a pathological hallmark of ischemia reperfusion (I/R) injury. The present study was conducted to explore the ability of a new anti-inflammatory compound, X22, to attenuate retinal I/R injury via cytokine-inhibitory mechanism. For the in vitro experiment, ARPE-19 cells were pretreated with X22 (5 or 10 μM) or saline for 2 h, followed by stimulation with tert-butyl hydroperoxide (TBHP, 1000 μM) for an indicated amount of time. The expression of inflammatory mediators, cell viability, and cell apoptosis were evaluated. For the in vivo experiment, the rats were randomized to receive treatment with saline or X22 (0.1 μM/kg, 3 μL) before the induction of I/R injury. Histological evaluation, apoptosis of retinal cells, macrophage infiltration, and retina functional changes were further determined. Our data showed that pretreatment with X22 significantly inhibited TBHP-induced inflammatory cytokine expression in ARPE-19 cells. The anti-inflammatory activity of X22 may be associated with its inhibition on MAPKs, rather than NF-κB. Subsequently, our data proved that TBHP induced apoptosis in ARPE-19 cells, while pretreatment of X22 significantly suppressed TBHP-caused ARPE-19 apoptosis. Finally, the in vivo data revealed that X22 administration maintained better inner retinal layer structures, reduced apoptosis of retinal ganglion cell, and improved retinal function in retinal I/R rat models, which were accompanied with a remarkable decrease in retinal macrophage infiltration. These results suggest that the novel compound X22 is a potential agent for the treatment of retinal I/R-related diseases via the MAPKs-targeting anti-inflammatory mechanism and deserves the further development. Copyright © 2015 Elsevier Ltd. All rights reserved.

  17. Inhibition of inflammation and oxidative stress by an imidazopyridine derivative X22 prevents heart injury from obesity.

    Science.gov (United States)

    Qian, Yuanyuan; Zhang, Yali; Zhong, Peng; Peng, Kesong; Xu, Zheng; Chen, Xuemei; Lu, Kongqin; Chen, Gaozhi; Li, Xiaokun; Liang, Guang

    2016-08-01

    Inflammation and oxidative stress plays an important role in the development of obesity-related complications and cardiovascular disease. Benzimidazole and imidazopyridine compounds are a class of compounds with a variety of activities, including anti-inflammatory, antioxidant and anti-cancer. X22 is an imidazopyridine derivative we synthesized and evaluated previously for anti-inflammatory activity in lipopolysaccharide-stimulated macrophages. However, its ability to alleviate obesity-induced heart injury via its anti-inflammatory actions was unclear. This study was designed to evaluate the cardioprotective effects of X22 using cell culture studies and a high-fat diet rat model. We observed that palmitic acid treatment in cardiac-derived H9c2 cells induced a significant increase in reactive oxygen species, inflammation, apoptosis, fibrosis and hypertrophy. All of these changes were inhibited by treatment with X22. Furthermore, oral administration of X22 suppressed high-fat diet-induced oxidative stress, inflammation, apoptosis, hypertrophy and fibrosis in rat heart tissues and decreased serum lipid concentration. We also found that the anti-inflammatory and anti-oxidative actions of X22 were associated with Nrf2 activation and nuclear factor-kappaB (NF-κB) inhibition, respectively, both in vitro and in vivo. The results of this study indicate that X22 may be a promising cardioprotective agent and that Nrf2 and NF-κB may be important therapeutic targets for obesity-related complications. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  18. Neogambogic acid prevents silica-induced fibrosis via inhibition of high-mobility group box 1 and MCP-1-induced protein 1

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Wei [Department of Physiology, School of Medicine, Southeast University, Nanjing, Jiangsu 210009 (China); Department of Pharmacology, School of Medicine, Southeast University, Nanjing, Jiangsu 210009 (China); Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing 210096 (China); Department of Respiration, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009 (China); Zhang, Mei, E-mail: meizhang1717@163.com [Department of Respiration, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009 (China); Wang, Zhongjiang [Department of Radiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009 (China); Cheng, Yusi; Liu, Haijun [Department of Physiology, School of Medicine, Southeast University, Nanjing, Jiangsu 210009 (China); Zhou, Zewei [Department of Physiology, School of Medicine, Southeast University, Nanjing, Jiangsu 210009 (China); Department of Pharmacology, School of Medicine, Southeast University, Nanjing, Jiangsu 210009 (China); Han, Bing [Department of Pharmacology, School of Medicine, Southeast University, Nanjing, Jiangsu 210009 (China); Chen, Baoan [Department of Hematology and Oncology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009 (China); Yao, Honghong, E-mail: yaohh@seu.edu.cn [Department of Pharmacology, School of Medicine, Southeast University, Nanjing, Jiangsu 210009 (China); Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing 210096 (China); Chao, Jie, E-mail: chaojie@seu.edu.cn [Department of Physiology, School of Medicine, Southeast University, Nanjing, Jiangsu 210009 (China); Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing 210096 (China); Department of Respiration, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009 (China)

    2016-10-15

    Background: Silicosis is a systemic disease caused by inhaling silicon dioxide (SiO{sub 2}); early stages are characterized by alveolar inflammation, and later stages are characterized by progressive lung fibrosis. Mounting evidence indicates that high-mobility group box 1 (HMGB1) is involved in pulmonary fibrosis. Whether neogambogic acid (NGA) inhibits macrophage and fibroblast activation induced by SiO{sub 2} by targeting HMGB1 remains unclear. Methods and results: Experiments using cultured mouse macrophages (RAW264.7 cells) demonstrated that SiO{sub 2} treatment induces the expression of HMGB1 in a time- and dose-dependent manner via mitogen-activated protein kinases (MAPKs) and the phosphatidylinositol 3-kinase (PI3K)/Akt pathway; in turn, this expression causes macrophage apoptosis and fibroblast activation. Pretreating macrophages with NGA inhibited the HMGB1 expression induced by SiO{sub 2} and attenuated both macrophage apoptosis and fibroblast activation. Moreover, NGA directly inhibited MCP-1-induced protein 1 (MCPIP1) expression, as well as markers of fibroblast activation and migration induced by SiO{sub 2}. Furthermore, the effects of NGA on macrophages and fibroblasts were confirmed in vivo by exposing mice to SiO{sub 2}. Conclusion: NGA can prevent SiO{sub 2}-induced macrophage activation and apoptosis via HMGB1 inhibition and SiO{sub 2}-induced fibrosis via the MCPIP1 pathway. Targeting HMGB1 and MCPIP1 with NGA could provide insights into the potential development of a therapeutic approach for alleviating the inflammation and fibrosis induced by SiO{sub 2}. - Highlights: • The SiO{sub 2} induced HMGB1 in alveolar macrophage and MCPIP1 in fibroblast. • NGA rescued the SiO{sub 2}-induced apoptosis of alveolar macrophages via HMGB1 signaling. • NGA inhibited the fibroblast activation induced by SiO{sub 2} via MCPIP1 signaling. • NGA might represent a potential therapeutic approach for silicosis.

  19. [EIA-IgG antibody measles prevention level estimated from measles neutralizing, particle agglutination and hemagglutination-inhibition antibody titer].

    Science.gov (United States)

    Takayama, Naohide; Saika, Shizuko; Ichinohe, Sadato

    2009-09-01

    Measles hemagglutination inhibition (HI) antibody titer, widely used in clinical practice to simply and easily determine the measles immunity level has, in recent years, been increasingly replaced by measles IgG-antibody titer determined by enzyme-immunoassay (EIA). HI antibody titer appears to reflect this protective level, because HI measures the antibody against H protein required for the measles virus to adhere to host cells. EIA-IgG antibody titer does not correlate with the protective level, similar to particle agglutination (PA) titer, because EIA measures different antibodies, including those unrelated to measles protection. After determining HI, PA, neutralizing test (NT) results, and EIA-IgG antibody titer for individual specimens, we compared EIA-IgG antibody titer obtained using an EIA-Kit (Denka Seiken) to HI, PA, and NT titer with the following results: (1) Subjects with EIA-IgG titer of > or = 12.0 may be protected against measles: (2) Subjects with EIA-IgG titer of 4.0 to 8.0 appear to be protected insufficiently requiring a booster dose against measles: (3) Subjects with EIA-IgG titer of 8.0 to 12.0 may benefit from booster vaccination.

  20. Inhibition of the prostaglandin E2 receptor EP2 prevents status epilepticus-induced deficits in the novel object recognition task in rats

    Science.gov (United States)

    Rojas, Asheebo; Ganesh, Thota; Manji, Zahra; O’neill, Theon; Dingledine, Raymond

    2016-01-01

    Survivors of exposure to an organophosphorus nerve agent may develop a number of complications including long-term cognitive deficits (Miyaki et al., 2005; Nishiwaki et al., 2001). We recently demonstrated that inhibition of the prostaglandin E2 receptor, EP2, attenuates neuroinflammation and neurodegeneration caused by status epilepticus (SE) induced by the soman analog, diisopropylfluorophosphate (DFP), which manifest within hours to days of the initial insult. Here, we tested the hypothesis that DFP exposure leads to a loss of cognitive function in rats that is blocked by early, transient EP2 inhibition. Adult male Sprague-Dawley rats were administered vehicle or the competitive EP2 antagonist, TG6-10-1, (ip) at various times relative to DFP-induced SE. DFP administration resulted in prolonged seizure activity as demonstrated by cortical electroencephalography (EEG). A single intraperitoneal injection of TG6-10-1 or vehicle 1 h prior to DFP did not alter the development of seizures, the latency to SE or the duration of SE. Rats administered six injections of TG6-10-1 starting 90 min after the onset of DFP-induced SE could discriminate between a novel and familiar object 6–12 weeks after SE, unlike vehicle treated rats which showed no preference for the novel object. By contrast, behavioral changes in the light-dark box and open field assays were not affected by TG6-10-1. Delayed mortality after DFP was also unaffected by TG6-10-1. Thus, selective inhibition of the EP2 receptor may prevent SE-induced memory impairment in rats caused by exposure to a high dose of DFP. PMID:27477533

  1. Design, characterization, and in vitro cellular inhibition and uptake of optimized genistein-loaded NLC for the prevention of posterior capsular opacification using response surface methodology.

    Science.gov (United States)

    Zhang, Wenji; Li, Xuedong; Ye, Tiantian; Chen, Fen; Sun, Xiao; Kong, Jun; Yang, Xinggang; Pan, Weisan; Li, Sanming

    2013-09-15

    This study was to design an innovative nanostructured lipid carrier (NLC) for drug delivery of genistein applied after cataract surgery for the prevention of posterior capsular opacification. NLC loaded with genistein (GEN-NLC) was produced with Compritol 888 ATO, Gelucire 44/14 and Miglyol 812N, stabilized by Solutol(®) HS15 by melt emulsification method. A 2(4) central composite design of 4 independent variables was performed for optimization. Effects of drug concentration, Gelucire 44/14 concentration in total solid lipid, liquid lipid concentration, and surfactant concentration on the mean particle size, polydispersity index, zeta potential and encapsulation efficiency were investigated. Analysis of variance (ANOVA) statistical test was used to assess the optimization. The optimized GEN-NLC showed a homogeneous particle size of 90.16 nm (with PI=0.33) of negatively charged surface (-25.08 mv) and high encapsulation efficiency (91.14%). Particle morphology assessed by TEM revealed a spherical shape. DSC analyses confirmed that GEN was mostly entrapped in amorphous state. In vitro release experiments indicated a prolonged and controlled genistein release for 72 h. In vitro growth inhibition assay showed an effective growth inhibition of GEN-NLCs on human lens epithelial cells (HLECs). Preliminary cellular uptake test proved a enhanced penetration of genistein into HLECs when delivered in NLC. Copyright © 2013 Elsevier B.V. All rights reserved.

  2. 1-L-MT, an IDO inhibitor, prevented colitis-associated cancer by inducing CDC20 inhibition-mediated mitotic death of colon cancer cells.

    Science.gov (United States)

    Liu, Xiuting; Zhou, Wei; Zhang, Xin; Ding, Yang; Du, Qianming; Hu, Rong

    2018-04-01

    Indoleamine 2,3-dioxygenase 1 (IDO1), known as IDO, catabolizes tryptophan through kynurenine pathway, whose activity is correlated with impaired clinical outcome of colorectal cancer. Here we showed that 1-L-MT, a canonical IDO inhibitor, suppressed proliferation of human colorectal cancer cells through inducing mitotic death. Our results showed that inhibition of IDO decreased the transcription of CDC20, which resulted in G2/M cycle arrest of HCT-116 and HT-29. Furthermore, 1-L-MT induced mitochondria injuries and caused apoptotic cancer cells. Importantly, 1-L-MT protected mice from azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colon carcinogenesis, with reduced mortality, tumor number and size. What is more, IDO1-/- mice exhibited fewer tumor burdens and reduced proliferation in the neoplastic epithelium, while, 1-L-MT did not exhibit any further protective effects on IDO-/- mice, confirming the critical role of IDO and the protective effect of 1-L-MT-mediated IDO inhibition in CRC. Furthermore, 1-L-MT also alleviated CRC in Rag1-/- mice, demonstrating the modulatory effects of IDO independent of its role in modulating adaptive immunity. Taken together, our findings validated that the anti-proliferation effect of 1-L-MT in vitro and the prevention of CRC in vivo were through IDO-induced cell cycle disaster of colon cancer cells. Our results identified 1-L-MT as a promising candidate for the chemoprevention of CRC. © 2018 UICC.

  3. Curcumin inhibition of JNKs prevents dopaminergic neuronal loss in a mouse model of Parkinson’s disease through suppressing mitochondria dysfunction

    Directory of Open Access Journals (Sweden)

    Pan Jing

    2012-08-01

    Full Text Available Abstract Curcumin,a natural polyphenol obtained from turmeric,has been implicated to be neuroprotective in a variety of neurodegenerative disorders although the mechanism remains poorly understood. The results of our recent experiments indicated that curcumin could protect dopaminergic neurons from apoptosis in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP mouse model of Parkinson’s disease (PD. The death of dopaminergic neurons and the loss of dopaminergic axon in the striatum were significantly suppressed by curcumin in MPTP mouse model. Further studies showed that curcumin inhibited JNKs hyperphosphorylation induced by MPTP treatment. JNKs phosphorylation can cause translocation of Bax to mitochondria and the release of cytochrome c which both ultimately contribute to mitochondria-mediated apoptosis. These pro-apoptosis effect can be diminished by curcumin. Our experiments demonstrated that curcumin can prevent nigrostriatal degeneration by inhibiting the dysfunction of mitochondrial through suppressing hyperphosphorylation of JNKs induced by MPTP. Our results suggested that JNKs/mitochondria pathway may be a novel target in the treatment of PD patients.

  4. Inhibition of UDP-glucosylceramide synthase in mice prevents Gaucher disease-associated B-cell malignancy.

    Science.gov (United States)

    Pavlova, Elena V; Archer, Joy; Wang, Susan; Dekker, Nick; Aerts, Johannes Mfg; Karlsson, Stefan; Cox, Timothy M

    2015-01-01

    Clonal B-cell proliferation is a frequent manifestation of Gaucher disease - a sphingolipidosis associated with a high risk of multiple myeloma and non-Hodgkin lymphoma. Gaucher disease is caused by genetic deficiency of acid β-glucosidase, the natural substrates of which (β-d-glucosylceramide and β-d-glucosylsphingosine) accumulate, principally in macrophages. Mice with inducible deficiency of β-glucosidase [Gba(tm1Karl/tm1Karl)Tg(MX1-cre)1Cgn/0] serve as an authentic model of human Gaucher disease; we have recently reported clonal B-cell proliferation accompanied by monoclonal serum paraproteins and cognate tumours in these animals. To explore the relationship between B-cell malignancy and the biochemical defect, we treated Gaucher mice with eliglustat tartrate (GENZ 112638), a potent and selective inhibitor of the first committed step in glycosphingolipid biosynthesis. Twenty-two Gaucher mice received 300 mg/kg of GENZ 112638 daily for 3-10 months from 6 weeks of age. Plasma concentrations of β-d-glucosylceramide and the unacylated glycosphingolipid, β-d-glucosylsphingosine, declined. After administration of GENZ 112638 to Gaucher mice for 3-10 months, serum paraproteins were not detected and there was a striking reduction in the malignant lymphoproliferation: neither lymphomas nor plasmacytomas were found in animals that had received the investigational agent. In contrast, 14 out of 60 Gaucher mice without GENZ 112638 treatment developed these tumours; monoclonal paraproteins were detected in plasma from 18 of the 44 age-matched mice with Gaucher disease that had not received GENZ 112638. Long-term inhibition of glycosphingolipid biosynthesis suppresses the development of spontaneous B-cell lymphoma and myeloma in Gaucher mice. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  5. Getting PrEPared for HIV Prevention Navigation: Young Black Gay Men Talk About HIV Prevention in the Biomedical Era.

    Science.gov (United States)

    Mutchler, Matt G; McDavitt, Bryce; Ghani, Mansur A; Nogg, Kelsey; Winder, Terrell J A; Soto, Juliana K

    2015-09-01

    Biomedical HIV prevention strategies, such as pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP), represent new opportunities to reduce critically high HIV infection rates among young black men who have sex with men (YBMSM). We report results of 24 dyadic qualitative interviews (N=48), conducted in Los Angeles, CA, exploring how YBMSM and their friends view PrEP and PEP. Interviews were analyzed using a grounded theory approach. Participants had widely divergent levels of knowledge about these prevention methods. Misconceptions and mistrust regarding PrEP were common, and concerns were expressed about PrEP-related stigma and the potential for gossip among peers who might assume a person on PrEP was HIV-positive. Yet participants also framed PrEP and PEP as valuable new options within an expanded "tool kit" of HIV prevention strategies that created possibilities for preventing new HIV infections, dating men with a different HIV status, and decreased anxiety about exposure to HIV. We organized themes around four main areas: (1) information and misinformation about biomedical HIV prevention; (2) expectations about PrEP, sexual behavior, and stigma; (3) gossip, disclosure, and "spreading the word" about PrEP and PEP; and (4) the roles of PrEP and PEP in an expanded HIV prevention tool kit. The findings suggest a need for guidance in navigating the increasingly complex array of HIV-prevention options available to YBMSM. Such "prevention navigation" could counter misconceptions and address barriers, such as stigma and mistrust, while helping YBMSM make informed selections from among expanded HIV prevention options.

  6. Some schemes for on-line correction of the closed orbit, dispersion and beta functions in PEP

    International Nuclear Information System (INIS)

    Donald, M.H.R.; Blocker, C.; Chao, A.W.; Hollebeek, R.J.; Lee, M.J.; Linstadt, J.E.; Siegrist, J.L.; Spencer, N.

    1981-02-01

    PEP has been operated successfully under computer control. It is necessary for colliding beam operation that the errors in closed orbits, dispersion and beta functions be corrected. The schemes in the PEP control program for on-line correction of these errors are described in this paper. The orbit control tasks in the PEP control system perform the functions of data gathering, data presentation (color display, printing), calculation and setting of corrector magnets. The tasks are generally small and modular, taking information from the database, processing it, then returning the results to the database. The PEP operator communicates with the tasks through touch panels monitored by the Director program. The display task, which displays orbit and corrector information on a TV color display, provides the main information required by the operator

  7. X-prolyl dipeptidyl aminopeptidase gene (pepX) is part of the glnRA operon in Lactobacillus rhamnosus.

    Science.gov (United States)

    Varmanen, P; Savijoki, K; Avall, S; Palva, A; Tynkkynen, S

    2000-01-01

    A peptidase gene expressing X-prolyl dipeptidyl aminopeptidase (PepX) activity was cloned from Lactobacillus rhamnosus 1/6 by using the chromogenic substrate L-glycyl-L-prolyl-beta-naphthylamide for screening of a genomic library in Escherichia coli. The nucleotide sequence of a 3.5-kb HindIII fragment expressing the peptidase activity revealed one complete open reading frame (ORF) of 2,391 nucleotides. The 797-amino-acid protein encoded by this ORF was shown to be 40, 39, and 36% identical with PepXs from Lactobacillus helveticus, Lactobacillus delbrueckii, and Lactococcus lactis, respectively. By Northern analysis with a pepX-specific probe, transcripts of 4.5 and 7.0 kb were detected, indicating that pepX is part of a polycistronic operon in L. rhamnosus. Cloning and sequencing of the upstream region of pepX revealed the presence of two ORFs of 360 and 1,338 bp that were shown to be able to encode proteins with high homology to GlnR and GlnA proteins, respectively. By multiple primer extension analyses, the only functional promoter in the pepX region was located 25 nucleotides upstream of glnR. Northern analysis with glnA- and pepX-specific probes indicated that transcription from glnR promoter results in a 2.0-kb dicistronic glnR-glnA transcript and also in a longer read-through polycistronic transcript of 7.0 kb that was detected with both probes in samples from cells in exponential growth phase. The glnA gene was disrupted by a single-crossover recombinant event using a nonreplicative plasmid carrying an internal part of glnA. In the disruption mutant, glnRA-specific transcription was derepressed 10-fold compared to the wild type, but the 7.0-kb transcript was no longer detectable with either the glnA- or pepX-specific probe, demonstrating that pepX is indeed part of glnRA operon in L. rhamnosus. Reverse transcription-PCR analysis further supported this operon structure. An extended stem-loop structure was identified immediately upstream of pepX in the glnA-pep

  8. Swamp plots for dynamic aperture studies of PEP-II lattices

    International Nuclear Information System (INIS)

    Yan, Y.T.; Irwin, J.; Cai, Y.; Chen, T.; Ritson, D.

    1995-01-01

    With a newly developed algorithm using resonance basis Lie generators and their evaluation with action-angle Poisson bracket maps (nPB tracking) the authors have been able to perform fast tracking for dynamic aperture studies of PEP-II lattices as well as incorporate lattice nonlinearities in beam-beam studies. They have been able to better understand the relationship between dynamic apertures and the tune shift and resonance coefficients in the generators of the one-turn maps. To obtain swamp plots (dynamic aperture vs. working point) of the PEP-II lattices, they first compute a one-turn resonance basis map for a nominal working point and then perform nPB tracking by switching the working point while holding fixed all other terms in the map. Results have been spot-checked by comparing with element-by-element tracking

  9. A zero-length bellows for the PEP-II High-Energy Ring

    International Nuclear Information System (INIS)

    Nordby, M.; Daly, E.F.; Kurita, N.; Langton, J.

    1995-08-01

    Due to the beamline space constrictions and the modular design of the vacuum system, a conventional bellows can not be used everywhere in the PEP-II High-Energy Ring (HER) arcs. A zero-length ''Flex Flange'' was developed which actually performs better than a more standard bellows. The Flex Flange fits the space available while still preserving the modularity of the system. Furthermore, the design provides for an accurate match-up between adjoining octagonal copper chambers despite the large fabrication and assembly tolerances and high operational loads. Beam chamber continuity is ensured by an integral RF seal ring which is easy to install and fault-tolerant. Heating from synchrotron radiation and higher-order mode trapping is managed to ensure a robust connection despite the 3,000 mA beam current of the PEP-II HER. The Flex Flange concept is versatile and adaptable to many applications, yet economical both in space needed and cost

  10. EFRT M12 Issue Resolution: Comparison of PEP and Bench-Scale Oxidative Leaching Results

    Energy Technology Data Exchange (ETDEWEB)

    Rapko, Brian M.; Brown, Christopher F.; Eslinger, Paul W.; Fountain, Matthew S.; Hausmann, Tom S.; Huckaby, James L.; Hanson, Brady D.; Kurath, Dean E.; Minette, Michael J.

    2009-08-14

    Pacific Northwest National Laboratory (PNNL) has been tasked by Bechtel National Inc. (BNI) on the River Protection Project-Hanford Tank Waste Treatment and Immobilization Plant (RPP-WTP) project to perform research and development activities to resolve technical issues identified for the Pretreatment Facility (PTF). The Pretreatment Engineering Platform (PEP) was designed and constructed and is to be operated as part of a plan to respond to issue M12, “Undemonstrated Leaching Processes.” The PEP is a 1/4.5-scale test platform designed to simulate the WTP pretreatment caustic leaching, oxidative leaching, ultrafiltration solids concentration, and slurry washing processes. The PEP replicates the WTP leaching processes using prototypic equipment and control strategies. The PEP also includes non-prototypic ancillary equipment to support the core processing. Two operating scenarios are currently being evaluated for the ultrafiltration process (UFP) and leaching operations. The first scenario has caustic leaching performed in the UFP-2 ultrafiltration feed vessels (i.e., vessel UFP-VSL-T02A in the PEP; and vessels UFP-VSL-00002A and B in the WTP PTF). The second scenario has caustic leaching conducted in the UFP-1 ultrafiltration feed preparation vessels (i.e., vessels UFP-VSL-T01A and B in the PEP; vessels UFP-VSL-00001A and B in the WTP PTF). In both scenarios, 19-M sodium hydroxide solution (NaOH, caustic) is added to the waste slurry in the vessels to dissolve solid aluminum compounds (e.g., gibbsite, boehmite). Caustic addition is followed by a heating step that uses direct steam injection to accelerate the leaching process. Following the caustic leach, the vessel contents are cooled using vessel cooling jackets and/or external heat exchangers. The main difference between the two scenarios is that for leaching in UFP1, the 19-M NaOH is added to un-concentrated waste slurry (3 to 8 wt% solids), while for leaching in UFP2, the slurry is concentrated to nominally

  11. PepJ is a new extracellular proteinase of Aspergillus nidulans.

    Science.gov (United States)

    Emri, T; Szilágyi, M; László, K; M-Hamvas, M; Pócsi, I

    2009-01-01

    Under carbon starvation, Aspergillus nidulans released a metallo-proteinase with activities comparable to those of PrtA, the major extracellular serine proteinase of the fungus. The relative molar mass of the enzyme was 19 kDa as determined with both denaturing and renaturing SDS PAGE, while its isoelectric point and pH and temperature optima were 8.6, 5.5 and 65 degrees C, respectively. The enzyme was stable at pH 3.5-10.5 and was still active at 95 degrees C in the presence of azocasein substrate. MALDI-TOF MS analysis demonstrated that the proteinase was encoded by the pepJ gene (locus ID AN7962.3), and showed high similarity to deuterolysin from Aspergillus oryzae. The size of the mature enzyme, its EDTA sensitivity and heat stability also supported the view that A. nidulans PepJ is a deuterolysin-type metallo-proteinase.

  12. Study of an instability of the PEP-II positron beam (Ohmi effect and Multipactoring)

    Energy Technology Data Exchange (ETDEWEB)

    Heifets, S A [Stanford Linear Accelerator Center, Menlo Park, CA (United States)

    1996-08-01

    The processes defining the density distribution of the photoelectrons are quite complicated. In this study, a simplified model of the instability was used to get a quick estimate of the growth rate of the instability and the relative importance of the parameters, as has been done in Ohmi`s paper. The production rate and dynamics of the photoelectrons are studied for the PEP-II parameters. The growth rate of the transverse instability driven by the primary photoelectrons is of the order of 0.7 msec for the PEP-II parameters. The multipactoring at resonance currents cannot produce large electron density due to the final energy spread caused by the finite bunch length and the intrinsic energy spread of the secondary electrons. Production of the secondary electrons may lead to large average densities. The ion can be produced in electron collisions with the residual gas with density of the order of the electron density. (G.K.)

  13. Radiosynthesis of a new PSMA targeting ligand ([{sup 18}F]FPy-DUPA-Pep)

    Energy Technology Data Exchange (ETDEWEB)

    Malik, Noeen, E-mail: noeen.malik@uniklinik-ulm.d [Clinic for Nuclear Medicine, University Hospital, Ulm (Germany); Machulla, Hans-Juergen; Solbach, Christoph; Winter, Gordon; Reske, Sven N.; Zlatopolskiy, Boris [Clinic for Nuclear Medicine, University Hospital, Ulm (Germany)

    2011-07-15

    Due to the specificity of expression of PSMA (prostate specific membrane antigen) particularly in prostate cancer cells (e.g. LNCaP), numerous PSMA ligands have been synthesized until now. In the current study, we synthesized DUPA-Pep having 2-[3-(1,3-dicarboxypropyl)ureido]pentanedioic acid (DUPA) linked via 8-aminooctanoic acid to two phenylalanine residues and chose 6-[{sup 18}F]fluoronicotinic acid 2,3,5,6-tetrafluorophenyl ester [{sup 18}F]FPy-TFP as a prosthetic group for coupling. [{sup 18}F]FPy-DUPA-Pep was obtained in a radiochemical yield of 48{+-}0.9% (decay uncorrected) within 50 min with a chemical purity of >98%.

  14. Radiosynthesis of a new PSMA targeting ligand ([18F]FPy-DUPA-Pep)

    International Nuclear Information System (INIS)

    Malik, Noeen; Machulla, Hans-Juergen; Solbach, Christoph; Winter, Gordon; Reske, Sven N.; Zlatopolskiy, Boris

    2011-01-01

    Due to the specificity of expression of PSMA (prostate specific membrane antigen) particularly in prostate cancer cells (e.g. LNCaP), numerous PSMA ligands have been synthesized until now. In the current study, we synthesized DUPA-Pep having 2-[3-(1,3-dicarboxypropyl)ureido]pentanedioic acid (DUPA) linked via 8-aminooctanoic acid to two phenylalanine residues and chose 6-[ 18 F]fluoronicotinic acid 2,3,5,6-tetrafluorophenyl ester [ 18 F]FPy-TFP as a prosthetic group for coupling. [ 18 F]FPy-DUPA-Pep was obtained in a radiochemical yield of 48±0.9% (decay uncorrected) within 50 min with a chemical purity of >98%.

  15. Radiosynthesis of a new PSMA targeting ligand ([18F]FPy-DUPA-Pep).

    Science.gov (United States)

    Malik, Noeen; Machulla, Hans-Jürgen; Solbach, Christoph; Winter, Gordon; Reske, Sven N; Zlatopolskiy, Boris

    2011-07-01

    Due to the specificity of expression of PSMA (prostate specific membrane antigen) particularly in prostate cancer cells (e.g. LNCaP), numerous PSMA ligands have been synthesized until now. In the current study, we synthesized DUPA-Pep having 2-[3-(1,3-dicarboxypropyl)ureido]pentanedioic acid (DUPA) linked via 8-aminooctanoic acid to two phenylalanine residues and chose 6-[(18)F]fluoronicotinic acid 2,3,5,6-tetrafluorophenyl ester [(18)F]FPy-TFP as a prosthetic group for coupling. [(18)F]FPy-DUPA-Pep was obtained in a radiochemical yield of 48±0.9% (decay uncorrected) within 50 min with a chemical purity of >98%. Copyright © 2011 Elsevier Ltd. All rights reserved.

  16. Calibration of the beam-position monitor system for the SLAC PEP-II B factory

    International Nuclear Information System (INIS)

    Johnson, R.; Smith, S.; Kurita, N.

    1997-06-01

    The Beam-Position Monitors (BPM) for the PEP-II B Factory consist of four 1.5-cm diameter button style pickups mounted on the diagonals of the quadrupole vacuum chambers. Before installation of the vacuum chambers in the quadrupole assemblies, the electrical center of the BPMs is measured with respect to the mechanical center in a calibration test stand. In this paper the calibration test stand is described and the precision and accuracy of the calibrations are presented. After installation of the quadrupole assemblies in the PEP-II tunnel, the passive attenuation for each channel of the system is measured to preserve the accuracy of the calibration. Finally, the active electronics includes an onboard calibrator. Results for these portions of the calibration are presented

  17. Operator interface for the PEP-II low level RF control system

    International Nuclear Information System (INIS)

    Allison, S.; Claus, R.

    1997-05-01

    This paper focuses on the operational aspects of the low level RF control system being built for the PEP-II storage rings at SLAC. Subsystems requiring major operational considerations include displays for monitor and control from UNIX workstations, slow feedback loops and control sequences residing on microprocessors, and various client applications in the existing SLAC Linear Collider (SLC) control system. Since commissioning of PEP-II RF is currently in-progress, only those parts of the control system used during this phase are discussed in detail. Based on past experience with the SLC control system, it is expected that effort expended during commissioning on a solid user interface will result in smoother transition to full reliable 24-hour-a-day operation

  18. Operation and performance of the PEP-II prototype longitudinal damping system at ALS

    International Nuclear Information System (INIS)

    Teytelman, D.; Claus, R.; Fox, J.

    1995-05-01

    A modular programmable longitudinal feedback system has been developed as a component of the PEP-II R+D program. This system is based on a family of VME and VXI packaged signal processing functions which implement a general purpose digital feedback controller for accelerators with bunch spacings of 2 ns. A complete PEP-II prototype system has been configured and installed for use at the LBL Advanced Light Source. The system configuration used for tests at the ALS is described and results are presented showing the action of the feedback system. Open and closed loop results showing the detection and calculation of feedback signals from bunch motion are presented and the system is shown to damp coupled-bunch instabilities in the ALS. Use of the system for accelerator diagnostics is illustrated via measurement of grow-damp transients which quantify growth rates without feedback, damping rates with feedback, and identify unstable modes

  19. The PEP-II Asymmetric B Factory: Design details and R ampersand D results

    International Nuclear Information System (INIS)

    Bloom, E.; DeStaebler, H.; Dorfan, J.

    1994-06-01

    PEP-II, a 9 GeV x 3.1 GeV electron-positron collider with a design luminosity of 3 x 10 33 cm -2 s -1 has now been approved for construction by SLAC, LBL and LLNL for the purpose of studying CP violation in the B bar B system. This upgrade project involves replacing the vacuum and RF systeum of PEP, which will serve as the high-energy ring (HER), along with the addition of a new low-energy ring (LER) mounted atop the HER. Designs for both rings are described, and the anticipated project construction schedule is indicated. Collider operation will begin at the end of 1998. An aggressive R ampersand D program has been carried out to validate our design choices; key results in the areas of lattice design, vacuum, RF, and multibunch feedback are summarized

  20. Transverse feedback systems for the PEP-II B-factory

    International Nuclear Information System (INIS)

    Corlett, J.N.; Barry, W.; Byrd, J.M.; Lambertson, G.; Johnson, J.; Fahmie, M.

    1995-10-01

    Growth rates of coherent beam oscillations are faster than the natural damping mechanisms for the parameters of the PEP-II B-factory storage rings at nominal currents, even with damping of cavity higher order modes (HOM's). With 165 8 bunches separated by 4.2 ns, and a large current of up to 3A (2.14 A nominal in the low energy ring), many coupled-bunch modes are excited by the resistive wall impedance and cavity higher order mode impedance. Fastest growth times of transverse rigid-bunch modes of approximately 300 ps are expected, two orders of magnitude faster than the radiation damping time. We will provide broadband, bunch-by-bunch feedback to suppress this coherent motion of the beam. Experience gained with a prototype system, installed and successfully operating at the LBNL Advanced Light Source (ALS), has been used extensively in developing the design of the PEP-II systems

  1. Ethanol injected into the hypothalamic arcuate nucleus induces behavioral stimulation in rats: an effect prevented by catalase inhibition and naltrexone.

    Science.gov (United States)

    Pastor, Raúl; Aragon, Carlos M G

    2008-10-01

    It is suggested that some of the behavioral effects of ethanol, including its psychomotor properties, are mediated by beta-endorphin and opioid receptors. Ethanol-induced increases in the release of hypothalamic beta-endorphin depend on the catalasemic conversion of ethanol to acetaldehyde. Here, we evaluated the locomotor activity in rats microinjected with ethanol directly into the hypothalamic arcuate nucleus (ArcN), the main site of beta-endorphin synthesis in the brain and a region with high levels of catalase expression. Intra-ArcN ethanol-induced changes in motor activity were also investigated in rats pretreated with the opioid receptor antagonist, naltrexone (0-2 mg/kg) or the catalase inhibitor 3-amino-1,2,4-triazole (AT; 0-1 g/kg). We found that ethanol microinjections of 64 or 128, but not 256 microg, produced locomotor stimulation. Intra-ArcN ethanol (128 microg)-induced activation was prevented by naltrexone and AT, whereas these compounds did not affect spontaneous activity. The present results support earlier evidence indicating that the ArcN and the beta-endorphinic neurons of this nucleus are necessary for ethanol to induce stimulation. In addition, our data suggest that brain structures that, as the ArcN, are rich in catalase may support the formation of ethanol-derived pharmacologically relevant concentrations of acetaldehyde and, thus be of particular importance for the behavioral effects of ethanol.

  2. Letter of intent for the study of CP violation and heavy flavor physics at PEP-II

    International Nuclear Information System (INIS)

    1994-01-01

    This report discusses the following topics on CP violation and heavy flavor physics experiments: Physics at PEP-II; detector overview; PEP-II and the interaction region; vertex detector; main tracking chamber; particle identification; electromagnetic calorimeter; muon and neutral hadron detector; magnet coil and flux return; electronics, trigger, and data acquisition; computing; CP asymmetry simulations; collaboration issues; project organization and management; and budget and schedule

  3. EFRT M-12 Issue Resolution: Caustic-Leach Rate Constants from PEP and Laboratory-Scale Tests

    Energy Technology Data Exchange (ETDEWEB)

    Mahoney, Lenna A.; Rassat, Scot D.; Eslinger, Paul W.; Aaberg, Rosanne L.; Aker, Pamela M.; Golovich, Elizabeth C.; Hanson, Brady D.; Hausmann, Tom S.; Huckaby, James L.; Kurath, Dean E.; Minette, Michael J.; Sundaram, S. K.; Yokuda, Satoru T.

    2010-01-01

    Pacific Northwest National Laboratory (PNNL) has been tasked by Bechtel National Inc. (BNI) on the River Protection Project-Hanford Tank Waste Treatment and Immobilization Plant (RPP-WTP) project to perform research and development activities to resolve technical issues identified for the Pretreatment Facility (PTF). The Pretreatment Engineering Platform (PEP) was designed, constructed and operated as part of a plan to respond to issue M12, “Undemonstrated Leaching Processes” of the External Flowsheet Review Team (EFRT) issue response plan.( ) The PEP is a 1/4.5-scale test platform designed to simulate the WTP pretreatment caustic leaching, oxidative leaching, ultrafiltration solids concentration, and slurry washing processes. The PEP replicates the WTP leaching processes using prototypic equipment and control strategies. The PEP also includes non-prototypic ancillary equipment to support the core processing. The work described in this report addresses caustic leaching under WTP conditions, based on tests performed with a Hanford waste simulant. Because gibbsite leaching kinetics are rapid (gibbsite is expected to be dissolved by the time the final leach temperature is reached), boehmite leach kinetics are the main focus of the caustic-leach tests. The tests were completed at the laboratory-scale and in the PEP, which is a 1/4.5-scale mock-up of key PTF process equipment. Two laboratory-scale caustic-leach tests were performed for each of the PEP runs. For each PEP run, unleached slurry was taken from the PEP caustic-leach vessel for one batch and used as feed for both of the corresponding laboratory-scale tests.

  4. Letter of intent for the study of CP violation and heavy flavor physics at PEP-II

    Energy Technology Data Exchange (ETDEWEB)

    BaBar Collaboration

    1994-06-18

    This report discusses the following topics on CP violation and heavy flavor physics experiments: Physics at PEP-II; detector overview; PEP-II and the interaction region; vertex detector; main tracking chamber; particle identification; electromagnetic calorimeter; muon and neutral hadron detector; magnet coil and flux return; electronics, trigger, and data acquisition; computing; CP asymmetry simulations; collaboration issues; project organization and management; and budget and schedule.

  5. Lychee Seed Saponins Improve Cognitive Function and Prevent Neuronal Injury via Inhibiting Neuronal Apoptosis in a Rat Model of Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    Xiuling Wang

    2017-02-01

    Full Text Available Lychee seed is a traditional Chinese medicine and possesses many activities, including hypoglycemia, liver protection, antioxidation, antivirus, and antitumor. However, its effect on neuroprotection is still unclear. The present study investigated the effects of lychee seed saponins (LSS on neuroprotection and associated mechanisms. We established a rat model of Alzheimer’s disease (AD by injecting Aβ25–35 into the lateral ventricle of rats and evaluated the effect of LSS on spatial learning and memory ability via the Morris water maze. Neuronal apoptosis was analyzed by hematoxylin and eosin stain and terminal deoxynucleotidyl transferase (Tdt-mediated dUTP nick-end labeling analysis, and mRNA expression of caspase-3 and protein expressions of Bax and Bcl-2 by reverse transcription-polymerase chain reaction (RT-PCR and Western blotting, respectively. The results showed that LSS remarkably improved cognitive function and alleviated neuronal injury by inhibiting apoptosis in the hippocampus of AD rats. Furthermore, the mRNA expression of caspase-3 and the protein expression of Bax were downregulated, while the protein expression of Bcl-2 and the ratio of Bcl-2/Bax were increased by LSS. We demonstrate that LSS significantly improves cognitive function and prevent neuronal injury in the AD rats via regulation of the apoptosis pathway. Therefore, LSS may be developed as a nutritional supplement and sold as a drug for AD prevention and/or treatment.

  6. High-power RF window and coupler development for the PEP-II B Factory

    International Nuclear Information System (INIS)

    Neubauer, M.; Fant, K.; Hodgson, J.; Judkins, J.; Schwarz, H.; Rimmer, R.A.

    1995-05-01

    We describe the fabrication and testing of the RF windows designed to transmit power to the PEP-II 476 MHz cavities. Design choices to maximize the reliability of the window are discussed. Fabrication technologies for the window are described and finite-element analysis of the assembly process is presented. Conditioning and high-power testing of the window are discussed. Design of the coupler assembly including the integration of the window and other components is reported

  7. Pep2Path: automated mass spectrometry-guided genome mining of peptidic natural products.

    Directory of Open Access Journals (Sweden)

    Marnix H Medema

    2014-09-01

    Full Text Available Nonribosomally and ribosomally synthesized bioactive peptides constitute a source of molecules of great biomedical importance, including antibiotics such as penicillin, immunosuppressants such as cyclosporine, and cytostatics such as bleomycin. Recently, an innovative mass-spectrometry-based strategy, peptidogenomics, has been pioneered to effectively mine microbial strains for novel peptidic metabolites. Even though mass-spectrometric peptide detection can be performed quite fast, true high-throughput natural product discovery approaches have still been limited by the inability to rapidly match the identified tandem mass spectra to the gene clusters responsible for the biosynthesis of the corresponding compounds. With Pep2Path, we introduce a software package to fully automate the peptidogenomics approach through the rapid Bayesian probabilistic matching of mass spectra to their corresponding biosynthetic gene clusters. Detailed benchmarking of the method shows that the approach is powerful enough to correctly identify gene clusters even in data sets that consist of hundreds of genomes, which also makes it possible to match compounds from unsequenced organisms to closely related biosynthetic gene clusters in other genomes. Applying Pep2Path to a data set of compounds without known biosynthesis routes, we were able to identify candidate gene clusters for the biosynthesis of five important compounds. Notably, one of these clusters was detected in a genome from a different subphylum of Proteobacteria than that in which the molecule had first been identified. All in all, our approach paves the way towards high-throughput discovery of novel peptidic natural products. Pep2Path is freely available from http://pep2path.sourceforge.net/, implemented in Python, licensed under the GNU General Public License v3 and supported on MS Windows, Linux and Mac OS X.

  8. Modeling Lost-Particle Accelerator Backgrounds in PEP-II Using LPTURTLE

    CERN Document Server

    Fieguth, Theodore; Kozanecki, Witold

    2005-01-01

    Background studies during the design, construction, commissioning, operation and improvement of BaBar and PEP-II have been greatly influenced by results from a program referred to as LPTURTLE (Lost Particle TURTLE a modified version of Decay TURTLE) which was originally conceived for the purpose of studying gas background for SLC. This venerable program is still in use today. We describe its use, capabilities and improvements and refer to current results now being applied to BaBar.

  9. Scaling of gain with energy spread and energy in the PEP FEL

    International Nuclear Information System (INIS)

    Fisher, A.S.

    1992-01-01

    The Sag Harbor paper on the PEP FEL discusses the scaling of various FEL parameters with energy spread σ var-epsilon . I will repeat some of this material here and then examine the benefit of increasing the energy spread. How much energy spread can be achieved with damping wigglers is the next topic. Finally, I consider the dependence of gain and saturation length on beam energy and undulator field

  10. The PEP-II Project: Low-Energy Ring Design and Project Status

    International Nuclear Information System (INIS)

    Zisman, Michael S.

    2006-01-01

    We describe the present status of the PEP-II project. The project comprises four major systems: Injector, High-Energy Ring (HER), Low-Energy Ring (LER), and Interaction Region (IR). We focus in detail on the design of the LER, as its parameters and requirements are most closely related to those required for the Beijing Tau-Charm Factory rings. The PEP-II LER is a high-current, 3.1-GeV positron ring mounted above the 9-GeV HER. The LER uses a wiggler located in one of its six straight sections to provide emittance control and additional damping. We describe the rather complicated IR, which must transport the LER beam into the plane of the HER, focus it to a common beam size, and separate the beams after the head-on collisions. Both permanent magnet and conventional electromagnets are used in this area. The LER lattice has now adopted a simplified non-interleaved sextupole correction scheme that has reduced the required number of sextupoles substantially. We describe the LER vacuum system, one of the most challenging subsystems in PEP-II. It employs several technologies. In the arcs, aluminum extrusions and titanium sublimation pumps are employed; the straight sections use stainless steel chambers with lumped ion pumps. In the wiggler area, an extended copper photon dump with nonevaporable getter (NEG) pumps is employed to handle the very large synchrotron radiation power. The design of the room-temperature RF system, the bunch-by-bunch longitudinal and transverse feedback systems, and some of the special diagnostics will be described briefly. The PEP-II project remains on schedule to begin commissioning of the HER in April 1997, followed by the LER a year later

  11. RF Feedback Analysis for 4 cavities per klystron in PEP-II

    International Nuclear Information System (INIS)

    Corredoura, P.; Tighe, R.

    1994-06-01

    Lattice changes in the PEP-II high energy ring have made the concept of driving four cavities with a single klystron an attractive option. This paper examines the topology from a RF feedback point of view. Sources of error are identified and their magnitudes are estimated. The effect on the performance of the longitudinal impedance reducing feedback loops is calculated using control theory and Mathematica

  12. Study of heavy quark production with the Mark II at PEP

    International Nuclear Information System (INIS)

    Abrams, G.; Amidei, D.; Baden, A.

    1983-10-01

    The methods adopted by the Mark II collaboration to study heavy quark production at PEP are described. Two complementary techniques are used: D* tagging using the decay chain D* + . D 0 π + , D 0 → K - π + , and inclusive lepton tagging using the characteristic p/sub T/ distributions to distinguish contributions from b and c quarks. These techniques are used to derive information about heavy quark fragmentation and about the weak coupling of heavy quarks

  13. The key determinants of perceived external prestige (PEP) – Qualitative research approach

    OpenAIRE

    Tamara Sušanj Šulentić; Krešimir Žnidar; Jurica Pavičić

    2017-01-01

    Perceived external prestige (PEP) is a well-known concept oriented towards describing the way members of a certain organization interpret and assess their organisational reputation. Such perception can significantly affect employees’ identification and loyalty to the organisation as well as their job satisfaction and work performance. According to the social identification theory, people define themselves and others with respect to their belonging to a particular group or organization, and th...

  14. Mesomorphic phase behaviour of low molar mass PEP-PDMS diblock copolymers synthesized by anionic polymerization

    Energy Technology Data Exchange (ETDEWEB)

    Vigild, M.E.

    1997-10-01

    The phase behaviour of low molar mass poly(ethylene-alt-propylene) -poly(dimethylsiloxane) (PEP-PDMS) is investigated in this thesis by the combination of dynamical mechanical spectroscopy (rheology) to measure phase transition temperatures, and small-angle x-ray scattering to identify the morphology of encountered phases. Samples of PEP-PDMS in the range of 0.2-0.7 in volume fraction of PEP are studied. This diblock copolymer system exhibits the three classical phases of lamellar sandwich structure (LAM), hexagonally packed cylinders (HEX), and spheres arranged on a body centered cubic lattice (BCC). Furthermore the gyroid phase (Ia3d symmetry) of two interpenetrating networks was also identified as a stable phase of the PEP-PDMS system. Time resolved measurements of small-angle neutron scattering in tandem with simultaneous in-situ rheological measurements are performed on samples showing transitions between different ordered phases. The identification of especially the BCC and gyroid phases from scattering experiments is treated. By performing mesoscopic crystallographic measurements using a custom built goniometer it was unambiguously shown that the application of shear to an unoriented powder-like sample introduces uniaxial orientation of the gyroid phase. The orientation of the ordered phase is otherwise random, causing a two-dimensional powder. Finally this dissertation presents a discussion of relevant parameters for the description of diblock copolymer phase behaviour together with descriptions of anionic polymerization for the synthesis of copolymers, and various experimental techniques for the characterization of diblocks. (au). 9 tabs., 40 ills., 81 refs.

  15. Inhibition of VDAC1 prevents Ca²⁺-mediated oxidative stress and apoptosis induced by 5-aminolevulinic acid mediated sonodynamic therapy in THP-1 macrophages.

    Science.gov (United States)

    Chen, Haibo; Gao, Weiwei; Yang, Yang; Guo, Shuyuan; Wang, Huan; Wang, Wei; Zhang, Shuisheng; Zhou, Qi; Xu, Haobo; Yao, Jianting; Tian, Zhen; Li, Bicheng; Cao, Wenwu; Zhang, Zhiguo; Tian, Ye

    2014-12-01

    Ultrasound combined with endogenous protoporphyrin IX derived from 5-aminolevulinic acid (ALA-SDT) is known to induce apoptosis in multiple cancer cells and macrophages. Persistent retention of macrophages in the plaque has been implicated in the pathophysiology and progression of atherosclerosis. Here we investigated the effects of inhibition of voltage-dependent anion channel 1 (VDAC1) on ALA-SDT-induced THP-1 macrophages apoptosis. Cells were pre-treated with VDAC1 inhibitor 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) disodium salt for 1 h or downregulated VDAC1 expression by small interfering RNA and exposed to ultrasound. Cell viability was assessed by MTT assay, and cell apoptosis along with necrosis was evaluated by Hoechst 33342/propidium iodide staining and flow cytometry. Levels of cytochrome c release was assessed by confocal microscope and Western blot. The levels of full length caspases, caspase activation, and VDAC isoforms were analyzed by Western blot. Intracellular reactive oxygen species generation, mitochondrial membrane permeability, and intracellular Ca(2+) [Ca(2+)]i levels were measured with fluorescent probes. We confirmed that the pharmacological inhibition of VDAC1 by DIDS notably prevented ALA-SDT-induced cell apoptosis in THP-1 macrophages. Additionally, DIDS significantly inhibited intracellular ROS generation and apoptotic biochemical changes such as inner mitochondrial membrane permeabilization, loss of mitochondrial membrane potential, cytochrome c release and activation of caspase-3 and caspase-9. Moreover, ALA-SDT elevated the [Ca(2+)]i levels and it was also notably reduced by DIDS. Furthermore, both of intracellular ROS generation and cell apoptosis were predominately inhibited by Ca(2+) chelating reagent BAPTA-AM. Intriguingly, ALA-treatment markedly augmented VDAC1 protein levels exclusively, and the downregulation of VDAC1 expression by specific siRNA also significantly abolished cell apoptosis. Altogether, these

  16. PKMζ inhibition prevents the metaplastic change induced by conditioned taste aversion on insular cortex long-term potentiation in vivo.

    Science.gov (United States)

    Ángeles-Durán, Sandybel; Ramos-Languren, Laura E; Escobar, Martha L

    2012-01-01

    The activity history of a given neuron or pathway has been suggested to influence its future responses to synaptic inputs. In particular, training in several learning tasks produces a metaplastic change, that is, a change in the ability to induce subsequent synaptic plasticity. Experimental evidence shows that the maintenance of long term memory and long-term potentiation (LTP) requires the persistent action of the atypical protein kinase Cisoform, protein kinase M ζ (PKM ζ ). Recent work has demonstrated that the inactivation of PKM ζ in the insular cortex (IC) abolishes conditioned taste aversion (CTA) long term memory. Our previous studies in the IC have demonstrated that the induction of LTP in the basolateral amygdaloid nucleus (Bla)-IC projection previous to CTA training enhances the retention of this task. Moreover, recently, we have observed that CTA training blocks the subsequent induction of LTP in the Bla-IC projection. The aim of the present study was to investigate the participation of PKM ζon the CTA-dependent modification of the ability to induce subsequent LTP in the Bla-IC projection in vivo . Thus, we have delivered high-frequency stimulation in the Bla-IC projection in order to induce in vivo IC-LTP in the rats that underwent or did not have an impairment of CTA retention due to the intracortical administration of the selective PKM ζ pseudosubstrate inhibitory peptide, ZIP. Our results show that the microinfusion of ZIP into the IC of the behaving rats impairs long-term memory of CTA and prevents its effects on IC-LTP. These results indicate that PKM ζ is a key component of the cellular mechanisms necessary for the persistence of lasting memory traces as well as for those underlying metaplastic changes in neocortex, contributing to the persistence of aversive memories.

  17. PARP Inhibition Prevents Ethanol-Induced Neuroinflammatory Signaling and Neurodegeneration in Rat Adult-Age Brain Slice Cultures

    Science.gov (United States)

    Tajuddin, Nuzhath; Kim, Hee-Yong

    2018-01-01

    Using rat adult-age hippocampal-entorhinal cortical (HEC) slice cultures, we examined the role of poly [ADP-ribose] polymerase (PARP) in binge ethanol’s brain inflammatory and neurodegenerative mechanisms. Activated by DNA strand breaks, PARP (principally PARP1 in the brain) promotes DNA repair via poly [ADP-ribose] (PAR) products, but PARP overactivation triggers regulated neuronal necrosis (e.g., parthanatos). Previously, we found that brain PARP1 levels were upregulated by neurotoxic ethanol binges in adult rats and HEC slices, and PARP inhibitor PJ34 abrogated slice neurodegeneration. Binged HEC slices also exhibited increased Ca+2-dependent phospholipase A2 (PLA2) isoenzymes (cPLA2 IVA and sPLA2 IIA) that mobilize proinflammatory ω6 arachidonic acid (ARA). We now find in 4-day–binged HEC slice cultures (100 mM ethanol) that PARP1 elevations after two overnight binges precede PAR, cPLA2, and sPLA2 enhancements by 1 day and high-mobility group box-1 (HMGB1), an ethanol-responsive alarmin that augments proinflammatory cytokines via toll-like receptor-4 (TLR4), by 2 days. After verifying that PJ34 effectively blocks PARP activity (↑PAR), we demonstrated that, like PJ34, three other PARP inhibitors—olaparib, veliparib, and 4-aminobenzamide—provided neuroprotection from ethanol. Importantly, PJ34 and olaparib also prevented ethanol’s amplification of the PLA2 isoenzymes, and two PLA2 inhibitors were neuroprotective—thus coupling PARP to PLA2, with PLA2 activity promoting neurodegeneration. Also, PJ34 and olaparib blocked ethanol-induced HMGB1 elevations, linking brain PARP induction to TLR4 activation. The results provide evidence in adult brains that induction of PARP1 may mediate dual neuroinflammatory pathways (PLA2→phospholipid→ARA and HMGB1→TLR4→proinflammatory cytokines) that are complicit in binge ethanol-induced neurodegeneration. PMID:29339456

  18. Pep1, a secreted effector protein of Ustilago maydis, is required for successful invasion of plant cells.

    Directory of Open Access Journals (Sweden)

    Gunther Doehlemann

    2009-02-01

    Full Text Available The basidiomycete Ustilago maydis causes smut disease in maize. Colonization of the host plant is initiated by direct penetration of cuticle and cell wall of maize epidermis cells. The invading hyphae are surrounded by the plant plasma membrane and proliferate within the plant tissue. We identified a novel secreted protein, termed Pep1, that is essential for penetration. Disruption mutants of pep1 are not affected in saprophytic growth and develop normal infection structures. However, Deltapep1 mutants arrest during penetration of the epidermal cell and elicit a strong plant defense response. Using Affymetrix maize arrays, we identified 116 plant genes which are differentially regulated in Deltapep1 compared to wild type infections. Most of these genes are related to plant defense. By in vivo immunolocalization, live-cell imaging and plasmolysis approaches, we detected Pep1 in the apoplastic space as well as its accumulation at sites of cell-to-cell passages. Site-directed mutagenesis identified two of the four cysteine residues in Pep1 as essential for function, suggesting that the formation of disulfide bridges is crucial for proper protein folding. The barley covered smut fungus Ustilago hordei contains an ortholog of pep1 which is needed for penetration of barley and which is able to complement the U. maydis Deltapep1 mutant. Based on these results, we conclude that Pep1 has a conserved function essential for establishing compatibility that is not restricted to the U. maydis / maize interaction.

  19. Measurement of the leptonic structure functions of the photon at PEP [Positron Electron Project

    International Nuclear Information System (INIS)

    Cain, M.P.

    1987-01-01

    At beam energies available at the PEP e + e - storage ring at the Stanford Linear Accelerator Center the cross-section for two-photon particle production is sufficiently large to warrant an investigation of this O(α 4 ) process. Of particular interest is the two-photon process ee → eeμμ at non-zero Q 2 . This channel is not only relatively easy to observe experimentally but also serves as a model for the process ee → eeq bar q. For the case of inelastic eγ scattering the cross-section could be parameterized in terms of the photon structure functions F 1 (x,Q 2 ) and F 2 (x,Q 2 ). In this thesis I will present data on the process ee → eeμμ collected by the Two-Photon collaboration (PEP-9) at PEP. For the subset of data which proceeds by inelastic eγ scattering I will present a procedure for extracting the QED photon structure functions and apply this method to the data. 42 refs., 44 figs

  20. SwePep, a database designed for endogenous peptides and mass spectrometry.

    Science.gov (United States)

    Fälth, Maria; Sköld, Karl; Norrman, Mathias; Svensson, Marcus; Fenyö, David; Andren, Per E

    2006-06-01

    A new database, SwePep, specifically designed for endogenous peptides, has been constructed to significantly speed up the identification process from complex tissue samples utilizing mass spectrometry. In the identification process the experimental peptide masses are compared with the peptide masses stored in the database both with and without possible post-translational modifications. This intermediate identification step is fast and singles out peptides that are potential endogenous peptides and can later be confirmed with tandem mass spectrometry data. Successful applications of this methodology are presented. The SwePep database is a relational database developed using MySql and Java. The database contains 4180 annotated endogenous peptides from different tissues originating from 394 different species as well as 50 novel peptides from brain tissue identified in our laboratory. Information about the peptides, including mass, isoelectric point, sequence, and precursor protein, is also stored in the database. This new approach holds great potential for removing the bottleneck that occurs during the identification process in the field of peptidomics. The SwePep database is available to the public.

  1. PepArML: A Meta-Search Peptide Identification Platform for Tandem Mass Spectra.

    Science.gov (United States)

    Edwards, Nathan J

    2013-12-01

    The PepArML meta-search peptide identification platform for tandem mass spectra provides a unified search interface to seven search engines; a robust cluster, grid, and cloud computing scheduler for large-scale searches; and an unsupervised, model-free, machine-learning-based result combiner, which selects the best peptide identification for each spectrum, estimates false-discovery rates, and outputs pepXML format identifications. The meta-search platform supports Mascot; Tandem with native, k-score and s-score scoring; OMSSA; MyriMatch; and InsPecT with MS-GF spectral probability scores—reformatting spectral data and constructing search configurations for each search engine on the fly. The combiner selects the best peptide identification for each spectrum based on search engine results and features that model enzymatic digestion, retention time, precursor isotope clusters, mass accuracy, and proteotypic peptide properties, requiring no prior knowledge of feature utility or weighting. The PepArML meta-search peptide identification platform often identifies two to three times more spectra than individual search engines at 10% FDR.

  2. Effect of the Electron Cloud and CSR on the Upgrade of the PEP-II

    International Nuclear Information System (INIS)

    Heifets, Samuel A

    2001-01-01

    Effects of the electron cloud and of the coherent synchrotron radiation (CSR) on the possible upgrade of the PEP-II B-factory are studied. PEP-II B factory operates with parameters shown in Table 1 and already exceeds the design luminosity. Nevertheless, a possibility of upgrading the machine to even higher luminosities is under consideration [1]. Several scenarios are summarized in Table 2. This paper describes effects of the electron cloud and of the coherent synchrotron radiation (CSR) on the proposed upgrades of the PEP-II B-factory. The first effect was observed [3] and caused [4] the degradation of the emittance at KEK B-factory. The analytic expression for the e-wake [2] is used in calculations of the head-tail instability. Other obvious effects of higher beam currents such as additional heat load are not considered. The short wave length CSR has been recently observed at Brookhaven [6]. Consideration of the effect of such CSR on the beam dynamics is based on our previous paper [7

  3. ARA-PEPs: a repository of putative sORF-encoded peptides in Arabidopsis thaliana.

    Science.gov (United States)

    Hazarika, Rashmi R; De Coninck, Barbara; Yamamoto, Lidia R; Martin, Laura R; Cammue, Bruno P A; van Noort, Vera

    2017-01-17

    Many eukaryotic RNAs have been considered non-coding as they only contain short open reading frames (sORFs). However, there is increasing evidence for the translation of these sORFs into bioactive peptides with potent signaling, antimicrobial, developmental, antioxidant roles etc. Yet only a few peptides encoded by sORFs are annotated in the model organism Arabidopsis thaliana. To aid the functional annotation of these peptides, we have developed ARA-PEPs (available at http://www.biw.kuleuven.be/CSB/ARA-PEPs ), a repository of putative peptides encoded by sORFs in the A. thaliana genome starting from in-house Tiling arrays, RNA-seq data and other publicly available datasets. ARA-PEPs currently lists 13,748 sORF-encoded peptides with transcriptional evidence. In addition to existing data, we have identified 100 novel transcriptionally active regions (TARs) that might encode 341 novel stress-induced peptides (SIPs). To aid in identification of bioactivity, we add functional annotation and sequence conservation to predicted peptides. To our knowledge, this is the largest repository of plant peptides encoded by sORFs with transcript evidence, publicly available and this resource will help scientists to effortlessly navigate the list of experimentally studied peptides, the experimental and computational evidence supporting the activity of these peptides and gain new perspectives for peptide discovery.

  4. Status of the Object Oriented Program based Graphic User Interface Development for HyPEP

    International Nuclear Information System (INIS)

    Lee, Young Jin; Park, Ji Won; Hwang, Moon Kyu

    2007-01-01

    Hydrogen is being promoted as the energy-carrier for the future under the proposed hydrogen economy. As large reservoirs of hydrogen molecules do not exist in nature, the hydrogen needs to be produced using other energies such as nuclear, coal, natural gas, etc. The nuclear hydrogen production facility, where nuclear power is used to split water to produce hydrogen molecules, is presented as one of the optimal solutions for the large scale hydrogen production. Compared to other large scale hydrogen production methods, the nuclear hydrogen production can have better overall economics and less damaging environmental impacts such as global warming and pollution. In order to assess the overall economics of the hydrogen production, it is important to assess the hydrogen production efficiencies. In the conceptual design stage of the plant, various different plant layouts need to be studied to optimize the production efficiency. The main development aim of the HyPEP (Hydrogen Production Efficiency calculator Program) is the rapid assessment of the overall hydrogen production efficiency of a nuclear hydrogen production facility. The program is being developed with extensive GUI features to enhance the user-friendliness and the rapid model build-ups. This paper presents the current status of the development of HyPEP especially the GUI. HyPEP is being developed under an International Nuclear Engineering Research Initiative (I-NERI) Project

  5. A Parallel Controls Software Approach for PEP II: AIDA and Matlab Middle Layer

    International Nuclear Information System (INIS)

    Wittmer, W.; Colocho, W.; White, G.

    2007-01-01

    The controls software in use at PEP II (Stanford Control Program - SCP) had originally been developed in the eighties. It is very successful in routine operation but due to its internal structure it is difficult and time consuming to extend its functionality. This is problematic during machine development and when solving operational issues. Routinely, data has to be exported from the system, analyzed offline, and calculated settings have to be reimported. Since this is a manual process, it is time consuming and error-prone. Setting up automated processes, as is done for MIA (Model Independent Analysis), is also time consuming and specific to each application. Recently, there has been a trend at light sources to use MATLAB as the platform to control accelerators using a 'MATLAB Middle Layer' (MML), and so called channel access (CA) programs to communicate with the low level control system (LLCS). This has proven very successful, especially during machine development time and trouble shooting. A special CA code, named AIDA (Accelerator Independent Data Access), was developed to handle the communication between MATLAB, modern software frameworks, and the SCP. The MML had to be adapted for implementation at PEP II. Colliders differ significantly in their designs compared to light sources, which poses a challenge. PEP II is the first collider at which this implementation is being done. We will report on this effort, which is still ongoing

  6. Glutamate-induced apoptosis in primary cortical neurons is inhibited by equine estrogens via down-regulation of caspase-3 and prevention of mitochondrial cytochrome c release

    Directory of Open Access Journals (Sweden)

    Zhang YueMei

    2005-02-01

    absence of 17β-estradiol or Δ8, 17β-estradiol (10 nM-10 μM resulted in the prevention of cell death and was associated with a significant dose-dependent decrease in caspase-3 protein levels, with Δ8, 17β-E2 being more potent than 17β-E2. Protein levels of Fas receptor remained unchanged in the presence of glutamate. In contrast, treatment with glutamate induced, in a time-dependent manner, the release of cytochrome c into the cytosol. Cytosolic cytochrome c increased as early as 1.5 h after glutamate treatment and these levels were 5 fold higher after 6 h, compared to levels in the untreated cells. Concomitant with these changes, the levels of cytochrome c in mitochondria decreased significantly. Both 17β-E2 and Δ8, 17β-E2 reduced the release of cytochrome c from mitochondria into the cytosol and this decrease in cytosolic cytochrome c was associated with inhibition of glutamate-induced cell death. Conclusion In the primary cortical cells, glutamate-induced apoptosis is accompanied by up-regulation of caspase-3 and its activity is blocked by caspase protease inhibitors. These effects of glutamate on caspase-3 appear to be independent of changes in Fas receptor, but are associated with the rapid release of mitochondrial cytochrome c, which precedes changes in caspase-3 protein levels leading to apoptotic cell death. This process was differentially inhibited by estrogens with the novel equine estrogen Δ8, 17β-E2 being more potent than 17β-E2. To our knowledge, this is the first study to demonstrate that equine estrogens can prevent glutamate-induced translocation of cytochrome c from mitochondria to cytosol in rat primary cortical cells.

  7. EFRT M-12 Issue Resolution: Caustic Leach Rate Constants from PEP and Laboratory-Scale Tests

    Energy Technology Data Exchange (ETDEWEB)

    Mahoney, Lenna A.; Rassat, Scot D.; Eslinger, Paul W.; Aaberg, Rosanne L.; Aker, Pamela M.; Golovich, Elizabeth C.; Hanson, Brady D.; Hausmann, Tom S.; Huckaby, James L.; Kurath, Dean E.; Minette, Michael J.; Sundaram, S. K.; Yokuda, Satoru T.

    2009-08-14

    Testing Summary Pacific Northwest National Laboratory (PNNL) has been tasked by Bechtel National Inc. (BNI) on the River Protection Project-Hanford Tank Waste Treatment and Immobilization Plant (RPP-WTP) project to perform research and development activities to resolve technical issues identified for the Pretreatment Facility (PTF). The Pretreatment Engineering Platform (PEP) was designed and constructed and is to be operated as part of a plan to respond to issue M12, “Undemonstrated Leaching Processes.” The PEP is a 1/4.5-scale test platform designed to simulate the WTP pretreatment caustic leaching, oxidative leaching, ultrafiltration solids concentration, and slurry washing processes. The PEP replicates the WTP leaching processes using prototypic equipment and control strategies. The PEP also includes non-prototypic ancillary equipment to support the core processing. Two operating scenarios are currently being evaluated for the ultrafiltration process (UFP) and leaching operations. The first scenario has caustic leaching performed in the UFP-2 ultrafiltration feed vessels (i.e., vessel UFP-VSL-T02A in the PEP and vessels UFP-VSL-00002A and B in the WTP PTF). The second scenario has caustic leaching conducted in the UFP-1 ultrafiltration feed preparation vessels (i.e., vessels UFP-VSL-T01A and B in the PEP; vessels UFP-VSL-00001A and B in the WTP PTF). In both scenarios, 19-M sodium hydroxide solution (NaOH, caustic) is added to the waste slurry in the vessels to leach solid aluminum compounds (e.g., gibbsite, boehmite). Caustic addition is followed by a heating step that uses direct injection of steam to accelerate the leaching process. Following the caustic leach, the vessel contents are cooled using vessel cooling jackets and/or external heat exchangers. The main difference between the two scenarios is that for leaching in UFP-1, the 19-M NaOH is added to un-concentrated waste slurry (3 to 8 wt% solids), while for leaching in UFP-2, the slurry is

  8. EFRT M-12 Issue Resolution: Comparison of Filter Performance at PEP and CUF Scale

    Energy Technology Data Exchange (ETDEWEB)

    Daniel, Richard C.; Billing, Justin M.; Bontha, Jagannadha R.; Brown, Christopher F.; Eslinger, Paul W.; Hanson, Brady D.; Huckaby, James L.; Karri, Naveen K.; Kimura, Marcia L.; Kurath, Dean E.; Minette, Michael J.

    2009-08-13

    Pacific Northwest National Laboratory (PNNL) has been tasked by Bechtel National Inc. (BNI) on the River Protection Project-Hanford Tank Waste Treatment and Immobilization Plant (RPP-WTP) project to perform research and development activities to resolve technical issues identified for the Pretreatment Facility (PTF). The Pretreatment Engineering Platform (PEP) was designed and constructed and is to be operated as part of a plan to respond to issue M12, Undemonstrated Leaching Processes. The PEP is a 1/4.5-scale test platform designed to simulate the WTP pretreatment caustic leaching, oxidative leaching, ultrafiltration solids concentration, and slurry washing processes. The PEP replicates the WTP leaching processes using prototypic equipment and control strategies. The PEP also includes non-prototypic ancillary equipment to support the core processing. Two operating scenarios are currently being evaluated for the ultrafiltration process (UFP) and leaching operations. The first scenario has caustic leaching performed in the UFP-2 ultrafiltration feed vessels (i.e., vessel UFP-VSL-T02A in the PEP and vessels UFP-VSL-00002A and B in the WTP PTF). The second scenario has caustic leaching conducted in the UFP-1 ultrafiltration feed-preparation vessels (i.e., vessels UFP-VSL-T01A and B in the PEP; vessels UFP-VSL-00001A and B in the WTP PTF). In both scenarios, 19-M sodium hydroxide solution (NaOH, caustic) is added to the waste slurry in the vessels to leach solid aluminum compounds (e.g., gibbsite, boehmite). Caustic addition is followed by a heating step that uses direct injection of steam to accelerate the leach process. Following the caustic leach, the vessel contents are cooled using vessel cooling jackets and/or external heat exchangers. The main difference between the two scenarios is that for leaching in UFP1, the 19-M NaOH is added to un-concentrated waste slurry (3 to 8 wt% solids), while for leaching in UFP2, the slurry is concentrated to nominally 20 wt

  9. EFRT M-12 Issue Resolution: Caustic Leach Rate Constants from PEP and Laboratory-Scale Tests

    International Nuclear Information System (INIS)

    Mahoney, Lenna A.; Rassat, Scot D.; Eslinger, Paul W.; Aaberg, Rosanne L.; Aker, Pamela M.; Golovich, Elizabeth C.; Hanson, Brady D.; Hausmann, Tom S.; Huckaby, James L.; Kurath, Dean E.; Minette, Michael J.; Sundaram, S. K.; Yokuda, Satoru T.

    2009-01-01

    Testing Summary Pacific Northwest National Laboratory (PNNL) has been tasked by Bechtel National Inc. (BNI) on the River Protection Project-Hanford Tank Waste Treatment and Immobilization Plant (RPP-WTP) project to perform research and development activities to resolve technical issues identified for the Pretreatment Facility (PTF). The Pretreatment Engineering Platform (PEP) was designed and constructed and is to be operated as part of a plan to respond to issue M12, 'Undemonstrated Leaching Processes.' The PEP is a 1/4.5-scale test platform designed to simulate the WTP pretreatment caustic leaching, oxidative leaching, ultrafiltration solids concentration, and slurry washing processes. The PEP replicates the WTP leaching processes using prototypic equipment and control strategies. The PEP also includes non-prototypic ancillary equipment to support the core processing. Two operating scenarios are currently being evaluated for the ultrafiltration process (UFP) and leaching operations. The first scenario has caustic leaching performed in the UFP-2 ultrafiltration feed vessels (i.e., vessel UFP-VSL-T02A in the PEP and vessels UFP-VSL-00002A and B in the WTP PTF). The second scenario has caustic leaching conducted in the UFP-1 ultrafiltration feed preparation vessels (i.e., vessels UFP-VSL-T01A and B in the PEP; vessels UFP-VSL-00001A and B in the WTP PTF). In both scenarios, 19-M sodium hydroxide solution (NaOH, caustic) is added to the waste slurry in the vessels to leach solid aluminum compounds (e.g., gibbsite, boehmite). Caustic addition is followed by a heating step that uses direct injection of steam to accelerate the leaching process. Following the caustic leach, the vessel contents are cooled using vessel cooling jackets and/or external heat exchangers. The main difference between the two scenarios is that for leaching in UFP-1, the 19-M NaOH is added to un-concentrated waste slurry (3 to 8 wt% solids), while for leaching in UFP-2, the slurry is concentrated

  10. EFRT M-12 Issue Resolution: Comparison of Filter Performance at PEP and CUF Scale

    International Nuclear Information System (INIS)

    Daniel, Richard C.; Billing, Justin M.; Bontha, Jagannadha R.; Brown, Christopher F.; Eslinger, Paul W.; Hanson, Brady D.; Huckaby, James L.; Karri, Naveen K.; Kimura, Marcia L.; Kurath, Dean E.; Minette, Michael J.

    2009-01-01

    Pacific Northwest National Laboratory (PNNL) has been tasked by Bechtel National Inc. (BNI) on the River Protection Project-Hanford Tank Waste Treatment and Immobilization Plant (RPP-WTP) project to perform research and development activities to resolve technical issues identified for the Pretreatment Facility (PTF). The Pretreatment Engineering Platform (PEP) was designed and constructed and is to be operated as part of a plan to respond to issue M12, Undemonstrated Leaching Processes. The PEP is a 1/4.5-scale test platform designed to simulate the WTP pretreatment caustic leaching, oxidative leaching, ultrafiltration solids concentration, and slurry washing processes. The PEP replicates the WTP leaching processes using prototypic equipment and control strategies. The PEP also includes non-prototypic ancillary equipment to support the core processing. Two operating scenarios are currently being evaluated for the ultrafiltration process (UFP) and leaching operations. The first scenario has caustic leaching performed in the UFP-2 ultrafiltration feed vessels (i.e., vessel UFP-VSL-T02A in the PEP and vessels UFP-VSL-00002A and B in the WTP PTF). The second scenario has caustic leaching conducted in the UFP-1 ultrafiltration feed-preparation vessels (i.e., vessels UFP-VSL-T01A and B in the PEP; vessels UFP-VSL-00001A and B in the WTP PTF). In both scenarios, 19-M sodium hydroxide solution (NaOH, caustic) is added to the waste slurry in the vessels to leach solid aluminum compounds (e.g., gibbsite, boehmite). Caustic addition is followed by a heating step that uses direct injection of steam to accelerate the leach process. Following the caustic leach, the vessel contents are cooled using vessel cooling jackets and/or external heat exchangers. The main difference between the two scenarios is that for leaching in UFP1, the 19-M NaOH is added to un-concentrated waste slurry (3 to 8 wt% solids), while for leaching in UFP2, the slurry is concentrated to nominally 20 wt

  11. Melatonin prevents human pancreatic carcinoma cell PANC-1-induced human umbilical vein endothelial cell proliferation and migration by inhibiting vascular endothelial growth factor expression.

    Science.gov (United States)

    Cui, Peilin; Yu, Minghua; Peng, Xingchun; Dong, Lv; Yang, Zhaoxu

    2012-03-01

    Melatonin is an important natural oncostatic agent, and our previous studies have found its inhibitory action on tumor angiogenesis, but the mechanism remains unclear. It is well known that vascular endothelial growth factor (VEGF) plays key roles in tumor angiogenesis and has become an important target for antitumor therapy. Pancreatic cancer is a representative of the most highly vascularized and angiogenic solid tumors, which responds poorly to chemotherapy and radiation. Thus, seeking new treatment strategies targeting which have anti-angiogenic capability is urgent in clinical practice. In this study, a co-culture system between human umbilical vein endothelial cells (HUVECs) and pancreatic carcinoma cells (PANC-1) was used to investigate the direct effect of melatonin on the tumor angiogenesis and its possible action on VEGF expression. We found HUVECs exhibited an increased cell proliferation and cell migration when co-cultured with PANC-1 cells, but the process was prevented when melatonin added to the incubation medium. Melatonin at concentrations of 1 μm and 1 mm inhibited the cell proliferation and migration of HUVECs and also decreased both the VEGF protein secreted to the cultured medium and the protein produced by the PANC-1 cells. In addition, the VEGF mRNA expression was also down-regulated by melatonin. Taken together, our present study shows that melatonin at pharmacological concentrations inhibited the elevated cell proliferation and cell migration of HUVECs stimulated by co-culturing them with PANC-1 cells; this was associated with a suppression of VEGF expression in PANC-1 cells. © 2011 John Wiley & Sons A/S.

  12. The ovarian DNA damage repair response is induced prior to phosphoramide mustard-induced follicle depletion, and ataxia telangiectasia mutated inhibition prevents PM-induced follicle depletion

    Energy Technology Data Exchange (ETDEWEB)

    Ganesan, Shanthi, E-mail: shanthig@iastate.edu; Keating, Aileen F., E-mail: akeating@iastate.edu

    2016-02-01

    Phosphoramide mustard (PM) is an ovotoxic metabolite of cyclophosphamide and destroys primordial and primary follicles potentially by DNA damage induction. The temporal pattern by which PM induces DNA damage and initiation of the ovarian response to DNA damage has not yet been well characterized. This study investigated DNA damage initiation, the DNA repair response, as well as induction of follicular demise using a neonatal rat ovarian culture system. Additionally, to delineate specific mechanisms involved in the ovarian response to PM exposure, utility was made of PKC delta (PKCδ) deficient mice as well as an ATM inhibitor (KU 55933; AI). Fisher 344 PND4 rat ovaries were cultured for 12, 24, 48 or 96 h in medium containing DMSO ± 60 μM PM or KU 55933 (48 h; 10 nM). PM-induced activation of DNA damage repair genes was observed as early as 12 h post-exposure. ATM, PARP1, E2F7, P73 and CASP3 abundance were increased but RAD51 and BCL2 protein decreased after 96 h of PM exposure. PKCδ deficiency reduced numbers of all follicular stages, but did not have an additive impact on PM-induced ovotoxicity. ATM inhibition protected all follicle stages from PM-induced depletion. In conclusion, the ovarian DNA damage repair response is active post-PM exposure, supporting that DNA damage contributes to PM-induced ovotoxicity. - Highlights: • PM exposure induces DNA damage repair gene expression. • Inhibition of ATM prevented PM-induced follicle depletion. • PKCδ deficiency did not impact PM-induced ovotoxicity.

  13. Inhibition of bone resorption in vitro and prevention of ovariectomy-induced bone loss in vivo by flurbiprofen nitroxybutylester (HCT1026).

    Science.gov (United States)

    Armour, K J; van 't Hof, R J; Armour, K E; Torbergsen, A C; Del Soldato, P; Ralston, S H

    2001-09-01

    Inhibitors of prostaglandin production, such as nonsteroidal antiinflammatory drugs (NSAIDs), and pharmacologic nitric oxide (NO) donors, such as organic nitrates, have been suggested to protect against bone loss in both humans and experimental animals. Recently, a new class of nitrosylated NSAID (known as NO-NSAIDs) has been developed, which combines the properties of a NO donor with those of a cyclooxygenase (COX) inhibitor. This study investigated the effects of one of these compounds, flurbiprofen nitroxybutylester (HCT1026), on bone metabolism in vitro and in vivo. The effects of HCT1026 on osteoclast formation and resorption were determined in vitro using cocultures of primary mouse osteoblasts and osteoclasts. The effect of HCT1026 in vivo was assessed using a mouse model of ovariectomy-induced bone loss. HCT1026 was significantly more efficacious than the parent compound, flurbiprofen, at inhibiting osteoclast formation and bone resorption in vitro, and these effects could not be reproduced by combinations of flurbiprofen with a variety of NO donors. Studies in vivo showed that HCT1026 protected against ovariectomy-induced bone loss by inhibiting osteoclastic bone resorption, whereas flurbiprofen at similar concentrations was ineffective. These data indicate that HCT1026 is a potent inhibitor of bone resorption in vitro and protects against ovariectomy-induced bone loss in vivo by a novel mechanism that appears to be distinct from its NO donor properties and from its inhibitory effects on COX activity. We conclude that HCT1026 may be of clinical value in the prevention and treatment of inflammatory diseases such as rheumatoid arthritis, which are characterized by joint inflammation as well as periarticular and systemic bone loss.

  14. Inhibition of Chondrocyte Hypertrophy of Osteoarthritis by Disruptor Peptide

    Science.gov (United States)

    2017-07-01

    with PTHR and inhibits the pathogenic beta-catenin- mediated PTHR signaling switch. In Aim 2, we will define the role of disruptor peptide in...confirmed that disruptor peptide conjugated to penetratin can enter cells. Importantly, disruptor peptide can reverse the beta-catenin- mediated PTH... mediated PTHR signaling switch in chondrocytes. Mouse primary chondrocytes express both β-catenin and PTHR. Our data showed that Pen-dis- pep

  15. Pep-3D-Search: a method for B-cell epitope prediction based on mimotope analysis.

    Science.gov (United States)

    Huang, Yan Xin; Bao, Yong Li; Guo, Shu Yan; Wang, Yan; Zhou, Chun Guang; Li, Yu Xin

    2008-12-16

    The prediction of conformational B-cell epitopes is one of the most important goals in immunoinformatics. The solution to this problem, even if approximate, would help in designing experiments to precisely map the residues of interaction between an antigen and an antibody. Consequently, this area of research has received considerable attention from immunologists, structural biologists and computational biologists. Phage-displayed random peptide libraries are powerful tools used to obtain mimotopes that are selected by binding to a given monoclonal antibody (mAb) in a similar way to the native epitope. These mimotopes can be considered as functional epitope mimics. Mimotope analysis based methods can predict not only linear but also conformational epitopes and this has been the focus of much research in recent years. Though some algorithms based on mimotope analysis have been proposed, the precise localization of the interaction site mimicked by the mimotopes is still a challenging task. In this study, we propose a method for B-cell epitope prediction based on mimotope analysis called Pep-3D-Search. Given the 3D structure of an antigen and a set of mimotopes (or a motif sequence derived from the set of mimotopes), Pep-3D-Search can be used in two modes: mimotope or motif. To evaluate the performance of Pep-3D-Search to predict epitopes from a set of mimotopes, 10 epitopes defined by crystallography were compared with the predicted results from a Pep-3D-Search: the average Matthews correlation coefficient (MCC), sensitivity and precision were 0.1758, 0.3642 and 0.6948. Compared with other available prediction algorithms, Pep-3D-Search showed comparable MCC, specificity and precision, and could provide novel, rational results. To verify the capability of Pep-3D-Search to align a motif sequence to a 3D structure for predicting epitopes, 6 test cases were used. The predictive performance of Pep-3D-Search was demonstrated to be superior to that of other similar programs

  16. Preventive effects of physical exercise on the inhibition of creatine kinase in the cerebral cortex of mice exposed to cigarette smoke. DOI: 10.5007/1980-0037.2011v13n2p106

    Directory of Open Access Journals (Sweden)

    Daiane Bittencourt Fraga

    2011-02-01

    Full Text Available Recent studies have shown the health benefits of physical exercise, increasing the oxidative response of muscle. However, the effects of exercise on the brain are poorly understood and contradictory. The inhibition of creatine kinase (CK activity has been associated with the pathogenesis of a large number of diseases, especially in the brain. The objective of this study was to determine the preventive effects of physical exercise in the hippocampus and cerebral cortex of mice after chronic cigarette smoke exposure. Eight to 10-week-old male mice (C57BL-6 were divided into four groups and submitted to an exercise program (swimming, 5 times a week, for 8 weeks. After this period, the animals were passively exposed to cigarette smoke for 60 consecutive days, 3 times a day (4 Marlboro red cigarettes per session, for a total of 12 cigarettes. CK activity was measured in cerebral cortex and hippocampal homogenates. Enzyme activity was inhibited in the cerebral cortex of animals submitted to the inhalation of cigarette smoke. However, exercise prevented this inhibition. In contrast, CK activity remained unchanged in the hippocampus. This inhibition of CK by inhalation of cigarette smoke might be related to the process of cell death. Physical exercise played a preventive role in the inhibition of CK activity caused by exposure to cigarette smoke.

  17. Preventive effects of physical exercise on the inhibition of creatine kinase in the cerebral cortex of mice exposed to cigarette smoke. DOI: 10.5007/1980-0037.2011v13n2p106

    Directory of Open Access Journals (Sweden)

    Daiane Bittencourt Fraga

    2011-03-01

    Full Text Available Recent studies have shown the health benefits of physical exercise, increasing the oxidative response of muscle. However, the effects of exercise on the brain are poorly understood and contradictory. The inhibition of creatine kinase (CK activity has been associated with the pathogenesis of a large number of diseases, especially in the brain. The objective of this study was to determine the preventive effects of physical exercise in the hippocampus and cerebral cortex of mice after chronic cigarette smoke exposure. Eight to 10-week-old male mice (C57BL-6 were divided into four groups and submitted to an exercise program (swimming, 5 times a week, for 8 weeks. After this period, the animals were passively exposed to cigarette smoke for 60 consecutive days, 3 times a day (4 Marlboro red cigarettes per session, for a total of 12 cigarettes. CK activity was measured in cerebral cortex and hippocampal homogenates. Enzyme activity was inhibited in the cerebral cortex of animals submitted to the inhalation of cigarette smoke. However, exercise prevented this inhibition. In contrast, CK activity remained unchanged in the hippocampus. This inhibition of CK by inhalation of cigarette smoke might be related to the process of cell death. Physical exercise played a preventive role in the inhibition of CK activity caused by exposure to cigarette smoke.

  18. The inhibition of the kynurenine pathway prevents behavioral disturbances and oxidative stress in the brain of adult rats subjected to an animal model of schizophrenia.

    Science.gov (United States)

    Réus, Gislaine Z; Becker, Indianara R T; Scaini, Giselli; Petronilho, Fabricia; Oses, Jean P; Kaddurah-Daouk, Rima; Ceretta, Luciane B; Zugno, Alexandra I; Dal-Pizzol, Felipe; Quevedo, João; Barichello, Tatiana

    2018-02-02

    Evidence has shown that the kynurenine pathway (KP) plays a role in the onset of oxidative stress and also in the pathophysiology of schizophrenia. The aim of this study was to use a pharmacological animal model of schizophrenia induced by ketamine to investigate if KP inhibitors could protect the brains of Wistar rats against oxidative stress and behavioral changes. Ketamine, injected at the dose of 25mg/kg, increased spontaneous locomotor activity. However, the inhibitors of tryptophan 2,3-dioxygenase (TDO), indoleamine 2,3-dioxygenase (IDO) and kynurenine-3-monooxygenase (KMO) were able to reverse these changes. In addition, the IDO inhibitor prevented lipid peroxidation, and decreased the levels of protein carbonyl in the prefrontal cortex (PFC), hippocampus and striatum. It also increased the activity of superoxide dismutase (SOD) in the hippocampus, as well as increasing the levels of catalase activity in the PFC and hippocampus. The TDO inhibitor prevented lipid damage in the striatum and reduced the levels of protein carbonyl in the hippocampus and striatum. Also, the TDO inhibitor increased the levels of SOD activity in the striatum and CAT activity in the hippocampus of ketamine-induced pro-oxidant effects. Lipid damage was not reversed by the KMO inhibitor. The KMO inhibitor increased the levels of SOD activity in the hippocampus, and reduced the levels of protein carbonyl while elevating the levels of CAT activity in the striatum of rats that had been injected with ketamine. Our findings revealed that the KP pathway could be a potential mechanism by which a schizophrenia animal model induced by ketamine could cause interference by producing behavioral disturbance and inducing oxidative stress in the brain, suggesting that the inhibition of the KP pathway could be a potential target in treating schizophrenia. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Bilirubin Prevents Atherosclerotic Lesion Formation in Low-Density Lipoprotein Receptor-Deficient Mice by Inhibiting Endothelial VCAM-1 and ICAM-1 Signaling.

    Science.gov (United States)

    Vogel, Megan E; Idelman, Gila; Konaniah, Eddy S; Zucker, Stephen D

    2017-04-01

    Numerous epidemiological studies support an inverse association between serum bilirubin levels and the incidence of cardiovascular disease; however, the mechanism(s) by which bilirubin may protect against atherosclerosis is undefined. The goals of the present investigations were to assess the ability of bilirubin to prevent atherosclerotic plaque formation in low-density lipoprotein receptor-deficient ( Ldlr -/- ) mice and elucidate the molecular processes underlying this effect. Bilirubin, at physiological concentrations (≤20 μmol/L), dose-dependently inhibits THP-1 monocyte migration across tumor necrosis factor α-activated human umbilical vein endothelial cell monolayers without altering leukocyte binding or cytokine production. A potent antioxidant, bilirubin effectively blocks the generation of cellular reactive oxygen species induced by the cross-linking of endothelial vascular cell adhesion molecule 1 (VCAM-1) or intercellular adhesion molecule 1 (ICAM-1). These findings were validated by treating cells with blocking antibodies or with specific inhibitors of VCAM-1 and ICAM-1 signaling. When administered to Ldlr -/- mice on a Western diet, bilirubin (30 mg/kg intraperitoneally) prevents atherosclerotic plaque formation, but does not alter circulating cholesterol or chemokine levels. Aortic roots from bilirubin-treated animals exhibit reduced lipid and collagen deposition, decreased infiltration of monocytes and lymphocytes, fewer smooth muscle cells, and diminished levels of chlorotyrosine and nitrotyrosine, without changes in VCAM-1 or ICAM-1 expression. Bilirubin suppresses atherosclerotic plaque formation in Ldlr -/- mice by disrupting endothelial VCAM-1- and ICAM-1-mediated leukocyte migration through the scavenging of reactive oxygen species signaling intermediaries. These findings suggest a potential mechanism for the apparent cardioprotective effects of bilirubin. © 2017 The Authors. Published on behalf of the American Heart Association, Inc

  20. Design and mechanism of action of a novel bacteria-selective antimicrobial peptide from the cell-penetrating peptide Pep-1

    International Nuclear Information System (INIS)

    Zhu, W.L.; Lan Hongliang; Park, Il-Seon; Kim, Jae Il; Jin, H.Z.; Hahm, Kyung-Soo; Shin, S.Y.

    2006-01-01

    Here, we report the successful design of a novel bacteria-selective antimicrobial peptide, Pep-1-K (KKTWWKTWWTKWSQPKKKRKV). Pep-1-K was designed by replacing Glu-2, Glu-6, and Glu-11 in the cell-penetrating peptide Pep-1 with Lys. Pep-1-K showed strong antibacterial activity against reference strains (MIC = 1-2 μM) of Gram-positive and Gram-negative bacteria as well as against clinical isolates (MIC = 1-8 μM) of methicillin-resistant Staphylococcus aureus and multidrug-resistant Pseudomonas aeruginosa. In contrast, Pep-1-K did not cause hemolysis of human erythrocytes even at 200 μM. These results indicate that Pep-1-K may be a good candidate for antimicrobial drug development, especially as a topical agent against antibiotic-resistant microorganisms. Tryptophan fluorescence studies indicated that the lack of hemolytic activity of Pep-1-K correlated with its weak ability to penetrate zwitterionic phosphatidylcholine/cholesterol (10:1, w/w) vesicles, which mimic eukaryotic membranes. Furthermore, Pep-1-K caused little or no dye leakage from negatively charged phosphatidylethanolamine/phosphatidylglycerol (7:3, w/w) vesicles, which mimic bacterial membranes but had a potent ability to cause depolarization of the cytoplasmic membrane potential of intact S. aureus cells. These results suggested that Pep-1-K kills microorganisms by not the membrane-disrupting mode but the formation of small channels that permit transit of ions or protons but not molecules as large as calcein

  1. Sulfatide-activated type II NKT cells prevent allergic airway inflammation by inhibiting type I NKT cell function in a mouse model of asthma.

    Science.gov (United States)

    Zhang, Guqin; Nie, Hanxiang; Yang, Jiong; Ding, Xuhong; Huang, Yi; Yu, Hongying; Li, Ruyou; Yuan, Zhuqing; Hu, Suping

    2011-12-01

    Asthma is a common chronic inflammatory disease involving many different cell types. Recently, type I natural killer T (NKT) cells have been demonstrated to play a crucial role in the development of asthma. However, the roles of type II NKT cells in asthma have not been investigated before. Interestingly, type I and type II NKT cells have been shown to have opposing roles in antitumor immunity, antiparasite immunity, and autoimmunity. We hypothesized that sulfatide-activated type II NKT cells could prevent allergic airway inflammation by inhibiting type I NKT cell function in asthma. Strikingly, in our mouse model, activation of type II NKT cells by sulfatide administration and adoptive transfer of sulfatide-activated type II NKT cells result in reduced-inflammation cell infiltration in the lung and bronchoalveolar lavage fluid, decreased levels of IL-4 and IL-5 in the BALF; and decreased serum levels of ovalbumin-specific IgE and IgG1. Furthermore, it is found that the activation of sulfatide-reactive type II NKT cells leads to the functional inactivation of type I NKT cells, including the proliferation and cytokine secretion. Our data reveal that type II NKT cells activated by glycolipids, such as sulfatide, may serve as a novel approach to treat allergic diseases and other disorders characterized by inappropriate type I NKT cell activation.

  2. LKB1 inhibition of NF-κB in B cells prevents T follicular helper cell differentiation and germinal center formation.

    Science.gov (United States)

    Walsh, Nicole C; Waters, Lynnea R; Fowler, Jessica A; Lin, Mark; Cunningham, Cameron R; Brooks, David G; Rehg, Jerold E; Morse, Herbert C; Teitell, Michael A

    2015-06-01

    T-cell-dependent antigenic stimulation drives the differentiation of B cells into antibody-secreting plasma cells and memory B cells, but how B cells regulate this process is unclear. We show that LKB1 expression in B cells maintains B-cell quiescence and prevents the premature formation of germinal centers (GCs). Lkb1-deficient B cells (BKO) undergo spontaneous B-cell activation and secretion of multiple inflammatory cytokines, which leads to splenomegaly caused by an unexpected expansion of T cells. Within this cytokine response, increased IL-6 production results from heightened activation of NF-κB, which is suppressed by active LKB1. Secreted IL-6 drives T-cell activation and IL-21 production, promoting T follicular helper (TFH ) cell differentiation and expansion to support a ~100-fold increase in steady-state GC B cells. Blockade of IL-6 secretion by BKO B cells inhibits IL-21 expression, a known inducer of TFH -cell differentiation and expansion. Together, these data reveal cell intrinsic and surprising cell extrinsic roles for LKB1 in B cells that control TFH -cell differentiation and GC formation, and place LKB1 as a central regulator of T-cell-dependent humoral immunity. © 2015 The Authors.

  3. Cardiac-specific overexpression of catalase prevents diabetes-induced pathological changes by inhibiting NF-κB signaling activation in the heart.

    Science.gov (United States)

    Cong, Weitao; Ruan, Dandan; Xuan, Yuanhu; Niu, Chao; Tao, Youli; Wang, Yang; Zhan, Kungao; Cai, Lu; Jin, Litai; Tan, Yi

    2015-12-01

    Catalase is an antioxidant enzyme that specifically catabolizes hydrogen peroxide (H2O2). Overexpression of catalase via a heart-specific promoter (CAT-TG) was reported to reduce diabetes-induced accumulation of reactive oxygen species (ROS) and further prevent diabetes-induced pathological abnormalities, including cardiac structural derangement and left ventricular abnormity in mice. However, the mechanism by which catalase overexpression protects heart function remains unclear. This study found that activation of a ROS-dependent NF-κB signaling pathway was downregulated in hearts of diabetic mice overexpressing catalase. In addition, catalase overexpression inhibited the significant increase in nitration levels of key enzymes involved in energy metabolism, including α-oxoglutarate dehydrogenase E1 component (α-KGD) and ATP synthase α and β subunits (ATP-α and ATP-β). To assess the effects of the NF-κB pathway activation on heart function, Bay11-7082, an inhibitor of the NF-κB signaling pathway, was injected into diabetic mice, protecting mice against the development of cardiac damage and increased nitrative modifications of key enzymes involved in energy metabolism. In conclusion, these findings demonstrated that catalase protects mouse hearts against diabetic cardiomyopathy, partially by suppressing NF-κB-dependent inflammatory responses and associated protein nitration. Copyright © 2015 Elsevier Ltd. All rights reserved.

  4. Transduced PEP-1-PON1 proteins regulate microglial activation and dopaminergic neuronal death in a Parkinson's disease model.

    Science.gov (United States)

    Kim, Mi Jin; Park, Meeyoung; Kim, Dae Won; Shin, Min Jea; Son, Ora; Jo, Hyo Sang; Yeo, Hyeon Ji; Cho, Su Bin; Park, Jung Hwan; Lee, Chi Hern; Kim, Duk-Soo; Kwon, Oh-Shin; Kim, Joon; Han, Kyu Hyung; Park, Jinseu; Eum, Won Sik; Choi, Soo Young

    2015-09-01

    Parkinson's disease (PD) is an oxidative stress-mediated neurodegenerative disorder caused by selective dopaminergic neuronal death in the midbrain substantia nigra. Paraoxonase 1 (PON1) is a potent inhibitor of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) against oxidation by destroying biologically active phospholipids with potential protective effects against oxidative stress-induced inflammatory disorders. In a previous study, we constructed protein transduction domain (PTD) fusion PEP-1-PON1 protein to transduce PON1 into cells and tissue. In this study, we examined the role of transduced PEP-1-PON1 protein in repressing oxidative stress-mediated inflammatory response in microglial BV2 cells after exposure to lipopolysaccharide (LPS). Moreover, we identified the functions of transduced PEP-1-PON1 proteins which include, mitigating mitochondrial damage, decreasing reactive oxidative species (ROS) production, matrix metalloproteinase-9 (MMP-9) expression and protecting against 1-methyl-4-phenylpyridinium (MPP(+))-induced neurotoxicity in SH-SY5Y cells. Furthermore, transduced PEP-1-PON1 protein reduced MMP-9 expression and protected against dopaminergic neuronal cell death in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice model. Taken together, these results suggest a promising therapeutic application of PEP-1-PON1 proteins against PD and other inflammation and oxidative stress-related neuronal diseases. Copyright © 2015 Elsevier Ltd. All rights reserved.

  5. High-power RF window design for the PEP-II B Factory

    International Nuclear Information System (INIS)

    Neubauer, M.; Hodgson, J.; Ng, C.; Schwarz, H.; Skarpaas, K.; Kroll, N.; Rimmer, R.

    1994-06-01

    We describe the design of RF windows to transmit up to 500 kW CW to the PEP-II 476 MHz cavities. RF analysis of the windows using high-frequency simulation codes are described. These provide information about the power loss distribution in the ceramic and tim matching properties of the structure. Finite-element analyses of the resulting temperature distribution and thermal stresses are presented. Fabrication methods including a proposed scheme to compensate for thermal expansion s are discussed and hardware tests to validate this approach are described. The effects of surface coatings (intentional and otherwise) and the application of air cooling are considered

  6. Design of a high-power test model of the PEP-II rf cavity

    International Nuclear Information System (INIS)

    Schwarz, H.D.; Bell, R.A.; Hodgson, J.A.

    1993-05-01

    The design of a normal-conducting high-power test cavity (HPTC) for PEP-II is described. The cavity includes HOM loading waveguides and provisions for testing two alternate input coupling schemes. 3-D electromagnetic field simulations provided input information for the surface power deposition. Finite element codes were utilized for thermal and stress analyses of the cavity to arrive at a suitable mechanical design capable of handling the high power dissipation. The mechanical design approach with emphasis on the cooling channel layout and mechanical stress reduction is described

  7. PEGASYS---A proposed internal target facility for the PEP storage ring

    International Nuclear Information System (INIS)

    Van Biber, K.

    1988-07-01

    A proposal for an integral gas-jet target and forward spectrometer for the PEP storage ring is described. The beam structure, allowable, luminosity (L = 10 33 cm/sup /minus/2/s/sup /minus/1/ for H 2 , D 2 ) and energy (E/sub e/ ≤ 15 GeV) make the ring ideal for multiparticle coincidence studies in the scaling regime, and where perturbative QCD may be an apt description of some exclusive and semi-inclusive reactions. 14 refs., 7 figs

  8. Bunch-by-bunch longitudinal feedback system for PEP-II

    International Nuclear Information System (INIS)

    Oxoby, G.; Claus, R.; Fox, J.

    1994-06-01

    This paper describes the implementation of the bunch-by-bunch longitudinal feedback system for the PEP-II B Factory. Bunch spacing down to 2 ns is achieved using 500 Megasamples per second A/D and D/A converters, and AT ampersand T 1610 Digital Signal Processors are integrated to run a downsampled feedback algorithm for each bunch in parallel. This general purpose programmable system, packaged in VXI and VME, is modular and scalable to offer portability to other accelerator rings. The control and monitoring hardware and software architecture have been developed to provide ease of operation as well as diagnostic tools for machine physics

  9. Dynamic Aperture Improvement of PEP-II Lattices Using Resonance Basis Lie Generators

    Energy Technology Data Exchange (ETDEWEB)

    Yan, Yiton T

    2003-08-11

    To simplify the engineering efforts of implementing the PEP-II lattices, many modifications have been made to these lattices since the conceptual design report. During the development and evolution of the lattices, changes in a lattice would often result in a significant reduction in the dynamic aperture. At such times, we often relied on a non-linear analysis using the one-turn resonance basis Lie generator to identify the cause of the degradation. In this paper, we will present such examples to facilitate the usage of map for diagnosing the problems in lattice design.

  10. A test of planar spark counters at the PEP storage ring

    International Nuclear Information System (INIS)

    Atwood, W.B.; Bowden, G.B.; Bonneaud, G.R.; Klem, D.E.; Ogawa, A.; Pestov, Yu.N.; Pitthan, R.; Sugahara, R.

    1983-01-01

    A test of planar spar counters (PSCs) at the PEP electron-positron storage ring showed the following. PSCs can be used under harsh experimental conditions without long term degradation of resolution. On-line time-of-flight resolutions were below 200 ps, coordinate resolutions better than 4 mm, both limited to these values by the resistivity of the semiconducting glass and the electronics used. The best single counter time resolution under realistic conditions at the storage ring was 76 ps. Pulse height was a good indicator of the number of particles striking a counter. Subsequent measurements using cosmis rays gave a single counter time resolution of 50 ps. (orig.)

  11. Design of traveling wave windows for the PEP-II RF coupling network

    International Nuclear Information System (INIS)

    Kroll, N.M.; Ng, C.K.; Judkins, J.; Neubauer, M.

    1995-05-01

    The waveguide windows in the PEP-II RF coupling network have to withstand high power of 500 kW. Traveling wave windows have lower power dissipation than conventional self-matched windows, thus rendering the possibility of less stringent mechanical design. The traveling wave behavior is achieved by providing a reflecting iris on each side of the window, and depending on the configuration of the irises, traveling wave windows are characterized as inductive or capacitive types. A numerical design procedure using MAFIA has been developed for traveling wave windows. The relative advantages of inductive and capacitive windows are discussed. Furthermore, the issues of bandwidth and multipactoring are also addressed

  12. Higher order mode damping studies on the PEP-II B-Factory RF cavity

    International Nuclear Information System (INIS)

    Rimmer, R.; Goldberg, D.; Lambertson, G.; Voelker, F.; Ko, K.; Kroll, N.; Pendleton, R.; Schwarz, H.; Adams, F.; De Jong, M.

    1992-03-01

    We describe studies of the higher-order-mode (HOM) properties of the prototype 476 MHz RF cavity for the proposed PEP-II B-Factory and a waveguide damping scheme to reduce possible HOM-driven coupled-bunch beam instability growth. Numerical studies include modelling of the HOM spectrum using MAFIA and ARGUS, and calculation of the loaded Q's of the damped modes using data from these codes and the Kroll-Yu method. We discuss briefly the experimental investigations of the modes, which will be made in a full-size low-power test cavity, using probes, wire excitation and bead perturbation methods

  13. High-power RF cavity R ampersand D for the PEP-II B Factory

    International Nuclear Information System (INIS)

    Rimmer, R.; Lambertson, G.; Hodgson, J.

    1994-06-01

    We describe the development of a high-power test model of the 476 MHz RF cavity for the PEP-II B Factory. This cavity is designed to demonstrate the feasibility of a high-power design with higher-order mode (HOM) damping waveguides and the fabrication technologies involved, and it can also be used to evaluate aperture or loop couplers and various RF windows. Changes to the RF design to reduce peak surface heating are discussed and results of finite-element analyses of temperature and stress are presented. Fabrication methods for the prototype and subsequent production cavities are discussed

  14. Developing Novel PepT1-Targeted Modulators for Inflammatory Bowel Disease (IBD) Therapy

    Science.gov (United States)

    2016-10-01

    physiological roles. PepT1 is found in the small intestine where it absorbs dietary degradation products and therapeutic agents such as antibiotics ...results provide a framework for developing more potent ligands in various cellular and animal IBD models, directly addressing Aims 2 and 3 of our... Products …………………………………….………….……………4 7. Participants & Other Collaborating Organizations…….…………….5 8. Special Reporting Requirements…………..………………………5 9

  15. TRACKING SIMULATIONS NEAR HALF-INTEGER RESONANCE AT PEP-II

    International Nuclear Information System (INIS)

    Nosochkov, Yuri

    2003-01-01

    Beam-beam simulations predict that PEP-II luminosity can be increased by operating the horizontal betatron tune near and above a half-integer resonance. However, effects of the resonance and its synchrotron sidebands significantly enhance betatron and chromatic perturbations which tend to reduce dynamic aperture. In the study, chromatic variation of horizontal tune near the resonance was minimized by optimizing local sextupoles in the Interaction Region. Dynamic aperture was calculated using tracking simulations in LEGO code. Dependence of dynamic aperture on the residual orbit, dispersion and β distortion after correction was investigated

  16. Computational tools and lattice design for the PEP-II B-Factory

    International Nuclear Information System (INIS)

    Cai Yunhai; Irwin, John; Nosochkov, Yuri; Yan, Yiton

    1997-01-01

    Several accelerator codes were used to design the PEP-II lattices, ranging from matrix-based codes, such as MAD and DIMAD, to symplectic-integrator codes, such as TRACY and DESPOT. In addition to element-by-element tracking, we constructed maps to determine aberration strengths. Furthermore, we have developed a fast and reliable method (nPB tracking) to track particles with a one-turn map. This new technique allows us to evaluate performance of the lattices on the entire tune-plane. Recently, we designed and implemented an object-oriented code in C++ called LEGO which integrates and expands upon TRACY and DESPOT

  17. Study of coupled-bunch collective effects in the PEP-II B-Factory

    International Nuclear Information System (INIS)

    Byrd, J.

    1993-05-01

    We present an overview of the calculated longitudinal and transverse coupled-bunch (CB) growth using the measured RF cavity higher order mode impedance and estimated resistive wall (RW) impedance for the proposed PEP-II B-Factory, a dual-ring electron-positron collider. We also describe a visual method of representing the effective beam impedance and corresponding growth rates which is especially useful for understanding the dependence of growth rate on higher order mode frequency and Q, spread of HOM frequencies between cells, and for determining the requirements of the CB feedback systems

  18. Injection system for the PEP II asymmetric B Factory at SLAC

    International Nuclear Information System (INIS)

    Fieguth, T.; Bloom, E.; Bulos, F.; Davies-White, W.; Donald, M.; Fairfield, K.; Godfrey, G.; Holtzapple, R.; Ronan, M.; Zisman, M.

    1992-01-01

    The asymmetric energy B Factory proposed as an upgrade of PEP at Stanford Linear Accelerator Center will require a highly reliable and efficient injection system. The conceptual design has shown the feasibility of extracting 9 GeV electrons and 3.1 GeV positrons from the existing linac and injecting equal charges into 1658 buckets in each of the two rings of the collider. An injection study group has continued the development and study of this proposal and has generated workable designs for many related systems and subsystems. (author) 3 refs.; 4 figs.; 2 tabs

  19. The vacuum system for the PEP II high energy ring straight sections

    International Nuclear Information System (INIS)

    Wienands, U.; Daly, E.; Heifets, S.A.; Kulikov, A.; Kurita, N.; Nordby, M.; Perkins, C.; Reuter, E.; Seeman, J.T.; Belser, F.C.; Berg, J.; Holdener, F.R.; Kerns, J.A.; McDaniel, M.R.; Stoeffl, W.

    1995-01-01

    The six straight sections of the PEP II High Energy Ring (HER) serve various functions: lattice tuning, beam injection and abort, providing space for rf cavities, longitudinal and transverse feedback, beam diagnostics and the interaction point. A stainless steel vacuum system has been designed; prototypes are currently being built. Cooling is required due to radiation coming from the last arc dipole and resistive losses in the vacuum chamber. Although the nominal beam current of the HER is 1 A the vacuum system is designed for 3 A to provide margin and an upgrade path. 5 refs., 7 figs

  20. Anti-retroviral Therapy Based HIV Prevention Among a Sample of Men Who Have Sex with Men in Cape Town, South Africa: Use of Post-exposure Prophylaxis and Knowledge on Pre-exposure Prophylaxis.

    Science.gov (United States)

    Hugo, J M; Stall, R D; Rebe, K; Egan, J E; De Swardt, G; Struthers, H; McIntyre, J A

    2016-12-01

    Men who have Sex with Men (MSM) have been affected disproportionately by the global HIV pandemic. Rates of consistent condom-use are low and there is a need for further biomedical prevention interventions to prevent new HIV infections. Post exposure prophylaxis (PEP) can reduce the risk of HIV, but uptake among MSM is low. Pre-exposure prophylaxis (PrEP), an innovative anti-retroviral-based HIV prevention tool might be an appropriate intervention for MSM who have recently accessed PEP that involves HIV negative individuals taking daily tenofovir+emtricitabine for HIV prevention. 44 MSM, attending a primary health-care level MSM-focused sexual health clinic in Cape Town, South Africa, who had initiated PEP were enrolled in this study. Participants were followed up after 2, 4 and 12 weeks. Self-administered electronic surveys were completed at the initial, 4 and 12 week visit. Barriers and facilitators to accessing PEP and remaining adherent were examined, as was knowledge about PrEP. Thirty-two participants (80 %) were <40 years of age (range 20-65 years). 35 % of the participants reported their reason for requiring PEP as condomless receptive anal intercourse. A further 20 % required PEP following condomless penetrative anal intercourse; 27.5 % required PEP due to a broken condom during receptive anal sex and 2 participants during insertive anal sex. Three participants did not complete 28 days of PEP or were lost to follow up. Over half (58.5 %) of the participants reported being completely adherent to their regime; under a third (31.7 %) reported missing one PEP dose; and 9.8 % reported missing more than one dose. 36/40 (90 %) had heard of PrEP and 30/40 (75 %) indicated that they would use PrEP if it were accessible to them. That we enrolled 44 MSM who accessed PEP from a Department of Health affiliated clinic over 12 months, speaks to the low uptake by MSM of PEP services in South Africa. Adherence was high and demonstrates that adherence

  1. Development of the Positive Emotions Program for Schizophrenia (PEPS: an intervention to improve pleasure and motivation in schizophrenia

    Directory of Open Access Journals (Sweden)

    Alexandra eNguyen

    2016-02-01

    Full Text Available Objectives: The efficacy of drug-based treatments and psychological interventions on the primary negative symptoms of schizophrenia remains limited. Recent literature has distinguished negative symptoms associated with a diminished capacity to experience, from those associated with a limited capacity for expression. The Positive Emotions Program for Schizophrenia (PEPS is a new method that specifically aims to reduce the syndrome of a diminished capacity to experience. Methods: The intervention’s vital ingredients were identified through a literature review of emotion in schizophrenia and positive psychology. The program has been beta-tested on various groups of healthcare professionals. Results: A detailed description of the final version of PEPS is presented here. The French version of the program is freely downloadable. Conclusions: PEPS is a specific, short, easy to use, group-based intervention to improve pleasure and motivation in schizophrenia. It was built considering a recovery-oriented approach to schizophrenia.

  2. Effect of vaginal progesterone suppository (200 mg on preventing preterm labor after the inhibition of uterine contractions: A randomized clinical trial

    Directory of Open Access Journals (Sweden)

    Azin Alavi

    2016-10-01

    Full Text Available Preterm labor implies a childbirth before the completion of 37 weeks, and accounts for the majority of infant mortalities. Finding proper medications is essential in the treatment procedure. The present research aimed to investigate the effect of vaginal progesterone suppository (200 mg on the prevention of preterm labor after inhibiting uterine contractions. Participants were patients hospitalized in Shariati Hospital of Bandar Abbas in 2014-15. As a randomized clinical trial, the present research focused on all pregnant women who referred to Shariati Hospital in Bandar Abbas due to preterm uterine contractions in 2014-15. The inclusion criteria were: pregnancy with a singleton and passing one’s 26th-34th week of pregnancy. Through convenient sampling method, 200 women were selected to enter the study. According to the table obtained from Random Allocation software, they were randomly divided into two groups, each comprised of 100 subjects. They were monitored for 48 hours in terms of uterine contractions and then if there were no contractions and change of dilatation or cervical effacement, they were discharged. They were asked to return for a revisit one week later in their 34th week of pregnancy. SPSS (version 17 was used to analyze the data through Man-Whitney U-test, Fisher’s exact test, t-test and chi-squared test. P-value of significance was set at ≤.05. A statistically significant difference was found between the two groups in terms of the frequency of term and preterm labors (P<0.05. The Apgar score of infants in the intervention group was higher than the control (P<0.05. The rate of respiratory problems in the intervention group was significantly lower than the control (P<0.001. The rate of septicemia in the infants of the intervention group was 8% as compared to the control group 20%. The weight of infants in the intervention group was significantly higher than the control (P<0.05. Prescribing vaginal progesterone suppository

  3. Research advances in the prevention and treatment of pancreatitis after endoscopic retrograde cholangiopancreatography

    Directory of Open Access Journals (Sweden)

    ZHANG Weifeng

    2018-03-01

    Full Text Available Endoscopic retrograde cholangiopancreatography (ERCP is an important technique for the diagnosis and treatment of biliary and pancreatic diseases and post-ERCP pancreatitis (PEP is the most common complication of ERCP. Since the birth of ERCP, the prevention and treatment of PEP has become the focus of international research. In recent years, much progress has been made in the aspects of risk factors, pharmacological prevention, and prophylactic stent implantation in the pancreatic duct. Since these research findings are not consistent, further clinical studies are needed to demonstrate such findings.

  4. Epidermal growth factor inhibits rat pancreatic cell proliferation, causes acinar cell hypertrophy, and prevents caerulein-induced desensitization of amylase release.

    Science.gov (United States)

    Morisset, J; Larose, L; Korc, M

    1989-06-01

    The in vivo effects of epidermal growth factor (EGF) on pancreatic growth and digestive enzyme concentrations were compared with the actions of the pancreatic secretagogue caerulein in the adult rat. EGF (10 micrograms/kg BW) did not alter pancreatic weight or protein content. However, this concentration of EGF inhibited [3H]thymidine incorporation into DNA by 44%, decreased DNA content by 20%, and increased the concentrations of amylase, chymotrypsinogen, and protein by 106%, 232%, and 42%, respectively. Pancreatic acini prepared from EGF-treated rats exhibited a characteristic secretory response to caerulein that was superimposable to that obtained in acini from saline-treated rats. In both groups of acini half-maximal and maximal stimulation of amylase release occurred at approximately 5 pM and 50 pM caerulein, respectively. In contrast to EGF, caerulein (1 microgram/kg BW) increased pancreatic weight by 29% and protein content by 59%, and enhanced [3H]thymidine incorporation into DNA by 70%. Although caerulein increased the concentrations of pancreatic amylase and chymotrypsinogen by 38% and 297%, respectively, pancreatic acini prepared from caerulein-treated rats were less sensitive to the actions of caerulein in vitro when compared with acini from control rats. Indeed, the EC50 was shift from 4.8 pM to 9.8 pM after 4 days of treatment. EGF potentiated the actions of caerulein on pancreatic weight, protein content, and chymotrypsinogen concentration, and prevented the caerulein-induced alteration in the secretory responsiveness of the acinar cell. Conversely, caerulein reversed the inhibitory effect of EGF on thymidine incorporation. These findings suggest that EGF may modulate the trophic effects of certain gastrointestinal hormones, and may participate in the regulation of pancreatic exocrine function in vivo.

  5. Vesicles mimicking normal and cancer cell membranes exhibit differential responses to the cell-penetrating peptide Pep-1.

    Science.gov (United States)

    Almarwani, Bashiyar; Phambu, Esther Nzuzi; Alexander, Christopher; Nguyen, Ha Aimee T; Phambu, Nsoki; Sunda-Meya, Anderson

    2018-06-01

    The cell-penetrating peptide (CPP) Pep-1 presents a great potential in drug delivery due to its intrinsic property to cross plasma membrane. However, its mechanism of entry into the cell remains unresolved. In this study, we compare the selectivity of Pep-1 towards vesicles mimicking normal and cancer cell membranes. The interaction was performed in a wide range of peptide-to-lipid molar ratios using infrared (IR), fluorescence, scanning electron microscopy (SEM), thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) techniques. At low peptide concentration, fluorescence experiments show that lipid-phosphatidylserine (PS) seems to enable Pep-1 translocation into cancer cell membrane as evidenced by the blue shift of its maximal emission wavelength. DSC data show that Pep-1 induces segregation of lipids. At high peptide concentration, IR data indicate that the interaction of Pep-1 is relatively stronger with normal cell membrane than with cancer cell membrane through the phosphate groups, while the interaction is weaker with normal cell membrane than with cancer cell membrane through the carbonyl groups. TGA and DSC data reveal that vesicles of normal cell membrane are thermally more stable than vesicles of cancer cell membrane. This suggests that the additional lipid PS included in cancer cell membrane has a destabilizing effect on the membrane structure. SEM images reveal that Pep-1 form superstructures including spherical particles and fibrils in the presence of both model membranes. PS seems to enhance peptide transport across cellular membranes. The biophysical techniques in this study provide valuable insights into the properties of CPPs in drug delivery systems. Copyright © 2018 Elsevier B.V. All rights reserved.

  6. PEP-X: An Ultimate Storage Ring Based on Fourth-Order Geometric Achromats

    Energy Technology Data Exchange (ETDEWEB)

    Cai, Yunhai; Bane, Karl; Hettel, Robert; Nosochkov, Yuri; Wang, Min-Huey; /SLAC

    2012-04-06

    We have designed an 'ultimate' storage ring for the PEP-X light source that achieves the diffraction limited emittances (at 1.5 {angstrom}) of 12 pm-rad in both horizontal and vertical planes with a 4.5-GeV beam. These emittances include the contribution of intrabeam scattering at a nominal current of 200 mA in 3300 bunches. This quality beam in conjunction with a conventional 4-m undulator in a straight section can generate synchrotron radiation having a spectral brightness above 10{sup 22} [photons/s/mm{sup 2}/mrad{sup 2}/0.1% BW] at a 10 keV photon energy. The high coherence at the diffraction limit makes PEP-X competitive with 4th generation light sources based on an energy recovery linac. In addition, the beam lifetime is several hours and the dynamic aperture is large enough to allow off-axis injection. The alignment and stability tolerances, though challenging, are achievable. A ring with all these properties is only possible because of several major advances in mitigating the effects of nonlinear resonances.

  7. In Depth Diagnostics for RF System Operation in the PEP-II B Factory

    International Nuclear Information System (INIS)

    Van Winkle, Daniel; Fox, John; Teytelman, Dmitry; SLAC

    2005-01-01

    The PEP-II RF systems incorporate numerous feedback loops in the low-level processing for impedance control and operating point regulation. The interaction of the multiple loops with the beam is complicated, and the systems incorporate online diagnostic tools to configure the feedback loops as well as to record fault files in the case of an RF abort. Rapid and consistent analysis of the RF-related beam aborts and other failures is critical to the reliable operation of the B-Factory, especially at the recently achieved high beam currents. Procedures and algorithms used to extract diagnostic information from time domain fault files are presented and illustrated via example interpretations of PEP-II fault file data. Example faults presented will highlight the subtle interpretation required to determine the root cause. Some such examples are: abort kicker firing asynchronously, klystron and cavity arcs, beam loss leading to longitudinal instability, tuner read back jumps and poorly configured low-level RF feedback loop

  8. PEP-II asymmetric B Factory: Design update and R ampersand D results

    International Nuclear Information System (INIS)

    Zisman, M.S.; Bell, R.A.; Dorfan, J.; Schwarz, H.; Barletta, W.A.; Calderon, M.

    1992-07-01

    PEP-II, a 9 GeV x 3.1 GeV e + e - collider with a design luminosity of 3 x 10 33 cm -2 s -1 , was proposed jointly by SLAC, LBL, and LLNL. Recent efforts have continued towards an optimized design. In addition, an aggressive R ampersand D program is under way to validate our design choices. Fabrication of a low-power prototype RF cavity is complete, and impedance measurements are beginning. A 500-kW, 476-MHz klystron has been completed; it will be used for testing both high-power RF windows and a prototype high-power cavity (now under design in collaboration with Chalk River Laboratory). Vacuum studies have demonstrated that chambers with suitable photodesorption properties can be fabricated. A mockup of the two-ring arc area has been completed and used to investigate alignment and stability issues. The PEP-II project is ready to begin construction as soon as funds become available

  9. A unique power supply for the PEP II klystron at SLAC

    International Nuclear Information System (INIS)

    Cassel, R.; Nguyen, M.N.

    1997-07-01

    Each of the eight 1.2 MW RF klystrons for the PEP-II storage rings require a 2.5 MVA DC power supply of 83 Kv at 23 amps. The design for the supply was base on three factors, low cost, small size to fit existing substation pads, and good protection against damage to the klystron including klystron gun arcs. The supply uses a 12 pulse 12.5 KV primary thyristor star point controller with primary filter inductor to provide rapid voltage control, good voltage regulation, and fast turn off during klystron tube faults. The supply also uses a unique secondary rectifier, filter capacitor configuration to minimize the energy available under a klystron fault. The voltage control is from 0--90 KV with a regulation of < 0.1% and voltage ripple of < 1% P-P, (< 0.2% RMS) above 60 KV. The supply utilizes a thyristor crowbar, which under a klystron tube arc limits the energy in the klystron arc to < 5 joules. If the thyristor crowbar is disabled the energy supplied is < 40 joules into the arc. The size of the supply was reduced small enough to fit the existing PEP transformer yard pads. The cost of the power supply was < $140 per KVA

  10. The PEP-II/BaBar Project-Wide Database using World Wide Web and Oracle*Case

    International Nuclear Information System (INIS)

    Chan, A.; Crane, G.; MacGregor, I.; Meyer, S.

    1995-12-01

    The PEP-II/BaBar Project Database is a tool for monitoring the technical and documentation aspects of the accelerator and detector construction. It holds the PEP-II/BaBar design specifications, fabrication and installation data in one integrated system. Key pieces of the database include the machine parameter list, components fabrication and calibration data, survey and alignment data, property control, CAD drawings, publications and documentation. This central Oracle database on a UNIX server is built using Oracle*Case tools. Users at the collaborating laboratories mainly access the data using World Wide Web (WWW). The Project Database is being extended to link to legacy databases required for the operations phase

  11. The HtrA-like serine protease PepD interacts with and modulates the Mycobacterium tuberculosis 35-kDa antigen outer envelope protein.

    Directory of Open Access Journals (Sweden)

    Mark J White

    2011-03-01

    Full Text Available Mycobacterium tuberculosis remains a significant global health concern largely due to its ability to persist for extended periods within the granuloma of the host. While residing within the granuloma, the tubercle bacilli are likely to be exposed to stress that can result in formation of aberrant proteins with altered structures. Bacteria encode stress responsive determinants such as proteases and chaperones to deal with misfolded or unfolded proteins. pepD encodes an HtrA-like serine protease and is thought to process proteins altered following exposure of M. tuberculosis to extra-cytoplasmic stress. PepD functions both as a protease and chaperone in vitro, and is required for aspects of M. tuberculosis virulence in vivo. pepD is directly regulated by the stress-responsive two-component signal transduction system MprAB and indirectly by extracytoplasmic function (ECF sigma factor SigE. Loss of PepD also impacts expression of other stress-responsive determinants in M. tuberculosis. To further understand the role of PepD in stress adaptation by M. tuberculosis, a proteomics approach was taken to identify binding proteins and possible substrates of this protein. Using subcellular fractionation, the cellular localization of wild-type and PepD variants was determined. Purified fractions as well as whole cell lysates from Mycobacterium smegmatis or M. tuberculosis strains expressing a catalytically compromised PepD variant were immunoprecipitated for PepD and subjected to LC-MS/MS analyses. Using this strategy, the 35-kDa antigen encoding a homolog of the PspA phage shock protein was identified as a predominant binding partner and substrate of PepD. We postulate that proteolytic cleavage of the 35-kDa antigen by PepD helps maintain cell wall homeostasis in Mycobacterium and regulates specific stress response pathways during periods of extracytoplasmic stress.

  12. HyPEP-FY 07 Annual Report: A Hydrogen Production Plant Efficiency Calculation Program

    Energy Technology Data Exchange (ETDEWEB)

    Chang Oh

    2007-09-01

    The Very High Temperature Gas-Cooled Reactor (VHTR) coupled to the High Temperature Steam Electrolysis (HTSE) process is one of two reference integrated systems being investigated by the U.S. Department of Energy and Idaho National Laboratory for the production of hydrogen. In this concept the VHTR outlet temperature of 900 °C provides thermal energy and high efficiency electricity for the electrolysis of steam in the HTSE process. In the second reference system the Sulfur Iodine (SI) process is coupled to the VHTR to produce hydrogen thermochemically. In the HyPEP project we are investigating and characterizing these two reference systems with respect to production, operability, and safety performance criteria. Under production, plant configuration and working fluids are being studied for their effect on efficiency. Under operability, control strategies are being developed with the goal of maintaining equipment within operating limits while meeting changes in demand. Safety studies are to investigate plant response for equipment failures. Specific objectives in FY07 were (1) to develop HyPEP Beta and verification and validation (V&V) plan, (2) to perform steady state system integration, (3) to perform parametric studies with various working fluids and power conversion unit (PCU) configurations, (4) the study of design options such as pressure, temperature, etc. (5) to develop a control strategy and (6) to perform transient analyses for plant upsets, control strategy, etc for hydrogen plant with PCU. This report describes the progress made in FY07 in each of the above areas. (1) The HyPEP code numeric scheme and Graphic User Interface have been tested and refined since the release of the alpha version a year ago. (2) The optimal size and design condition for the intermediate heat exchanger, one of the most important components for integration of the VHTR and HTSE plants, was estimated. (3) Efficiency calculations were performed for a variety of working fluids for

  13. Enrofloxacin and Probiotic Lactobacilli Influence PepT1 and LEAP-2 mRNA Expression in Poultry.

    Science.gov (United States)

    Pavlova, Ivelina; Milanova, Aneliya; Danova, Svetla; Fink-Gremmels, Johanna

    2016-12-01

    Expression of peptide transporter 1 (PepT1) and liver-expressed antimicrobial peptide 2 (LEAP-2) in chickens can be influenced by food deprivation, pathological conditions and drug administration. Effect of three putative probiotic Lactobacillus strains and enrofloxacin on the expression of PepT1 and LEAP-2 mRNA was investigated in Ross 308 chickens. One-day-old chicks (n = 24) were allocated to following groups: control (without treatment); group treated with probiotics via feed; group treated with a combination of probiotics and enrofloxacin; and a group given enrofloxacin only. The drug was administered at a dose of 10 mg kg -1 , via drinking water for 5 days. Samples from liver, duodenum and jejunum were collected 126 h after the start of the treatment. Expression levels of PepT1 and LEAP-2 were determined by real-time polymerase chain reaction and were statistically evaluated by Mann-Whitney test. Enrofloxacin administered alone or in combination with probiotics provoked a statistically significant up-regulation of PepT1 mRNA levels in the measured organ sites. These changes can be attributed to a tendency of improvement in utilization of dietary peptide and in body weight gain. LEAP-2 mRNA expression levels did not change significantly in enrofloxacin-treated chickens in comparison with control group.

  14. PEP3 overexpression shortens lag phase but does not alter growth rate in Saccharomyces cerevisiae exposed to acetic acid stress

    Science.gov (United States)

    Ding, Jun; Holzwarth, Garrett; Bradford, C. Samuel; Cooley, Ben; Yoshinaga, Allen S.; Patton-Vogt, Jana; Abeliovich, Hagai; Penner, Michael H.; Bakalinsky, Alan T.

    2017-01-01

    In fungi, two recognized mechanisms contribute to pH homeostasis: the plasma membrane proton-pumping ATPase that exports excess protons and the vacuolar proton-pumping ATPase (V-ATPase) that mediates vacuolar proton uptake. Here, we report that overexpression of PEP3 which encodes a component of the HOPS and CORVET complexes involved in vacuolar biogenesis, shortened lag phase in Saccharomyces cerevisiae exposed to acetic acid stress. By confocal microscopy, PEP3-overexpressing cells stained with the vacuolar membrane-specific dye, FM4-64 had more fragmented vacuoles than the wild-type control. The stained overexpression mutant was also found to exhibit about 3.6-fold more FM4-64 fluorescence than the wild-type control as determined by flow cytometry. While the vacuolar pH of the wild-type strain grown in the presence of 80 mM acetic acid was significantly higher than in the absence of added acid, no significant difference was observed in vacuolar pH of the overexpression strain grown either in the presence or absence of 80 mM acetic acid. Based on an indirect growth assay, the PEP3-overexpression strain exhibited higher V-ATPase activity. We hypothesize that PEP3 overexpression provides protection from acid stress by increasing vacuolar surface area and V-ATPase activity and, hence, proton-sequestering capacity. PMID:26051671

  15. Pizza Parties, Pep Rallies, and Practice Tests: Strategies Used by High School Principals to Raise Percent Proficient

    Science.gov (United States)

    Hollingworth, Liz; Dude, David J.; Shepherd, Julie K.

    2010-01-01

    This study explores ways high school principals are responding to the demands of education reform to raise student test scores on achievement tests used for accountability purposes. Anecdotal evidence suggests administrators have instituted pizza parties and pep rallies to motivate students to do their best and practice tests to prepare students…

  16. Use of NSAIDs via the Rectal Route for the Prevention of Pancreatitis after ERCP in All-Risk Patients: An Updated Meta-Analysis

    Directory of Open Access Journals (Sweden)

    Lei-Min Yu

    2018-01-01

    Full Text Available The aim of this study was to assess the efficacy of the rectal administration of nonsteroidal anti-inflammatory drugs (NSAIDs in preventing post-ERCP pancreatitis (PEP. We searched database for randomized controlled trials (RCTs comparing periprocedural rectal administration of NSAIDs with placebo for the prevention of PEP. The rectal administration of NSAIDs significantly decreased the incidence of PEP in the whole patient population (odds ratio (OR: 0.44, 95% confidence interval (CI: 0.30–0.64, P<0.0001, high-risk patients (OR: 0.34, 95% CI: 0.19–0.58, P=0.0001, and all-risk patients (OR: 0.51, 95% CI: 0.31–0.84, P=0.008. The incidence of PEP was reduced by indomethacin (OR: 0.54, 95% CI: 0.36–0.82, P=0.004 and diclofenac (OR: 0.27, 95% CI: 0.15–0.46, P<0.00001. The administration of NSAIDs before (OR: 0.42, 95% CI: 0.25–0.73, P=0.002 or after (OR: 0.39, 95% CI: 0.27–0.56, P<0.00001 ERCP reduced PEP. The NSAIDs were associated with a reduction in mild PEP (OR: 0.55, 95% CI: 0.36–0.83, P=0.004 and moderate-to-severe PEP (OR: 0.47, 95% CI: 0.28–0.79, P=0.004. The rectal administration of NSAIDs reduced the incidence of PEP in high-risk and all-risk patients.

  17. Progress on the superconducting magnet for the time projection chamber experiment (TPC) at PEP

    International Nuclear Information System (INIS)

    Green, M.A.; Eberhard, P.H.; Burns, W.A.

    1980-01-01

    The TPC (Time Projection Chamber) experiment at PEP will have a two meter inside diameter superconducting magnet which creatests a 1.5 T uniform solenoidal field for the TPC. The superconducting magnet coil, cryostat, cooling system, and the TPC gas pressure vessel (which operatests at 11 atm) were designed to be about two thirds of a radiation length thick. As a result, a high current density coil design was chosen. The magnet is cooled by forced flow two phase helium. The TPC magnet is the largest adiabatically stable superconducting magnet built to date. The paper presents the parameters of the TPC thin solenoid and its subsystems. Tests results from the Spring 1980 cryogenic tes are presented. The topics to be dealt with in the paper are cryogenic services and the tests of magnet subsystems such as the folded current leads. Large thin superconducting magnet technology will be important to large detectors to be used on LEP

  18. Vacuum system of the high energy ring of an asymmetric B-factory based on PEP

    International Nuclear Information System (INIS)

    Barletta, W.A.; Calderon, M.O.; Wong, R.; Jenkins, T.M.

    1991-01-01

    The multi-ampere currents required for high luminosity operation of an asymmetric B factory leads to extremely stressing requirements on a vacuum system suitable for maintaining long beam-gas lifetimes and acceptable background levels in the detector. We present the design for a Cu alloy vacuum chamber and its associated pumping system for the 9 GeV electron storage ring of the proposed B factory based on PEP. The excellent thermal and photo-desorption properties of Cu allows handling the high proton flux in a conventional, single chamber design with distributed ion pumps. The x-ray opacity of the Cu is sufficiently high that no additional lead shielding is necessary to protect the dipoles from the intense synchrotron radiation generated by the beam. The design allows chamber commissioning in <500 hr of operation. 5 refs., 3 figs., 2 tabs

  19. Meson and baryon correlation studies using the PEP-TPC/2γ Facility

    International Nuclear Information System (INIS)

    Ronan, M.T.

    1991-03-01

    Results on vector meson, and strange and charmed-baryon production are presented for data taken during the period 1982--1986 using the TPC/2γ detector at PEP. Vector mesons (ρ 0 , K * and φ) with 0, 1 and 2 strange quarks are used to obtain redundant measures of strange-quark suppression and of the vector to pseudoscalar ratio in hadronization. Measurements of the production rates of Λ, Ξ - , Ω and Ξ *0 hyperons and for the Λ c and of rapidity correlations between Λ bar Λ pairs provide sensitive tests of baryon production in fragmentation models. In addition, two- and three-particle correlations between like sign pions provide further evidence for the Bose-Einstein effect in e + e - interactions including the relativistic motion of particle sources. 9 refs., 7 figs

  20. Computational tools and lattice design for the PEP-II B-Factory

    International Nuclear Information System (INIS)

    Cai, Y.; Irwin, J.; Nosochkov, Y.; Yan, Y.

    1997-01-01

    Several accelerator codes were used to design the PEP-II lattices, ranging from matrix-based codes, such as MAD and DIMAD, to symplectic-integrator codes, such as TRACY and DESPOT. In addition to element-by-element tracking, we constructed maps to determine aberration strengths. Furthermore, we have developed a fast and reliable method (nPB tracking) to track particles with a one-turn map. This new technique allows us to evaluate performance of the lattices on the entire tune-plane. Recently, we designed and implemented an object-oriented code in C++ called LEGO which integrates and expands upon TRACY and DESPOT. copyright 1997 American Institute of Physics