WorldWideScience

Sample records for prevention p2 compliance

  1. Major weapon system environmental life-cycle cost estimating for Conservation, Cleanup, Compliance and Pollution Prevention (C3P2)

    Science.gov (United States)

    Hammond, Wesley; Thurston, Marland; Hood, Christopher

    1995-01-01

    The Titan 4 Space Launch Vehicle Program is one of many major weapon system programs that have modified acquisition plans and operational procedures to meet new, stringent environmental rules and regulations. The Environmental Protection Agency (EPA) and the Department of Defense (DOD) mandate to reduce the use of ozone depleting chemicals (ODC's) is just one of the regulatory changes that has affected the program. In the last few years, public environmental awareness, coupled with stricter environmental regulations, has created the need for DOD to produce environmental life-cycle cost estimates (ELCCE) for every major weapon system acquisition program. The environmental impact of the weapon system must be assessed and budgeted, considering all costs, from cradle to grave. The Office of the Secretary of Defense (OSD) has proposed that organizations consider Conservation, Cleanup, Compliance and Pollution Prevention (C(sup 3)P(sup 2)) issues associated with each acquisition program to assess life-cycle impacts and costs. The Air Force selected the Titan 4 system as the pilot program for estimating life-cycle environmental costs. The estimating task required participants to develop an ELCCE methodology, collect data to test the methodology and produce a credible cost estimate within the DOD C(sup 3)P(sup 2) definition. The estimating methodology included using the Program Office weapon system description and work breakdown structure together with operational site and manufacturing plant visits to identify environmental cost drivers. The results of the Titan IV ELCCE process are discussed and expanded to demonstrate how they can be applied to satisfy any life-cycle environmental cost estimating requirement.

  2. Microglia P2Y13 Receptors Prevent Astrocyte Proliferation Mediated by P2Y1 Receptors

    Directory of Open Access Journals (Sweden)

    Clara Quintas

    2018-05-01

    Full Text Available Cerebral inflammation is a common feature of several neurodegenerative diseases that requires a fine interplay between astrocytes and microglia to acquire appropriate phenotypes for an efficient response to neuronal damage. During brain inflammation, ATP is massively released into the extracellular medium and converted into ADP. Both nucleotides acting on P2 receptors, modulate astrogliosis through mechanisms involving microglia-astrocytes communication. In previous studies, primary cultures of astrocytes and co-cultures of astrocytes and microglia were used to investigate the influence of microglia on astroglial proliferation induced by ADPβS, a stable ADP analog. In astrocyte cultures, ADPβS increased cell proliferation through activation of P2Y1 and P2Y12 receptors, an effect abolished in co-cultures (of astrocytes with ∼12.5% microglia. The possibility that the loss of the ADPβS-mediated effect could have been caused by a microglia-induced degradation of ADPβS or by a preferential microglial localization of P2Y1 or P2Y12 receptors was excluded. Since ADPβS also activates P2Y13 receptors, the contribution of microglial P2Y13 receptors to prevent the proliferative effect of ADPβS in co-cultures was investigated. The results obtained indicate that P2Y13 receptors are low expressed in astrocytes and mainly expressed in microglia. Furthermore, in co-cultures, ADPβS induced astroglial proliferation in the presence of the selective P2Y13 antagonist MRS 2211 (3 μM and of the selective P2Y12 antagonist AR-C66096 (0.1 μM, suggesting that activation of microglial P2Y12 and P2Y13 receptors may induce the release of messengers that inhibit astroglial proliferation mediated by P2Y1,12 receptors. In this microglia-astrocyte paracrine communication, P2Y12 receptors exert opposite effects in astroglial proliferation as a result of its cellular localization: cooperating in astrocytes with P2Y1 receptors to directly stimulate proliferation and in

  3. Pollution Prevention Successes Database (P2SDb) user guide

    International Nuclear Information System (INIS)

    1995-07-01

    When Pollution Prevention Opportunity Assessments (P2OAs) were launched at the Hanford Site during the summer of 1994, the first comment received from those using them expressed the desire for a method to report assessments electronically. As a temporary measure, macros were developed for use on word processing systems, but a more formal database was obviously needed. Additionally, increased DOE and Washington state reporting requirements for pollution prevention suggested that a database system would streamline the reporting process. The Pollution Prevention Group of Westinghouse Hanford Company (WHC) contracted with the Data Automation Engineering Department from ICF Kaiser Hanford Company (ICFKH) to develop the system. The scope was to develop a database that will track P2OAs conducted by the facilities and contractors at the Hanford Site. It will also track pollution prevention accomplishments that are not the result of P2OAs and document a portion of the Process Waste Assessments conducted in the past. To accommodate the above criteria, yet complete the system in a timely manner, the Pollution Prevention Successes Database (P2SDb) is being implemented in three phases. The first phase will automate the worksheets to provide both input and output of the data associated with the worksheets. The second phase will automate standard summary reports and ad hoc reports. The third phase will provide automated searching of the database to facilitate the sharing of pollution prevention experiences among various users. This User's Guide addresses only the Phase 1 system

  4. Pollution Prevention Successes Database (P2SDb) user guide

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1995-07-01

    When Pollution Prevention Opportunity Assessments (P2OAs) were launched at the Hanford Site during the summer of 1994, the first comment received from those using them expressed the desire for a method to report assessments electronically. As a temporary measure, macros were developed for use on word processing systems, but a more formal database was obviously needed. Additionally, increased DOE and Washington state reporting requirements for pollution prevention suggested that a database system would streamline the reporting process. The Pollution Prevention Group of Westinghouse Hanford Company (WHC) contracted with the Data Automation Engineering Department from ICF Kaiser Hanford Company (ICFKH) to develop the system. The scope was to develop a database that will track P2OAs conducted by the facilities and contractors at the Hanford Site. It will also track pollution prevention accomplishments that are not the result of P2OAs and document a portion of the Process Waste Assessments conducted in the past. To accommodate the above criteria, yet complete the system in a timely manner, the Pollution Prevention Successes Database (P2SDb) is being implemented in three phases. The first phase will automate the worksheets to provide both input and output of the data associated with the worksheets. The second phase will automate standard summary reports and ad hoc reports. The third phase will provide automated searching of the database to facilitate the sharing of pollution prevention experiences among various users. This User`s Guide addresses only the Phase 1 system.

  5. Improving compliance with hormonal replacement therapy in primary osteoporosis prevention

    DEFF Research Database (Denmark)

    Vestergaard, P; Hermann, A P; Gram, J

    1997-01-01

    To evaluate whether introduction of treatment alternatives would improve compliance with hormonal replacement therapy (HRT) as primary osteoporosis prevention in women not tolerating the first line osteoporosis prevention schedule.......To evaluate whether introduction of treatment alternatives would improve compliance with hormonal replacement therapy (HRT) as primary osteoporosis prevention in women not tolerating the first line osteoporosis prevention schedule....

  6. P2X4 receptors (P2X4Rs represent a novel target for the development of drugs to prevent and/or treat alcohol use disorders

    Directory of Open Access Journals (Sweden)

    Kelle M. Franklin

    2014-06-01

    Full Text Available Alcohol use disorders (AUDs have a staggering socioeconomic impact. Few therapeutic options are available, and they are largely inadequate. These shortcomings highlight the urgent need to develop effective medications to prevent and/or treat AUDs. A critical barrier is the lack of information regarding the molecular target(s by which ethanol (EtOH exerts its pharmacological activity. This review highlights findings implicating P2X4 receptors (P2X4Rs as a target for the development of therapeutics to treat AUDs and discusses the use of ivermectin (IVM as a potential clinical tool for treatment of AUDs. P2XRs are a family of ligand-gated ion channels activated by extracellular ATP. Of the P2XR subtypes, P2X4Rs are expressed the most abundantly in the CNS. Converging evidence suggests that P2X4Rs are involved in the development and progression of AUDs. First, in vitro studies report that pharmacologically relevant EtOH concentrations can negatively modulate ATP-activated currents. Second, P2X4Rs in the mesocorticolimbic dopamine system are thought to play a role in synaptic plasticity and are located ideally to modulate brain reward systems. Third, alcohol-preferring (P rats have lower functional expression of the p2rx4 gene than alcohol-non-preferring (NP rats suggesting an inverse relationship between alcohol intake and P2X4R expression. Similarly, whole brain p2rx4 expression has been shown to relate inversely to innate 24 hr alcohol preference across 28 strains of rats. Fourth, mice lacking the p2rx4 gene drink more EtOH than wildtype controls. Fifth, IVM, a positive modulator of P2X4Rs, antagonizes EtOH-mediated inhibition of P2X4Rs in vitro and reduces EtOH intake and preference in vivo. These findings suggest that P2X4Rs contribute to EtOH intake. The present review summarizes recent findings focusing on the P2X4R as a molecular target of EtOH action, its role in EtOH drinking behavior and modulation of its activity by IVM as a potential

  7. Improving compliance with hormonal replacement therapy in primary osteoporosis prevention

    DEFF Research Database (Denmark)

    Vestergaard, P; Hermann, A P; Gram, J

    1997-01-01

    To evaluate whether introduction of treatment alternatives would improve compliance with hormonal replacement therapy (HRT) as primary osteoporosis prevention in women not tolerating the first line osteoporosis prevention schedule....

  8. Compliance With Infection Prevention Guidelines By Health Care ...

    African Journals Online (AJOL)

    USER

    infection prevention. The study further reviewed revealed varied levels of compliance on different components of infection prevention. The highest level of compliance (100%) was ... having a Surgical Site Infection (SSI) increases a patient's hospital stay by ... operative wound infection rate of 5%10. LITERATURE REVIEW.

  9. Compliance With Infection Prevention Guidelines By Health Care ...

    African Journals Online (AJOL)

    Objective: To determine the level of health-care workers' compliance with Infection Prevention Guidelines and identify factors that influence compliance at Ronald Ross General Hospital, Mufulira District. Methods: A quantitative study was carried out in 2007. Convenient sampling method was used. Data was obtained using ...

  10. 76 FR 72120 - Oil Pollution Prevention; Spill Prevention, Control, and Countermeasure (SPCC) Rule-Compliance...

    Science.gov (United States)

    2011-11-22

    ... Oil Pollution Prevention; Spill Prevention, Control, and Countermeasure (SPCC) Rule--Compliance Date... rule will be effective November 22, 2011. List of Subjects in 40 CFR Part 112 Oil pollution prevention... Regulations is amended as follows: PART 112--OIL POLLUTION PREVENTION 0 1. The authority citation for part 112...

  11. Making The Decision: Pollution Prevention (P2) Equipment Evaluation, Procurement, Implementation and Monitoring

    National Research Council Canada - National Science Library

    Smith, Timothy C

    1998-01-01

    .... What is your primary objective? Is it waste reduction or saving money? Are you planning to select the best P2 options for achieving your waste reduction goals, or are you limited to selecting those options that show significant cost savings...

  12. P2X7R antagonism after subfailure overstretch injury of blood vessels reverses vasomotor dysfunction and prevents apoptosis.

    Science.gov (United States)

    Luo, Weifeng; Feldman, Daniel; McCallister, Reid; Brophy, Colleen; Cheung-Flynn, Joyce

    2017-12-01

    Human saphenous vein (HSV) is harvested and prepared prior to implantation as an arterial bypass graft. Injury and the response to injury from surgical harvest and preparation trigger cascades of molecular events and contribute to graft remodeling and intimal hyperplasia. Apoptosis is an early response after implantation that contributes the development of neointimal lesions. Here, we showed that surgical harvest and preparation of HSV leads to vasomotor dysfunction, increased apoptosis and downregulation of the phosphorylation of the anti-apoptotic protein, Niban. A model of subfailure overstretch injury in rat aorta (RA) was used to demonstrate impaired vasomotor function, increased extracellular ATP (eATP) release, and increased apoptosis following pathological vascular injury. The subfailure overstretch injury was associated with activation of p38 MAPK stress pathway and decreases in the phosphorylation of the anti-apoptotic protein Niban. Treatment of RA after overstretch injury with antagonists to purinergic P2X7 receptor (P2X7R) antagonists or P2X7R/pannexin (PanX1) complex, but not PanX1 alone, restored vasomotor function. Inhibitors to P2X7R and PanX1 reduced stretch-induced eATP release. P2X7R/PanX1 antagonism led to decrease in p38 MAPK phosphorylation, restoration of Niban phosphorylation and increases in the phosphorylation of the anti-apoptotic protein Akt in RA and reduced TNFα-stimulated caspase 3/7 activity in cultured rat vascular smooth muscle cells. In conclusion, inhibition of P2X7R after overstretch injury restored vasomotor function and inhibited apoptosis. Treatment with P2X7R/PanX1 complex inhibitors after harvest and preparation injury of blood vessels used for bypass conduits may prevent the subsequent response to injury that lead to apoptosis and represents a novel therapeutic approach to prevent graft failure.

  13. Compliance with Sport Injury Prevention Interventions in Randomised Controlled Trials: A Systematic Review.

    Science.gov (United States)

    van Reijen, Miriam; Vriend, Ingrid; van Mechelen, Willem; Finch, Caroline F; Verhagen, Evert A

    2016-08-01

    Sport injury prevention studies vary in the way compliance with an intervention is defined, measured and adjusted for. The objective of this systematic review was to assess the extent to which sport injury prevention randomised controlled trials (RCTs) have defined, measured and adjusted results for compliance with an injury prevention intervention. An electronic search was performed in MEDLINE, PubMed, the Cochrane Center of Controlled Trials, CINAHL (Cumulative Index to Nursing and Allied Health Literature), PEDro (Physiotherapy Evidence Database) and SPORTDiscus. English RCTs, quasi-RCTs and cluster-RCTs were considered eligible. Trials that involved physically active individuals or examined the effects of an intervention aimed at the prevention of sport- or physical activity-related injuries were included. Of the total of 100 studies included, 71.6 % mentioned compliance or a related term, 68.8 % provided details on compliance measurement and 51.4 % provided compliance data. Only 19.3 % analysed the effect of compliance rates on study outcomes. While studies used heterogeneous methods, pooled effects could not be presented. Studies that account for compliance demonstrated that compliance significant affects study outcomes. The way compliance is dealt with in preventions studies is subject to a large degree of heterogeneity. Valid and reliable tools to measure and report compliance are needed and should be matched to a uniform definition of compliance.

  14. 78 FR 32235 - Availability of Compliance Guide for Residue Prevention and Response to Comments

    Science.gov (United States)

    2013-05-29

    ... discrimination in all its programs and activities on the basis of race, color, national origin, gender, religion...] Availability of Compliance Guide for Residue Prevention and Response to Comments AGENCY: Food Safety and... (FSIS) is announcing the availability of the final revision of the compliance guide for the prevention...

  15. 77 FR 24671 - Compliance Guide for Residue Prevention and Agency Testing Policy for Residues

    Science.gov (United States)

    2012-04-25

    ... Food Safety and Inspection Service Compliance Guide for Residue Prevention and Agency Testing Policy for Residues AGENCY: Food Safety and Inspection Service, USDA. ACTION: Notice of availability and... availability of a compliance guide for the prevention of violative residues in livestock slaughter...

  16. Interventions preventing ankle sprains; previous injury and high-risk sport participation as predictors of compliance.

    Science.gov (United States)

    Janssen, Kasper W; van der Zwaard, Babette C; Finch, Caroline F; van Mechelen, Willem; Verhagen, Evert A L M

    2016-06-01

    To describe the association between participants' person-related potential predictor variables and cumulative compliance with interventions for preventing ankle sprains: neuromuscular training, wearing an ankle brace, and a combined training and bracing. Secondary analysis of compliance data from a randomized controlled trial (RCT) comparing measures preventing ankle ligament injuries. Ordinal regression with a backward selection method was used to obtain a descriptive statistical model linking participants' person-related potential predictor variables with the monthly cumulative compliance measurements for three interventions preventing ankle ligament injuries. Having had a previous ankle injury was significantly associated with a higher compliance with all of the preventive measures trialed. Overall compliance with bracing and the combined intervention was significantly lower than the compliance with NM training. Per group analysis found that participating in a high-risk sport, like soccer, basketball, and volleyball, was significantly associated with a higher compliance with bracing, or a combined bracing and NM training. In contrast, participating in a high-risk sport was significantly associated with a lower per group compliance with NM training. Future studies should include at least registration of previous ankle sprains, sport participation (high- or low-risk), experience in NM training, and hours of sport exposure as possible predictors of compliance with interventions preventing ankle sprains. Practitioners should take into account these variables when prescribing preventive neuromuscular training or bracing. Copyright © 2015 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.

  17. (Non)Compliance with disease prevention and control messages: communication correlates and psychological predictors.

    Science.gov (United States)

    Burgoon, M

    1996-07-01

    This article argues that while compliance with disease prevention and control messages should be high given the unique characteristics of this persuasive situation, the data indicate that non compliance is a major social problem. Two communication theories, Language Expectancy Theory and Reinforcement Expectancy Theory, offer promising new conceptualizations of how more compliance can be obtained with health-related messages. Both theories are supported by empirical evidence. Also, ongoing research programs with three psychological predictors (misanthropy, acculturation and sensation-seeking) show promise in providing evidence on how to tailor health-related, compliance-gaining messages to subgroups within the general population.

  18. Compliance of post-radiation therapy head and neck cancer patients with caries preventive protocols.

    Science.gov (United States)

    Frydrych, A M; Slack-Smith, L M; Parsons, R

    2017-06-01

    Caries prevention is paramount in safeguarding the life quality of head and neck cancer patients and is dependent on patient compliance with caries preventive protocols. The purpose of this study was to examine this compliance. All records of patients referred to one public oral medicine clinic servicing a head and neck oncology unit of one major Western Australian hospital, between January 2005 and December 2011, were examined. Data extracted included patient and cancer characteristics and compliance with dietary advice, dental care, oral hygiene instruction and fluoride use over a follow-up period of at least 12 months. Compliance was assessed against various oral health outcomes and patient characteristics. Of the 116 participants, 75.9% complied with all caries preventive measures over a mean follow-up period of 45 months. Non-compliance with regular dental attendance (P = 0.004), oral hygiene instruction (P = 0.009), dietary advice (P = 0.034) and daily fluoride use (P = 0.018) were associated with the development of dental caries post-treatment. The presence of dental caries at the time of cancer diagnosis was predictive of poorer compliance. High compliance with caries preventive measures is attainable in the head and neck cancer patient group. Factors other than fluoride use seem important in caries prevention. © 2016 Australian Dental Association.

  19. Tool for evaluation compliance standards and expectations in occupational risk prevention by collaborating companies

    International Nuclear Information System (INIS)

    Duran Perez, A.; Gomez Pardo, M. A.; Cao Tejero, R.; Millan Verdejo, J. A.; Blas Perez, P.

    2013-01-01

    Within the framework of a single security in ANAV, in our Action Plan on prevention, we consider it essential to include workers from ECCE working for and by ANAV in compliance with standards and expectations both in the accounts of the incidents. With this system is intended to standardize a set of observed deviations report and a tool for measuring the degree of compliance, allowing to monitor the evolution of each company and the effectiveness of prevention plan.

  20. The effectiveness of a multidisciplinary QI activity for accidental fall prevention: Staff compliance is critical

    Directory of Open Access Journals (Sweden)

    Ohde Sachiko

    2012-07-01

    Full Text Available Abstract Background Accidental falls among inpatients are a substantial cause of hospital injury. A number of successful experimental studies on fall prevention have shown the importance and efficacy of multifactorial intervention, though success rates vary. However, the importance of staff compliance with these effective, but often time-consuming, multifactorial interventions has not been fully investigated in a routine clinical setting. The purpose of this observational study was to describe the effectiveness of a multidisciplinary quality improvement (QI activity for accidental fall prevention, with particular focus on staff compliance in a non-experimental clinical setting. Methods This observational study was conducted from July 2004 through December 2010 at St. Luke’s International Hospital in Tokyo, Japan. The QI activity for in-patient falls prevention consisted of: 1 the fall risk assessment tool, 2 an intervention protocol to prevent in-patient falls, 3 specific environmental safety interventions, 4 staff education, and 5 multidisciplinary healthcare staff compliance monitoring and feedback mechanisms. Results The overall fall rate was 2.13 falls per 1000 patient days (350/164331 in 2004 versus 1.53 falls per 1000 patient days (263/172325 in 2010, representing a significant decrease (p = 0.039. In the first 6 months, compliance with use of the falling risk assessment tool at admission was 91.5% in 2007 (3998/4368, increasing to 97.6% in 2010 (10564/10828. The staff compliance rate of implementing an appropriate intervention plan was 85.9% in 2007, increasing to 95.3% in 2010. Conclusion In our study we observed a substantial decrease in patient fall rates and an increase of staff compliance with a newly implemented falls prevention program. A systematized QI approach that closely involves, encourages, and educates healthcare staff at multiple levels is effective.

  1. Compliance to infection prevention and control guidelines among ...

    African Journals Online (AJOL)

    Nosocomial infections ,commonly known as hospital acquired infections (HAI) include several pathogens like Escherichia coli, Hepatitis viruses, HIV, Pseudomonas and Staphylococcus etc. These agents are transmitted directly or indirectly. Prevention and control of Nosocomial infections is the most important approach in ...

  2. Spousal concordance for overall health risk status and preventive service compliance.

    Science.gov (United States)

    Pai, Chih-Wen; Godboldo-Brooks, Ambyr; Edington, Dee W

    2010-07-01

    In this study we examined spousal concordance for two aggregate measures of health risk status and compliance with preventive service recommendations among 9620 pairs of cohabitating, opposite-sex married couples. Health risk appraisals were the primary data source to measure two outcome variables. Health risk status was compiled from 12 health risks and categorized into three levels (low-, medium-, and high-risk status). Overall preventive service compliance status was estimated by seven age-sex specific preventive service recommendations and dichotomized into lower and higher compliance status. For each of the husband and wife populations, we conducted proportional odds models and logistic regression models to assess spousal concordance for the two aggregate measures respectively. All models were adjusted for household income, one's characteristics (age, race, education, disease burden), and the same set of characteristics and the corresponding outcome variable from the spouse. A positive correlation within spousal pairs was statistically significant for both health risk status and compliance status (p education. 2010 Elsevier Inc. All rights reserved.

  3. Oral administration of Lactococcus lactis-expressing heat shock protein 65 and tandemly repeated IA2P2 prevents type 1 diabetes in NOD mice.

    Science.gov (United States)

    Liu, Kun-Feng; Liu, Xiao-Rui; Li, Guo-Liang; Lu, Shi-Ping; Jin, Liang; Wu, Jie

    2016-06-01

    Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease characterized by the destruction of insulin-secreting β cells upon autoreactive T cell attack. Oral administration of autoantigens is an attractive approach to treating T1DM, but an effective carrier should be used in order to protect antigens. Lactococcus lactis, a safe engineering strain, was used for this task in the present study. Two recombinant L. lactis expressing protein HSP65-6IA2P2 were used and be investigated the effects and mechanisms against T1DM in NOD mice. Our findings demonstrate that recombinant L. lactis strains can successfully both deliver antigens to intestinal mucosa and maintain the epitopes for a long time in NOD mice. Oral administration of recombinant L. lactis could prevent hyperglycemia, improve glucose tolerance, and reduce insulitis by inhibiting antigen-specific proliferation of T cells, augmenting regulatory immune reactions, and balancing ratios of Th17/Tregs and Th1/Th2. These results prove that orally administrated L. lactis expressing HSP65-6IA2P2 is an effective approach for the prevention of T1DM in NOD mice. Copyright © 2016 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

  4. Preventive Neuromuscular Training for Young Female Athletes: Comparison of Coach and Athlete Compliance Rates.

    Science.gov (United States)

    Sugimoto, Dai; Mattacola, Carl G; Bush, Heather M; Thomas, Staci M; Foss, Kim D Barber; Myer, Gregory D; Hewett, Timothy E

    2017-01-01

     Fewer athletic injuries and lower anterior cruciate ligament injury incidence rates were noted in studies of neuromuscular-training (NMT) interventions that had high compliance rates. However, several groups have demonstrated that preventive NMT interventions were limited by low compliance rates.  To descriptively analyze coach and athlete compliance with preventive NMT and compare the compliance between study arms as well as among school levels and sports.  Randomized, controlled clinical trial.  Middle and high school athletic programs. Participants or Other Participants: A total of 52 teams, comprising 547 female athletes, were randomly assigned to the experimental or control group and followed for 1 athletic season.  The experimental group (n = 30 teams [301 athletes]: 12 basketball teams [125 athletes], 6 soccer teams [74 athletes], and 12 volleyball teams [102 athletes]) participated in an NMT program aimed at reducing traumatic knee injuries through a trunk-stabilization and hip-strengthening program. The control group (n = 22 teams [246 athletes]: 11 basketball teams [116 athletes], 5 soccer teams [68 athletes], and 6 volleyball teams [62 athletes]) performed a resistive rubber-band running program.  Compliance with the assigned intervention protocols (3 times per week during the preseason [mean = 3.4 weeks] and 2 times per week in-season [mean = 11.9 weeks] of coaches [coach compliance] and athletes [athlete compliance]) was measured descriptively. Using an independent t test, we compared coach and athlete compliance between the study arms. A 2-way analysis of variance was calculated to compare differences between coach and athlete compliance by school level (middle and high schools) and sport (basketball, soccer, and volleyball).  The protocols were completed at a mean rate of 1.3 ± 1.1 times per week during the preseason and 1.2 ± 0.5 times per week in-season. A total of 88.4% of athletes completed 2/3 of the intervention sessions

  5. Compliance with infection prevention and control in oral health-care facilities: a global perspective.

    Science.gov (United States)

    Oosthuysen, Jeanné; Potgieter, Elsa; Fossey, Annabel

    2014-12-01

    Many publications are available on the topic of compliance with infection prevention and control in oral health-care facilities all over the world. The approaches of developing and developed countries show wide variation, but the principles of infection prevention and control are the same globally. This study is a systematic review and global perspective of the available literature on infection prevention and control in oral health-care facilities. Nine focus areas on compliance with infection-control measures were investigated: knowledge of infectious occupational hazards; personal hygiene and care of hands; correct application of personal protective equipment; use of environmental barriers and disposable items; sterilisation (recirculation) of instruments and handpieces; disinfection (surfaces) and housekeeping; management of waste disposal; quality control of dental unit waterlines, biofilms and water; and some special considerations. Various international studies from developed countries have reported highly scientific evidence-based information. In developed countries, the resources for infection prevention and control are freely available, which is not the case in developing countries. The studies in developing countries also indicate serious shortcomings with regard to infection prevention and control knowledge and education in oral health-care facilities. This review highlights the fact that availability of resources will always be a challenge, but more so in developing countries. This presents unique challenges and the opportunity for innovative thinking to promote infection prevention and control. © 2014 FDI World Dental Federation.

  6. Improving Patient Compliance With Post-EVAR Surveillance May Prevent Late Rupture.

    Science.gov (United States)

    Skervin, Alicia L; Lim, Chung S; Sritharan, Kaji

    2017-10-01

    Endovascular aneurysm repair (EVAR) has gained increasing popularity in the treatment of infrarenal abdominal aortic aneurysm. Despite its favorable early outcomes, the long-term efficacy of EVAR remains a concern. Late rupture is the ultimate treatment failure and continues to complicate EVAR. Univariate and multivariate analyses have identified factors predictive of late rupture. The importance of EVAR surveillance to prevent late complications is equally widely acknowledged. This article aims to present our current understanding of the precipitating factors of late rupture after EVAR and explores whether the key to its prevention lies within improving patient factors, particularly compliance to follow-up appointments or whether physicians hold the solution.

  7. Environmental implementation plan: Chapter 5, Chemical management, pollution prevention and other compliance programs

    International Nuclear Information System (INIS)

    Peterson, G.L.

    1993-01-01

    Compliance with environmental regulations and US Department of Energy Orders (DOE) relating to environmental protection is an important part of SRS's program. Over the past few years, the number of environmental regulations has increased. The strategy to comply with new and existing environmental regulations and DOE orders is described in chapter two. In this chapter, the following environmental programs are described: Toxic Substances Control Act (TSCA); Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA); Emergency Planning and Community Right-to-Know Act (EPCRA); and SPCC/BMP/Pollution Prevention Plans;The implementation section identifies issues and those responsible to achieve defined objectives

  8. Aspirin for Evidence-Based Preeclampsia Prevention trial: influence of compliance on beneficial effect of aspirin in prevention of preterm preeclampsia.

    Science.gov (United States)

    Wright, David; Poon, Liona C; Rolnik, Daniel L; Syngelaki, Argyro; Delgado, Juan Luis; Vojtassakova, Denisa; de Alvarado, Mercedes; Kapeti, Evgenia; Rehal, Anoop; Pazos, Andrea; Carbone, Ilma Floriana; Dutemeyer, Vivien; Plasencia, Walter; Papantoniou, Nikos; Nicolaides, Kypros H

    2017-12-01

    The Aspirin for Evidence-Based Preeclampsia Prevention trial was a multicenter study in women with singleton pregnancies. Screening was carried out at 11-13 weeks' gestation with an algorithm that combines maternal factors and biomarkers (mean arterial pressure, uterine artery pulsatility index, and maternal serum pregnancy-associated plasma protein A and placental growth factor). Those with an estimated risk for preterm preeclampsia of >1 in 100 were invited to participate in a double-blind trial of aspirin (150 mg/d) vs placebo from 11-14 until 36 weeks' gestation. Preterm preeclampsia with delivery at aspirin group, as compared with 4.3% (35/822) in the placebo group (odds ratio in the aspirin group, 0.38; 95% confidence interval, 0.20 to 0.74). We sought to examine the influence of compliance on the beneficial effect of aspirin in prevention of preterm preeclampsia in the Aspirin for Evidence-Based Preeclampsia Prevention trial. This was a secondary analysis of data from the trial. The proportion of prescribed tablets taken was used as an overall measure of compliance. Logistic regression analysis was used to estimate the effect of aspirin on the incidence of preterm preeclampsia according to compliance of aspirin group with compliance ≥90%, in 8/243 (3.3%) of participants in the aspirin group with compliance aspirin group for preterm preeclampsia was 0.24 (95% confidence interval, 0.09-0.65) for compliance ≥90% and 0.59 (95% confidence interval, 0.23-1.53) for compliance aspirin in the prevention of preterm preeclampsia appears to depend on compliance. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. P2X receptors

    OpenAIRE

    North, R. Alan

    2016-01-01

    Extracellular adenosine 5′-triphosphate (ATP) activates cell surface P2X and P2Y receptors. P2X receptors are membrane ion channels preferably permeable to sodium, potassium and calcium that open within milliseconds of the binding of ATP. In molecular architecture, they form a unique structural family. The receptor is a trimer, the binding of ATP between subunits causes them to flex together within the ectodomain and separate in the membrane-spanning region so as to open a central channel. P2...

  10. P2X7R Blockade Prevents NLRP3 Inflammasome Activation and Pancreatic Fibrosis in a Mouse Model of Chronic Pancreatitis.

    Science.gov (United States)

    Zhang, Gui-Xian; Wang, Man-Xue; Nie, Wei; Liu, Da-Wei; Zhang, Yi; Liu, Hong-Bin

    The aim of this study was to investigate the role of P2X7R (purinergic 2X7 receptor) and NLRP3 (NACHT, LRR, and PYD domains-containing protein 3) inflammasome activation in the process of pancreatic fibrosis in a mouse model of chronic pancreatitis (CP). Chronic pancreatitis was induced by repeated intraperitoneal injections of 50 μg/kg cerulein for 6 weeks in mice. P2X7R antagonist oxidized ATP (OxATP) or brilliant blue G (BBG) was administered after the last cerulein injection for 2 weeks. Pancreatic chronic inflammation and fibrosis were evaluated by histological score, Sirius red staining, and alpha-smooth muscle actin immunohistochemical staining. We further determined pancreatic P2X7R, NLRP3, and caspase-1 expressions in gene and protein levels and the pancreatic concentrations of caspase-1, interleukin 1β (IL-1β), and IL-18. The pancreatic P2X7R, NLRP3, and caspase-1 expressions in gene and protein levels and the pancreatic concentrations of caspase-1, IL-1β, and IL-18 were all reduced significantly in both the OxATP and BBG groups (P P2X7R antagonist OxATP and BBG significantly decreased pancreatic chronic inflammation and fibrosis in a mouse CP model and suggested that blockade of P2X7R-NLRP3 inflammasome signaling pathway may represent a novel therapeutic strategy for CP and its fibrotic process.

  11. P2X receptors.

    Science.gov (United States)

    North, R Alan

    2016-08-05

    Extracellular adenosine 5'-triphosphate (ATP) activates cell surface P2X and P2Y receptors. P2X receptors are membrane ion channels preferably permeable to sodium, potassium and calcium that open within milliseconds of the binding of ATP. In molecular architecture, they form a unique structural family. The receptor is a trimer, the binding of ATP between subunits causes them to flex together within the ectodomain and separate in the membrane-spanning region so as to open a central channel. P2X receptors have a widespread tissue distribution. On some smooth muscle cells, P2X receptors mediate the fast excitatory junction potential that leads to depolarization and contraction. In the central nervous system, activation of P2X receptors allows calcium to enter neurons and this can evoke slower neuromodulatory responses such as the trafficking of receptors for the neurotransmitter glutamate. In primary afferent nerves, P2X receptors are critical for the initiation of action potentials when they respond to ATP released from sensory cells such as taste buds, chemoreceptors or urothelium. In immune cells, activation of P2X receptors triggers the release of pro-inflammatory cytokines such as interleukin 1β. The development of selective blockers of different P2X receptors has led to clinical trials of their effectiveness in the management of cough, pain, inflammation and certain neurodegenerative diseases.This article is part of the themed issue 'Evolution brings Ca(2+) and ATP together to control life and death'. © 2016 The Author(s).

  12. P2X7R blockade prevents NLRP3 inflammasome activation and brain injury in a rat model of intracerebral hemorrhage: involvement of peroxynitrite.

    Science.gov (United States)

    Feng, Liang; Chen, Yizhao; Ding, Rui; Fu, Zhenghao; Yang, Shuo; Deng, Xinqing; Zeng, Jun

    2015-10-17

    The NLR family, pyrin domain-containing 3 (NLRP3) inflammasome plays a key role in intracerebral hemorrhage (ICH)-induced inflammatory injury, and the purinergic 2X7 receptor (P2X7R) is upstream of NLRP3 activation. This study aimed to investigate how P2X7R functions in ICH-induced inflammatory injury and how the receptor interacts with the NLRP3 inflammasome. Rats were treated with P2X7R small interfering RNA (siRNA) 24 h before undergoing collagenase-induced ICH. A selective P2X7R inhibitor (blue brilliant G, BBG) or a peroxynitrite (ONOO(-)) decomposition catalyst (5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrinato iron(III) [FeTPPS]) was injected 30 min after ICH. Brain water content, hemorrhagic lesion volume, and neurological deficits were evaluated, and western blot, immunofluorescence, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) were carried out. Striatal P2X7R and NLRP3 inflammasomes were activated after ICH. Gene silencing of P2X7R suppressed NLRP3 inflammasome activation and interleukin (IL)-1β/IL-18 release and significantly ameliorated brain edema and neurological deficits. Additionally, enhanced NADPH oxidase 2 (NOX2, gp91(phox)) and inducible nitric oxide synthase (iNOS), as well as their cytotoxic product (ONOO(-)) were markedly attenuated by BBG treatment following ICH. This was accompanied by downregulations of the inflammasome components, IL-1β/IL-18 and myeloperoxidase (MPO, a neutrophil marker). Most importantly, inflammasome activation and IL-1β/IL-18 release were significantly inhibited by ONOO(-) decomposition with FeTPPS. Our findings implicate that P2X7R exacerbated inflammatory progression and brain damage in ICH rats possibly via NLRP3 inflammasome-dependent IL-1β/IL-18 release and neutrophil infiltration. ONOO(-), a potential downstream signaling molecule of P2X7R, may play a critical role in triggering NLRP3 inflammasome activation.

  13. EVALUATING POLLUTION PREVENTION PROGRESS (P2P) III: AN ENVIRONMENTAL TOOL FOR SCREENING IN PRODUCT LIFE CYCLE ASSESSMENT AND CHEMICAL PROCESS DESIGN

    Science.gov (United States)

    P2P is a computer-based tool that supports the comparison of process and product alternatives in terms of environmental impacts. This tool provides screening-level information for use in process design and in product LCA. Twenty one impact categories and data for approximately ...

  14. [Compliance with recommendations in secondary prevention of stroke in primary care].

    Science.gov (United States)

    Tamayo-Ojeda, Carmen; Parellada-Esquius, Neus; Salvador-González, Betlem; Oriol-Torón, Pilar Ángeles; Rodríguez-Garrido, M Dolores; Muñoz-Segura, Dolores

    Knowing compliance with secondary prevention recommendations of stroke in primary care and to identify factors associated with compliance. Multi-centre cross-sectional. Health primary care centres in a metropolitan area (944,280 inhabitants). Patients aged 18years and over with ischemic brain disease diagnosis prior to 6months before the study. Clinical history records of demographic variables, risk factors and cardiovascular comorbidity, drugs, blood pressure values (BP), LDL-cholesterol and medical visits by doctor and nurses after the event. Good adherence was considered when BP <140/90 mmHg, LDL-cholesterol <100 mg/dL, smoking abstention and preventive drugs prescription (anti-platelet/anticoagulants, statins and angiotensin-converting-enzyme inhibitors/angiotensin-receptor-antagonists or diuretics) during the last 18months. A total of 21,976 patients, mean age 73.12 years (SD: 12.13), 48% women, 72.7% with stroke. Co-morbidity: hypertension 70.8%, dyslipidemia 55.1%, DM 30.9%, atrial fibrillation 14.1%, ischemic heart disease 13.5%, chronic renal failure 12.5%, heart failure 8.8%, peripheral arterial disease 6.2%, dementia 7.8%. No record was found for smoking in 3.7%, for BP in 3.5% and for LDL in 6.5%. Optimal control: abstention smoking in 3.7%, BP <140/90 in 65.7% and LDL <100 mg/dL in 41.0%. 86.2% anti-platelet/anticoagulants, 61.3% statins and 61.8% angiotensin-converting-enzyme inhibitors, angiotensin-receptor-antagonists or diuretic. Registration and risk factors control was higher in 66-79years aged and lower in 18-40years aged. The implementation of clinical guidelines recommendations for stroke prevention in primary care must be improved, especially among younger population. Organizational changes and more active involvement by professionals and strategies against therapeutic inertia must be taken. Copyright © 2016 Elsevier España, S.L.U. All rights reserved.

  15. Compliance of an elderly hip fracture population with secondary preventative measures. Efficacy of a simple clinical practice intervention.

    LENUS (Irish Health Repository)

    Street, John

    2012-02-03

    Secondary pharmaceutical measures are effective in all age groups for the prevention of osteoporotic fractures. This prospective study determines the demographics of 566 consecutive osteoporotic hip fractures presenting to a Level 1 Trauma Center. We examine the efficacy of simple treatment recommendations for pharmaceutical treatment of osteoporosis and the factors determining general practitioner and patient compliance with these recommendations in a community setting. One out of four patients (24.5%) had sustained a previous fragility fracture. Mean age was 80 years. Twenty five percent were resident in a nursing home and only 10% were taking anti-resorptive therapy preoperatively. In hospital mortality was 6%, and 39% of recruited patients were dead at 12 months. By this time more than half the survivors were resident in a nursing home. The compliance with anti-resorptive therapy had increased to over 70% consequent to our simple recommendations. Significant differences in GP and patient compliance were observed between nursing home and own residence dwellers. This study demonstrates the efficacy of a simple clinical practice intervention in increasing patient and GP compliance with secondary fracture prevention measures. We also discuss many of the confounding issues determining this compliance.

  16. Saperi P2P

    Directory of Open Access Journals (Sweden)

    Salvatore Iaconesi

    2009-10-01

    Full Text Available Il paper presenta l'architettura filosofica e logica di un progetto ongoing per la creazione di un'infrastruttura peer to peer per la diffusione dei saperi. Tale infrastruttura p2p vuole essere la base per costruire un framework aperto e orizzontale, che ospiti pratiche innovative di creazione, condivisione e disseminazione di informazioni e conoscenza.

  17. Study of compliance with a new, targeted antenatal D immunization prevention programme in Denmark

    DEFF Research Database (Denmark)

    Damkjaer, M B; Perslev, A; Clausen, F B

    2012-01-01

    A targeted routine antenatal anti-D prophylaxis programme was implemented in Denmark where anti-D immunoglobulin is given based on the result from noninvasive antenatal screening for fetal RHD. Our objective was to evaluate compliance with this new programme right after its initiation. Materials and...

  18. Compliance With Protocols for Prevention of Neonatal Group B Streptococcal Sepsis: Practicalities and Limitations

    Directory of Open Access Journals (Sweden)

    Gwendolyn L. Gilbert

    2003-01-01

    Full Text Available Objective: To compare two protocols for intrapartum antibiotic prophylaxis (IAP against neonatal group B streptococcal (GBS sepsis, with respect to staff compliance, in a prospective cohort study in the obstetric units of a community hospital (A and a university teaching hospital (B.

  19. Corruption and compliance: preventive legislations and policies in international business projects

    Directory of Open Access Journals (Sweden)

    Harsh PATHAK

    2013-12-01

    Full Text Available This article seeks to provide an insight on the international phenomenon of corruption, dealing with its existence, and whether compliance is higher with Anti-Corruption laws or with corruption itself, resulting in anti-corruption laws being much less effective than the legislators intended it to be and the reasons for increasing demand worldwide for new governance standards and higher compliance controls and other effective anti-corruption laws and policies in light of rapid increase in corruption every year. This article further deals with the diagnosis and measures to deal with the cause of corruption – the short-comings in anti-corruption law – the reasons why corporations are willing to face continuing legal risks and adverse publicity but still indulge in corrupt practices and the extent of negative impact the prevailing levels of corruption ultimately have on international business and trade. Strict compliance controls are being introduced with increasing enforcement of anti-corruption laws internationally and nations have also started to focus on individual and corporate liability in cases of violation of anti-corruption laws, for both government and private organisations. In this context of far-reaching developments, whether European and South-east Asian Countries like India and International Business Organisations can act in ignorance or buck up and accept this trend, slowly and steadily moving towards a less corrupt nation and International business projects – if not towards a totally corruption free one, keeping in mind the growth of international trade and Commerce and its sustainability.

  20. Transcriptional targeting of sphingosine-1- phosphate receptor S1P2 by epigallocatechin- 3-gallate prevents sphingosine-1-phosphate- mediated signaling in macrophage-differentiated HL-60 promyelomonocytic leukemia cells

    Directory of Open Access Journals (Sweden)

    Chokor R

    2014-05-01

    Full Text Available Rima Chokor, Sylvie Lamy, Borhane AnnabiLaboratoire d'Oncologie Moléculaire, Centre de recherche BIOMED, Département de Chimie, Université du Québec à Montréal, Montreal, QC, CanadaBackground: Macrophage chemotaxis followed by blood–brain barrier transendothelial migration is believed to be associated with inflammation in the central nervous system. Antineuroinflammatory strategies have identified the dietary-derived epigallocatechin-3-gallate (EGCG as an efficient agent to prevent neuroinflammation-associated neurodegenerative diseases by targeting proinflammatory mediator signaling.Methods: Given that high levels of sphingosine kinase and its product, sphingosine-1-phosphate (S1P, are present in brain tumors, we used quantitative reverse-transcription polymerase chain reaction (qRT-PCR and immunoblotting to test whether EGCG may impact on S1P receptor gene expression and prevent S1P response in undifferentiated and in terminally differentiated macrophages.Results: Promyelomonocytic human leukemia (HL-60 cells were differentiated into macrophages, and S1P triggered phosphorylation in extracellular signal-regulated kinase (ERK, c-Jun N-terminal kinase (JNK, and P38 mitogen-activated protein kinase (MAPK intracellular signaling, as shown by Western blot analysis. Pretreatment of cells with EGCG prior to differentiation inhibited the response to S1P in all three pathways, while EGCG abrogated P38 MAPK phosphorylation when present only during differentiation. Terminally-differentiated macrophages were, however, insensitive to EGCG treatment. Using qRT-PCR, gene expression of the S1P receptors S1P1, S1P2, and S1P5 was predominantly induced in terminally-differentiated macrophages, while the S1P2 was decreased by EGCG treatment.Conclusion: Our data suggest that diet-derived EGCG achieves efficient effects as a preventive agent, targeting signaling pathways prior to cell terminal differentiation. Such properties could impact on cell chemotaxis

  1. [An alarming threat to secondary prevention: low compliance (lifestyle) and poor adherence (drugs)].

    Science.gov (United States)

    Fuster, Valentín

    2012-07-01

    The deteriorating health of the general population and the increasing prevalence of chronic disease combine to present a problem of global proportions whose causes are both multifactorial and complex. The consumer society we live in does not encourage healthy living, and the consequences are even most devastating when social inequalities, the economic situation and the population explosion in recent decades are taken into account. The growth of poor eating habits, obesity, and hypertension are relentlessly contributing to the development of an epidemic of cardiovascular disease. In this context, the ability of national and international bodies and regulatory agencies to have an effect on commercial interests is very limited and alternative ways of reducing the disease burden are needed. Recent studies on patient compliance with lifestyle changes and on adherence to prescribed medication have produced alarming findings. Over 50% of patients, on average, choose to abandon the treatment they have been prescribed, and the percentage that achieve the targets proposed for improving habitual behaviors (e.g. quitting smoking, losing weight or increasing physical activity) is similar or lower. It is essential that solutions to these problems are found because, in addition to their implications for the health of the individual, poor compliance and adherence threaten to undermine the relevance of clinical study findings and are associated with substantial economic costs, given that they result in the failure to achieve therapeutic goals and increase rates of hospitalization and death. Improved communication between doctors and patients, the active participation of other health professionals and the development of combination drug formulations (e.g. the polypill) appear to be the most promising strategies for improving patient adherence to treatment and reducing the economic burden. Copyright © 2012. Published by Elsevier Espana.

  2. Pollution prevention program implementation plan

    International Nuclear Information System (INIS)

    Engel, J.A.

    1996-09-01

    The Pollution Prevention Program Implementation Plan (the Plan) describes the Pacific Northwest National Laboratory's (PNNL) Pollution Prevention (P2) Program. The Plan also shows how the P2 Program at PNNL will be in support of and in compliance with the Hanford Site Waste Minimization and Pollution Prevention (WMin/P2) Awareness Program Plan and the Hanford Site Guide for Preparing and Maintaining Generator Group Pollution Prevention Program Documentation. In addition, this plan describes how PNNL will demonstrate compliance with various legal and policy requirements for P2. This plan documents the strategy for implementing the PNNL P2 Program. The scope of the P2 Program includes implementing and helping to implement P2 activities at PNNL. These activities will be implemented according to the Environmental Protection Agency's (EPA) hierarchy of source reduction, recycling, treatment, and disposal. The PNNL P2 Program covers all wastes generated at the Laboratory. These include hazardous waste, low-level radioactive waste, radioactive mixed waste, radioactive liquid waste system waste, polychlorinated biphenyl waste, transuranic waste, and sanitary waste generated by activities at PNNL. Materials, resource, and energy conservation are also within the scope of the PNNL P2 Program

  3. Nurses’ compliance with prevention of mother-to-child transmission national guidelines in selected sites in Kinshasa, Democratic Republic of Congo

    Directory of Open Access Journals (Sweden)

    Augustin R.M. Amboko

    2015-02-01

    Full Text Available Background: The Democratic Republic of Congo (DRC implemented a prevention of mother-to-child transmission (PMTCT of HIV infection programme in maternal, newborn and child health (MNCH services in 2001 with nurses as key personnel. To date there is no informationin the DRC and specifically in Kinshasa with respect to compliance with PMTCT national guidelines.Aim: The study aimed at describing nurses’ compliance with the PMTCT national guidelines in selected PMTCT sites of Kinshasa.Methods: A descriptive cross-sectional study was conducted in Kinshasa with 76 nurses in 18 selected PMTCT sites. The nurses’ compliance with PMTCT national guidelines was assessed using a healthcare provider self-reporting questionnaire developed by the researchers.Results: The study showed that the mean score of nurses’ compliance with PMTCT nationalg uidelines was 74% (95% CI: 69% – 78% which progressively decreased and was significantly different across different MNCH services (p = 0.025. With respect to categories of PMTCT recommendations, nurses were compliant with those related to education in labour and delivery, and antenatal services. Sociodemographic characteristics such as training, length of service and category of nurses did not influence nurses’ compliance score.Conclusion: These findings showed that nurses were noncompliant with PMTCT national guidelines, with the score level being 80% or more in the three MNCH services/units. Improvement of nurses’ ‘compliance with the PMTCT national guidelines requires effective monitoring of full integration of PMTCT as routine activities in MNCH care.

  4. Oil spill prevention: Regulatory trends and compliance at existing storage terminals and refineries

    International Nuclear Information System (INIS)

    Janisz, A.J.

    1993-01-01

    In 1973, the Spill Prevention, Control, and Countermeasure (SPCC) regulations were promulgated. The objective of the regulations was to prevent oil spills. However, in the late 1980s and early 1990s, several catastrophic spills of oils led to review of oil spill prevention regulations by the U.S. Environmental Protection Agency, the US Coast Guard, and the Department of the Interior's Minerals Management Service. The reviews led to promulgation of various acts and regulations including the proposed revisions to the SPCC regulations, the Oil Pollution Act of 1990 (OPA-90), and others. Numerous facilities within the petroleum and chemical industry were or will be affected by these regulations. This paper discusses regulatory trends for spill planning and prevention in general, but principally concentrates on above ground storage tanks at facilities storing or refining petroleum products. The paper includes discussions of bills on above ground storage tanks and proposed national standards, as well as regulatory trends in various states. Proposed SPCC regulations and their effects on the industry are also discussed, including requirements for impermeable surfaces and increasing secondary containment capacity. Management strategies to review facility operations and prepare for upgrades are outlined. The paper discusses the types of upgrades typically necessary at existing storage terminals and refineries and discusses information necessary to prepare conceptual designs and cost estimates. Cost estimates for typical upgrades, such as raising earthen berms and installing isolation valves, are presented. Facilities in the state of New Jersey are used as examples, because regulations in New Jersey are similar to the proposed federal regulations

  5. Achieving multiple compliance objectives through a storm water pollution prevention plan

    Energy Technology Data Exchange (ETDEWEB)

    Wagner, K.J.; Cataldo, R. [ENSR, Acton, MA (United States)

    1997-09-01

    All across the US, facility managers and environmental staff are trying to keep up with proliferating regulations and associated filing and reporting requirements. Added to the already full plate of regulations is the National Pollutant Discharge Elimination System (NPDES) program for storm water management. The NPDES program requires a permit for the discharge of runoff from facilities based on Standard Industrial Classification (SIC) code. Some businesses do not yet need to comply with NPDES, as not all types of facilities were included in the Phase 1 list of regulated activities (September 1992). However, most businesses will be included as part of Phase 2 by 2002. Furthermore, states adopting administration of the NPDES program have the option of accelerating the process. In addition to filing for a permit, the NPDES storm water program requires the preparation and implementation of a Storm Water Pollution Prevention Plan (SWPPP). A properly prepared SWPPP can help facilities more easily comply with regulatory requirements and serve as an overall facility management tool.

  6. Semisymmetric cubic graphs of order 16p2 16p2 16p2

    Indian Academy of Sciences (India)

    Abstract. An undirected graph without isolated vertices is said to be semisymmetric if its full automorphism group acts transitively on its edge set but not on its vertex set. In this paper, we inquire the existence of connected semisymmetric cubic graphs of order. 16p2. It is shown that for every odd prime p, there exists a ...

  7. Worker education level is a factor in self-compliance with dust-preventive methods among small-scale agate industrial workers.

    Science.gov (United States)

    Aggarwal, Bhagwan D

    2013-01-01

    High incidences of silicosis are continuing to be reported among the agate workers of small-scale household agate processing units in the Khambhat region of Gujarat (India). The objective of this study was to investigate reasons behind the high prevalence of silicosis, and factors affecting the noncompliance with preventive methods among agate workers. The study was conducted using a questionnaire-based structured interview method among 82 agate workers in Khambhat to assess their awareness level about silicosis and preventive methods, existing morbidity, worker's attitude toward health, and the prevalence of actual use of preventive methods to avoid silica exposure. The majority of the workers (55%) were aware of silicosis and the harmful effects of silica dust exposure (72%) and knew about simple preventive methods to avoid silica dust exposure (80%), but only a minority of the workers (22%) were actually using the simple and available dust-preventive methods. Only 9% of the uneducated workers were using the preventive methods, while usage was higher among educated workers (28%), who had five or more years of schooling, and these workers had fewer health conditions or less morbidity. Gender and job duration had no effect on the usage of dust-preventive methods. The data suggest that noncompliance with use of dust-preventive methods could be the reason behind the higher prevalence of silicosis and health morbidity in agate workers, and that years of schooling plays a significant role in the increased usage and self-compliance with dust-preventive methods among agate workers.

  8. Single administration of p2TA (AB103, a CD28 antagonist peptide, prevents inflammatory and thrombotic reactions and protects against gastrointestinal injury in total-body irradiated mice.

    Directory of Open Access Journals (Sweden)

    Salida Mirzoeva

    Full Text Available The goal of this study was to elucidate the action of the CD28 mimetic peptide p2TA (AB103 that attenuates an excessive inflammatory response in mitigating radiation-induced inflammatory injuries. BALB/c and A/J mice were divided into four groups: Control (C, Peptide (P; 5 mg/kg of p2TA peptide, Radiation (R; total body irradiation with 8 Gy γ-rays, and Radiation + Peptide (RP; irradiation followed by p2TA peptide 24 h later. Gastrointestinal tissue damage was evaluated by analysis of jejunum histopathology and immunohistochemistry for cell proliferation (Cyclin D1 and inflammation (COX-2 markers, as well as the presence of macrophages (F4/80. Pro-inflammatory cytokines IL-6 and KC as well as fibrinogen were quantified in plasma samples obtained from the same mice. Our results demonstrated that administration of p2TA peptide significantly reduced the irradiation-induced increase of IL-6 and fibrinogen in plasma 7 days after exposure. Seven days after total body irradiation with 8 Gy of gamma rays numbers of intestinal crypt cells were reduced and villi were shorter in irradiated animals compared to the controls. The p2TA peptide delivery 24 h after irradiation led to improved morphology of villi and crypts, increased Cyclin D1 expression, decreased COX-2 staining and decreased numbers of macrophages in small intestine of irradiated mice. Our study suggests that attenuation of CD28 signaling is a promising therapeutic approach for mitigation of radiation-induced tissue injury.

  9. Tool for evaluation compliance standards and expectations in occupational risk prevention by collaborating companies; Herramienta para evaluacion cumplimiento normas y expectativas en prevencion de riesgos laborales por pare de empresas colaboradoras

    Energy Technology Data Exchange (ETDEWEB)

    Duran Perez, A.; Gomez Pardo, M. A.; Cao Tejero, R.; Millan Verdejo, J. A.; Blas Perez, P.

    2013-07-01

    Within the framework of a single security in ANAV, in our Action Plan on prevention, we consider it essential to include workers from ECCE working for and by ANAV in compliance with standards and expectations both in the accounts of the incidents. With this system is intended to standardize a set of observed deviations report and a tool for measuring the degree of compliance, allowing to monitor the evolution of each company and the effectiveness of prevention plan.

  10. Transforming environmental permitting and compliance policies to promote pollution prevention: Removing barriers and providing incentives to foster technology innovation, economic productivity, and environmental protection. Final report

    International Nuclear Information System (INIS)

    Berg, D.R.; Kerr, R.L.; Fleischer, S.; Gorsen, M.; Harris, E.

    1993-04-01

    The Technology Innovation and Economics (TIE) Committee, a standing committee of EPA's National Advisory Council for Environmental Policy and Technology (NACEPT), has concluded that major changes are needed in federal and state permitting and compliance programs to encourage adoption of practical pollution prevention approaches to environmental protection. The Committee recommends seven major areas for improvement, including: (1) Redesigning permit procedures to encourage regulated facilities to expand multi-media and pollution prevention environmental improvement efforts; (2) Accelerating development and use of innovative pollution prevention technologies and techniques through special permitting and review procedures during RD ampersand D and commercialization phases; (3) Developing and expanding federal and state pollution prevention enforcement initiative; (4) Supporting state initiatives in pollution prevention facility planning; (5) Expanding pollution prevention-related training, educational and technology diffusion efforts to better reach managers in all sectors of the economy; (6) Altering personnel reward systems to encourage EPA staff to champion pollution prevention; (7) Expanding and publicizing the system of national awards honoring outstanding pollution prevention research, training and technology implementation

  11. Taxonomy of P2P Applications

    NARCIS (Netherlands)

    Brands, E.H.T.B.; Karagiannis, Georgios

    2009-01-01

    Peer-to-peer (p2p) networks have gained immense popularity in recent years and the number of services they provide continuously rises. Where p2p-networks were formerly known as file-sharing networks, p2p is now also used for services like VoIP and IPTV. With so many different p2p applications and

  12. Randomized Trial of Pentoxifylline and Vitamin E vs Standard Follow-up After Breast Irradiation to Prevent Breast Fibrosis, Evaluated by Tissue Compliance Meter

    Energy Technology Data Exchange (ETDEWEB)

    Jacobson, Geraldine, E-mail: geraldine-jacobson@uiowa.edu [Department of Radiation Oncology, University of Iowa Hospitals and Clinics, Iowa City, Iowa (United States); Bhatia, Sudershan [Department of Radiation Oncology, University of Iowa Hospitals and Clinics, Iowa City, Iowa (United States); Smith, Brian J.; Button, Anna M. [Biostatistics Core, Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, Iowa City, Iowa (United States); Bodeker, Kellie; Buatti, John [Department of Radiation Oncology, University of Iowa Hospitals and Clinics, Iowa City, Iowa (United States)

    2013-03-01

    Purpose: To conduct a randomized clinical trial to determine whether the combination of pentoxifylline (PTX) and vitamin E given for 6 months after breast/chest wall irradiation effectively prevents radiation-induced fibrosis (RIF). Methods and Materials: Fifty-three breast cancer patients with localized disease were enrolled and randomized to treatment with oral PTX 400 mg 3 times daily and oral vitamin E 400 IU daily for 6 months after radiation (n=26), or standard follow up (n=27). Tissue compliance meter (TCM) measurements were obtained at 18 months to compare tissue compliance in the irradiated and untreated breast/chest wall in treated subjects and controls. Measurements were obtained at 2 mirror image sites on each breast/chest wall, and the average difference in tissue compliance was scored. Differences in TCM measurements were compared using a t test. Subjects were followed a minimum of 2 years for local recurrence, disease-free survival, and overall survival. Results: The mean difference in TCM measurements in the 2 groups was 0.88 mm, median of 1.00 mm (treated) and 2.10 mm, median of 2.4 mm (untreated). The difference between the 2 groups was significant (P=.0478). Overall survival (100% treated, 90.6% controls at 5 years) and disease-free survival (96.2% treated, 86.8% controls at 5 years) were not significantly different in the 2 groups. Conclusions: This study of postirradiation breast cancer patients treated with PTX/vitamin E or standard follow-up indicated a significant difference in radiation-induced fibrosis as measured by TCM. There was no observed impact on local control or survival within the first 2 years of follow-up. The treatment was safe and well tolerated. Pentoxifylline/vitamin E may be clinically useful in preventing fibrosis after radiation in high-risk patients.

  13. p38 MAPK Mediates Glial P2X7R-Neuronal P2Y1R Inhibitory Control of P2X3R Expression in Dorsal Root Ganglion Neurons.

    Science.gov (United States)

    Chen, Yong; Li, Guangwen; Huang, Li-Yen Mae

    2015-01-01

    We have previously shown that endogenously active purinergic P2X7 receptors (P2X7Rs) in satellite glial cells of dorsal root ganglia (DRGs) stimulate ATP release. The ATP activates P2Y1Rs located in the enwrapped neuronal somata, resulting in down-regulation of P2X3Rs. This P2X7R-P2Y1-P2X3R inhibitory control significantly reduces P2X3R-mediated nociceptive responses. The underlying mechanism by which the activation of P2Y1Rs inhibits the expression of P2X3Rs remains unexplored. Examining the effect of the activation of p38 mitogen-activated protein kinase on the expression of P2X3Rs in DRGs, we found that the p38 activator, anisomycin (Anis), reduced the expression of P2X3Rs. Blocking the activity of SGCs by the glial Krebs cycle inhibitor, fluorocitrate, did not change the effect of Anis. These results suggest that neuronal p38 plays a major role in the inhibition of P2X3R expression. Western blotting analyses showed that inhibiting P2Y1Rs by MRS2179 (MRS) or blocking P2X7Rs by either oxATP or A740003 reduced pp38 and increased P2X3R expression in DRGs. These results are further supported by the immunohistochemical study showing that P2X7R and P2Y1R antagonists reduce the percentage of pp38-positive neurons. These observations suggest that activation of P2X7Rs and P2Y1Rs promotes p38 activity to exert inhibitory control on P2X3R expression. Since activation of p38 by Anis in the presence of either A740003 or MRS could overcome the block of P2X7R-P2Y1R inhibitory control, p38 in DRG neurons is downstream of P2Y1Rs. In addition, inhibition of p38 by SB202190 was found to prevent the P2X7R and P2Y1R block of P2X3R expression and increase P2X3R-mediated nociceptive flinch behaviors. p38 in DRG neurons downstream of P2Y1R is necessary and sufficient for the P2X7R-P2Y1R inhibitory control of P2X3R expression. © 2015 Chen et al.

  14. Criminal Compliance

    Directory of Open Access Journals (Sweden)

    Cristina Antonella Andretta

    2015-10-01

    The article discusses the concepts of both compliance and criminal compliance, its main components and structure as well as the main rules relating to its global application, and finally his emergence in the Ecuadorian legal system.

  15. Towards P2P XML Database Technology

    NARCIS (Netherlands)

    Y. Zhang (Ying)

    2007-01-01

    textabstractTo ease the development of data-intensive P2P applications, we envision a P2P XML Database Management System (P2P XDBMS) that acts as a database middle-ware, providing a uniform database abstraction on top of a dynamic set of distributed data sources. In this PhD work, we research which

  16. Bullying Prevention in District of Columbia Educational Institutions: School Year 2013-14 Compliance Report. Publication #2014-49

    Science.gov (United States)

    Temkin, Deborah; Horton, Susannah; Kim, Audrey

    2014-01-01

    The Robert F. Kennedy Center for Justice and Human Rights' bullying prevention initiative, RFK Project SEATBELT (RFKC) was contracted by the DC Office of Human Rights (OHR), in June 2013, to provide resources and support for DC public and public charter schools' bullying prevention efforts. This contract moved to Child Trends in August 2014. From…

  17. Awareness of and compliance with healthy oral habits reported by children and their parents in Democratic People's Republic of Korea after a preventive programme.

    Science.gov (United States)

    Tarvonen, Pirkko-Liisa; Sipilä, Kirsi; Ri, Yon Sil; Jang, Jong Hyon; Kim, Jong Hyok; Suominen, Anna L

    2016-10-01

    The study aimed to examine awareness of and compliance with healthy oral habits reported by children and their parents in Pyongyang, Democratic People's Republic of Korea (DPRK), after a preventive programme. The data were collected in 2013 with self-completed, partly structured questionnaires from 1994 children aged 10 and 13 years and from 200 parents. Association between awareness of and compliance with healthy oral habits reported by the children and their parents was evaluated using Chi square tests and multivariate logistic regression analyses, children's oral health habits according to themselves and their parents were analysed using McNemar's test. Both children and their parents seemed to be familiar with healthy oral habits, although the awareness was not directly related to the reports of the children's oral practices. Most of the children reported brushing their teeth at least twice a day, using fluoride toothpaste and drinking water for thirst but frequent sweet snacking was common. Children's and their parents' reports were consistent with regard to sweet snacking frequency (p = 0.736) and the main thirst quencher (p = 0.349). Awareness of healthy oral habits appeared to be good among children and their parents. Unhealthy oral habits seemed to coincide with one another.

  18. Awareness of need and actual use of prophylaxis: lack of patient compliance in the prevention of bacterial endocarditis

    NARCIS (Netherlands)

    van der Meer, J. T.; van Wijk, W.; Thompson, J.; Valkenburg, H. A.; Michel, M. F.

    1992-01-01

    Antibiotics are given before some medical and dental procedures to patients with congenital or acquired heart disease to prevent endocarditis. The majority of practitioners and patients are aware of the need for this prophylaxis, although in practice prophylaxis is administered infrequently. It is

  19. P2X receptors in epithelia

    DEFF Research Database (Denmark)

    Leipziger, Jens Georg

    2015-01-01

    P2X receptors are ubiquitously expressed in all epithelial tissues but their functional roles are less well studied. Here we review the current state of knowledge by focusing on functional effects of P2X receptor in secretory and in absorptive tissues. In glandular tissue like the parotid gland b...

  20. The Compliance Review and Beyond.

    Science.gov (United States)

    Regan, Janet; Heneghan, John M.

    1979-01-01

    The Office of Federal Contract Compliance Programs (OFCCP) can initiate a compliance review of any company receiving a federal contract. The OFCCP equal opportunity specialist looks for discriminatory patterns of hiring, firing, promotion, and pay. Any company not complying with recommendations of the OFCCP may be prevented from obtaining future…

  1. Compliance Issues in Higher Education

    Science.gov (United States)

    Benedek, Petra

    2016-01-01

    Efficiency in the 1980's, quality in the 1990's, compliance in the 2010's - private sector management techniques and mechanisms find their way to public services. This paper facilitates the understanding of how compliance management controls can improve operations and prevent or detect failure or wrong doing. The last few years' empirical research…

  2. Performing compliance

    DEFF Research Database (Denmark)

    Wimmelmann, Camilla Lawaetz

    2017-01-01

    the local policy workers front-staged some practices in the implementation process and back-staged others. The local policy workers deliberately performed ‘guideline compliance’ by using information control and impression management techniques. The findings suggest that local guideline compliance should...... be regarded as a staged performance in which deliberate techniques are used to produce and manage certain impressions of compliance....

  3. Compliance status

    International Nuclear Information System (INIS)

    Black, D.G.

    1995-01-01

    This section of the 1994 Hanford Site Environmental Report summarizes the activities conducted to ensure that the Hanford Site is in compliance with federal environmental protection statutes and related Washington State and local environmental protection regulations and the status of Hanford's compliance with these requirements. Environmental permits required under the environmental protection regulations are discussed under the applicable statute

  4. A critical look at the function of the P2Y11 receptor

    DEFF Research Database (Denmark)

    Dreisig, Karin; Kornum, Birgitte Rahbek

    2016-01-01

    The P2Y11 receptor is a member of the purinergic receptor family. It has been overlooked, somewhat due to the lack of a P2ry11 gene orthologue in the murine genome, which prevents the generation of knockout mice, which have been so helpful for defining the roles of other P2Y receptors. Furthermor...

  5. Intermittent preventive treatment of malaria in pregnancy: the effect of new delivery approaches on access and compliance rates in Uganda

    DEFF Research Database (Denmark)

    Mbonye, Anthony K; Magnussen, Pascal; Bygbjerg, Ib Christian

    2007-01-01

    OBJECTIVE: To assess whether traditional birth attendants, drug-shop vendors, community reproductive health workers and adolescent peer mobilizers can administer intermittent preventive treatment (IPT) with sulfadoxine-pyremethamine to pregnant women, and reach those most at risk of malaria...... and the proportion of women who completed two doses of sulfadoxine-pyremethamine. RESULTS: Two thousand seven hundred and eighty-five pregnant women (78% of those in the study area) participated. With new approaches, 92.4% of the women received IPT during the second trimester as recommended by the policy, vs. 76.......1% at health units, P women who received two doses of sulfadoxine-pyremethamine, 39.9% were at health units (control) vs. 67.5% through new approaches (P Women using the new approaches also accessed IPT early: the mean gestational age when receiving the first dose of sulfadoxine...

  6. Characterization of P2P Systems

    Science.gov (United States)

    Stutzbach, Daniel; Rejaie, Reza

    The combination of large scale and geographically distributed nature of P2P system has led to their significant impact on the Internet. It is essential to characterize deployed P2P system for at least three reasons: (1) Accurately assessing their impact on the Internet, (2) identifying any performance bottleneck as well as any opportunity for performance improvement, (3) understanding user-driven dynamics in P2P systems. To characterize a P2P system, one needs to accurately capture snapshots of the resulting P2P overlay. This is challenging because the overlay is often large and dynamic. While the overlay is discovered by a crawler, it is changing which leads to a distorted view of the system. Capturing unbiased view of the traffic in the overlay is equally challenging because it is difficult to show that the captured behavior represent the observed behavior by all peers. In this chapter, we describe some of the fundamental problems in empirical characterization of widely deployed P2P systems. We present several examples to illustrate the effect of ad-hoc measurement/data collection on the resulting analysis/characterization. We then present two sampling techniques as a powerful approach to capture unbiased view of peer properties in a scalable fashion.

  7. 10 CFR 850.13 - Compliance.

    Science.gov (United States)

    2010-01-01

    ... 10 Energy 4 2010-01-01 2010-01-01 false Compliance. 850.13 Section 850.13 Energy DEPARTMENT OF ENERGY CHRONIC BERYLLIUM DISEASE PREVENTION PROGRAM Administrative Requirements § 850.13 Compliance. (a) The responsible employer must conduct activities in compliance with its CBDPP. (b) The responsible...

  8. Relationship between Risk Factor Control and Compliance with a Lifestyle Modification Program in the Stenting Aggressive Medical Management for Prevention of Recurrent Stroke in Intracranial Stenosis Trial.

    Science.gov (United States)

    Turan, Tanya N; Al Kasab, Sami; Nizam, Azhar; Lynn, Michael J; Harrell, Jamie; Derdeyn, Colin P; Fiorella, David; Janis, L Scott; Lane, Bethany F; Montgomery, Jean; Chimowitz, Marc I

    2018-03-01

    Lifestyle modification programs have improved the achievement of risk factor targets in a variety of clinical settings, including patients who have previously suffered a stroke or transient ischemic attack and those with multiple risk factors. Stenting Aggressive Medical Management for Prevention of Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) was the first vascular disease prevention trial to provide a commercially available lifestyle modification program to enhance risk factor control. We sought to determine the relationship between compliance with this program and risk factor control in SAMMPRIS. SAMMPRIS aggressive medical management included a telephonic lifestyle modification program provided free of charge to all subjects (n = 451) during their participation in the study. Subjects with fewer than 3 expected lifestyle-coaching calls were excluded from these analyses. Compliant subjects (n = 201) had  greater than or equal to 78.5% of calls (median % of completed/expected calls). Noncompliant subjects (n = 200) had less than 78.5% of calls or refused to participate. Mean risk factor values or % in-target for each risk factor was compared between compliant versus noncompliant subjects, using t tests and chi-square tests. Risk factor changes from baseline to follow-up were compared between the groups to account for baseline differences. Compliant subjects had better risk factor control throughout follow-up for low-density lipoprotein, systolic blood pressure (SBP), hemoglobin A1c (HgA1c), non-high-density lipoprotein, nonsmoking, and exercise than noncompliant subjects, but there was no difference for body mass index. After adjusting for baseline differences between the groups, compliant subjects had a greater change from baseline than noncompliant subjects for SBP did at 24 months and HgA1c at 6 months. SAMMPRIS subjects who were compliant with the lifestyle modification program had better risk factor control during the study for almost

  9. Thermoelastic properties of Zn3P2

    DEFF Research Database (Denmark)

    Gerward, Leif; Olsen, J. Staun; Waśkowska, A.

    2011-01-01

    The bulk modulus and thermal expansion of Zn3P2 has been investigated at pressures up to 21GPa and temperatures down to 100K. The experimental zero-pressure bulk modulus is 80.7 ± 1.8GPa, in accordance with the bulk modulus scaling and lattice properties of the related compound Cd3P2. A tetragonal...... to orthorhombic phase transformation occurs above 11GPa with a relative volume change of-7.1%. Values for the thermal expansion coefficient are reported at 293, 200 and 100K....

  10. P2X Receptors and Synaptic Plasticity

    Czech Academy of Sciences Publication Activity Database

    Pankratov, Y.; Lalo, U.; Krishtal, A.; Verkhratsky, Alexei

    2009-01-01

    Roč. 158, č. 1 (2009), s. 137-148 ISSN 0306-4522 Institutional research plan: CEZ:AV0Z50390512 Keywords : ATP * P2X receptors * synaptic plasticity Subject RIV: FH - Neurology Impact factor: 3.292, year: 2009

  11. P2X receptory v bolesti

    Czech Academy of Sciences Publication Activity Database

    Jindřichová, Marie; Zemková, Hana

    2014-01-01

    Roč. 63, č. 2 (2014), s. 74-77 ISSN 1210-6313 R&D Projects: GA ČR(CZ) GPP304/12/P371 Institutional support: RVO:67985823 Keywords : extracellular ATP * purinergic P2X receptors * neuropathic pain Subject RIV: ED - Physiology

  12. PPADS and suramin as antagonists at cloned P2Y- and P2U-purinoceptors.

    Science.gov (United States)

    Charlton, S J; Brown, C A; Weisman, G A; Turner, J T; Erb, L; Boarder, M R

    1996-06-01

    1. The effect of suramin and pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS) on the stimulation of phospholipase C in 1321N1 cells transfected with the human P2U-purinoceptor (h-P2U-1321N1 cells) or with the turkey P2Y-purinoceptor (t-P2Y-1321N1 cells) was investigated. 2-Methylthioadenosine triphosphate (2MeSATP) was used as the agonist at t-P2Y-1321N1 cells and uridine triphosphate (UTP) at h-P2U-1321N1 cells. 2. Suramin caused a parallel shift to the right of the concentration-response curves for 2MeSATP in the t-P2Y-1321N1 cells, yielding a Schild plot with a slope of 1.16 +/- 0.08 and a pA2 value of 5.77 +/- 0.11. 3. Suramin also caused a shift to the right of concentration-response curves for UTP in the h-P2U-1321N1 cells, and on Schild plots gave a slope different from unity (1.57 +/- 0.19) and an apparent pA2 value of 4.32 +/- 0.13. Suramin was therefore a less potent antagonist at the P2U-purinoceptor than the P2Y-purinoceptor. 4. In the presence of the ectonucleotidase inhibitor, ARL 67156 (6-N,N-diethyl-beta,gamma-dibromomethylene-D-ATP) there was no significant difference in the EC50 or shapes of curves with either cell type, and no difference in pA2 values for suramin. 5. PPADS caused an increase in the EC50 for 2MeSATP in the t-P2Y-1321N1 cells. The Schild plot had a slope different from unity (0.55 +/- 0.15) and an X-intercept corresponding to an apparent pA2 of 5.98 +/- 0.65. 6. PPADS up to 30 microM had no effect on the concentration-response curve for UTP with the h-P2U-1321N1 cells. 7. In conclusion, suramin and PPADS show clear differences in their action at the 2 receptor types, in each case being substantially more effective as an antagonist at the P2Y-purinoceptor than at the P2U-purinoceptor. Ectonucleotidase breakdown had little influence on the nature of the responses at the two receptor types, or in their differential sensitivity to suramin.

  13. Medicinal chemistry of adenosine, P2Y and P2X receptors.

    Science.gov (United States)

    Jacobson, Kenneth A; Müller, Christa E

    2016-05-01

    Pharmacological tool compounds are now available to define action at the adenosine (ARs), P2Y and P2X receptors. We present a selection of the most commonly used agents to study purines in the nervous system. Some of these compounds, including A1 and A3 AR agonists, P2Y1R and P2Y12R antagonists, and P2X3, P2X4 and P2X7 antagonists, are potentially of clinical use in treatment of disorders of the nervous system, such as chronic pain, neurodegeneration and brain injury. Agonists of the A2AAR and P2Y2R are already used clinically, P2Y12R antagonists are widely used antithrombotics and an antagonist of the A2AAR is approved in Japan for treating Parkinson's disease. The selectivity defined for some of the previously introduced compounds has been revised with updated pharmacological characterization, for example, various AR agonists and antagonists were deemed A1AR or A3AR selective based on human data, but species differences indicated a reduction in selectivity ratios in other species. Also, many of the P2R ligands still lack bioavailability due to charged groups or hydrolytic (either enzymatic or chemical) instability. X-ray crystallographic structures of AR and P2YRs have shifted the mode of ligand discovery to structure-based approaches rather than previous empirical approaches. The X-ray structures can be utilized either for in silico screening of chemically diverse libraries for the discovery of novel ligands or for enhancement of the properties of known ligands by chemical modification. Although X-ray structures of the zebrafish P2X4R have been reported, there is scant structural information about ligand recognition in these trimeric ion channels. In summary, there are definitive, selective agonists and antagonists for all of the ARs and some of the P2YRs; while the pharmacochemistry of P2XRs is still in nascent stages. The therapeutic potential of selectively modulating these receptors is continuing to gain interest in such fields as cancer, inflammation, pain

  14. Python passive network mapping P2NMAP

    CERN Document Server

    Hosmer, Chet

    2015-01-01

    Python Passive Network Mapping: P2NMAP is the first book to reveal a revolutionary and open source method for exposing nefarious network activity. The ""Heartbleed"" vulnerability has revealed significant weaknesses within enterprise environments related to the lack of a definitive mapping of network assets. In Python Passive Network Mapping, Chet Hosmer shows you how to effectively and definitively passively map networks. Active or probing methods to network mapping have traditionally been used, but they have many drawbacks - they can disrupt operations, crash systems, and - most important

  15. Retailer opinions about and compliance with family smoking prevention and tobacco control act point of sale provisions: a survey of tobacco retailers.

    Science.gov (United States)

    Rose, Shyanika W; Emery, Sherry L; Ennett, Susan; Reyes, Heathe Luz McNaughton; Scott, John C; Ribisl, Kurt M

    2015-09-11

    The objectives of this study were to document retailer opinions about tobacco control policy at the point of sale (POS) and link these opinions with store level compliance with sales and marketing provisions of the Tobacco Control Act. This study conducted interviews of 252 tobacco retailers in three counties in North Carolina and linked their opinions with in-person observational audit data of their stores' compliance with POS policies. We conducted analyses examining retailer factors associated with noncompliance using Generalized Estimating Equations (GEE) controlling for individual, store, neighborhood, and county factors. Over 90 % of retailers support minors' access provisions and a large minority (over 40 %) support graphic warnings and promotion bans. Low levels of support were found for a potential ban on menthol cigarettes (17 %). Store noncompliance with tobacco control policies was associated with both more reported retailer barriers to compliance and less support for POS policies. Awareness of and source of information about tobacco control regulations were not associated with compliance when accounting for neighborhood and county characteristics. Retailers expressed some support for a wide range of POS policies. Advocates and government agencies tasked with enforcement can work with retailers as stakeholders to enhance support, mitigate barriers, and promote compliance with tobacco control efforts at the point of sale.

  16. The P2X7 Receptor Supports Both Life and Death in Fibrogenic Pancreatic Stellate Cells

    DEFF Research Database (Denmark)

    Haanes, Kristian; Schwab, Albrecht; Novak, Ivana

    2012-01-01

    inhibitor az10606120. The P2X7 receptor-pore inhibitor A438079 partially prevented cell death induced by millimolar ATP concentrations. This study shows that ATP and P2X7 receptors are important regulators of PSC proliferation and death, and therefore might be potential targets for treatments of pancreatic...

  17. TRI P2 and Automotive Suppliers: Supplier information specific to the automotive industry sector

    Science.gov (United States)

    TRI’s Pollution Prevention (P2) Search Tool is one source of information to identify how facilities work with their suppliers and how suppliers work with their customers to achieve environmental improvement.

  18. Prevention

    Science.gov (United States)

    ... Error processing SSI file About Heart Disease & Stroke Prevention Heart disease and stroke are an epidemic in ... secondhand smoke. Barriers to Effective Heart Disease & Stroke Prevention Many people with key risk factors for heart ...

  19. Compliance among soft contact lens wearers.

    OpenAIRE

    Kuzman, Tomislav; Barišić Kutija, Marija; Masnec, Sanja; Jandroković, Sonja; Mrazovac, Danijela; Jurišić, Darija; Škegro, Ivan; Kalauz, Miro; Kordić, Rajko

    2014-01-01

    Contact lens compliance is proven to be crucial for preventing lens wear-related complications because of the interdependence of the steps in lens care regime and their influence on lens system microbial contamination. Awareness of the patients' lens handling compliance as well as correct recognition of non-compliant behaviours is the basis for creating more targeted strategies for patient education. The aim of this study was to investigate compliance among soft contact lens (SCL) wearers in ...

  20. Localized Multistreams for P2P Streaming

    Directory of Open Access Journals (Sweden)

    Majed Alhaisoni

    2010-01-01

    Full Text Available Streaming video over the Internet, including cellular networks, has now become a commonplace. Network operators typically use multicasting or variants of multiple unicasting to deliver streams to the user terminal in a controlled fashion. P2P streaming is an emerging alternative, which is theoretically more scalable but suffers from other issues arising from the dynamic nature of the system. Users' terminals become streaming nodes but they are not constantly connected. Another issue is that they are based on logical overlays, which are not optimized for the physical underlay infrastructure. An important proposition is to find effective ways to increase the resilience of the overlay whilst at the same time not conflicting with the network. In this article we look at the combination of two techniques, redundant streaming and locality awareness, in the context of both live and video-on-demand streaming. We introduce a new technique and assess it via a comparative, simulation-based study. We find that redundancy affects network utilization only marginally if traffic is kept at the edges via localization techniques.

  1. Functional and molecular evidence for heteromeric association of P2Y1 receptor with P2Y2 and P2Y4 receptors in mouse granulocytes.

    Science.gov (United States)

    Ribeiro-Filho, Antonio Carlos; Buri, Marcus Vinicius; Barros, Carlos Castilho; Dreyfuss, Juliana Luporini; Nader, Helena Bonciani; Justo, Giselle Zenker; Craveiro, Rogério Bastos; Pesquero, João Bosco; Miranda, Antonio; Ferreira, Alice Teixeira; Paredes-Gamero, Edgar Julian

    2016-07-07

    All hematopoietic cells express P2 receptors, however pharmacological characteristics such as expression and affinity in granulocytes are unknown. Pharmacological characteristics of P2 receptors were evaluated by Ca(2+) measurements using Fura-2 fluorophore. P2 receptors expression were analyzed by flow cytometry and RT-PCR. P2 interaction were shown by coimmunoprecipitation, western blotting and FRET. Granulocytes were responsive to P2Y agonists, whereas P2X agonists were ineffective. Ca(2+) increase, elicited by ADP and UTP was dependent on intracellular stocks and sensitive to G-coupled receptor inhibition. Moreover, MRS2179, a specific antagonist of the P2Y1 receptor, abolished ADP response. Interestingly, ADP and UTP exhibited full heterologous desensitization, suggesting that these agonists interact with the same receptor. The heteromeric association between P2Y1 receptor and the P2Y2 and P2Y4 receptors was shown by immunoprecipitation and FRET analysis. Clear evidence of heteromeric association of P2Y receptors was found during the evaluation of P2 receptors present in mice granulocytes, which could impact in the classical pharmacology of P2Y receptors in granulocytes.

  2. Environmental Compliance Mechanisms

    NARCIS (Netherlands)

    Merkouris, Panagiotis; Fitzmaurice, Malgosia

    2017-01-01

    Compliance mechanisms can be found in treaties regulating such diverse issues as human rights, disarmament law, and environmental law. In this bibliography, the focus will be on compliance mechanisms of multilateral environmental agreements (MEAs). Compliance with norms of international

  3. Awareness and Compliance with Guidelines on Occupational ...

    African Journals Online (AJOL)

    Saharan Africa is increased by non-adherence to the principles of infection prevention practices. This study assessed the level of awareness and compliance with guideline on occupational exposure to HIV by health care workers (HCW).

  4. Bone phenotypes of P2 receptor knockout mice

    DEFF Research Database (Denmark)

    Orriss, Isabel; Syberg, Susanne; Wang, Ning

    2011-01-01

    The action of extracellular nucleotides is mediated by ionotropic P2X receptors and G-protein coupled P2Y receptors. The human genome contains 7 P2X and 8 P2Y receptor genes. Knockout mice strains are available for most of them. As their phenotypic analysis is progressing, bone abnormalities have...... been observed in an impressive number of these mice: distinct abnormalities in P2X7-/- mice, depending on the gene targeting construct and the genetic background, decreased bone mass in P2Y1-/- mice, increased bone mass in P2Y2-/- mice, decreased bone resorption in P2Y6-/- mice, decreased bone...... formation and bone resorption in P2Y13-/- mice. These findings demonstrate the unexpected importance of extracellular nucleotide signalling in the regulation of bone metabolism via multiple P2 receptors and distinct mechanisms involving both osteoblasts and osteoclasts....

  5. Prevention

    Science.gov (United States)

    ... Contact Aging & Health A to Z Find a Geriatrics Healthcare Professional Medications & Older Adults Making Your Wishes ... Prevention Hearing Loss Heart Attack High Blood Pressure Nutrition Osteoporosis Shingles Skin Cancer Related News Quitting Smoking, ...

  6. Identification of a New Morpholine Scaffold as a P2Y12 Receptor Antagonist

    Directory of Open Access Journals (Sweden)

    Young Ha Ahn

    2016-08-01

    Full Text Available The P2Y12 receptor is critical for platelet activation and is an attractive drug target for the prevention of atherothrombotic events. Despite the proven antithrombotic efficacy of P2Y12 inhibitors, these thienopyridine scaffolds are prodrugs that lack important features of the ideal antithrombotic agent. For this reason, ticagrelor—a new chemical class of P2Y12 receptor antagonist—was developed, but it can cause shortness of breath and various types of bleeding. Moreover, ticagrelor is a cytochrome P450 3A4 substrate/inhibitor and, therefore, caution should be exercised when it is used concomitantly with strong CYP3A4 inducers/inhibitors. There is a need for novel P2Y12 receptor antagonist scaffolds that are reversible and have high efficacy without associated side effects. Here, we describe a novel antagonist containing a morpholine moiety that was identified by screening libraries of commercially available compounds. The molecule, Compound E, acted on P2Y12, but not P2Y1 and P2Y13, and exhibited pharmacological characteristics that were distinct from those of ticagrelor, acting instead on P2Y12 via an allosteric mechanism. These results provide a basis for the development/optimization of a new class of P2Y12 antagonists.

  7. Compliance to The Joint Commission proposed Core Measure set on osteoporosis-associated fracture: review of different secondary fracture prevention programs in an open medical system from 2010 to 2015.

    Science.gov (United States)

    Fojas, Ma Conchitina; Southerland, Lauren T; Phieffer, Laura S; Stephens, Julie A; Srivastava, Tanya; Ing, Steven W

    2017-12-01

    There are care gaps in the evaluation and treatment of osteoporosis after a fragility fracture. The Joint Commission is considering adoption of core measures. We compared compliance between two secondary fracture prevention programs in our institution. Incorporating strengths of both may provide the best outcomes for secondary fracture prevention. There are significant care gaps in the evaluation and treatment of osteoporosis after occurrence of fragility fracture. The Joint Commission is considering adoption of a core measure set on osteoporosis-associated fractures, including laboratory assessment, bone density testing, and osteoporosis pharmacologic therapy. We compared compliance to these proposed measures between two secondary fracture prevention programs in patients hospitalized for acute fracture in an open medical system. We conducted a retrospective, single center medical records review of a nurse practitioner-led Fracture Liaison Service (FLS), a physician-led Fracture Prevention Program (FPP), and a historical time without any secondary fracture prevention program (Usual Care) for baseline care. Primary outcomes were the completion of five laboratory tests (calcium, 25-hydroxy vitamin D, renal function, liver function, and complete blood count), order placement and completion of dual x-ray absorptiometry (DXA) scan within 3 months, prescription of osteoporosis medication within 3 months, and medication adherence at 6 months after hospital discharge. Completion of all five laboratory tests was higher in FPP versus FLS (84.7 vs. 36.9%, p < 0.001). DXA scan completion was higher in FPP than FLS but not statistically significant (66.7 vs. 54.9%, p = 0.11). Medication prescription at 3 months and adherence at 6 months were significantly higher in FPP versus FLS (65.3 vs. 24.0%, p < 0.001 and 70.8 vs. 27.7%, p < 0.001, respectively). Incorporating strengths of both FLS (care coordination) and FPP (physician direction) may provide the best outcomes

  8. 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....

  9. Structural and Molecular Modeling Features of P2X Receptors

    Directory of Open Access Journals (Sweden)

    Luiz Anastacio Alves

    2014-03-01

    Full Text Available Currently, adenosine 5'-triphosphate (ATP is recognized as the extracellular messenger that acts through P2 receptors. P2 receptors are divided into two subtypes: P2Y metabotropic receptors and P2X ionotropic receptors, both of which are found in virtually all mammalian cell types studied. Due to the difficulty in studying membrane protein structures by X-ray crystallography or NMR techniques, there is little information about these structures available in the literature. Two structures of the P2X4 receptor in truncated form have been solved by crystallography. Molecular modeling has proven to be an excellent tool for studying ionotropic receptors. Recently, modeling studies carried out on P2X receptors have advanced our knowledge of the P2X receptor structure-function relationships. This review presents a brief history of ion channel structural studies and shows how modeling approaches can be used to address relevant questions about P2X receptors.

  10. Environmental Restoration Contractor Waste Minimization and Pollution Prevention Plan. Revision 1

    International Nuclear Information System (INIS)

    Lewis, R.A.

    1996-03-01

    This plan contains the Environmental Restoration Contractor (ERC) Waste Minimization and Pollution Prevention (WMin/P2) Program. The plan outlines the activities and schedules developed by the ERC to reduce the quantity and toxicity of waste dispositioned as a result of restoration and remediation activities. This plan satisfies US Department of Energy (DOE) requirements including the Pollution Prevention Awareness program required by DOE Order 5400.1 (DOE 1988). This plan is consistent with Executive Order 12856 and Secretary O'Leary's pollution prevention Policy Statement of December 27, 1994, which set US and DOE pollution prevention policies, respectively. It is also consistent with the DOE Pollution Prevention Crosscut Plan, 1994, which provides guidance in meeting the DOE goals in pollution prevention. The purpose of this plan is to aid ERC projects in meeting and documenting compliance with requirements for WMin/P2. This plan contains the objectives, strategy, and support activities of the ERC Team WMin/P2 program. The basic elements of the plan are pollution prevention goals, waste assessments of major waste streams, implementation of feasible waste minimization opportunities, and a process for reporting achievements. Wherever appropriate, the ERC will integrate the pollution prevention activities in this plan into regular program activities rather than establishing separate WMin/P2 activities. Moreover, wherever possible, existing documents, procedures, and activities will be used to meet WMin/P2 requirements

  11. Hypermethylation downregulates P2X7 receptor expression in astrocytoma

    OpenAIRE

    Liu, Jing; Li, Ningning; Sheng, Ruofan; Wang, Rui; Xu, Zude; Mao, Ying; Wang, Yin; Liu, Ying

    2017-01-01

    The present study investigated the altered expression of p2X purinoceptor (P2X7R) in astrocytoma. Reverse transcription-quantitative polymerase chain reaction and western blot analysis were used to determine the P2X7R expression in glioblastoma (GBM) and surrounding normal brain tissue. DNA methylation levels of P2X7R gene promoter in GBM were analyzed using a Sequenom MassARRAY® System. Immunohistochemistry (IHC) was used to detect the expression of P2X7R in astrocytoma at different malignan...

  12. Two open states of P2X receptor channels

    Directory of Open Access Journals (Sweden)

    Milos B. Rokic

    2013-11-01

    Full Text Available The occupancy of the ATP binding sites of P2X receptor (P2XR channels causes the rapid opening of a small cation-permeable pore, followed by a gradual dilation that renders the pore permeable to large organic cations. Electrophysiologically, this phenomenon was shown using whole-cell current recording on P2X2R-, P2X2/X5R-, P2X4R- and P2X7R-expressing cells that were bathed in N-methyl-D-glucamine-containing buffers in the presence and/or absence of small monovalent and divalent cations. The pore dilation of P2X4R and P2X7R caused a secondary current growth, whereas that of P2X2R showed a sustained kinetic coupling of dilation and desensitization, leading to receptor channel closure. The pore size of the P2X7R open and dilated states was estimated to be approximately 0.85 nm and greater than 1 nm, respectively. The P2XR pore dilation was also observed in intact cells by measurement of fluorescent dye uptake/release, application of polyethylene glycols of different sizes, and atomic force microscopy. However, pore dilation was not observed at the single channel level. Structural data describing the dilated state are not available, and the relevance of orthosteric and allosteric ligand interactions to pore dilation was not studied.

  13. P2X4: A fast and sensitive purinergic receptor

    Directory of Open Access Journals (Sweden)

    Jaanus Suurväli

    2017-10-01

    Full Text Available Extracellular nucleotides have been recognized as important mediators of activation, triggering multiple responses via plasma membrane receptors known as P2 receptors. P2 receptors comprise P2X ionotropic receptors and G protein-coupled P2Y receptors. P2X receptors are expressed in many tissues, where they are involved in a number of functions including synaptic transmission, muscle contraction, platelet aggregation, inflammation, macrophage activation, differentiation and proliferation, neuropathic and inflammatory pain. P2X4 is one of the most sensitive purinergic receptors (at nanomolar ATP concentrations, about one thousand times more than the archetypal P2X7. P2X4 is widely expressed in central and peripheral neurons, in microglia, and also found in various epithelial tissues and endothelial cells. It localizes on the plasma membrane, but also in intracellular compartments. P2X4 is preferentially localized in lysosomes, where it is protected from proteolysis by its glycosylation. High ATP concentration in the lysosomes does not activate P2X4 at low pH; P2X4 gets activated by intra-lysosomal ATP only in its fully dissociated tetra-anionic form, when the pH increases to 7.4. Thus, P2X4 is functioning as a Ca2+-channel after the fusion of late endosomes and lysosomes. P2X4 modulates major neurotransmitter systems and regulates alcohol-induced responses in microglia. P2X4 is one of the key receptors mediating neuropathic pain. However, injury-induced upregulation of P2X4 expression is gender dependent and plays a key role in pain difference between males and females. P2X4 is also involved in inflammation. Extracellular ATP being a pro-inflammatory molecule, P2X4 can trigger inflammation in response to high ATP release. It is therefore involved in multiple pathologies, like post-ischemic inflammation, rheumatoid arthritis, airways inflammation in asthma, neurodegenerative diseases and even metabolic syndrome. Although P2X4 remains poorly

  14. P2X1 receptors and the endothelium

    Directory of Open Access Journals (Sweden)

    LS Harrington

    2005-03-01

    Full Text Available Adenosine triphosphate (ATP is now established as a principle vaso-active mediator in the vasculature. Its actions on arteries are complex, and are mediated by the P2X and P2Y receptor families. It is generally accepted that ATP induces a bi-phasic response in arteries, inducing contraction via the P2X and P2Y receptors on the smooth muscle cells, and vasodilation via the actions of P2Y receptors located on the endothelium. However, a number of recent studies have placed P2X1 receptors on the endothelium of some arteries. The use of a specific P2X1 receptor ligand, a, b methylene ATP has demonstrated that P2X1 receptors also have a bi-functional role. The actions of ATP on P2X1 receptors is therefore dependant on its location, inducing contraction when located on the smooth muscle cells, and dilation when expressed on the endothelium, comparable to that of P2Y receptors.

  15. Purinergic P2 receptors as targets for novel analgesics.

    Science.gov (United States)

    Burnstock, Geoffrey

    2006-06-01

    Following hints in the early literature about adenosine 5'-triphosphate (ATP) injections producing pain, an ion-channel nucleotide receptor was cloned in 1995, P2X3 subtype, which was shown to be localized predominantly on small nociceptive sensory nerves. Since then, there has been an increasing number of papers exploring the role of P2X3 homomultimer and P2X2/3 heteromultimer receptors on sensory nerves in a wide range of organs, including skin, tongue, tooth pulp, intestine, bladder, and ureter that mediate the initiation of pain. Purinergic mechanosensory transduction has been proposed for visceral pain, where ATP released from epithelial cells lining the bladder, ureter, and intestine during distension acts on P2X3 and P2X2/3, and possibly P2Y, receptors on subepithelial sensory nerve fibers to send messages to the pain centers in the brain as well as initiating local reflexes. P1, P2X, and P2Y receptors also appear to be involved in nociceptive neural pathways in the spinal cord. P2X4 receptors on spinal microglia have been implicated in allodynia. The involvement of purinergic signaling in long-term neuropathic pain and inflammation as well as acute pain is discussed as well as the development of P2 receptor antagonists as novel analgesics.

  16. Isotretinoin use and compliance with the Dutch Pregnancy Prevention Programme: a retrospective cohort study in females of reproductive age using pharmacy dispensing data.

    NARCIS (Netherlands)

    Teichert, M.; Visser, L.E.; Dufour, M.; Rodenburg, E.; Straus, S.M.; Smet, P.A.G.M. de; Stricker, B.H.C.

    2010-01-01

    BACKGROUND: Isotretinoin is very effective in the treatment of severe acne. However, because of the teratogenic properties of this agent an isotretinoin Pregnancy Prevention Programme (PPP) was implemented in the Netherlands to guarantee that treatment is contraindicated in women of reproductive age

  17. A randomized preventive rehabilitation trial in advanced head and neck cancer patients treated with chemoradiotherapy: feasibility, compliance, and short-term effects

    NARCIS (Netherlands)

    van der Molen, L.; van Rossum, M.A.; Burkhead, L.M.; Smeele, L.E.; Rasch, C.R.N.; Hilgers, F.J.M.

    2011-01-01

    The aim of this study was to assess the effect of (preventive) rehabilitation on swallowing and mouth opening after concomitant chemoradiotherapy (CCRT). Forty-nine patients with advanced oral cavity, oropharynx, hypopharynx and larynx, or nasopharynx cancer treated with CCRT were randomized into a

  18. A Randomized Preventive Rehabilitation Trial in Advanced Head and Neck Cancer Patients Treated with Chemoradiotherapy: Feasibility, Compliance, and Short-term Effects

    NARCIS (Netherlands)

    van der Molen, Lisette; van Rossum, Maya A.; Burkhead, Lori M.; Smeele, Ludi E.; Rasch, Coen R. N.; Hilgers, Frans J. M.

    2011-01-01

    The aim of this study was to assess the effect of (preventive) rehabilitation on swallowing and mouth opening after concomitant chemoradiotherapy (CCRT). Forty-nine patients with advanced oral cavity, oropharynx, hypopharynx and larynx, or nasopharynx cancer treated with CCRT were randomized into a

  19. The role of the purinergic P2X7 receptor in inflammation

    Directory of Open Access Journals (Sweden)

    Rossi Adriano G

    2007-03-01

    Full Text Available Abstract The inflammatory process, orchestrated against a variety of injurious stimuli, is composed of three inter-related phases; initiation, propagation and resolution. Understanding the interplay between these three phases and harnessing the beneficial properties of inflammation whilst preventing its damaging effects, will undoubtedly lead to the advent of much needed therapies, particularly in chronic disease states. The P2X7 receptor (P2X7R is increasingly recognised as an important cell surface regulator of several key inflammatory molecules including IL-1β, IL-18, TNF-α and IL-6. Moreover, as P2X7R-dependent cytokine production is driven by activating the inflammasome, antagonists of this receptor are likely to have therapeutic potential as novel anti-inflammatory therapies. The function of the P2X7R in inflammation, immunity and its potential role in disease will be reviewed and discussed.

  20. Hyperglycemia-induced Renal P2X7 Receptor Activation Enhances Diabetes-related Injury

    Directory of Open Access Journals (Sweden)

    Robert I. Menzies

    2017-05-01

    Full Text Available Diabetes is a leading cause of renal disease. Glomerular mesangial expansion and fibrosis are hallmarks of diabetic nephropathy and this is thought to be promoted by infiltration of circulating macrophages. Monocyte chemoattractant protein-1 (MCP-1 has been shown to attract macrophages in kidney diseases. P2X7 receptors (P2X7R are highly expressed on macrophages and are essential components of pro-inflammatory signaling in multiple tissues. Here we show that in diabetic patients, renal P2X7R expression is associated with severe mesangial expansion, impaired glomerular filtration (≤40 ml/min/1.73 sq. m., and increased interstitial fibrosis. P2X7R activation enhanced the release of MCP-1 in human mesangial cells cultured under high glucose conditions. In mice, P2X7R-deficiency prevented glomerular macrophage attraction and collagen IV deposition; however, the more severe interstitial inflammation and fibrosis often seen in human diabetic kidney diseases was not modelled. Finally, we demonstrate that a P2X7R inhibitor (AZ11657312 can reduce renal macrophage accrual following the establishment of hyperglycemia in a model of diabetic nephropathy. Collectively these data suggest that P2X7R activation may contribute to the high prevalence of kidney disease found in diabetics.

  1. Cryptocurrency Networks: A New P2P Paradigm

    Directory of Open Access Journals (Sweden)

    Sergi Delgado-Segura

    2018-01-01

    Full Text Available P2P networks are the mechanism used by cryptocurrencies to disseminate system information while keeping the whole system as much decentralized as possible. Cryptocurrency P2P networks have new characteristics that propose new challenges and avoid some problems of existing P2P networks. By characterizing the most relevant cryptocurrency network, Bitcoin, we provide details on different properties of cryptocurrency networks and their similarities and differences with standard P2P network paradigms. Our study allows us to conclude that cryptocurrency networks present a new paradigm of P2P networks due to the mechanisms they use to achieve high resilience and security. With this new paradigm, interesting research lines can be further developed, both in the focused field of P2P cryptocurrency networks and also when such networks are combined with other distributed scenarios.

  2. (p,2p) experiments at the University of Maryland cyclotron

    International Nuclear Information System (INIS)

    Roos, P.G.

    1976-11-01

    Some of the (p,2p) work which has been carried out at the Maryland Cyclotron is discussed. A brief introduction to the (p,2p) reaction is presented, and the types of experimental techniques utilized in (p,2p) studies are discussed. A brief introduction is given to the various theoretical treatments presently available to analyze (p,2p) reaction data. Secondly, experimental and theoretical studies of (p,2p) on d, 3 He, and 4 He carried out by the Maryland group are presented. Thirdly, (p,2p) results are discussed for 6 Li, 7 Li, and 12 C at 100 MeV. Fourthly, the effects of distortion on the experimental data are considered by presenting theoretical calculations for 12 C and 40 Ca at various bombarding energies

  3. P2X7 Receptors in Neurological and Cardiovascular Disorders

    Directory of Open Access Journals (Sweden)

    Stephen D. Skaper

    2009-01-01

    Full Text Available P2X receptors are ATP-gated cation channels that mediate fast excitatory transmission in diverse regions of the brain and spinal cord. Several P2X receptor subtypes, including P2X7, have the unusual property of changing their ion selectivity during prolonged exposure to ATP, which results in a channel pore permeable to molecules as large as 900 daltons. The P2X7 receptor was originally described in cells of hematopoietic origin, and mediates the influx of Ca2+ and Na+ and Ca2+ and Na+ ions as well as the release of proinflammatory cytokines. P2X7 receptors may affect neuronal cell death through their ability to regulate the processing and release of interleukin-1, a key mediator in neurodegeneration, chronic inflammation, and chronic pain. Activation of P2X7, a key mediator in neurodegeneration, chronic inflammation, and chronic pain. Activation of P2X7 receptors provides an inflammatory stimulus, and P2X7 receptor-deficient mice have substantially attenuated inflammatory responses, including models of neuropathic and chronic inflammatory pain. Moreover, P2X7 receptor activity, by regulating the release of proinflammatory cytokines, may be involved in the pathophysiology of depression. Apoptotic cell death occurs in a number of vascular diseases, including atherosclerosis, restenosis, and hypertension, and may be linked to the release of ATP from endothelial cells, P2X7 receptor activation, proinflammatory cytokine production, and endothelial cell apoptosis. In this context, the P2X7 receptor may be viewed as a gateway of communication between the nervous, immune, and cardiovascular systems.

  4. Hanford site guide for preparing and maintaining generator group pollution prevention program documentation

    International Nuclear Information System (INIS)

    1995-12-01

    This manual provides the necessary guidance to contractor generator groups for developing and maintaining documentation of their pollution prevention (P2) program activities. Preparation of program documentation will demonstrate compliance with contractor and U.S. Department of Energy (DOE) requirements, as well as state and federal regulations. Contractor waste generator groups are no longer required to prepare and update facility waste minimization plans. Developing and maintaining program documentation replace this requirement

  5. The role of P2X receptors in bone biology

    DEFF Research Database (Denmark)

    Jørgensen, N R; Syberg, S; Ellegaard, M

    2015-01-01

    come from studies on murine knockout models and from pharmacologic studies on cells and animals. More recently, the role of P2X receptors in human bone diseases has been documented. Loss-of-functions polymorphisms in the P2X7 receptorare associated with bone loss and increased fracture risk. Very...

  6. Binary phosphates NaLnP2O7

    International Nuclear Information System (INIS)

    Anisimova, N.Yu.; Trunov, V.K.; Chudinova, N.N.

    1988-01-01

    The results of synthesis and identification of compounds of the NaLnP 2 O 7 (Ln=La,...Lu) composition are presented. 14 compounds of the above composition referring to two structural types are prepared and characterized. The data on NaLnP 2 O 7 synthesis in the Na 2 O-Ln:2O 3 -P 2 O 5 system are given. Binary phosphates of the NaLnP 2 O 7 -type (Ln=La,...Lu) are separated and identified in the subsolidus part of the Na 2 O-Ln 2 O 3 -P 2 O 5 system. Their crystallochemical parameters are determined and the presence of two structural types in the La-Lu series is shown. Thermal stability of binary phosphates is studied

  7. Faktor-Faktor yang Mempengaruhi Penerimaan PBB P2 di Kota Yogyakarta Pasca Pelimpahan Kewenangan Pengelolaan PBB P2 Oleh Pusat Kepada Daerah

    Directory of Open Access Journals (Sweden)

    Lastria Nurtanzila

    2015-11-01

    Full Text Available One of the efforts to achieve fiscal independence of local governments is to provide authority in the management of land and property tax as a part of local taxes (Law No.28 of 2009. Yogyakarta has delegated authority to implement this law since 2011. The revenue of PBB P2 pretty much accounted for the PAD, which is why in this study tried to examine the factors that influence Earth Building Tax receipts in the city of Yogyakarta in 2013-2014. So from this study establishes framework there are three factors that can affect PBB P2 in the city of Yogyakarta, which is a factor of tax administration efficiency, effectiveness socialization factor taxation and tax compliance. Based on the research results that the tax administration can efficiently determine the level of awareness of the taxpayer to pay taxes on time, as well as tax sosialization can increase the public's attention on the importance of paying taxes, in addition to the flavor abide by the rules are also important in creating awareness to pay tax.

  8. P2X-Receptor Antagonists Inhibit the Interaction of S. aureus Hemolysin A with Membranes

    Directory of Open Access Journals (Sweden)

    Markus Schwiering

    2017-10-01

    Full Text Available The pore forming hemolysin A, Hla, is a major virulence factor of Staphylococcus aureus. Apparently, 1–2 pore(s per cell suffice(s to cause cell death. Accumulated experimental evidence points towards a major role of ATP-gated purinergic receptors (P2XR for hemolysis caused by Hla, complement and other pore forming proteins, presumably by increasing membrane permeability. Indeed, in experiments employing rabbit erythrocytes, inhibitory concentrations of frequently employed P2XR-antagonists were in a similar range as previously reported for erythrocytes of other species and other toxins. However, Hla-dependent hemolysis was not enhanced by extracellular ATP, and oxidized adenosinetriphosphate (oxATP had only a minor inhibitory effect. Unexpectedly, P2XR-inhibitors also prevented Hla-induced lysis of pure lipid membranes, demonstrating that the inhibition did not even depend on the presence of P2XR. Fluorescence microscopy and gel-electrophoresis clearly revealed that P2XR-inhibitors interfere with binding and subsequent oligomerisation of Hla with membranes. Similar results were obtained employing HaCaT-cells. Furthermore, calorimetric data and hemolysis experiments with Hla pre-treated with pyridoxal phosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS showed that this compound directly binds to Hla. Our results call for a critical re-assessment of the appealing concept, which suggests that P2XR are general amplifiers of damage by pore-forming proteins.

  9. Purinergní P2X rodina a specifické vlastnosti P2X7 podtypu

    Czech Academy of Sciences Publication Activity Database

    Jindřichová, Marie; Zemková, Hana

    2013-01-01

    Roč. 62, č. 2 (2013), s. 40-46 ISSN 1210-6313 R&D Projects: GA ČR(CZ) GPP304/12/P371 Institutional support: RVO:67985823 Keywords : extracellular ATP * purinergic P2X family * P2X7 receptor * cell proliferation and apoptosis Subject RIV: ED - Physiology

  10. P2MP MPLS-Based Hierarchical Service Management System

    Science.gov (United States)

    Kumaki, Kenji; Nakagawa, Ikuo; Nagami, Kenichi; Ogishi, Tomohiko; Ano, Shigehiro

    This paper proposes a point-to-multipoint (P2MP) Multi-Protocol Label Switching (MPLS) based hierarchical service management system. Traditionally, general management systems deployed in some service providers control MPLS Label Switched Paths (LSPs) (e.g., RSVP-TE and LDP) and services (e.g., L2VPN, L3VPN and IP) separately. In order for dedicated management systems for MPLS LSPs and services to cooperate with each other automatically, a hierarchical service management system has been proposed with the main focus on point-to-point (P2P) TE LSPs in MPLS path management. In the case where P2MP TE LSPs and services are deployed in MPLS networks, the dedicated management systems for P2MP TE LSPs and services must work together automatically. Therefore, this paper proposes a new algorithm that uses a correlation between P2MP TE LSPs and multicast VPN services based on a P2MP MPLS-based hierarchical service management architecture. Also, the capacity and performance of the proposed algorithm are evaluated by simulations, which are actually based on certain real MPLS production networks, and are compared to that of the algorithm for P2P TE LSPs. Results show this system is very scalable within real MPLS production networks. This system, with the automatic correlation, appears to be deployable in real MPLS production networks.

  11. From Client-Server to P2P Networking

    Science.gov (United States)

    Liu, Lu; Antonopoulos, Nick

    Peer-to-peer (P2P) networks attract attentions worldwide with their great success in file sharing networks (such as Napster, Gnutella, Freenet, BitTorrent, Kazaa, and JXTA). An explosive increase in the popularity of P2P networks has been witnessed by millions of Internet users. In this chapter, an investigation of network architecture evolution, from client-server to P2P networking, will be given, underlining the benefits and the potential problems of existing approaches, which provides essential theoretical base to drive future generation of distributed systems.

  12. PPADS: an antagonist at endothelial P2Y-purinoceptors but not P2U-purinoceptors.

    Science.gov (United States)

    Brown, C; Tanna, B; Boarder, M R

    1995-11-01

    1. Bovine aortic endothelial (BAE) cells contain two co-existing receptors for extracellular ATP, the P2Y and P2U-purinoceptors. Here we have determined whether the proposed P2X-purinoceptor antagonist, pyridoxalphosphate-6-azophenyl-2', 4'-disulphonic acid (PPADS) could distinguish between these two receptor subtypes. 2. Cells labelled with myo-[2-3H]-inositol were stimulated with increasing concentrations of either the P2Y-agonist, 2MeSATP, or the P2U-agonist, UTP in the absence or presence of 30 microM PPADS. The accumulation of total [3H]-inositol (poly)phosphates mediated by 2MeSATP was markedly attenuated by PPADS, whereas the response to UTP was not significantly affected. 3. Stimulation of BAE cells with increasing concentrations of ATP showed a reduced response in the presence of 10 microM PPADS, but this effect of the antagonist was not significant. By contrast, inhibition of the response to ADP was profound and highly significant. 4. These observations show that PPADS is not a selective P2X-purinoceptor antagonist, but is able to distinguish between P2Y- and P2YU-purinoceptors in BAE cells, and indicate that this compound may provide a useful tool in the study of multiple subtypes of P2-purinoceptors. Furthermore the results are consistent with the hypothesis that ATP interacts with both receptor subtypes, but that the action of ADP is primarily at the P2Y-purinoceptor in these endothelial cells.

  13. The role of P2X receptors in bone biology

    DEFF Research Database (Denmark)

    Jørgensen, N R; Syberg, S; Ellegaard, M

    2015-01-01

    Bone is a highly dynamic organ, being constantly modeled and remodeled in order to adapt to the changing need throughout life. Bone turnover involves the coordinated actions of bone formation and bone degradation. Over the past decade great effort has been put into the examination of how P2X...... receptors regulate bone metabolism and especially for the P2X7 receptor an impressive amount of evidence has now documented its expression in osteoblasts, osteoclasts, and osteocytes as well as important functional roles in proliferation, differentiation, and function of the cells of bone. Key evidence has...... come from studies on murine knockout models and from pharmacologic studies on cells and animals. More recently, the role of P2X receptors in human bone diseases has been documented. Loss-of-functions polymorphisms in the P2X7 receptorare associated with bone loss and increased fracture risk. Very...

  14. Tetravalent one-regular graphs of order 4p2

    DEFF Research Database (Denmark)

    Feng, Yan-Quan; Kutnar, Klavdija; Marusic, Dragan

    2014-01-01

    A graph is one-regular if its automorphism group acts regularly on the set of its arcs. In this paper tetravalent one-regular graphs of order 4p2, where p is a prime, are classified.......A graph is one-regular if its automorphism group acts regularly on the set of its arcs. In this paper tetravalent one-regular graphs of order 4p2, where p is a prime, are classified....

  15. The role of P2X receptors in bone biology.

    Science.gov (United States)

    Jørgensen, N R; Syberg, S; Ellegaard, M

    2015-01-01

    Bone is a highly dynamic organ, being constantly modeled and remodeled in order to adapt to the changing need throughout life. Bone turnover involves the coordinated actions of bone formation and bone degradation. Over the past decade great effort has been put into the examination of how P2X receptors regulate bone metabolism and especially for the P2X7 receptor an impressive amount of evidence has now documented its expression in osteoblasts, osteoclasts, and osteocytes as well as important functional roles in proliferation, differentiation, and function of the cells of bone. Key evidence has come from studies on murine knockout models and from pharmacologic studies on cells and animals. More recently, the role of P2X receptors in human bone diseases has been documented. Loss-of-functions polymorphisms in the P2X7 receptorare associated with bone loss and increased fracture risk. Very recently a report from a genetic study in multiple myeloma demonstrated that decreased P2X7 receptor function was associated with increased risk of developing multiple myeloma. In contrast, the risk of developing myeloma bone disease and subsequent vertebral fractures was increased in subjects carrying P2X7 receptor gain-of-function alleles as compared to subjects only carrying loss-of-function or normal functioning alleles. It is evident that P2X receptors are important in regulating bone turnover and maintaining bone mass, and thereby holding great potential as novel drug targets for treatment of bone diseases. However, further research is needed before we fully understand the roles and effects of P2X receptors in bone.

  16. Meeting of the ITER SWG-P2 in Vienna

    International Nuclear Information System (INIS)

    Pinkau, K.; Kishimoto, H.

    1999-01-01

    The Special Working Group established under Protocol 2 to the ITER IDA Agreement (SWG-P2) met at the IAEA in Vienna in 6-9 December 1999. This report contains excerpts from the report of the ITER SWG-P2 to the ITER Council on the Joint Implementation of ITER, detailing benefits, contributions, the legal framework, siting, licensing and decommissioning as well as procurement, staffing and intellectual property rights

  17. microRNA targeting of the P2X7 purinoceptor opposes a contralateral epileptogenic focus in the hippocampus.

    Science.gov (United States)

    Jimenez-Mateos, Eva M; Arribas-Blazquez, Marina; Sanz-Rodriguez, Amaya; Concannon, Caoimhin; Olivos-Ore, Luis A; Reschke, Cristina R; Mooney, Claire M; Mooney, Catherine; Lugara, Eleonora; Morgan, James; Langa, Elena; Jimenez-Pacheco, Alba; Silva, Luiz Fernando Almeida; Mesuret, Guillaume; Boison, Detlev; Miras-Portugal, M Teresa; Letavic, Michael; Artalejo, Antonio R; Bhattacharya, Anindya; Diaz-Hernandez, Miguel; Henshall, David C; Engel, Tobias

    2015-12-03

    The ATP-gated ionotropic P2X7 receptor (P2X7R) modulates glial activation, cytokine production and neurotransmitter release following brain injury. Levels of the P2X7R are increased in experimental and human epilepsy but the mechanisms controlling P2X7R expression remain poorly understood. Here we investigated P2X7R responses after focal-onset status epilepticus in mice, comparing changes in the damaged, ipsilateral hippocampus to the spared, contralateral hippocampus. P2X7R-gated inward currents were suppressed in the contralateral hippocampus and P2rx7 mRNA was selectively uploaded into the RNA-induced silencing complex (RISC), suggesting microRNA targeting. Analysis of RISC-loaded microRNAs using a high-throughput platform, as well as functional assays, suggested the P2X7R is a target of microRNA-22. Inhibition of microRNA-22 increased P2X7R expression and cytokine levels in the contralateral hippocampus after status epilepticus and resulted in more frequent spontaneous seizures in mice. The major pro-inflammatory and hyperexcitability effects of microRNA-22 silencing were prevented in P2rx7(-/-) mice or by treatment with a specific P2X7R antagonist. Finally, in vivo injection of microRNA-22 mimics transiently suppressed spontaneous seizures in mice. The present study supports a role for post-transcriptional regulation of the P2X7R and suggests therapeutic targeting of microRNA-22 may prevent inflammation and development of a secondary epileptogenic focus in the brain.

  18. Accelerated FoxP2 Evolution in Echolocating Bats

    Science.gov (United States)

    Li, Gang; Wang, Jinhong; Rossiter, Stephen J.; Jones, Gareth; Zhang, Shuyi

    2007-01-01

    FOXP2 is a transcription factor implicated in the development and neural control of orofacial coordination, particularly with respect to vocalisation. Observations that orthologues show almost no variation across vertebrates yet differ by two amino acids between humans and chimpanzees have led to speculation that recent evolutionary changes might relate to the emergence of language. Echolocating bats face especially challenging sensorimotor demands, using vocal signals for orientation and often for prey capture. To determine whether mutations in the FoxP2 gene could be associated with echolocation, we sequenced FoxP2 from echolocating and non-echolocating bats as well as a range of other mammal species. We found that contrary to previous reports, FoxP2 is not highly conserved across all nonhuman mammals but is extremely diverse in echolocating bats. We detected divergent selection (a change in selective pressure) at FoxP2 between bats with contrasting sonar systems, suggesting the intriguing possibility of a role for FoxP2 in the evolution and development of echolocation. We speculate that observed accelerated evolution of FoxP2 in bats supports a previously proposed function in sensorimotor coordination. PMID:17878935

  19. P2P Data Management in Mobile Wireless Sensor Network

    Directory of Open Access Journals (Sweden)

    Nida Sahar Sayeda

    2013-04-01

    Full Text Available The rapid growth in wireless technologies has made wireless communication an important source for transporting data across different domains. In the same way, there are possibilities of many potential applications that can be deployed using WSNs (Wireless Sensor Networks. However, very limited applications are deployed in real life due to the uncertainty and dynamics of the environment and scare resources. This makes data management in WSN a challenging area to find an approach that suits its characteristics. Currently, the trend is to find efficient data management schemes using evolving technologies, i.e. P2P (Peer-to-Peer systems. Many P2P approaches have been applied in WSNs to carry out the data management due to similarities between WSN and P2P. With the similarities, there are differences too that makes P2P protocols inefficient in WSNs. Furthermore, to increase the efficiency and to exploit the delay tolerant nature of WSNs, where ever possible, the mobile WSNs are gaining importance. Thus, creating a three dimensional problem space to consider, i.e. mobility, WSNs and P2P. In this paper, an efficient algorithm is proposed for data management using P2P techniques for mobile WSNs. The real world implementation and deployment of proposed algorithm is also presented

  20. Accelerated FoxP2 evolution in echolocating bats.

    Directory of Open Access Journals (Sweden)

    Gang Li

    Full Text Available FOXP2 is a transcription factor implicated in the development and neural control of orofacial coordination, particularly with respect to vocalisation. Observations that orthologues show almost no variation across vertebrates yet differ by two amino acids between humans and chimpanzees have led to speculation that recent evolutionary changes might relate to the emergence of language. Echolocating bats face especially challenging sensorimotor demands, using vocal signals for orientation and often for prey capture. To determine whether mutations in the FoxP2 gene could be associated with echolocation, we sequenced FoxP2 from echolocating and non-echolocating bats as well as a range of other mammal species. We found that contrary to previous reports, FoxP2 is not highly conserved across all nonhuman mammals but is extremely diverse in echolocating bats. We detected divergent selection (a change in selective pressure at FoxP2 between bats with contrasting sonar systems, suggesting the intriguing possibility of a role for FoxP2 in the evolution and development of echolocation. We speculate that observed accelerated evolution of FoxP2 in bats supports a previously proposed function in sensorimotor coordination.

  1. Environmental Restoration Contractor Waste Minimization and Pollution Prevention Plan

    International Nuclear Information System (INIS)

    Lewis, R.A.

    1994-11-01

    The purpose of this plan is to establish the Environmental Restoration Contractor (ERC) Waste Minimization and Pollution Prevention (WMin/P2) Program and outline the activities and schedules that will be employed to reduce the quantity and toxicity of wastes generated as a result of restoration and remediation activities. It is intended to satisfy the US Department of Energy (DOE) and other legal requirements. As such, the Pollution Prevention Awareness program required by DOE Order 5400.1 is included with the Pollution Prevention Program. This plan is also intended to aid projects in meeting and documenting compliance with the various requirements for WMin/P2, and contains the policy, objectives, strategy, and support activities of the WMin/P2 program. The basic elements of the plan are pollution prevention goals, waste assessments of major waste streams, implementation of feasible waste minimization opportunities, and a process for reporting achievements. Various pollution prevention techniques will be implemented with the support of employee training and awareness programs to reduce waste and still meet applicable requirements. Information about the Hanford Site is in the Hanford Site Waste Minimization and Pollution Prevention Awareness Program Plan

  2. Mapping Tax Compliance

    DEFF Research Database (Denmark)

    Boll, Karen

    2014-01-01

    compliance is constructed, challenges the explanatory reaches of today's social science approaches, arguing that an alternative approach to understanding tax compliance is worthwhile exploring. This other choice of approach, inspired by actor–network theory (ANT), adopts a more practice-oriented focus...... that studies tax compliance where it takes place as well as what it is made of. Consequently, this article argues that tax compliance is a socio-material assemblage and that complying is a distributed action. The article concludes by highlighting how an ANT approach contributes to the further theoretical...

  3. P2X7 Receptor Activation Modulates Autophagy in SOD1-G93A Mouse Microglia

    Directory of Open Access Journals (Sweden)

    Paola Fabbrizio

    2017-08-01

    Full Text Available Autophagy and inflammation play determinant roles in the pathogenesis of Amyotrophic Lateral Sclerosis (ALS, an adult-onset neurodegenerative disease characterized by deterioration and final loss of upper and lower motor neurons (MN priming microglia to sustain neuroinflammation and a vicious cycle of neurodegeneration. Given that extracellular ATP through P2X7 receptor constitutes a neuron-to-microglia alarm signal implicated in ALS, and that P2X7 affects autophagy in immune cells, we have investigated if autophagy can be directly triggered by P2X7 activation in primary microglia from superoxide dismutase 1 (SOD1-G93A mice. We report that P2X7 enhances the expression of the autophagic marker microtubule-associated protein 1 light chain 3 (LC3-II, via mTOR pathway and concomitantly with modulation of anti-inflammatory M2 microglia markers. We also demonstrate that the autophagic target SQSTM1/p62 is decreased in SOD1-G93A microglia after a short stimulation of P2X7, but increased after a sustained challenge. These effects are prevented by the P2X7 antagonist A-804598, and the autophagy/phosphoinositide-3-kinase inhibitor wortmannin (WM. Finally, a chronic in vivo treatment with A-804598 in SOD1-G93A mice decreases the expression of SQSTM1/p62 in lumbar spinal cord at end stage of disease. These data identify the modulation of the autophagic flux as a novel mechanism by which P2X7 activates ALS-microglia, to be considered for further investigations in ALS.

  4. Pollution Prevention Opportunity Assessment for the SNL/NM cafeterias.

    Energy Technology Data Exchange (ETDEWEB)

    McCord, Samuel Adam

    2005-12-01

    This Pollution Prevention Opportunity Assessment (PPOA) was conducted for the two Sandia National Laboratories/New Mexico cafeteria facilities between May and August 2005. The primary purpose of this PPOA is to assess waste and resource reduction opportunities and issue Pollution Prevention (P2) recommendations for Sandia's food service facilities. This PPOA contains recommendations for energy, water and resource reduction, as well as material substitution based upon environmentally preferable purchasing. Division 3000 has requested the PPOA report as part of the Division's compliance effort to implement the Environmental Management System (EMS) per DOE Order 450.1. This report contains a summary of the information collected and analyses performed with recommended options for implementation. The SNL/NM P2 Group will work with Division 3000 and the respective cafeteria facilities to implement these options.

  5. Synaptosomal protein synthesis in P2 and Ficoll purified fractions.

    Science.gov (United States)

    Eyman, Maria; Cefaliello, Carolina; Bruno, Anna Paola; Bruno, Annapaola; Crispino, Marianna; Giuditta, Antonio

    2012-01-30

    Cytoplasmic protein synthesis of brain synaptosomes has generally been determined in the Ficoll purified fraction which contains fewer contaminating mitochondria, microsomes and myelin fragments than the parent P2 fraction. Using a highly selective assay of this activity we have compared the total translation activity and the specific activity of the proteins synthesized by either fraction in control rats and in rats trained for a two-way active avoidance task. In control rats the specific activity remained essentially the same in both fractions but in trained rats the value of the Ficoll fraction was markedly lower (38.5%) than in the P2 fraction. Furthermore, the total translation activity of the Ficoll fraction was 30% lower than in the P2 fraction in control rats and 62% lower in trained rats. These decrements indicate that a large proportion of active synaptosomes present in the P2 fraction is not recovered in the Ficoll fraction, notably in rats undergoing plastic brain changes. We conclude that cytoplasmic protein synthesis of brain synaptosomes is better preserved in the P2 fraction. Copyright © 2011 Elsevier B.V. All rights reserved.

  6. Determinants of Default in P2P Lending

    Science.gov (United States)

    2015-01-01

    This paper studies P2P lending and the factors explaining loan default. This is an important issue because in P2P lending individual investors bear the credit risk, instead of financial institutions, which are experts in dealing with this risk. P2P lenders suffer a severe problem of information asymmetry, because they are at a disadvantage facing the borrower. For this reason, P2P lending sites provide potential lenders with information about borrowers and their loan purpose. They also assign a grade to each loan. The empirical study is based on loans’ data collected from Lending Club (N = 24,449) from 2008 to 2014 that are first analyzed by using univariate means tests and survival analysis. Factors explaining default are loan purpose, annual income, current housing situation, credit history and indebtedness. Secondly, a logistic regression model is developed to predict defaults. The grade assigned by the P2P lending site is the most predictive factor of default, but the accuracy of the model is improved by adding other information, especially the borrower’s debt level. PMID:26425854

  7. Determinants of Default in P2P Lending.

    Directory of Open Access Journals (Sweden)

    Carlos Serrano-Cinca

    Full Text Available This paper studies P2P lending and the factors explaining loan default. This is an important issue because in P2P lending individual investors bear the credit risk, instead of financial institutions, which are experts in dealing with this risk. P2P lenders suffer a severe problem of information asymmetry, because they are at a disadvantage facing the borrower. For this reason, P2P lending sites provide potential lenders with information about borrowers and their loan purpose. They also assign a grade to each loan. The empirical study is based on loans' data collected from Lending Club (N = 24,449 from 2008 to 2014 that are first analyzed by using univariate means tests and survival analysis. Factors explaining default are loan purpose, annual income, current housing situation, credit history and indebtedness. Secondly, a logistic regression model is developed to predict defaults. The grade assigned by the P2P lending site is the most predictive factor of default, but the accuracy of the model is improved by adding other information, especially the borrower's debt level.

  8. Determinants of Default in P2P Lending.

    Science.gov (United States)

    Serrano-Cinca, Carlos; Gutiérrez-Nieto, Begoña; López-Palacios, Luz

    2015-01-01

    This paper studies P2P lending and the factors explaining loan default. This is an important issue because in P2P lending individual investors bear the credit risk, instead of financial institutions, which are experts in dealing with this risk. P2P lenders suffer a severe problem of information asymmetry, because they are at a disadvantage facing the borrower. For this reason, P2P lending sites provide potential lenders with information about borrowers and their loan purpose. They also assign a grade to each loan. The empirical study is based on loans' data collected from Lending Club (N = 24,449) from 2008 to 2014 that are first analyzed by using univariate means tests and survival analysis. Factors explaining default are loan purpose, annual income, current housing situation, credit history and indebtedness. Secondly, a logistic regression model is developed to predict defaults. The grade assigned by the P2P lending site is the most predictive factor of default, but the accuracy of the model is improved by adding other information, especially the borrower's debt level.

  9. Synthesis of Amylose-b-P2 VP Block Copolymers.

    Science.gov (United States)

    Kumar, Kamlesh; Woortman, Albert J J; Loos, Katja

    2015-12-01

    A new class of rod-coil block copolymers is synthesized by chemoenzymatic polymerization. In the first step, maltoheptaose, which acts as a primer for the synthesis of amylose, is attached to poly(2-vinyl pyridine) (P2 VP). The enzymatic polymerization of maltoheptaose is carried out by phosphorylase to obtain amylose-b-P2 VP block copolymers. The block copolymer is characterized by Fourier transform infrared spectroscopy, nuclear magnetic resonance, gel permeation chromatography, and wide-angle X-ray scattering techniques. The designed molecules combine the inclusion complexation ability of amylose with the supramolecular complexation ability of P2 VP and therefore this kind of rod-coil block copolymers can be used to generate well-organized novel self-assembled structures. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  10. Mobile P2P Web Services Using SIP

    Directory of Open Access Journals (Sweden)

    Guido Gehlen

    2007-01-01

    Full Text Available Telecommunication networks and the Internet are growing together. Peer-to-Peer (P2P services which are originally offered by network providers, like telephony and messaging, are provided through VoIP and Instant Messaging (IM by Internet service providers, too. The IP Multimedia Subsystem (IMS is the answer of the telecommunication industry to this trend and aims at providing Internet P2P and multimedia services controlled by the network operators. The IMS provides mobility and session management as well as message routing, security, and billing.

  11. Secure P2P Data Storage and Maintenance

    Directory of Open Access Journals (Sweden)

    Nouha Oualha

    2010-01-01

    Full Text Available P2P data storage requires strong reliability and security assurances. Existing data storage solutions have been designed for centralized as well as distributed settings; yet they do not address the security and cooperation issues raised by self-organization. P2P systems also introduce new needs regarding data availability due to the dynamicity of the infrastructure, which are unaddressed so far. This paper first discusses the approaches for tackling these problems. A solution is then introduced that relies on self-organizing security mechanisms in conjunction with a data rejuvenation scheme using erasure codes.

  12. The Social Impact of P2P Systems

    Science.gov (United States)

    Glorioso, Andrea; Pagallo, Ugo; Ruffo, Giancarlo

    The chapter deals with the social impact of P2P systems in light of a bidirectional connection by which technological developments influence, in a complex and often unpredictable way, the social environment whereas the dynamic evolution of the latter does affect technological progress. From this perspective, the aim is to deepen legal issues, sociological trends, economical aspects, and political dimensions of P2P technology, along with some of its next possible outputs, in order to assess one of the most compelling alternatives to the traditional frame of highly centralized human interaction.

  13. Compliance with RSV prophylaxis: Global physicians’ perspectives

    Directory of Open Access Journals (Sweden)

    Kari S Anderson

    2009-07-01

    Full Text Available Kari S Anderson, Victoria M Mullally, Linda M Fredrick, Andrew L CampbellAbbott Laboratories, Abbott Park, IL, USAAbstract: Respiratory syncytial virus (RSV is a significant cause of morbidity in high-risk infants. Palivizumab is proven to prevent serious RSV disease, but compliance with prophylaxis (monthly doses during the RSV season is essential to ensure protection. We invited 453 pediatricians to participate in a survey to identify their perspectives of barriers to compliance and interventions to improve compliance with palivizumab prophylaxis schedules. One hundred physicians from five continents completed the survey, identifying caregiver inconvenience, distance to clinic, cost of prophylaxis, and lack of understanding of the severity of RSV as the most common reasons for noncompliance. They recommended provision of educational materials about RSV, reminders from hospital or clinic, and administration of prophylaxis at home to increase compliance. Globally, physicians recognize several obstacles to prophylaxis compliance. This survey suggests that focused proactive interventions such as empowering caregivers with educational materials and reducing caregiver inconvenience may be instrumental to increase compliance.Keywords: medication adherence, respiratory syncytial virus infections, infant, premature, immunization, passive

  14. Comparing Pedophile Activity in Different P2P Systems

    Directory of Open Access Journals (Sweden)

    Raphaël Fournier

    2014-07-01

    Full Text Available Peer-to-peer (P2P systems are widely used to exchange content over the Internet. Knowledge of pedophile activity in such networks remains limited, despite having important social consequences. Moreover, though there are different P2P systems in use, previous academic works on this topic focused on one system at a time and their results are not directly comparable. We design a methodology for comparing KAD and eDonkey, two P2P systems among the most prominent ones and with different anonymity levels. We monitor two eDonkey servers and the KAD network during several days and record hundreds of thousands of keyword-based queries. We detect pedophile-related queries with a previously validated tool and we propose, for the first time, a large-scale comparison of pedophile activity in two different P2P systems. We conclude that there are significantly fewer pedophile queries in KAD than in eDonkey (approximately 0.09% vs. 0.25%.

  15. P2X(3) receptor gating near normal body temperature

    Czech Academy of Sciences Publication Activity Database

    Kmyhz, V.; Maximyuk, O.; Teslenko, V.; Verkhratsky, Alexei; Krishtal, O.

    2008-01-01

    Roč. 456, č. 12 (2008), s. 339-347 ISSN 0031-6768 Institutional research plan: CEZ:AV0Z50390703 Keywords : P2X3 receptors * Temperature-sensitivity * Gating Subject RIV: FH - Neurology Impact factor: 3.526, year: 2008

  16. Measurement and analysis of P2P IPTV program resource.

    Science.gov (United States)

    Wang, Wenxian; Chen, Xingshu; Wang, Haizhou; Zhang, Qi; Wang, Cheng

    2014-01-01

    With the rapid development of P2P technology, P2P IPTV applications have received more and more attention. And program resource distribution is very important to P2P IPTV applications. In order to collect IPTV program resources, a distributed multi-protocol crawler is proposed. And the crawler has collected more than 13 million pieces of information of IPTV programs from 2009 to 2012. In addition, the distribution of IPTV programs is independent and incompact, resulting in chaos of program names, which obstructs searching and organizing programs. Thus, we focus on characteristic analysis of program resources, including the distributions of length of program names, the entropy of the character types, and hierarchy depth of programs. These analyses reveal the disorderly naming conventions of P2P IPTV programs. The analysis results can help to purify and extract useful information from chaotic names for better retrieval and accelerate automatic sorting of program and establishment of IPTV repository. In order to represent popularity of programs and to predict user behavior and popularity of hot programs over a period, we also put forward an analytical model of hot programs.

  17. Measurement and Analysis of P2P IPTV Program Resource

    Directory of Open Access Journals (Sweden)

    Wenxian Wang

    2014-01-01

    Full Text Available With the rapid development of P2P technology, P2P IPTV applications have received more and more attention. And program resource distribution is very important to P2P IPTV applications. In order to collect IPTV program resources, a distributed multi-protocol crawler is proposed. And the crawler has collected more than 13 million pieces of information of IPTV programs from 2009 to 2012. In addition, the distribution of IPTV programs is independent and incompact, resulting in chaos of program names, which obstructs searching and organizing programs. Thus, we focus on characteristic analysis of program resources, including the distributions of length of program names, the entropy of the character types, and hierarchy depth of programs. These analyses reveal the disorderly naming conventions of P2P IPTV programs. The analysis results can help to purify and extract useful information from chaotic names for better retrieval and accelerate automatic sorting of program and establishment of IPTV repository. In order to represent popularity of programs and to predict user behavior and popularity of hot programs over a period, we also put forward an analytical model of hot programs.

  18. P2X receptor channels in endocrine glands

    Czech Academy of Sciences Publication Activity Database

    Stojilkovic, S. S.; Zemková, Hana

    2013-01-01

    Roč. 2, č. 4 (2013), s. 173-180 ISSN 2190-460X R&D Projects: GA ČR(CZ) GBP304/12/G069 Institutional support: RVO:67985823 Keywords : ATP * purinergic P2X receptor channels * pituitary * endocrine glands Subject RIV: ED - Physiology

  19. The P2 Masonic Lodge and Ceaușescu

    Directory of Open Access Journals (Sweden)

    Sabin Drăgulin

    2013-02-01

    Full Text Available In the following article the author aims at proving that Nicolae Ceausescu wasn't e member of the P2 masonic lodge. The conclusion has been driven following an in depth research conducted in the archives of the Italian state.

  20. Review of Brookhaven nuclear transparency measurements in (p,2p ...

    Indian Academy of Sciences (India)

    Review of Brookhaven nuclear transparency measurements in (p,2p) reactions at large Q. 2. ALAN S CARROLL. Collider-Accelerator Department, Brookhaven National Laboratory, Upton, NY 11973, USA. Abstract. In this contribution we summarize the results of two experiments to measure the trans- parency of nuclei in ...

  1. Functionalized Congeners of P2Y1 Receptor Antagonists:

    Energy Technology Data Exchange (ETDEWEB)

    de Castro, Sonia [National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; Maruoka, Hiroshi [National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; Hong, Kunlun [ORNL; Kilbey, II, S Michael [ORNL; Costanzi, Stefano [National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; Hechler, Béatrice [University of Strasbourg; Gachet, Christian [EFS-Alsace, Strasbourg, France; Harden, T. Kendall [University of North Carolina School of Medicine; Jacobson, Kenneth A. [National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health

    2010-01-01

    The P2Y{sub 1} receptor is a prothrombotic G protein-coupled receptor (GPCR) activated by ADP. Preference for the North (N) ring conformation of the ribose moiety of adenine nucleotide 3',5'-bisphosphate antagonists of the P2Y{sub 1} receptor was established by using a ring-constrained methanocarba (a bicyclo[3.1.0]hexane) ring as a ribose substitute. A series of covalently linkable N{sup 6}-methyl-(N)-methanocarba-2'-deoxyadenosine-3',5'-bisphosphates containing extended 2-alkynyl chains was designed, and binding affinity at the human (h) P2Y{sub 1} receptor determined. The chain of these functionalized congeners contained hydrophilic moieties, a reactive substituent, or biotin, linked via an amide. Variation of the chain length and position of an intermediate amide group revealed high affinity of carboxylic congener 8 (K{sub i} 23 nM) and extended amine congener 15 (K{sub i} 132 nM), both having a 2-(1-pentynoyl) group. A biotin conjugate 18 containing an extended {epsilon}-aminocaproyl spacer chain exhibited higher affinity than a shorter biotinylated analogue. Alternatively, click coupling of terminal alkynes of homologous 2-dialkynyl nucleotide derivatives to alkyl azido groups produced triazole derivatives that bound to the P2Y{sub 1} receptor following deprotection of the bisphosphate groups. The preservation of receptor affinity of the functionalized congeners was consistent with new P2Y{sub 1} receptor modeling and ligand docking. Attempted P2Y{sub 1} antagonist conjugation to PAMAM dendrimer carriers by amide formation or palladium-catalyzed reaction between an alkyne on the dendrimer and a 2-iodopurine-derivatized nucleotide was unsuccessful. A dialkynyl intermediate containing the chain length favored in receptor binding was conjugated to an azide-derivatized dendrimer, and the conjugate inhibited ADP-promoted human platelet aggregation. This is the first example of attaching a strategically functionalized P2Y receptor

  2. Evidence for requirement of tyrosine phosphorylation in endothelial P2Y- and P2U- purinoceptor stimulation of prostacyclin release.

    Science.gov (United States)

    Bowden, A.; Patel, V.; Brown, C.; Boarder, M. R.

    1995-01-01

    1. The release of prostacyclin (PGI2) from vascular endothelial cells is stimulated by ATP acting at G protein-coupled P2-purinoceptors. Here we investigate the hypothesis that tyrosine protein phosphorylations are involved in this response. 2. The use of Western blots with anti-phosphotyrosine antibodies showed that 30 microM 2MeSATP (selective for P2Y-purinoceptors), 300 microM UTP (selective for P2U-purinoceptors) and 300 microM ATP (effective at both these purinoceptors), each stimulate the tyrosine phosphorylation of proteins in bovine cultured aortic endothelial cells. Each of these agonists also stimulates 6-keto PGF1 alpha accumulation in the medium (an index of PGI2 release) in these cells in the same period. 3. The tyrosine kinase inhibitor, genistein, inhibits the 6-keto PGF1 alpha response with the same concentration-dependency (1-100 microM) as the tyrosine phosphorylation response. 4. Tyrphostin, a structurally and functionally distinct tyrosine kinase inhibitor, is also a potent inhibitor (0.1-10 microM) of the 6-keto PGF1 alpha response. 5. Neither tyrphostin nor genistein inhibit the phospholipase C response to P2-purinoceptor stimulation. Furthermore, these inhibitors do not affect the 6-keto PGF1 alpha response to ionomycin. 6. These results show that the regulation of vascular endothelial cells by ATP acting at both P2Y- and P2U-purinoceptors involves the stimulation of tyrosine phosphorylation, and suggest that this is a necessary event for the purinoceptor-mediated stimulation of PGI2 production. Images Figure 1 Figure 5 PMID:8590971

  3. Environmental compliance management system

    Energy Technology Data Exchange (ETDEWEB)

    Cason, A. [Dow Chemical Co., Midland, MI (United States); Larrinaga, L.

    1995-12-01

    A cross-functional team of environmental regulatory experts, plant managers, and plant engineers have been working since 1991 on the development, implementation and maintenance of the Environmental Compliance Management System. The Environmental Compliance Management System is a practical and accurate method of determining the applicability of the state and federal environmental regulations and of establishing standard and straightforward procedures to meet these requirements. The Environmental Compliance Management System allows individual manufacturing facilities to avoid the additional manpower that would be required to read, digest and decide on the applicability and plan of action to meet the requirements of all the environmental regulations.

  4. Regulatory Enforcement and Compliance

    DEFF Research Database (Denmark)

    May, Peter J.; Winter, Søren

    1999-01-01

    This study of municipal enforcement of agro-environmental regulations in Denmark provides an empirical understanding of how enforcement affects compliance. A key contribution is sorting out the relative influence of inspectors' different styles of enforcement and choices made by enforcement...... agencies. The latter are shown to be more important in bringing about compliance than are inspectors' enforcement styles. Municipal agencies are shown to increase compliance through the use of third parties, more frequent inspection, and setting priorities for inspection of major items. The findings about...

  5. Theatrical distribution and P2P movie piracy: a survey of P2P networks in Hungary using transactional data

    NARCIS (Netherlands)

    Bodó, B.; Lakatos, Z.

    2012-01-01

    This article examines what appears to be the most important factor shaping file sharing: the failure of traditional cultural markets to efficiently supply the demand in the online environment. Its findings are based on tracking the traffic of movies on three Hungarian P2P networks. This dataset is

  6. Role of P2X purinoceptor 7 in neurogenic pulmonary edema after subarachnoid hemorrhage in rats.

    Directory of Open Access Journals (Sweden)

    Sheng Chen

    Full Text Available INTRODUCTION: Neurogenic pulmonary edema (NPE is an acute and serious complication after subarachnoid hemorrhage (SAH with high mortality. The present study aimed to test the therapeutic potential of brilliant blue G (BBG, a selective P2X purinoceptor 7 (P2X7R antagonist, on NPE in a rat SAH model. METHODS: SAH was induced by endovascular perforation. 86 Sprague-Dawley rats were randomly divided into sham, vehicle-, or BBG-treatment groups. Mortality, body weight, SAH grading, neurological deficits, NPE clinical symptoms, and pulmonary index were measured at 24 hours following SAH. Western blot, gelatin zymography, lung histopathology, and immunofluorescence staining were performed in the left lung lobe to explore the underlying mechanisms at 24 hours post-surgery. RESULTS: The incidence of clinical symptoms was correlated with pulmonary index. P2X7R and the marker of alveolar type I epithelial cells (the mucin-type glycoprotein T1-α immunoreactivities were generally co-localized. BBG administration decreased mature interleukin-1β, myeloperoxidase, and matrix metallopeptidase-9 activation, but increased tight junction proteins, such as ZO-1 and occludin, which ameliorated pulmonary edema via anti-inflammation and improved neurological deficits. CONCLUSION: P2X7R inhibition prevented NPE after SAH by attenuating inflammation. Thus, BBG is a potential therapeutic application for NPE after SAH and warrants further research.

  7. Procedures to characterize and study P2Z/P2X7 purinoceptor: flow cytometry as a promising practical, reliable tool

    Directory of Open Access Journals (Sweden)

    Nihei Oscar Kenji

    2000-01-01

    Full Text Available The expression of P2Z/P2X7 purinoceptor in different cell types is well established. This receptor is a member of the ionotropic P2X receptor family, which is composed by seven cloned receptor subtypes (P2X1 - P2X7. Interestingly, the P2Z/P2X7 has a unique feature of being linked to a non-selective pore which allows the passage of molecules up to 900 Da depending on the cell type. Early studies of P2Z/P2X7 purinoceptor were exclusively based on classical pharmacological studies but the recent tools of molecular biology have enriched the analysis of the receptor expression. The majority of assays and techniques chosen so far to study the expression of P2Z/P2X7 receptor explore directly or indirectly the effects of the opening of P2Z/P2X7 linked pore. In this review we describe the main techniques used to study the expression and functionality of P2Z/P2X7 receptor. Additionally, the increasing need and importance of a multifunctional analysis of P2Z/P2X7 expression based on flow cytometry technology is discussed, as well as the adoption of a more complete analysis of P2Z/P2X7 expression involving different techniques.

  8. Supporting seamless mobility for P2P live streaming.

    Science.gov (United States)

    Kim, Eunsam; Kim, Sangjin; Lee, Choonhwa

    2014-01-01

    With advent of various mobile devices with powerful networking and computing capabilities, the users' demand to enjoy live video streaming services such as IPTV with mobile devices has been increasing rapidly. However, it is challenging to get over the degradation of service quality due to data loss caused by the handover. Although many handover schemes were proposed at protocol layers below the application layer, they inherently suffer from data loss while the network is being disconnected during the handover. We therefore propose an efficient application-layer handover scheme to support seamless mobility for P2P live streaming. By simulation experiments, we show that the P2P live streaming system with our proposed handover scheme can improve the playback continuity significantly compared to that without our scheme.

  9. Supporting Seamless Mobility for P2P Live Streaming

    Directory of Open Access Journals (Sweden)

    Eunsam Kim

    2014-01-01

    Full Text Available With advent of various mobile devices with powerful networking and computing capabilities, the users' demand to enjoy live video streaming services such as IPTV with mobile devices has been increasing rapidly. However, it is challenging to get over the degradation of service quality due to data loss caused by the handover. Although many handover schemes were proposed at protocol layers below the application layer, they inherently suffer from data loss while the network is being disconnected during the handover. We therefore propose an efficient application-layer handover scheme to support seamless mobility for P2P live streaming. By simulation experiments, we show that the P2P live streaming system with our proposed handover scheme can improve the playback continuity significantly compared to that without our scheme.

  10. Environmental Compliance Guide

    International Nuclear Information System (INIS)

    1981-02-01

    The Guide is intended to assist Department of Energy personnel by providing information on the NEPA process, the processes of other environmental statutes that bear on the NEPA process, the timing relationships between the NEPA process and these other processes, as well as timing relationships between the NEPA process and the development process for policies, programs, and projects. This information should be helpful not only in formulating environmental compliance plans but also in achieving compliance with NEPA and various other environmental statutes. The Guide is divided into three parts with related appendices: Part I provides guidance for developing environmental compliance plans for DOE actions; Part II is devoted to NEPA with detailed flowcharts depicting the compliance procedures required by CEQ regulations and Department of Energy NEPA Guidelines; and Part III contains a series of flowcharts for other Federal environmental requirements that may apply to DOE projects

  11. Environmental Compliance Issue Coordination

    Science.gov (United States)

    An order to establish the Department of Energy (DOE) requirements for coordination of significant environmental compliance issues to ensure timely development and consistent application of Departmental environmental policy and guidance

  12. Compliance for Green IT

    CERN Document Server

    Calder, Alan

    2009-01-01

    The growing range of Green IT regulations are challenging more and more organisations to take specific steps to ensure they are in compliance with sometimes complex regulations, ranging from cap & trade requirements through to regulations concerning IT equipment disposal.

  13. Environmental Compliance Guide

    Energy Technology Data Exchange (ETDEWEB)

    None

    1981-02-01

    The Guide is intended to assist Department of Energy personnel by providing information on the NEPA process, the processes of other environmental statutes that bear on the NEPA process, the timing relationships between the NEPA process and these other processes, as well as timing relationships between the NEPA process and the development process for policies, programs, and projects. This information should be helpful not only in formulating environmental compliance plans but also in achieving compliance with NEPA and various other environmental statutes. The Guide is divided into three parts with related appendices: Part I provides guidance for developing environmental compliance plans for DOE actions; Part II is devoted to NEPA with detailed flowcharts depicting the compliance procedures required by CEQ regulations and Department of Energy NEPA Guidelines; and Part III contains a series of flowcharts for other Federal environmental requirements that may apply to DOE projects.

  14. P2X1 Receptor Antagonists Inhibit HIV-1 Fusion by Blocking Virus-Coreceptor Interactions

    Science.gov (United States)

    Giroud, Charline; Marin, Mariana; Hammonds, Jason; Spearman, Paul

    2015-01-01

    ABSTRACT HIV-1 Env glycoprotein-mediated fusion is initiated upon sequential binding of Env to CD4 and the coreceptor CXCR4 or CCR5. Whereas these interactions are thought to be necessary and sufficient to promote HIV-1 fusion, other host factors can modulate this process. Previous studies reported potent inhibition of HIV-1 fusion by selective P2X1 receptor antagonists, including NF279, and suggested that these receptors play a role in HIV-1 entry. Here we investigated the mechanism of antiviral activity of NF279 and found that this compound does not inhibit HIV-1 fusion by preventing the activation of P2X1 channels but effectively blocks the binding of the virus to CXCR4 or CCR5. The notion of an off-target effect of NF279 on HIV-1 fusion is supported by the lack of detectable expression of P2X1 receptors in cells used in fusion experiments and by the fact that the addition of ATP or the enzymatic depletion of ATP in culture medium does not modulate viral fusion. Importantly, NF279 fails to inhibit HIV-1 fusion with cell lines and primary macrophages when added at an intermediate stage downstream of Env-CD4-coreceptor engagement. Conversely, in the presence of NF279, HIV-1 fusion is arrested downstream of CD4 binding but prior to coreceptor engagement. NF279 also antagonizes the signaling function of CCR5, CXCR4, and another chemokine receptor, as evidenced by the suppression of calcium responses elicited by specific ligands and by recombinant gp120. Collectively, our results demonstrate that NF279 is a dual HIV-1 coreceptor inhibitor that interferes with the functional engagement of CCR5 and CXCR4 by Env. IMPORTANCE Inhibition of P2X receptor activity suppresses HIV-1 fusion and replication, suggesting that P2X signaling is involved in HIV-1 entry. However, mechanistic experiments conducted in this study imply that P2X1 receptor is not expressed in target cells or involved in viral fusion. Instead, we found that inhibition of HIV-1 fusion by a specific P2X1

  15. Efficient Content Distribution in P2P and Cloud Service

    OpenAIRE

    E. Priya; A. Samydurai; T. Amitha

    2014-01-01

    Increasing the performance of cloud downloading service in a peer-peer network by efficient mode selection method. Using P2P to download video content often faces challenges like high bandwidth requirement, dealing with a huge number of peer requests, resulting in inefficient system performance. The latest premium service to have been developed is the cloud downloading. In this service, cloud storage is used to store the video content. The server is used to cache the user interested video con...

  16. Pure P2P mediation system: A mappings discovery approach

    Science.gov (United States)

    selma, El yahyaoui El idrissi; Zellou, Ahmed; Idri, Ali

    2015-02-01

    The information integration systems consist in offering a uniform interface to provide access to a set of autonomous and distributed information sources. The most important advantage of this system is that it allows users to specify what they want, rather than thinking about how to get the responses. The works realized in this area have particular leads to two major classes of integration systems: the mediation systems based on the paradigm mediator / adapter and peer to peer systems (P2P). The combination of both systems has led to a third type; is the mediation P2P systems. The P2P systems are large-scale systems, self-organized and distributed. They allow the resource management in a completely decentralized way. However, the integration of structured information sources, heterogeneous and distributed proves to be a complex problem. The objective of this work is to propose an approach to resolve conflicts and establish a mapping between the heterogeneous elements. This approach is based on clustering; the latter is to group similar Peers that share common information in the same subnet. Thus, to facilitate the heterogeneity, we introduced three additional layers of our hierarchy of peers: internal schema, external schema and Schema directory peer. We used linguistic techniques, and precisely the name correspondence technique, that is based on the similarity of names to propose a correspondence.

  17. An Overlapping Structured P2P for REIK Overlay Network

    Science.gov (United States)

    Liu, Wenjun; Song, Jingjing; Yu, Jiguo

    REIK is based on a ring which embedded an inverse Kautz digraph, to enable multi-path P2P routing. It has the constant degree and the logarithmic diameter DHT scheme with constant congestion and Byzantine fault tolerance. However, REIK did not consider the interconnection of many independent smaller networks. In this paper, we propose a new approach to build overlay network, OLS-REIK which is an overlapping structured P2P for REIK overlay network. It is a more flexible interconnecting different REIK network. Peers can belong to several rings, allowing this interconnection. By connecting smaller structured overlay networks in an unstructured way, it provides a cost effective alternative to hierarchical structured P2P systems requiring costly merging. Routing of lookup messages is performed as in REIK within one ring, but a peer belonging to several rings forwards the request to the different rings it belongs to. Furthermore a small number of across point is enough to ensure a high exhaustiveness level.

  18. Detecting P2P Botnet in Software Defined Networks

    Directory of Open Access Journals (Sweden)

    Shang-Chiuan Su

    2018-01-01

    Full Text Available Software Defined Network separates the control plane from network equipment and has great advantage in network management as compared with traditional approaches. With this paradigm, the security issues persist to exist and could become even worse because of the flexibility on handling the packets. In this paper we propose an effective framework by integrating SDN and machine learning to detect and categorize P2P network traffics. This work provides experimental evidence showing that our approach can automatically analyze network traffic and flexibly change flow entries in OpenFlow switches through the SDN controller. This can effectively help the network administrators manage related security problems.

  19. P2X7 receptors in satellite glial cells mediate high functional expression of P2X3 receptors in immature dorsal root ganglion neurons

    Directory of Open Access Journals (Sweden)

    Chen Yong

    2012-02-01

    Full Text Available Abstract Background The purinergic P2X3 receptor (P2X3R expressed in the dorsal root ganglion (DRG sensory neuron and the P2X7 receptor (P2X7R expressed in the surrounding satellite glial cell (SGC are two major receptors participating in neuron-SGC communication in adult DRGs. Activation of P2X7Rs was found to tonically reduce the expression of P2X3Rs in DRGs, thus inhibiting the abnormal pain behaviors in adult rats. P2X receptors are also actively involved in sensory signaling in developing rodents. However, very little is known about the developmental change of P2X7Rs in DRGs and the interaction between P2X7Rs and P2X3Rs in those animals. We therefore examined the expression of P2X3Rs and P2X7Rs in postnatal rats and determined if P2X7R-P2X3R control exists in developing rats. Findings We immunostained DRGs of immature rats and found that P2X3Rs were expressed only in neurons and P2X7Rs were expressed only in SGCs. Western blot analyses indicated that P2X3R expression decreased while P2X7R expression increased with the age of rats. Electrophysiological studies showed that the number of DRG neurons responding to the stimulation of the P2XR agonist, α,β-meATP, was higher and the amplitudes of α,β-meATP-induced depolarizations were larger in immature DRG neurons. As a result, P2X3R-mediated flinching responses were much more pronounced in immature rats than those found in adult rats. When we reduced P2X7R expression with P2X7R-siRNA in postnatal and adult rats, P2X3R-mediated flinch responses were greatly enhanced in both rat populations. Conclusions These results show that the P2X7R expression increases as rats age. In addition, P2X7Rs in SGCs exert inhibitory control on the P2X3R expression and function in sensory neurons of immature rats, just as observed in adult rats. Regulation of P2X7R expression is likely an effective way to control P2X3R activity and manage pain relief in infants.

  20. Parameterization-based tracking for the P2 experiment

    Science.gov (United States)

    Sorokin, Iurii

    2017-08-01

    The P2 experiment in Mainz aims to determine the weak mixing angle θW at low momentum transfer by measuring the parity-violating asymmetry of elastic electronproton scattering. In order to achieve the intended precision of Δ(sin2 θW)/sin2θW = 0:13% within the planned 10 000 hours of running the experiment has to operate at the rate of 1011 detected electrons per second. Although it is not required to measure the kinematic parameters of each individual electron, every attempt is made to achieve the highest possible throughput in the track reconstruction chain. In the present work a parameterization-based track reconstruction method is described. It is a variation of track following, where the results of the computation-heavy steps, namely the propagation of a track to the further detector plane, and the fitting, are pre-calculated, and expressed in terms of parametric analytic functions. This makes the algorithm extremely fast, and well-suited for an implementation on an FPGA. The method also takes implicitly into account the actual phase space distribution of the tracks already at the stage of candidate construction. Compared to a simple algorithm, that does not use such information, this allows reducing the combinatorial background by many orders of magnitude, down to O(1) background candidate per one signal track. The method is developed specifically for the P2 experiment in Mainz, and the presented implementation is tightly coupled to the experimental conditions.

  1. Decrease of serum adenine nucleotide hydrolysis in an irritant contact dermatitis mice model: potential P2X7R involvement.

    Science.gov (United States)

    Zanin, R F; da Silva, G L; Erig, T; Sperotto, N D M; Leite, C E; Coutinho-Silva, R; Batastini, A M O; Morrone, Fernanda Bueno

    2015-06-01

    Extracellular adenosine 5'-triphosphate (ATP) has significant effects on a variety of pathological conditions and it is the main physiological agonist of P2X7 purinergic receptor (P2X7R). It is known that ATP acting via purinergic receptors plays a relevant role on skin inflammation, and P2X7R is required to neutrophil recruitment in a mice model of irritant contact dermatitis (ICD).The present study investigated the effects of chemical irritant croton oil (CrO) upon ATP, ADP, and AMP hydrolysis in mice blood serum, and the potential involvement of P2X7R. The topical application CrO induced a decrease on soluble ATP/ADPase activities (~50 %), and the treatment with the selective P2X7R antagonist, A438079, reversed these effects to control level. Furthermore, we showed that CrO decreased cellular viability (52.6 % ± 3.9) in relation to the control and caused necrosis in keratinocytes (PI positive cells). The necrosis induced by CrO was prevented by the pre-treatment with the selective P2X7R antagonist A438079. The results presented herein suggest that CrO exerts an inhibitory effect on the activity of ATPDase in mouse serum, reinforcing the idea that ICD has a pathogenic mechanism dependent of CD39. Furthermore, it is tempting to suggest that P2X7R may act as a controller of the extracellular levels of ATP.

  2. Issues in patient compliance.

    Science.gov (United States)

    Murphy, J; Coster, G

    1997-12-01

    Patient compliance refers to the willingness and ability of an individual to follow health-related advice, to take medication as prescribed, to attend scheduled clinic appointments and to complete recommended investigations. It is a major health issue, with outcomes related to levels of morbidity, mortality and cost utilisation. Poor compliance has been reported as the most common cause of nonresponse to medication, with evidence to show that patients who adhere to treatment recommendations have better health outcomes than those who do not adhere, even when taking a placebo. Evidence-based practice guidelines, founded on clinical, behavioural and educational concepts, provide a means of measuring outcomes related to health status, patient satisfaction and cost-benefit issues, and may help to ensure that responsibility for compliance is shared between the clinician and the patient.

  3. Adaptive Streaming of Scalable Videos over P2PTV

    Directory of Open Access Journals (Sweden)

    Youssef Lahbabi

    2015-01-01

    Full Text Available In this paper, we propose a new Scalable Video Coding (SVC quality-adaptive peer-to-peer television (P2PTV system executed at the peers and at the network. The quality adaptation mechanisms are developed as follows: on one hand, the Layer Level Initialization (LLI is used for adapting the video quality with the static resources at the peers in order to avoid long startup times. On the other hand, the Layer Level Adjustment (LLA is invoked periodically to adjust the SVC layer to the fluctuation of the network conditions with the aim of predicting the possible stalls before their occurrence. Our results demonstrate that our mechanisms allow quickly adapting the video quality to various system changes while providing best Quality of Experience (QoE that matches current resources of the peer devices and instantaneous throughput available at the network state.

  4. The P2X7 receptor regulates cell survival, migration and invasion of pancreatic ductal adenocarcinoma cells.

    Science.gov (United States)

    Giannuzzo, Andrea; Pedersen, Stine Falsig; Novak, Ivana

    2015-11-25

    Pancreatic ductal adenocarcinoma (PDAC) is presently one of the cancers with the worst survival rates and least effective treatments. Moreover, total deaths due to PDAC are predicted to increase in the next 15 years. Therefore, novel insights into basic mechanism of PDAC development and therapies are needed. PDAC is characterized by a complex microenvironment, in which cancer and stromal cells release different molecules, such as ATP. ATP can be transported and/or exocytosed from active cancer cells and released from dying cells in the necrotic core of the cancer. We hypothesized that one of the ATP receptors, the P2X7 receptor (P2X7R) could be an important player in PDAC behaviour. We determined the expression (real time PCR and Western blot) and localization (immunofluorescence) of P2X7R in human PDAC cell lines (AsPC-1, BxPC-3, Capan-1, MiaPaCa-2, Panc-1) and a "normal" human pancreatic duct epithelial cell line (HPDE). The function of P2X7R in proliferation (BrdU assay), migration (wound assay) and invasion (Boyden chamber with matrigel) was characterized. Furthermore, we studied P2X7R-dependent pore formation (YoPro-1 assay) and cell death (caspase and annexin V / propidium iodide assays). We found higher expression of P2X7R protein in PDAC compared to HPDE cells. P2X7R had notable disparate effects on PDAC survival. Firstly, high concentrations of ATP or the specific P2X7R agonist, BzATP, had cytotoxic effects in all cell lines, and cell death was mediated by necrosis. Moreover, the P2X7R-pore antagonist, A438079, prevented ATP-induced pore formation and cell death. Second, in basal conditions and with low concentrations of ATP/BzATP, the P2X7R allosteric inhibitor AZ10606120 reduced proliferation in all PDAC cell lines. P2X7R also affected other key characteristics of cancer cell behavior. AZ10606120 reduced cell migration and invasion in PDAC cell lines compared to that of untreated/vehicle-treated control cells, and stimulation with sub

  5. The Amsterdam Hip Protector Study: Compliance and determinants of compliance

    NARCIS (Netherlands)

    van Schoor, N.M.; Asma, G.; Smit, J.H.; Bouter, L.M.; Lips, P.T.A.M.

    2003-01-01

    Hip protectors appear to be effective in reducing the incidence of hip fractures. However, compliance is often poor. Therefore, the objective of this study was to examine the compliance and determinants of compliance with external hip protectors. A prospective study was performed in residents from

  6. Rocky Flats Compliance Program

    International Nuclear Information System (INIS)

    1994-02-01

    The Department of Energy (DOE) established the Office of Technology Development (EM-50) (OTD) as an element of Environmental Restoration and Waste Management (EM) in November 1989. The primary objective of the Office of Technology Development, Rocky Flats Compliance Program (RFCP), is to develop altemative treatment technologies for mixed low-level waste (wastes containing both hazardous and radioactive components) to use in bringing the Rocky Flats Plant (RFP) into compliance with Federal and state regulations and agreements. Approximately 48,000 cubic feet of untreated low-level mixed waste, for which treatment has not been specified, are stored at the RFP. The cleanup of the Rocky Flats site is driven by agreements between DOE, the Environmental Protection Agency (EPA), and the Colorado Department of Health (CDH). Under these agreements, a Comprehensive Treatment and Management Plan (CTMP) was drafted to outline the mechanisms by which RFP will achieve compliance with the regulations and agreements. This document describes DOE's strategy to treat low-level mixed waste to meet Land Disposal Restrictions and sets specific milestones related to the regulatory aspects of technology development. These milestones detail schedules for the development of technologies to treat all of the mixed wastes at the RFP. Under the Federal Facilities Compliance Act (FFCA), the CTMP has been incorporated into Rocky Flats Plant Conceptual Site Treatment Plan (CSTP). The CSTP will become the Rocky Flats Plant site Treatment Plan in 1995 and will supersede the CTMP

  7. Strategisk compliance og regulering

    DEFF Research Database (Denmark)

    Kühn Pedersen, Mogens

    2016-01-01

    Denne artikel introducerer strategisk compliance og påpeger dens samspil med klassiske og nyere former for reguleringer i digital værdiskabelse. Konteksten er den digitale økonomi, som vokser frem imellem den materielle økonomis bærepiller: Virksomheder og markeder, men består af en helt ny...... materialitet, som er det digitale univers og dets modsvarighed i nye krav til compliance. Den nye materialitet stiller nye krav, hvad angår digitale processer og transaktioner. Klassisk regulering, som aktører ikke selv kan ændre, støder på egenregulering, hvor aktørerne selv opsætter regler for at skabe...... digital værdi. Dette kalder på strategisk compliance. Med digitalisering er strategisk compliance sat på dagsordnen i reguleringsdebatten. Vi hævder, at regulering og egenregulering kan komme til at virke komplementært i det post-industrielle, digitaliserede samfund....

  8. Environmental compliance and cleanup

    International Nuclear Information System (INIS)

    Black, D.G.

    1995-01-01

    This section of the 1994 Hanford Site Environmental Report summarizes the roles of the principal agencies, organizations, and public in environmental compliance and cleanup of the Hanford Site. Regulatory oversight, the Federal Facility Agreement and Consent Order, the role of Indian tribes, public participation, and CERCLA Natural Resource Damage Assessment Trustee Activities are all discussed

  9. Validating year 2000 compliance

    NARCIS (Netherlands)

    A. van Deursen (Arie); P. Klint (Paul); M.P.A. Sellink

    1997-01-01

    textabstractValidating year 2000 compliance involves the assessment of the correctness and quality of a year 2000 conversion. This entails inspecting both the quality of the conversion emph{process followed, and of the emph{result obtained, i.e., the converted system. This document provides an

  10. Financial Markets and Compliance

    NARCIS (Netherlands)

    van de Laar, T.A.H.M.; Bleker, Sylvie; Houben, Raf

    2017-01-01

    This chapter will focus on the goals of financial market regulation through the rules of economics, the strategies financial regulation employs to achieve these goals and the insights this provides for the compliance profession. For an overview of the goals and strategies of financial regulation

  11. The USAID Environmental Compliance Database

    Data.gov (United States)

    US Agency for International Development — The Environmental Compliance Database is a record of environmental compliance submissions with their outcomes. Documents in the database can be found by visiting the...

  12. Patient compliance with antimicrobial drugs: A Chinese survey.

    Science.gov (United States)

    Tong, Shuangmei; Pan, Jiaqian; Lu, Shan; Tang, Jing

    2018-04-01

    Antimicrobial therapy is among the mainstream treatment modalities employed in clinical settings. Antimicrobial sensitivity of the pathogen and patient compliance are key determinants of the efficacy of antimicrobial therapy. In this study, we sought to investigate the factors that affect patient compliance to antimicrobial therapy in a Chinese teaching hospital to enhance patient compliance and to prevent abuse and misuse of antibiotics by patients. A questionnaire survey was conducted among patients willing to answer all the questions who were prescribed antimicrobial drugs orally, and for whom at least half of the duration of therapy was not under the supervision of a doctor or nurse. Data analyses were performed using Kruskal-Wallis test and multivariate logistic regression. A total of 720 patients participated in the survey; of these, 714 patients provided complete data and were included in the analysis. Up to 86.97% of patients showed noncompliance to antimicrobial therapy (total compliance score compliance (total compliance score = 8). On multivariate analyses, understanding of the treatment was an important factor associated with compliance. A range of factors were associated with compliance to antimicrobial therapy, including understanding of the treatment, gender, age, home address, education level, and family income. Copyright © 2018 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.

  13. C/2013 P2 Pan STARRS - The Manx Comet

    Science.gov (United States)

    Meech, Karen J.; Yang, Bin; Keane, Jacqueline; Hainaut, Olivier; Kleyna, Jan; Hsieh, Henry; Bauer, James; Wainscoat, Richard; Veres, Peter

    2014-11-01

    On Aug 4, 2013 an apparently asteroidal object was discovered by the Pan STARRS1 (PS1) survey telescope on Haleakala at magnitude 20.4 (corresponding to a nucleus radius between 1.4-2.9 km for albedos between 0.25-0.04). PS1 pre-recovery images taken on July 26 and on Aug. 3 allowed a good orbit to be determined. The orbit looks like that of a long-period comet with a semi major axis of 2720 AU and an eccentricity of 0.999. Shortly following the discovery, reports from small telescopes came in that there was low level activity associated with this object (at r = 3.45 AU), and the object was designated P/2013 P2 (Pan STARRS). The activity was not seen in images obtained with PS1, the Faulkes N telescope or the CFHT 3.6m, however the object was passing through a region of significant nebulosity. Deep images obtained on the CFHT on Aug. 8 and follow up images obtained with the Gemini North 8m telescope on Sep. 9 showed a very faint tail extending a few arcsec to PA=45 deg (inconsistent with the earlier reports). The object was observed using several facilities up until solar conjunction, and again after perihelion (Feb. 17, 2014) in March, with little increase in activity. A search of the NEOWISE archives show no detection during the cryogenic and immediate pos-cryogenic phases, so we can only place an upper limit on the nucleus size from these data. An object on a long-period comet orbit at this heliocentric distance typically should be very active, and our team hypothesized that this could either be a nearly-extinct comet or possibly inner solar system material ejected to the outer solar system during planet migration as predicted by various dynamical models. To distinguish between these scenarios, we obtained both optical and near-IR spectra of P/2013 P2 on 2014 May 7 and 21, when the object was at r=2.97 and 2.99 AU, respectively. Initial reductions show no emission lines. We will report on our spectra and imaging data, and discuss the implications for the origin

  14. Opposing Roles of Calcium and Intracellular ATP on Gating of the Purinergic P2X2 Receptor Channel

    Directory of Open Access Journals (Sweden)

    Milos B. Rokic

    2018-04-01

    Full Text Available P2X2 receptors (P2X2R exhibit a slow desensitization during the initial ATP application and a progressive, calcium-dependent increase in rates of desensitization during repetitive stimulation. This pattern is observed in whole-cell recordings from cells expressing recombinant and native P2X2R. However, desensitization is not observed in perforated-patched cells and in two-electrode voltage clamped oocytes. Addition of ATP, but not ATPγS or GTP, in the pipette solution also abolishes progressive desensitization, whereas intracellular injection of apyrase facilitates receptor desensitization. Experiments with injection of alkaline phosphatase or addition of staurosporine and ATP in the intracellular solution suggest a role for a phosphorylation-dephosphorylation in receptor desensitization. Mutation of residues that are potential phosphorylation sites identified a critical role of the S363 residue in the intracellular ATP action. These findings indicate that intracellular calcium and ATP have opposing effects on P2X2R gating: calcium allosterically facilitates receptor desensitization and ATP covalently prevents the action of calcium. Single cell measurements further revealed that intracellular calcium stays elevated after washout in P2X2R-expressing cells and the blockade of mitochondrial sodium/calcium exchanger lowers calcium concentrations during washout periods to basal levels, suggesting a role of mitochondria in this process. Therefore, the metabolic state of the cell can influence P2X2R gating.

  15. Improved Degree Search Algorithms in Unstructured P2P Networks

    Directory of Open Access Journals (Sweden)

    Guole Liu

    2012-01-01

    Full Text Available Searching and retrieving the demanded correct information is one important problem in networks; especially, designing an efficient search algorithm is a key challenge in unstructured peer-to-peer (P2P networks. Breadth-first search (BFS and depth-first search (DFS are the current two typical search methods. BFS-based algorithms show the perfect performance in the aspect of search success rate of network resources, while bringing the huge search messages. On the contrary, DFS-based algorithms reduce the search message quantity and also cause the dropping of search success ratio. To address the problem that only one of performances is excellent, we propose two memory function degree search algorithms: memory function maximum degree algorithm (MD and memory function preference degree algorithm (PD. We study their performance including the search success rate and the search message quantity in different networks, which are scale-free networks, random graph networks, and small-world networks. Simulations show that the two performances are both excellent at the same time, and the performances are improved at least 10 times.

  16. Synthesis and Potency of Novel Uracil Nucleotides and Derivatives as P2Y2 and P2Y6 Receptor Agonists

    OpenAIRE

    Ko, Hyojin; Carter, Rhonda L.; Cosyn, Liesbet; Petrelli, Riccardo; de Castro, Sonia; Besada, Pedro; Zhou, Yixing; Cappellacci, Loredana; Franchetti, Palmarisa; Grifantini, Mario; Van Calenbergh, Serge; Harden, T. Kendall; Jacobson, Kenneth A.

    2008-01-01

    The phosphate, uracil, and ribose moieties of uracil nucleotides were varied structurally for evaluation of agonist activity at the human P2Y2, P2Y4, and P2Y6 receptors. The 2-thio modification, found previously to enhance P2Y2 receptor potency, could be combined with other favorable modifications to produce novel molecules that exhibit high potencies and receptor selectivities. Phosphonomethylene bridges introduced for stability in analogues of UDP, UTP and uracil dinucleotides markedly redu...

  17. Peripheral nerve P2 basic protein and the Guillain-Barre syndrome : In vitro demonstration of P2-specific antibody-secreting cells

    NARCIS (Netherlands)

    Luijten, J.A.F.M.; Jong, W.A.C. de; Demel, R.A.; Heijnen, C.J.; Ballieux, R.E.

    1984-01-01

    An immune response to the peripheral nerve basic protein P2 may be operative in the pathogenesis of the Guillain-Barré syndrome (GBS). A method is described for the purification of P2 of human origin. Purified P2 was used to investigate whether lymphocytes derived from peripheral blood of GBS

  18. A potential therapeutic role for P2X7 receptor (P2X7R) antagonists in the treatment of inflammatory diseases.

    Science.gov (United States)

    Arulkumaran, Nishkantha; Unwin, Robert J; Tam, Frederick Wk

    2011-07-01

    The P2X7 receptor (P2X7R) has an important role in inflammation and immunity, but until recently, clinical application has been limited by a lack of specific antagonists. Recent studies using P2X7R knockout mice and specific receptor antagonists have shown that the P2X7R is an important therapeutic target in inflammatory diseases. We have reviewed the current literature on the role of the P2X7R in inflammatory diseases, focusing on potential therapeutic applications of selective P2X7R antagonists as anti-inflammatory agents. Particular emphasis has been placed on the potential role of P2X7R in common inflammatory diseases. The latest developments in Phase I and II clinical trials of P2X7R antagonists are covered. Recent studies using gene knockout mice and selective P2X7R antagonists suggest that P2X7R is a viable therapeutic target for inflammatory diseases. However, efficacious P2X7R antagonists for use in clinical studies are still at an early stage of development. Future challenges include: identifying potential toxicity and side effects of treatment, timing of treatment initiation and its duration in chronic inflammatory conditions, optimum dosage and development of a functional assay for P2X7R that would help to guide treatment.

  19. Double P2X2/P2X3 Purinergic Receptor Knockout Mice Do Not Taste NaCl or the Artificial Sweetener SC45647

    Science.gov (United States)

    Eddy, Meghan C.; Eschle, Benjamin K.; Barrows, Jennell; Hallock, Robert M.; Finger, Thomas E.

    2009-01-01

    The P2X ionotropic purinergic receptors, P2X2 and P2X3, are essential for transmission of taste information from taste buds to the gustatory nerves. Mice lacking both P2X2 and P2X3 purinergic receptors (P2X2/P2X3Dbl−/−) exhibit no taste-evoked activity in the chorda tympani and glossopharyngeal nerves when stimulated with taste stimuli from any of the 5 classical taste quality groups (salt, sweet, sour, bitter, and umami) nor do the mice show taste preferences for sweet or umami, or avoidance of bitter substances (Finger et al. 2005. ATP signaling is crucial for communication from taste buds to gustatory nerves. Science. 310[5753]:1495–1499). Here, we compare the ability of P2X2/P2X3Dbl−/− mice and P2X2/P2X3Dbl+/+ wild-type (WT) mice to detect NaCl in brief-access tests and conditioned aversion paradigms. Brief-access testing with NaCl revealed that whereas WT mice decrease licking at 300 mM and above, the P2X2/P2X3Dbl−/− mice do not show any change in lick rates. In conditioned aversion tests, P2X2/P2X3Dbl−/− mice did not develop a learned aversion to NaCl or the artificial sweetener SC45647, both of which are easily avoided by conditioned WT mice. The inability of P2X2/P2X3Dbl−/− mice to show avoidance of these taste stimuli was not due to an inability to learn the task because both WT and P2X2/P2X3Dbl−/− mice learned to avoid a combination of SC45647 and amyl acetate (an odor cue). These data suggest that P2X2/P2X3Dbl−/− mice are unable to respond to NaCl or SC45647 as taste stimuli, mirroring the lack of gustatory nerve responses to these substances. PMID:19833661

  20. An integral approach to compliance.

    Science.gov (United States)

    Goddard, T G

    2000-08-01

    Financial managers of managed care organizations should structure their compliance plans to conform with requirements shaped by forces such as judicial decisions and extralegal standards for managed care operations, in addition to state and Federal laws and regulations. In addition to researching the law and training employees, an integral compliance plan should include monitoring organizational systems that can encourage or impede compliance, measuring employees' motivation to adhere to compliance standards, and modifying corporate culture to support compliance goals. Managed care organizations should empower compliance officers with a broad range of tools to assess and improve compliance efforts, or risk having organizational decisions examined externally through the lens of an onerous, dynamic system of laws and judicial decisions.

  1. Role of spinal P2Y6 and P2Y11 receptors in neuropathic pain in rats: possible involvement of glial cells

    OpenAIRE

    Barragán-Iglesias, Paulino; Pineda-Farias, Jorge Baruch; Cervantes-Durán, Claudia; Bravo-Hernández, Mariana; Rocha-González, Héctor Isaac; Murbartián, Janet; Granados-Soto, Vinicio

    2014-01-01

    Background The participation of spinal P2X receptors in neuropathic pain is well recognized. However, the role of P2Y receptors has been less studied. The purpose of this study was to investigate the contribution of spinal P2Y6,11 receptors following peripheral nerve damage induced by spinal nerve ligation. In addition, we determined the expression of P2Y6,11 receptors in the dorsal spinal cord in presence of the selective P2Y6,11 receptors antagonists. Furthermore, we evaluated the participa...

  2. 4-Alkyloxyimino derivatives of uridine-5'-triphosphate: distal modification of potent agonists as a strategy for molecular probes of P2Y2, P2Y4, and P2Y6 receptors.

    Science.gov (United States)

    Jayasekara, P Suresh; Barrett, Matthew O; Ball, Christopher B; Brown, Kyle A; Hammes, Eva; Balasubramanian, Ramachandran; Harden, T Kendall; Jacobson, Kenneth A

    2014-05-08

    Extended N(4)-(3-arylpropyl)oxy derivatives of uridine-5'-triphosphate were synthesized and potently stimulated phospholipase C stimulation in astrocytoma cells expressing G protein-coupled human (h) P2Y receptors (P2YRs) activated by UTP (P2Y2/4R) or UDP (P2Y6R). The potent P2Y4R-selective N(4)-(3-phenylpropyl)oxy agonist was phenyl ring-substituted or replaced with terminal heterocyclic or naphthyl rings with retention of P2YR potency. This broad tolerance for steric bulk in a distal region was not observed for dinucleoside tetraphosphate agonists with both nucleobases substituted. The potent N(4)-(3-(4-methoxyphenyl)-propyl)oxy analogue 19 (EC50: P2Y2R, 47 nM; P2Y4R, 23 nM) was functionalized for chain extension using click tethering of fluorophores as prosthetic groups. The BODIPY 630/650 conjugate 28 (MRS4162) exhibited EC50 values of 70, 66, and 23 nM at the hP2Y2/4/6Rs, respectively, and specifically labeled cells expressing the P2Y6R. Thus, an extended N(4)-(3-arylpropyl)oxy group accessed a structurally permissive region on three Gq-coupled P2YRs, and potency and selectivity were modulated by distal structural changes. This freedom of substitution was utilized to design of a pan-agonist fluorescent probe of a subset of uracil nucleotide-activated hP2YRs.

  3. Action of Natural Products on P2 Receptors: A Reinvented Era for Drug Discovery

    Directory of Open Access Journals (Sweden)

    Luiz Alves

    2012-11-01

    Full Text Available Natural products contribute significantly to available drug therapies and have been a rich source for scientific investigation. In general, due to their low cost and traditional use in some cultures, they are an object of growing interest as alternatives to synthetic drugs. With several diseases such as cancer, and inflammatory and neuropathic diseases having been linked to the participation of purinergic (P2 receptors, there has been a flurry of investigations on ligands within natural products. Thirty-four different sources of these compounds have been found so far, that have shown either agonistic or antagonistic effects on P2 receptors. Of those, nine different plant sources demonstrated effects on P2X2, P2X3, P2X7, and possibly P2Y12 receptor subtypes. Microorganisms, which represent the largest group, with 26 different sources, showed effects on both receptor subtypes, ranging from P2X1 to P2X4 and P2X7, and P2Y1, P2Y2, P2Y4, and P2Y6. In addition, there were seventeen animal sources that affected P2X7 and P2Y1 and P2Y12 receptors. Natural products have provided some fascinating new mechanisms and sources to better understand the P2 receptor antagonism. Moreover, current investigations should clarify further pharmacological mechanisms in order to consider these products as potential new medicines.

  4. Role of spinal P2Y6 and P2Y11 receptors in neuropathic pain in rats: possible involvement of glial cells.

    Science.gov (United States)

    Barragán-Iglesias, Paulino; Pineda-Farias, Jorge Baruch; Cervantes-Durán, Claudia; Bravo-Hernández, Mariana; Rocha-González, Héctor Isaac; Murbartián, Janet; Granados-Soto, Vinicio

    2014-05-20

    The participation of spinal P2X receptors in neuropathic pain is well recognized. However, the role of P2Y receptors has been less studied. The purpose of this study was to investigate the contribution of spinal P2Y6,11 receptors following peripheral nerve damage induced by spinal nerve ligation. In addition, we determined the expression of P2Y6,11 receptors in the dorsal spinal cord in presence of the selective P2Y6,11 receptors antagonists. Furthermore, we evaluated the participation of spinal microglia and astrocytes in the pronociceptive role of P2Y6,11 receptors. Spinal administration of the selective P2Y6 (MRS2578, 10-100 μM) and P2Y11 (NF340, 0.3-30 μM) receptor antagonists reduced tactile allodynia in spinal nerve ligated rats. Nerve injury increased the expression of P2Y6,11 receptors at 7, 14 and 21 days after injury. Furthermore, intrathecal administration of MRS2578 (100 μM/day) and NF340 (30 μM/day) for 3 days significantly reduced spinal nerve injury-induced increase in P2Y6,11 receptors expression, respectively. Spinal treatment (on day 14 after injury) with minocycline (100 μg/day) or fluorocitrate (1 nmol/day) for 7 days reduced tactile allodynia and spinal nerve injury-induced up-regulation in Iba-1 and GFAP, respectively. In addition, minocycline reduced nerve injury-induced up-regulation in P2Y6,11 receptors whereas that fluorocitrate diminished P2Y11, but not P2Y6, receptors up-regulation. Intrathecal treatment (on day 21 after injury) with the selective P2Y6 (PSB0474, 3-30 μM) and P2Y11 (NF546, 1-10 μM) receptor agonists produced remarkable tactile allodynia in nerve ligated rats previously treated with minocycline or fluorocitrate for 7 days. Our data suggest that spinal P2Y6 is present in spinal microglia while P2Y11 receptors are present in both spinal microglia and astrocytes, and both receptors are up-regulated in rats subjected to spinal nerve injury. In addition, our data suggest that the spinal P2Y6 and P2Y11

  5. P2X7R: a potential key regulator of acute gouty arthritis.

    Science.gov (United States)

    Tao, Jin-Hui; Zhang, Yong; Li, Xiang-Pei

    2013-12-01

    Acute gouty arthritis is an inflammatory disease resulting from the precipitation of long-term hyperuricemia-induced monosodium urate (MSU) crystals in joints, which stimulates the production of interleukin-1beta (IL-1β) and initiates an inflammatory reaction. However, some patients having MSU crystals in the joints never develop acute gouty arthritis, indicating that other predisposing factors are required for the disease onset. This review described the mechanism of production of IL-1β by MSU crystals and other possible factors during a gout attack. The relevant English literature on IL-1β secretion stimulated by MSU crystals and other possible factors during acute gouty arthritis flares was searched and carefully reviewed. MSU crystals lead to the onset of acute gouty arthritis mainly through the activation of Toll-like receptors (TLRs) and NACHT-LRR-PYD-containing protein 3 (NALP3) inflammasome signaling and downstream IL-1β production. The predisposing factors of acute gouty arthritis, such as strenuous exercise, cold, alcolholism, and overeating have a common characteristic inducing dramatic changes of adenosine triphosphate (ATP) in the body. The ATP changes can activate the purinergic receptor P2X ligand-gated ion channel 7 (P2X7R) signaling system to regulate IL-1β secretion. We hypothesize that acute gouty arthritis is induced by two synergistic effects; one is the stimulation of MSU crystals and the other is the activation of P2X7R signaling pathways by extracellular ATP changes, which together lead to the production of IL-1β and the initiation of acute gouty arthritis. This hypothesis will provide a new avenue for the prevention and treatment of acute gouty arthritis. Copyright © 2013 Elsevier Inc. All rights reserved.

  6. Physiological effects of ovarian hormones: clinical aspects and compliance

    DEFF Research Database (Denmark)

    Ottesen, B; Pedersen, A T

    1996-01-01

    Menopause is marked by the permanent cessation of menstrual bleeding. Deprivation of ovarian hormones due to decreasing ovarian activity causes widespread physiological effects. Disturbances in menstrual pattern and hot flashes are major reasons for hormone replacement therapy (HRT), but prevention...... of osteoporosis and cardiovascular disease are other considerations. Despite the large number of different hormone treatment regimens available, such problems as continued bleeding and concern about side effects engenders low compliance. To enhance compliance, it is important to ensure that post-menopausal women...... and their physicians are aware of the probable risks and benefits of hormone therapy before deciding whether or not to use preventive HRT....

  7. Physiopathological implications of P2X1 and P2X7 receptors in regulation of glomerular hemodynamics in angiotensin II-induced hypertension.

    Science.gov (United States)

    Franco, Martha; Bautista-Pérez, Rocío; Cano-Martínez, Agustina; Pacheco, Ursino; Santamaría, José; Del Valle Mondragón, Leonardo; Pérez-Méndez, Oscar; Navar, L Gabriel

    2017-07-01

    Deleterious effects of purinergic P2X 1 and P2X 7 receptors (P2XRs) in ANG II-dependent hypertension include increased renal vascular resistance, and impaired autoregulation and pressure natriuresis. However, their specific effects on the determinants of glomerular hemodynamics remain incompletely delineated. To investigate the P2XR contributions to altered glomerular hemodynamics in hypertension, the effects of acute blockade of P2X 1 R, P2X 7 R, and P2X 4 R with NF449, A438079, and PSB12054, respectively, were evaluated in ANG II-infused rats (435 ng·kg -1 ·min -1 ). P2X 1 R or P2X 7 R blockade reduced afferent (6.85 ± 1.05 vs. 2.37 ± 0.20 dyn·s -1 ·cm -5 ) and efferent (2.85 ± 0.38 vs. 0.99 ± 0.07 dyn·s -1 ·cm -5 ) arteriolar resistances, leading to increases in glomerular plasma flow (75.82 ± 5.58 vs. 206.7 ± 16.38 nl/min), ultrafiltration coefficient (0.0198 ± 0.0024 vs. 0.0512 ± 0.0046 nl·min -1 ·mmHg -1 ), and single-nephron glomerular filtration rate (22.73 ± 2.02 vs. 51.56 ± 3.87 nl/min) to near normal values. Blockade of P2X 4 R did not elicit effects in hypertensive rats. In normotensive sham-operated rats, only the P2X 1 R antagonist caused an increase plasma flow and single-nephron glomerular filtration rate, whereas the P2X 4 R antagonist induced glomerular vasoconstriction that was consistent with evidence that P2X 4 R stimulation increases release of nitric oxide from endothelial cells. Mean arterial pressure remained unchanged in both hypertensive and normotensive groups. Western blot analysis showed overexpression of P2X 1 R, P2X 7 R, and P2X 4 R proteins in hypertensive rats. Whereas it has been generally assumed that the altered glomerular vascular resistances in ANG II hypertension are due to AT 1 receptor-mediated vasoconstriction, these data indicate a predominant P2X 1 R and P2X 7 R control of glomerular hemodynamics in ANG II hypertension. Copyright © 2017 the American Physiological Society.

  8. Compliance among soft contact lens wearers.

    Science.gov (United States)

    Kuzman, Tomislav; Kutija, Marija Barisić; Masnec, Sanja; Jandroković, Sonja; Mrazovac, Danijela; Jurisić, Darija; Skegro, Ivan; Kalauz, Miro; Kordić, Rajko

    2014-12-01

    Contact lens compliance is proven to be crucial for preventing lens wear-related complications because of the interdependence of the steps in lens care regime and their influence on lens system microbial contamination. Awareness of the patients' lens handling compliance as well as correct recognition of non-compliant behaviours is the basis for creating more targeted strategies for patient education. The aim of this study was to investigate compliance among soft contact lens (SCL) wearers in different aspects of lens care handling and wearing habits. In our research 50 asymptomatic lens wearers filled out a questionnaire containing demographic data, lens type, hygiene and wearing habits, lenses and lens care system replacement schedule and self-evaluation of contact lens handling hygiene. We established criteria of compliance according to available manufacturer's recommendations, prior literature and our clinical experience. Only 2 (4%) of patients were fully compliant SCL wearers. The most common non-compliant behaviours were insufficient lens solution soaking time (62%), followed by failure to daily exchange lens case solution and showering while wearing lenses. 44% of patients reported storing lenses in saline solution. Mean lens storage case replacement was 3.6 months, with up to 78% patients replacing lens case at least once in 3 months. Average grade in self evaluating level of compliance was very good (4 +/- 0.78) (from 1-poor level of hygiene to 5-great level of hygiene). Lens wearers who reported excessive daily lens wear and more than 10 years of lens wearing experience were also found to be less compliant with other lens system care procedures. (t = -2.99, df=47, p lens system maintenance steps. Most common non-compliant behaviours were the ones that are crucial for maintaining lens sterility and preventing infection. Despite the low objective compliance rate, self grading was relatively high. Therefore, these results indicate the need for patient

  9. Activation of P2X7 promotes cerebral edema and neurological injury after traumatic brain injury in mice.

    Science.gov (United States)

    Kimbler, Donald E; Shields, Jessica; Yanasak, Nathan; Vender, John R; Dhandapani, Krishnan M

    2012-01-01

    Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Cerebral edema, the abnormal accumulation of fluid within the brain parenchyma, contributes to elevated intracranial pressure (ICP) and is a common life-threatening neurological complication following TBI. Unfortunately, neurosurgical approaches to alleviate increased ICP remain controversial and medical therapies are lacking due in part to the absence of viable drug targets. In the present study, genetic inhibition (P2X7-/- mice) of the purinergic P2x7 receptor attenuated the expression of the pro-inflammatory cytokine, interleukin-1β (IL-1β) and reduced cerebral edema following controlled cortical impact, as compared to wild-type mice. Similarly, brilliant blue G (BBG), a clinically non-toxic P2X7 inhibitor, inhibited IL-1β expression, limited edemic development, and improved neurobehavioral outcomes after TBI. The beneficial effects of BBG followed either prophylactic administration via the drinking water for one week prior to injury or via an intravenous bolus administration up to four hours after TBI, suggesting a clinically-implementable therapeutic window. Notably, P2X7 localized within astrocytic end feet and administration of BBG decreased the expression of glial fibrillary acidic protein (GFAP), a reactive astrocyte marker, and attenuated the expression of aquaporin-4 (AQP4), an astrocytic water channel that promotes cellular edema. Together, these data implicate P2X7 as a novel therapeutic target to prevent secondary neurological injury after TBI, a finding that warrants further investigation.

  10. Activation of P2X7 promotes cerebral edema and neurological injury after traumatic brain injury in mice.

    Directory of Open Access Journals (Sweden)

    Donald E Kimbler

    Full Text Available Traumatic brain injury (TBI is a leading cause of death and disability worldwide. Cerebral edema, the abnormal accumulation of fluid within the brain parenchyma, contributes to elevated intracranial pressure (ICP and is a common life-threatening neurological complication following TBI. Unfortunately, neurosurgical approaches to alleviate increased ICP remain controversial and medical therapies are lacking due in part to the absence of viable drug targets. In the present study, genetic inhibition (P2X7-/- mice of the purinergic P2x7 receptor attenuated the expression of the pro-inflammatory cytokine, interleukin-1β (IL-1β and reduced cerebral edema following controlled cortical impact, as compared to wild-type mice. Similarly, brilliant blue G (BBG, a clinically non-toxic P2X7 inhibitor, inhibited IL-1β expression, limited edemic development, and improved neurobehavioral outcomes after TBI. The beneficial effects of BBG followed either prophylactic administration via the drinking water for one week prior to injury or via an intravenous bolus administration up to four hours after TBI, suggesting a clinically-implementable therapeutic window. Notably, P2X7 localized within astrocytic end feet and administration of BBG decreased the expression of glial fibrillary acidic protein (GFAP, a reactive astrocyte marker, and attenuated the expression of aquaporin-4 (AQP4, an astrocytic water channel that promotes cellular edema. Together, these data implicate P2X7 as a novel therapeutic target to prevent secondary neurological injury after TBI, a finding that warrants further investigation.

  11. Compliance. Regulatory policy P-211

    International Nuclear Information System (INIS)

    2001-05-01

    This regulatory policy describes the basic principles and directives for establishing and conducting the Canadian Nuclear Safety Commission (CNSC) Compliance Program. The program is aimed at securing compliance by regulated persons with regulatory requirements made under the Nuclear Safety and Control Act ('the Act'). The policy applies to persons who are regulated by the CNSC through the Act, regulations and licences, as well as by decisions and orders made under the Act. The policy applies to officers and employees of the CNSC, and its authorized representatives or agents, who are involved in developing and carrying out compliance activities. Compliance, in the context of this policy, means conformity by regulated persons with the legally binding requirements of the Act, and the CNSC regulations, licences, decisions, and orders made under the Act. Compliance activities are CNSC measures of promotion, verification and enforcement aimed at securing compliance by regulated person with the applicable legally binding requirements. (author)

  12. Compliance. Regulatory policy P-211

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2001-05-01

    This regulatory policy describes the basic principles and directives for establishing and conducting the Canadian Nuclear Safety Commission (CNSC) Compliance Program. The program is aimed at securing compliance by regulated persons with regulatory requirements made under the Nuclear Safety and Control Act ('the Act'). The policy applies to persons who are regulated by the CNSC through the Act, regulations and licences, as well as by decisions and orders made under the Act. The policy applies to officers and employees of the CNSC, and its authorized representatives or agents, who are involved in developing and carrying out compliance activities. Compliance, in the context of this policy, means conformity by regulated persons with the legally binding requirements of the Act, and the CNSC regulations, licences, decisions, and orders made under the Act. Compliance activities are CNSC measures of promotion, verification and enforcement aimed at securing compliance by regulated person with the applicable legally binding requirements. (author)

  13. Compliance to two city convenience store ordinance requirements.

    Science.gov (United States)

    Chaumont Menéndez, Cammie K; Amandus, Harlan E; Wu, Nan; Hendricks, Scott A

    2016-04-01

    Robbery-related homicides and assaults are the leading cause of death in retail businesses. Robbery reduction approaches focus on compliance to Crime Prevention Through Environmental Design (CPTED) guidelines. We evaluated the level of compliance to CPTED guidelines specified by convenience store safety ordinances effective in 2010 in Dallas and Houston, Texas, USA. Convenience stores were defined as businesses less than 10 000 square feet that sell grocery items. Store managers were interviewed for store ordinance requirements from August to November 2011, in a random sample of 594 (289 in Dallas, 305 in Houston) convenience stores that were open before and after the effective dates of their city's ordinance. Data were collected in 2011 and analysed in 2012-2014. Overall, 9% of stores were in full compliance, although 79% reported being registered with the police departments as compliant. Compliance was consistently significantly higher in Dallas than in Houston for many requirements and by store type. Compliance was lower among single owner-operator stores compared with corporate/franchise stores. Compliance to individual requirements was lowest for signage and visibility. Full compliance to the required safety measures is consistent with industry 'best practices' and evidence-based workplace violence prevention research findings. In Houston and Dallas compliance was higher for some CPTED requirements but not the less costly approaches that are also the more straightforward to adopt. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  14. Synthesis and potency of novel uracil nucleotides and derivatives as P2Y2 and P2Y6 receptor agonists.

    Science.gov (United States)

    Ko, Hyojin; Carter, Rhonda L; Cosyn, Liesbet; Petrelli, Riccardo; de Castro, Sonia; Besada, Pedro; Zhou, Yixing; Cappellacci, Loredana; Franchetti, Palmarisa; Grifantini, Mario; Van Calenbergh, Serge; Harden, T Kendall; Jacobson, Kenneth A

    2008-06-15

    The phosphate, uracil, and ribose moieties of uracil nucleotides were varied structurally for evaluation of agonist activity at the human P2Y(2), P2Y(4), and P2Y(6) receptors. The 2-thio modification, found previously to enhance P2Y(2) receptor potency, could be combined with other favorable modifications to produce novel molecules that exhibit high potencies and receptor selectivities. Phosphonomethylene bridges introduced for stability in analogues of UDP, UTP, and uracil dinucleotides markedly reduced potency. Truncation of dinucleotide agonists of the P2Y(2) receptor, in the form of Up(4)-sugars, indicated that a terminal uracil ring is not essential for moderate potency at this receptor and that specific SAR patterns are observed at this distal end of the molecule. Key compounds reported in this study include 9, alpha,beta-methylene-UDP, a P2Y(6) receptor agonist; 30, Up(4)-phenyl ester and 34, Up(4)-[1]glucose, selective P2Y(2) receptor agonists; dihalomethylene phosphonate analogues 16 and 41, selective P2Y(2) receptor agonists; 43, the 2-thio analogue of INS37217 (P(1)-(uridine-5')-P(4)-(2'-deoxycytidine-5')tetraphosphate), a potent and selective P2Y(2) receptor agonist.

  15. Proactive compliance report 2004

    International Nuclear Information System (INIS)

    2005-01-01

    The Alberta Energy and Utilities Board (EUB) stipulates requirements to protect public safety, minimize environmental impacts, improve conservation, and ensure equity by promoting orderly and responsible energy development. Surveillance activities by the EUB, such as inspections and audits, ensures compliance with these requirements. This report presents statistical results of the enforcement ladder process (inspections, complaints, activities, major initiatives, and enforcement) for 2004 across ten EUB groups, including, Field Surveillance, Resources Applications Group, Operations Group, Environment Group, Utilities Branch, Facilities Applications Group, Corporate Compliance Group, Fort McMurray, Information and Dissemination Group, and Financial Management Group. When a noncompliance is identified, the EUB uses a process that has an established policy for EUB enforcement actions. Enforcement actions are determined by the severity of the noncompliance event and are escalated for subsequent noncompliance or failure to comply with the EUB's corrective order. Within the process, the EUB provides a grace period after an initial enforcement action. During this period, the EUB will take appropriate enforcement actions for subsequent noncompliances but will not escalate enforcement consequences. Enforcement consequences are escalated after the grace period has expired. 72 tabs

  16. Tools and drugs for uracil nucleotide-activated P2Y receptors.

    Science.gov (United States)

    Rafehi, Muhammad; Müller, Christa E

    2018-04-13

    P2Y receptors (P2YRs) are a family of G protein-coupled receptors activated by extracellular nucleotides. Physiological P2YR agonists include purine and pyrimidine nucleoside di- and triphosphates, such as ATP, ADP, UTP, UDP, nucleotide sugars, and dinucleotides. Eight subtypes exist, P2Y 1 , P2Y 2 , P2Y 4 , P2Y 6 , P2Y 11 , P2Y 12 , P2Y 13 , and P2Y 14 , which represent current or potential future drug targets. Here we provide a comprehensive overview of ligands for the subgroup of the P2YR family that is activated by uracil nucleotides: P2Y 2 (UTP, also ATP and dinucleotides), P2Y 4 (UTP), P2Y 6 (UDP), and P2Y 14 (UDP, UDP-glucose, UDP-galactose). The physiological agonists are metabolically unstable due to their fast hydrolysis by ectonucleotidases. A number of agonists with increased potency, subtype-selectivity and/or enzymatic stability have been developed in recent years. Useful P2Y 2 R agonists include MRS2698 (6-01, highly selective) and PSB-1114 (6-05, increased metabolic stability). A potent and selective P2Y 2 R antagonist is AR-C118925 (10-01). For studies of the P2Y 4 R, MRS4062 (3-15) may be used as a selective agonist, while PSB-16133 (10-06) represents a selective antagonist. Several potent P2Y 6 R agonists have been developed including 5-methoxyuridine 5'-O-((R p )α-boranodiphosphate) (6-12), PSB-0474 (3-11), and MRS2693 (3-26). The isocyanate MRS2578 (10-08) is used as a selective P2Y 6 R antagonist, although its reactivity and low water-solubility are limiting. With MRS2905 (6-08), a potent and metabolically stable P2Y 14 R agonist is available, while PPTN (10-14) represents a potent and selective P2Y 14 R antagonist. The radioligand [ 3 H]UDP can be used to label P2Y 14 Rs. In addition, several fluorescent probes have been developed. Uracil nucleotide-activated P2YRs show great potential as drug targets, especially in inflammation, cancer, cardiovascular and neurodegenerative diseases. Copyright © 2018. Published by Elsevier Inc.

  17. Formalizing and applying compliance patterns for business process compliance

    NARCIS (Netherlands)

    Elgammal, A.F.S.A.; Türetken, O.; van den Heuvel, W.J.A.M.; Papazoglou, M.

    Today’s enterprises demand a high degree of compliance of business processes to meet diverse regulations and legislations. Several industrial studies have shown that compliance management is a daunting task, and organizations are still struggling and spending billions of dollars annually to ensure

  18. 49 CFR 1119.1 - Compliance.

    Science.gov (United States)

    2010-10-01

    ... 49 Transportation 8 2010-10-01 2010-10-01 false Compliance. 1119.1 Section 1119.1 Transportation... TRANSPORTATION RULES OF PRACTICE COMPLIANCE WITH BOARD DECISIONS § 1119.1 Compliance. A defendant or respondent... compliance date specified in the decision of the manner of compliance. Notification should be by verified...

  19. Ion channel regulation by phosphoinositides analyzed with VSPs—PI(4,5)P2 affinity, phosphoinositide selectivity, and PI(4,5)P2 pool accessibility

    Science.gov (United States)

    Rjasanow, Alexandra; Leitner, Michael G.; Thallmair, Veronika; Halaszovich, Christian R.; Oliver, Dominik

    2015-01-01

    The activity of many proteins depends on the phosphoinositide (PI) content of the membrane. E.g., dynamic changes of the concentration of PI(4,5)P2 are cellular signals that regulate ion channels. The susceptibility of a channel to such dynamics depends on its affinity for PI(4,5)P2. Yet, measuring affinities for endogenous PIs has not been possible directly, but has relied largely on the response to soluble analogs, which may not quantitatively reflect binding to native lipids. Voltage-sensitive phosphatases (VSPs) turn over PI(4,5)P2 to PI(4)P when activated by depolarization. In combination with voltage-clamp electrophysiology VSPs are useful tools for rapid and reversible depletion of PI(4,5)P2. Because cellular PI(4,5)P2 is resynthesized rapidly, steady state PI(4,5)P2 changes with the degree of VSP activation and thus depends on membrane potential. Here we show that titration of endogenous PI(4,5)P2 with Ci-VSP allows for the quantification of relative PI(4,5)P2 affinities of ion channels. The sensitivity of inward rectifier and voltage-gated K+ channels to Ci-VSP allowed for comparison of PI(4,5)P2 affinities within and across channel subfamilies and detected changes of affinity in mutant channels. The results also reveal that VSPs are useful only for PI effectors with high binding specificity among PI isoforms, because PI(4,5)P2 depletion occurs at constant overall PI level. Thus, Kir6.2, a channel activated by PI(4,5)P2 and PI(4)P was insensitive to VSP. Surprisingly, despite comparable PI(4,5)P2 affinity as determined by Ci-VSP, the Kv7 and Kir channel families strongly differed in their sensitivity to receptor-mediated depletion of PI(4,5)P2. While Kv7 members were highly sensitive to activation of PLC by Gq-coupled receptors, Kir channels were insensitive even when PI(4,5)P2 affinity was lowered by mutation. We hypothesize that different channels may be associated with distinct pools of PI(4,5)P2 that differ in their accessibility to PLC and VSPs. PMID

  20. Ion channel regulation by phosphoinositides analyzed with VSPs – PI(4,5P2 affinity, phosphoinositide selectivity, and PI(4,5P2 pool accessibility

    Directory of Open Access Journals (Sweden)

    Alexandra eRjasanow

    2015-06-01

    Full Text Available The activity of many proteins depends on the phosphoinositide (PI content of the membrane. E.g., dynamic changes of the concentration of PI(4,5P2 are cellular signals that regulate ion channels. The susceptibility of a channel to such dynamics depends on its affinity for PI(4,5P2. Yet, measuring affinities for endogenous PIs has not been possible directly, but has relied largely on the response to soluble analogs, which may not quantitatively reflect binding to native lipids.Voltage-sensitive phosphatases (VSPs turn over PI(4,5P2 to PI(4P when activated by depolarization. In combination with voltage-clamp electrophysiology VSPs are useful tools for rapid and reversible depletion of PI(4,5P2. Because cellular PI(4,5P2 is resynthesized rapidly, steady state PI(4,5P2 changes with the degree of VSP activation and thus depends on membrane potential.Here we show that titration of endogenous PI(4,5P2 with Ci-VSP allows for the quantification of relative PI(4,5P2 affinities of ion channels. The sensitivity of inward rectifier and voltage-gated K+ channels to Ci-VSP allowed for comparison of PI(4,5P2 affinities within and across channel subfamilies and detected changes of affinity in mutant channels. The results also reveal that VSPs are useful only for PI effectors with high binding specificity among PI isoforms, because PI(4,5P2 depletion occurs at constant overall PI level. Thus, Kir6.2, a channel activated by PI(4,5P2 and PI(4P was insensitive to VSP.Surprisingly, despite comparable PI(4,5P2 affinity as determined by Ci-VSP, the Kv7 and Kir channel families strongly differed in their sensitivity to receptor-mediated depletion of PI(4,5P2. While Kv7 members were highly sensitive to activation of PLC by Gq-coupled receptors, Kir channels were insensitive even when PI(4,5P2 affinity was lowered by mutation. We hypothesize that different channels may be associated with distinct pools of PI(4,5P2 that differ in their accessibility to PLC and VSPs.

  1. Circadian ATP Release in Organotypic Cultures of the Rat Suprachiasmatic Nucleus Is Dependent on P2X7 and P2Y Receptors

    Directory of Open Access Journals (Sweden)

    Irena Svobodova

    2018-03-01

    Full Text Available The circadian rhythms in physiological and behavioral functions are driven by a pacemaker located in the suprachiasmatic nucleus (SCN. The rhythms continue in constant darkness and depend on cell-cell communication between neurons and glia. The SCN astrocytes generate also a circadian rhythm in extracellular adenosine 5′-triphosphate (ATP accumulation, but molecular mechanisms that regulate ATP release are poorly understood. Here, we tested the hypothesis that ATP is released via the plasma membrane purinergic P2X7 receptors (P2X7Rs and P2Y receptors (P2YRs which have been previously shown to be expressed in the SCN tissue at transcriptional level. We have investigated this hypothesis using SCN organotypic cultures, primary cultures of SCN astrocytes, ATP bioluminescent assays, immunohistochemistry, patch-clamping, and calcium imaging. We found that extracellular ATP accumulation in organotypic cultures followed a circadian rhythm, with a peak between 24:00 and 04:00 h, and the trough at ~12:00 h. ATP rhythm was inhibited by application of AZ10606120, A438079, and BBG, specific blockers of P2X7R, and potentiated by GW791343, a positive allosteric modulator of this receptor. Double-immunohistochemical staining revealed high expression of the P2X7R protein in astrocytes of SCN slices. PPADS, a non-specific P2 antagonist, and MRS2179, specific P2Y1R antagonist, also abolished ATP rhythm, whereas the specific P2X4R blocker 5-BDBD was not effective. The pannexin-1 hemichannel blocker carbenoxolone displayed a partial inhibitory effect. The P2Y1R agonist MRS2365, and the P2Y2R agonist MRS2768 potentiated ATP release in organotypic cultures and increase intracellular Ca2+ level in cultured astrocytes. Thus, SCN utilizes multiple purinergic receptor systems and pannexin-1 hemichannels to release ATP.

  2. Acceptance and compliance with external hip protectors: A systematic review of the literature

    NARCIS (Netherlands)

    van Schoor, N.M.; Deville, W.L.J.M.; Bouter, L.M.; Lips, P.T.A.M.

    2002-01-01

    Hip fractures may be prevented by the use of external hip protectors, but compliance is often poor. Therefore, the objective of this study was to assess the determinants of compliance with hip protectors by systematically reviewing the literature. A literature search was performed in PubMed, Embase

  3. Acceptance and compliance with external hip protectors: a systematic review of the literature.

    NARCIS (Netherlands)

    Schoor, N.M. van; Devillé, W.L.; Bouter, L.M.; Lips, P.

    2002-01-01

    Hip fractures may be prevented by the use of external hip protectors, but compliance is often poor. Therefore, the objective of this study was to assess the determinants of compliance with hip protectors by systematically reviewing the literature. A literature search was performed in PubMed, Embase

  4. Compliance with national guidelines for the management of drug-drug interactions in Dutch community pharmacies.

    NARCIS (Netherlands)

    Buurma, H.; Schalekamp, T.; Egberts, A.C.G.; Smet, P.A.G.M. de

    2007-01-01

    BACKGROUND: Pharmacists contribute to the detection and prevention of drug therapy-related problems, including drug-drug interactions. Little is known about compliance with pharmacy practice guidelines for the management of drug-drug interaction alerts. OBJECTIVE: To measure the compliance of

  5. Purinergic receptors P2Y12R and P2X7R: potential targets for PET imaging of microglia phenotypes in multiple sclerosis.

    Science.gov (United States)

    Beaino, Wissam; Janssen, Bieneke; Kooij, Gijs; van der Pol, Susanne M A; van Het Hof, B; van Horssen, Jack; Windhorst, Albert D; de Vries, Helga E

    2017-12-22

    Microglia are major players in the pathogenesis of multiple sclerosis (MS) and may play a dual role in disease progression. The activation status of microglia in vivo is highly dynamic and occurs as a continuum, with the pro-inflammatory and anti-inflammatory phenotypes on either end of this spectrum. Little is known about in vivo dynamics of microglia phenotypes in MS due to the lack of diagnostic tools. Positron emission tomography (PET) imaging is a powerful non-invasive technique that allows real-time imaging of microglia activation phenotypes in the central nervous system, depending on the availability of selective PET tracers. Our objective is to investigate and characterize the expression of the purinergic receptors P2Y12R and P2X7R as potential targets for PET tracer development and subsequent PET imaging in order to evaluate the dynamics of microglia status in vivo. We used immunohistochemical analysis to explore the expression of P2Y12R and P2X7R in experimental autoimmune encephalomyelitis (EAE) post-mortem tissues and different stages of well-characterized MS lesions. We evaluated by quantitative real-time polymerase chain reaction the expression of P2Y12R and P2X7R in human polarized microglia, and we performed autoradiography binding assay with radiolabeled P2Y12R and P2X7R antagonists using MS and rat EAE tissues. Here, we demonstrate that P2X7R is associated with a pro-inflammatory phenotype of human microglia in vitro, and is highly expressed in microglia in MS lesions as well as during the peak of EAE. In contrast, P2Y12R was associated with an anti-inflammatory phenotype in human microglia in vitro and was expressed at lower levels in active inflammatory MS lesions compared to normal-appearing white matter (NAWM) and similarly in EAE, while its expression increased in the remission phase of EAE. Binding of radiolabeled tracers specific for P2Y12R and P2X7R on ex vivo tissues validated the value of these receptors as PET imaging targets for

  6. The Strategic Nature of Compliance

    DEFF Research Database (Denmark)

    König, Thomas; Mäder, Lars Kai

    2014-01-01

    This compliance study models correct and timely implementation of policies in a multilevel system as a strategic game between a central monitoring agency and multiple implementers and evaluates statistically the empirical implications of this model. We test whether compliance is determined...

  7. Hypoxia attenuates purinergic P2X receptor-induced inflammatory gene expression in brainstem microglia

    Directory of Open Access Journals (Sweden)

    Smith SMC

    2013-08-01

    Full Text Available Stephanie MC Smith,1,2 Gordon S Mitchell,1,2 Scott A Friedle,3 Christine M Sibigtroth,1 Stéphane Vinit,1 Jyoti J Watters1–31Department of Comparative Biosciences, 2Comparative Biomedical Sciences Training Program, 3Program in Cellular and Molecular Biology, University of Wisconsin, Madison, WI, USAAbstract: Hypoxia and increased extracellular nucleotides are frequently coincident in the brainstem. Extracellular nucleotides are potent modulators of microglial inflammatory gene expression via P2X purinergic receptor activation. Although hypoxia is also known to modulate inflammatory gene expression, little is known about how hypoxia or P2X receptor activation alone affects inflammatory molecule production in brainstem microglia, nor how hypoxia and P2X receptor signaling interact when they occur together. In the study reported here, we investigated the ability of a brief episode of hypoxia (2 hours in the presence and absence of the nonselective P2X receptor agonist 2′(3′-O-(4-benzoylbenzoyladenosine-5′-triphosphate (BzATP to promote inflammatory gene expression in brainstem microglia in adult rats. We evaluated inducible nitric oxide synthase (iNOS, tumor necrosis factor alpha (TNFα, and interleukin (IL-6 messenger RNA levels in immunomagnetically isolated brainstem microglia. While iNOS and IL-6 gene expression increased with hypoxia and BzATP alone, TNFα expression was unaffected. Surprisingly, BzATP-induced inflammatory effects were lost after hypoxia, suggesting that hypoxia impairs proinflammatory P2X-receptor signaling. We also evaluated the expression of key P2X receptors activated by BzATP, namely P2X1, P2X4, and P2X7. While hypoxia did not alter their expression, BzATP upregulated P2X4 and P2X7 mRNAs; these effects were ablated in hypoxia. Although both P2X4 and P2X7 receptor expression correlated with increased microglial iNOS and IL-6 levels in microglia from normoxic rats, in hypoxia, P2X7 only correlated with IL-6, and P2X

  8. Peristalsis is impaired in the small intestine of mice lacking the P2X3 subunit.

    Science.gov (United States)

    Bian, Xiaochun; Ren, Jianhua; DeVries, Matthew; Schnegelsberg, Birthe; Cockayne, Debra A; Ford, Anthony P D W; Galligan, James J

    2003-08-15

    P2X receptors are ATP-gated cation channels composed of one or more of seven different subunits. P2X receptors participate in intestinal neurotransmission but the subunit composition of enteric P2X receptors is unknown. In this study, we used tissues from P2X3 wild-type (P2X3+/+) mice and mice in which the P2X3 subunit gene had been deleted (P2X3-/-) to investigate the role of this subunit in neurotransmission in the intestine. RT-PCR analysis of mRNA from intestinal tissues verified P2X3 gene deletion. Intracellular electrophysiological methods were used to record synaptic and drug-induced responses from myenteric neurons in vitro. Drug-induced longitudinal muscle contractions were studied in vitro. Intraluminal pressure-induced reflex contractions (peristalsis) of ileal segments were studied in vitro using a modified Trendelenburg preparation. Gastrointestinal transit was measured as the progression in 30 min of a liquid radioactive marker administered by gavage to fasted mice. Fast excitatory postsynaptic potentials recorded from S neurons (motoneurons and interneurons) were similar in tissues from P2X3+/+ and P2X3-/- mice. S neurons from P2X3+/+ and P2X3-/- mice were depolarized by application of ATP but not alpha,beta-methylene ATP, an agonist of P2X3 subunit-containing receptors. ATP and alpha,beta-methylene ATP induced depolarization of AH (sensory) neurons from P2X3+/+ mice. ATP, but not alpha,beta-methylene ATP, caused depolarization of AH neurons from P2X3-/- mice. Peristalsis was inhibited in ileal segments from P2X3-/- mice but longitudinal muscle contractions caused by nicotine and bethanechol were similar in segments from P2X3+/+ and P2X3-/- mice. Gastrointestinal transit was similar in P2X3+/+ and P2X3-/- mice. It is concluded that P2X3 subunit-containing receptors participate in neural pathways underlying peristalsis in the mouse intestine in vitro. P2X3 subunits are localized to AH (sensory) but not S neurons. P2X3 receptors may contribute to

  9. Compliance with physical exercise

    DEFF Research Database (Denmark)

    Gram, Anne Sofie; Bønnelycke, Julie; Rosenkilde Larsen, Mads

    2014-01-01

    , a moderate (MOD; 300 kcal/day) or a high-dose (HIGH; 600 kcal/day) endurance exercise group for 12 weeks. A sub-set of the subjects were interviewed using pre-determined, qualitative questions to elucidate physical activity and health behaviour. In combination with the Theory of Planned Behaviour (TPB......, and thereby may have increased physical activity levels in areas of their everyday lives that were not related to the intervention. Conclusions: A multidisciplinary approach provided explanations for similar effects of two different doses of exercise. This could not have been determined via either qualitative......Aims: Sixty-one healthy, sedentary, moderately overweight young men participated in a randomised controlled trial to examine the effects of two different doses of endurance exercise on health behaviour and exercise compliance. Methods: Participants were randomised to a sedentary control group...

  10. Environmental compliance assessment review

    International Nuclear Information System (INIS)

    Hilliday, G.H.

    1991-01-01

    During the period 1972-1991, The United States Congress passed stringent environmental statues which the Environment Protection Agency implemented via regulations. The statues and regulations contain severe civil and criminal penalties. Civil violations resulted in fines, typically payable by the company. The act of willfully and knowingly violating the permit conditions or regulations can result in criminal charges being imposed upon the responsible part, i.e., either the company or individual. Criminal charges can include fines, lawyer fees, court costs and incarceration. This paper describes steps necessary to form an effective Environmental Compliance Assessment Review [CAR] program, train field and engineering personnel and perform a CAR audit. Additionally, the paper discusses the findings of a number of Exploration and Production [E and P] field audits

  11. Band offset at the heterojunction interfaces of CdS/ZnSnP2, ZnS/ZnSnP2, and In2S3/ZnSnP2

    Science.gov (United States)

    Nakatsuka, Shigeru; Nose, Yoshitaro; Shirai, Yasuharu

    2016-05-01

    Heterojunctions were formed between ZnSnP2 and buffer materials, CdS, ZnS, and In2S3, using chemical bath deposition. The band offset was investigated by X-ray photoelectron spectroscopy based on Kraut method. The conduction band offset, ΔEC, between ZnSnP2 and CdS was estimated to be -1.2 eV, which significantly limits the open circuit voltage, VOC. Conversely, ΔEC at the heterojunction between ZnSnP2 and ZnS was +0.3 eV, which is within the optimal offset range. In the case of In2S3, ΔEC was a relatively small value, -0.2 eV, and In2S3 is potentially useful as a buffer layer in ZnSnP2 solar cells. The J-V characteristics of heterojunction diodes with an Al/sulfides/ZnSnP2 bulk/Mo structure also suggested that ZnS and In2S3 are promising candidates for buffer layers in ZnSnP2 thin film solar cells, and the band alignment is a key factor for the higher efficiency of solar cells with heterojunctions.

  12. Imipramine compliance in adolescents.

    Science.gov (United States)

    Bernstein, G A; Anderson, L K; Hektner, J M; Realmuto, G M

    2000-03-01

    To investigate side effects, medication compliance, and assumption of medication assignment in adolescents taking imipramine versus placebo in a clinical trial. Sixty-three anxious-depressed adolescents in an 8-week double-blind study of imipramine versus placebo, each in combination with cognitive-behavioral therapy for school refusal, were evaluated. Measures of side effects, global improvement, family functioning, medication compliance based on pill counts, and guesses of drug assignment (imipramine versus placebo) were analyzed. Mean side effects ratings were significantly higher for the imipramine group compared with the placebo group (p = .001). Side effects were not associated with noncompliance or with dropping out. Oppositional defiant disorder (ODD) in the adolescents was significantly associated with medication noncompliance (p = .036). On the Family Adaptability and Cohesion Evaluation Scale II (FACES II), low family adaptability (i.e., rigidity), low family cohesion (i.e., disengagement), and extreme family type were significantly associated with greater noncompliance with medications. Accuracy rates for guessing medication assignment (imipramine versus placebo) were 66% for subjects, 62.5% for mothers, and 79.5% for the psychiatrist. Logistic regression demonstrated that side effects (p = .005) and global improvement scores (p = .06) predicted the psychiatrist's guesses of drug assignment. Side effects were not associated with noncompliance. Nonadherence with taking medications was associated with ODD in the adolescents and problematic family functioning on FACES II. The psychiatrist, who was blind to treatment condition, guessed the subjects' medication assignments with high accuracy. Thus, because of expectancy bias, the data support the use of blind independent evaluators for rating changes in medication trials.

  13. Framing of information on the use of public finances, regulatory fit of recipients and tax compliance

    Science.gov (United States)

    Holler, Marianne; Hoelzl, Erik; Kirchler, Erich; Leder, Susanne; Mannetti, Lucia

    2010-01-01

    Information campaigns to increase tax compliance could be framed in different ways. They can either highlight the potential gains when tax compliance is high, or the potential losses when compliance is low. According to regulatory focus theory, such framing should be most effective when it is congruent with the promotion or prevention focus of its recipients. Two studies confirmed the hypothesized interaction effects between recipients' regulatory focus and framing of information campaigns, with tax compliance being highest under conditions of regulatory fit. To address taxpayers effectively, information campaigns by tax authorities should consider the positive and negative framing of information, and the moderating effect of recipients' regulatory focus. PMID:20495689

  14. Effect of hand sanitizer location on hand hygiene compliance.

    Science.gov (United States)

    Cure, Laila; Van Enk, Richard

    2015-09-01

    Hand hygiene is the most important intervention to prevent infection in hospitals. Health care workers should clean their hands at least before and after contact with patients. Hand sanitizer dispensers are important to support hand hygiene because they can be made available throughout hospital units. The aim of this study was to determine whether the usability of sanitizer dispensers correlates with compliance of staff in using the sanitizer in a hospital. This study took place in a Midwest, 404-bed, private, nonprofit community hospital with 15 inpatient care units in addition to several ambulatory units. The usability and standardization of sanitizers in 12 participating inpatient units were evaluated. The hospital measured compliance of staff with hand hygiene as part of their quality improvement program. Data from 2010-2012 were analyzed to measure the relationship between compliance and usability using mixed-effects logistic regression models. The total usability score (P = .0046), visibility (P = .003), and accessibility of the sanitizer on entrance to the patient room (P = .00055) were statistically associated with higher observed compliance rates. Standardization alone showed no significant impact on observed compliance (P = .37). Hand hygiene compliance can be influenced by visibility and accessibility of dispensers. The sanitizer location should be part of multifaceted interventions to improve hand hygiene. Copyright © 2015 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.

  15. Physician compliance with mammography guidelines: barriers and enhancers.

    Science.gov (United States)

    Costanza, M E; Stoddard, A M; Zapka, J G; Gaw, V P; Barth, R

    1992-01-01

    Primary care physicians are increasingly the gatekeepers to clinical preventive services including mammography utilization. Moreover, lack of physician recommendation is a major reason for patient failure to obtain screening. A study was designed to examine the attitudes, beliefs, and practices with regard to breast cancer screening as self-reported by primary care physicians. The variables associated with compliance or lack of compliance with screening guidelines are emphasized. One hundred sixteen primary care physicians practicing in two New England communities responded to a mailed survey. The survey included questions on attitudes and beliefs about breast cancer screening, as well as questions about perceived barriers and actual screening practices. Fifty-seven percent of the respondents reported ordering annual mammograms for their female patients aged 50 to 75 years. An additional 21 percent reported ordering biannual mammograms for women in this age group. Strongly associated with ordering annual mammograms were beliefs in the benefits of mammography and the perception of community consensus regarding breast cancer screening. A strong positive association of practicing in a group setting and mammography guideline compliance was documented. Middle-aged physicians in solo practice reported the poorest screening compliance. The level of physician compliance with the standard of annual mammography screening is low (57 percent). The three most important determinants of annual screening suggest ways to improve physician compliance: improve physician attitudes about the benefits of mammography, build further on the medical community's consensus regarding the appropriateness and importance of the annual guidelines, target the poorest compliers with special messages or programs.

  16. Endothelial P2X7 receptors’ expression is reduced by schistosomiasis

    OpenAIRE

    Oliveira, Suellen D’Arc dos Santos; Coutinho-Silva, Robson; Silva, Claudia Lucia Martins

    2012-01-01

    Endothelial cells control vascular tone, permeability and leukocyte transmigration and are modulated by pro-inflammatory mediators. Schistosomiasis is an intravascular disease associated with inflammation, therefore altering endothelial cells’ phenotype. Purinergic P2X7 receptors (P2X7R) play an important role in inflammation; however, the impact of the disease upon endothelial P2X7R function or expression has not been explored. Using ethidium bromide uptake to investigate P2X7R function, we ...

  17. P2P Evolution: from file-sharing to decentralized workflows

    NARCIS (Netherlands)

    Risse, Thomas; Knezevic, Predrag; Wombacher, Andreas

    Peer-to-peer (P2P) computing is currently receiving a great deal of attention. Much of the current attention is focused on the use of P2P computing for exchanging media files. But P2P systems have actually been around for a long time and many application scenarios exist. In this paper we discuss on

  18. Music2Share - Copyright-Compliant Music Sharing in P2P Systems

    NARCIS (Netherlands)

    Kalker, Ton; Epema, Dick H.J.; Hartel, Pieter H.; Lagendijk, R. (Inald) L.; van Steen, Martinus Richardus; van Steen, Maarten

    Peer-to-Peer (P2P) networks are generally considered to be free havens for pirated content, in particular with respect to music. We describe a solution for the problem of copyright infringement in P2P networks for music sharing. In particular, we propose a P2P protocol that integrates the functions

  19. Music2Share --- Copyright-Compliant Music Sharing in P2P Systems

    NARCIS (Netherlands)

    Kalker, T.; Epema, D.; Hartel, P.; Lagendijk, I.; van Steen, M.R.

    2004-01-01

    Peer-to-peer (P2P) networks are generally considered to be free havens for pirated content, in particular with respect to music. We describe a solution for the problem of copyright infringement in P2P networks for music sharing. In particular, we propose a P2P protocol that integrates the functions

  20. Ezrin/Radixin/Moesin Are Required for the Purinergic P2X7 Receptor (P2X7R)-dependent Processing of the Amyloid Precursor Protein*

    Science.gov (United States)

    Darmellah, Amaria; Rayah, Amel; Auger, Rodolphe; Cuif, Marie-Hélène; Prigent, Magali; Arpin, Monique; Alcover, Andres; Delarasse, Cécile; Kanellopoulos, Jean M.

    2012-01-01

    The amyloid precursor protein (APP) can be cleaved by α-secretases in neural cells to produce the soluble APP ectodomain (sAPPα), which is neuroprotective. We have shown previously that activation of the purinergic P2X7 receptor (P2X7R) triggers sAPPα shedding from neural cells. Here, we demonstrate that the activation of ezrin, radixin, and moesin (ERM) proteins is required for the P2X7R-dependent proteolytic processing of APP leading to sAPPα release. Indeed, the down-regulation of ERM by siRNA blocked the P2X7R-dependent shedding of sAPPα. We also show that P2X7R stimulation triggered the phosphorylation of ERM. Thus, ezrin translocates to the plasma membrane to interact with P2X7R. Using specific pharmacological inhibitors, we established the order in which several enzymes trigger the P2X7R-dependent release of sAPPα. Thus, a Rho kinase and the MAPK modules ERK1/2 and JNK act upstream of ERM, whereas a PI3K activity is triggered downstream. For the first time, this work identifies ERM as major partners in the regulated non-amyloidogenic processing of APP. PMID:22891241

  1. Ezrin/radixin/moesin are required for the purinergic P2X7 receptor (P2X7R)-dependent processing of the amyloid precursor protein.

    Science.gov (United States)

    Darmellah, Amaria; Rayah, Amel; Auger, Rodolphe; Cuif, Marie-Hélène; Prigent, Magali; Arpin, Monique; Alcover, Andres; Delarasse, Cécile; Kanellopoulos, Jean M

    2012-10-05

    The amyloid precursor protein (APP) can be cleaved by α-secretases in neural cells to produce the soluble APP ectodomain (sAPPα), which is neuroprotective. We have shown previously that activation of the purinergic P2X7 receptor (P2X7R) triggers sAPPα shedding from neural cells. Here, we demonstrate that the activation of ezrin, radixin, and moesin (ERM) proteins is required for the P2X7R-dependent proteolytic processing of APP leading to sAPPα release. Indeed, the down-regulation of ERM by siRNA blocked the P2X7R-dependent shedding of sAPPα. We also show that P2X7R stimulation triggered the phosphorylation of ERM. Thus, ezrin translocates to the plasma membrane to interact with P2X7R. Using specific pharmacological inhibitors, we established the order in which several enzymes trigger the P2X7R-dependent release of sAPPα. Thus, a Rho kinase and the MAPK modules ERK1/2 and JNK act upstream of ERM, whereas a PI3K activity is triggered downstream. For the first time, this work identifies ERM as major partners in the regulated non-amyloidogenic processing of APP.

  2. A survey of simulators for P2P overlay networks with a case study of the P2P tree overlay using an event-driven simulator

    Directory of Open Access Journals (Sweden)

    Shivangi Surati

    2017-04-01

    Full Text Available Implementation of a P2P (Peer-to-Peer overlay network directly on the realistic network environments is not a feasible initiative as scalability is a major challenge for P2P. The implementation of newly created P2P networks must be analyzed, well tested and evaluated through experiments by researchers and organizations. Various simulators have been developed to analyze and simulate P2P protocols before applying to real applications. However, selection of an appropriate simulator suitable for a given application requires a prior comprehensive survey of P2P simulators. The existing literature survey of P2P simulators has limitations viz. (i all P2P related simulators have not been included, (ii all design criteria for comparison and appropriate selection of the simulator may not be considered, (iii appropriate practical application through the simulation has not been presented to enhance the outcome of a survey. To overcome these limitations, we survey existing simulators with classifications, additional design parameters, limitations and comparison using various criteria. In addition, we discuss about common interface concept that creates a generic application to make the implementation of targeted application portable. Not only that, we present a case study of implementation of BATON (BAlanced Tree Overlay Network and BATON* using an event-driven model of PeerSim simulator that helps the developers to simulate the tree overlays efficiently.

  3. Activation of neuronal P2X7 receptor-pannexin-1 mediates death of enteric neurons during colitis.

    Science.gov (United States)

    Gulbransen, Brian D; Bashashati, Mohammad; Hirota, Simon A; Gui, Xianyong; Roberts, Jane A; MacDonald, Justin A; Muruve, Daniel A; McKay, Derek M; Beck, Paul L; Mawe, Gary M; Thompson, Roger J; Sharkey, Keith A

    2012-03-18

    Inflammatory bowel diseases (IBDs) are chronic relapsing and remitting conditions associated with long-term gut dysfunction resulting from alterations to the enteric nervous system and a loss of enteric neurons. The mechanisms underlying inflammation-induced enteric neuron death are unknown. Here using in vivo models of experimental colitis we report that inflammation causes enteric neuron death by activating a neuronal signaling complex composed of P2X7 receptors (P2X7Rs), pannexin-1 (Panx1) channels, the Asc adaptor protein and caspases. Inhibition of P2X7R, Panx1, Asc or caspase activity prevented inflammation-induced neuron cell death. Preservation of enteric neurons by inhibiting Panx1 in vivo prevented the onset of inflammation-induced colonic motor dysfunction. Panx1 expression was reduced in Crohn's disease but not ulcerative colitis. We conclude that activation of neuronal Panx1 underlies neuron death and the subsequent development of abnormal gut motility in IBD. Targeting Panx1 represents a new neuroprotective strategy to ameliorate the progression of IBD-associated dysmotility.

  4. Trophic activity of human P2X7 receptor isoforms A and B in osteosarcoma.

    Directory of Open Access Journals (Sweden)

    Anna Lisa Giuliani

    Full Text Available The P2X7 receptor (P2X7R is attracting increasing attention for its involvement in cancer. Several recent studies have shown a crucial role of P2X7R in tumour cell growth, angiogenesis and invasiveness. In this study, we investigated the role of the two known human P2X7R functional splice variants, the full length P2X7RA and the truncated P2X7RB, in osteosarcoma cell growth. Immunohistochemical analysis of a tissue array of human osteosarcomas showed that forty-four, of a total fifty-four tumours (81.4%, stained positive for both P2X7RA and B, thirty-one (57.4% were positive using an anti-P2X7RA antibody, whereas fifteen of the total number (27.7% expressed only P2X7RB. P2X7RB positive tumours showed increased cell density, at the expense of extracellular matrix. The human osteosarcoma cell line Te85, which lacks endogenous P2X7R expression, was stably transfected with either P2X7RA, P2X7RB, or both. Receptor expression was a powerful stimulus for cell growth, the most efficient growth-promoting isoform being P2X7RB alone. Growth stimulation was matched by increased Ca(2+ mobilization and enhanced NFATc1 activity. Te85 P2X7RA+B cells presented pore formation as well as spontaneous extracellular ATP release. The ATP release was sustained in all clones by P2X7R agonist (BzATP and reduced following P2X7R antagonist (A740003 application. BzATP also increased cell growth and activated NFATc1 levels. On the other hand cyclosporin A (CSA affected both NFATc1 activation and cell growth, definitively linking P2X7R stimulation to NFATc1 and cell proliferation. All transfected clones also showed reduced RANK-L expression, and an overall decreased RANK-L/OPG ratio. Mineralization was increased in Te85 P2X7RA+B cells while it was significantly diminished in Te85 P2X7RB clones, in agreement with immunohistochemical results. In summary, our data show that the majority of human osteosarcomas express P2X7RA and B and suggest that expression of either isoform is

  5. THE ROLE OF COMPLIANCE IN AN ORGANIZATION. WAYS OF IMPLEMENTATION

    Directory of Open Access Journals (Sweden)

    Andreescu Nicoleta Alina

    2014-07-01

    Full Text Available In this paper we analyzed the importance of ethical and conduct codes in implementing the compliance programs in an organization. We presented the assumptions that were the basis for the forming of ethic and compliance programs, as well as their evolution in the last decades. In the first part of this paper we highlighted the legislation that outlined principles required for organizations to implement their compliance programs and business ethics. This legislation came as a response to corporate scandals relating to bribery, fraud and corruption in the 70s, and governments of the affected countries were forced to react in order to prevent, detect inappropriate behaviour, as well as improve corporate behaviour. After coming into force of the Federal Law "The Foreign Corrupt Practices Act of 1977" (FCPA, 1977, there was an increase in the number of codes of conduct and corporate involvement in adopting a conduct supported by consumers and stakeholders and to redefine the standards and values, to create a new image corresponding to the new market requirements. In the Guidelines 2002 basic principles are set out in order to efficiently implement a compliance and ethics program in business. The case study was materialized in the analysis of ethics and compliance codes, and the method used for implementing them in three Romanian companies. Analyzing the three ethics and conduct codes, we can conclude that the most important factor to successfully implement ethics and compliance within an organization is "tone from the top". CEO conduct is one that has a direct effect on members of the organization. Furthermore, we followed capturing developments in the rules governing the international business ethics and evaluated the legal framework regulating these issues. The primary aim was to assess how rules are implemented throughout business ethics compliance programs developed at company level and to identify ways to promote - at an organizational level

  6. Polymorphism of NaVO2F2: a P2₁/c superstructure with pseudosymmetry of P2₁/m in the subcell.

    Science.gov (United States)

    Yu, Zi-Qun; Wang, Jing-Quan; Huang, Ya-Xi; Botis, Sanda M; Pan, Yuanming; Mi, Jin-Xiao

    2015-06-01

    The ADDSYM routine in the program PLATON [Spek (2015). Acta Cryst. C71, 9-18] has helped researchers to avoid structures of (metal-)organic compounds being reported in an unnecessarily low symmetry space group. However, determination of the correct space group may get more complicated in cases of pseudosymmetric inorganic compounds. One example is NaVO2F2, which was reported [Crosnier-Lopez et al. (1994). Eur. J. Solid State Inorg. Chem. 31, 957-965] in the acentric space group P2₁ based on properties but flagged by ADDSYM as (pseudo)centrosymmetric P2₁/m within default distance tolerances. Herein a systematic investigation reveals that NaVO2F2 exists in at least four polymorphs: P2₁, (I), P2₁/m, (II), P2₁/c, (III), and one or more low-temperature ones. The new centrosymmetric modification, (III), with the space group P2₁/c has a similar atomic packing geometry to phase (I), except for having a doubled c axis. The double-cell of phase (III) arises from atomic shifts from the glide plane c at (x, ¼, z). With increasing temperature, the number of observed reflections decreases. The odd l reflections gradually become weaker and, correspondingly, all atoms shift towards the glide plane, resulting in a gradual second-order transformation of (III) into high-temperature phase (II) (P2₁/m) at below 493 K. At least one first-order enantiotropic phase transition was observed below 139 K from both the single-crystal X-ray diffraction and the differential scanning calorimetry analyses. Periodic first-principles calculations within density functional theory show that both P2₁/c superstructure (III) and P2₁ substructure (I) are more stable than P2₁/m structure (II), and that P2₁/c superstructure (III) is more stable that P2₁ substructure (I).

  7. Circadian ATP Release in Organotypic Cultures of the Rat Suprachiasmatic Nucleus Is Dependent on P2X7 and P2Y Receptors

    Czech Academy of Sciences Publication Activity Database

    Svobodová, Irena; Bhattacharya, Anirban; Ivetic, Milorad; Bendová, Z.; Zemková, Hana

    2018-01-01

    Roč. 9, Mar 6 (2018), č. článku 192. ISSN 1663-9812 R&D Projects: GA ČR(CZ) GA16-12695S; GA ČR(CZ) GBP304/12/G069; GA MŠk(CZ) LQ1604; GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:67985823 Keywords : suprachiasmatic nucleus * organotypic cultures * astrocytes * P2X7 receptor * P2Y1 receptor * P2Y2 receptor * pannexin-1 hemichannel * ATP release Subject RIV: FH - Neurology OBOR OECD: Neurosciences (including psychophysiology Impact factor: 4.400, year: 2016

  8. [ATP-P2X7R signalling pathway and its effects in parasitic diseases].

    Science.gov (United States)

    Wang-Fang, J; Chun-Jie, J; Fei, G; Jia-Hui, L; Ming, L

    2017-07-24

    ATP (Adenosine triphosphate) is an important endogenous damage - associated molecular pattern (DAMP). P2X 7 R is an ATP-gated cation channel. ATP-P2X 7 R plays a vital role in the pathophysiology of many diseases because P2X 7 R is distributed on various immune cells. ATP-P2X 7 R signal transduction pathway has been implicated to participate in the body's immune defense against pathogens. This paper reviews the recent progress regarding ATP-P2X 7 R and its effects on parasitic diseases.

  9. Direct Observation on Spin-Coating Process of PS- b -P2VP Thin Films

    Energy Technology Data Exchange (ETDEWEB)

    Ogawa, Hiroki; Takenaka, Mikihito; Miyazaki, Tsukasa; Fujiwara, Akihiko; Lee, Byeongdu; Shimokita, Keisuke; Nishibori, Eiji; Takata, Masaki

    2016-05-10

    We studied the structural development of symmetric poly(styrene-b-2-vinylpyridine) (PS-b-P2VP) block copolymers during spin-coating using in situ grazing incidence small angle X-ray scattering (GISAXS) measurements. During the spin-coating process, after the formation of the micelles in dilute solution, the selective solvent induced two kinds of the morphological transition. Firstly, the disordered spherical micelles were transformed into a BCC lattice of spheres of which the (110) plane was oriented perpendicularly to the substrate surface. Secondly, further evaporation induced a transition from spheres on the BCC lattice into cylindrical structures. The orientation of the cylinders perpendicular to the substrate surface was induced by solvent convection perpendicular to the substrate, which occurs during rapid solvent evaporation. After this transition, vitrification of PS and P2VP prevented any further transition from cylinders to the more thermodynamically stable lamellar structures, as are generally observed as the bulk equilibrium state.

  10. Anisotropic thermal properties and ferroelectric phase transitions in layered CuInP2S6 and CuInP2Se6 crystals

    Science.gov (United States)

    Liubachko, V.; Shvalya, V.; Oleaga, A.; Salazar, A.; Kohutych, A.; Pogodin, A.; Vysochanskii, Yu. M.

    2017-12-01

    Thermal diffusivity and thermal conductivity have been studied for the layered crystals CuInP2S6, CuInP2Se6 from 30 K to 350 K, showing a relevant thermal anisotropy. Heat is much more efficiently transferred within the layers than perpendicular to them. The ferrielectric transition in CuInP2S6 is proven to be clearly first order while the ferroelectric one in CuInP2Se6 has a weak first order character. The behavior of the thermal conductivity as a function of temperature in the ferroelectric phases shows that heat conduction is phonon driven. Disorder in the paraelectric phases due to hopping motions of Cu ions significantly reduces the thermal conductivity to extremely low values.

  11. PI(4,5)P2-binding effector proteins for vesicle exocytosis

    Science.gov (United States)

    Martin, Thomas F. J.

    2014-01-01

    PI(4,5)P2 participates directly in priming and possibly fusion steps of Ca2+-triggered vesicle exocytosis. High concentration nanodomains of PI(4,5)P2 reside on the plasma membrane of neuroendocrine cells. A subset of vesicles that co-localize with PI(4,5)P2 domains appear to undergo preferential exocytosis in stimulated cells. PI(4,5)P2 directly regulates vesicle exocytosis by recruiting and activating PI(4,5)P2-binding proteins that regulate SNARE protein function including CAPS, Munc13-1/2, synaptotagmin-1, and other C2 domain-containing proteins. These PI(4,5)P2 effector proteins are coincidence detectors that engage in multiple interactions at vesicle exocytic sites. The SNARE protein syntaxin-1 also binds to PI(4,5)P2, which promotes clustering, but an activating role for PI(4,5)P2 in syntaxin-1 function remains to be fully characterized. Similar principles underlie polarized constitutive vesicle fusion mediated in part by the PI(4,5)P2-binding subunits of the exocyst complex (Sec3, Exo70). Overall, focal vesicle exocytosis occurs at sites landmarked by PI(4,5)P2, which serves to recruit and/or activate multifunctional PI(4,5)P2-binding proteins. PMID:25280637

  12. P2X7 receptor-deficient mice are susceptible to bone cancer pain

    DEFF Research Database (Denmark)

    Hansen, RR; Nielsen, CK; Nasser, A

    2011-01-01

    The purinergic P2X7 receptor is implicated in both neuropathic and inflammatory pain, and has been suggested as a possible target in pain treatment. However, the specific role of the P2X7 receptor in bone cancer pain is unknown. We demonstrated that BALB/cJ P2X7 receptor knockout (P2X7R KO) mice...... of the P2X7R KO mouse. Further experiments are needed to elucidate the exact role of the P2X7 receptors in bone cancer pain. Pain-related behaviours had an earlier onset in bone cancer-bearing, P2X7 receptor-deficient mice, and treatment with A-438079 failed to alleviate pain-related behaviours....

  13. Canada's Patented Medicines (Notice of Compliance) Proceedings and Intellectual Property.

    Science.gov (United States)

    Bian, Henry; McCourt, Conor

    2015-01-08

    Canada's Patent Register is a tool created by the Patented Medicines (Notice of Compliance) Regulations to help innovators protect their inventions relating to pharmaceuticals. This tool exists at the intersection between the intellectual property and drug approval regimes. By listing a patent on the Patent Register, an innovator can prevent a generic manufacturer from entering the marketplace rather than having to wait for his or her patent to be infringed. This article provides information on the requirements for listing a patent on the Patent Register and an overview of how the Patent Medicines (Notice of Compliance) Regulations affect the drug approval process. Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.

  14. P2X1 stimulation promotes thrombin receptor-mediated platelet aggregation.

    Science.gov (United States)

    Erhardt, J A; Toomey, J R; Douglas, S A; Johns, D G

    2006-04-01

    P2X1 receptors are ATP-gated channel demonstrated to be involved in multiple platelet responses, although in vitro analysis has been complicated by the effects of rapid desensitization. To further investigate potential roles of P2X1 receptors in platelet activation, the current study employed methods which maximally preserved P2X1 functionality. In preliminary in vivo studies, P2X1-deficiency reduced thrombus formation following the laser-induced, but not FeCl3-induced injury. Given the multiple potential mechanisms involved in thrombus formation in vivo, including tissue-factor/thrombin generation pathways, subsequent studies were designed to investigate the effects of P2X1 inhibition or stimulation on platelet activation in vitro; specifically, the interaction of P2X1 with thrombin receptor stimulation. Aggregation initiated by low/threshold levels of a protease-activated receptor (PAR)4 agonist was reduced in P2X1-deficient murine platelets, and inhibition of P2X1 in wild-type platelets similarly reduced PAR4-mediated aggregation. In human platelets, aggregation to low/threshold stimulation of PAR1 was inhibited with the P2X1 antagonist MRS2159. In addition, P2X1 stimulation primed human platelet responses, such that subsequent sub-threshold PAR1 responses were converted into significant aggregation. Selective ADP receptor inhibitors attenuated P2X1-mediated priming, suggesting that the synergy between P2X1 and sub-threshold PAR1 stimulation was in part because of enhanced granular release of ADP. Overall, the present study defines a novel interaction between platelet P2X1 and thrombin receptors, with P2X1 functioning to amplify aggregation responses at low levels of thrombin receptor stimulation.

  15. Potential role of P2X7R in esophageal squamous cell carcinoma proliferation.

    Science.gov (United States)

    Santos, André A; Cappellari, Angélica R; de Marchi, Fernanda O; Gehring, Marina P; Zaparte, Aline; Brandão, Caroline A; Lopes, Tiago Giuliani; da Silva, Vinicius D; Pinto, Luis Felipe Ribeiro; Savio, Luiz Eduardo Baggio; Moreira-Souza, Aline Cristina Abreu; Coutinho-Silva, Robson; Paccez, Juliano D; Zerbini, Luiz F; Morrone, Fernanda B

    2017-09-01

    Esophageal cancer is an aggressive tumor and is the sixth leading cause of cancer death worldwide. ATP is well known to regulate cancer progression in a variety of models by different mechanisms, including P2X7R activation. This study aimed to evaluate the role of P2X7R in esophageal squamous cell carcinoma (ESCC) proliferation. Our results show that treatment with high ATP concentrations induced a decrease in cell number, cell viability, number of polyclonal colonies, and reduced migration of ESCC. The treatment with the selective P2X7R antagonist A740003 or siRNA for P2X7 reverted this effect in the KYSE450 cell line. In addition, results showed that P2X7R is highly expressed, at mRNA and protein levels, in KYSE450 lineage. Additionally, KYSE450, KYSE30, and OE21 cells express P2X3R, P2X4R, P2X5R, P2X6R, and P2X7R genes. P2X1R is expressed by KYSE30 and KYSE450, and only KYSE450 expresses the P2X2R gene. Furthermore, esophageal cancer cell line KYSE450 presented higher expression of E-NTPDases 1 and 2 and of Ecto-5'-NT/CD73 when compared to normal cells. This cell line also exhibits ATPase, ADPase, and AMPase activity, although in different levels, and the co-treatment of apyrase was able to revert the antiproliferative effects of ATP. Moreover, results showed high immunostaining for P2X7R in biopsies of patients with esophageal carcinoma, indicating the involvement of this receptor in the growth of this type of cancer. The results suggest that P2X7R may be a potential pharmacological target to treat ESCC and can lead us to further investigate the effect of this receptor in cancer cell progression.

  16. Vascular surgical stretch injury leads to activation of P2X7 receptors and impaired endothelial function.

    Directory of Open Access Journals (Sweden)

    Padmini Komalavilas

    Full Text Available A viable vascular endothelial layer prevents vasomotor dysfunction, thrombosis, inflammation, and intimal hyperplasia. Injury to the endothelium occurs during harvest and "back table" preparation of human saphenous vein prior to implantation as an arterial bypass conduit. A subfailure overstretch model of rat aorta was used to show that subfailure stretch injury of vascular tissue leads to impaired endothelial-dependent relaxation. Stretch-induced impaired relaxation was mitigated by treatment with purinergic P2X7 receptor (P2X7R inhibitors, brilliant blue FCF (FCF and A740003, or apyrase, an enzyme that catalyzes the hydrolysis of ATP. Alternatively, treatment of rat aorta with exogenous ATP or 2'(3'-O-(4-Benzoyl benzoyl-ATP (BzATP also impaired endothelial-dependent relaxation. Treatment of human saphenous vein endothelial cells (HSVEC with exogenous ATP led to reduced nitric oxide production which was associated with increased phosphorylation of the stress activated protein kinase, p38 MAPK. ATP- stimulated p38 MAPK phosphorylation of HSVEC was inhibited by FCF and SB203580. Moreover, ATP inhibition of nitric oxide production in HSVEC was prevented by FCF, SB203580, L-arginine supplementation and arginase inhibition. Finally, L-arginine supplementation and arginase inhibition restored endothelial dependent relaxation after stretch injury of rat aorta. These results suggest that vascular stretch injury leads to ATP release, activation of P2X7R and p38 MAPK resulting in endothelial dysfunction due to arginase activation. Endothelial function can be restored in both ATP treated HSVEC and intact stretch injured rat aorta by P2X7 receptor inhibition with FCF or L-arginine supplementation, implicating straightforward therapeutic options for treatment of surgical vascular injury.

  17. P2X receptors in the cardiovascular system and their potential as therapeutic targets in disease.

    Science.gov (United States)

    Ralevic, Vera

    2015-01-01

    This review considers the expression and roles of P2X receptors in the cardiovascular system in health and disease and their potential as therapeutic targets. P2X receptors are ligand gated ion channels which are activated by the endogenous ligand ATP. They are formed from the assembly of three P2X subunit proteins from the complement of seven (P2X1-7), which can associate to form homomeric or heteromeric P2X receptors. The P2X1 receptor is widely expressed in the cardiovascular system, being located in the heart, in the smooth muscle of the majority of blood vessels and in platelets. P2X1 receptors expressed in blood vessels can be activated by ATP coreleased with noradrenaline as a sympathetic neurotransmitter, leading to smooth muscle depolarisation and contraction. There is evidence that the purinergic component of sympathetic neurotransmission is increased in hypertension, identifying P2X1 receptors as a possible therapeutic target in this disorder. P2X3 and P2X2/3 receptors are expressed on cardiac sympathetic neurones and may, through positive feedback of neuronal ATP at this prejunctional site, amplify sympathetic neurotransmission. Activation of P2X receptors expressed in the heart increases cardiac myocyte contractility, and an important role of the P2X4 receptor in this has been identified. Deletion of P2X4 receptors in the heart depresses contractile performance in models of heart failure, while overexpression of P2X4 receptors has been shown to be cardioprotective, thus P2X4 receptors may be therapeutic targets in the treatment of heart disease. P2X receptors have been identified on endothelial cells. Although immunoreactivity for all P2X1-7 receptor proteins has been shown on the endothelium, relatively little is known about their function, with the exception of the endothelial P2X4 receptor, which has been shown to mediate endothelium-dependent vasodilatation to ATP released during shear stress. The potential of P2X receptors as therapeutic targets

  18. Methamphetamine alters microglial immune function through P2X7R signaling.

    Science.gov (United States)

    Fernandes, Nicole C; Sriram, Uma; Gofman, Larisa; Cenna, Jonathan M; Ramirez, Servio H; Potula, Raghava

    2016-04-26

    Purinoceptors have emerged as mediators of chronic inflammation and neurodegenerative processes. The ionotropic purinoceptor P2X7 (P2X7R) is known to modulate proinflammatory signaling and integrate neuronal-glial circuits. Evidence of P2X7R involvement in neurodegeneration, chronic pain, and chronic inflammation suggests that purinergic signaling plays a major role in microglial activation during neuroinflammation. In this study, we investigated the effects of methamphetamine (METH) on microglial P2X7R. ESdMs were used to evaluate changes in METH-induced P2X7R gene expression via Taqman PCR and protein expression via western blot analysis. Migration and phagocytosis assays were used to evaluate functional changes in ESdMs in response to METH treatment. METH-induced proinflammatory cytokine production following siRNA silencing of P2X7R in ESdMs measured P2X7R-dependent functional changes. In vivo expression of P2X7R and tyrosine hydroxylase (TH) was visualized in an escalating METH dose mouse model via immunohistochemical analysis. Stimulation of ESdMs with METH for 48 h significantly increased P2X7R mRNA (*p P2X7R protein in cellular fractionations revealed increases in membrane P2X7R (*p P2X7R-dependent through the use of A 438079, a P2X7R-competitive antagonist, which reversed the METH effects (****p P2X7R antagonist reduced METH-induced phagocytosis (****p P2X7R decreased TNF-α (*p P2X7R and decreased TH expression in the striata of escalating dose METH animal model compared to controls. This study sheds new light on the functional role of P2X7R in the regulation of microglial effector functions during substance abuse. Our findings suggest that P2X7R plays an important role in METH-induced microglial activation responses. P2X7R antagonists may thus constitute a novel target of therapeutic utility in neuroinflammatory conditions by regulating pathologically activated glial cells in stimulant abuse.

  19. A haplotype spanning P2X7R, P2X4R and CAMKK2 may mark susceptibility to pulmonary non-tuberculous mycobacterial disease.

    Science.gov (United States)

    Halstrom, Samuel; Cherry, Catherine L; Black, Michael; Thomson, Rachel; Goullee, Hayley; Baltic, Svetlana; Allcock, Richard; Temple, Suzanna E L; Price, Patricia

    2017-05-01

    Despite widespread exposure to potentially pathogenic mycobacteria present in the soil and in domestic water supplies, it is not clear why only a small proportion of individuals contract pulmonary nontuberculous mycobacterial (NTM) infections. Here, we explore the impact of polymorphisms within three genes: P2X ligand gated ion channel 7 (P2X7R), P2X ligand gated ion channel 4 (P2X4R) and calcium/calmodulin-dependent protein kinase kinase 2 beta (CAMKK2) on susceptibility. Thirty single nucleotide polymorphisms (SNPs) were genotyped in NTM patients (n = 124) and healthy controls (n = 229). Weak associations were found between individual alleles in P2X7R and disease but were not significant in multivariate analyses adjusted to account for gender. Haplotypes spanning the three genes were derived using the fastPHASE algorithm. This yielded 27 haplotypes with frequencies >1% and accounting for 63.3% of the combined cohort. In univariate analyses, seven of these haplotypes displayed associations with NTM disease above our preliminary cut-off (p ≤ 0.20). When these were carried forward in a logistic regression model, gender and one haplotype (SH95) were independently associated with the disease (model p P2X7R and CAMKK2 in pathways affecting pulmonary NTM disease.

  20. ATP and UTP responses of cultured rat aortic smooth muscle cells revisited: dominance of P2Y2 receptors

    Science.gov (United States)

    Kumari, Rajendra; Goh, Gareth; Ng, Leong L; Boarder, Michael R

    2003-01-01

    It has previously been shown that ATP and UTP stimulate P2Y receptors in vascular smooth muscle cells (VSMCs), but the nature of these receptors, in particular the contribution of P2Y2 and P2Y4 subtypes, has not been firmly established. Here we undertake a further pharmacological analysis of [3H]inositol polyphosphate responses to nucleotides in cultured rat VSMCs. ATP generated a response that was partial compared to UTP, as reported earlier. In the presence of a creatine phosphokinase (CPK) system for regenerating nucleoside triphosphates, the response to ATP was increased, the response to UTP was unchanged, and the difference between UTP and ATP concentration–response curves disappeared. Chromatographic analysis showed that ATP was degraded slightly faster than UTP. The response to UDP was always smaller than that to UTP, but with a shallow slope and a high potency component. In the presence of hexokinase (which prevents the accumulation of ATP/UTP from ADP/UDP), the maximum response to UDP was reduced and the high-potency component of the curve was retained. By contrast, the response to ADP was weaker throughout in the presence of hexokinase. ATPγS was an effective agonist with a similar EC50 to UTP, but with a lower maximum. ITP was a weak agonist compared with UTP. Suramin was an effective antagonist of the response to UTP (pA2=4.48), but not when ATP was the agonist. However, suramin was an effective antagonist (pA2=4.45) when stimulation with ATP was in the presence of the CPK regenerating system. Taken together with the results of others, these findings indicate that the response of cultured rat VSMCs to UTP and to ATP is predominantly at the P2Y2 receptor, and that there is also a response to UDP at the P2Y6 receptor. PMID:14597595

  1. Oil Mist Compliance

    Energy Technology Data Exchange (ETDEWEB)

    Lazarus, Lloyd

    2009-02-02

    This report summarizes activities at the KCP related to evaluating and modifying machine tools in order to be in compliance with Section 23 of DOE 10 CFR 851, Worker Safety and Health Program. Section 851.23 (a) states that “Contractors must comply with the following safety and health standards that are applicable to the hazards in their covered workplace”, and subsection 9 contains the following applicable standard: “American Congress of Governmental Industrial Hygienists (ACGIH), ‘Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices,’ (2005) (incorporated by reference, see §851.27) when the ACGIH Threshold Limit Values are lower (more protective) than permissible exposure limits in 29 CFR 1910.” In the 2005 ACGIH – Threshold Limit Value book a Notice of Change was issued for exposure to mineral oil mist used in metalworking fluids (MWFs). The effects of planning for the new facility and which machine tools would be making the transition to the new facility affected which machine tools were modified.

  2. Oil Mist Compliance

    International Nuclear Information System (INIS)

    Lazarus, Lloyd

    2009-01-01

    This report summarizes activities at the KCP related to evaluating and modifying machine tools in order to be in compliance with Section 23 of DOE 10 CFR 851, Worker Safety and Health Program. Section 851.23 (a) states that 'Contractors must comply with the following safety and health standards that are applicable to the hazards in their covered workplace', and subsection 9 contains the following applicable standard: 'American Congress of Governmental Industrial Hygienists (ACGIH), 'Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices,' (2005) (incorporated by reference, see (section)851.27) when the ACGIH Threshold Limit Values are lower (more protective) than permissible exposure limits in 29 CFR 1910'. In the 2005 ACGIH Threshold Limit Value book a Notice of Change was issued for exposure to mineral oil mist used in metalworking fluids (MWFs). The effects of planning for the new facility and which machine tools would be making the transition to the new facility affected which machine tools were modified

  3. Environmental Compliance Management System

    International Nuclear Information System (INIS)

    Brownson, L.W.; Krsul, T.; Peralta, R.A.; Knudson, D.A.; Rosignolo, C.L.

    1992-01-01

    Argonne National Laboratory (ANL) is developing the Environmental Compliance Management System (ECMS) as a comprehensive, cost-effective tool to ensure (1) that the Laboratory complies with all applicable federal and state environmental laws and regulations, (2) that environmental issues and concerns are recognized and considered in the early phases of projects; and (3) that Laboratory personnel conduct Laboratory operations in the most environmentally acceptable manner. The ECMS is an expert computer system which is designed to allow project engineers to perform an environmental evaluation of their projects. The system includes a Master Program which collects basic project information, provide utility functions, and access the environmental expert modules, environmental expert system modules for each federal and state environmental law which allows the user to obtain specific information on how an individual law may affect his project; and site-specific databases which contain information necessary for effective management of the site under environmental regulations. The ECMS will have the capability to complete and print many of the necessary environmental forms required by federal and state agencies, including the Department of Energy

  4. Magnified Bacteria Powerful Motivator for Hand Hygiene Compliance.

    Science.gov (United States)

    Gregory, Ashley

    2016-08-01

    Infection prevention specialists at Henry Ford Hospital in Detroit have found that showing healthcare workers magnified pictures of bacteria found ontheir hands and in their surrounding units can be a powerful motivator for improved hand hygiene compliance. When tested in four units during a one-month period, the intervention boosted hand hygiene compliance by an average of 24%. Investigators note that to be successful, the intervention must be paired with an effective compliance monitoring program. For the study, investigators visited each unit twice per week, during which they would swab various items as well as employees' hands using and adenosine triphosphate (ATP) meter, a hand-held device that measures living organisms. During each unit visit, infection prevention specialists would show unit personnel pictures from a compilation of 12 magnified images of bacteria that had been lifted from the unit. This was to demonstrate what the bacteria would look like under a microscope. The unsavory pictures produced immediate increases in had hygiene compliance, and prompted healthcare workers to see who could produce the best ATP meter readings on subsequent infection prevention specialist visits.

  5. Air Compliance Complaint Database (ACCD)

    Data.gov (United States)

    U.S. Environmental Protection Agency — THIS DATA ASSET NO LONGER ACTIVE: This is metadata documentation for the Region 7 Air Compliance Complaint Database (ACCD) which logs all air pollution complaints...

  6. Small Airplane Certification Compliance Program

    Science.gov (United States)

    1997-01-02

    This advisory circular (AC) provides a compilation of historically acceptable means of compliance to specifically selected sections of Part 23 of the Federal Aviation Regulations that have become burdensome for small low performance airplanes to show...

  7. Compliance with Segment Disclosure Initiatives

    DEFF Research Database (Denmark)

    Arya, Anil; Frimor, Hans; Mittendorf, Brian

    2013-01-01

    Regulatory oversight of capital markets has intensified in recent years, with a particular emphasis on expanding financial transparency. A notable instance is efforts by the Financial Accounting Standards Board that push firms to identify and report performance of individual business units...... compliance or mandates strict compliance from firms. Under voluntary compliance, a firm is able to credibly withhold individual segment information from its competitors by disclosing data only at the aggregate firm level. Consistent with regulatory hopes, we show that mandatory compliance enhances welfare...... by increasing transparency and leveling the playing field. However, our analysis also demonstrates that in the long run, if firms are unable to use discretion in reporting to maintain their competitive edge, they may seek more destructive alternatives. Accounting for such concerns, in the long run, voluntary...

  8. Integrated Compliance Information System (ICIS)

    Data.gov (United States)

    U.S. Environmental Protection Agency — The purpose of ICIS is to meet evolving Enforcement and Compliance business needs for EPA and State users by integrating information into a single integrated data...

  9. Amplification loop of the inflammatory process is induced by P2X7R activation in intestinal epithelial cells in response to neutrophil transepithelial migration.

    Science.gov (United States)

    Cesaro, Annabelle; Brest, Patrick; Hofman, Véronique; Hébuterne, Xavier; Wildman, Scott; Ferrua, Bernard; Marchetti, Sandrine; Doglio, Alain; Vouret-Craviari, Valérie; Galland, Franck; Naquet, Philippe; Mograbi, Baharia; Unwin, Robert; Hofman, Paul

    2010-07-01

    Inflammatory bowel diseases (IBD) are characterized during their active phase by polymorphonuclear leukocyte (PMNL) transepithelial migration. The efflux of PMNL into the mucosa is associated with the production of proinflammatory cytokines and the release of ATP from damaged and necrotic cells. The expression and function of purinergic P2X(7) receptor (P2X(7)R) in intestinal epithelial cells (IEC) and its potential role in the "cross talk" between IEC and PMNL have not been explored. The aims of the present study were 1) to examine P2X(7)R expression in IEC (T84 cells) and in human intestinal biopsies; 2) to detect any changes in P2X(7)R expression in T84 cells during PMNL transepithelial migration, and during the active and quiescent phases of IBD; and 3) to test whether P2X(7)R stimulation in T84 monolayers can induce caspase-1 activation and IL-1beta release by IEC. We found that a functional ATP-sensitive P2X(7)R is constitutively expressed at the apical surface of IEC T84 cells. PMNL transmigration regulates dynamically P2X(7)R expression and alters its distribution from the apical to basolateral surface of IEC during the early phase of PMNL transepithelial migration in vitro. P2X(7)R expression was weak in intestinal biopsies obtained during the active phase of IBD. We show that activation of epithelial P2X(7)R is mandatory for PMNL-induced caspase-1 activation and IL-1beta release by IEC. Overall, these changes in P2X(7)R function may serve to tailor the intensity of the inflammatory response and to prevent IL-1beta overproduction and inflammatory disease.

  10. Post-translational regulation of P2X receptor channels: modulation by phospholipids

    Directory of Open Access Journals (Sweden)

    Louis-Philippe eBernier

    2013-11-01

    Full Text Available P2X receptor channels mediate fast excitatory signaling by ATP and play major roles in sensory transduction, neuro-immune communication and inflammatory response. P2X receptors constitute a gene family of calcium-permeable ATP-gated cation channels therefore the regulation of P2X signaling is critical for both membrane potential and intracellular calcium homeostasis. Phosphoinositides (PIPn are anionic signaling phospholipids that act as functional regulators of many types of ion channels. Direct PIPn binding was demonstrated for several ligand- or voltage-gated ion channels, however no generic motif emerged to accurately predict lipid-protein binding sites. This review presents what is currently known about the modulation of the different P2X subtypes by phospholipids and about critical determinants underlying their sensitivity to PIPn levels in the plasma membrane.All functional mammalian P2X subtypes tested, with the notable exception of P2X5, have been shown to be positively modulated by PIPn, i.e. homomeric P2X1, P2X2, P2X3, P2X4, and P2X7, as well as heteromeric P2X1/5 and P2X2/3 receptors. Based on various results reported on the aforementioned subtypes including mutagenesis of the prototypical PIPn-sensitive P2X4 and PIPn-insensitive P2X5 receptor subtypes, an increasing amount of functional, biochemical and structural evidence converges on the modulatory role of a short polybasic domain located in the proximal C-terminus of P2X subunits. This linear motif, semi-conserved in the P2X family, seems necessary and sufficient for encoding direct modulation of ATP-gated channels by PIPn. Furthermore, the physiological impact of the regulation of ionotropic purinergic responses by phospholipids on pain pathways was recently revealed in the context of native crosstalks between phospholipase C-linked metabotropic receptors and P2X receptor channels in DRG sensory neurons and microglia.

  11. Glutathione induces GABA release through P2X7R activation on Müller glia.

    Science.gov (United States)

    Freitas, Hércules Rezende; Reis, Ricardo A de Melo

    2017-01-01

    The retinal tissue of warm-blooded vertebrates performs surprisingly complex and accurate transduction of visual information. To achieve precision, a multilayered neuroglia structure is established throughout the embryonic development, and the presence of radial Müller (glial) cells ensure differentiation, growth and survival for the neuronal elements within retinal environment. It is assumed that Müller cells serve as a dynamic reservoir of progenitors, capable of expressing transcription factors, differentiating and proliferating as either neuronal or glial cells depending on extrinsic cues. In the postnatal period, Müller glia may re-enter cell cycle and produce new retinal neurons in response to acute damage. In this context, glutathione (GSH), a virtually ubiquitous tripeptide antioxidant, which is found at milimolar concentrations in central glial cells, plays a vital role as a reducing agent, buffering radical oxygen species (ROS) and preventing cell death in severely injured retinal tissues. Despite its antioxidant role, data also point to GSH as a signaling agent, suggesting that GABA release and P2X 7 R-mediated calcium inwards occur in Müller cells in a GSH-enriched environment. These phenomena indicate a novel mechanistic response to damage in the vertebrate retinal tissue, particularly in neuron-glia networks.

  12. Macrophage activation and polarization modify P2X7 receptor secretome influencing the inflammatory process.

    Science.gov (United States)

    de Torre-Minguela, Carlos; Barberà-Cremades, Maria; Gómez, Ana I; Martín-Sánchez, Fátima; Pelegrín, Pablo

    2016-03-03

    The activation of P2X7 receptor (P2X7R) on M1 polarized macrophages induces the assembly of the NLRP3 inflammasome leading to the release of pro-inflammatory cytokines and the establishment of the inflammatory response. However, P2X7R signaling to the NLRP3 inflammasome is uncoupled on M2 macrophages without changes on receptor activation. In this study, we analyzed P2X7R secretome in wild-type and P2X7R-deficient macrophages polarized either to M1 or M2 and proved that proteins released after P2X7R stimulation goes beyond caspase-1 secretome. The characterization of P2X7R-secretome reveals a new function of this receptor through a fine-tuning of protein release. We found that P2X7R stimulation in macrophages is able to release potent anti-inflammatory proteins, such as Annexin A1, independently of their polarization state suggesting for first time a potential role for P2X7R during resolution of the inflammation and not linked to the release of pro-inflammatory cytokines. These results are of prime importance for the development of therapeutics targeting P2X7R.

  13. 10 CFR 434.604 - Compliance.

    Science.gov (United States)

    2010-01-01

    ... 10 Energy 3 2010-01-01 2010-01-01 false Compliance. 434.604 Section 434.604 Energy DEPARTMENT OF ENERGY ENERGY CONSERVATION ENERGY CODE FOR NEW FEDERAL COMMERCIAL AND MULTI-FAMILY HIGH RISE RESIDENTIAL BUILDINGS Building Energy Compliance Alternative § 434.604 Compliance. 604.1 Compliance with this section is...

  14. 28 CFR 811.11 - Compliance.

    Science.gov (United States)

    2010-07-01

    ... 28 Judicial Administration 2 2010-07-01 2010-07-01 false Compliance. 811.11 Section 811.11... OFFENDER REGISTRATION § 811.11 Compliance. (a) A sex offender may be excused from strict compliance with... circumstances that will interfere with compliance and makes alternative arrangements to satisfy the requirements...

  15. 30 CFR 840.16 - Compliance conference.

    Science.gov (United States)

    2010-07-01

    ... 30 Mineral Resources 3 2010-07-01 2010-07-01 false Compliance conference. 840.16 Section 840.16... ENFORCEMENT § 840.16 Compliance conference. (a) The State program may provide for compliance conferences... paragraphs (b) through (e) of this section. (b) A permittee may request an on-site compliance conference with...

  16. Membrane Order Is a Key Regulator of Divalent Cation-Induced Clustering of PI(3,5)P2and PI(4,5)P2.

    Science.gov (United States)

    Sarmento, Maria J; Coutinho, Ana; Fedorov, Aleksander; Prieto, Manuel; Fernandes, Fábio

    2017-10-31

    Although the evidence for the presence of functionally important nanosized phosphorylated phosphoinositide (PIP)-rich domains within cellular membranes has accumulated, very limited information is available regarding the structural determinants for compartmentalization of these phospholipids. Here, we used a combination of fluorescence spectroscopy and microscopy techniques to characterize differences in divalent cation-induced clustering of PI(4,5)P 2 and PI(3,5)P 2 . Through these methodologies we were able to detect differences in divalent cation-induced clustering efficiency and cluster size. Ca 2+ -induced PI(4,5)P 2 clusters are shown to be significantly larger than the ones observed for PI(3,5)P 2 . Clustering of PI(4,5)P 2 is also detected at physiological concentrations of Mg 2+ , suggesting that in cellular membranes, these molecules are constitutively driven to clustering by the high intracellular concentration of divalent cations. Importantly, it is shown that lipid membrane order is a key factor in the regulation of clustering for both PIP isoforms, with a major impact on cluster sizes. Clustered PI(4,5)P 2 and PI(3,5)P 2 are observed to present considerably higher affinity for more ordered lipid phases than the monomeric species or than PI(4)P, possibly reflecting a more general tendency of clustered lipids for insertion into ordered domains. These results support a model for the description of the lateral organization of PIPs in cellular membranes, where both divalent cation interaction and membrane order are key modulators defining the lateral organization of these lipids.

  17. Synthesis of CaO-SiO2-P2O5 mesoporous bioactive glasses with high P2O5 content by evaporation induced self assembly process.

    Science.gov (United States)

    Zhao, Shan; Li, Yanbao; Li, Dongxu

    2011-02-01

    Mesoporous bioactive glasses (MBGs) of the CaO-SiO(2)-P(2)O(5) system containing relatively high P(2)O(5) contents (10-30 mol%) were prepared from a sol-gel. An evaporation-induced self-assembly (EISA) technique was used with poly(ethylene oxide)-block-poly(propylene oxide)-block-poly(ethylene oxide) (EO(20)-PO(70)-EO(20), P123) acting as a template. The structural, morphological and textural properties of MBGs were investigated by small-angle X-ray diffraction (SAXRD), transmission electron microscopy (TEM), Fourier transform infrared (FTIR) spectroscopy and a N(2) sorption/desorption technique. SAXRD and TEM results display the reduced long-range ordering of mesopores with increasing P(2)O(5) content. N(2) sorption/desorption analysis shows that all three samples exhibit a type IV isotherm with type H1 hysteresis loops, characteristic of independent cylindrical slim pore channels and this material has a Barret-Joyner-Halenda (BJH) model pore size of ~4 nm and BET specific surface area ~430 m(2)/g. NMR results indicate a more condensed framework for samples with 30 mol% P(2)O(5) than samples with 10 mol% P(2)O(5). For in vitro bioactivity tests where samples were soaked in simulated body fluid (SBF), samples with 30 mol% P(2)O(5) showed higher crystallinity than those with lower P(2)O(5) contents Silicon concentration increased in SBF solution during the soaking period, which indicates MBGs can be degradable in SBF solution.

  18. Activation of P2Y6 Receptors Facilitates Nonneuronal Adenosine Triphosphate and Acetylcholine Release from Urothelium with the Lamina Propria of Men with Bladder Outlet Obstruction.

    Science.gov (United States)

    Silva, Isabel; Ferreirinha, Fátima; Magalhães-Cardoso, Maria Teresa; Silva-Ramos, Miguel; Correia-de-Sá, Paulo

    2015-10-01

    Deregulation of purinergic bladder signaling may contribute to persistent detrusor overactivity in patients with bladder outlet obstruction. Activation of uridine diphosphate sensitive P2Y6 receptors increases voiding frequency in rats indirectly by releasing adenosine triphosphate from the urothelium. To our knowledge this mechanism has never been tested in the human bladder. We examined the role of the uridine diphosphate sensitive P2Y6 receptor on tetrodotoxin insensitive nonneuronal adenosine triphosphate and [(3)H]acetylcholine release from the human urothelium with the lamina propria of control organ donors and patients with benign prostatic hyperplasia. The adenosine triphosphate-to-[(3)H]acetylcholine ratio was fivefold higher in mucosal urothelium/lamina propria strips from benign prostatic hyperplasia patients than control men. The selective P2Y6 receptor agonist PSB0474 (100 nM) augmented by a similar amount adenosine triphosphate and [(3)H]acetylcholine release from mucosal urothelium/lamina propria strips from both groups of individuals. The facilitatory effect of PSB0474 was prevented by MRS2578 (50 nM) and by carbenoxolone (10 μM), which block P2Y6 receptor and pannexin-1 hemichannels, respectively. Blockade of P2X3 (and/or P2X2/3) receptors with A317491 (100 nM) also attenuated release facilitation by PSB0474 in control men but not in patients with benign prostatic hyperplasia. Immunolocalization studies showed that P2Y6, P2X2 and P2X3 receptors were present in choline acetyltransferase positive urothelial cells. In contrast to P2Y6 staining, choline acetyltransferase, P2X2 and P2X3 immunoreactivity decreased in the urothelium of benign prostatic hyperplasia patients. Activation of P2Y6 receptor amplifies mucosal adenosine triphosphate release underlying bladder overactivity in patients with benign prostatic hyperplasia. Therefore, we propose selective P2Y6 receptor blockade as a novel therapeutic strategy to control persistent storage symptoms in

  19. Expression of P2X7R in breast cancer tissue and the induction of apoptosis by the gene-specific shRNA in MCF-7 cells.

    Science.gov (United States)

    Tan, Chao; Han, L I; Zou, Lili; Luo, Chunhua; Liu, Aihua; Sheng, Xiejing; Xi, Dee

    2015-10-01

    significantly reduced rates of proliferation when compared with the normal control group. In addition, flow cytometry revealed that the P2X7R-shRNA and KN-62 groups exhibited a reduced level of cell proliferation and a higher rate of apoptosis. In conclusion, P2X7R was shown to be overexpressed in breast cancer tissues and positively associated with ER expression. A P2X7R-shRNA expression vector effectively inhibited P2X7R expression in MCF-7 breast cancer cells, which subsequently induced cell apoptosis and reduced the levels of cell proliferation. These results indicated that P2X7R may serve as a potential target for breast cancer treatment and prevention.

  20. Protein kinase C isoforms in bovine aortic endothelial cells: role in regulation of P2Y- and P2U-purinoceptor-stimulated prostacyclin release.

    Science.gov (United States)

    Patel, V; Brown, C; Boarder, M R

    1996-05-01

    1. Enhanced synthesis of prostacyclin (PGI2) and inositol polyphosphates in bovine aortic endothelial cells in response to ATP and ADP is mediated by co-existing P2Y- and P2U-purinoceptors. Here we examine the regulation of these responses by isoforms of protein kinase C (PKC). 2. Immunoblots with antisera specific for 8 different PKC isoforms revealed the presence of alpha, epsilon and zeta, while no immunoreactivity was found for beta, gamma, delta, eta and theta isoforms. PKC-alpha was largely cytosolic in unstimulated cells and almost all translocated to the membrane (Triton X-100 soluble) after a 1 min treatment with the PKC activating phorbol myristate acetate (PMA); PKC-epsilon was always in a Triton X-100 insoluble membrane fraction, while PKC-zeta was found in both soluble and membrane bound (Triton X-100 soluble) forms in the unstimulated cells and was unaffected by PMA. 3. Treatment with PMA for 6 h led to a 90% downregulation of PKC-alpha, while the immunoreactivity to the epsilon and zeta isoforms remained largely unchanged. 4. After either 10 min or 6 h exposure to PMA the PGI2 response to activation of both receptors was enhanced, while the inositol 1,4,5-trisphosphate response to P2Y-purinoceptor activation was substantially attenuated and the P2U-purinoceptor response was unchanged. Thus the PGI2 response to PMA under conditions when 90% of the PKC-alpha was lost resembles that seen on acute stimulation of PKC by PMA, and the PGI2 response does not correlate with phospholipase C response. 5. Inhibition of PKC with the isoform non-selective inhibitors, Ro 31-8220 and Go 6850 abolished the PGI2 response to both P2U- and P2Y-purinoceptor stimulation. However, Go 6976, which preferentially inhibits Ca2+ sensitive isoforms (such as PKC-alpha) and not Ca2+ insensitive isoforms (such as PKC-epsilon), had no effect on the PGI2 response. 6. The results show that there is a requirement for PKC in the stimulation of PGI2 production by endothelial P2Y- and P2U

  1. P2Y Receptors in Synaptic Transmission and Plasticity: Therapeutic Potential in Cognitive Dysfunction

    Directory of Open Access Journals (Sweden)

    Segundo J. Guzman

    2016-01-01

    Full Text Available ATP released from neurons and astrocytes during neuronal activity or under pathophysiological circumstances is able to influence information flow in neuronal circuits by activation of ionotropic P2X and metabotropic P2Y receptors and subsequent modulation of cellular excitability, synaptic strength, and plasticity. In the present paper we review cellular and network effects of P2Y receptors in the brain. We show that P2Y receptors inhibit the release of neurotransmitters, modulate voltage- and ligand-gated ion channels, and differentially influence the induction of synaptic plasticity in the prefrontal cortex, hippocampus, and cerebellum. The findings discussed here may explain how P2Y1 receptor activation during brain injury, hypoxia, inflammation, schizophrenia, or Alzheimer’s disease leads to an impairment of cognitive processes. Hence, it is suggested that the blockade of P2Y1 receptors may have therapeutic potential against cognitive disturbances in these states.

  2. P2Y6 Receptor Activation Promotes Inflammation and Tissue Remodeling in Pulmonary Fibrosis

    Directory of Open Access Journals (Sweden)

    Tobias Müller

    2017-08-01

    Full Text Available Idiopathic pulmonary fibrosis (IPF is a disease with a poor prognosis and very few available treatment options. The involvement of the purinergic receptor subtypes P2Y2 and P2X7 in fibrotic lung disease has been demonstrated recently. In this study, we investigated the role of P2Y6 receptors in the pathogenesis of IPF in humans and in the animal model of bleomycin-induced lung injury. P2Y6R expression was upregulated in lung structural cells but not in bronchoalveolar lavage (BAL cells derived from IPF patients as well as in animals following bleomycin administration. Furthermore, BAL fluid levels of the P2Y6R agonist uridine-5′-diphosphate were elevated in animals with bleomycin-induced pulmonary fibrosis. Inflammation and fibrosis following bleomycin administration were reduced in P2Y6R-deficient compared to wild-type animals confirming the pathophysiological relevance of P2Y6R subtypes for fibrotic lung diseases. Experiments with bone marrow chimeras revealed the importance of P2Y6R expression on lung structural cells for pulmonary inflammation and fibrosis. Similar effects were obtained when animals were treated with the P2Y6R antagonist MRS2578. In vitro studies demonstrated that proliferation and secretion of the pro-inflammatory/pro-fibrotic cytokine IL-6 by lung fibroblasts are P2Y6R-mediated processes. In summary, our results clearly demonstrate the involvement of P2Y6R subtypes in the pathogenesis of pulmonary fibrosis. Thus, blocking pulmonary P2Y6 receptors might be a new target for the treatment of IPF.

  3. Novel protective role of endogenous cardiac myocyte P2X4 receptors in heart failure.

    Science.gov (United States)

    Yang, Tiehong; Shen, Jian-bing; Yang, Ronghua; Redden, John; Dodge-Kafka, Kimberly; Grady, James; Jacobson, Kenneth A; Liang, Bruce T

    2014-05-01

    Heart failure (HF), despite continuing progress, remains a leading cause of mortality and morbidity. P2X4 receptors (P2X4R) have emerged as potentially important molecules in regulating cardiac function and as potential targets for HF therapy. Transgenic P2X4R overexpression can protect against HF, but this does not explain the role of native cardiac P2X4R. Our goal is to define the physiological role of endogenous cardiac myocyte P2X4R under basal conditions and during HF induced by myocardial infarction or pressure overload. Mice established with conditional cardiac-specific P2X4R knockout were subjected to left anterior descending coronary artery ligation-induced postinfarct or transverse aorta constriction-induced pressure overload HF. Knockout cardiac myocytes did not show P2X4R by immunoblotting or by any response to the P2X4R-specific allosteric enhancer ivermectin. Knockout hearts showed normal basal cardiac function but depressed contractile performance in postinfarct and pressure overload models of HF by in vivo echocardiography and ex vivo isolated working heart parameters. P2X4R coimmunoprecipitated and colocalized with nitric oxide synthase 3 (eNOS) in wild-type cardiac myocytes. Mice with cardiac-specific P2X4R overexpression had increased S-nitrosylation, cyclic GMP, NO formation, and were protected from postinfarct and pressure overload HF. Inhibitor of eNOS, L-N(5)-(1-iminoethyl)ornithine hydrochloride, blocked the salutary effect of cardiac P2X4R overexpression in postinfarct and pressure overload HF as did eNOS knockout. This study establishes a new protective role for endogenous cardiac myocyte P2X4R in HF and is the first to demonstrate a physical interaction between the myocyte receptor and eNOS, a mediator of HF protection. © 2014 American Heart Association, Inc.

  4. Methamphetamine alters microglial immune function through P2X7R signaling

    OpenAIRE

    Fernandes, Nicole C.; Sriram, Uma; Gofman, Larisa; Cenna, Jonathan M.; Ramirez, Servio H.; Potula, Raghava

    2016-01-01

    Background Purinoceptors have emerged as mediators of chronic inflammation and neurodegenerative processes. The ionotropic purinoceptor P2X7 (P2X7R) is known to modulate proinflammatory signaling and integrate neuronal-glial circuits. Evidence of P2X7R involvement in neurodegeneration, chronic pain, and chronic inflammation suggests that purinergic signaling plays a major role in microglial activation during neuroinflammation. In this study, we investigated the effects of methamphetamine (MET...

  5. Research of using mobile agents for information discovery in P2P networks

    International Nuclear Information System (INIS)

    Lan Yan; Yao Qing

    2003-01-01

    The technology of P2P is a new network-computing model that has great value of commerce and technology. After analyzing the current information discovery technology in P2P network, a new solution that is based on mobile agent is proposed. The mobile agent solution can reduce the need of bandwidth, be adapt to the dynamic of P2P network, and be asynchronous and be very fault tolerant. (authors)

  6. Purinergic receptor P2RY12-dependent microglial closure of the injured blood-brain barrier

    DEFF Research Database (Denmark)

    Lou, Nanhong; Takano, Takahiro; Pei, Yong

    2016-01-01

    Microglia are integral functional elements of the central nervous system, but the contribution of these cells to the structural integrity of the neurovascular unit has not hitherto been assessed. We show here that following blood-brain barrier (BBB) breakdown, P2RY12 (purinergic receptor P2Y, G......-protein coupled, 12)-mediated chemotaxis of microglia processes is required for the rapid closure of the BBB. Mice treated with the P2RY12 inhibitor clopidogrel, as well as those in which P2RY12 was genetically ablated, exhibited significantly diminished movement of juxtavascular microglial processes and failed...

  7. Lipopolysaccharide Inhibits the Channel Activity of the P2X7 Receptor

    Directory of Open Access Journals (Sweden)

    Elias Leiva-Salcedo

    2011-01-01

    Full Text Available The purinergic P2X7 receptor (P2X7R plays an important role during the immune response, participating in several events such as cytokine release, apoptosis, and necrosis. The bacterial endotoxin lipopolysaccharide (LPS is one of the strongest stimuli of the immune response, and it has been shown that P2X7R activation can modulate LPS-induced responses. Moreover, a C-terminal binding site for LPS has been proposed. In order to evaluate if LPS can directly modulate the activity of the P2X7R, we tested several signaling pathways associated with P2X7R activation in HEK293 cells that do not express the TLR-4 receptor. We found that LPS alone was unable to induce any P2X7R-related activity, suggesting that the P2X7R is not directly activated by the endotoxin. On the other hand, preapplication of LPS inhibited ATP-induced currents, intracellular calcium increase, and ethidium bromide uptake and had no effect on ERK activation in HEK293 cells. In splenocytes-derived T-regulatory cells, in which ATP-induced apoptosis is driven by the P2X7R, LPS inhibited ATP-induced apoptosis. Altogether, these results demonstrate that LPS modulates the activity of the P2X7R and suggest that this effect could be of physiological relevance.

  8. Microglia P2Y6 receptor is related to Parkinson’s disease through neuroinflammatory process

    Directory of Open Access Journals (Sweden)

    Xiaodong Yang

    2017-02-01

    Full Text Available Abstract Background Microglia in the central nervous system (CNS were reported to play crucial role in neurodegeneration. Previous studies showed that P2Y6 receptor (P2Y6R mainly contributed to microglia activation and phagocytosis in CNS. However, the level of P2Y6R in Parkinson’s disease (PD patients is unclear. Therefore, we measured the level of P2Y6R in PD patients and speculated whether it could be a potential biomarker for PD. Given on the basis that P2Y6R was higher in PD patients, we further explored the mechanisms underlying P2Y6R in the pathogenesis of PD. Methods We tested the expression level of P2Y6R in the peripheral blood mononuclear cells (PBMCs among 145 PD patients, 170 healthy controls, and 30 multiple system atrophy (MSA patients. We also used a lipopolysaccharide (LPS-stimulated microglial cell culture model to investigate (i the effects of LPS on P2Y6R expression with western blot and RT-PCR, (ii the effects of LPS on UDP expression using HPLC, (iii the effects of UDP/P2Y6R signaling on cytokine expression using western blot, RT-PCR, and ELISA, and (iv the signaling pathways activated by the P2Y6R involved in the neuroinflammation. Results Expression levels of P2Y6R in PD patients were higher than healthy controls and MSA patients. P2Y6R could be a good biomarker of PD. P2Y6R was also upregulated in LPS-treated BV-2 cells and involved in proinflammatory cytokine release through an autocrine loop based on LPS-triggered UDP secretion and accelerated neuroinflammatory responses through the ERK1/2 pathway. Importantly, blocking UDP/P2Y6R signaling could reverse these pathological processes. Conclusions P2Y6R may be a potential clinical biomarker of PD. Blocking P2Y6R may be a potential therapeutic approach to the treatment of PD patients through inhibition of microglia-activated neuroinflammation.

  9. Lipopolysaccharide Inhibits the Channel Activity of the P2X7 Receptor

    Science.gov (United States)

    Leiva-Salcedo, Elias; Coddou, Claudio; Rodríguez, Felipe E.; Penna, Antonello; Lopez, Ximena; Neira, Tanya; Fernández, Ricardo; Imarai, Mónica; Rios, Miguel; Escobar, Jorge; Montoya, Margarita; Huidobro-Toro, J. Pablo; Escobar, Alejandro; Acuña-Castillo, Claudio

    2011-01-01

    The purinergic P2X7 receptor (P2X7R) plays an important role during the immune response, participating in several events such as cytokine release, apoptosis, and necrosis. The bacterial endotoxin lipopolysaccharide (LPS) is one of the strongest stimuli of the immune response, and it has been shown that P2X7R activation can modulate LPS-induced responses. Moreover, a C-terminal binding site for LPS has been proposed. In order to evaluate if LPS can directly modulate the activity of the P2X7R, we tested several signaling pathways associated with P2X7R activation in HEK293 cells that do not express the TLR-4 receptor. We found that LPS alone was unable to induce any P2X7R-related activity, suggesting that the P2X7R is not directly activated by the endotoxin. On the other hand, preapplication of LPS inhibited ATP-induced currents, intracellular calcium increase, and ethidium bromide uptake and had no effect on ERK activation in HEK293 cells. In splenocytes-derived T-regulatory cells, in which ATP-induced apoptosis is driven by the P2X7R, LPS inhibited ATP-induced apoptosis. Altogether, these results demonstrate that LPS modulates the activity of the P2X7R and suggest that this effect could be of physiological relevance. PMID:21941410

  10. Tungsten phosphanylarylthiolato complexes [W{PhP(2-SC6H4)2-kappa3S,S',P} 2] and [W{P(2-SC6H4)3-kappa4S,S',S",P}2]: synthesis, structures and redox chemistry.

    Science.gov (United States)

    Hildebrand, Alexandra; Lönnecke, Peter; Silaghi-Dumitrescu, Luminita; Hey-Hawkins, Evamarie

    2008-09-14

    PhP(2-SHC6H4)2 (PS2H2) reacts with WCl6 with reduction of tungsten to give the air-sensitive tungsten(IV) complex [W{PhP(2-SC6H4)2-kappa(3)S,S',P}2] (1). 1 is oxidised in air to [WO{PhPO(2-SC6H4)2-kappa(3)S,S',O}{PhP(2-SC6H4)2-kappa(3)S,S',P}] (2). The attempted synthesis of 2 by reaction of 1 with iodosobenzene as oxidising agent was unsuccessful. [W{P(2-SC6H4)3-kappa(4)S,S',S",P}2] (3) was formed in the reaction of P(2-SHC6H4)3 (PS3H3) with WCl6. The W(VI) complex 3 contains two PS3(3-) ligands, each coordinated in a tetradentate fashion resulting in a tungsten coordination number of eight. The reaction of 3 with AgBF4 yields the dinuclear tungsten complex [W2{P(2-SC6H4)3-kappa(4)S,S',S",P}3]BF4 (4). Complexes 1-4 were characterised by spectral methods and X-ray structure determination.

  11. Cell type-specific expression of FoxP2 in the ferret and mouse retina.

    Science.gov (United States)

    Sato, Chihiro; Iwai-Takekoshi, Lena; Ichikawa, Yoshie; Kawasaki, Hiroshi

    2017-04-01

    Although the anatomical and physiological properties of subtypes of retinal ganglion cells (RGCs) have been extensively investigated, their molecular properties are still unclear. Here, we examined the expression patterns of FoxP2 in the retina of ferrets and mice. We found that FoxP2 was expressed in small subsets of neurons in the adult ferret retina. FoxP2-positive neurons in the ganglion cell layer were divided into two groups. Large FoxP2-positive neurons expressed Brn3a and were retrogradely labeled with cholera toxin subunit B injected into the optic nerve, indicating that they are RGCs. The soma size and the projection pattern of FoxP2-positive RGCs were consistent with those of X cells. Because we previously reported that FoxP2 was selectively expressed in X cells in the ferret lateral geniculate nucleus (LGN), our findings indicate that FoxP2 is specifically expressed in the parvocellular pathway from the retina to the LGN. Small FoxP2-positive neurons were positive for GAD65/67, suggesting that they are GABAergic amacrine cells. Most Foxp2-positive cells were RGCs in the adult mouse retina. Dendritic morphological analyses suggested that Foxp2-positive RGCs included direction-selective RGCs in mice. Thus, our findings suggest that FoxP2 is expressed in specific subtypes of RGCs in the retina of ferrets and mice. Copyright © 2016 Elsevier Ireland Ltd and Japan Neuroscience Society. All rights reserved.

  12. Transformation of Astrocytes to a Neuroprotective Phenotype by Microglia via P2Y1 Receptor Downregulation

    Directory of Open Access Journals (Sweden)

    Youichi Shinozaki

    2017-05-01

    Full Text Available Microglia and astrocytes become reactive following traumatic brain injury (TBI. However, the coordination of this reactivity and its relation to pathophysiology are unclear. Here, we show that microglia transform astrocytes into a neuroprotective phenotype via downregulation of the P2Y1 purinergic receptor. TBI initially caused microglial activation in the injury core, followed by reactive astrogliosis in the peri-injured region and formation of a neuroprotective astrocyte scar. Equivalent changes to astrocytes were observed in vitro after injury. This change in astrocyte phenotype resulted from P2Y1 receptor downregulation, mediated by microglia-derived cytokines. In mice, astrocyte-specific P2Y1 receptor overexpression (Astro-P2Y1OE counteracted scar formation, while astrocyte-specific P2Y1 receptor knockdown (Astro-P2Y1KD facilitated scar formation, suggesting critical roles of P2Y1 receptors in the transformation. Astro-P2Y1OE and Astro-P2Y1KD mice showed increased and reduced neuronal damage, respectively. Altogether, our findings indicate that microglia-astrocyte interaction, involving a purinergic signal, is essential for the formation of neuroprotective astrocytes.

  13. Accelerated tumor progression in mice lacking the ATP receptor P2X7

    DEFF Research Database (Denmark)

    Adinolfi, Elena; Capece, Marina; Franceschini, Alessia

    2015-01-01

    The ATP receptor P2X7 (P2X7R or P2RX7) has a key role in inflammation and immunity, but its possible roles in cancer are not firmly established. In the present study, we investigated the effect of host genetic deletion of P2X7R in the mouse on the growth of B16 melanoma or CT26 colon carcinoma...... IL-1β and VEGF release were drastically reduced, and inflammatory cell infiltration was abrogated nearly completely. Similarly, tumor growth was also greatly accelerated in wt chimeric mice implanted with P2X7R-deficient bone marrow cells, defining hematopoietic cells as a sufficient site of P2X7R...... action. Finally, dendritic cells from P2X7R-deficient mice were unresponsive to stimulation with tumor cells, and chemotaxis of P2X7R-less cells was impaired. Overall, our results showed that host P2X7R expression was critical to support an antitumor immune response, and to restrict tumor growth...

  14. Non-nucleotide Agonists Triggering P2X7 Receptor Activation and Pore Formation

    OpenAIRE

    Francesco Di Virgilio; Anna L. Giuliani; Valentina Vultaggio-Poma; Simonetta Falzoni; Alba C. Sarti

    2018-01-01

    The P2X7 receptor (P2X7R) is a ligand-gated plasma membrane ion channel belonging to the P2X receptor subfamily activated by extracellular nucleotides. General consensus holds that the physiological (and maybe the only) agonist is ATP. However, scattered evidence generated over the last several years suggests that ATP might not be the only agonist, especially at inflammatory sites. Solid data show that NAD+ covalently modifies the P2X7R of mouse T lymphocytes, thus lowering the ATP threshold ...

  15. Purinergic P2X7 receptor regulates lung surfactant secretion in a paracrine manner

    Science.gov (United States)

    Mishra, Amarjit; Chintagari, Narendranath Reddy; Guo, Yujie; Weng, Tingting; Su, Lijing; Liu, Lin

    2011-01-01

    Alveolar epithelium is composed of alveolar epithelial cells of type I (AEC I) and type II (AEC II). AEC II secrete lung surfactant by means of exocytosis. P2X7 receptor (P2X7R), a P2 purinergic receptor, has been implicated in the regulation of synaptic transmission and inflammation. Here, we report that P2X7R, which is expressed in AEC I but not AEC II, is a novel mediator for the paracrine regulation of surfactant secretion in AEC II. In primary co-cultures of AEC I and AEC II benzoyl ATP (BzATP; an agonist of P2X7R) increased surfactant secretion, which was blocked by the P2X7R antagonist Brilliant Blue G. This effect was observed in AEC II co-cultured with human embryonic kidney HEK-293 cells stably expressing rat P2X7R, but not when co-cultured with AEC I in which P2X7R was knocked down or in co-cultures of AEC I and AEC II isolated from P2X7R−/− mice. BzATP-mediated secretion involved P2Y2 receptor signaling because it was reduced by the addition of the ATP scavengers apyrase and adenosine deaminase and the P2Y2 receptor antagonist suramin. However, the stimulation with BzATP might also release other substances that potentially increase surfactant secretion as a greater stimulation of secretion was observed in AEC II incubated with BzATP when co-cultured with E10 or HEK-293-P2X7R cells than with ATP alone. P2X7R−/− mice failed to increase surfactant secretion in response to hyperventilation, pointing to the physiological relevance of P2X7R in maintaining surfactant homeostasis in the lung. These results suggest that the activation of P2X7R increases surfactant secretion by releasing ATP from AEC I and subsequently stimulating P2Y2 receptors in AEC II. PMID:21266468

  16. Transformation of Astrocytes to a Neuroprotective Phenotype by Microglia via P2Y1Receptor Downregulation.

    Science.gov (United States)

    Shinozaki, Youichi; Shibata, Keisuke; Yoshida, Keitaro; Shigetomi, Eiji; Gachet, Christian; Ikenaka, Kazuhiro; Tanaka, Kenji F; Koizumi, Schuichi

    2017-05-09

    Microglia and astrocytes become reactive following traumatic brain injury (TBI). However, the coordination of this reactivity and its relation to pathophysiology are unclear. Here, we show that microglia transform astrocytes into a neuroprotective phenotype via downregulation of the P2Y 1 purinergic receptor. TBI initially caused microglial activation in the injury core, followed by reactive astrogliosis in the peri-injured region and formation of a neuroprotective astrocyte scar. Equivalent changes to astrocytes were observed in vitro after injury. This change in astrocyte phenotype resulted from P2Y 1 receptor downregulation, mediated by microglia-derived cytokines. In mice, astrocyte-specific P2Y 1 receptor overexpression (Astro-P2Y 1 OE) counteracted scar formation, while astrocyte-specific P2Y 1 receptor knockdown (Astro-P2Y 1 KD) facilitated scar formation, suggesting critical roles of P2Y 1 receptors in the transformation. Astro-P2Y 1 OE and Astro-P2Y 1 KD mice showed increased and reduced neuronal damage, respectively. Altogether, our findings indicate that microglia-astrocyte interaction, involving a purinergic signal, is essential for the formation of neuroprotective astrocytes. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  17. Colchicine inhibits cationic dye uptake induced by ATP in P2X2 and P2X7 receptor-expressing cells: implications for its therapeutic action

    Science.gov (United States)

    Marques-da-Silva, C; Chaves, MM; Castro, NG; Coutinho-Silva, R; Guimaraes, MZP

    2011-01-01

    BACKGROUND AND PURPOSE The two longest C-termini of the purinergic P2X receptors occur in the P2X2 and P2X7 receptors and are thought to interact with multiple cytoplasmic proteins, among which are members of the cytoskeleton, including microtubules. In this work we asked whether disrupting the microtubule cytoskeleton might affect the functions of these receptors. EXPERIMENTAL APPROACH Functions of heterologously expressed P2X2 and P2X7 receptors were evaluated with electrophysiology and dye uptake following ATP application. Permeabilization and secretion of pro-inflammatory agents were quantified from fresh or cultured peritoneal mouse macrophages, treated in vitro or in vivo with colchicine. KEY RESULTS Disrupting the microtubule network with colchicine did not affect currents generated by ATP in P2X2 and P2X7 receptor-expressing cells but inhibited uptake of the dye Yo-Pro-1 in Xenopus oocytes and HEK293 cells expressing these channels. Peritoneal mouse macrophages showed less ATP-induced permeabilization to ethidium bromide in the presence of colchicine, and less reactive oxygen species (ROS) formation, nitric oxide (NO) and interleukin (IL)-1β release. Colchicine treatment did not affect ATP-evoked currents in macrophages. Finally, in vivo assays with mice inoculated with lipopolysaccharide and ATP showed diminished ROS, IL-1β, interferon-γ and NO production after colchicine treatment. CONCLUSIONS AND IMPLICATIONS Colchicine has known anti-inflammatory actions and is used to treat several conditions involving innate immunity, including gout and familial Mediterranean fever. Here we propose a new mechanism of action – inhibition of pore formation induced by activation of P2X receptors – which could explain some of the anti-inflammatory effects of colchicine. LINKED ARTICLE This article is commented on by Pelegrín, pp. 908–911 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2011.01325.x PMID:21306580

  18. Identification and characterization of a selective allosteric antagonist of human P2X4 receptor channels.

    Science.gov (United States)

    Ase, Ariel R; Honson, Nicolette S; Zaghdane, Helmi; Pfeifer, Tom A; Séguéla, Philippe

    2015-04-01

    P2X4 is an ATP-gated nonselective cation channel highly permeable to calcium. There is increasing evidence that this homomeric purinoceptor, which is expressed in several neuronal and immune cell types, is involved in chronic pain and inflammation. The current paucity of unambiguous pharmacological tools available to interrogate or modulate P2X4 function led us to pursue the search for selective antagonists. In the high-throughput screen of a compound library, we identified the phenylurea BX430 (1-(2,6-dibromo-4-isopropyl-phenyl)-3-(3-pyridyl)urea, molecular weight = 413), with antagonist properties on human P2X4-mediated calcium uptake. Patch-clamp electrophysiology confirmed direct inhibition of P2X4 currents by extracellular BX430, with submicromolar potency (IC50 = 0.54 µM). BX430 is highly selective, having virtually no functional impact on all other P2X subtypes, namely, P2X1-P2X3, P2X5, and P2X7, at 10-100 times its IC50. Unexpected species differences were noticed, as BX430 is a potent antagonist of zebrafish P2X4 but has no effect on rat and mouse P2X4 orthologs. The concentration-response curve for ATP on human P2X4 in the presence of BX430 shows an insurmountable blockade, indicating a noncompetitive allosteric mechanism of action. Using a fluorescent dye uptake assay, we observed that BX430 also effectively suppresses ATP-evoked and ivermectin-potentiated membrane permeabilization induced by P2X4 pore dilation. Finally, in single-cell calcium imaging, we validated its selective inhibitory effects on native P2X4 channels at the surface of human THP-1 cells that were differentiated into macrophages. In summary, this ligand provides a novel molecular probe to assess the specific role of P2X4 in inflammatory and neuropathic conditions, where ATP signaling has been shown to be dysfunctional. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

  19. Immunocytochemical analysis of P2X2 in rat circumvallate taste buds

    Directory of Open Access Journals (Sweden)

    Yang Ruibiao

    2012-05-01

    Full Text Available Abstract Background Our laboratory has shown that classical synapses and synaptic proteins are associated with Type III cells. Yet it is generally accepted that Type II cells transduce bitter, sweet and umami stimuli. No classical synapses, however, have been found associated with Type II cells. Recent studies indicate that the ionotropic purinergic receptors P2X2/P2X3 are present in rodent taste buds. Taste nerve processes express the ionotropic purinergic receptors (P2X2/P2X3. P2X2/P2X3Dbl−/− mice are not responsive to sweet, umami and bitter stimuli, and it has been proposed that ATP acts as a neurotransmitter in taste buds. The goal of the present study is to learn more about the nature of purinergic contacts in rat circumvallate taste buds by examining immunoreactivity to antisera directed against the purinergic receptor P2X2. Results P2X2-like immunoreactivity is present in intragemmal nerve processes in rat circumvallate taste buds. Intense immunoreactivity can also be seen in the subgemmal nerve plexuses located below the basal lamina. The P2X2 immunoreactive nerve processes also display syntaxin-1-LIR. The immunoreactive nerves are in close contact with the IP3R3-LIR Type II cells and syntaxin-1-LIR and/or 5-HT-LIR Type III cells. Taste cell synapses are observed only from Type III taste cells onto P2X2-LIR nerve processes. Unusually large, “atypical” mitochondria in the Type II taste cells are found only at close appositions with P2X2-LIR nerve processes. P2X2 immunogold particles are concentrated at the membranes of nerve processes at close appositions with taste cells. Conclusions Based on our immunofluorescence and immunoelectron microscopical studies we believe that both perigemmal and most all intragemmal nerve processes display P2X2-LIR. Moreover, colloidal gold immunoelectron microscopy indicates that P2X2-LIR in nerve processes is concentrated at sites of close apposition with Type II cells. This supports the hypothesis

  20. Non-nucleotide Agonists Triggering P2X7 Receptor Activation and Pore Formation

    Directory of Open Access Journals (Sweden)

    Francesco Di Virgilio

    2018-02-01

    Full Text Available The P2X7 receptor (P2X7R is a ligand-gated plasma membrane ion channel belonging to the P2X receptor subfamily activated by extracellular nucleotides. General consensus holds that the physiological (and maybe the only agonist is ATP. However, scattered evidence generated over the last several years suggests that ATP might not be the only agonist, especially at inflammatory sites. Solid data show that NAD+ covalently modifies the P2X7R of mouse T lymphocytes, thus lowering the ATP threshold for activation. Other structurally unrelated agents have been reported to activate the P2X7R via a poorly understood mechanism of action: (a the antibiotic polymyxin B, possibly a positive allosteric P2X7R modulator, (b the bactericidal peptide LL-37, (c the amyloidogenic β peptide, and (d serum amyloid A. Some agents, such as Alu-RNA, have been suggested to activate the P2X7R acting on the intracellular N- or C-terminal domains. Mode of P2X7R activation by these non-nucleotide ligands is as yet unknown; however, these observations raise the intriguing question of how these different non-nucleotide ligands may co-operate with ATP at inflammatory or tumor sites. New information obtained from the cloning and characterization of the P2X7R from exotic mammalian species (e.g., giant panda and data from recent patch-clamp studies are strongly accelerating our understanding of P2X7R mode of operation, and may provide hints to the mechanism of activation of P2X7R by non-nucleotide ligands.

  1. Long-term heart transplant survival by targeting the ionotropic purinergic receptor P2X7.

    Science.gov (United States)

    Vergani, Andrea; Tezza, Sara; D'Addio, Francesca; Fotino, Carmen; Liu, Kaifeng; Niewczas, Monika; Bassi, Roberto; Molano, R Damaris; Kleffel, Sonja; Petrelli, Alessandra; Soleti, Antonio; Ammirati, Enrico; Frigerio, Maria; Visner, Gary; Grassi, Fabio; Ferrero, Maria E; Corradi, Domenico; Abdi, Reza; Ricordi, Camillo; Sayegh, Mohamed H; Pileggi, Antonello; Fiorina, Paolo

    2013-01-29

    Heart transplantation is a lifesaving procedure for patients with end-stage heart failure. Despite much effort and advances in the field, current immunosuppressive regimens are still associated with poor long-term cardiac allograft outcomes, and with the development of complications, including infections and malignancies, as well. The development of a novel, short-term, and effective immunomodulatory protocol will thus be an important achievement. The purine ATP, released during cell damage/activation, is sensed by the ionotropic purinergic receptor P2X7 (P2X7R) on lymphocytes and regulates T-cell activation. Novel clinical-grade P2X7R inhibitors are available, rendering the targeting of P2X7R a potential therapy in cardiac transplantation. We analyzed P2X7R expression in patients and mice and P2X7R targeting in murine recipients in the context of cardiac transplantation. Our data demonstrate that P2X7R is specifically upregulated in graft-infiltrating lymphocytes in cardiac-transplanted humans and mice. Short-term P2X7R targeting with periodate-oxidized ATP promotes long-term cardiac transplant survival in 80% of murine recipients of a fully mismatched allograft. Long-term survival of cardiac transplants was associated with reduced T-cell activation, T-helper cell 1/T-helper cell 17 differentiation, and inhibition of STAT3 phosphorylation in T cells, thus leading to a reduced transplant infiltrate and coronaropathy. In vitro genetic upregulation of the P2X7R pathway was also shown to stimulate T-helper cell 1/T-helper cell 17 cell generation. Finally, P2X7R targeting halted the progression of coronaropathy in a murine model of chronic rejection as well. P2X7R targeting is a novel clinically relevant strategy to prolong cardiac transplant survival.

  2. Modulation of P2X7 Receptor during Inflammation in Multiple Sclerosis

    Directory of Open Access Journals (Sweden)

    Susanna Amadio

    2017-11-01

    Full Text Available Multiple sclerosis (MS is characterized by macrophage accumulation and inflammatory infiltrates into the CNS contributing to demyelination. Because purinergic P2X7 receptor (P2X7R is known to be abundantly expressed on cells of the hematopoietic lineage and of the nervous system, we further investigated its phenotypic expression in MS and experimental autoimmune encephalomyelitis conditions. By quantitative reverse transcription polymerase chain reaction and flow cytometry, we analyzed the P2X7R expression in human mononuclear cells of peripheral blood from stable and acute relapsing-remitting MS phases. Human monocytes were also challenged in vitro with pro-inflammatory stimuli such as the lipopolysaccharide, or the P2X7R preferential agonist 2′(3′-O-(4 Benzoylbenzoyladenosine 5′-triphosphate, before evaluating P2X7R protein expression. Finally, by immunohistochemistry and immunofluorescence confocal analysis, we investigated the P2X7R expression in frontal cortex from secondary progressive MS cases. We demonstrated that P2X7R is present and inhibited on peripheral monocytes isolated from MS donors during the acute phase of the disease, moreover it is down-regulated in human monocytes after pro-inflammatory stimulation in vitro. P2X7R is instead up-regulated on astrocytes in the parenchyma of frontal cortex from secondary progressive MS patients, concomitantly with monocyte chemoattractant protein-1 chemokine, while totally absent from microglia/macrophages or oligodendrocytes, despite the occurrence of inflammatory conditions. Our results suggest that inhibition of P2X7R on monocytes and up-regulation in astrocytes might contribute to sustain inflammatory mechanisms in MS. By acquiring further knowledge about P2X7R dynamics and identifying P2X7R as a potential marker for the disease, we expect to gain insights into the molecular pathways of MS.

  3. Targeting of the P2X7 receptor in pancreatic cancer and stellate cells.

    Science.gov (United States)

    Giannuzzo, Andrea; Saccomano, Mara; Napp, Joanna; Ellegaard, Maria; Alves, Frauke; Novak, Ivana

    2016-12-01

    The ATP-gated receptor P2X7 (P2X7R) is involved in regulation of cell survival and has been of interest in cancer field. Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer and new markers and therapeutic targets are needed. PDAC is characterized by a complex tumour microenvironment, which includes cancer and pancreatic stellate cells (PSCs), and potentially high nucleotide/side turnover. Our aim was to determine P2X7R expression and function in human pancreatic cancer cells in vitro as well as to perform in vivo efficacy study applying P2X7R inhibitor in an orthotopic xenograft mouse model of PDAC. In the in vitro studies we show that human PDAC cells with luciferase gene (PancTu-1 Luc cells) express high levels of P2X7R protein. Allosteric P2X7R antagonist AZ10606120 inhibited cell proliferation in basal conditions, indicating that P2X7R was tonically active. Extracellular ATP and BzATP, to which the P2X7R is more sensitive, further affected cell survival and confirmed complex functionality of P2X7R. PancTu-1 Luc migration and invasion was reduced by AZ10606120, and it was stimulated by PSCs, but not by PSCs from P2X7(-/-) animals. PancTu-1 Luc cells were orthotopically transplanted into nude mice and tumour growth was followed noninvasively by bioluminescence imaging. AZ10606120-treated mice showed reduced bioluminescence compared to saline-treated mice. Immunohistochemical analysis confirmed P2X7R expression in cancer and PSC cells, and in metaplastic/neoplastic acinar and duct structures. PSCs number/activity and collagen deposition was reduced in AZ10606120-treated tumours. © 2016 The Authors International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.

  4. Non-nucleotide Agonists Triggering P2X7 Receptor Activation and Pore Formation.

    Science.gov (United States)

    Di Virgilio, Francesco; Giuliani, Anna L; Vultaggio-Poma, Valentina; Falzoni, Simonetta; Sarti, Alba C

    2018-01-01

    The P2X7 receptor (P2X7R) is a ligand-gated plasma membrane ion channel belonging to the P2X receptor subfamily activated by extracellular nucleotides. General consensus holds that the physiological (and maybe the only) agonist is ATP. However, scattered evidence generated over the last several years suggests that ATP might not be the only agonist, especially at inflammatory sites. Solid data show that NAD + covalently modifies the P2X7R of mouse T lymphocytes, thus lowering the ATP threshold for activation. Other structurally unrelated agents have been reported to activate the P2X7R via a poorly understood mechanism of action: (a) the antibiotic polymyxin B, possibly a positive allosteric P2X7R modulator, (b) the bactericidal peptide LL-37, (c) the amyloidogenic β peptide, and (d) serum amyloid A. Some agents, such as Alu-RNA, have been suggested to activate the P2X7R acting on the intracellular N- or C-terminal domains. Mode of P2X7R activation by these non-nucleotide ligands is as yet unknown; however, these observations raise the intriguing question of how these different non-nucleotide ligands may co-operate with ATP at inflammatory or tumor sites. New information obtained from the cloning and characterization of the P2X7R from exotic mammalian species (e.g., giant panda) and data from recent patch-clamp studies are strongly accelerating our understanding of P2X7R mode of operation, and may provide hints to the mechanism of activation of P2X7R by non-nucleotide ligands.

  5. Modulation of P2X7 Receptor during Inflammation in Multiple Sclerosis.

    Science.gov (United States)

    Amadio, Susanna; Parisi, Chiara; Piras, Eleonora; Fabbrizio, Paola; Apolloni, Savina; Montilli, Cinzia; Luchetti, Sabina; Ruggieri, Serena; Gasperini, Claudio; Laghi-Pasini, Franco; Battistini, Luca; Volonté, Cinzia

    2017-01-01

    Multiple sclerosis (MS) is characterized by macrophage accumulation and inflammatory infiltrates into the CNS contributing to demyelination. Because purinergic P2X7 receptor (P2X7R) is known to be abundantly expressed on cells of the hematopoietic lineage and of the nervous system, we further investigated its phenotypic expression in MS and experimental autoimmune encephalomyelitis conditions. By quantitative reverse transcription polymerase chain reaction and flow cytometry, we analyzed the P2X7R expression in human mononuclear cells of peripheral blood from stable and acute relapsing-remitting MS phases. Human monocytes were also challenged in vitro with pro-inflammatory stimuli such as the lipopolysaccharide, or the P2X7R preferential agonist 2'(3')-O-(4 Benzoylbenzoyl)adenosine 5'-triphosphate, before evaluating P2X7R protein expression. Finally, by immunohistochemistry and immunofluorescence confocal analysis, we investigated the P2X7R expression in frontal cortex from secondary progressive MS cases. We demonstrated that P2X7R is present and inhibited on peripheral monocytes isolated from MS donors during the acute phase of the disease, moreover it is down-regulated in human monocytes after pro-inflammatory stimulation in vitro . P2X7R is instead up-regulated on astrocytes in the parenchyma of frontal cortex from secondary progressive MS patients, concomitantly with monocyte chemoattractant protein-1 chemokine, while totally absent from microglia/macrophages or oligodendrocytes, despite the occurrence of inflammatory conditions. Our results suggest that inhibition of P2X7R on monocytes and up-regulation in astrocytes might contribute to sustain inflammatory mechanisms in MS. By acquiring further knowledge about P2X7R dynamics and identifying P2X7R as a potential marker for the disease, we expect to gain insights into the molecular pathways of MS.

  6. P2X7R suppression promotes glioma growth through epidermal growth factor receptor signal pathway.

    Science.gov (United States)

    Fang, Jingqin; Chen, Xiao; Zhang, Letian; Chen, Jinhua; Liang, Yi; Li, Xue; Xiang, Jianbo; Wang, Lili; Guo, Guangkuo; Zhang, Bo; Zhang, Weiguo

    2013-06-01

    P2X7 receptor (P2X7R) has been shown to mediate an anticancer effect via apoptosis in different types of cancer. However, whether P2X7R exerts a promoting or suppressive effect on brain glioma is still a controversial issue and its underlying mechanism remains unknown. We showed here that P2X7R suppression exerted a pro-growth effect on glioma through directly promoting cells proliferation and pro-angiogenesis, which was associated with epidermal growth factor receptor (EGFR) signaling. The P2X7R was markedly downregulated by cells exposure to the P2X7R antagonist, brilliant blue G (BBG), moreover, the cells proliferation was enhanced in a dose-dependent manner and the expression of EGFR or p-EGFR protein was significantly upregulated. By constructing C6 cells with reduced expression of P2X7R using shRNA, we also demonstrated strong upregulation in cells proliferation and EGFR/p-EGFR expression. However, this effect of BBG was reversed in the presence of gefitinib or suramin. Magnetic resonance imaging and computed tomography perfusion showed that the BBG or P2X7R shRNA promoted the tumor growth by about 40% and 50%, respectively, and significantly increased angiogenesis. Nissl and Ki-67 staining also confirmed that BBG or P2X7R shRNA notably increased the tumor growth. More importantly, either BBG or P2X7R shRNA could markedly upregulated the expression of EGFR, p-EGFR, HIF-1α and VEGF in glioma cells. In conclusion, P2X7R suppression exerts a promoting effect on glioma growth, which is likely to be related to upregulated EGFR, HIF-1α and VEGF expression. These findings provide important clues to the molecular basis of anticancer effect of targeting purinergic receptors. Copyright © 2013 Elsevier Ltd. All rights reserved.

  7. Osmoregulatory inositol transporter SMIT1 modulates electrical activity by adjusting PI(4,5)P2 levels.

    Science.gov (United States)

    Dai, Gucan; Yu, Haijie; Kruse, Martin; Traynor-Kaplan, Alexis; Hille, Bertil

    2016-06-07

    Myo-inositol is an important cellular osmolyte in autoregulation of cell volume and fluid balance, particularly for mammalian brain and kidney cells. We find it also regulates excitability. Myo-inositol is the precursor of phosphoinositides, key signaling lipids including phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2]. However, whether myo-inositol accumulation during osmoregulation affects signaling and excitability has not been fully explored. We found that overexpression of the Na(+)/myo-inositol cotransporter (SMIT1) and myo-inositol supplementation enlarged intracellular PI(4,5)P2 pools, modulated several PI(4,5)P2-dependent ion channels including KCNQ2/3 channels, and attenuated the action potential firing of superior cervical ganglion neurons. Further experiments using the rapamycin-recruitable phosphatase Sac1 to hydrolyze PI(4)P and the P4M probe to visualize PI(4)P suggested that PI(4)P levels increased after myo-inositol supplementation with SMIT1 expression. Elevated relative levels of PIP and PIP2 were directly confirmed using mass spectrometry. Inositol trisphosphate production and release of calcium from intracellular stores also were augmented after myo-inositol supplementation. Finally, we found that treatment with a hypertonic solution mimicked the effect we observed with SMIT1 overexpression, whereas silencing tonicity-responsive enhancer binding protein prevented these effects. These results show that ion channel function and cellular excitability are under regulation by several "physiological" manipulations that alter the PI(4,5)P2 setpoint. We demonstrate a previously unrecognized linkage between extracellular osmotic changes and the electrical properties of excitable cells.

  8. Physiological contribution of P2X receptors in postreceptoral signal processing in the mouse retina.

    Science.gov (United States)

    Ichinohe, Sho; Ishii, Toshiyuki; Takahashi, Hiroshi; Kaneda, Makoto

    2017-02-01

    ATP activates P2X receptors and acts as a neurotransmitter in the nervous system. We have previously reported that P2X receptors modulate the firing rate of retinal ganglion cells. Since many subtypes of P2X receptors are distributed in the mouse retina, it is likely that the modulatory effects of P2X receptor-mediated signaling can occur at multiple synaptic levels in the retina. In this study, we investigated whether P2X receptors expressed between the photoreceptor layer and the inner nuclear layer in the mouse retina were physiologically functional, by electroretinography (ERG). In the combined rod-cone ERG and the scotopic ERG, intravitreal injection of PPADS, an antagonist of P2X receptors, had no effects on the amplitude of the a-wave, but decreased the amplitude of the b-wave. In the photopic ERG, intravitreal injection of PPADS significantly decreased the amplitude of both the a-wave and the b-wave. In ex vivo recordings, a decrease in the b-wave amplitude was observed at 20μM PPADS, confirming that the inhibition of the b-wave by intravitreal injection of PPADS is due to the inhibition of P2X receptors. Our findings suggest that P2X receptor-mediated signaling has a physiological effect in both the rod and the cone pathways in postreceptoral processing. Copyright © 2016 Elsevier Ireland Ltd and Japan Neuroscience Society. All rights reserved.

  9. On the non-existence of orthogonal instanton bundles on P^{2n+1}

    Directory of Open Access Journals (Sweden)

    Łucja Farnik

    2009-11-01

    Full Text Available In this paper we prove that there do not exist orthogonal instanton bundles on P^{2n+1} . In order to demonstrate this fact, we propose a new way of representing the invariant, introduced by L. Costa and G. Ottaviani, related to a rank 2n instanton bundle on P^{2n+1}.

  10. Evaluating Application-Layer Traffic Optimization Cost Metrics for P2P Multimedia Streaming

    DEFF Research Database (Denmark)

    Poderys, Justas; Soler, José

    2017-01-01

    To help users of P2P communication systems perform better-than-random selection of communication peers, Internet Engineering Task Force standardized the Application Layer Traffic Optimization (ALTO) protocol. The ALTO provided data-routing cost metric, can be used to rank peers in P2P communicati...

  11. PTEN Regulates PI(3,4)P2 Signaling Downstream of Class I PI3K.

    Science.gov (United States)

    Malek, Mouhannad; Kielkowska, Anna; Chessa, Tamara; Anderson, Karen E; Barneda, David; Pir, Pınar; Nakanishi, Hiroki; Eguchi, Satoshi; Koizumi, Atsushi; Sasaki, Junko; Juvin, Véronique; Kiselev, Vladimir Y; Niewczas, Izabella; Gray, Alexander; Valayer, Alexandre; Spensberger, Dominik; Imbert, Marine; Felisbino, Sergio; Habuchi, Tomonori; Beinke, Soren; Cosulich, Sabina; Le Novère, Nicolas; Sasaki, Takehiko; Clark, Jonathan; Hawkins, Phillip T; Stephens, Len R

    2017-11-02

    The PI3K signaling pathway regulates cell growth and movement and is heavily mutated in cancer. Class I PI3Ks synthesize the lipid messenger PI(3,4,5)P 3 . PI(3,4,5)P 3 can be dephosphorylated by 3- or 5-phosphatases, the latter producing PI(3,4)P 2 . The PTEN tumor suppressor is thought to function primarily as a PI(3,4,5)P 3 3-phosphatase, limiting activation of this pathway. Here we show that PTEN also functions as a PI(3,4)P 2 3-phosphatase, both in vitro and in vivo. PTEN is a major PI(3,4)P 2 phosphatase in Mcf10a cytosol, and loss of PTEN and INPP4B, a known PI(3,4)P 2 4-phosphatase, leads to synergistic accumulation of PI(3,4)P 2 , which correlated with increased invadopodia in epidermal growth factor (EGF)-stimulated cells. PTEN deletion increased PI(3,4)P 2 levels in a mouse model of prostate cancer, and it inversely correlated with PI(3,4)P 2 levels across several EGF-stimulated prostate and breast cancer lines. These results point to a role for PI(3,4)P 2 in the phenotype caused by loss-of-function mutations or deletions in PTEN. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  12. Personalised Peer-Supported Learning: The Peer-to-Peer Learning Environment (P2PLE)

    Science.gov (United States)

    Corneli, Joseph; Mikroyannidis, Alexander

    2011-01-01

    The Peer-to-Peer Learning Environment (P2PLE) is a proposed approach to helping learners co-construct their learning environment using recommendations about people, content, and tools. The work draws on current research on PLEs, and participant observation at the Peer-to-Peer University (P2PU). We are particularly interested in ways of eliciting…

  13. Roles for PI(3,5)P2 in nutrient sensing through TORC1

    Science.gov (United States)

    Jin, Natsuko; Mao, Kai; Jin, Yui; Tevzadze, Gela; Kauffman, Emily J.; Park, Sujin; Bridges, Dave; Loewith, Robbie; Saltiel, Alan R.; Klionsky, Daniel J.; Weisman, Lois S.

    2014-01-01

    TORC1, a conserved protein kinase, regulates cell growth in response to nutrients. Localization of mammalian TORC1 to lysosomes is essential for TORC1 activation. Phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2), an endosomal signaling lipid, is implicated in insulin-dependent stimulation of TORC1 activity in adipocytes. This raises the question of whether PI(3,5)P2 is an essential general regulator of TORC1. Moreover, the subcellular location where PI(3,5)P2 regulates TORC1 was not known. Here we report that PI(3,5)P2 is required for TORC1 activity in yeast and regulates TORC1 on the vacuole (lysosome). Furthermore, we show that the TORC1 substrate, Sch9 (a homologue of mammalian S6K), is recruited to the vacuole by direct interaction with PI(3,5)P2, where it is phosphorylated by TORC1. Of importance, we find that PI(3,5)P2 is required for multiple downstream pathways via TORC1-dependent phosphorylation of additional targets, including Atg13, the modification of which inhibits autophagy, and phosphorylation of Npr1, which releases its inhibitory function and allows nutrient-dependent endocytosis. These findings reveal PI(3,5)P2 as a general regulator of TORC1 and suggest that PI(3,5)P2 provides a platform for TORC1 signaling from lysosomes. PMID:24478451

  14. Modulation of P2X7 Receptor during Inflammation in Multiple Sclerosis

    NARCIS (Netherlands)

    Amadio, Susanna; Parisi, Chiara; Piras, Eleonora; Fabbrizio, Paola; Apolloni, Savina; Montilli, Cinzia; Luchetti, S.; Ruggieri, Serena; Gasperini, Claudio; Laghi-Pasini, Franco; Battistini, Luca; Volonté, Cinzia

    2017-01-01

    Multiple sclerosis (MS) is characterized by macrophage accumulation and inflammatory infiltrates into the CNS contributing to demyelination. Because purinergic P2X7 receptor (P2X7R) is known to be abundantly expressed on cells of the hematopoietic lineage and of the nervous system, we further

  15. P2P XQuery and the StreetTiVo application

    NARCIS (Netherlands)

    P.A. Boncz (Peter); Y. Zhang (Ying)

    2007-01-01

    textabstractIn the AmbientDB project, we are building MonetDB/XQuery, an open-source XML DBMS (XDBMS) with support for distributed querying and P2P services. Our work is motivated by the hypothesis that P2P is a disruptive paradigm that should change the nature of database technology. Most of the

  16. Expression of the house dust mite allergen Der p 2 in the baker's yeast Saccharomyces cerevisiae

    NARCIS (Netherlands)

    Hakkaart, G. A.; Harmsen, M. M.; Chua, K. Y.; Thomas, W. R.; Aalberse, R. C.; van Ree, R.

    1998-01-01

    BACKGROUND AND RESULTS: The major house dust mite allergen Der p 2 was expressed as a recombinant mature protein in the baker's yeast Saccharomyces cerevisiae. The yeast produces the protein fused to the invertase signal peptide, leading to the secretion of Der p 2 as a soluble protein into the

  17. P2X7 on mouse T cells: one channel, many functions

    Directory of Open Access Journals (Sweden)

    Björn eRissiek

    2015-05-01

    Full Text Available The P2X7 receptor is an adenosine triphosphate (ATP-gated cation channel that is expressed by several cells of the immune system. P2X7 is best known for its proinflammatory role in promoting inflammasome formation and release of mature IL-1β by innate immune cells. Mounting evidence indicates that P2X7 is also an important regulatory receptor of murine and human T cell functions. Murine T cells express a sensitive splice variant of P2X7 that can be activated either by non-covalent binding of ATP or, in the presence of nicotinamide adenine dinucleotide (NAD+, by its covalent ADP-ribosylation catalyzed by the ecto-ADP-ribosyltransferase ARTC2.2. Prolonged activation of P2X7 by either one of these pathways triggers the induction of T cell death. Conversely, lower concentrations of ATP can activate P2X7 to enhance T cell proliferation and production of IL-2. In this review we will highlight the molecular and cellular consequences of P2X7 activation on mouse T cells and its versatile role in T cell homeostasis and activation. Further, we will discuss important differences in the function of P2X7 on human and murine T cells.

  18. Residue level description of in vivo self-association of Plasmodium falciparum P2.

    Science.gov (United States)

    Mishra, Pushpa; Sharma, Shobhona; Hosur, Ramakrishna V

    2014-04-01

    Plasmodium falciparum P2 (PfP2) is a ribosomal stalk protein. It also performs extra ribosomal novel functions that seem to be associated with homo oligomerization . Previous in vitro studies have demonstrated that the protein has a high tendency to self-associate predominantly into an 8-mer. In vitro Heteronuclear Single Quantum Coherence (HSQC) of the pure recombinant protein (rPfP2) and its in-cell (Escherichia coli) HSQC spectrum has very similar features, indicating that the protein intrinsically, both inside the cell and under in vitro conditions, has similar aggregation tendencies. In view of this, we have characterized here the folding and concomitant self-association of rPfP2, using an in vitro dissociation-association strategy. We observed that the residue stretch, (Met31-Leu44) of the rPfP2, mapping to Met1-Leu14 of PfP2 protein acts as a nucleation site for helix formation and subsequent self-association. Further association appears to be driven by hydrophobic and complimentary electrostatic charge interactions on the surfaces formed. One stretch of rPfP2, (Ile97-Ala116), always remains floppy, and this may serve as "hinge" for protein segmental motions. Based on these, we have proposed a possible model for rPfP2 self-association into an 8-mer.

  19. ATP analogues with modified phosphate chains and their selectivity for rat P2X(2) and P2X(2/3) receptors

    Czech Academy of Sciences Publication Activity Database

    Spelta, V.; Mekhalfia, A.; Rejman, Dominik; Thompson, M.; Blackburn, G. M.; North, R. A.

    2003-01-01

    Roč. 140, č. 6 (2003), s. 1027-1034 ISSN 0007-1188 Institutional research plan: CEZ:AV0Z4055905 Keywords : P2X receptors * electrophysiology * phosphate chain Subject RIV: CC - Organic Chemistry Impact factor: 3.611, year: 2003

  20. PRNGAWASAN TERHADAP P2KP-3 DI TATARAN MASYARAKAT KOTA BANDAR LAMPUNG

    Directory of Open Access Journals (Sweden)

    Upik Hamidah

    2014-04-01

    Full Text Available Dalam P2KP merupakan dana publik yang diwakafkan oleh pemerintah Indonesia kepada masyarakat di lokasi sasaaran P2KP. yang dalam pengaturan dan pengelolaannya melibatkan berbagai pihak. Dalam pengaturan dan pelaksanaannya diperlukan adanya pengawasan. Permasalahan dalam penelitian ini bagaimanakah pengaturan dan pelaksanaan pengawasan terhadap P2KP di tataran masyarakat. Hasil penelitian meneunjukan bahwa pengaturan pengawasan P2KP sangat ketat, berdasarkan kesepakatan bersama pemerintah Indonesia dan Bank Dunia, meliputi pengawasan intern dan pengaawasan extern. Tetapi tidak melibatkan pemerintah daerah. Pengawasan bersiafat educative atau pengawasan bertujuan untuk mendidik masyarakat pelaku P2KP di tataran masyarakat untuk bekerja dengan baik dan jujur. Dalam pengaturannya belum ada nampak adanya Standar Oprasional Prosedur pengawasan, sehingga dikhawatirkan dalam pelaksanaan pengawasan akan tumpang tindih.

  1. Common variants in P2RY11 are associated with narcolepsy

    DEFF Research Database (Denmark)

    Kornum, Birgitte R; Kawashima, Minae; Faraco, Juliette

    2011-01-01

    Americans). We identify a SNP in the 3' untranslated region of P2RY11, the purinergic receptor subtype P2Y11 gene, which is associated with narcolepsy (rs2305795, combined P = 6.1 × 10¿¹°, odds ratio = 1.28, 95% CI 1.19-1.39, n = 5689). The disease-associated allele is correlated with reduced expression...... of P2RY11 in CD8(+) T lymphocytes (339% reduced, P = 0.003) and natural killer (NK) cells (P = 0.031), but not in other peripheral blood mononuclear cell types. The low expression variant is also associated with reduced P2RY11-mediated resistance to ATP-induced cell death in T lymphocytes (P = 0.......0007) and natural killer cells (P = 0.001). These results identify P2RY11 as an important regulator of immune-cell survival, with possible implications in narcolepsy and other autoimmune diseases....

  2. Effective role of CaO/P2O5 ratio on SiO2-CaO-P2O5 glass system

    Directory of Open Access Journals (Sweden)

    P. Kiran

    2017-05-01

    Full Text Available In the present work, the effect of the CaO/P2O5 ratio on the composition of sol-gel synthesized 58SiO2-(19 − xP2O5–(23 + xCaO (x = 0, 5, 10 and 15 mol% glass samples was studied. Further, the effect of NBO/BO ratio on hydroxy carbonated apatite layer (HCA forming ability based on dissolution behavior in simulated body fluid (SBF solution was also investigated. CaO/P2O5 ratios of synthesized glass samples were 1.2, 2, 3.6, and 9.5, respectively. NBO/BO ratios were obtained using Raman spectroscopic analysis as 0.58, 1.20, 1.46, and 1.78, respectively. All samples were soaked in the SBF solution for 7 days. The calculated weight losses of these samples were 58%, 64%, 83%, and 89% for corresponding NBO/BO ratios. The increase in CaO/P2O5 ratio increases the NBO/BO ratios. However, the increase in NBO/BO ratio increases HCA forming ability of SBF treated samples. The HCA crystalline layer formation was confirmed through X-ray Diffraction (XRD, Transmission Electron Microscopy (TEM, Scanning Electron Microscopy (SEM, Raman and Infrared spectroscopic analysis. Higher CaO/P2O5 ratio favors the increase in HCA formation for SBF treated calcium phospho silicate glasses.

  3. Cloning and pharmacological characterization of the dog P2X7 receptor.

    Science.gov (United States)

    Roman, S; Cusdin, F S; Fonfria, E; Goodwin, J A; Reeves, J; Lappin, S C; Chambers, L; Walter, D S; Clay, W C; Michel, A D

    2009-11-01

    Human and rodent P2X7 receptors exhibit differences in their sensitivity to antagonists. In this study we have cloned and characterized the dog P2X7 receptor to determine if its antagonist sensitivity more closely resembles the human or rodent orthologues. A cDNA encoding the dog P2X7 receptor was isolated from a dog heart cDNA library, expressed in U-2 OS cells using the BacMam viral expression system and characterized in electrophysiological, ethidium accumulation and radioligand binding studies. Native P2X7 receptors were examined by measuring ATP-stimulated interleukin-1beta release in dog and human whole blood. The dog P2X7 receptor was 595 amino acids long and exhibited high homology (>70%) to the human and rodent orthologues although it contained an additional threonine at position 284 and an amino acid deletion at position 538. ATP possessed low millimolar potency at dog P2X7 receptors. 2'-&3'-O-(4benzoylbenzoyl) ATP had slightly higher potency but was a partial agonist. Dog P2X7 receptors possessed relatively high affinity for a number of selective antagonists of the human P2X7 receptor although there were some differences in potency between the species. Compound affinities in human and dog blood exhibited a similar rank order of potency as observed in studies on the recombinant receptor although absolute potency was considerably lower. Dog recombinant and native P2X7 receptors display a number of pharmacological similarities to the human P2X7 receptor. Thus, dog may be a suitable species for assessing target-related toxicity of antagonists intended for evaluation in the clinic.

  4. The role of P2X7R purinoreceptor in osteosarcoma

    Directory of Open Access Journals (Sweden)

    Manish Yadav

    2015-12-01

    Full Text Available Osteosarcoma is the most common type of bone cancer, which appears mainly in the metaphysis of long bones, especially in males between the age of 0–14 years. Malignancy usually emerges with the abnormal growth of tumor-forming bone cells. These tumor cells act like new bones that are responsible for the spread of sarcoma throughout the bone matrix. In this review, we focused on the expression and function of the P2X7 receptor (P2X7R as a therapeutic target in osteosarcoma malignancy. Two known human P2X7R functional splice variants in osteosarcoma cell growth are the full length P2X7RA and the truncated P2X7RB. The stimulation of growth is attributed to an increase (i in the mobilization of Ca2+ ions, and (ii in the nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1 activity. Furthermore, Te85 P2X7RA+B cells caused membrane depolarization and spontaneous release of extracellular adenosine triphosphate (ATP. The P2X7R agonist, benzoyl adenosine triphosphate (BzATP, may increase the liberation of ATP and this may be regulated by P2X7R. As a result, cell proliferation occurs with the spread of osteosarcoma throughout the bone matrix. BzATP also increases cell growth and activates NFATc1 to make it cancerous. In this review, we have highlighted the crucial role of the P2X7R purinoreceptor in osteosarcoma pathogenesis. It is an upstream regulator of all paths that may inhibit the receptor activator of nuclear factor kappa-B ligand (RANKL and a mechanistic target of rapamycin (mTOR blockers. This review suggests that P2X7R is an attractive therapeutic target for osteosarcoma.

  5. P2X7 receptor-dependent tuning of gut epithelial responses to infection.

    Science.gov (United States)

    Huang, Szu-Wei; Walker, Catherine; Pennock, Joanne; Else, Kathryn; Muller, Werner; Daniels, Michael Jd; Pellegrini, Carolina; Brough, David; Lopez-Castejon, Gloria; Cruickshank, Sheena M

    2017-02-01

    Infection and injury of the gut are associated with cell damage and release of molecules such as extracellular adenosine 5'-triphosphate (ATP), which is recognised by the purinergic P2X7 receptor (P2X7R). P2X7R is widely expressed in the gut by antigen-presenting cells (APCs) and epithelial cells, but the role of the P2X7R on epithelial cells is poorly understood. We investigated P2X7R in intestinal epithelium in vitro and in vivo using two model infections, Toxoplasma gondii and Trichinella spiralis. Lipopolysaccharide and ATP treatment of intestinal epithelial cells and infection with T. gondii in vitro did not promote inflammasome-associated interleukin-1β (IL-1β) or IL-18 secretion, but promoted C-C motif chemokine ligand 5 (CCL5), tumour necrosis factor-α and IL-6 production that were significantly reduced when the P2X7R was blocked. Similarly, in vivo, infection with either T. spiralis or T. gondii induced rapid upregulation of epithelial CCL5 in wild-type (wild-type (WT)) mice that was significantly reduced in P2X7R -/- littermate controls. The effects of reduced epithelial CCL5 were assayed by investigating recruitment of dendritic cells (DCs) to the epithelium. Infection induced a rapid recruitment of CD11c + CD103 + DC subsets into the epithelial layer of WT mice but not P2X7R -/- mice. In vitro chemotaxis assays and bone marrow chimeras demonstrated the importance of epithelial P2X7R in DC recruitment. P2X7R signalling in epithelial cells mediates chemokine responses to promote initiation of host immunity to infection.

  6. P2X7 receptor cross-talk regulates ATP-induced pannexin 1 internalization.

    Science.gov (United States)

    Boyce, Andrew K J; Swayne, Leigh Anne

    2017-06-13

    In the nervous system, extracellular ATP levels transiently increase in physiological and pathophysiological circumstances, effecting key signalling pathways in plasticity and inflammation through purinergic receptors. Pannexin 1 (Panx1) forms ion- and metabolite-permeable channels that mediate ATP release and are particularly enriched in the nervous system. Our recent study demonstrated that elevation of extracellular ATP triggers Panx1 internalization in a concentration- and time-dependent manner. Notably, this effect was sensitive to inhibition of ionotropic P2X7 purinergic receptors (P2X7Rs). Here, we report our novel findings from the detailed investigation of the mechanism underlying P2X7R-Panx1 cross-talk in ATP-stimulated internalization. We demonstrate that extracellular ATP triggers and is required for the clustering of P2X7Rs and Panx1 on Neuro2a cells through an extracellular physical interaction with the Panx1 first extracellular loop (EL1). Importantly, disruption of P2X7R-Panx1 clustering by mutation of tryptophan 74 within the Panx1 EL1 inhibits Panx1 internalization. Notably, P2X7R-Panx1 clustering and internalization are independent of P2X7R-associated intracellular signalling pathways (Ca 2+ influx and Src activation). Further analysis revealed that cholesterol is required for ATP-stimulated P2X7R-Panx1 clustering at the cell periphery. Taken together, our data suggest that extracellular ATP induces and is required for Panx1 EL1-mediated, cholesterol-dependent P2X7R-Panx1 clustering and endocytosis. These findings have important implications for understanding the role of Panx1 in the nervous system and provide important new insights into Panx1-P2X7R cross-talk. © 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society.

  7. Contemplating compliance: European compliance mechanisms in international perspective

    NARCIS (Netherlands)

    Koops, C.E.

    2014-01-01

    How can international organizations make their Member States comply with the rules of the organization? Which is the more effective method: to coax and entice, to argue and persuade, or to threaten and punish? On the basis of which criteria should a compliance mechanism be construed and applied,

  8. 75 FR 70270 - Submission for OMB Review; Comment Request; Pretesting of NIAID's Biomedical HIV Prevention...

    Science.gov (United States)

    2010-11-17

    ... NIAID's Biomedical HIV Prevention Research Communication Messages SUMMARY: In compliance with the... Collection: Title: Pretesting of NIAID's Biomedical HIV Prevention Research Communication Messages. Type of... biomedical HIV prevention research. The primary objectives of the pretests are to (1) Assess audience...

  9. Bandwidth Reduction via Localized Peer-to-Peer (P2P Video

    Directory of Open Access Journals (Sweden)

    Ken Kerpez

    2010-01-01

    Full Text Available This paper presents recent research into P2P distribution of video that can be highly localized, preferably sharing content among users on the same access network and Central Office (CO. Models of video demand and localized P2P serving areas are presented. Detailed simulations of passive optical networks (PON are run, and these generate statistics of P2P video localization. Next-Generation PON (NG-PON is shown to fully enable P2P video localization, but the lower rates of Gigabit-PON (GPON restrict performance. Results here show that nearly all of the traffic volume of unicast video could be delivered via localized P2P. Strong growth in video delivery via localized P2P could lower overall future aggregation and core network bandwidth of IP video traffic by 58.2%, and total consumer Internet traffic by 43.5%. This assumes aggressive adoption of technologies and business practices that enable highly localized P2P video.

  10. Blockade of P2X7 receptors or pannexin-1 channels similarly attenuates postischemic damage.

    Science.gov (United States)

    Cisneros-Mejorado, Abraham; Gottlieb, Miroslav; Cavaliere, Fabio; Magnus, Tim; Koch-Nolte, Friederich; Scemes, Eliana; Pérez-Samartín, Alberto; Matute, Carlos

    2015-05-01

    The role of P2X7 receptors and pannexin-1 channels in ischemic damage remains controversial. Here, we analyzed their contribution to postanoxic depolarization after ischemia in cultured neurons and in brain slices. We observed that pharmacological blockade of P2X7 receptors or pannexin-1 channels delayed the onset of postanoxic currents and reduced their slope, and that simultaneous inhibition did not further enhance the effects of blocking either one. These results were confirmed in acute cortical slices from P2X7 and pannexin-1 knockout mice. Oxygen-glucose deprivation in cortical organotypic cultures caused neuronal death that was reduced with P2X7 and pannexin-1 blockers as well as in organotypic cultures derived from mice lacking P2X7 and pannexin 1. Subsequently, we used transient middle cerebral artery occlusion to monitor the neuroprotective effect of those drugs in vivo. We found that P2X7 and pannexin-1 antagonists, and their ablation in knockout mice, substantially attenuated the motor symptoms and reduced the infarct volume to ~50% of that in vehicle-treated or wild-type animals. These results show that P2X7 receptors and pannexin-1 channels are major mediators of postanoxic depolarization in neurons and of brain damage after ischemia, and that they operate in the same deleterious signaling cascade leading to neuronal and tissue demise.

  11. Important roles of P2Y receptors in the inflammation and cancer of digestive system.

    Science.gov (United States)

    Wan, Han-Xing; Hu, Jian-Hong; Xie, Rei; Yang, Shi-Ming; Dong, Hui

    2016-05-10

    Purinergic signaling is important for many biological processes in humans. Purinoceptors P2Y are widely distributed in human digestive system and different subtypes of P2Y receptors mediate different physiological functions from metabolism, proliferation, differentiation to apoptosis etc. The P2Y receptors are essential in many gastrointestinal functions and also involve in the occurrence of some digestive diseases. Since different subtypes of P2Y receptors are present on the same cell of digestive organs, varying subtypes of P2Y receptors may have opposite or synergetic functions on the same cell. Recently, growing lines of evidence strongly suggest the involvement of P2Y receptors in the pathogenesis of several digestive diseases. In this review, we will focus on their important roles in the development of digestive inflammation and cancer. We anticipate that as the special subtypes of P2Y receptors are studied in depth, specific modulators for them will have good potentials to become promising new drugs to treat human digestive diseases in the near future.

  12. Orientation of Zn3P2 films via phosphidation of Zn precursors

    Science.gov (United States)

    Katsube, Ryoji; Nose, Yoshitaro

    2017-02-01

    Orientation of solar absorber is an important factor to achieve high efficiency of thin film solar cells. In the case of Zn3P2 which is a promising absorber of low-cost and high-efficiency solar cells, (110)/(001) orientation was only reported in previous studies. We have successfully prepared (101)-oriented Zn3P2 films by phosphidation of (0001)-oriented Zn films at 350 °C. The phosphidation mechanism of Zn is discussed through STEM observations on the partially-reacted sample and the consideration of the relationship between the crystal structures of Zn and Zn3P2 . We revealed that (0001)-oriented Zn led to nucleation of (101)-oriented Zn3P2 due to the similarity in atomic arrangement between Zn and Zn3P2 . The electrical resistivity of the (101)-oriented Zn3P2 film was lower than those of (110)/(001)-oriented films, which is an advantage of the phosphidation technique to the growth processes in previous works. The results in this study demonstrated that well-conductive Zn3P2 films could be obtained by controlling orientations of crystal grains, and provide a guiding principle for microstructure control in absorber materials.

  13. P2X7 receptor-mediated analgesia in cancer-induced bone pain

    DEFF Research Database (Denmark)

    Falk, Sarah; D. Schwab, Samantha; Frøsig-Jørgensen, Majbrit

    2015-01-01

    for cancer-induced bone pain. The P2X7 receptor (P2X7R) is involved in a variety of cellular functions and has been linked to both inflammatory and neuropathic pain. Here we study the analgesic potential of P2X7 receptor antagonism in a rat model of cancer-induced bone pain. In cancer-bearing animals, the P2....... The results suggest that the P2X7R is involved in the mechanisms of cancer-induced bone pain, and that P2X7R antagonism might be a useful analgesic target. No effect was observed in sham or naïve animals, indicating that the P2X7R-mediated effect is state-dependent, and might therefore be an advantageous......X7R antagonist A839977 attenuated dorsal horn neuronal responses in a modality and intensity specific way. Spinal application of 0.4mg/kg and 1.2mg/kg A839977 significantly reduced the evoked responses to high intensity mechanical and thermal stimulation, whereas no effect was seen in response...

  14. Rab5 regulates internalisation of P2X4 receptors and potentiation by ivermectin.

    Science.gov (United States)

    Stokes, Leanne

    2013-03-01

    The P2X4 receptor is an ATP-gated ion channel expressed in neurons, endothelia and immune cells. Plasma membrane expression of P2X4 is regulated by dynamin-dependent endocytosis, and this study identifies a Rab5-dependent pathway of receptor internalisation. Expression of Rab5 constructs altered the distribution of P2X4 in HEK-293 cells, and both constitutive internalisation and agonist-induced desensitisation of P2X4 were increased by co-expression of wild-type Rab5 or constitutively active Rab5 (Q79L). Expression of inactive dynamin K44A and Rab5 S34N constructs abolished agonist-induced desensitisation, suggesting internalisation as the underlying mechanism. Blocking P2X4 internalisation in this way also abolished potentiation of ATP-induced currents by the allosteric modulator ivermectin. This suggests that the dynamin-Rab5 internalisation pathway is essential for the ivermectin potentiation effect. In agreement with this hypothesis, the co-expression of wild-type dynamin, wild-type Rab5 or active Rab5 (Q79L) could increase the potentiation of the ATP-induced P2X4 response by ivermectin. These findings highlight Rab5 GTPase as a key regulator of P2X4 receptor cell surface expression and internalisation.

  15. Two disparate ligand binding sites in the human P2Y1 receptor

    Science.gov (United States)

    Zhang, Dandan; Gao, Zhan-Guo; Zhang, Kaihua; Kiselev, Evgeny; Crane, Steven; Wang, Jiang; Paoletta, Silvia; Yi, Cuiying; Ma, Limin; Zhang, Wenru; Han, Gye Won; Liu, Hong; Cherezov, Vadim; Katritch, Vsevolod; Jiang, Hualiang; Stevens, Raymond C.; Jacobson, Kenneth A.; Zhao, Qiang; Wu, Beili

    2015-01-01

    In response to adenosine 5′-diphosphate, the P2Y1 receptor (P2Y1R) facilitates platelet aggregation, and thus serves as an important antithrombotic drug target. Here we report the crystal structures of the human P2Y1R in complex with a nucleotide antagonist MRS2500 at 2.7Å resolution, and with a non-nucleotide antagonist BPTU at 2.2Å resolution. The structures reveal two distinct ligand binding sites, providing atomic details of P2Y1R’s unique ligand binding modes. MRS2500 recognizes a binding site within the seven transmembrane bundle of P2Y1R, which, however, is different in shape and location from the nucleotide binding site in previously determined P2Y12R structure. BPTU binds to an allosteric pocket on the external receptor interface with the lipid bilayer, making it the first structurally characterized selective G protein-coupled receptor (GPCR) ligand located entirely outside of the helical bundle. These high-resolution insights into P2Y1R should enable discovery of new orthosteric and allosteric antithrombotic drugs with reduced adverse effects. PMID:25822790

  16. Single-nucleotide polymorphisms in the P2X7 receptor gene are associated with post-menopausal bone loss and vertebral fractures

    DEFF Research Database (Denmark)

    Rye Jørgensen, Niklas; Husted, Lise Bjerre; Skarratt, Kristen K

    2012-01-01

    to bone mass and fracture incidence in post-menopausal women. A total of 1694 women (aged 45-58) participating in the Danish Osteoporosis Prevention Study were genotyped for 12 functional P2X7 receptor variants. Bone mineral density was determined at baseline and after 10 years. In addition, vertebral...... had increased bone loss. In contrast, the Gln460Arg polymorphism was associated with protection against bone loss. The Ala348Thr polymorphism was associated with a lower vertebral fracture incidence 10 years after menopause. Finally, we developed a risk model, which integrated P2RX7 genotypes. Using...

  17. Impaired P2X signalling pathways in renal microvascular myocytes in genetic hypertension

    KAUST Repository

    Gordienko, Dmitri V.

    2014-12-16

    Aims P2X receptors (P2XRs) mediate sympathetic control and autoregulation of renal circulation triggering preglomerular vasoconstriction, which protects glomeruli from elevated pressures. Although previous studies established a casual link between glomerular susceptibility to hypertensive injury and decreased preglomerular vascular reactivity to P2XR activation, the mechanisms of attenuation of the P2XR signalling in hypertension remained unknown. We aimed to analyse molecular mechanisms of the impairment of P2XR signalling in renal vascular smooth muscle cells (RVSMCs) in genetic hypertension. Methods and results We compared the expression of pertinent genes and P2XR-linked Ca2+ entry and Ca2+ release mechanisms in RVSMCs of spontaneously hypertensive rats (SHRs) and their normotensive controls, Wistar Kyoto (WKY) rats. We found that, in SHR RVSMCs, P2XR-linked Ca2+ entry and Ca2+ release from the sarcoplasmic reticulum (SR) are both significantly reduced. The former is due to down-regulation of the P2X1 subunit. The latter is caused by a decrease of the SR Ca2+ load. The SR Ca2+ load reduction is caused by attenuated Ca2+ uptake via down-regulated sarco-/endoplasmic reticulum Ca2+-ATPase 2b and elevated Ca2+ leak from the SR via ryanodine receptors (RyRs) and inositol 1,4,5-trisphosphate receptors. Spontaneous activity of these Ca2+-release channels is augmented due to up-regulation of RyR type 2 and elevated IP3 production by up-regulated phospholipase C-β1. Conclusions Our study unravels the cellular and molecular mechanisms of attenuation of P2XR-mediated preglomerular vasoconstriction that elevates glomerular susceptibility to harmful hypertensive pressures. This provides an important impetus towards understanding of the pathology of hypertensive renal injury.

  18. Increased platelet activation and thrombosis in transgenic mice expressing constitutively active P2Y12 receptor

    Science.gov (United States)

    Zhang, Y.; Ye, J.; Hu, L.; Zhang, S.; Zhang, S.H.; Li, Y.; Kunapuli, S.P.; Ding, Z.

    2012-01-01

    Summary Background In our previous in vitro study we reported a constitutively active chimeric P2Y12 receptor (cP2Y12) and found AR-C78511 is a potent inverse agonist at this receptor. The role of this cP2Y12 receptor in platelet activation and thrombosis is not clear. Objectives To investigate the physiological implications of the constitutively active P2Y12 receptor in platelet activation, thrombus formulation and evaluate the antiplatelet activity of AR-C78511 as an inverse agonist. Methods and Results We generated transgenic mice conditionally and platelet-specifically expressing cP2Y12. High expression of cP2Y12 receptor in platelets increased platelet reactivity as evidenced by increased platelet aggregation in response to multiple platelet agonists. Moreover, transgenic mice displayed shortened bleeding time, more rapid and stable thrombus formation in mesenteric artery injured with FeCl3. The constitutive activity of cP2Y12 in platelets was confirmed by decreased platelet cAMP levels and constitutive Akt phosphorylation in the absence of agonists. AR-C78511 reversed the cAMP decrease in transgenic mouse platelets, and exhibited superior antiplatelet effect over AR-C69931MX in transgenic mice. Conclusions These findings further emphasize the importance of P2Y12 in platelet activation, hemostasis and thrombosis, as well as the prothrombotic role of constitutive activity of P2Y12. Our data also validates the in vivo inverse agonist activity of AR-C78511 and confirms its superior antiplatelet activity over neutral antagonist. PMID:22906019

  19. Increased P2X7R expression in atrial cardiomyocytes of caveolin-1 deficient mice.

    Science.gov (United States)

    Barth, K; Pfleger, C; Linge, A; Sim, J A; Surprenant, A; Steinbronn, N; Strasser, R H; Kasper, M

    2010-07-01

    It has recently been shown in epithelial cells that the ATP-gated ion channel P2X7R is in part, associated with caveolae and colocalized with caveolin-1. In the present study of the mouse heart, we show for the first time, using immunohistochemistry and cryoimmunoelectron microscopy, that P2X7R is expressed in atrial cardiomyocytes and in cardiac microvascular endothelial cells, but not in the ventricle cardiomyocytes. Furthermore, biochemical data indicate the presence of two forms of P2X7R, the classical glycosylated 80 kDa isoform and a protein with the molecular weight of 56 kDa, in both cardiomyocytes and endothelial cells of the mouse heart. The functionality of both proteins in heart cells is still unclear. In cardiac tissue homogenates derived from caveolin-1 deficient mice (cav-1(-/-)), an increase of the P2Xrx7 mRNA and P2X7R protein (80 kDa) was found, particularly in atrial samples. In addition, P2rx7(-/-) mice showed enhanced protein levels of caveolin-1 in their atrial tissues. Although the details of cellular mechanisms that underlie the relationship between caveolin-1 and P2X7R in atrial cardiomyocytes and the electrophysiological consequences of the increased P2X7R expression in atrial cells of cav-1(-/-) mice remain to be elucidated, the cardiomyopathy detectable in cav-1(-/-) mice is possibly related to a disturbed crosstalk between P2X7R and caveolin-1 in different heart cell populations.

  20. Ant Colony Algorithms for the Resolution of Semantic Searches in P2P Networks

    OpenAIRE

    Krynicki, Kamil Krzysztof

    2016-01-01

    [EN] The long-lasting trend in the field of computation of stress and resource distribution has found its way into computer networks via the concept of peer-to-peer (P2P) connectivity. P2P is a symmetrical model, where each network node is enabled a comparable range of capacities and resources. It stands in a stark contrast to the classical, strongly asymmetrical client-server approach. P2P, originally considered only a complimentary, server-side structure to the straightforward client-server...

  1. Modulation of Central Synapses by Astrocyte-Released ATP and Postsynaptic P2X Receptors

    Science.gov (United States)

    Pankratov, Yuriy

    2017-01-01

    Communication between neuronal and glial cells is important for neural plasticity. P2X receptors are ATP-gated cation channels widely expressed in the brain where they mediate action of extracellular ATP released by neurons and/or glia. Recent data show that postsynaptic P2X receptors underlie slow neuromodulatory actions rather than fast synaptic transmission at brain synapses. Here, we review these findings with a particular focus on the release of ATP by astrocytes and the diversity of postsynaptic P2X-mediated modulation of synaptic strength and plasticity in the CNS. PMID:28845311

  2. Targeting of the P2X7 receptor in pancreatic cancer and stellate cells

    DEFF Research Database (Denmark)

    Giannuzzo, Andrea; Saccomano, Mara; Napp, Joanna

    2016-01-01

    The ATP-gated receptor P2X7 (P2X7R) is involved in regulation of cell survival and has been of interest in cancer field. Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer and new markers and therapeutic targets are needed. PDAC is characterized by a complex tumour microenvironment, which...... into nude mice and tumour growth was followed noninvasively by bioluminescence imaging. AZ10606120-treated mice showed reduced bioluminescence compared to saline-treated mice. Immunohistochemical analysis confirmed P2X7R expression in cancer and PSC cells, and in metaplastic/neoplastic acinar and duct...

  3. PIP kinases define PI4,5P2 signaling specificity by association with effectors

    OpenAIRE

    Choi, Suyong; Thapa, Narendra; Tan, Xiaojun; Hedman, Andrew C.; Anderson, Richard A.

    2015-01-01

    Phosphatidylinositol 4,5-bisphosphate (PI4,5P2) is an essential lipid messenger with roles in all eukaryotes and most aspects of human physiology. By controlling the targeting and activity of its effectors, PI4,5P2 modulates processes, such as cell migration, vesicular trafficking, cellular morphogenesis, signaling and gene expression. In cells, PI4,5P2 has a much higher concentration than other phosphoinositide species and its total content is largely unchanged in response to extracellular s...

  4. P2X7R/cryopyrin inflammasome axis inhibition reduces neuroinflammation after SAH.

    Science.gov (United States)

    Chen, Sheng; Ma, Qingyi; Krafft, Paul R; Hu, Qin; Rolland, William; Sherchan, Prativa; Zhang, Jianmin; Tang, Jiping; Zhang, John H

    2013-10-01

    Neuroinflammation contributes to the pathogenesis of early brain injury (EBI) after subarachnoid hemorrhage (SAH). Cytotoxic events following SAH, such as extracellular accumulation of adenosine triphosphate (ATP), may activate the P2X purinoceptor 7 (P2X7R)/cryopyrin inflammasome axis, thus inducing the proinflammatory cytokine IL-1β/IL-18 secretion. We therefore hypothesized that inhibition of P2X7R/cryopyrin inflammasome axis would ameliorate neuroinflammation after SAH. In the present study, SAH was induced by the endovascular perforation in rats. Small interfering RNAs (siRNAs) of P2X7R or cryopyrin were administered intracerebroventricularly 24h before SAH. Brilliant blue G (BBG), a non-competitive antagonist of P2X7R, was administered intraperitoneally 30min following SAH. Post-assessments including SAH severity score, neurobehavioral test, brain water content, Western blot and immunofluorescence, were performed. Administration of P2X7R and cryopyrin siRNA as well as pharmacologic blockade of P2X7R by BBG ameliorated neurological deficits and brain edema at 24h following SAH. Inhibition of P2X7R/cryopyrin inflammasome axis suppressed caspase-1 activation, which subsequently decreased maturation of IL-1β/IL-18. To investigate the link between P2X7R and cryopyrin inflammasome in vivo, Benzoylbenzoyl-ATP (BzATP), a P2X7R agonist, was given to lipopolysaccharide (LPS) primed naive rats with scramble or cryopyrin siRNAs. In LPS-primed naive rats, BzATP induced caspase-1 activation and mature IL-1β release were neutralized by cryopyrin siRNA. Thus, the P2X7R/cryopyrin inflammasome axis may contribute to neuroinflammation via activation of caspase-1 and thereafter mature IL-1β/IL-18 production following SAH. Therapeutic interventions targeting P2X7R/cryopyrin pathway may be a novel approach to ameliorate EBI following SAH. © 2013.

  5. Activation of P2X7R and downstream effects in bleomycin treated lung epithelial cells.

    Science.gov (United States)

    Bläsche, Robert; Ebeling, Georg; Perike, Srikanth; Weinhold, Karina; Kasper, Michael; Barth, Kathrin

    2012-03-01

    Changes in intracellular calcium concentration [Ca(2+)](i) are believed to influence the proliferation and differentiation of airway epithelial cells both in vivo and in vitro. In the present study, using mouse alveolar epithelial E10 cells, we demonstrated that the treatment of lung epithelial cells with BLM resulted in elevated intracellular Ca(2+) levels. BLM further increased P2rx7 mRNA expression and P2X7R protein levels, paralleled by increased PKC-β1 levels. BLM treatment or stimulation of the P2X7R with the P2X7R agonist BzATP induced translocation of PKC-β1 from the cytoplasm to the membrane. The expression of PKC-β1 was repressed by the P2X7R inhibitor oxATP, suggesting that PKC-β1 is downstream of P2X7R activation. Furthermore, cells exposed to BLM contained increased amounts of P2X7R and PKC-β1 in Cav-1 containing lipid raft fractions. The comparison of lung tissues from wild-type and P2rx7(-/-) mice revealed decreased protein and mRNA levels of PKC-β1 and CaM as well as decreased immunoreactivity for PKC-β1. The knockdown of P2X7R in alveolar epithelial cells resulted also in a loss of PKC-β1. These data suggest that the effect of P2X7R on expression of PKC-β1 detected in alveolar epithelial cells is also functioning in the animal model. Immunohistochemical evaluation of fibrotic lungs derived from a BLM-induced mouse model revealed a strong increase in PKC-β1 immunoreactivity. The present experiments demonstrated that the increased expression of P2X7R influences PKC-β1. We predict that increased Ca(2+) concentration stimulates PKC-β1, whereas the prerequisite for activating PKC-β1 after P2X7R increase remained to be determined. Our findings suggest that PKC-β1 is important in the pathogenesis of pulmonary fibrosis. Copyright © 2011 Elsevier Ltd. All rights reserved.

  6. Aneurysms of the P2P Segment of Posterior Cerebral Artery: Case Report and Surgical Steps

    Directory of Open Access Journals (Sweden)

    Paulo Aguiar

    2014-01-01

    Full Text Available The posterior cerebral artery (PCA is divided into 4 segments: precommunicating segment (P1, postcommunicating segment (P2, quadrigeminal segment (P3, and calcarine segment (P4. Small aneurysms are more prevalent than large aneurysms in patients with ruptured aneurysms. P2 and P3 aneurysms are usually managed by the subtemporal approach. This is a case report of rupture saccular aneurysm of posterior cerebral artery on P2P segment. The authors show the surgical steps of these rare aneurysms with an illustrative case.

  7. Mobility Impact in Initializing Ring-Based P2P Systems over MANETs

    Directory of Open Access Journals (Sweden)

    Wei Ding

    2008-10-01

    Full Text Available With the encouragement from success of P2P systems in real world application, recently we have seen active research on synergy of P2P systems and mobile ad hoc networks. The paper proposes a solution for mobility disturbance problem in initialization of ring-based P2P systems over ad hoc networks. It is a decentralized ring construction protocol in presence of mobility. A Mobile Ring Ad-hoc Networks (MRAN protocol is presented. MRAN is an extension of RAN [1] under the mobile condition. Simulation result shows MRAN works well with mobility. Upper bound of maximum speed of moving nodes is investigated in simulation.

  8. Modulation of Central Synapses by Astrocyte-Released ATP and Postsynaptic P2X Receptors

    Directory of Open Access Journals (Sweden)

    Eric Boué-Grabot

    2017-01-01

    Full Text Available Communication between neuronal and glial cells is important for neural plasticity. P2X receptors are ATP-gated cation channels widely expressed in the brain where they mediate action of extracellular ATP released by neurons and/or glia. Recent data show that postsynaptic P2X receptors underlie slow neuromodulatory actions rather than fast synaptic transmission at brain synapses. Here, we review these findings with a particular focus on the release of ATP by astrocytes and the diversity of postsynaptic P2X-mediated modulation of synaptic strength and plasticity in the CNS.

  9. Presynaptic inhibition of spontaneous acetylcholine release mediated by P2Y receptors at the mouse neuromuscular junction.

    Science.gov (United States)

    De Lorenzo, S; Veggetti, M; Muchnik, S; Losavio, A

    2006-09-29

    At the neuromuscular junction, ATP is co-released with the neurotransmitter acetylcholine (ACh) and once in the synaptic space, it is degraded to the presynaptically active metabolite adenosine. Intracellular recordings were performed on diaphragm fibers of CF1 mice to determine the action of extracellular ATP (100 muM) and the slowly hydrolysable ATP analog 5'-adenylylimidodiphosphate lithium (betagamma-imido ATP) (30 muM) on miniature end-plate potential (MEPP) frequency. We found that application of ATP and betagamma-imido ATP decreased spontaneous secretion by 45.3% and 55.9% respectively. 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX), a selective A(1) adenosine receptor antagonist and alpha,beta-methylene ADP sodium salt (alphabeta-MeADP), which is an inhibitor of ecto-5'-nucleotidase, did not prevent the inhibitory effect of ATP, demonstrating that the nucleotide is able to modulate spontaneous ACh release through a mechanism independent of the action of adenosine. Blockade of Ca(2+) channels by both, Cd(2+) or the combined application of nitrendipine and omega-conotoxin GVIA (omega-CgTx) (L-type and N-type Ca(2+) channel antagonists, respectively) prevented the effect of betagamma-imido ATP, indicating that the nucleotide modulates Ca(2+) influx through the voltage-dependent Ca(2+) channels related to spontaneous secretion. betagamma-Imido ATP-induced modulation was antagonized by the non-specific P2 receptor antagonist suramin and the P2Y receptor antagonist 1-amino-4-[[4-[[4-chloro-6-[[3(or4)-sulfophenyl] amino]-1,3,5-triazin-2-yl]amino]-3-sulfophenyl] amino]-9,10-dihydro-9,10-dioxo-2-anthracenesulfonic acid (reactive blue-2), but not by pyridoxal phosphate-6-azo(benzene-2,4-disulfonic acid) tetrasodium salt (PPADS), which has a preferential antagonist effect on P2X receptors. Pertussis toxin and N-ethylmaleimide (NEM), which are blockers of G(i/o) proteins, prevented the action of the nucleotide, suggesting that the effect is mediated by P2Y receptors

  10. AWARENESS AND COMPLIANCE OF ANTITETANUS ...

    African Journals Online (AJOL)

    The purpose of this study was to investigate the awareness level and the compliance to anti-tetanus immunization among adult females in an urban community in South West of Nigeria. The rationale for the study was informed by the fact that high incidence of tetanus infections and deaths are still being reported from our ...

  11. Audit-based compliance control

    NARCIS (Netherlands)

    Cederquist, J.G.; Dimitrakos, T.; Corin, R.J.; Martinelli, F.; Ryan, P.Y.A.; Dekker, M.A.C.; Etalle, Sandro; Schneider, S.; den Hartog, Jeremy; Lenzini, Gabriele

    2007-01-01

    In this paper we introduce a new framework for controlling compliance to discretionary access control policies [Cederquist et al. in Proceedings of the International Workshop on Policies for Distributed Systems and Networks (POLICY), 2005; Corin et al. in Proceedings of the IFIP Workshop on Formal

  12. Project Compliance with Enterprise Architecture

    NARCIS (Netherlands)

    Foorthuis, R.M.

    2012-01-01

    This research project set out to identify effective practices and models for working with projects that are required to comply with Enterprise Architecture (EA), and investigate the benefits and drawbacks brought about by compliance. Research methods used are canonical action research, a statistical

  13. ETHICS AND COMPLIANCE IN BUSINESS

    Directory of Open Access Journals (Sweden)

    ANDREESCU Nicoleta Alina

    2015-05-01

    Full Text Available In this paper, we have studied the evolution of the business ethics concept through the prism of definitions from some renowned authors in the field and through the approach model of the business ethics and by implementing it in the company level. We have found out that in the last 40 years this concept has evolved from a theoretical aspect, as well as a practical one. Companies are motivated to implement ethics and compliance programs in business so that they can manage the changes that come from society. If, until recently, all that mattered for a company was profit, in the last decades, the situation changed. In order to develop a durable business, it is essential to have a good reputation. Owning and implementing an ethics and compliance program in business has become an imperative for companies, regardless of their activity sector. The role of the compliance department becomes more pregnant in each company: the employees need safety, the existence of communication lines provides comfort. From the partners in business’ point of view, owning such a program is a necessity, a condition, and not conforming to the principles of business ethics can lead to the isolation of the company. The ethics and compliance programs in business are instruments that protect the company by implementing certain proactive identification mechanisms that ensure the development of an ethical organizational culture.

  14. Impact of ticagrelor on P2Y1 and P2Y12 localization and on cholesterol levels in platelet plasma membrane.

    Science.gov (United States)

    Rabani, Vahideh; Montange, Damien; Meneveau, Nicolas; Davani, Siamak

    2017-10-11

    Ticagrelor is an antiplatelet agent that inhibits platelet activation via P2Y12 antagonism. There are several studies showing that P2Y12 needs lipid rafts to be activated, but there are few data about how ticagrelor impacts lipid raft organization. Therefore, we aimed to investigate how ticagrelor could impact the distribution of cholesterol and consequently alter the organization of lipid rafts on platelet plasma membranes. We identified cholesterol-enriched raft fractions in platelet membranes by quantification of their cholesterol levels. Modifications in cholesterol and protein profiles (Flotillin 1, Flotillin 2, CD36, P2Y1, and P2Y12) were studied in platelets stimulated by ADP, treated by ticagrelor, or both. In ADP-stimulated and ticagrelor-treated groups, we found a decreased level of cholesterol in raft fractions of platelet plasma membrane compared to the control group. In addition, the peak of cholesterol in different experimental groups changed its localization on membrane fractions. In the control group, it was situated on fraction 2, while in ADP-stimulated platelets, it was located in fractions 3 to 5, and in fraction 4 in ticagrelor-treated group. The proteins studied also showed changes in their level of expression and localization in fractions of plasma membrane. Cholesterol levels of plasma membranes have a direct role in the organization of platelet membranes and could be modified by stimulation or drug treatment. Since ticagrelor and ADP both changed lipid composition and protein profile, investigating the lipid and protein composition of platelet membranes is of considerable importance as a focus for further research in anti-platelet management.

  15. Phosphoinositide 5-phosphatase activities control cell motility in glioblastoma: Two phosphoinositides PI(4,5)P2 and PI(3,4)P2 are involved.

    Science.gov (United States)

    Ramos, Ana Raquel; Elong Edimo, William's; Erneux, Christophe

    2018-01-01

    Inositol polyphosphate 5-phosphatases or phosphoinositide 5-phosphatases (PI 5-phosphatases) are enzymes that can act on soluble inositol phosphates and/or phosphoinositides (PIs). Several PI 5-phosphatases have been linked to human genetic diseases, in particular the Lowe protein or OCRL which is mutated in the Lowe syndrome. There are 10 different members of this family and 9 of them can use PIs as substrate. One of these substrates, PI(3,4,5)P3 binds to specific PH domains and recruits as effectors specific proteins to signaling complexes. Protein kinase B is one target protein and activation of the kinase will have a major impact on cell proliferation, survival and cell metabolism. Two other PIs, PI(4,5)P2 and PI(3,4)P2, are produced or used as substrates of PI 5-phosphatases (OCRL, INPP5B, SHIP1/2, SYNJ1/2, INPP5K, INPP5J, INPP5E). The inositol lipids may influence many aspects of cytoskeletal organization, lamellipodia formation and F-actin polymerization. PI 5-phosphatases have been reported to control cell migration, adhesion, polarity and cell invasion particularly in cancer cells. In glioblastoma, reducing SHIP2 expression can positively or negatively affect the speed of cell migration depending on the glioblastoma cell type. The two PI 5-phosphatases SHIP2 or SKIP could be localized at the plasma membrane and can reduce either PI(3,4,5)P3 or PI(4,5)P2 abundance. In the glioblastoma 1321 N1 cells, SHIP2 controls plasma membrane PI(4,5)P2 thereby participating in the control of cell migration. Copyright © 2017 Elsevier Ltd. All rights reserved.

  16. Mobile Source Emissions Regulatory Compliance Data

    Data.gov (United States)

    U.S. Environmental Protection Agency — The Engine and Vehicle Compliance Certification and Fuel Economy Inventory contains measured emissions and fuel economy compliance information for all types of...

  17. Clean Air Markets - Compliance Query Wizard

    Data.gov (United States)

    U.S. Environmental Protection Agency — The Compliance Query Wizard is part of a suite of Clean Air Markets-related tools that are accessible at http://ampd.epa.gov/ampd/. The Compliance module provides...

  18. Mobile Source Emissions Regulatory Compliance Data Inventory

    Data.gov (United States)

    U.S. Environmental Protection Agency — The Mobile Source Emissions Regulatory Compliance Data Inventory data asset contains measured summary compliance information on light-duty, heavy-duty, and non-road...

  19. 300 area TEDF permit compliance monitoring plan

    International Nuclear Information System (INIS)

    BERNESKI, L.D.

    1998-01-01

    This document presents the permit compliance monitoring plan for the 300 Area Treated Effluent Disposal Facility (TEDF). It addresses the compliance with the National Pollutant Discharge Elimination System (NPDES) permit and Department of Natural Resources Aquatic Lands Sewer Outfall Lease

  20. 300 area TEDF permit compliance monitoring plan

    Energy Technology Data Exchange (ETDEWEB)

    BERNESKI, L.D.

    1998-11-20

    This document presents the permit compliance monitoring plan for the 300 Area Treated Effluent Disposal Facility (TEDF). It addresses the compliance with the National Pollutant Discharge Elimination System (NPDES) permit and Department of Natural Resources Aquatic Lands Sewer Outfall Lease.

  1. Hand hygiene compliance in the intensive care units of a tertiary care hospital

    Directory of Open Access Journals (Sweden)

    Sarit Sharma

    2011-01-01

    Full Text Available Context: Hand hygiene (HH is the most important measure to prevent hospital-acquired infections but the compliance is still low. Aims: To assess the compliance, identify factors influencing compliance and to study the knowledge, attitude and perceptions associated with HH among health care workers (HCW. Settings and Design: Cross-sectional study conducted in 42 bedded Medical (Pulmonary, Medicine and Stroke intensive care units (ICU of a tertiary care hospital. Materials and Methods: HCWs (doctors and nurses were observed during routine patient care by observers posted in each ICU and their HH compliance was noted. Thereafter, questionnaire regarding knowledge, perception and attitudes toward HH was filled by each HCW. Statistical Analysis: Percentages and χ2 test. Results: The overall compliance was 43.2% (394/911 opportunities. It was 68.9% (31/45 in the intensivists, 56.3% (18/32 in attending physicians, 40.0% (28/70 in the postgraduate residents and 41.3% (301/728 in the nurses. Compliance was inversely related to activity index. Compliance for high, medium and low risk of cross-transmission was 38.8% (67/170, 43.8% (175/401 and 44.7% (152/340, respectively. Conclusions: Compliance of the study group is affected by the activity index (number of opportunities they come across per hour and professional status. The HCWs listed less knowledge, lack of motivation, increased workload as some of the factors influencing HH.

  2. GENDER AND ETHNICITY DIFFERENCES IN TAX COMPLIANCE

    OpenAIRE

    Jeyapalan Kasipillai; Hijattulah Abdul Jabbar

    2006-01-01

    The purpose of this study is to investigate whether gender and ethnicity differences occur in relation to tax compliance attitude and behavior. Prior studies on tax compliance have focused little on gender as a predictor of compliance. In Malaysia, ethnic background of a taxpayer could be a major determinant of tax compliance. A personal interview approach is used to obtain information from taxpayers in urban towns. A t-test suggests that males and females were found to have similar compliant...

  3. Hazardous Materials Pharmacies - A Vital Component of a Robust P2 Program

    International Nuclear Information System (INIS)

    McCarter, S.

    2006-01-01

    Integrating pollution prevention (P2) into the Department of Energy Integrated Safety Management (ISM) - Environmental Management System (EMS) approach, required by DOE Order 450.1, leads to an enhanced ISM program at large and complex installations and facilities. One of the building blocks to integrating P2 into a comprehensive environmental and safety program is the control and tracking of the amounts, types, and flow of hazardous materials used on a facility. Hazardous materials pharmacies (typically called HazMarts) provide a solid approach to resolving this issue through business practice changes that reduce use, avoid excess, and redistribute surplus. If understood from concept to implementation, the HazMart is a powerful tool for reducing pollution at the source, tracking inventory storage, controlling usage and flow, and summarizing data for reporting requirements. Pharmacy options can range from a strict, single control point for all hazardous materials to a virtual system, where the inventory is user controlled and reported over a common system. Designing and implementing HazMarts on large, diverse installations or facilities present a unique set of issues. This is especially true of research and development (R and D) facilities where the chemical use requirements are extensive and often classified. There are often multiple sources of supply; a wide variety of chemical requirements; a mix of containers ranging from small ampoules to large bulk storage tanks; and a wide range of tools used to track hazardous materials, ranging from simple purchase inventories to sophisticated tracking software. Computer systems are often not uniform in capacity, capability, or operating systems, making it difficult to use a server-based unified tracking system software. Each of these issues has a solution or set of solutions tied to fundamental business practices. Each requires an understanding of the problem at hand, which, in turn, requires good communication among all

  4. Probenecid directly impairs activation of the canine P2X7 receptor.

    Science.gov (United States)

    Bartlett, Rachael; Stokes, Leanne; Curtis, Stephen J; Curtis, Belinda L; Sluyter, Ronald

    2017-12-02

    The current study aimed to determine if probenecid could directly impair the canine P2X7 receptor, a ligand-gated cation channel activated by extracellular adenosine 5'-triphosphate (ATP). Patch clamp measurements demonstrated that probenecid impairs ATP-induced inward currents in HEK-293 cells expressing canine P2X7. Flow cytometric measurements of ethidium + uptake into HEK-293 cells expressing canine P2X7 showed that probenecid impairs ATP-induced pore formation in a concentration-dependent manner, with a half maximal inhibitory concentration of 158 µM. Finally, ELISA measurements revealed that probenecid impairs ATP-induced interleukin-1β release in dog blood. In conclusion, this study reveals that probenecid can directly impair canine P2X7 activation.

  5. Expression, purification, crystallization and structure of human adipocyte lipid-binding protein (aP2)

    International Nuclear Information System (INIS)

    Marr, Eric; Tardie, Mark; Carty, Maynard; Brown Phillips, Tracy; Wang, Ing-Kae; Soeller, Walt; Qiu, Xiayang; Karam, George

    2006-01-01

    The crystal structure of human adipocyte lipid-binding protein (aP2) with a bound palmitate is reported at 1.5 Å resolution. Human adipocyte lipid-binding protein (aP2) belongs to a family of intracellular lipid-binding proteins involved in the transport and storage of lipids. Here, the crystal structure of human aP2 with a bound palmitate is described at 1.5 Å resolution. Unlike the known crystal structure of murine aP2 in complex with palmitate, this structure shows that the fatty acid is in a folded conformation and that the loop containing Phe57 acts as a lid to regulate ligand binding by excluding solvent exposure to the central binding cavity

  6. Porous Photocatalytic Membrane Microreactor (P2M2): A new reactor concept for photochemistry

    NARCIS (Netherlands)

    Aran, H.C.; Salamon, David; Rijnaarts, Timon; Rijnaarts, T.; Mul, Guido; Wessling, Matthias; Lammertink, Rob G.H.

    2011-01-01

    In this study, a new membrane microreactor concept for multiphase photocatalytic reactions is demonstrated. Microfabrication, photocatalyst immobilization and surface modification steps were performed to develop a Porous Photocatalytic Membrane Microreactor (P2M2). This concept benefits from a

  7. A Local Scalable Distributed EM Algorithm for Large P2P Networks

    Data.gov (United States)

    National Aeronautics and Space Administration — his paper describes a local and distributed expectation maximization algorithm for learning parameters of Gaussian mixture models (GMM) in large peer-to-peer (P2P)...

  8. Up-regulation of P2X7 receptor-mediated inhibition of GABA uptake by nerve terminals of the human epileptic neocortex.

    Science.gov (United States)

    Barros-Barbosa, Aurora R; Fonseca, Ana L; Guerra-Gomes, Sónia; Ferreirinha, Fátima; Santos, Agostinho; Rangel, Rui; Lobo, M Graça; Correia-de-Sá, Paulo; Cordeiro, J Miguel

    2016-01-01

    Thirty percent of patients with epilepsy are refractory to medication. The majority of these patients have mesial temporal lobe epilepsy (MTLE). This prompts for new pharmacologic targets, like ATP-mediated signaling pathways, since the extracellular levels of the nucleotide dramatically increase during in vitro epileptic seizures. In this study, we investigated whether sodium-dependent high-affinity γ-aminobutyric acid (GABA) and glutamate uptake by isolated nerve terminals of the human neocortex could be modulated by ATP acting via slow-desensitizing P2X7 receptor (P2X7R). Modulation of [(3) H]GABA and [(14) C]glutamate uptake by ATP, through activation of P2X7R, was investigated in isolated nerve terminals of the neocortex of cadaveric controls and patients with drug-resistant epilepsy (non-MTLE or MTLE) submitted to surgery. Tissue density and distribution of P2X7R in the human neocortex was assessed by Western blot analysis and immunofluorescence confocal microscopy. The P2X7R agonist, 2'(3')-O-(4-benzoylbenzoyl)ATP (BzATP, 3-100 μm) decreased [(3) H]GABA and [(14) C]glutamate uptake by nerve terminals of the neocortex of controls and patients with epilepsy. The inhibitory effect of BzATP (100 μm) was prevented by the selective P2X7R antagonist, A-438079 (3 μm). Down-modulation of [(14) C]glutamate uptake by BzATP (100 μm) was roughly similar in controls and patients with epilepsy, but the P2X7R agonist inhibited more effectively [(3) H]GABA uptake in the epileptic tissue. Neocortical nerve terminals of patients with epilepsy express higher amounts of the P2X7R protein than control samples. High-frequency cortical activity during epileptic seizures releases huge amounts of ATP, which by acting on low-affinity slowly desensitizing ionotropic P2X7R, leads to down-modulation of neuronal GABA and glutamate uptake. Increased P2X7R expression in neocortical nerve terminals of patients with epilepsy may, under high-frequency firing, endure GABA signaling and

  9. 12 CFR 1710.19 - Compliance and risk management programs; compliance with other laws.

    Science.gov (United States)

    2010-01-01

    ... 12 Banks and Banking 7 2010-01-01 2010-01-01 false Compliance and risk management programs; compliance with other laws. 1710.19 Section 1710.19 Banks and Banking OFFICE OF FEDERAL HOUSING ENTERPRISE... Practices and Procedures § 1710.19 Compliance and risk management programs; compliance with other laws. (a...

  10. DESENSITIZATION PROPERTIES OF P2X3 RECEPTORS SHAPING PAIN SIGNALLING

    Directory of Open Access Journals (Sweden)

    Rashid eGiniatullin

    2013-12-01

    Full Text Available ATP-gated P2X3 receptors are mostly expressed by nociceptive sensory neurons and participate in transduction of pain signals. P2X3 receptors show a combination of fast desensitization onset and slow recovery. Moreover, even low nanomolar agonist concentrations unable to evoke a response, can induce desensitization via a phenomenon called ‘high affinity desensitization’. We have also observed that recovery from desensitization is agonist-specific and can range from seconds to minutes. The recovery process displays unusually high temperature dependence. Likewise, recycling of P2X3 receptors in peri-membrane regions shows unexpectedly large temperature sensitivity. By applying kinetic modeling, we have previously shown that desensitization characteristics of P2X3 receptor are best explained with a cyclic model of receptor operation involving three agonist molecules binding a single receptor and that desensitization is primarily developing from the open receptor state. Mutagenesis experiments suggested that desensitization depends on a certain conformation of the ATP binding pocket and on the structure of the transmembrane domains forming the ion pore. Further molecular determinants of desensitization have been identified by mutating the intracellular N- and C-termini of P2X3 receptor. Unlike other P2X receptors, the P2X3 subtype is facilitated by extracellular calcium that acts via specific sites in the ectodomain neighboring the ATP binding pocket. Thus, substitution of serine275 in this region (called ‘left flipper’ converts the natural facilitation induced by extracellular calcium to receptor inhibition. Given such their strategic location in nociceptive neurons and unique desensitization properties, P2X3 receptors represent an attractive target for development of new analgesic drugs via promotion of desensitization aimed at suppressing chronic pain.

  11. Drug-like antagonists of P2Y receptors — from lead identification to drug development

    OpenAIRE

    Conroy, Sean; Kindon, Nicholas; Kellam, Barrie; Stocks, Michael

    2016-01-01

    P2Y receptors are expressed in virtually all cells and tissue types and mediate an astonishing array of biological functions, including platelet aggregation, smooth muscle cell proliferation, and immune regulation. The P2Y receptors belong to the G protein-coupled receptor superfamily and are composed of eight members encoded by distinct genes that can be subdivided into two groups on the basis of their coupling to specific G-proteins. Extensive research has been undertaken to find modulators...

  12. HFsub(1-x)2Rsub(x) 3P2O11 luminescent material

    International Nuclear Information System (INIS)

    Chenot, C.F.; Mathers, J.E.; Shaffer, F.N.

    1980-01-01

    A new compound corresponding to an oxide composition of 3:1 (HFsub(1-x)Zrsub(x))O 2 :P 2 O 5 . and having the empircal formula (HFsub(1-x)Zrsub(x)) 3 P 2 O 11 . where x is in the range of about 0 to 0.5. is an effective luminescent material for use in x-ray intensifying screens, and also an effective luminescent material host for Eusup(+2) blue emissions. (auth)

  13. Synthesis and structural characterization of Na2MnP2O7 crystal

    Indian Academy of Sciences (India)

    Unknown

    The starting mixture consists of manganese oxide, 85% orthophos- phoric acid and 2⋅5–5 M NaOH solution which acts as a mineralizer. Na2MnP2O7 crystals could be synthesized under the following molar ratio. Na2O : MnO : P2O5 = 3–5 : 0⋅5–0⋅75 : 12–16. The following reaction explains the synthesis of the compound.

  14. Critical Evaluation of P2X7 Receptor Antagonists in Selected Seizure Models

    Science.gov (United States)

    Fischer, Wolfgang; Franke, Heike; Krügel, Ute; Müller, Heiko; Dinkel, Klaus; Lord, Brian; Letavic, Michael A.; Henshall, David C.; Engel, Tobias

    2016-01-01

    The ATP-gated P2X7 receptor (P2X7R) is a non-selective cation channel which senses high extracellular ATP concentrations and has been suggested as a target for the treatment of neuroinflammation and neurodegenerative diseases. The use of P2X7R antagonists may therefore be a viable approach for treating CNS pathologies, including epileptic disorders. Recent studies showed anticonvulsant potential of P2X7R antagonists in certain animal models. To extend this work, we tested three CNS-permeable P2X7R blocker (Brilliant Blue G, AFC-5128, JNJ-47965567) and a natural compound derivative (tanshinone IIA sulfonate) in four well-characterized animal seizure models. In the maximal electroshock seizure threshold test and the pentylenetetrazol (PTZ) seizure threshold test in mice, none of the four compounds demonstrated anticonvulsant effects when given alone. Notably, in combination with carbamazepine, both AFC-5128 and JNJ-47965567 increased the threshold in the maximal electroshock seizure test. In the PTZ-kindling model in rats, useful for testing antiepileptogenic activities, Brilliant Blue G and tanshinone exhibited a moderate retarding effect, whereas the potent P2X7R blocker AFC-5128 and JNJ-47965567 showed a significant and long-lasting delay in kindling development. In fully kindled rats, the investigated compounds revealed modest effects to reduce the mean seizure stage. Furthermore, AFC-5128- and JNJ-47965567-treated animals displayed strongly reduced Iba 1 and GFAP immunoreactivity in the hippocampal CA3 region. In summary, our results show that P2X7R antagonists possess no remarkable anticonvulsant effects in the used acute screening tests, but can attenuate chemically-induced kindling. Further studies would be of interest to support the concept that P2X7R signalling plays a crucial role in the pathogenesis of epileptic disorders. PMID:27281030

  15. Point Mutation in the Mouse P2X7 Receptor Affects Intercellular Calcium Waves in Astrocytes

    Directory of Open Access Journals (Sweden)

    Sylvia O Suadicani

    2009-03-01

    Full Text Available Purinergic P2 receptors and gap junctions are two groups of proteins involved in the transmission of ICWs (intercellular calcium waves between astrocytes. The extent to which ICWs spread among these glial cells depends on the amount of ATP released, which can occur through membrane channels, as well as other pathways. Our previous studies have shown that the pore-forming P2X7R (P2X7 receptor contributes to the amplification of ICW spread by providing sites of ATP release through Panx1 (Pannexin1 channels. To gain insight into the signal transduction events mediating this response we compared the properties of the P2X7R–Panx1 complex in astrocytes from a mouse strain (C57Bl/6 containing a naturally occurring point mutation (P451L in the C-terminus of the P2X7R to that of non-mutated receptors (Balb/C mice. Electrophysiological, biochemical, pharmacological and fluorescence imaging techniques revealed that the P451L mutation located in the SH3 domain (a Src tyrosine kinase-binding site of the C-terminus of the P2X7R attenuates Panx1 currents, ATP release and the distance of ICW spread between astrocytes. Similar results were obtained when using the Src tyrosine inhibitor (PP2 and a membrane-permeant peptide spanning the P451L mutation of the P2X7R of the C57Bl6 astrocytes. These results support the participation of a tyrosine kinase of the Src family in the initial steps mediating the opening of Panx1 channels following P2X7R stimulation and in the transmission of calcium signals among astrocytes.

  16. Role of P2X7R in the development and progression of pulmonary hypertension.

    Science.gov (United States)

    Yin, Jie; You, Shuling; Liu, Haopeng; Chen, Li; Zhang, Chengdong; Hu, Hesheng; Xue, Mei; Cheng, Wenjuan; Wang, Ye; Li, Xinran; Shi, Yugen; Li, Nannan; Yan, Suhua; Li, Xiaolu

    2017-06-24

    Pulmonary arterial hypertension (PAH) is a devastating disease that lacks sufficient treatment. Studies have shown that the Nod-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome contributes to PAH pathogenesis, but the role of the upstream molecular P2X 7 receptor (P2X 7 R) has remained unexplored. We investigated the role of P2X7R in the pathogenesis of PAH. PH was induced by a single subcutaneous injection of monocrotaline (MCT) (60 mg/kg) on left pneumonectomised Sprague-Dawley rats, as validated by significant increases in pulmonary artery pressure and vessel wall thickness. Marked P2X 7 R was detected by predominant PA immunostaining in lungs from PH rats. Western blot revealed a significant increase in the protein levels of P2X 7 R as well as NLRP3 and caspase-1 in the diseased lung tissue compared with normal tissue. The rats received A-740003 (a selective P2X 7 receptor antagonist, 30 mg/kg) daily starting from 1 week before or 2 weeks after MCT injection. Consequently, A-740003 reversed the NLRP3 inflammasome upregulation, significantly decreased the mean right ventricular (RV) pressure and RV hypertrophy, and reversed pulmonary arterial remodelling 4 weeks after MCT injection, as both a pretreatment and rescue intervention. Notably, A-740003 significantly reduced macrophage and pro-inflammatory cytokine levels, as measured via bronchoalveolar lavage. The recruitment of macrophages as well as collagen fibre deposition in the perivascular areas were also reduced, as confirmed by histological staining. P2X 7 R contributes to the pathogenesis of PH, probably in association with activation of the NLRP3 inflammasome. Blockade of P2X7R might be applied as a novel therapeutic approach for the treatment of PAH.

  17. Critical Evaluation of P2X7 Receptor Antagonists in Selected Seizure Models.

    Directory of Open Access Journals (Sweden)

    Wolfgang Fischer

    Full Text Available The ATP-gated P2X7 receptor (P2X7R is a non-selective cation channel which senses high extracellular ATP concentrations and has been suggested as a target for the treatment of neuroinflammation and neurodegenerative diseases. The use of P2X7R antagonists may therefore be a viable approach for treating CNS pathologies, including epileptic disorders. Recent studies showed anticonvulsant potential of P2X7R antagonists in certain animal models. To extend this work, we tested three CNS-permeable P2X7R blocker (Brilliant Blue G, AFC-5128, JNJ-47965567 and a natural compound derivative (tanshinone IIA sulfonate in four well-characterized animal seizure models. In the maximal electroshock seizure threshold test and the pentylenetetrazol (PTZ seizure threshold test in mice, none of the four compounds demonstrated anticonvulsant effects when given alone. Notably, in combination with carbamazepine, both AFC-5128 and JNJ-47965567 increased the threshold in the maximal electroshock seizure test. In the PTZ-kindling model in rats, useful for testing antiepileptogenic activities, Brilliant Blue G and tanshinone exhibited a moderate retarding effect, whereas the potent P2X7R blocker AFC-5128 and JNJ-47965567 showed a significant and long-lasting delay in kindling development. In fully kindled rats, the investigated compounds revealed modest effects to reduce the mean seizure stage. Furthermore, AFC-5128- and JNJ-47965567-treated animals displayed strongly reduced Iba 1 and GFAP immunoreactivity in the hippocampal CA3 region. In summary, our results show that P2X7R antagonists possess no remarkable anticonvulsant effects in the used acute screening tests, but can attenuate chemically-induced kindling. Further studies would be of interest to support the concept that P2X7R signalling plays a crucial role in the pathogenesis of epileptic disorders.

  18. FoxP2 expression in avian vocal learners and non-learners.

    Science.gov (United States)

    Haesler, Sebastian; Wada, Kazuhiro; Nshdejan, A; Morrisey, Edward E; Lints, Thierry; Jarvis, Eric D; Scharff, Constance

    2004-03-31

    Most vertebrates communicate acoustically, but few, among them humans, dolphins and whales, bats, and three orders of birds, learn this trait. FOXP2 is the first gene linked to human speech and has been the target of positive selection during recent primate evolution. To test whether the expression pattern of FOXP2 is consistent with a role in learned vocal communication, we cloned zebra finch FoxP2 and its close relative FoxP1 and compared mRNA and protein distribution in developing and adult brains of a variety of avian vocal learners and non-learners, and a crocodile. We found that the protein sequence of zebra finch FoxP2 is 98% identical with mouse and human FOXP2. In the avian and crocodilian forebrain, FoxP2 was expressed predominantly in the striatum, a basal ganglia brain region affected in patients with FOXP2 mutations. Strikingly, in zebra finches, the striatal nucleus Area X, necessary for vocal learning, expressed more FoxP2 than the surrounding tissue at post-hatch days 35 and 50, when vocal learning occurs. In adult canaries, FoxP2 expression in Area X differed seasonally; more FoxP2 expression was associated with times when song becomes unstable. In adult chickadees, strawberry finches, song sparrows, and Bengalese finches, Area X expressed FoxP2 to different degrees. Non-telencephalic regions in both vocal learning and non-learning birds, and in crocodiles, were less variable in expression and comparable with regions that express FOXP2 in human and rodent brains. We conclude that differential expression of FoxP2 in avian vocal learners might be associated with vocal plasticity.

  19. PON-P2: prediction method for fast and reliable identification of harmful variants.

    Directory of Open Access Journals (Sweden)

    Abhishek Niroula

    Full Text Available More reliable and faster prediction methods are needed to interpret enormous amounts of data generated by sequencing and genome projects. We have developed a new computational tool, PON-P2, for classification of amino acid substitutions in human proteins. The method is a machine learning-based classifier and groups the variants into pathogenic, neutral and unknown classes, on the basis of random forest probability score. PON-P2 is trained using pathogenic and neutral variants obtained from VariBench, a database for benchmark variation datasets. PON-P2 utilizes information about evolutionary conservation of sequences, physical and biochemical properties of amino acids, GO annotations and if available, functional annotations of variation sites. Extensive feature selection was performed to identify 8 informative features among altogether 622 features. PON-P2 consistently showed superior performance in comparison to existing state-of-the-art tools. In 10-fold cross-validation test, its accuracy and MCC are 0.90 and 0.80, respectively, and in the independent test, they are 0.86 and 0.71, respectively. The coverage of PON-P2 is 61.7% in the 10-fold cross-validation and 62.1% in the test dataset. PON-P2 is a powerful tool for screening harmful variants and for ranking and prioritizing experimental characterization. It is very fast making it capable of analyzing large variant datasets. PON-P2 is freely available at http://structure.bmc.lu.se/PON-P2/.

  20. High-pressure and high-temperature powder diffraction on molybdenum diphosphide, MoP2

    International Nuclear Information System (INIS)

    Soto, V.; Knorr, K.; Ehm, L.; Baehtz, C.; Winkler, B.; Avalos-Borja, M.

    2004-01-01

    The isothermal compressibility and bulk thermal expansion of molybdenum diphosphide, MoP 2 , were measured by in-situ X-ray powder diffraction from ambient conditions to 6.8 GPa and 839 K, respectively. A small anisotropy of the compressibilities in MoP 2 appears to be governed by non-bonding interactions in this layer-like material. The thermal expansion data are compared to molybdenum phosphide, MoP, which was measured to 1262 K. (orig.)

  1. Expression and characterization of natural-like recombinant Der p 2 for sublingual immunotherapy.

    Science.gov (United States)

    Bordas-Le Floch, Véronique; Bussières, Laetitia; Airouche, Sabi; Lautrette, Aurélie; Bouley, Julien; Berjont, Nathalie; Horiot, Stéphane; Huet, Axelle; Jain, Karine; Lemoine, Pierrick; Chabre, Henri; Batard, Thierry; Mascarell, Laurent; Baron-Bodo, Véronique; Tourdot, Sophie; Nony, Emmanuel; Moingeon, Philippe

    2012-01-01

    Recombinant allergens with a native conformation represent an alternative to natural extracts for immunotherapy and diagnostic purposes. We produced the Der p 2 mite allergen in Pichia pastoris and Escherichia coli. After purification by cation exchange chromatography, recombinant molecules were compared to their natural counterpart based upon structural (disulfide bonds, secondary structure, thermal stability) and immunological properties (antibody reactivity, basophil and T cell activation, tolerance induction in a murine sublingual immunotherapy model). The Der p 2.0101 isoform was confirmed to be prevalent in Dermatophagoides pteronyssinus extracts. It was then produced as a secreted molecule in P. pastoris or refolded from E. coli inclusion bodies. The yeast-expressed rDer p 2 molecule exhibits a natural-like disulfide bridge distribution and secondary structure, whereas the E. coli-derived rDer p 2 presents some heterogeneity in cysteine bonds and a lower stability following thermal stress. The two recombinant as well as natural Der p 2 molecules exhibit comparable IgE recognition and activate basophil and CD4+ T cells. Sublingual immunotherapy of nDer p 2- sensitized mice using either one of the rDer p 2 molecules efficiently decreases airway hyperresponsiveness as well as Th2 responses. Natural and recombinant Der p 2 molecules produced in P. pastoris and E. coli exhibit comparable immunological properties despite distinct structural features. Natural-like cysteine pairing is a critical parameter to identify stable, well-folded and homogenous proteins appropriate for immunotherapy and diagnostic purposes. Copyright © 2012 S. Karger AG, Basel.

  2. 36 CFR 223.13 - Compliance.

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    2010-07-01

    ... 36 Parks, Forests, and Public Property 2 2010-07-01 2010-07-01 false Compliance. 223.13 Section... OF NATIONAL FOREST SYSTEM TIMBER General Provisions § 223.13 Compliance. Forest officers authorizing free use shall ensure that such use is in compliance with applicable land management plans and is...

  3. 44 CFR 206.402 - Compliance.

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    ... 44 Emergency Management and Assistance 1 2010-10-01 2010-10-01 false Compliance. 206.402 Section... HOMELAND SECURITY DISASTER ASSISTANCE FEDERAL DISASTER ASSISTANCE Minimum Standards § 206.402 Compliance. A... compliance with this subpart following the completion of any repair or construction activities. ...

  4. 5 CFR 2424.41 - Compliance.

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    ... 5 Administrative Personnel 3 2010-01-01 2010-01-01 false Compliance. 2424.41 Section 2424.41... FEDERAL LABOR RELATIONS AUTHORITY NEGOTIABILITY PROCEEDINGS Decision and Order § 2424.41 Compliance. The... compliance with its order, including enforcement under 5 U.S.C. 7123(b). ...

  5. 7 CFR 993.518 - Compliance.

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    ... 7 Agriculture 8 2010-01-01 2010-01-01 false Compliance. 993.518 Section 993.518 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements... Pack Specification as to Size Compliance § 993.518 Compliance. Whenever the season average price to...

  6. 7 CFR 959.81 - Compliance.

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  7. 40 CFR 97.54 - Compliance.

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    2010-07-01

    ... 40 Protection of Environment 20 2010-07-01 2010-07-01 false Compliance. 97.54 Section 97.54... Compliance. (a) NOX allowance transfer deadline. The NOX allowances are available to be deducted for compliance with a unit's NOX Budget emissions limitation for a control period in a given year only if the NOX...

  8. 7 CFR 15.5 - Compliance.

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    ... 7 Agriculture 1 2010-01-01 2010-01-01 false Compliance. 15.5 Section 15.5 Agriculture Office of... Department of Agriculture-Effectuation of Title VI of the Civil Rights Act of 1964 § 15.5 Compliance. (a... recipients in obtaining compliance with the regulations and this part and shall provide assistance and...

  9. 45 CFR 1356.85 - Compliance.

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    ... 45 Public Welfare 4 2010-10-01 2010-10-01 false Compliance. 1356.85 Section 1356.85 Public Welfare....85 Compliance. (a) File submission standards. A State agency must submit a data file in accordance... compliance. (1) ACF will determine whether a State agency's data file for each reporting period is in...

  10. 7 CFR 16.5 - Compliance.

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  11. 7 CFR 945.70 - Compliance.

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    2010-01-01

    ... 7 Agriculture 8 2010-01-01 2010-01-01 false Compliance. 945.70 Section 945.70 Agriculture... DESIGNATED COUNTIES IN IDAHO, AND MALHEUR COUNTY, OREGON Order Regulating Handling Compliance § 945.70 Compliance. Except as provided in this part, no handler shall ship potatoes, the shipment of which has been...

  12. 49 CFR 663.15 - Compliance.

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  13. 33 CFR 104.115 - Compliance.

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  14. 24 CFR 200.635 - Compliance.

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  15. 14 CFR 25.1207 - Compliance.

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    2010-01-01

    ... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Compliance. 25.1207 Section 25.1207... STANDARDS: TRANSPORT CATEGORY AIRPLANES Powerplant Powerplant Fire Protection § 25.1207 Compliance. Unless otherwise specified, compliance with the requirements of §§ 25.1181 through 25.1203 must be shown by a full...

  16. 10 CFR 851.13 - Compliance.

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    2010-01-01

    ... 10 Energy 4 2010-01-01 2010-01-01 false Compliance. 851.13 Section 851.13 Energy DEPARTMENT OF ENERGY WORKER SAFETY AND HEALTH PROGRAM Program Requirements § 851.13 Compliance. (a) Contractors must achieve compliance with all the requirements of Subpart C of this part, and their approved worker safety...

  17. 7 CFR 772.3 - Compliance.

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  18. 40 CFR 129.5 - Compliance.

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    ... 40 Protection of Environment 21 2010-07-01 2010-07-01 false Compliance. 129.5 Section 129.5... STANDARDS Toxic Pollutant Effluent Standards and Prohibitions § 129.5 Compliance. (a)(1) Within 60 days from... standard established for any particular pollutant. (d)(1) Upon the compliance date for any section 307(a...

  19. 14 CFR 417.203 - Compliance.

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  20. 40 CFR 73.35 - Compliance.

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  1. 31 CFR 208.9 - Compliance.

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  2. 5 CFR 900.604 - Compliance.

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  3. 40 CFR 1507.1 - Compliance.

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    ... 40 Protection of Environment 32 2010-07-01 2010-07-01 false Compliance. 1507.1 Section 1507.1 Protection of Environment COUNCIL ON ENVIRONMENTAL QUALITY AGENCY COMPLIANCE § 1507.1 Compliance. All agencies of the Federal Government shall comply with these regulations. It is the intent of these...

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  5. 14 CFR 417.402 - Compliance.

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    2010-01-01

    ... 14 Aeronautics and Space 4 2010-01-01 2010-01-01 false Compliance. 417.402 Section 417.402... TRANSPORTATION LICENSING LAUNCH SAFETY Ground Safety § 417.402 Compliance. (a) General. A launch operator's... of compliance to the FAA if: (1) A launch operator has contracted with a Federal launch range for the...

  6. 40 CFR 96.54 - Compliance.

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    2010-07-01

    ... 40 Protection of Environment 20 2010-07-01 2010-07-01 false Compliance. 96.54 Section 96.54... Tracking System § 96.54 Compliance. (a) NO X allowance transfer deadline. The NOX allowances are available to be deducted for compliance with a unit's NOX Budget emissions limitation for a control period in a...

  7. 40 CFR 720.120 - Compliance.

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  8. 7 CFR 948.81 - Compliance.

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  9. 10 CFR 434.509 - Compliance.

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  10. 10 CFR 2.1012 - Compliance.

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  11. 22 CFR 209.6 - Compliance information.

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  12. 38 CFR 18.6 - Compliance information.

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  13. Tax compliance depends on voice of taxpayers

    NARCIS (Netherlands)

    Casal, Sandro; Kogler, C.; Mittone, Luigi; Kirchler, Erich

    2016-01-01

    Reducing the social distance between taxpayers and tax authorities boosts taxpayers' acceptance of tax load and tax compliance. In the present experiment participants had the opportunity to pay their tax due either as one single compliance decision or as separate compliance decisions for each type

  14. 42 CFR 124.503 - Compliance level.

    Science.gov (United States)

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false Compliance level. 124.503 Section 124.503 Public... Unable To Pay § 124.503 Compliance level. (a) Annual compliance level. Subject to the provisions of this... persons unable to pay if it provides for the fiscal year uncompensated services at a level not less than...

  15. 30 CFR 843.20 - Compliance conference.

    Science.gov (United States)

    2010-07-01

    ... 30 Mineral Resources 3 2010-07-01 2010-07-01 false Compliance conference. 843.20 Section 843.20... PERMANENT PROGRAM INSPECTION AND ENFORCEMENT PROCEDURES FEDERAL ENFORCEMENT § 843.20 Compliance conference. (a) A permittee may request an on-site compliance conference with an authorized representative to...

  16. Data transport and management in P2P Data Management in Mobile Wireless Sensor Network

    International Nuclear Information System (INIS)

    Sahar, S.; Shaikh, F.K.

    2013-01-01

    The rapid growth in wireless technologies has made wireless communication an important source for transporting data across different domains. In the same way, there are possibilities of many potential applications that can be deployed using WSNs (Wireless Sensor Networks). However, very limited applications are deployed in real life due to the uncertainty and dynamics of the environment and scare resources. This makes data management in WSN a challenging area to find an approach that suits its characteristics. Currently, the trend is to find efficient data management schemes using evolving technologies, i.e. P2P (Peer-to-Peer) systems. Many P2P approaches have been applied in WSNs to carry out the data management due to similarities between WSN and P2P. With the similarities, there are differences too that makes P2P protocols inefficient in WSNs. Furthermore, to increase the efficiency and to exploit the delay tolerant nature of WSNs, where ever possible, the mobile WSNs are gaining importance. Thus, creating a three dimensional problem space to consider, i.e. mobility, WSNs and P2P. In this paper, an efficient algorithm is proposed for data management using P2P techniques for mobile WSNs. The real world implementation and deployment of proposed algorithm is also presented. (author)

  17. P2X7 receptor-deficient mice are susceptible to bone cancer pain

    DEFF Research Database (Denmark)

    Hansen, Rikke Rie; Nielsen, Christian K.; Nasser, Arafat

    2011-01-01

    The purinergic P2X7 receptor is implicated in both neuropathic and inflammatory pain, and has been suggested as a possible target in pain treatment. However, the specific role of the P2X7 receptor in bone cancer pain is unknown. We demonstrated that BALB/cJ P2X7 receptor knockout (P2X7R KO) mice...... were susceptible to bone cancer pain and moreover had an earlier onset of pain-related behaviours compared with cancer-bearing, wild-type mice. Furthermore, acute treatment with the selective P2X7 receptor antagonist, A-438079, failed to alleviate pain-related behaviours in models of bone cancer pain...... with and without astrocyte activation (BALB/cJ or C3H mice inoculated with 4T1 mammary cancer cells or NCTC 2472 osteosarcoma cells, respectively), suggesting that astrocytic P2X7 receptors play a negligible role in bone cancer pain. The results support the hypothesis that bone cancer pain is a separate pain state...

  18. Extracellular ATP in the lymphohematopoietic system: P2Z purinoceptors and membrane permeabilization

    Directory of Open Access Journals (Sweden)

    Persechini P.M.

    1998-01-01

    Full Text Available The effects of extracellular nucleosides and nucleotides on many organs and systems have been recognized for almost 50 years. The effects of extracellular ATP (ATPo, UTPo, ADPo, and other agonists are mediated by P2 purinoceptors. One of the most dramatic effects of ATPo is the permeabilization of plasma membranes to low molecular mass solutes of up to 900 Da. This effect is evident in several cells of the lymphohematopoietic system and is supposed to be mediated by P2Z, an ATP4--activated purinoceptor. Here, we review some basic information concerning P2 purinoceptors and focus our attention on P2Z-associated phenomena displayed by macrophages. Using fluorescent dye uptake, measurement of free intracellular Ca2+ concentration and electrophysiological recordings, we elucidate some of the events that follow the application of ATP to the extracellular surface of macrophages. We propose a regulatory mechanism for the P2Z-associated permeabilization pore. The presence of P2 purinoceptors in cells of the lymphohematopoietic system makes them potential candidates to mediate immunoregulatory events

  19. Decentralized Scheduling Algorithm for DAG Based Tasks on P2P Grid

    Directory of Open Access Journals (Sweden)

    Piyush Chauhan

    2014-01-01

    Full Text Available Complex problems consisting of interdependent subtasks are represented by a direct acyclic graph (DAG. Subtasks of this DAG are scheduled by the scheduler on various grid resources. Scheduling algorithms for grid strive to optimize the schedule. Nowadays a lot of grid resources are attached by P2P approach. Grid systems and P2P model both are newfangled distributed computing approaches. Combining P2P model and grid systems we get P2P grid systems. P2P grid systems require fully decentralized scheduling algorithm, which can schedule interreliant subtasks among nonuniform computational resources. Absence of central scheduler caused the need for decentralized scheduling algorithm. In this paper we have proposed scheduling algorithm which not only is fruitful in optimizing schedule but also does so in fully decentralized fashion. Hence, this unconventional approach suits well for P2P grid systems. Moreover, this algorithm takes accurate scheduling decisions depending on both computation cost and communication cost associated with DAG’s subtasks.

  20. Music training enhances rapid plasticity of N1 and P2 source activation for unattended sounds

    Directory of Open Access Journals (Sweden)

    Miia eSeppänen

    2012-03-01

    Full Text Available Neurocognitive studies demonstrate that long-term musical training enhances the processing of unattended sounds. It is not clear, however, whether musical training modulates also rapid (within tens of minutes neural plasticity for sound encoding. To study this, we examined whether adult musicians display enhanced rapid neural plasticity when compared to nonmusicians. More specifically, we examined the modulation of P1, N1, and P2 responses to regular standard sounds in an oddball paradigm between unattended passive blocks which were separated by an active task. Source analysis for event-related potentials showed that N1 and P2 source activation decreased selectively in musicians already after fifteen minutes of passive exposure to sounds and that P2 source activation re-enhanced after the active task in musicians. Additionally, event-related potential (ERP analysis revealed that in both musicians and nonmusicians, P2 ERP amplitude enhanced after fifteen minutes of passive exposure but only at frontal electrodes. Furthermore, in musicians, N1 ERP enhanced after the active discrimination task but only at parietal electrodes. Musical training modulates the rapid plasticity reflected in N1 and P2 source activation for unattended regular standard sounds. Enhanced rapid plasticity of N1 and P2 might reflect the faster auditory perceptual learning in musicians when compared to nonmusicians.

  1. P2X7 receptor activation regulates rapid unconventional export of transglutaminase-2

    Science.gov (United States)

    Adamczyk, Magdalena; Griffiths, Rhiannon; Dewitt, Sharon; Knäuper, Vera; Aeschlimann, Daniel

    2015-01-01

    ABSTRACT Transglutaminases (denoted TG or TGM) are externalized from cells via an unknown unconventional secretory pathway. Here, we show for the first time that purinergic signaling regulates active secretion of TG2 (also known as TGM2), an enzyme with a pivotal role in stabilizing extracellular matrices and modulating cell–matrix interactions in tissue repair. Extracellular ATP promotes TG2 secretion by macrophages, and this can be blocked by a selective antagonist against the purinergic receptor P2X7 (P2X7R, also known as P2RX7). Introduction of functional P2X7R into HEK293 cells is sufficient to confer rapid, regulated TG2 export. By employing pharmacological agents, TG2 release could be separated from P2X7R-mediated microvesicle shedding. Neither Ca2+ signaling alone nor membrane depolarization triggered TG2 secretion, which occurred only upon receptor membrane pore formation and without pannexin channel involvement. A gain-of-function mutation in P2X7R associated with autoimmune disease caused enhanced TG2 externalization from cells, and this correlated with increased pore activity. These results provide a mechanistic explanation for a link between active TG2 secretion and inflammatory responses, and aberrant enhanced TG2 activity in certain autoimmune conditions. PMID:26542019

  2. Role of P2X7 Receptor in Pancreatic Cancer Progression

    DEFF Research Database (Denmark)

    Giannuzzo, Andrea

    in the extracellular compartment. Among all the purinergic receptors, P2X7 receptor (P2X7R), with its peculiar double-faced role in both cell death and cell proliferation, has been shown to be involved in the progression of some types of cancer. Thus, the aim of our study was to investigate the possible role of P2X7R...... in PDAC behaviour in vitro and in vivo. We detected a higher P2X7R protein level in several human PDAC cells compared to a “normal” human pancreatic duct epithelial cell line, which localized mostly on the plasma membrane. From the functional point of view, we observed that a sustained activation of the P......2X7 receptor using ATP and BzATP (a more potent agonist) resulted in a cytotoxic effect, mainly ascribed to necrosis. The allosteric inhibition of the receptor led to a drastic reduction in cell proliferation in all PDAC cell lines. Moreover, P2X7R showed a crucial role in PDAC cell migration...

  3. Monitoring and Resource Management in P2P Grid-Based Web Services

    Directory of Open Access Journals (Sweden)

    Djafri Laouni

    2012-12-01

    Full Text Available Grid computing has recently emerged as a response to the growing demand for resources (processing power, storage, etc. exhibited by scientific applications. However, as grid sizes increase, the need for self-organization and dynamic reconfigurations is becoming more and more important. Since such properties are exhibited by P2P systems, the convergence of grid computing and P2P computing seems natural. However, using P2P systems (usually running on the Internet on a grid infrastructure (generally available as a federation of SAN-based clusters interconnected by high-bandwidth WANs may raise the issue of the adequacy of the P2P communication mechanisms. Among the interesting properties of P2P systems is the  volatility of  peers  which  causes  the  need  for  integration  of  a  service fault tolerance. And service Load balancing,   As a solution, we proposed a mechanism of fault tolerance and model of Load balancing  adapted to a grid P2P model, named SGRTE (Monitoring and Resource Management, Fault Tolerances and Load Balancing.

  4. Blockade of ATP P2X7 receptor enhances ischiatic nerve regeneration in mice following a crush injury.

    Science.gov (United States)

    Ribeiro, Tatianne; Oliveira, Júlia Teixeira; Almeida, Fernanda Martins; Tomaz, Marcelo Amorim; Melo, Paulo A; Marques, Suelen Adriani; de Andrade, Geanne Matos; Martinez, Ana Maria Blanco

    2017-08-15

    Preventing damage caused by nerve degeneration is a great challenge. There is a growing body of evidence implicating extracellular nucleotides and their P2 receptors in many pathophysiological mechanisms. In this work we aimed to investigate the effects of the administration of Brilliant Blue G (BBG) and Pyridoxalphosphate-6-azophenyl-2', 4'- disulphonic acid (PPADS), P2X7 and P2 non-selective receptor antagonists, respectively, on sciatic nerve regeneration. Four groups of mice that underwent nerve crush lesion were used: two control groups treated with vehicle (saline), a group treated with BBG and a group treated with PPADS during 28days. Gastrocnemius muscle weight was evaluated. For functional evaluation we used the Sciatic Functional Index (SFI) and the horizontal ladder walking test. Nerves, dorsal root ganglia and spinal cords were processed for light and electron microscopy. Antinoceptive effects of BBG and PPADS were evaluated through von Frey E, and the levels of IL-1β and TNF-α were analyzed by ELISA. BBG promoted an increase in the number of myelinated fibers and on axon, fiber and myelin areas. BBG and PPADS led to an increase of TNF-α and IL-1β in the nerve on day 1 and PPADS caused a decrease of IL-1β on day 7. Mechanical allodynia was reversed on day 7 in the groups treated with BBG and PPADS. We concluded that BBG promoted a better morphological regeneration after ischiatic crush injury, but this was not followed by anticipation of functional improvement. In addition, both PPADS and BBG presented anti-inflammatory as well as antinociceptive effects. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. 3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) disrupts blood-brain barrier integrity through a mechanism involving P2X7 receptors.

    Science.gov (United States)

    Rubio-Araiz, Ana; Perez-Hernandez, Mercedes; Urrutia, Andrés; Porcu, Francesca; Borcel, Erika; Gutierrez-Lopez, Maria Dolores; O'Shea, Esther; Colado, Maria Isabel

    2014-08-01

    The recreational drug 3,4-methylenedioxymethamphetamine (MDMA; 'ecstasy') produces a neuro-inflammatory response in rats characterized by an increase in microglial activation and IL-1β levels. The integrity of the blood-brain barrier (BBB) is important in preserving the homeostasis of the brain and has been shown to be affected by neuro-inflammatory processes. We aimed to study the effect of a single dose of MDMA on the activity of metalloproteinases (MMPs), expression of extracellular matrix proteins, BBB leakage and the role of the ionotropic purinergic receptor P2X7 (P2X7R) in the changes induced by the drug. Adult male Dark Agouti rats were treated with MDMA (10 mg/kg, i.p.) and killed at several time-points in order to evaluate MMP-9 and MMP-3 activity in the hippocampus and laminin and collagen-IV expression and IgG extravasation in the dentate gyrus. Microglial activation, P2X7R expression and localization were also determined in the dentate gyrus. Separate groups were treated with MDMA and the P2X7R antagonists Brilliant Blue G (BBG; 50 mg/kg, i.p.) or A-438079 (30 mg/kg, i.p.). MDMA increased MMP-3 and MMP-9 activity, reduced laminin and collagen-IV expression and increased IgG immunoreactivity. In addition, MDMA increased microglial activation and P2X7R immunoreactivity in these cells. BBG suppressed the increase in MMP-9 and MMP-3 activity, prevented basal lamina degradation and IgG extravasation into the brain parenchyma. A-438079 also prevented the MDMA-induced reduction in laminin and collagen-IV immunoreactivity. These results indicate that MDMA alters BBB permeability through an early P2X7R-mediated event, which in turn leads to enhancement of MMP-9 and MMP-3 activity and degradation of extracellular matrix.

  6. P2P-based botnets: structural analysis, monitoring, and mitigation

    Energy Technology Data Exchange (ETDEWEB)

    Yan, Guanhua [Los Alamos National Laboratory; Eidenbenz, Stephan [Los Alamos National Laboratory; Ha, Duc T [UNIV AT BUFFALO; Ngo, Hung Q [UNIV AT BUFFALO

    2008-01-01

    Botnets, which are networks of compromised machines that are controlled by one or a group of attackers, have emerged as one of the most serious security threats on the Internet. With an army of bots at the scale of tens of thousands of hosts or even as large as 1.5 million PCs, the computational power of botnets can be leveraged to launch large-scale DDoS (Distributed Denial of Service) attacks, sending spamming emails, stealing identities and financial information, etc. As detection and mitigation techniques against botnets have been stepped up in recent years, attackers are also constantly improving their strategies to operate these botnets. The first generation of botnets typically employ IRC (Internet Relay Chat) channels as their command and control (C&C) centers. Though simple and easy to deploy, the centralized C&C mechanism of such botnets has made them prone to being detected and disabled. Against this backdrop, peer-to-peer (P2P) based botnets have emerged as a new generation of botnets which can conceal their C&C communication. Recently, P2P networks have emerged as a covert communication platform for malicious programs known as bots. As popular distributed systems, they allow bots to communicate easily while protecting the botmaster from being discovered. Existing work on P2P-based hotnets mainly focuses on measurement of botnet sizes. In this work, through simulation, we study extensively the structure of P2P networks running Kademlia, one of a few widely used P2P protocols in practice. Our simulation testbed incorporates the actual code of a real Kademlia client software to achieve great realism, and distributed event-driven simulation techniques to achieve high scalability. Using this testbed, we analyze the scaling, reachability, clustering, and centrality properties of P2P-based botnets from a graph-theoretical perspective. We further demonstrate experimentally and theoretically that monitoring bot activities in a P2P network is difficult

  7. Activation of P2X7-mediated apoptosis Inhibits DMBA/TPA-induced formation of skin papillomas and cancer in mice

    International Nuclear Information System (INIS)

    Fu, Wen; Gorodeski, George I; McCormick, Tom; Qi, Xiaoping; Luo, Liping; Zhou, Lingyin; Li, Xin; Wang, Bing-Cheng; Gibbons, Heidi E; Abdul-Karim, Fadi W

    2009-01-01

    The study tested the hypothesis that apoptosis can prevent and control growth of neoplastic cells. Previous studies in-vitro have shown that the pro-apoptotic P2X 7 receptor regulates growth of epithelial cells. The specific objective of the present study was to understand to what degree the P2X 7 system controls development and growth of skin cancer in vivo, and what cellular and molecular mechanisms are involved in the P2X 7 action. Skin neoplasias in mice (papillomas, followed by squamous spindle-cell carcinomas) were induced by local application of DMBA/TPA. Experiments in-vitro utilized cultured epidermal keratinocytes generated from wild-type or from P2X 7 -null mice. Assays involved protein immunostaining and Western blots; mRNA real-time qPCR; and apoptosis (evaluated in situ by TUNEL and quantified in cultured keratinocytes as solubilized DNA or by ELISA). Changes in cytosolic calcium or in ethidium bromide influx (P2X 7 pore formation) were determined by confocal laser microscopy. (a) Co-application on the skin of the P2X 7 specific agonist BzATP inhibited formation of DMBA/TPA-induced skin papillomas and carcinomas. At the completion of study (week 28) the proportion of living animals with cancers in the DMBA/TPA group was 100% compared to 43% in the DMBA/TPA+BzATP group. (b) In the normal skin BzATP affected mainly P2X 7 -receptor – expressing proliferating keratinocytes, where it augmented apoptosis without evoking inflammatory changes. (c) In BzATP-treated mice the degree of apoptosis was lesser in cancer than in normal or papilloma keratinocytes. (d) Levels of P2X 7 receptor, protein and mRNA were 4–5 fold lower in cancer tissues than in normal mouse tissues. (e) In cultured mouse keratinocytes BzATP induced apoptosis, formation of pores in the plasma membrane, and facilitated prolonged calcium influx. (f) The BzATP-induced apoptosis, pore-formation and augmented calcium influx had similar dose-dependence for BzATP. (g) Pore formation and the

  8. Activation of P2X7-mediated apoptosis Inhibits DMBA/TPA-induced formation of skin papillomas and cancer in mice

    Directory of Open Access Journals (Sweden)

    Fu Wen

    2009-04-01

    Full Text Available Abstract Background The study tested the hypothesis that apoptosis can prevent and control growth of neoplastic cells. Previous studies in-vitro have shown that the pro-apoptotic P2X7 receptor regulates growth of epithelial cells. The specific objective of the present study was to understand to what degree the P2X7 system controls development and growth of skin cancer in vivo, and what cellular and molecular mechanisms are involved in the P2X7 action. Methods Skin neoplasias in mice (papillomas, followed by squamous spindle-cell carcinomas were induced by local application of DMBA/TPA. Experiments in-vitro utilized cultured epidermal keratinocytes generated from wild-type or from P2X7-null mice. Assays involved protein immunostaining and Western blots; mRNA real-time qPCR; and apoptosis (evaluated in situ by TUNEL and quantified in cultured keratinocytes as solubilized DNA or by ELISA. Changes in cytosolic calcium or in ethidium bromide influx (P2X7 pore formation were determined by confocal laser microscopy. Results (a Co-application on the skin of the P2X7 specific agonist BzATP inhibited formation of DMBA/TPA-induced skin papillomas and carcinomas. At the completion of study (week 28 the proportion of living animals with cancers in the DMBA/TPA group was 100% compared to 43% in the DMBA/TPA+BzATP group. (b In the normal skin BzATP affected mainly P2X7-receptor – expressing proliferating keratinocytes, where it augmented apoptosis without evoking inflammatory changes. (c In BzATP-treated mice the degree of apoptosis was lesser in cancer than in normal or papilloma keratinocytes. (d Levels of P2X7 receptor, protein and mRNA were 4–5 fold lower in cancer tissues than in normal mouse tissues. (e In cultured mouse keratinocytes BzATP induced apoptosis, formation of pores in the plasma membrane, and facilitated prolonged calcium influx. (f The BzATP-induced apoptosis, pore-formation and augmented calcium influx had similar dose-dependence for

  9. Antidepressants inhibit P2X4 receptor function: a possible involvement in neuropathic pain relief

    Directory of Open Access Journals (Sweden)

    Tozaki-Saitoh Hidetoshi

    2009-04-01

    Full Text Available Abstract Background Neuropathic pain is characterized by pain hypersensitivity to innocuous stimuli (tactile allodynia that is nearly always resistant to known treatments such as non-steroidal anti-inflammatory drugs or even opioids. It has been reported that some antidepressants are effective for treating neuropathic pain. However, the underlying molecular mechanisms are not well understood. We have recently demonstrated that blocking P2X4 receptors in the spinal cord reverses tactile allodynia after peripheral nerve injury in rats, implying that P2X4 receptors are a key molecule in neuropathic pain. We investigated a possible role of antidepressants as inhibitors of P2X4 receptors and analysed their analgesic mechanism using an animal model of neuropathic pain. Results Antidepressants strongly inhibited ATP-mediated Ca2+ responses in P2X4 receptor-expressing 1321N1 cells, which are known to have no endogenous ATP receptors. Paroxetine exhibited the most powerful inhibition of calcium influx via rat and human P2X4 receptors, with IC50 values of 2.45 μM and 1.87 μM, respectively. Intrathecal administration of paroxetine produced a striking antiallodynic effect in an animal model of neuropathic pain. Co-administration of WAY100635, ketanserin or ondansetron with paroxetine induced no significant change in the antiallodynic effect of paroxetine. Furthermore, the antiallodynic effect of paroxetine was observed even in rats that had received intrathecal pretreatment with 5,7-dihydroxytryptamine, which dramatically depletes spinal 5-hydroxytryptamine. Conclusion These results suggest that paroxetine acts as a potent analgesic in the spinal cord via a mechanism independent of its inhibitory effect on serotonin transporters. Powerful inhibition on P2X4 receptors may underlie the analgesic effect of paroxetine, and it is possible that some antidepressants clinically used in patients with neuropathic pain show antiallodynic effects, at least in part

  10. Inhibitory effect of estrogen receptor beta on P2X3 receptors during inflammation in rats.

    Science.gov (United States)

    Jiang, Qian; Li, Wen-Xin; Sun, Jia-Run; Zhu, Tian-Tian; Fan, Juan; Yu, Li-Hua; Burnstock, Geoffrey; Yang, Hua; Ma, Bei

    2017-03-01

    Estrogen receptor beta (ERβ) has been shown to play a therapeutic role in inflammatory bowel disease (IBD). However, the mechanism underlying how ERβ exerts therapeutic effects and its relationship with P2X3 receptors (P2X3R) in rats with inflammation is not known. In our study, animal behavior tests, visceromotor reflex recording, and Western blotting were used to determine whether the therapeutic effect of ERβ in rats with inflammation was related with P2X3R. In complete Freund adjuvant (CFA)-induced chronic inflammation in rats, paw withdrawal threshold was significantly decreased which were then reversed by systemic injection of ERβ agonists, DPN or ERB-041. In 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats, weight loss, higher DAI scores, increased visceromotor responses, and inflammatory responses were reversed by application of DPN or ERB-041. The higher expressions of P2X3R in dorsal root ganglia (DRG) of CFA-treated rats and those in rectocolon and DRG of TNBS-treated rats were all decreased by injection of DPN or ERB-041. DPN application also inhibited P2X3R-evoked inward currents in DRG neurons from TNBS rats. Mechanical hyperalgesia and increased P2X3 expression in ovariectomized (OVX) CFA-treated rats were reversed by estrogen replacements. Furthermore, the expressions of extracellular signal-regulated kinase (ERK) in DRG and spinal cord dorsal horn (SCDH) and c-fos in SCDH were significantly decreased after estrogen replacement compared with those of OVX rats. The ERK antagonist U0126 significantly reversed mechanical hyperalgesia in the OVX rats. These results suggest that estrogen may play an important therapeutic role in inflammation through down-regulation of P2X3R in peripheral tissues and the nervous system, probably via ERβ, suggesting a novel therapeutic strategy for clinical treatment of inflammation.

  11. Platelets Express Activated P2Y12 Receptor in Patients With Diabetes Mellitus.

    Science.gov (United States)

    Hu, Liang; Chang, Lin; Zhang, Yan; Zhai, Lili; Zhang, Shenghui; Qi, Zhiyong; Yan, Hongmei; Yan, Yan; Luo, Xinping; Zhang, Si; Wang, Yiping; Kunapuli, Satya P; Ye, Hongying; Ding, Zhongren

    2017-08-29

    Platelets from patients with diabetes mellitus are hyperactive. Hyperactivated platelets may contribute to cardiovascular complications and inadequate responses to antiplatelet agents in the setting of diabetes mellitus. However, the underlying mechanism of hyperactivated platelets is not completely understood. We measured P2Y 12 expression on platelets from patients with type 2 diabetes mellitus and on platelets from rats with diabetes mellitus. We also assayed platelet P2Y 12 activation by measuring cAMP and VASP phosphorylation. The antiplatelet and antithrombotic effects of AR-C78511 and cangrelor were compared in rats. Finally, we explored the role of the nuclear factor-κB pathway in regulating P2Y 12 receptor expression in megakaryocytes. Platelet P2Y 12 levels are 4-fold higher in patients with type 2 diabetes mellitus compared with healthy subjects. P2Y 12 expression correlates with ADP-induced platelet aggregation (r=0.89, P diabetes mellitus is constitutively activated. Although both AR-C78511, a potent P2Y 12 inverse agonist, and cangrelor have similar antiplatelet efficacy on platelets from healthy subjects, AR-C78511 exhibits more powerful antiplatelet effects on diabetic platelets than cangrelor (aggregation ratio 36±3% versus 49±5%, respectively, P diabetes mellitus than cangrelor (thrombus weight 4.9±0.3 mg versus 8.3±0.4 mg, respectively, P diabetes mellitus. Platelet P2Y 12 receptor expression is significantly increased and the receptor is constitutively activated in patients with type 2 diabetes mellitus, which contributes to platelet hyperactivity and limits antiplatelet drug efficacy in type 2 diabetes mellitus. © 2017 American Heart Association, Inc.

  12. An Improved Method for P2X7R Antagonist Screening.

    Directory of Open Access Journals (Sweden)

    Rômulo José Soares-Bezerra

    Full Text Available ATP physiologically activates the P2X7 receptor (P2X7R, a member of the P2X ionotropic receptor family. When activated by high concentrations of ATP (i.e., at inflammation sites, this receptor is capable of forming a pore that allows molecules of up to 900 Da to pass through. This receptor is upregulated in several diseases, particularly leukemia, rheumatoid arthritis and Alzheimer's disease. A selective antagonist of this receptor could be useful in the treatment of P2X7R activation-related diseases. In the present study, we have evaluated several parameters using in vitro protocols to validate a high-throughput screening (HTS method to identify P2X7R antagonists. We generated dose-response curves to determine the EC50 value of the known agonist ATP and the ICs50 values for the known antagonists Brilliant Blue G (BBG and oxidized ATP (OATP. The values obtained were consistent with those found in the literature (0.7 ± 0.07 mM, 1.3-2.6 μM and 173-285 μM for ATP, BBG and OATP, respectively [corrected].The Z-factor, an important statistical tool that can be used to validate the robustness and suitability of an HTS assay, was 0.635 for PI uptake and 0.867 for LY uptake. No inter-operator variation was observed, and the results obtained using our improved method were reproducible. Our data indicate that our assay is suitable for the selective and reliable evaluation of P2X7 activity in multiwell plates using spectrophotometry-based methodology. This method might improve the high-throughput screening of conventional chemical or natural product libraries for possible candidate P2X7R antagonist or agonist.

  13. P2X7 receptor activation induces inflammatory responses in salivary gland epithelium

    Science.gov (United States)

    Woods, Lucas T.; Camden, Jean M.; Batek, Josef M.; Petris, Michael J.; Erb, Laurie

    2012-01-01

    Inflammation of the salivary gland is a well-documented aspect of salivary gland dysfunction that occurs in Sjogren's syndrome (SS), an autoimmune disease, and in γ-radiation-induced injury during treatment of head and neck cancers. Extracellular nucleotides have gained recognition as key modulators of inflammation through activation of cell surface ionotropic and metabotropic receptors, although the contribution of extracellular nucleotides to salivary gland inflammation is not well understood. In vitro studies using submandibular gland (SMG) cell aggregates isolated from wild-type C57BL/6 mice indicate that treatment with ATP or the high affinity P2X7R agonist 3′-O-(4-benzoyl)benzoyl-ATP (BzATP) induces membrane blebbing and enhances caspase activity, responses that were absent in SMG cell aggregates isolated from mice lacking the P2X7R (P2X7R−/−). Additional studies with SMG cell aggregates indicate that activation of the P2X7R with ATP or BzATP stimulates the cleavage and release of α-fodrin, a cytoskeletal protein thought to act as an autoantigen in the development of SS. In vivo administration of BzATP to ligated SMG excretory ducts enhances immune cell infiltration into the gland and initiates apoptosis of salivary epithelial cells in wild-type, but not P2X7R−/−, mice. These findings indicate that activation of the P2X7R contributes to salivary gland inflammation in vivo, suggesting that the P2X7R may represent a novel target for the treatment of salivary gland dysfunction. PMID:22875784

  14. Involvement of P2X7 Receptor in Proliferation and Migration of Human Glioma Cells

    Directory of Open Access Journals (Sweden)

    Zhenhua Ji

    2018-01-01

    Full Text Available Previous studies have demonstrated that activation of P2X7 receptors (P2X7R results in the proliferation and migration of some types of tumor. Here, we asked whether and how the activated P2X7R contribute to proliferation and migration of human glioma cells. Results showed that the number of P2X7R positive cells was increasing with grade of tumor. In U87 and U251 human glioma cell lines, both expressed P2X7R and the expression was enhanced by 3′-O-(4-benzoylbenzoyl ATP (BzATP, the agonist of P2X7R, and siRNA. Our results also showed that 10 μM BzATP was sufficient to induce the proliferation of glioma cell significantly, while the cell proliferation reached the peak with 100 μM BzATP. Also, the migration of U87 and U251 cells was significantly increased upon BzATP treatment. However, the number of apoptotic cells of U87 and U251 was not significantly changed by BzATP. In addition, the expression of ERK, p-ERK, and proliferating cell nuclear antigen (PCNA protein was increased in BzATP-treated U87 and U251 glioma cells. PD98059, an inhibitor of the MEK/ERK pathway, blocked the increased proliferation and migration of glioma cells activated by BzATP. These results suggest that ERK pathway is involved in the proliferation and migration of glioma cells induced by P2X7R activation.

  15. Involvement of P2X7 Receptor in Proliferation and Migration of Human Glioma Cells

    Science.gov (United States)

    Ji, Zhenhua; Xie, Yuting; Guan, Yu; Zhang, Yujian; Cho, Kin-Sang

    2018-01-01

    Previous studies have demonstrated that activation of P2X7 receptors (P2X7R) results in the proliferation and migration of some types of tumor. Here, we asked whether and how the activated P2X7R contribute to proliferation and migration of human glioma cells. Results showed that the number of P2X7R positive cells was increasing with grade of tumor. In U87 and U251 human glioma cell lines, both expressed P2X7R and the expression was enhanced by 3′-O-(4-benzoylbenzoyl) ATP (BzATP), the agonist of P2X7R, and siRNA. Our results also showed that 10 μM BzATP was sufficient to induce the proliferation of glioma cell significantly, while the cell proliferation reached the peak with 100 μM BzATP. Also, the migration of U87 and U251 cells was significantly increased upon BzATP treatment. However, the number of apoptotic cells of U87 and U251 was not significantly changed by BzATP. In addition, the expression of ERK, p-ERK, and proliferating cell nuclear antigen (PCNA) protein was increased in BzATP-treated U87 and U251 glioma cells. PD98059, an inhibitor of the MEK/ERK pathway, blocked the increased proliferation and migration of glioma cells activated by BzATP. These results suggest that ERK pathway is involved in the proliferation and migration of glioma cells induced by P2X7R activation. PMID:29546069

  16. An Improved Method for P2X7R Antagonist Screening.

    Science.gov (United States)

    Soares-Bezerra, Rômulo José; Ferreira, Natiele Carla da Silva; Alberto, Anael Viana Pinto; Bonavita, André Gustavo; Fidalgo-Neto, Antônio Augusto; Calheiros, Andrea Surrage; Frutuoso, Valber da Silva; Alves, Luiz Anastacio

    2015-01-01

    ATP physiologically activates the P2X7 receptor (P2X7R), a member of the P2X ionotropic receptor family. When activated by high concentrations of ATP (i.e., at inflammation sites), this receptor is capable of forming a pore that allows molecules of up to 900 Da to pass through. This receptor is upregulated in several diseases, particularly leukemia, rheumatoid arthritis and Alzheimer's disease. A selective antagonist of this receptor could be useful in the treatment of P2X7R activation-related diseases. In the present study, we have evaluated several parameters using in vitro protocols to validate a high-throughput screening (HTS) method to identify P2X7R antagonists. We generated dose-response curves to determine the EC50 value of the known agonist ATP and the ICs50 values for the known antagonists Brilliant Blue G (BBG) and oxidized ATP (OATP). The values obtained were consistent with those found in the literature (0.7 ± 0.07 mM, 1.3-2.6 μM and 173-285 μM for ATP, BBG and OATP, respectively) [corrected].The Z-factor, an important statistical tool that can be used to validate the robustness and suitability of an HTS assay, was 0.635 for PI uptake and 0.867 for LY uptake. No inter-operator variation was observed, and the results obtained using our improved method were reproducible. Our data indicate that our assay is suitable for the selective and reliable evaluation of P2X7 activity in multiwell plates using spectrophotometry-based methodology. This method might improve the high-throughput screening of conventional chemical or natural product libraries for possible candidate P2X7R antagonist or agonist.

  17. EuCo2P2 : A model molecular-field helical Heisenberg antiferromagnet

    Science.gov (United States)

    Sangeetha, N. S.; Cuervo-Reyes, Eduardo; Pandey, Abhishek; Johnston, D. C.

    2016-07-01

    The metallic compound EuCo2P2 with the body-centered tetragonal ThCr2Si2 structure containing Eu spins-7/2 was previously shown from single-crystal neutron diffraction measurements to exhibit a helical antiferromagnetic (AFM) structure below TN=66.5 K with the helix axis along the c axis and with the ordered moments aligned within the a b plane. Here we report crystallography, electrical resistivity, heat capacity, magnetization, and magnetic susceptibility measurements on single crystals of this compound. We demonstrate that EuCo2P2 is a model molecular-field helical Heisenberg antiferromagnet from comparisons of the anisotropic magnetic susceptibility χ , high-field magnetization, and magnetic heat capacity of EuCo2P2 single crystals at temperature T ≤TN with the predictions of our recent formulation of molecular-field theory. Values of the Heisenberg exchange interactions between the Eu spins are derived from the data. The low-T magnetic heat capacity ˜T3 arising from spin-wave excitations with no anisotropy gap is calculated and found to be comparable to the lattice heat capacity. The density of states at the Fermi energy of EuCo2P2 and the related compound BaCo2P2 are found from the heat capacity data to be large, 10 and 16 states/eV per formula unit for EuCo2P2 and BaCo2P2 , respectively. These values are enhanced by a factor of ˜2.5 above those found from DFT electronic structure calculations for the two compounds. The calculations also find ferromagnetic Eu-Eu exchange interactions within the a b plane and AFM interactions between Eu spins in nearest- and next-nearest planes, in agreement with the MFT analysis of χa b(T ≤TN) .

  18. P2X receptor-mediated ATP purinergic signaling in health and disease

    Directory of Open Access Journals (Sweden)

    Jiang LH

    2012-09-01

    Full Text Available Lin-Hua JiangSchool of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds, United KingdomAbstract: Purinergic P2X receptors are plasma membrane proteins present in a wide range of mammalian cells where they act as a cellular sensor, enabling cells to detect and respond to extracellular adenosine triphosphate (ATP, an important signaling molecule. P2X receptors function as ligand-gated Ca2+-permeable cationic channels that open upon ATP binding to elevate intracellular Ca2+ concentrations and cause membrane depolarization. In response to sustained activation, P2X receptors induce formation of a pore permeable to large molecules. P2X receptors also interact with distinct functional proteins and membrane lipids to form specialized signaling complexes. Studies have provided compelling evidence to show that such P2X receptor-mediated ATP-signaling mechanisms determine and regulate a growing number and diversity of important physiological processes, including neurotransmission, muscle contraction, and cytokine release. There is accumulating evidence to support strong causative relationships of altered receptor expression and function with chronic pain, inflammatory diseases, cancers, and other pathologies or diseases. Numerous high throughput screening drug discovery programs and preclinical studies have thus far demonstrated the proof of concepts that the P2X receptors are druggable targets and selective receptor antagonism is a promising therapeutics approach. This review will discuss the recent progress in understanding the mammalian P2X receptors with respect to the ATP-signaling mechanisms, physiological and pathophysiological roles, and development and preclinical studies of receptor antagonists.Keywords: extracellular ATP, ion channel, large pore, signaling complex, chronic pain, inflammatory diseases

  19. EFEKTIVITAS METODE P2R UNTUK MENINGKATKAN KECEPATAN EFEKTIF MEMBACA (KEM MAHASISWA CALON GURU BAHASA INDONESIA

    Directory of Open Access Journals (Sweden)

    Nurmina

    2015-12-01

    Full Text Available Reading is one of language skill which is not less important compared with others language skill such as scrutinizing, speaking, and writing. In this era which technology is flaring and developing rapidly, the students are prefer to play facebook, twitter, chatting, and many more than read a journal or articles. This phenomenon shows that the interest to read among students is needed to be increased. One of the way that can be taken is by having skills to read quickly or is known by scanning with P2R method. The P2R method itself is one of method or strategy that can be used to increase reading skill. The P2R method consists of stages pra-peninjauan, membaca, dan meninjau that commonly used by the most of quick reader / scanner and efficient. This research is done to obtain data about the effective reading speed of student as Indonesian language teacher candidate and the effort of its increasing through the P2R method. The population of this research is all students on program of study Indonesian language and literature education and also area of Almuslim University as much 149 students. The sample of this research is 30% of the total population or as much 45 strudents of Indonesia Language teacher candidate of Almuslim University who are taken randomly. The type of research is experimental research (true experimental and quantitative approach with the model of research is pretest-post test control group model. The result of research shows that the P2R method is effective to be implemented to increase the effective reading speed of students as Indonesian language teacher candidate. FKIP is obtained by researcher. The posttest result shows that there was an increasing of KEM learning outcomes meanwhile the observation result was seems that in the learning with P2R model, the students were very enthusiasm, more active, also more motivated in attending the learning. Besides that, the result of questionnaires also shows that the P2R method obtained

  20. Lack of chemopreventive effects of P2X7R inhibitors against pancreatic cancer.

    Science.gov (United States)

    Mohammed, Altaf; Janakiram, Naveena B; Madka, Venkateshwar; Pathuri, Gopal; Li, Qian; Ritchie, Rebekah; Biddick, Laura; Kutche, Hannah; Zhang, Yuting; Singh, Anil; Gali, Hariprasad; Lightfoot, Stan; Steele, Vernon E; Suen, Chen S; Rao, Chinthalapally V

    2017-11-17

    Pancreatic cancer (PC) is an almost uniformly lethal disease with inflammation playing an important role in its progression. Sustained stimulation of purinergic receptor P2X7 drives induction of NLRP inflammasome activation. To understand the role of P2X7 receptor and inflammasome, we performed transcriptomic analysis of p48 Cre/+ -LSL-Kras G12D/+ mice pancreatic tumors by next generation sequencing. Results showed that P2X7R's key inflammasome components, IL-1β and caspase-1 are highly expressed ( p P2X7R, we tested effects of two P2X7R antagonists, A438079 and AZ10606120, on pancreatic intraepithelial neoplasms (PanINs) and their progression to PC in p48 Cre/+ -LSL-Kras G12D/+ mice. Following dose optimization studies, for chemoprevention efficacy, six-week-old p48 Cre/+ -LSL-Kras G12D/+ mice (24-36/group) were fed modified AIN-76A diets containing 0, 50 or 100 ppm A438079 and AZ10606120 for 38 weeks. Pancreata were collected, weighed, and evaluated for PanINs and PDAC. Control diet-fed male mice showed 50% PDAC incidence. Dietary A438079 and AZ10606120 showed 60% PDAC incidence. A marginal increase of PanIN 3 (carcinoma in-situ ) was observed in drug-treated mice. Importantly, the carcinoma spread in untreated mice was 24% compared to 43-53% in treatment groups. Reduced survival rates were observed in mice exposed to P2X7R inhibitors. Both drugs showed a decrease in caspase-3, caspase-1, p21 and Cdc25c. Dietary A438079 showed modest inhibition of P2X7R, NLRP3, and IL-33, whereas AZ10606120 had no effects. In summary, targeting the P2X7R pathway by A438079 and AZ10606120 failed to show chemopreventive effects against PC and slightly enhanced PanIN progression to PDAC. Hence, caution is needed while treating high-risk individuals with P2X7R inhibitors.

  1. P2Y12 Receptor on the Verge of a Neuroinflammatory Breakdown

    Directory of Open Access Journals (Sweden)

    Susanna Amadio

    2014-01-01

    Full Text Available In the CNS, neuroinflammation occurring during pathologies as amyotrophic lateral sclerosis (ALS and multiple sclerosis (MS is the consequence of an intricate interplay orchestrated by various cell phenotypes. Among the molecular cues having a role in this process, extracellular nucleotides are responsible for intercellular communication and propagation of inflammatory stimuli. This occurs by binding to several receptor subtypes, defined P2X/P2Y, which are widespread in different tissues and simultaneously localized on multiple cells. For instance, the metabotropic P2Y12 subtype is found in the CNS on microglia, affecting activation and chemotaxis, on oligodendrocytes, possessing a hypothesized role in myelination, and on astrocytes. By comparative analysis, we have established here that P2Y12 receptor immunolabelled by antibodies against C-terminus or second intracellular loop, is, respectively, distributed and modulated under neuroinflammatory conditions on ramified microglia or myelinated fibers, in primary organotypic cerebellar cultures, tissue slices from rat striatum and cerebellum, spinal cord sections from symptomatic/end stage SOD1-G93A ALS mice, and finally autoptic cortical tissue from progressive MS donors. We suggest that modulation of P2Y12 expression might play a dual role as analytic marker of branched/surveillant microglia and demyelinating lesions, thus potentially acquiring a predictive value under neuroinflammatory conditions as those found in ALS and MS.

  2. Expression of purinergic P2X receptor subtypes 1, 2, 3 and 7 in equine laminitis.

    Science.gov (United States)

    Zamboulis, Danae E; Senior, Mark; Clegg, Peter D; Milner, Peter I

    2013-11-01

    Tissue sensitisation and chronic pain have been described in chronic-active laminitis in the horse, making treatment of such cases difficult. Purinergic P2X receptors are linked to chronic pain and inflammation. The aim of this study was to examine the expression of purinergic P2X receptor subtypes 1, 2, 3 and 7 in the hoof, palmar digital vessels and nerve, dorsal root ganglia and spinal cord in horses with chronic-active laminitis (n=5) compared to non-laminitic horses (n=5). Immunohistochemical analysis was performed on tissue sections using antibodies against P2X receptor subtypes 1-3 and 7. In horses with laminitis, there was a reduction in the thickness of the tunica media layer of the palmar digital vein as a proportion of the whole vessel diameter (0.48±0.05) compared to the non-laminitic group (0.57±0.04; P=0.02). P2X receptor subtype 3 was expressed in the smooth muscle layer (tunica media) of the palmar digital artery of horses with laminitis, but was absent in horses without laminitis. There was strong expression of P2X receptor subtype 7 in the proliferating, partially keratinised, epidermal cells of the secondary epidermal lamellae in the hooves of horses with laminitis, but no immunopositivity in horses without laminitis. Copyright © 2013 Elsevier Ltd. All rights reserved.

  3. Results of FE65-P2 Pixel Readout Test Chip for High Luminosity LHC Upgrades

    CERN Document Server

    AUTHOR|(SzGeCERN)394193

    2016-01-01

    A pixel readout test chip called FE65-P2 has been fabricated on 65 nm CMOS technology. FE65-P2 contains a matrix of 64 x 64 pixels on 50 micron by 50 micron pitch, designed to read out a bump bonded sensor. The goals of FE65-P2 are to demonstrate excellent analog performance isolated from digital activity well enough to achieve 500 electron stable threshold, be radiation hard to at least 500 Mrad, and prove the novel concept of isolated analog front ends embedded in a flat digital design, dubbed “analog islands in a digital sea”. Experience from FE65-P2 and hybrid assemblies will be applied to the design for a large format readout chip, called RD53A, to be produced in a wafer run in early 2017 by the RD53 collaboration. We review the case for 65 nm technology and report on threshold stability test results for the FE65-P2.

  4. Equations for effective nuclear fields taking account of 2p2h configurations

    International Nuclear Information System (INIS)

    Kamerdzhiev, S.P.

    1977-01-01

    Equations taking into account 1p1h and 2p2h configurations were obta+ned by means of effective fields in the nucleus. The consideration is restricted by the even-even Fermi system only with particle-hole interaction and by the first order with respect to an external field, which corresponds to the case of an even-even nucleus without pairing in a weak external field. The principal results of the investigation are as follows: a set of equations for effective fields V 2 and V 4 is obtained by the Green function method; the solutxon of the set makes it possible to consider 1p1h and 2p2h configurations consecutively and dispense with the Hartree-Fock self-consistence. The equations for V 2 and V 4 can be used to obtain quantum equations taking into account 2p2h configurations and their effect on 1p1h states. Allowance for integration regions far removed from the Fermi surface results in the appearance of the V 4 0 seed portion in the V 4 effective field. Taking into account 2p2h configurations at V 4 0 not equal to 0 changes the form of the seed multipole operator of a nucleus; a new term appears in the expression for transition probability. As a rule, the V 4 0 value was neglected in investigations dealing with the 2p2h configuration

  5. Lattice dynamics and phase transitions in Sn2P2S(Se6 ferroelectric crystals

    Directory of Open Access Journals (Sweden)

    R.M.Yevych

    2006-01-01

    Full Text Available Polarizable ion model was used in describing the lattice dynamics in the Sn2P2S6 and Sn2P2Se6 ferroelectric crystals and their solid solutions. There has been obtained a good agreement of the calculated phonon spectra with the experimental data of Raman and Brillouin spectroscopies, neutron scattering and ultrasound experiments. Paraelectric phase instability has been modelled by negative charge transferring from the tin cations to the chalcogen ions, and by increasing the polarizabilities of the latter. The ferroelectric phase has been stabilized by tin atom displacement from centrosymmetric positions and a partial reversal recharging between tin and chalcogen ions. The effective charges decreasing by moving from Sn2P2S6 to Sn2P2Se6 compounds determine the shift of condensation wave vector of soft optic phonons in paraelectric phase from q=0 in sulfur compound to q > 0 in selenium compound. Such a change of dynamical instability character is connected with the appearance of incommensurate phase in Sn2P2(SexS1-x6 solid solution under x > 0.28. The "two-mode" instability emerged as possible in the vicinity of Lifshitz point - there have been modelled the condensation of soft optic mode with q ≈ 0 and mixed optic and transversal acoustic phonons near q > 0. This fact requires further experimental and theoretical investigations.

  6. Production, crystallization and neutron diffraction of fully deuterated human myelin peripheral membrane protein P2.

    Science.gov (United States)

    Laulumaa, Saara; Blakeley, Matthew P; Raasakka, Arne; Moulin, Martine; Härtlein, Michael; Kursula, Petri

    2015-11-01

    The molecular details of the formation of the myelin sheath, a multilayered membrane in the nervous system, are to a large extent unknown. P2 is a peripheral membrane protein from peripheral nervous system myelin, which is believed to play a role in this process. X-ray crystallographic studies and complementary experiments have provided information on the structure-function relationships in P2. In this study, a fully deuterated sample of human P2 was produced. Crystals that were large enough for neutron diffraction were grown by a ten-month procedure of feeding, and neutron diffraction data were collected to a resolution of 2.4 Å from a crystal of 0.09 mm(3) in volume. The neutron crystal structure will allow the positions of H atoms in P2 and its fatty-acid ligand to be visualized, as well as shedding light on the fine details of the hydrogen-bonding networks within the P2 ligand-binding cavity.

  7. P2P Network Lending, Loss Given Default and Credit Risks

    Directory of Open Access Journals (Sweden)

    Guangyou Zhou

    2018-03-01

    Full Text Available Peer-to-peer (P2P network lending is a new mode of internet finance that still holds credit risk as its main risk. According to the internal rating method of the New Basel Accord, in addition to the probability of default, loss given default is also one of the important indicators of evaluation credit risks. Proceeding from the perspective of loss given default (LGD, this paper conducts an empirical study on the probability distribution of LGDs of P2P as well as its influencing factors with the transaction data of Lending Club. The results show that: (1 the LGDs of P2P loans presents an obvious unimodal distribution, the peak value is relatively high and tends to concentrate with the decrease of the borrower’s credit rating, indicating that the distribution of LGDs of P2P lending is similar to that of unsecured bonds; (2 The total asset of the borrower has no significant impact on LGD, the credit rating and the debt-to-income ratio exert a significant negative impact, while the term and amount of the loan produce a relatively strong positive impact. Therefore, when evaluating the borrower’s repayment ability, it is required to pay more attention to its assets structure rather than the size of its total assets. When carrying out risk control for the P2P platform, it is necessary to give priority to the control of default rate.

  8. A suffix arrays based approach to semantic search in P2P systems

    Science.gov (United States)

    Shi, Qingwei; Zhao, Zheng; Bao, Hu

    2007-09-01

    Building a semantic search system on top of peer-to-peer (P2P) networks is becoming an attractive and promising alternative scheme for the reason of scalability, Data freshness and search cost. In this paper, we present a Suffix Arrays based algorithm for Semantic Search (SASS) in P2P systems, which generates a distributed Semantic Overlay Network (SONs) construction for full-text search in P2P networks. For each node through the P2P network, SASS distributes document indices based on a set of suffix arrays, by which clusters are created depending on words or phrases shared between documents, therefore, the search cost for a given query is decreased by only scanning semantically related documents. In contrast to recently announced SONs scheme designed by using metadata or predefined-class, SASS is an unsupervised approach for decentralized generation of SONs. SASS is also an incremental, linear time algorithm, which efficiently handle the problem of nodes update in P2P networks. Our simulation results demonstrate that SASS yields high search efficiency in dynamic environments.

  9. Graft-versus-host disease is enhanced by extracellular ATP activating P2X7R.

    Science.gov (United States)

    Wilhelm, Konrad; Ganesan, Jayanthi; Müller, Tobias; Dürr, Christoph; Grimm, Melanie; Beilhack, Andreas; Krempl, Christine D; Sorichter, Stephan; Gerlach, Ulrike V; Jüttner, Eva; Zerweck, Alf; Gärtner, Frank; Pellegatti, Patrizia; Di Virgilio, Francesco; Ferrari, Davide; Kambham, Neeraja; Fisch, Paul; Finke, Jürgen; Idzko, Marco; Zeiser, Robert

    2010-12-01

    Danger signals released upon cell damage can cause excessive immune-mediated tissue destruction such as that found in acute graft-versus-host disease (GVHD), allograft rejection and systemic inflammatory response syndrome. Given that ATP is found in small concentrations in the extracellular space under physiological conditions, and its receptor P2X(7)R is expressed on several immune cell types, ATP could function as a danger signal when released from dying cells. We observed increased ATP concentrations in the peritoneal fluid after total body irradiation, and during the development of GVHD in mice and in humans. Stimulation of antigen-presenting cells (APCs) with ATP led to increased expression of CD80 and CD86 in vitro and in vivo and actuated a cascade of proinflammatory events, including signal transducer and activator of transcription-1 (STAT1) phosphorylation, interferon-γ (IFN-γ) production and donor T cell expansion, whereas regulatory T cell numbers were reduced. P2X(7)R expression increased when GVHD evolved, rendering APCs more responsive to the detrimental effects of ATP, thereby providing positive feedback signals. ATP neutralization, early P2X(7)R blockade or genetic deficiency of P2X(7)R during GVHD development improved survival without immune paralysis. These data have major implications for transplantation medicine, as pharmacological interference with danger signals that act via P2X(7)R could lead to the development of tolerance without the need for intensive immunosuppression.

  10. Improving Management Performance of P2PSIP for Mobile Sensing in Wireless Overlays

    Science.gov (United States)

    Sendín-Raña, Pablo; González-Castaño, Francisco Javier; Gómez-Cuba, Felipe; Asorey-Cacheda, Rafael; Pousada-Carballo, José María

    2013-01-01

    Future wireless communications are heading towards an all-Internet Protocol (all-IP) design, and will rely on the Session Initiation Protocol (SIP) to manage services, such as voice over IP (VoIP). The centralized architecture of traditional SIP has numerous disadvantages for mobile ad hoc services that may be possibly overcome by advanced peer-to-peer (P2P) technologies initially developed for the Internet. In the context of mobile sensing, P2PSIP protocols facilitate decentralized and fast communications with sensor-enabled terminals. Nevertheless, in order to make P2PSIP protocols feasible in mobile sensing networks, it is necessary to minimize overhead transmissions for signaling purposes, which reduces the battery lifetime. In this paper, we present a solution to improve the management of wireless overlay networks by defining an adaptive algorithm for the calculation of refresh time. The main advantage of the proposed algorithm is that it takes into account new parameters, such as the delay between nodes, and provides satisfactory performance and reliability levels at a much lower management overhead than previous approaches. The proposed solution can be applied to many structured P2P overlays or P2PSIP protocols. We evaluate it with Kademlia-based distributed hash tables (DHT) and dSIP PMID:24217358

  11. Information Exchange rather than Topology Awareness: Cooperation between P2P Overlay and Traffic Engineering

    Directory of Open Access Journals (Sweden)

    Jia Zhao

    2014-01-01

    Full Text Available Solutions to the routing strategic conflict between noncooperative P2P overlay and ISP underlay go separate ways: hyperselfishness and cooperation. Unpredictable (possibly adverse impact of the hyperselfish topology awareness, which is adopted in both overlay routing and traffic engineering, has not been sufficiently studied in the literature. Topology-related information exchange in a cooperatively efficient way should be highlighted to alleviate the cross-layer conflict. In this paper, we first illustrate the hyperselfish weakness with two dynamic noncooperative game models in which hyperselfish overlay or underlay has to accept a suboptimal profit. Then we build a synergistic cost-saving (SC game model to reduce the negative effects of noncooperation. In the SC model, through information exchange, that is, the classified path-delay metrics for P2P overlay and peer locations for underlay, P2P overlay selects proximity as well as saving traffic transit cost for underlay, and ISP underlay adjusts routing to optimize network cost as well as indicating short delay paths for P2P. Simulations based on the real and generated topologies validate cost improvement by SC model and find a proper remote threshold value to limit P2P traffic from remote area, cross-AS, or cross-ISP.

  12. Cross Layer Analysis of P2MP Hybrid FSO/RF Network

    KAUST Repository

    Rakia, Tamer

    2017-02-22

    This paper presents and analyzes a point-tomultipoint (P2MP) network that uses a number of freespace optical (FSO) links for data transmission from the central node to the different remote nodes of the network. A common backup radio frequency (RF) link can be used by the central node for data transmission to any remote node in case any one of the FSO links fails. Each remote node is assigned a transmit buffer at the central node. Considering the transmission link from the central node to a tagged remote node, we study various performance metrics. Specifically,we study the throughput from the central node to the tagged node, the average transmit buffer size, the symbol queuing delay in the transmit buffer, the efficiency of the queuing system, the symbol loss probability, and the RF link utilization. Numerical examples are presented to compare the performance of the proposed P2MP hybrid FSO/RF network with that of a P2MP FSO-only network and show that the P2MP hybrid FSO/RF network achieves considerable performance improvement over the P2MP FSO-only network.

  13. Municipal water pollution prevention program

    International Nuclear Information System (INIS)

    1991-03-01

    EPA believes that the most effective and equitable means of assuring viability of this infrastructure is through environmentally preferred pollution prevention approaches especially through application of Municipal Water Pollution Prevention (MWPP). These approaches may enhance worker safety, improve the usability of sludge, increase the ability for local community expansion, and reduce operation and compliance costs. State-based municipal pollution prevention programs focus attention on a series of actions to prevent pollution in advance rather than taking more expensive corrective actions. MWPP encourages resource conservation to reduce water and energy use, appropriate pricing, toxicity reductions at the source, BOD reductions, recycling, proper treatment of wastes, and beneficial uses of sludge

  14. Compliance with infection control practices by Veterinarians in Nigeria.

    Science.gov (United States)

    Makinde, G I; Ana, G R E E; Emikpe, B O; Fawole, O I

    2015-03-01

    There is a global increase in morbidity and mortality due to zoonotic diseases hence there is a need to identify possible sources of infections to human population. This study assessed veterinarians' compliance with standard infection control practices (ICPs) for prevention of zoonosis in Nigeria. A cross sectional survey of 320 veterinarians participating in the National Annual Conference of the Nigerian Veterinary Me ic Association was done in November, 2011 Characteristics related to compliance with standard infection control practices were assessed. Chi-square and logistic regression tests were done at 0.05 significant levels. More veterinarians (51.1% and 61.2%) did not comply with appropriate ICPs while carrying out medical procedures of necropsy and assisting in parturition. Those with longer years of practice (OR=0.42,95% CI=0.23-0.75) and with long working hours (OR=0.52, 95% CI=0.28-0.97) were less likely to comply with ICPS. Private practice veterinarians' were less likely than public practitioners to comply (OR=0.67, 95% CI = 0.15-0.69). Also veterinarians who had workplace IC policy were more likely than those without to be compliant with ICPs (OR=3.71, 95% CI = 1.87-7.37). Future conferences can be used to advise veterinarians on the importance of implementing appropriate IC measures. Also infection prevention practices laws and policies should be enacted to encourage compliance by veterinarians.

  15. Preventing Financial Crime

    DEFF Research Database (Denmark)

    Boll, Karen

    This paper investigates the Swedish tax authority’s (Skatteverkets) compliance initiative called Preventing Financial Crime. In Sweden tax evasion related to organised moon-lighting is defined as a major risk to the revenue collection and to the legitimacy of Skatteverket. The traditional approach...... to abating such tax evasion has been reformed and a new mix-method approach adopted. This approach combines a proactive strategy—Preventing Financial Crime—with a reactive inspection strategy. During one a month of intensive fieldwork in Sweden, I studied the daily work in Preventing Financial Crime. Based...... on this, the paper shows that the Swedish tax officials seek to motivate large construction contractors and municipalities to take preventive measures in relation to their sub-contractors to avoid and abate tax evasion. The paper shows the challenges in engaging and involving these external stakeholders...

  16. P2Y{sub 12} Platelet Receptors: Importance in Percutaneous Coronary Intervention

    Energy Technology Data Exchange (ETDEWEB)

    Falcão, Felipe Jose de Andrade, E-mail: felipejaf@gmail.com [Universidade Federal de São Paulo - Escola Paulista de Medicina, São Paulo, SP (Brazil); Carvalho, Leonardo; Chan, Mark [National University of Singapore - Yong Loo Lin School of Medicina (Singapore); Alves, Cláudia Maria Rodrigues; Carvalho, Antônio Carlos Camargo; Caixeta, Adriano Mendes [Universidade Federal de São Paulo - Escola Paulista de Medicina, São Paulo, SP (Brazil)

    2013-09-15

    Apart from their role in hemostasis and thrombosis, platelets are involved in many other biological processes such as wound healing and angiogenesis. Percutaneous coronary intervention is a highly thrombogenic procedure inducing platelets and monocytes activation through endothelial trauma and contact activation by intravascular devices. Platelet P2Y{sub 12} receptor activation by adenosine diphosphate facilitates non-ADP agonist-mediated platelet aggregation, dense granule secretion, procoagulant activity, and the phosphorylation of several intraplatelet proteins, making it an ideal drug target. However, not all compounds that target the P2Y{sub 12} receptor have similar efficacy and safety profiles. Despite targeting the same receptor, the unique pharmacologic properties of each of these P2Y{sub 12} receptor-directed compounds can lead to very different clinical effects.

  17. Potent P2Y12 Inhibitors in Men Versus Women

    DEFF Research Database (Denmark)

    Lau, Emily S.; Braunwald, Eugene; Murphy, Sabina A.

    2017-01-01

    Background Sex-specific differences in response to antiplatelet therapies have been described. Whether women and men derive comparable benefit from intensification of antiplatelet therapy remains uncertain. Objectives The study investigated the efficacy and safety of the potent P2Y12 inhibitors...... in patients with coronary artery disease. Methods A collaborative sex-specific meta-analysis was conducted of phase III or IV randomized trials of potent P2Y12 inhibitors, including prasugrel, ticagrelor, and intravenous cangrelor. Seven trials were included that enrolled a total of 24,494 women and 63......,346 men. Major adverse cardiovascular events (MACE) were defined as the primary endpoint for each trial. Results Potent P2Y12 inhibitors significantly reduced the risk of MACE by 14% in women (hazard ratio [HR]: 0.86; 95% confidence interval [CI]: 0.78 to 0.94) and by 15% in men (HR: 0.85; 95% CI: 0...

  18. Neutron scattering studies on protein dynamics using the human myelin peripheral membrane protein P2

    Science.gov (United States)

    Laulumaa, Saara; Kursula, Petri; Natali, Francesca

    2015-01-01

    Myelin is a multilayered proteolipid membrane structure surrounding selected axons in the vertebrate nervous system, which allows the rapid saltatory conduction of nerve impulses. Deficits in myelin formation and maintenance may lead to chronic neurological disease. P2 is an abundant myelin protein from peripheral nerves, binding between two apposing lipid bilayers. We studied the dynamics of the human myelin protein P2 and its mutated P38G variant in hydrated powders using elastic incoherent neutron scattering. The local harmonic vibrations at low temperatures were very similar for both samples, but the mutant protein had increased flexibility and softness close to physiological temperatures. The results indicate that a drastic mutation of proline to glycine at a functional site can affect protein dynamics, and in the case of P2, they may explain functional differences between the two proteins.

  19. Peer-to-peer I/O (P2PIO) protocol specification Version 0.6

    Energy Technology Data Exchange (ETDEWEB)

    Berket, Karlo; Essiari, Abdelilah; Gunter, Dan; Hoschek, Wolfgang

    2004-04-21

    Today's distributed systems require simple and powerful resource discovery queries in a dynamic environment consisting of a large number of resources spanning many autonomous administrative domains. The distributed search problem is hard due to the variety of query types, the number of resources and their autonomous, partitioned and dynamic nature. We propose a generalized resource discovery framework that is built around an application level messaging protocol called Peer-to-Peer I/O (P2PIO). P2PIO addresses a number of scalability problems in a general way. It provides flexible and uniform transport-independent resource discovery mechanisms to reduce both the client and network burden in multi-hop P2P systems.

  20. 11th International Conference on P2P, Parallel, Grid, Cloud and Internet Computing

    CERN Document Server

    Barolli, Leonard; Amato, Flora

    2017-01-01

    P2P, Grid, Cloud and Internet computing technologies have been very fast established as breakthrough paradigms for solving complex problems by enabling aggregation and sharing of an increasing variety of distributed computational resources at large scale. The aim of this volume is to provide latest research findings, innovative research results, methods and development techniques from both theoretical and practical perspectives related to P2P, Grid, Cloud and Internet computing as well as to reveal synergies among such large scale computing paradigms. This proceedings volume presents the results of the 11th International Conference on P2P, Parallel, Grid, Cloud And Internet Computing (3PGCIC-2016), held November 5-7, 2016, at Soonchunhyang University, Asan, Korea.

  1. Inhibitory Effect of Flavonolignans on the P2Y12 Pathway in Blood Platelets.

    Science.gov (United States)

    Bijak, Michal; Szelenberger, Rafal; Dziedzic, Angela; Saluk-Bijak, Joanna

    2018-02-10

    Adenosine diphosphate (ADP) is the major platelet agonist, which is important in the shape changes, stability, and growth of the thrombus. Platelet activation by ADP is associated with the G protein-coupled receptors P2Y1 and P2Y12. The pharmacologic blockade of the P2Y12 receptor significantly reduces the risk of peripheral artery disease, myocardial infarction, ischemic stroke, and vascular death. Recent studies demonstrated the inhibition of ADP-induced blood platelet activation by three major compounds of the flavonolignans group: silybin, silychristin, and silydianin. For this reason, the aim of the current work was to verify the effects of silybin, silychristin, and silydianin on ADP-induced physiological platelets responses, as well as mechanisms of P2Y12-dependent intracellular signal transduction. We evaluated the effect of tested flavonolignans on ADP-induced blood platelets' aggregation in platelet-rich plasma (PRP) (using light transmission aggregometry), adhesion to fibrinogen (using the static method), and the secretion of PF-4 (using the ELISA method). Additionally, using the double labeled flow cytometry method, we estimated platelet vasodilator-stimulated phosphoprotein (VASP) phosphorylation. We demonstrated a dose-dependent reduction of blood platelets' ability to perform ADP-induced aggregation, adhere to fibrinogen, and secrete PF-4 in samples treated with flavonolignans. Additionally, we observed that all of the tested flavonolignans were able to increase VASP phosphorylation in blood platelets samples, which is correlated with P2Y12 receptor inhibition. All of these analyses show that silychristin and silybin have the strongest inhibitory effect on blood platelet activation by ADP, while silydianin also inhibits the ADP pathway, but to a lesser extent. The results obtained in this study clearly demonstrate that silybin, silychristin, and silydianin have inhibitory properties against the P2Y12 receptor and block ADP-induced blood platelet

  2. Lung injury during LPS-induced inflammation occurs independently of the receptor P2Y1.

    Science.gov (United States)

    Liverani, Elisabetta

    2017-03-01

    Disruption of the lung endothelial and epithelial barriers during acute inflammation leads to excessive neutrophil migration. It is likely that activated platelets promote pulmonary recruitment of neutrophils during inflammation, and previous studies have found that anti-platelet therapy and depletion of circulating platelets have lung-protective effects in different models of inflammation. Because ADP signaling is important for platelet activation, I investigated the role of the ADP-receptor P2Y 1 , a G protein-coupled receptor expressed on the surface of circulating platelets, during lipopolysaccharide (LPS)-induced inflammation and lung injury in P2Y 1 -null and wild-type mice. Systemic inflammation was induced by a single intraperitoneal dose of LPS (3 mg/kg), and the mice were analyzed 24 h posttreatment. The data show that the LPS-induced inflammation levels were comparable in the P2Y 1 -null and wild-type mice. Specifically, splenomegaly, counts of circulating platelets and white blood cells (lymphocytes and neutrophils), and assessments of lung injury (tissue architecture and cell infiltration) were similar in the P2Y 1 -null and wild-type mice. Based on my results, I conclude that lung injury during LPS-induced inflammation in mice is independent of P2Y 1 signaling. I propose that if a blockade of purinergic signaling in platelets is a potential lung-protective strategy in the treatment of acute inflammation, then it is more likely to be a result of the disruption of the signaling pathway mediated by P2Y 12 , another G protein-coupled receptor that mediates platelet responses to ADP.

  3. The therapeutic promise of ATP antagonism at P2X3 receptors in respiratory & urological disorders

    Directory of Open Access Journals (Sweden)

    Anthony eFord

    2013-12-01

    Full Text Available A sensory role for ATP was proposed long before general acceptance of its extracellular role. ATP activates & sensitizes signal transmission at multiple sites along the sensory axis, across multiple synapses. P2X & P2Y receptors mediate ATP modulation of sensory pathways & participate in dysregulation, where ATP action directly on primary afferent neurons (PANs, linking receptive field to CNS, has received much attention. Many PANs, especially C-fibers, are activated by ATP, via P2X3-containing trimers. P2X3 knock-out mice & knock-down in rats led to reduced nocifensive activity & visceral reflexes, suggesting that antagonism may offer benefit in sensory disorders. Recently, drug-like P2X3 antagonists, active in a many inflammatory & visceral pain models, have emerged. Significantly, these compounds have no overt CNS action & are inactive versus acute nociception. Selectively targeting ATP sensitization of PANs may lead to therapies that block inappropriate chronic signals at their source, decreasing drivers of peripheral & central wind-up, yet leaving defensive nociceptive and brain functions unperturbed. This article reviews this evidence, focusing on how ATP sensitization of PANs in visceral hollow organs primes them to chronic discomfort, irritation & pain (symptoms as well as exacerbated autonomic reflexes (signs, & how the use of isolated organ-nerve preparations has revealed this mechanism. Urinary & airways systems share many features: dependence on continuous afferent traffic to brainstem centers to coordinate efferent autonomic outflow; loss of descending inhibitory influence in functional & sensory disorders; dependence on ATP in mediating sensory responses to diverse mechanical and chemical stimuli; a mechanistically overlapping array of existing medicines for pathological conditions. These similarities may also play out in terms of future treatment of signs & symptoms, in the potential for benefit of P2X3 antagonists.

  4. Pemetaan Pusat Pelayanan Terpadu Pemberdayaan Perempuan dan Anak (P2TP2A Provinsi Sumatera Bar

    Directory of Open Access Journals (Sweden)

    Hallen Abu Bakar

    2017-09-01

    Full Text Available The Center of Integrated Service for Women and Children Empowerment (P2TP2A is established by the government based community in order to eliminate the violence towards women and children. It also aims to empower the position of women and children. The purpose of the study is to describe comprehensively the existance of P2TP2A in sub-district, district, city, and province in West Sumatra. Descriptive qualitative research was used where the data taken from questionnaire and in-deepthinterview. The study found that the Center of Integrated Service for Women and Children Empowerment was established by following certain procedure, legality and personnel structure. It also found that the majority of P2TP2A in West Sumatra has insufficient infrastructures. Meanwhile, it is only P2TP2A Limpapeh Rumah Nan Gadang of West Sumatera, and P2TP2A Luhak Nan Tuo Batusangkar has sufficient infrastructures. Many of them were located at the corner of Community Empowerment and Women and Family Planning office (BPMPKB. Every P2TP2A in those district and city have made their programs, but they faced some difficulties in realize them doe to financial problems. The human resources were recruited from SKPD, academician, professional, society figures, LSM who concern on gender meanstreaming. They play the role more on providing the service than giving information and empowerment. The last finding of the study showed that the involvement of local government, Health offices, social services, police, ministry of religion, prosecutors and social services have been effective.

  5. Purinergic control of inflammation and thrombosis: Role of P2X1 receptors

    Directory of Open Access Journals (Sweden)

    Cécile Oury

    2015-01-01

    Full Text Available Inflammation shifts the hemostatic mechanisms in favor of thrombosis. Upon tissue damage or infection, a sudden increase of extracellular ATP occurs, that might contribute to the crosstalk between inflammation and thrombosis. On platelets, P2X1 receptors act to amplify platelet activation and aggregation induced by other platelet agonists. These receptors critically contribute to thrombus stability in small arteries. Besides platelets, studies by our group indicate that these receptors are expressed by neutrophils. They promote neutrophil chemotaxis, both in vitro and in vivo. In a laser-induced injury mouse model of thrombosis, it appears that neutrophils are required to initiate thrombus formation and coagulation activation on inflamed arteriolar endothelia. In this model, by using P2X1−/− mice, we recently showed that P2X1 receptors, expressed on platelets and neutrophils, play a key role in thrombus growth and fibrin generation. Intriguingly, in a model of endotoxemia, P2X1−/− mice exhibited aggravated oxidative tissue damage, along with exacerbated thrombocytopenia and increased activation of coagulation, which translated into higher susceptibility to septic shock. Thus, besides its ability to recruit neutrophils and platelets on inflamed endothelia, the P2X1 receptor also contributes to limit the activation of circulating neutrophils under systemic inflammatory conditions. Taken together, these data suggest that P2X1 receptors are involved in the interplay between platelets, neutrophils and thrombosis. We propose that activation of these receptors by ATP on neutrophils and platelets represents a new mechanism that regulates thrombo-inflammation.

  6. Electronic structure and X-ray spectroscopic properties of YbNi2P2

    International Nuclear Information System (INIS)

    Shcherba, I.D.; Bekenov, L.V.; Antonov, V.N.; Noga, H.; Uskokovic, D.; Zhak, O.; Kovalska, M.V.

    2016-01-01

    Highlights: • We present new experimental and theoretical data for YbNi 2 P 2 . • The presence of divalent and trivalent Yb ion found in YbNi 2 P 2 . • The calculation show good agreement with the experimental measurements. - Abstract: X-ray absorption spectrum at the Yb L 3 edge and X-ray emission spectra of Ni and P at the K and L 2,3 edges have been studied experimentally and theoretically in the mixed valent compound YbNi 2 P 2 with ThCr 2 Si 2 type crystal structure. The electronic structure of YbNi 2 P 2 is investigated using the fully relativistic Dirac linear muffin-tin orbital (LMTO) band-structure method. The effect of the spin–orbit (SO) interaction and Coulomb repulsion U on the electronic structure of YbNi 2 P 2 is examined in the frame of the LSDA + SO + U method. The core-hole effect in the final states as well as the effect of the electric quadrupole E 2 transitions have been investigated. A good agreement between the theory and the experiment was found. Both the trivalent and the divalent Yb ions in YbNi 2 P 2 are reflected in the experimentally measured Yb L 3 X-ray absorption spectrum simultaneously. We found that the best agreement between the experimental spectrum and sum of the theoretically calculated Yb 2+ and Yb 3+ spectra is achieved with 73% ytterbium ions in 2+ state and 27% ions in 3+ state.

  7. Luminescence in Eu2+ and Ce3+ doped SrCaP2O7 phosphors

    Directory of Open Access Journals (Sweden)

    K.N. Shinde

    Full Text Available Eu2+ and Ce3+ doped SrCaP2O7 has been achieved by modified solid state diffusion in reducing atmosphere. The prepared phosphor powders have been identified by their characteristic X-ray diffraction patterns. The mixed phases of α-Sr2P2O7 type with orthorhombic and α-Ca2P2O7 type with monoclinic form were investigated. Its excitation wavelength ranging from 250 to 430 nm fits well with the characteristic emission of UV light-emitting diode (LED. The excitation and emission spectra indicate that these phosphors can be effectively excited by the near-UV light, and emits blue (visible range due to 4f7 → 4f65d1 transition of Eu2+ particularly, SrCaP2O7: Eu2+ whereas, photoluminescence excitation spectrum measurements of Ce3+ activated SrCaP2O7 shows that the phosphor can be efficiently excited by UV–Vis light from 280 to 310 nm to realize emission in the near visible range due to the 5d–4f transition of Ce3+ ions which is applicable for scintillation purpose. The impacts of doping of divalent europium and trivalent cerium on photoluminescence properties on SrCaP2O7 pyrophosphate phosphors were investigated and I propose a feasible interpretation. Keywords: Phosphor, Luminescence, XRD, LED, FTIR

  8. Ectodomain Lysines and Suramin Block of P2X1 Receptors*

    Science.gov (United States)

    Sim, Joan A.; Broomhead, Helen E.; North, R. Alan

    2008-01-01

    P2X1 receptors belong to a family of cation channels gated by extracellular ATP; they are found inter alia in smooth muscle, platelets, and immune cells. Suramin has been widely used as an antagonist at P2X receptors, and its analog 4,4′,4″,4‴-[carbonylbis(imino-5,1,3-benzenetriylbis(carbonylimino))] tetrakis-benzene-1,3-disulfonic acid (NF449) is selective for the P2X1 subtype. Human and mouse P2X1 receptors were expressed in human embryonic kidney cells, and membrane currents evoked by ATP were recorded. ATP (10 nm to 100 μm) was applied only once to each cell, to avoid the profound desensitization exhibited by P2X1 receptors. Suramin (10 μm) and NF449 (3–300 nm) effectively blocked the human receptor. Suramin had little effect on the mouse receptor. Suramin and NF449 are polysulfonates, with six and eight negative charges, respectively. We hypothesized that species differences might result from differences in positive residues presented by the large receptor ectodomain. Four lysines in the human sequence (Lys111, Lys127, Lys138, and Lys148) were changed individually and together to their counterparts in the mouse sequence. The substitution K138E, either alone or together with K111Q, K127Q, and K148N, reduced the sensitivity to block by both suramin and NF449. Conversely, when lysine was introduced into the mouse receptor, the sensitivity to block by suramin and NF449 was much increased for E138K, but not for Q111K, Q127K, or N148K. The results explain the marked species difference in antagonist sensitivity and identify an ectodomain lysine residue that plays a key role in the binding of both suramin and NF449 to P2X1 receptors. PMID:18765669

  9. LPS-induced systemic inflammation is more severe in P2Y12 null mice

    Science.gov (United States)

    Liverani, Elisabetta; Rico, Mario C.; Yaratha, Laxmikausthubha; Tsygankov, Alexander Y.; Kilpatrick, Laurie E.; Kunapuli, Satya P.

    2014-01-01

    Thienopyridines are a class of antiplatelet drugs that are metabolized in the liver to several metabolites, of which only one active metabolite can irreversibly antagonize the platelet P2Y12 receptor. Possible effects of these drugs and the role of activated platelets in inflammatory responses have also been investigated in a variety of animal models, demonstrating that thienopyridines could alter inflammation. However, it is not clear whether it is caused only by the P2Y12 antagonism or whether off-target effects of other metabolites also intervene. To address this question, we investigated P2Y12 KO mice during a LPS-induced model of systemic inflammation, and we treated these KO mice with a thienopyridine drug (clopidogrel). Contrary to the reported effects of clopidogrel, numbers of circulating WBCs and plasma levels of cytokines were increased in LPS-exposed KO mice compared with WT in this inflammation model. Moreover, both spleen and bone marrow show an increase in cell content, suggesting a role for P2Y12 in regulation of bone marrow and spleen cellular composition. Finally, the injury was more severe in the lungs of KO mice compared with WT. Interestingly, clopidogrel treatments also exerted protective effects in KO mice, suggesting off-target effects for this drug. In conclusion, the P2Y12 receptor plays an important role during LPS-induced inflammation, and this signaling pathway may be involved in regulating cell content in spleen and bone marrow during LPS systemic inflammation. Furthermore, clopidogrel may have effects that are independent of P2Y12 receptor blockade. PMID:24142066

  10. Effectiveness of Mindfulness-Based Relapse Prevention in opioid Dependence Treatment &Mental Health

    Directory of Open Access Journals (Sweden)

    2008-11-01

    Findings: therapy compliance, retention in treatment, decrease in somatic symptoms, anxiety, social dysfunction and increase in health was significantly in both combination of psychological intervention method than the Naltroxan group. Mindfulness-based on relapse prevention was more effective than CBT relapse prevention in decreasing of, social dysfunction, relapse prevention, increase of therapy compliance, and health. Results: Mindfulness based relapse prevention was superior to CBT and Naltroxan and considerably increased effectiveness of opioid relapse prevention therapy.

  11. Autoradiography of P2x ATP receptors in the rat brain.

    OpenAIRE

    Balcar, V. J.; Li, Y.; Killinger, S.; Bennett, M. R.

    1995-01-01

    1. Binding of a P2x receptor specific radioligand, [3H]-alpha,beta-methylene adenosine triphosphate ([3H]-alpha,beta-MeATP) to sections of rat brain was reversible and association/dissociation parameters indicated that it consisted of two saturable components. Non-specific binding was very low (< 7% at 10 nM ligand concentration). 2. The binding was completely inhibited by suramin (IC50 approximately 14-26 microM) but none of the ligands specific for P2y receptors such as 2-methylthio-adenosi...

  12. Validation of antibodies for neuroanatomical localization of the P2Y11 receptor in macaque brain

    DEFF Research Database (Denmark)

    Dreisig, Karin; Degn, Matilda; Sund, Louise

    2016-01-01

    that produce the neuropeptide hypocretin/orexin. It is unknown how a decrease in expression of P2Y11 might contribute to an autoimmune reaction towards the hypocretin neurons and the development of narcolepsy. To advance narcolepsy research it is therefore extremely important to determine the neuroanatomical...... localization of P2Y11 in the brain with particular emphasis on the hypocretin neurons. In this article we used western blot, staining of blood smears, and flow cytometry to select two antibodies for immunohistochemical staining of macaque monkey brain. Staining was seen in neuron-like structures in cortical...

  13. Enabling Co-located Learning over Mobile Ad Hoc P2P with LightPeers

    DEFF Research Database (Denmark)

    Christensen, Bent Guldbjerg; Kristensen, Mads Darø; Hansen, Frank Allan

    2008-01-01

    This paper presents LightPeers – a new mobile P2P framework specifically tailored for use in a nomadic learning environment. A set of key requirements for the framework is identified based on nomadic learning, and these requirements are used as outset for designing and implementing the architecture...... and protocols. The main contributions of the LightPeers framework are: a mobile P2P framework including a specialized robust messaging protocol resilient to changes in the network topology, an developers API, and a suite of LightPeers applications supporting nomadic learning prototyping key features of LightPeers....

  14. Compliance management and corporate governance; Compliance Management und Corporate Governance

    Energy Technology Data Exchange (ETDEWEB)

    Becker, Uwe [Stadt Frankfurt am Main (Germany); Alsheimer, Constantin; Kassebohm, Kristian; Reutler, Susanne [Mainova AG, Frankfurt (Germany)

    2009-08-15

    Starting in the year 2009, numerous changes in the financial system and accountancy a well as in the corporate law come into effect for enterprises. Thereby, the requirements substantially are intensified to their corporate governance. The actual well-known reproaches of bribery, corruption and injuries of data protection intensify the pressure on executive committees and supervisory boards in order to meet normative and ethical requirements. All the more is valid for power suppliers whose reputation can already carry damage out with the first suspicion. Already in 2008, Mainova AG (Frnkfurt/Main, Federal Republic of Germany) implemented a compliance management.

  15. Transition probabilities for the 3s2 3p(2P0)-3s3p2(4P) intersystem lines of Si II

    Science.gov (United States)

    Calamai, Anthony G.; Smith, Peter L.; Bergeson, S. D.

    1993-01-01

    Intensity ratios of lines of the spin-changing 'intersystem' multiplet of S II (4P yields 2P0) at 234 nm have been used to determine electron densities and temperatures in a variety of astrophysical environments. However, the accuracy of these diagnostic calculations have been limited by uncertainties associated with the available atomic data. We report the first laboratory measurement, using an ion-trapping technique, of the radiative lifetimes of the three metastable levels of the 3s3p2 4P term of Si II. Our results are 104 +/- 16, 406 +/- 33, and 811 +/- 77 micro-s for lifetimes of the J = 1/2, 5/2, and 3/2 levels, respectively. A-values were derived from our lifetimes by use of measured branching fractions. Our A-values, which differ from calculated values by 30 percent or more, should give better agreement between modeled and observed Si II line ratios.

  16. Comparison of P2X and TRPV1 receptors in ganglia or primary culture of trigeminal neurons and their modulation by NGF or serotonin

    Directory of Open Access Journals (Sweden)

    Giniatullin Rashid

    2006-03-01

    Full Text Available Abstract Background Cultured sensory neurons are a common experimental model to elucidate the molecular mechanisms of pain transduction typically involving activation of ATP-sensitive P2X or capsaicin-sensitive TRPV1 receptors. This applies also to trigeminal ganglion neurons that convey pain inputs from head tissues. Little is, however, known about the plasticity of these receptors on trigeminal neurons in culture, grown without adding the neurotrophin NGF which per se is a powerful algogen. The characteristics of such receptors after short-term culture were compared with those of ganglia. Furthermore, their modulation by chronically-applied serotonin or NGF was investigated. Results Rat or mouse neurons in culture mainly belonged to small and medium diameter neurons as observed in sections of trigeminal ganglia. Real time RT-PCR, Western blot analysis and immunocytochemistry showed upregulation of P2X3 and TRPV1 receptors after 1–4 days in culture (together with their more frequent co-localization, while P2X2 ones were unchanged. TRPV1 immunoreactivity was, however, lower in mouse ganglia and cultures. Intracellular Ca2+ imaging and whole-cell patch clamping showed functional P2X and TRPV1 receptors. Neurons exhibited a range of responses to the P2X agonist α, β-methylene-adenosine-5'-triphosphate indicating the presence of homomeric P2X3 receptors (selectively antagonized by A-317491 and heteromeric P2X2/3 receptors. The latter were observed in 16 % mouse neurons only. Despite upregulation of receptors in culture, neurons retained the potential for further enhancement of P2X3 receptors by 24 h NGF treatment. At this time point TRPV1 receptors had lost the facilitation observed after acute NGF application. Conversely, chronically-applied serotonin selectively upregulated TRPV1 receptors rather than P2X3 receptors. Conclusion Comparing ganglia and cultures offered the advantage of understanding early adaptive changes of nociception

  17. Inherent dynamics of head domain correlates with ATP-recognition of P2X4 receptors: insights gained from molecular simulations.

    Directory of Open Access Journals (Sweden)

    Li-Dong Huang

    Full Text Available P2X receptors are ATP-gated ion channels involved in many physiological functions, and determination of ATP-recognition (AR of P2X receptors will promote the development of new therapeutic agents for pain, inflammation, bladder dysfunction and osteoporosis. Recent crystal structures of the zebrafish P2X4 (zfP2X4 receptor reveal a large ATP-binding pocket (ABP located at the subunit interface of zfP2X4 receptors, which is occupied by a conspicuous cluster of basic residues to recognize triphosphate moiety of ATP. Using the engineered affinity labeling and molecular modeling, at least three sites (S1, S2 and S3 within ABP have been identified that are able to recognize the adenine ring of ATP, implying the existence of at least three distinct AR modes in ABP. The open crystal structure of zfP2X4 confirms one of three AR modes (named AR1, in which the adenine ring of ATP is buried into site S1 while the triphosphate moiety interacts with clustered basic residues. Why architecture of ABP favors AR1 not the other two AR modes still remains unexplored. Here, we examine the potential role of inherent dynamics of head domain, a domain involved in ABP formation, in AR determinant of P2X4 receptors. In silico docking and binding free energy calculation revealed comparable characters of three distinct AR modes. Inherent dynamics of head domain, especially the downward motion favors the preference of ABP for AR1 rather than AR2 and AR3. Along with the downward motion of head domain, the closing movement of loop139-146 and loop169-183, and structural rearrangements of K70, K72, R298 and R143 enabled ABP to discriminate AR1 from other AR modes. Our observations suggest the essential role of head domain dynamics in determining AR of P2X4 receptors, allowing evaluation of new strategies aimed at developing specific blockers/allosteric modulators by preventing the dynamics of head domain associated with both AR and channel activation of P2X4 receptors.

  18. Dielectric relaxation and ionic conductivity studies of Na 2 ZnP 2 O 7

    Indian Academy of Sciences (India)

    The Na2ZnP2O7 compound was obtained by the conventional solid-state reaction. The sample was characterized by X-ray powder diffraction, infrared analysis and electrical impedance spectroscopy. The impedance plots show semicircle arcs at different temperatures and an electrical equivalent circuit has been proposed ...

  19. Analysis of the probability of channel satisfactory state in P2P live ...

    African Journals Online (AJOL)

    In this paper a model based on user behaviour of P2P live streaming systems was developed in order to analyse one of the key QoS parameter of such systems, i.e. the probability of channel-satisfactory state, the impact of upload bandwidths and channels' popularity on the probability of channel-satisfactory state was also ...

  20. Characterization of purinergic P2X4 receptor channels expressed in anterior pituitary cells

    Czech Academy of Sciences Publication Activity Database

    Zemková, Hana; Kučka, M.; Li, S.; Gonzales-Iglesias, A. E.; Tomic, M.; Stojilkovic, S. S.

    2010-01-01

    Roč. 298, č. 3 (2010), E664-E651 ISSN 0193-1849 R&D Projects: GA MŠk(CZ) LC554; GA ČR(CZ) GA305/07/0681 Institutional research plan: CEZ:AV0Z50110509 Keywords : P2X4 receptor * ATP * pituitary Subject RIV: ED - Physiology Impact factor: 4.686, year: 2010

  1. Time dependency on the fabrication of H 4 TPPS 4 2- -SnTPyP 2+ ...

    African Journals Online (AJOL)

    4-pyridyl)porphyrin dichloride (SnTPyP2+) porphyrin nanorods were prepared at room temperature by ionic self-assembly of these two oppositely charged porphyrins. The UV-VIS absorption spectra of the samples were measured hourly for the ...

  2. analysis of the probability of channel satisfactory state in p2p live

    African Journals Online (AJOL)

    userpc

    ABSTRACT. In this paper a model based on user behaviour of P2P live streaming systems was developed in order to analyse one of the key QoS parameter of such systems, i.e. the probability of channel-satisfactory state, the impact of upload bandwidths and channels' popularity on the probability of channel-satisfactory ...

  3. X-ray structures define human P2X3 receptor gating cycle and antagonist action

    NARCIS (Netherlands)

    Mansoor, Steven E.; Lü, Wei; Oosterheert, W.; Shekhar, Mrinal; Tajkhorshid, Emad; Gouaux, Eric

    2016-01-01

    P2X receptors are trimeric, non-selective cation channels activated by ATP that have important roles in the cardiovascular, neuronal and immune systems. Despite their central function in human physiology and although they are potential targets of therapeutic agents, there are no structures of human

  4. E2E blocking probability of IPTV and P2PTV

    NARCIS (Netherlands)

    Lu, Y.; Kuipers, F.; Janic, M.; Mieghem, P. van

    2008-01-01

    Increased Internet speeds together with new possibilities for tailor-made television services have spurred the interest in providing television via the Internet. Several television services are readily available and both IP-layer and application-layer (P2P) technologies are used. When disregarding

  5. PTEN interaction with tethered bilayer lipid membranes containing PI(4,5)P2

    Science.gov (United States)

    Moldovan, R.; Shenoy, S.; Shekhar, P.; Kalinowski, A.; Gericke, A.; Heinrich, F.; Loesche, M.

    2009-03-01

    Synthetic lipid membrane models are frequently used for the study of biophysical processes at cell membranes. We use a robust membrane model, the tethered bilayer lipid membrane (tBLM), based on a (C14)2-(PEO)6-thiol anchor, WC14 [1]. Such membranes can be prepared to contain single phospholipids or complex lipid mixtures [2], including functional lipids involved in cell signaling, such as the highly charged phosphatidylinositol phosphates (PIPs). To study the interaction between the tumor suppressor PTEN (phosphatase and tensin homologue deleted on chromosome 10) and model membranes we have incorporated phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) in tBLMs and use fluorescence correlation spectroscopy (FCS), neutron reflectometry (NR) and surface plasmon resonance (SPR) for their characterization. NR shows that tBLMs formed with PI(4,5)P2 are complete. FCS of labeled PI(4,5)P2 shows that diffusion occurs at the time scale characteristic of membrane-incorporated lipid. Finally, SPR shows specific binding of PTEN to the model membrane thus confirming the incorporation of PI(4,5)P2 into the tBLM. [1] McGillivray et al, Biointerphases 2, 21-33 (2007) [2] Heinrich et al, Langmuir, submitted

  6. Database selection and result merging in P2P web search

    NARCIS (Netherlands)

    Chernov, S.; Serdyukov, Pavel; Bender, M.; Michel, S.; Weikum, G.; Zimmer, C.

    Intelligent Web search engines are extremely popular now. Currently, only the commercial centralized search engines like Google can process terabytes of Web data. Alternative search engines fulfilling collaborative Web search on a voluntary basis are usually based on a blooming Peer-to-Peer (P2P)

  7. Prostaglandin H synthase-mediated bioactivation of the amino acid pyrolysate product Trp P-2

    Energy Technology Data Exchange (ETDEWEB)

    Petry, T.W.; Krauss, R.S.; Eling, T.E.

    1986-08-01

    We report evidence that the mutagen and carcinogen 3-amino-1-methyl-5H pyrido(4,3b)indole (Trp P-2) is a substrate for co-oxidation by prostaglandin H synthase (PHS) in ram seminal vesicle (RSV) microsomes. Trp P-2 serves as a reducing cofactor for the hydroperoxidase activity of PHS as shown by the concentration-dependent inhibition of the hydroperoxidase catalyzed incorporation of molecular oxygen into phenylbutazone. Spectral data suggest that this metabolism results in disruption of the double bond conjugation within the nucleus of the molecule. A single metabolite peak which was dependent upon arachidonic acid and substrate concentration was separated from the parent compound by h.p.l.c. following incubation with RSV microsomes. Co-oxidation of Trp P-2 produced reactive intermediates which bound covalently to microsomal protein (9 nmol/mg) and to calf thymus DNA (475 pmol/mg). Binding was inhibited by indomethacin, and supported by substitution of hydrogen peroxide for arachidonic acid. These data suggest a possible role for PHS in the in situ activation of Trp P-2 to its ultimate carcinogenic form in tissues which contain PHS.

  8. Acoustic study of nano-crystal embedded PbO–P2O5 glass

    Indian Academy of Sciences (India)

    Unknown

    Abstract. Nano-crystal embedded PbO–P2O5 glass has been prepared and characterized by XRD and TEM measurements. The ultrasonic velocity and attenuation measured within the temperature range 80–300 K show significant structure and interesting feature with the presence of nano-crystalline region. The glass ...

  9. Scalable P2P Overlays of Very Small Constant Degree: An Emerging Security Threat

    Science.gov (United States)

    Jelasity, Márk; Bilicki, Vilmos

    In recent years peer-to-peer (P2P) technology has been adopted by Internet-based malware as a fault tolerant and scalable communication medium for self-organization and survival. It has been shown that malicious P2P networks would be nearly impossible to uncover if they operated in a stealth mode, that is, using only a small constant number of fixed overlay connections per node for communication. While overlay networks of a small constant maximal degree are generally considered to be unscalable, we argue in this paper that it is possible to design them to be scalable, efficient and robust. This is an important finding from a security point of view: we show that stealth mode P2P malware that is very difficult to discover with state-of-the-art methods is a plausible threat. In this paper we discuss algorithms and theoretical results that support the scalability of stealth mode overlays, and we present realistic simulations using an event based implementation of a proof-of-concept system. Besides P2P botnets, our results are also applicable in scenarios where relying on a large number of overlay connections per node is not feasible because of cost or the limited number of communication channels available.

  10. Dual Gating Mechanism and Function of P2X7 Receptor Channels

    Czech Academy of Sciences Publication Activity Database

    Khadra, A.; Tomic, M.; Yan, Z.; Zemková, Hana; Sherman, A.; Stojilkovic, S. S.

    2013-01-01

    Roč. 104, č. 12 (2013), s. 2612-2621 ISSN 0006-3495 R&D Projects: GA ČR(CZ) GBP304/12/G069 Institutional support: RVO:67985823 Keywords : purinergic P2X7 receptors * ATP-gated channels * BzATP * dilation * Markov -state model Subject RIV: ED - Physiology Impact factor: 3.832, year: 2013

  11. Extraction du complexe (𕔣P 2 W 17 O 61 Fe)7-, par ...

    African Journals Online (AJOL)

    membrane The extraction of a Dawson-type heteropolyanion (∝1P2W17O61Fe) 7- was carried out by liquid surfactant membrane using (SPAN80) as surfactantand (TIBA) as extractant, internal phase used (NH4)2CO3. The extraction efficiency is 90 %. Then in order to regenerate the membrane, the stripping efficiency was ...

  12. Comparing manually-developed and data-driven rules for P2P learning

    CSIR Research Space (South Africa)

    Loots, L

    2009-11-01

    Full Text Available Phoneme-to-phoneme (P2P) learning provides a mechanism for predicting the pronunciation of a word based on its pronunciation in a different accent, dialect or language. The authors evaluate the effectiveness of manually-developed as well...

  13. A classification of cubic symmetric graphs of order 16p2

    Indian Academy of Sciences (India)

    In this paper, we classify all connected cubic symmetric graphs of order 16p2 for each prime p. Keywords. Regular coverings; symmetric graphs; invariant subspaces. 1. Introduction. Throughout this paper, graphs are assumed to be finite, simple, undirected and connected. For the group-theoretic concepts and notations not ...

  14. Planet-induced Stellar Pulsations in HAT-P-2's Eccentric System

    Energy Technology Data Exchange (ETDEWEB)

    Wit, Julien de [Department of Earth, Atmospheric and Planetary Sciences, MIT, 77 Massachusetts Avenue, Cambridge, MA 02139 (United States); Lewis, Nikole K. [Space Telescope Science Institute, 3700 San Martin Drive, Baltimore, MD 21218 (United States); Knutson, Heather A.; Batygin, Konstantin [Division of Geological and Planetary Sciences, California Institute of Technology, Pasadena, CA 91125 (United States); Fuller, Jim [TAPIR, Walter Burke Institute for Theoretical Physics, Mailcode 350-17, California Institute of Technology, Pasadena, CA 91125 (United States); Antoci, Victoria [Stellar Astrophysics Centre, Department of Physics and Astronomy, Aarhus University, Ny Munkegade 120, DK-8000 Aarhus C (Denmark); Fulton, Benjamin J. [Institute for Astronomy, University of Hawaii, Honolulu, HI 96822 (United States); Laughlin, Gregory [Department of Astronomy, Yale University, New Haven, CT 06511 (United States); Deming, Drake [Department of Astronomy, University of Maryland at College Park, College Park, MD 20742 (United States); Shporer, Avi [Jet Propulsion Laboratory, California Institute of Technology, 4800 Oak Grove Drive, Pasadena, CA 91009 (United States); Cowan, Nicolas B. [Department of Physics, Department of Earth and Planetary Sciences, McGill University, 3550 rue University, Montreal, QC H3A 2A7 (Canada); Agol, Eric [Department of Astronomy, University of Washington, Seattle, WA 98195 (United States); Burrows, Adam S. [Department of Astrophysical Sciences, Princeton University, Princeton, NJ 08544 (United States); Fortney, Jonathan J. [Department of Astronomy and Astrophysics, University of California, Santa Cruz, CA 95064 (United States); Langton, Jonathan [Department of Physics, Principia College, Elsah, IL 62028 (United States); Showman, Adam P. [Lunar and Planetary Laboratory, University of Arizona, Tucson, AZ 85721 (United States)

    2017-02-20

    Extrasolar planets on eccentric short-period orbits provide a laboratory in which to study radiative and tidal interactions between a planet and its host star under extreme forcing conditions. Studying such systems probes how the planet’s atmosphere redistributes the time-varying heat flux from its host and how the host star responds to transient tidal distortion. Here, we report the insights into the planet–star interactions in HAT-P-2's eccentric planetary system gained from the analysis of ∼350 hr of 4.5 μ m observations with the Spitzer Space Telescope . The observations show no sign of orbit-to-orbit variability nor of orbital evolution of the eccentric planetary companion, HAT-P-2 b. The extensive coverage allows us to better differentiate instrumental systematics from the transient heating of HAT-P-2 b’s 4.5 μ m photosphere and yields the detection of stellar pulsations with an amplitude of approximately 40 ppm. These pulsation modes correspond to exact harmonics of the planet’s orbital frequency, indicative of a tidal origin. Transient tidal effects can excite pulsation modes in the envelope of a star, but, to date, such pulsations had only been detected in highly eccentric stellar binaries. Current stellar models are unable to reproduce HAT-P-2's pulsations, suggesting that our understanding of the interactions at play in this system is incomplete.

  15. Planet-induced Stellar Pulsations in HAT-P-2's Eccentric System

    International Nuclear Information System (INIS)

    Wit, Julien de; Lewis, Nikole K.; Knutson, Heather A.; Batygin, Konstantin; Fuller, Jim; Antoci, Victoria; Fulton, Benjamin J.; Laughlin, Gregory; Deming, Drake; Shporer, Avi; Cowan, Nicolas B.; Agol, Eric; Burrows, Adam S.; Fortney, Jonathan J.; Langton, Jonathan; Showman, Adam P.

    2017-01-01

    Extrasolar planets on eccentric short-period orbits provide a laboratory in which to study radiative and tidal interactions between a planet and its host star under extreme forcing conditions. Studying such systems probes how the planet’s atmosphere redistributes the time-varying heat flux from its host and how the host star responds to transient tidal distortion. Here, we report the insights into the planet–star interactions in HAT-P-2's eccentric planetary system gained from the analysis of ∼350 hr of 4.5 μ m observations with the Spitzer Space Telescope . The observations show no sign of orbit-to-orbit variability nor of orbital evolution of the eccentric planetary companion, HAT-P-2 b. The extensive coverage allows us to better differentiate instrumental systematics from the transient heating of HAT-P-2 b’s 4.5 μ m photosphere and yields the detection of stellar pulsations with an amplitude of approximately 40 ppm. These pulsation modes correspond to exact harmonics of the planet’s orbital frequency, indicative of a tidal origin. Transient tidal effects can excite pulsation modes in the envelope of a star, but, to date, such pulsations had only been detected in highly eccentric stellar binaries. Current stellar models are unable to reproduce HAT-P-2's pulsations, suggesting that our understanding of the interactions at play in this system is incomplete.

  16. A study of a sector spectrophotometer and auroral O+(2P-2D) emissions

    Science.gov (United States)

    Swenson, G. R.

    1976-01-01

    The metastable O+(2P-2D) auroral emission was investigated. The neighboring OH contaminants and low intensity levels of the emission itself necessitated the evolution of an instrument capable of separating the emission from the contaminants and having a high sensitivity in the wavelength region of interest. A new type of scanning photometer was developed and its properties are discussed. The theoretical aspects of auroral electron interaction with atomic oxygen and the resultant O+(2P-2D) emissions were examined in conjunction with N2(+)1NEG emissions. Ground based measurements of O+(2P-2D) auroral emission intensities were made using the spatial scanning photometer (sector spectrophotometer). Simultaneous measurements of N2(+)1NEG sub 1,0 emission intensity were made in the same field of view using a tilting photometer. Time histories of the ratio of these two emissions made in the magnetic zenith during auroral breakup periods are given. Theories of I sub 7319/I sub 4278 of previous investigators were presented. A rocket measurement of N2(+)1NEG sub 0,0 and O+(2P-2D) emission in aurora was examined in detail and was found to agree with the ground based measurements. Theoretical examination resulted in the deduction of the electron impact efficiency generating O+(2P) and also suggests a large source of O+(2P) at low altitude. A possible source is charge exchange of N+(1S) with OI(3P).

  17. Synthesis and structural characterization of Na2MnP2O7 crystal

    Indian Academy of Sciences (India)

    Unknown

    C and 50–60 bars. The starting mixture consists of manganese oxide, 85% orthophos- phoric acid and 2⋅5–5 M NaOH solution which acts as a mineralizer. Na2MnP2O7 crystals could be synthesized under the following molar ratio.

  18. Unstructured P2P Network Load Balance Strategy Based on Multilevel Partitioning of Hypergraph

    Science.gov (United States)

    Feng, Lv; Chunlin, Gao; Kaiyang, Ma

    2017-05-01

    With rapid development of computer performance and distributed technology, P2P-based resource sharing mode plays important role in Internet. P2P network users continued to increase so the high dynamic characteristics of the system determine that it is difficult to obtain the load of other nodes. Therefore, a dynamic load balance strategy based on hypergraph is proposed in this article. The scheme develops from the idea of hypergraph theory in multilevel partitioning. It adopts optimized multilevel partitioning algorithms to partition P2P network into several small areas, and assigns each area a supernode for the management and load transferring of the nodes in this area. In the case of global scheduling is difficult to be achieved, the priority of a number of small range of load balancing can be ensured first. By the node load balance in each small area the whole network can achieve relative load balance. The experiments indicate that the load distribution of network nodes in our scheme is obviously compacter. It effectively solves the unbalanced problems in P2P network, which also improve the scalability and bandwidth utilization of system.

  19. Tetrahydro-4-quinolinamines identified as novel P2Y(1) receptor antagonists.

    Science.gov (United States)

    Morales-Ramos, Angel I; Mecom, John S; Kiesow, Terry J; Graybill, Todd L; Brown, Gregory D; Aiyar, Nambi V; Davenport, Elizabeth A; Kallal, Lorena A; Knapp-Reed, Beth A; Li, Peng; Londregan, Allyn T; Morrow, Dwight M; Senadhi, Shobha; Thalji, Reema K; Zhao, Steve; Burns-Kurtis, Cynthia L; Marino, Joseph P

    2008-12-01

    High-throughput screening of the GSK compound collection against the P2Y(1) receptor identified a novel series of tetrahydro-4-quinolinamine antagonists. Optimal substitution around the piperidine group was pivotal for ensuring activity. An exemplar analog from this series was shown to inhibit platelet aggregation.

  20. Benzofuran-substituted urea derivatives as novel P2Y(1) receptor antagonists.

    Science.gov (United States)

    Thalji, Reema K; Aiyar, Nambi; Davenport, Elizabeth A; Erhardt, Joseph A; Kallal, Lorena A; Morrow, Dwight M; Senadhi, Shobha; Burns-Kurtis, Cynthia L; Marino, Joseph P

    2010-07-15

    Benzofuran-substituted urea analogs have been identified as novel P2Y(1) receptor antagonists. Structure-activity relationship studies around the urea and the benzofuran moieties resulted in compounds having improved potency. Several analogs were shown to inhibit ADP-mediated platelet activation. 2010 Elsevier Ltd. All rights reserved.

  1. Dependence of purinergic P2X receptor activity on ectodomain structure

    Czech Academy of Sciences Publication Activity Database

    He, M. L.; Zemková, Hana; Stojilkovic, S. S.

    2003-01-01

    Roč. 278, č. 12 (2003), s. 10182-10188 ISSN 0021-9258 Institutional research plan: CEZ:AV0Z5011922 Keywords : P2X purinergic receptor * calcium signaling * membrane current Subject RIV: ED - Physiology Impact factor: 6.482, year: 2003

  2. From P2P to Web services and grids peers in a client/server world

    CERN Document Server

    Taylor, Ian J

    2005-01-01

    Provides an overview of peer-to-peer (P2P) technologies that have revolutionized the way we think about distributed computing and the internet. This book compares these technologies to alternative solutions, most notably web services and Grid computing but also other technologies, such as client/server based systems and agent technologies.

  3. Extending an Afrikaans pronunciation dictionary using Dutch resources and P2P/GP2P

    CSIR Research Space (South Africa)

    Loots, L

    2010-11-01

    Full Text Available . This is compared to the more common approach of extending the Afrikaans dictionary by means of graphemeto-phoneme (G2P) conversion. The results indicate that the Afrikaans pronunciations obtained by P2P and GP2P from the Dutch dictionary are more accurate than...

  4. Integrating XQuery and P2P in MonetDB/XQuery*

    NARCIS (Netherlands)

    Y. Zhang (Ying); P.A. Boncz (Peter); M. Arenas; J. Hidders

    2007-01-01

    textabstractMonetDB/XQuery* is a fully functional publicly available XML DBMS that has been extended with distributed and P2P data management functionality. Our (minimal) XQuery language extension XRPC adds the concept of RPC to XQuery, and exploits the set-at-a-time database processing model to

  5. A Novel Iterative and Dynamic Trust Computing Model for Large Scaled P2P Networks

    Directory of Open Access Journals (Sweden)

    Zhenhua Tan

    2016-01-01

    Full Text Available Trust management has been emerging as an essential complementary part to security mechanisms of P2P systems, and trustworthiness is one of the most important concepts driving decision making and establishing reliable relationships. Collusion attack is a main challenge to distributed P2P trust model. Large scaled P2P systems have typical features, such as large scaled data with rapid speed, and this paper presented an iterative and dynamic trust computation model named IDTrust (Iterative and Dynamic Trust model according to these properties. First of all, a three-layered distributed trust communication architecture was presented in IDTrust so as to separate evidence collector and trust decision from P2P service. Then an iterative and dynamic trust computation method was presented to improve efficiency, where only latest evidences were enrolled during one iterative computation. On the basis of these, direct trust model, indirect trust model, and global trust model were presented with both explicit and implicit evidences. We consider multifactors in IDTrust model according to different malicious behaviors, such as similarity, successful transaction rate, and time decay factors. Simulations and analysis proved the rightness and efficiency of IDTrust against attacks with quick respond and sensitiveness during trust decision.

  6. Incentivizing Cooperation in P2P File Sharing : Indirect Interaction as an Incentive to Seed

    NARCIS (Netherlands)

    Noroozian, A.; De Weerdt, M.M.; Witteveen, C.

    2012-01-01

    The fundamental problem with P2P networks is that quality of service depends on altruistic resource sharing by participating peers. Many peers freeride on the generosity of others. Current solutions like sharing ratio enforcement and reputation systems are complex, exploitable, inaccurate or unfair

  7. X-ray structures define human P2X3 receptor gating cycle and antagonist action

    Science.gov (United States)

    Mansoor, Steven E.; Lü, Wei; Oosterheert, Wout; Shekhar, Mrinal; Tajkhorshid, Emad; Gouaux, Eric

    2016-10-01

    P2X receptors are trimeric, non-selective cation channels activated by ATP that have important roles in the cardiovascular, neuronal and immune systems. Despite their central function in human physiology and although they are potential targets of therapeutic agents, there are no structures of human P2X receptors. The mechanisms of receptor desensitization and ion permeation, principles of antagonism, and complete structures of the pore-forming transmembrane domains of these receptors remain unclear. Here we report X-ray crystal structures of the human P2X3 receptor in apo/resting, agonist-bound/open-pore, agonist-bound/closed-pore/desensitized and antagonist-bound/closed states. The open state structure harbours an intracellular motif we term the ‘cytoplasmic cap’, which stabilizes the open state of the ion channel pore and creates lateral, phospholipid-lined cytoplasmic fenestrations for water and ion egress. The competitive antagonists TNP-ATP and A-317491 stabilize the apo/resting state and reveal the interactions responsible for competitive inhibition. These structures illuminate the conformational rearrangements that underlie P2X receptor gating and provide a foundation for the development of new pharmacological agents.

  8. Molecular mechanism of ATP binding and ion channel activation in P2X receptors

    Energy Technology Data Exchange (ETDEWEB)

    Hattori, Motoyuki; Gouaux, Eric (Oregon HSU)

    2012-10-24

    P2X receptors are trimeric ATP-activated ion channels permeable to Na{sup +}, K{sup +} and Ca{sup 2+}. The seven P2X receptor subtypes are implicated in physiological processes that include modulation of synaptic transmission, contraction of smooth muscle, secretion of chemical transmitters and regulation of immune responses. Despite the importance of P2X receptors in cellular physiology, the three-dimensional composition of the ATP-binding site, the structural mechanism of ATP-dependent ion channel gating and the architecture of the open ion channel pore are unknown. Here we report the crystal structure of the zebrafish P2X4 receptor in complex with ATP and a new structure of the apo receptor. The agonist-bound structure reveals a previously unseen ATP-binding motif and an open ion channel pore. ATP binding induces cleft closure of the nucleotide-binding pocket, flexing of the lower body {beta}-sheet and a radial expansion of the extracellular vestibule. The structural widening of the extracellular vestibule is directly coupled to the opening of the ion channel pore by way of an iris-like expansion of the transmembrane helices. The structural delineation of the ATP-binding site and the ion channel pore, together with the conformational changes associated with ion channel gating, will stimulate development of new pharmacological agents.

  9. Characterization of the contractile P2Y14 receptor in mouse coronary and cerebral arteries

    DEFF Research Database (Denmark)

    Haanes, Kristian Agmund; Edvinsson, Lars

    2014-01-01

    values and immunohistochemistry illustrated the strongest P2Y14 receptor expression in the basilar artery. In the presence of pertussis toxin, UDP-glucose inhibited contraction in coronary arteries and in the basilar artery it surprisingly caused relaxation. After organ culture of the coronary artery...

  10. Lack of a Functioning P2X7 Receptor Leads to Increased Susceptibility to Toxoplasmic Ileitis.

    Directory of Open Access Journals (Sweden)

    Catherine M Miller

    Full Text Available Oral infection of C57BL/6J mice with the protozoan parasite Toxoplasma gondii leads to a lethal inflammatory ileitis.Mice lacking the purinergic receptor P2X7R are acutely susceptible to toxoplasmic ileitis, losing significantly more weight than C57BL/6J mice and exhibiting much greater intestinal inflammatory pathology in response to infection with only 10 cysts of T. gondii. This susceptibility is not dependent on the ability of P2X7R-deficient mice to control the parasite, which they accomplish just as efficiently as C57BL/6J mice. Rather, susceptibility is associated with elevated ileal concentrations of pro-inflammatory cytokines, reactive nitrogen intermediates and altered regulation of elements of NFκB activation in P2X7R-deficient mice.Our data support the thesis that P2X7R, a well-documented activator of pro-inflammatory cytokine production, also plays an important role in the regulation of intestinal inflammation.

  11. Electronic Structure and Optical Properties Of EuIn2P2

    KAUST Repository

    Singh, Nirpendra

    2011-10-25

    The electronic structures and, optical and magneto‐optical properties of a newly found Zintl compound EuIn2P2 have been investigated within the density‐functional theory using the highly precise full‐potential linear‐augmented‐plane‐wave method. Results of detailed investigation of the electronic structure and related properties are reported.

  12. Quantum chemical investigation of the reaction of O( P2) with certain ...

    Indian Academy of Sciences (India)

    WINTEC

    Abstract. The reaction of ground-state atomic oxygen [O(3. P2)] with methyl, ethyl, n-propyl and iso- propyl radicals has been studied using the density functional method and the complete basis set model. The energies of the reactants, products, reaction intermediates and various transition states as well as the reaction ...

  13. SiO adsorption on a p(2 × 2) reconstructed Si(1 0 0) surface

    NARCIS (Netherlands)

    Violanda, M.|info:eu-repo/dai/nl/304840262; Rudolph, H.|info:eu-repo/dai/nl/304830496

    2009-01-01

    We have investigated the adsorption mechanism of SiO molecule incident on a clean Si(1 0 0) p(2 × 2) reconstructed surface using density functional theory based methods. Stable adsorption geometries of SiO on Si surface, as well as their corresponding activation and adsorption energies are

  14. The "P2P" Educational Model Providing Innovative Learning by Linking Technology, Business and Research

    Science.gov (United States)

    Dickinson, Paul Gordon

    2017-01-01

    This paper evaluates the effect and potential of a new educational learning model called Peer to Peer (P2P). The study was focused on Laurea, Hyvinkaa's Finland campus and its response to bridging the gap between traditional educational methods and working reality, where modern technology plays an important role. The study describes and evaluates…

  15. Common variants in P2RY11 are associated with narcolepsy

    DEFF Research Database (Denmark)

    Kornum, Birgitte R; Kawashima, Minae; Faraco, Juliette

    2011-01-01

    of P2RY11 in CD8(+) T lymphocytes (339% reduced, P = 0.003) and natural killer (NK) cells (P = 0.031), but not in other peripheral blood mononuclear cell types. The low expression variant is also associated with reduced P2RY11-mediated resistance to ATP-induced cell death in T lymphocytes (P = 0......Growing evidence supports the hypothesis that narcolepsy with cataplexy is an autoimmune disease. We here report genome-wide association analyses for narcolepsy with replication and fine mapping across three ethnic groups (3,406 individuals of European ancestry, 2,414 Asians and 302 African...... Americans). We identify a SNP in the 3' untranslated region of P2RY11, the purinergic receptor subtype P2Y₁₁ gene, which is associated with narcolepsy (rs2305795, combined P = 6.1 × 10⁻¹⁰, odds ratio = 1.28, 95% CI 1.19-1.39, n = 5689). The disease-associated allele is correlated with reduced expression...

  16. The effect of purinergic P2 receptor blockade on skeletal muscle exercise hyperemia in miniature swine

    DEFF Research Database (Denmark)

    Mortensen, Stefan Peter; McAllister, R M; Yang, H T

    2014-01-01

    -microsphere technique and systemic hemodynamics before and after arterial infusion of the P2 receptor antagonist reactive blue 2 during treadmill exercise (5.2 km/h, ~60 % VO2max) and arterial ATP infusion in female Yucatan miniature swine (~29 kg). RESULTS: Mean blood flow during exercise from the 16 sampled skeletal...

  17. Assisted reproductive technology in China: compliance and non-compliance.

    Science.gov (United States)

    Qiao, Jie; Feng, Huai L

    2014-04-01

    According to the WHO, infertility and sterility will be the third-most serious disease worldwide in the 21st century, after cancer and cardiovascular diseases. In contrast to developed countries, assisted reproductive technology (ART) were not offered in China until the mid-1980s with the first in vitro fertilization (IVF) infant born in Taiwan in 1985, then Hong Kong in 1986, and mainland China in 1988, respectively. Since those inceptions, the practice of ART in China has evoked a variety of social, cultural, political and one-child policy responses that have resulted in restrictions on the number of IVF cycles performed annually. According to recent survey, an estimate 40-50 million women and 45 million men suffered from infertility, which is estimated that more than ten million Chinese infertile couples require ART treatment. However, it has limited access to ART facilities, many of them may not have a child are whirling to all types of fertility therapies. Exposure to radiation, pesticides and other environmental pollutants, work-related stress and unhealthy lifestyles are believed to contribute to the increasing incidence of infertility in China. The aim of this first report is to provide China nationwide ART data and government policy in compliance and 
non-compliance, particularly related to family plan policy in China.

  18. Is the auditory evoked P2 response a biomarker of learning?

    Directory of Open Access Journals (Sweden)

    Kelly eTremblay

    2014-02-01

    Full Text Available Even though auditory training exercises for humans have been shown to improve certain perceptual skills of individuals with and without hearing loss, there is a lack of knowledge pertaining to which aspects of training are responsible for the perceptual gains, and which aspects of perception are changed. To better define how auditory training impacts brain and behavior, electroencephalography and magnetoencephalography have been used to determine the time course and coincidence of cortical modulations associated with different types of training. Here we focus on P1-N1-P2 auditory evoked responses (AEP, as there are consistent reports of gains in P2 amplitude following various types of auditory training experiences; including music and speech-sound training. The purpose of this experiment was to determine if the auditory evoked P2 response is a biomarker of learning. To do this, we taught native English speakers to identify a new pre-voiced temporal cue that is not used phonemically in the English language so that coinciding changes in evoked neural activity could be characterized. To differentiate possible effects of repeated stimulus exposure and a button-pushing task from learning itself, we examined modulations in brain activity in a group of participants who learned to identify the pre-voicing contrast and compared it to participants, matched in time, and stimulus exposure, that did not. The main finding was that the amplitude of the P2 auditory evoked response increased across repeated EEG sessions for all groups, regardless of any change in perceptual performance. What’s more, these effects were retained for months. Changes in P2 amplitude were attributed to changes in neural activity associated with the acquisition process and not the learned outcome itself. A further finding was the expression of a late negativity (LN wave 600-900 ms post-stimulus onset, post-training, exclusively for the group that learned to identify the pre

  19. Structure, Adsorption to Host, and Infection Mechanism of Virulent Lactococcal Phage p2

    Science.gov (United States)

    Bebeacua, Cecilia; Tremblay, Denise; Farenc, Carine; Chapot-Chartier, Marie-Pierre; Sadovskaya, Irina; van Heel, Marin; Veesler, David

    2013-01-01

    Lactococcal siphophages from the 936 and P335 groups infect the Gram-positive bacterium Lactococcus lactis using receptor binding proteins (RBPs) attached to their baseplate, a large multiprotein complex at the distal part of the tail. We have previously reported the crystal and electron microscopy (EM) structures of the baseplates of phages p2 (936 group) and TP901-1 (P335 group) as well as the full EM structure of the TP901-1 virion. Here, we report the complete EM structure of siphophage p2, including its capsid, connector complex, tail, and baseplate. Furthermore, we show that the p2 tail is characterized by the presence of protruding decorations, which are related to adhesins and are likely contributed by the major tail protein C-terminal domains. This feature is reminiscent of the tail of Escherichia coli phage λ and Bacillus subtilis phage SPP1 and might point to a common mechanism for establishing initial interactions with their bacterial hosts. Comparative analyses showed that the architecture of the phage p2 baseplate differs largely from that of lactococcal phage TP901-1. We quantified the interaction of its RBP with the saccharidic receptor and determined that specificity is due to lower koff values of the RBP/saccharidic dissociation. Taken together, these results suggest that the infection of L. lactis strains by phage p2 is a multistep process that involves reversible attachment, followed by baseplate activation, specific attachment of the RBPs to the saccharidic receptor, and DNA ejection. PMID:24027307

  20. P2X7R modulation of visually evoked synaptic responses in the retina.

    Science.gov (United States)

    Chavda, Seetal; Luthert, Philip J; Salt, Thomas E

    2016-12-01

    P2X 7 Rs are distributed throughout all layers of the retina, and thus, their localisation on various cell types puts into question their specific site(s) of action. Using a dark-adapted, ex vivo mouse retinal whole mount preparation, the present study aimed to characterise the effect of P2X 7 R activation on light-evoked, excitatory RGC ON-field excitatory post-synaptic potentials (fEPSPs) and on outer retinal electroretinogram (ERG) responses under comparable conditions. The pharmacologically isolated NMDA receptor-mediated RGC ON-fEPSP was reduced in the presence of BzATP, an effect which was significantly attenuated by A438079 and other selective P2X 7 R antagonists A804598 or AF27139. In physiological Krebs medium, BzATP induced a significant potentiation of the ERG a-wave, with a concomitant reduction in the b-wave and the power of the oscillatory potentials. Conversely, in the pharmacologically modified Mg 2+ -free perfusate, BzATP reduced both the a-wave and b-wave. The effects of BzATP on the ERG components were suppressed by A438079. A role for P2X 7 R function in visual processing in both the inner and outer retina under physiological conditions remains controversial. The ON-fEPSP was significantly reduced in the presence of A804598 but not by A438079 or AF27139. Furthermore, A438079 did not have any effect on the ERG components in physiological Krebs but potentiated and reduced the a-wave and b-wave, respectively, when applied to the pharmacologically modified medium. Therefore, activation of P2X 7 Rs affects the function in the retinal ON pathway. The presence of a high concentration of extracellular ATP would most likely contribute to the modulation of visual transmission in the retina in the pathophysiological microenvironment.