WorldWideScience

Sample records for levels mcl enforceable

  1. Mcl-1 Ubiquitination: Unique Regulation of an Essential Survival Protein

    Directory of Open Access Journals (Sweden)

    Barbara Mojsa

    2014-05-01

    Full Text Available Mcl-1 is an anti-apoptotic protein of the Bcl-2 family that is essential for the survival of multiple cell lineages and that is highly amplified in human cancer. Under physiological conditions, Mcl-1 expression is tightly regulated at multiple levels, involving transcriptional, post-transcriptional and post-translational processes. Ubiquitination of Mcl-1, that targets it for proteasomal degradation, allows for rapid elimination of the protein and triggering of cell death, in response to various cellular events. In the last decade, a number of studies have elucidated different pathways controlling Mcl-1 ubiquitination and degradation. Four different E3 ubiquitin-ligases (e.g., Mule, SCFβ-TrCP, SCFFbw7 and Trim17 and one deubiquitinase (e.g., USP9X, that respectively mediate and oppose Mcl-1 ubiquitination, have been formerly identified. The interaction between Mule and Mcl-1 can be modulated by other Bcl-2 family proteins, while recognition of Mcl-1 by the other E3 ubiquitin-ligases and deubiquitinase is influenced by phosphorylation of specific residues in Mcl-1. The protein kinases and E3 ubiquitin-ligases that are involved in the regulation of Mcl-1 stability vary depending on the cellular context, highlighting the complexity and pivotal role of Mcl-1 regulation. In this review, we attempt to recapitulate progress in understanding Mcl-1 regulation by the ubiquitin-proteasome system.

  2. Mcl-1 dynamics influence mitotic slippage and death in mitosis.

    Science.gov (United States)

    Sloss, Olivia; Topham, Caroline; Diez, Maria; Taylor, Stephen

    2016-02-02

    Microtubule-binding drugs such as taxol are frontline treatments for a variety of cancers but exactly how they yield patient benefit is unclear. In cell culture, inhibiting microtubule dynamics prevents spindle assembly, leading to mitotic arrest followed by either apoptosis in mitosis or slippage, whereby a cell returns to interphase without dividing. Myeloid cell leukaemia-1 (Mcl-1), a pro-survival member of the Bcl-2 family central to the intrinsic apoptosis pathway, is degraded during a prolonged mitotic arrest and may therefore act as a mitotic death timer. Consistently, we show that blocking proteasome-mediated degradation inhibits taxol-induced mitotic apoptosis in a Mcl-1-dependent manner. However, this degradation does not require the activity of either APC/C-Cdc20, FBW7 or MULE, three separate E3 ubiquitin ligases implicated in targeting Mcl-1 for degradation. This therefore challenges the notion that Mcl-1 undergoes regulated degradation during mitosis. We also show that Mcl-1 is continuously synthesized during mitosis and that blocking protein synthesis accelerates taxol induced death-in-mitosis. Modulating Mcl-1 levels also influences slippage; overexpressing Mcl-1 extends the time from mitotic entry to mitotic exit in the presence of taxol, while inhibiting Mcl-1 accelerates it. We suggest that Mcl-1 competes with Cyclin B1 for binding to components of the proteolysis machinery, thereby slowing down the slow degradation of Cyclin B1 responsible for slippage. Thus, modulating Mcl-1 dynamics influences both death-in-mitosis and slippage. However, because mitotic degradation of Mcl-1 appears not to be under the control of an E3 ligase, we suggest that the notion of network crosstalk is used with caution.

  3. 29 CFR 1952.155 - Level of Federal enforcement.

    Science.gov (United States)

    2010-07-01

    ... relinquishes concurrent Federal OSHA authority to issue citations for violations of such standards under... conduct enforcement proceedings in contested cases under section 10; to institute proceedings to correct...) determination. (b)(1) In accordance with section 18(e), final approval relinquishes Federal OSHA authority only...

  4. miR-193b Regulates Mcl-1 in Melanoma.

    Science.gov (United States)

    Chen, Jiamin; Zhang, Xiao; Lentz, Cindy; Abi-Daoud, Marie; Paré, Geneviève C; Yang, Xiaolong; Feilotter, Harriet E; Tron, Victor A

    2011-11-01

    MicroRNAs play important roles in gene regulation, and their expression is frequently dysregulated in cancer cells. In a previous study, we reported that miR-193b represses cell proliferation and regulates cyclin D1 in melanoma cells, suggesting that miR-193b could act as a tumor suppressor. Herein, we demonstrate that miR-193b also down-regulates myeloid cell leukemia sequence 1 (Mcl-1) in melanoma cells. MicroRNA microarray profiling revealed that miR-193b is expressed at a significantly lower level in malignant melanoma than in benign nevi. Consistent with this, Mcl-1 is detected at a higher level in malignant melanoma than in benign nevi. In a survey of melanoma samples, the level of Mcl-1 is inversely correlated with the level of miR-193b. Overexpression of miR-193b in melanoma cells represses Mcl-1 expression. Previous studies showed that Mcl-1 knockdown cells are hypersensitive to ABT-737, a small-molecule inhibitor of Bcl-2, Bcl-X(L), and Bcl-w. Similarly, overexpression of miR-193b restores ABT-737 sensitivity to ABT-737-resistant cells. Furthermore, the effect of miR-193b on the expression of Mcl-1 seems to be mediated by direct interaction between miR-193b and seed and seedless pairing sequences in the 3' untranslated region of Mcl-1 mRNA. Thus, this study provides evidence that miR-193b directly regulates Mcl-1 and that down-regulation of miR-193b in vivo could be an early event in melanoma progression. Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  5. Nordic MCL2 trial update

    DEFF Research Database (Denmark)

    Geisler, Christian H; Kolstad, Arne; Laurell, Anna

    2012-01-01

    Mantle cell lymphoma (MCL) is a heterogenic non-Hodgkin lymphoma entity, with a median survival of about 5 years. In 2008 we reported the early - based on the median observation time of 4 years - results of the Nordic Lymphoma Group MCL2 study of frontline intensive induction immunochemotherapy...... and autologous stem cell transplantation (ASCT), with more than 60% event-free survival at 5 years, and no subsequent relapses reported. Here we present an update after a median observation time of 6·5 years. The overall results are still excellent, with median overall survival and response duration longer than...

  6. Medial Collateral Ligament (MCL) Injuries

    Science.gov (United States)

    ... impact activities like swimming, bike riding, or protected running. Talk to your doctor about what you can do. Some of these activities might even work as rehab therapy. Coping With an MCL Injury Being told that you can't do the ...

  7. Image of а head of law-enforcement body on micro level (empirical experimentation

    Directory of Open Access Journals (Sweden)

    D. G. Perednya

    2016-01-01

    Full Text Available The article determines image of the head of law-enforcement body. Subjects and objects of image are described. Inhomogenuity of image is cleared up. Method of examination is shortly micro level described. It is talking about image, which is formed in mind of members of team of law-enforcement body, who are subordinated to object of image. State-of-the-art is illustrated, according to received data. Hypothesis about negative image of the head in mind of subordinates is disproved. It is shown contradiction of images in collective mind and social mind.

  8. A Quantitative Examination Whether Education Mitigates Stress Levels among Law Enforcement Officers

    Science.gov (United States)

    Metts, Gary A.

    2012-01-01

    Stress is damaging if it is continual, overwhelming. and prolonged. Law enforcement officers face stressful events daily. A relationship exists between stress levels and the physical and psychological effects to the human body. Although there is a general understanding of the damage stress can do physically and psychologically, many elements that…

  9. 76 FR 63190 - Michigan State Plan; Change in Level of Federal Enforcement: Indian Tribes

    Science.gov (United States)

    2011-10-12

    ... issues covered by the state's OSHA-approved occupational safety and health plan. Federal OSHA retained... DEPARTMENT OF LABOR Occupational Safety and Health Administration 29 CFR Part 1952 Michigan State Plan; Change in Level of Federal Enforcement: Indian Tribes AGENCY: Occupational Safety and Health...

  10. 40 CFR 93.125 - Enforceability of design concept and scope and project-level mitigation and control measures.

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 20 2010-07-01 2010-07-01 false Enforceability of design concept and... Transit Laws § 93.125 Enforceability of design concept and scope and project-level mitigation and control... determinations for a transportation plan or TIP and are included in the project design concept and scope which is...

  11. Elevated Mcl-1 perturbs lymphopoiesis, promotes transformation of hematopoietic stem/progenitor cells, and enhances drug resistance

    OpenAIRE

    Campbell, Kirsteen J.; Bath, Mary L.; Turner, Marian L.; Vandenberg, Cassandra J.; Bouillet, Philippe; Metcalf, Donald; Scott, Clare L.; Cory, Suzanne

    2010-01-01

    Diverse human cancers with poor prognosis, including many lymphoid and myeloid malignancies, exhibit high levels of Mcl-1. To explore the impact of Mcl-1 overexpression on the hematopoietic compartment, we have generated vavP-Mcl-1 transgenic mice. Their lymphoid and myeloid cells displayed increased resistance to a variety of cytotoxic agents. Myelopoiesis was relatively normal, but lymphopoiesis was clearly perturbed, with excess mature B and T cells accumulating. Rather than the follicular...

  12. Association of anti-apoptotic Mcl-1L isoform expression with radioresistance of oral squamous carcinoma cells

    International Nuclear Information System (INIS)

    Palve, Vinayak C; Teni, Tanuja R

    2012-01-01

    Oral cancer is a common cancer and a major health problem in the Indian subcontinent. At our laboratory Mcl-1, an anti-apoptotic member of the Bcl-2 family has been demonstrated to be overexpressed in oral cancers and to predict outcome in oral cancer patients treated with definitive radiotherapy. To study the role of Mcl-1 isoforms in radiation response of oral squamous carcinoma cells (OSCC), we investigated in the present study, the association of Mcl-1 isoform expression with radiosensitivity of OSCC, using siRNA strategy. The time course expression of Mcl-1 splice variants (Mcl-1L, Mcl-1S & Mcl-1ES) was studied by RT-PCR, western blotting & immunofluorescence, post-irradiation in oral cell lines [immortalized FBM (radiosensitive) and tongue cancer AW8507 & AW13516 (radioresistant)]of relatively differing radiosensitivities. The effect of Mcl-1L knockdown alone or in combination with ionizing radiation (IR) on cell proliferation, apoptosis & clonogenic survival, was investigated in AW8507 & AW13516 cells. Further the expression of Mcl-1L protein was assessed in radioresistant sublines generated by fractionated ionizing radiation (FIR). Three to six fold higher expression of anti-apoptotic Mcl-1L versus pro-apoptotic Mcl-1S was observed at mRNA & protein levels in all cell lines, post-irradiation. Sustained high levels of Mcl-1L, downregulation of pro-apoptotic Bax & Bak and a significant (P < 0.05) reduction in apoptosis was observed in the more radioresistant AW8507, AW13516 versus FBM cells, post-IR. The ratios of anti to pro-apoptotic proteins were high in AW8507 as compared to FBM. Treatment with Mcl-1L siRNA alone or in combination with IR significantly (P < 0.01) increased apoptosis viz. 17.3% (IR), 25.3% (siRNA) and 46.3% (IR plus siRNA) and upregulated pro-apoptotic Bax levels in AW8507 cells. Combination of siRNA & IR treatment significantly (P < 0.05) reduced cell proliferation and clonogenic survival of radioresistant AW8507 & AW13516 cells

  13. Degradation of Mcl-1 through GSK-3β Activation Regulates Apoptosis Induced by Bufalin in Non-Small Cell Lung Cancer H1975 Cells

    Directory of Open Access Journals (Sweden)

    Xiao-hong Kang

    2017-04-01

    Full Text Available Background/Aims: Mcl-1, an anti-apoptotic Bcl-2 family member, is often overexpressed in non-small cell lung cancer (NSCLC. Bufalin has been reported to induce apoptosis in various tumor cells. However, there is no report showing that bufalin could downregulate Mcl-1 expression in NSCLC. Methods: Cell proliferation was analyzed by cell counting kit-8 (CCK-8 assay in H1975 cells. Cell apoptosis was detected by flow cytometry. Mcl-1 mRNA was detected by RT-PCR. The expression of apoptosis-associated proteins in H1975 cells was detected by western blotting. The levels of Mcl-1 ubiquitination and NOXA were analyzed by Immunoprecipitation assay. Results: Cell growth was inhibited by bufalin in a time and dose-dependent manner. Bufalin induced apoptosis in NSCLC cells by activating caspase cascades and downregulating Mcl-1 expression. However, overexpression of Mcl-1 diminished bufalin-induced apoptosis. Furthermore, bufalin did not reduce Mcl-1 mRNA expression in H1975 cells, but strongly promoted Mcl-1 protein degradation. Proteasome inhibitor MG132 markedly prevented the degradation of Mcl-1 and blocked bufalin-induced Mcl-1 reduction. Bufalin did not significantly affect NOXA protein levels, but downregulated the expression of p-GSK-3β. GSK-3 inhibitor and GSK-3β siRNA resulted in increased levels of Mcl-1 and reversed the bufalin-induced Mcl-1 degradation. Conclusion: Bufalin induced cell apoptosis in H1975 cells may be through downregulation of Mcl-1. Proteasomal degradation of Mcl-1 via GSK-3β activation was involved in bufalin-induced apoptosis.

  14. Law enforcers recognition level emerging threats based on physical appearance and behavior signs the enemy

    Directory of Open Access Journals (Sweden)

    R.M. Radzievskiy

    2015-02-01

    Full Text Available Purpose: examine the effectiveness of the training method of differential approach to the choice of means of influence on the action of law enforcers opponent with different levels of aggressiveness. Material : the experiment involved 15 students of the Kyiv National Academy of Internal Affairs and the 15 employees of the State Guard of Ukraine. Results : presented curriculum for special physical and tactical training. The program details the conceptual apparatus of THREATS and DANGERS manifestations of different levels of aggressiveness opponent (case analysis of its motor behavior. The study participants underwent 7 day course focused training. The basis of the course is an advanced theoretical base. The base is aimed at developing knowledge and skills of employees in determining the level of danger. Including threats from testing and modeling episodes of extreme situations the options cadets. Conclusions : In the simulated collision situations with aggressive opponent to the students significantly improved the adequacy of the response to the threat of execution time and within the legal grounds. Recognition was determined by the level of aggressiveness manifest manners enemy, his emotions, motivation, motor behavior, positional arrangement for 2 - 3 seconds. The program contributed to the development of qualities: attention, orientation, perception, motor lead.

  15. MicroRNA-451 sensitizes lung cancer cells to cisplatin through regulation of Mcl-1.

    Science.gov (United States)

    Cheng, Dezhi; Xu, Yi; Sun, Changzheng; He, Zhifeng

    2016-12-01

    As one of the most widely used chemotherapy drugs for lung cancer, chemoresistance of cisplatin (DPP) is one of the major hindrances in treatment of this malignancy. The microRNAs (miRNAs) have been identified to mediate chemotherapy drug resistance. MiR-451 as a tumor suppressor has been evaluated its potential effect on the sensitivity of cancer cells to DDP. However, the role of miR-451 in regulatory mechanism of chemosensitivity in lung cancer cells is still largely unknown. In this study, we first constructed a cisplatin-resistant A549 cell line (A549/DPP) accompanied with a decreased expression of miR-451 and an increased expression of Mcl-1in the drug resistant cells compared with the parental cells. Exogenous expression of miR-451 level in A549/DPP was found to sensitize their reaction to the treatment of cisplatin, which coincides with reduced expression of Mcl-1. Interestingly, Mcl-1 knockdown in A549/DPP cells increased the chemosensitivity to DPP, suggesting the dependence of Mcl-1 regulation in miR-451 activity. Moreover, miR-451 can restore cisplatin treatment response in cisplatin-resistant xenografts in vivo, while Mcl-1 protein levels were decreased. Thus, these findings provided that in lung cancer cells, tumor suppressor miR-451 enhanced DPP sensitivity via regulation of Mcl-1 expression, which could be served as a novel therapeutic target for the treatment of chemotherapy resistant in lung cancer.

  16. Simultaneous targeting of ATM and Mcl-1 increases cisplatin sensitivity of cisplatin-resistant non-small cell lung cancer.

    Science.gov (United States)

    Zhang, Fuquan; Shen, Mingjing; Yang, Li; Yang, Xiaodong; Tsai, Ying; Keng, Peter C; Chen, Yongbing; Lee, Soo Ok; Chen, Yuhchyau

    2017-08-03

    Development of cisplatin-resistance is an obstacle in non-small cell lung cancer (NSCLC) therapeutics. To investigate which molecules are associated with cisplatin-resistance, we analyzed expression profiles of several DNA repair and anti-apoptosis associated molecules in parental (A549P and H157P) and cisplatin-resistant (A549CisR and H157CisR) NSCLC cells. We detected constitutively upregulated nuclear ATM and cytosolic Mcl-1 molcules in cisplatin-resistant cells compared with parental cells. Increased levels of phosphorylated ATM (p-ATM) and its downstream molecules, CHK2, p-CHK2, p-53, and p-p53 were also detected in cisplatin-resistant cells, suggesting an activation of ATM signaling in these cells. Upon inhibition of ATM and Mcl-1 expression/activity using specific inhibitors of ATM and/or Mcl-1, we found significantly enhanced cisplatin-cytotoxicity and increased apoptosis of A549CisR cells after cisplatin treatment. Several A549CisR-derived cell lines, including ATM knocked down (A549CisR-siATM), Mcl-1 knocked down (A549CisR-shMcl1), ATM/Mcl-1 double knocked down (A549CisR-siATM/shMcl1) as well as scramble control (A549CisR-sc), were then developed. Higher cisplatin-cytotoxicity and increased apoptosis were observed in A549CisR-siATM, A549CisR-shMcl1, and A549CisR-siATM/shMcl1 cells compared with A549CisR-sc cells, and the most significant effect was shown in A549CisR-siATM/shMcl1 cells. In in vivo mice studies using subcutaneous xenograft mouse models developed with A549CisR-sc and A549CisR-siATM/shMcl1 cells, significant tumor regression in A549CisR-siATM/shMcl1 cells-derived xenografts was observed after cisplatin injection, but not in A549CisR-sc cells-derived xenografts. Finally, inhibitor studies revealed activation of Erk signaling pathway was most important in upregulation of ATM and Mcl-1 molcules in cisplatin-resistant cells. These studies suggest that simultaneous blocking of ATM/Mcl-1 molcules or downstream Erk signaling may recover the

  17. The downregulation of Mcl-1 via USP9X inhibition sensitizes solid tumors to Bcl-xl inhibition

    International Nuclear Information System (INIS)

    Peddaboina, Chander; Smythe, W Roy; Cao, Xiaobo; Jupiter, Daniel; Fletcher, Steven; Yap, Jeremy L; Rai, Arun; Tobin, Richard P; Jiang, Weihua; Rascoe, Philip; Rogers, M Karen Newell

    2012-01-01

    It has been shown in many solid tumors that the overexpression of the pro-survival Bcl-2 family members Bcl-xL and Mcl-1 confers resistance to a variety of chemotherapeutic agents. Mcl-1 is a critical survival protein in a variety of cell lineages and is critically regulated via ubiquitination. The Mcl-1, Bcl-xL and USP9X expression patterns in human lung and colon adenocarcinomas were evaluated via immunohistochemistry. Interaction between USP9X and Mcl-1 was demonstrated by immunoprecipitation-western blotting. The protein expression profiles of Mcl-1, Bcl-xL and USP9X in multiple cancer cell lines were determined by western blotting. Annexin-V staining and cleaved PARP western blotting were used to assay for apoptosis. The cellular toxicities after various treatments were measured via the XTT assay. In our current analysis of colon and lung cancer samples, we demonstrate that Mcl-1 and Bcl-xL are overexpressed and also co-exist in many tumors and that the expression levels of both genes correlate with the clinical staging. The downregulation of Mcl-1 or Bcl-xL via RNAi was found to increase the sensitivity of the tumor cells to chemotherapy. Furthermore, our analyses revealed that USP9X expression correlates with that of Mcl-1 in human cancer tissue samples. We additionally found that the USP9X inhibitor WP1130 promotes Mcl-1 degradation and increases tumor cell sensitivity to chemotherapies. Moreover, the combination of WP1130 and ABT-737, a well-documented Bcl-xL inhibitor, demonstrated a chemotherapeutic synergy and promoted apoptosis in different tumor cells. Mcl-1, Bcl-xL and USP9X overexpression are tumor survival mechanisms protective against chemotherapy. USP9X inhibition increases tumor cell sensitivity to various chemotherapeutic agents including Bcl-2/Bcl-xL inhibitors

  18. Notch signaling regulates expression of Mcl-1 and apoptosis in PPD-treated macrophages.

    Science.gov (United States)

    Palaga, Tanapat; Ratanabunyong, Siriluk; Pattarakankul, Thitiporn; Sangphech, Naunpun; Wongchana, Wipawee; Hadae, Yukihiro; Kueanjinda, Patipark

    2013-09-01

    Macrophages are cellular targets for infection by bacteria and viruses. The fate of infected macrophages plays a key role in determining the outcome of the host immune response. Apoptotic cell death of macrophages is considered to be a protective host defense that eliminates pathogens and infected cells. In this study, we investigated the involvement of Notch signaling in regulating apoptosis in macrophages treated with tuberculin purified protein derivative (PPD). Murine bone marrow-derived macrophages (BMMs) treated with PPD or infected with Mycobacterium bovis Bacillus Calmette-Guérin (BCG) induced upregulation of Notch1. This upregulation correlated well with the upregulation of the anti-apoptotic gene mcl-1 both at the transcriptional and translational levels. Decreased levels of Notch1 and Mcl-1 were observed in BMM treated with PPD when a gamma secretase inhibitor (GSI), which inhibits the processing of Notch receptors, was used. Moreover, silencing Notch1 in the macrophage-like cell line RAW264.7 decreased Mcl-1 protein expression, suggesting that Notch1 is critical for Mcl-1 expression in macrophages. A significant increase in apoptotic cells was observed upon treatment of BMM with PPD in the presence of GSI compared to the vehicle-control treated cells. Finally, analysis of the mcl-1 promoter in humans and mice revealed a conserved potential CSL/RBP-Jκ binding site. The association of Notch1 with the mcl-1 promoter was confirmed by chromatin immunoprecipitation. Taken together, these results indicate that Notch1 inhibits apoptosis of macrophages stimulated with PPD by directly controlling the mcl-1 promoter.

  19. The Influence of Higher Education on Law Enforcement Entry Level Examination Outcomes

    Science.gov (United States)

    Paprota, David A.

    2012-01-01

    Entry into a career in law enforcement is most often dependent upon the aspiring candidate's relative success on a competitive, written, multiple-choice examination. In the state of New Jersey, as in many states, civil service laws preclude consideration of formal educational attainment when establishing the ordinal, eligibles lists for law…

  20. The E3 ubiquitin ligases β-TrCP and FBXW7 cooperatively mediates GSK3-dependent Mcl-1 degradation induced by the Akt inhibitor API-1, resulting in apoptosis.

    Science.gov (United States)

    Ren, Hui; Koo, Junghui; Guan, Baoxiang; Yue, Ping; Deng, Xingming; Chen, Mingwei; Khuri, Fadlo R; Sun, Shi-Yong

    2013-11-22

    The novel Akt inhibitor, API-1, induces apoptosis through undefined mechanisms. The current study focuses on revealing the mechanisms by which API-1 induces apoptosis. API-1 rapidly and potently reduced the levels of Mcl-1 primarily in API-1-senstive lung cancer cell lines. Ectopic expression of Mcl-1 protected cells from induction of apoptosis by API-1. API-1 treatment decreased the half-life of Mcl-1, whereas inhibition of the proteasome with MG132 rescued Mcl-1 reduction induced by API-1. API-1 decreased Mcl-1 levels accompanied with a rapid increase in Mcl-1 phosphorylation (S159/T163). Moreover, inhibition of GSK3 inhibited Mcl-1 phosphorylation and reduction induced by API-1 and antagonized the effect of API-1 on induction of apoptosis. Knockdown of either FBXW7 or β-TrCP alone, both of which are E3 ubiquitin ligases involved in Mcl-1 degradation, only partially rescued Mcl-1 reduction induced by API-1. However, double knockdown of both E3 ubiquitin ligases enhanced the rescue of API-1-induced Mcl-1 reduction. API-1 induces GSK3-dependent, β-TrCP- and FBXW7-mediated Mcl-1 degradation, resulting in induction of apoptosis.

  1. Value addition - a marketing strategy for MCL

    Energy Technology Data Exchange (ETDEWEB)

    Sagar, C.K.; Mishra, P.K.; Baranwal, P.K. [Central Mine Planning and Design Institute, Ranchi (India)

    2002-07-01

    The energy sector will remain dependent on coal because of depletion of oil reserves. With deterioration of power grade coal, the emission of greenhouse gas is going to increase thereby stressing the need of using prepared low ash coal for protection of global environment. Further, recent stipulation of MOEF imposing restriction on use of high ash coal at distant power houses and those at sensitive localities and critically polluted areas have made the aspect of marketing of coal more challenging. This has necessitated a long-term strategy for improving the quality of coal in light of national environment policy. This is more relevant in the present scenario of open market, where we need to market our coal rather simply supplying r.o.m. coal to the linked users. Mahanadi Coalfields, Limited (MCL), the youngest subsidiary of Coal India Limited bestowed with a huge reserve of inferior grade and mainly linked to power sector, is taken as a sample case study. To fulfil the demand of coal with due regard to the national environmental policy, there is need of value addition as strategy of marketing for power coal of MCL. Value addition of coal can be achieved by two distinct different ways i.e. beneficiating high ash coal at pit head or blending high ash coal with low ash coal which is a less preferred option due to non-availability of low ash coal in MCL. 7 refs., 7 tabs.

  2. Reducing the Impact of Immigration Enforcement Policies to Ensure the Health of North Carolinians: Statewide Community-Level Recommendations.

    Science.gov (United States)

    Mann, Lilli; Simán, Florence M; Downs, Mario; Sun, Christina J; de Hernandez, Brisa Urquieta; García, Manuel; Alonzo, Jorge; Lawlor, Emma; Rhodes, Scott D

    2016-01-01

    Research indicates that fear of immigration enforcement among Latinos in North Carolina results in limited access to and utilization of health services and negative health consequences. This project developed recommendations to mitigate the public health impact of immigration enforcement policies in North Carolina. Our community-based participatory research partnership conducted 6 Spanish-language report-backs (an approach to sharing, validating, and interpreting data) and 3 bilingual forums with community members and public health leaders throughout North Carolina. The goals of these events were to discuss the impact of immigration enforcement on Latino health and develop recommendations to increase health services access and utilization. Findings from the report-backs and forums were analyzed using grounded theory to identify and refine common recommendations. A total of 344 people participated in the report-backs and forums. Eight recommendations emerged: increase knowledge among Latinos about local health services; build capacity to promote policy changes; implement system-level changes among organizations providing health services; train lay health advisors to help community members navigate systems; share Latinos' experiences with policy makers; reduce transportation barriers; increase schools' support of Latino families; and increase collaboration among community members, organizations, health care providers, and academic researchers. Representatives from 16 of 100 North Carolina counties participated. These 16 counties represent geographically diverse regions, and many of these counties have large Latino populations. Immigration enforcement is a public health issue. Participants proposed developing new partnerships, identifying strategies, and implementing action steps for carrying out recommendations to reduce negative health outcomes among Latinos in North Carolina. ©2016 by the North Carolina Institute of Medicine and The Duke Endowment. All rights

  3. Application of clustering methods: Regularized Markov clustering (R-MCL) for analyzing dengue virus similarity

    Science.gov (United States)

    Lestari, D.; Raharjo, D.; Bustamam, A.; Abdillah, B.; Widhianto, W.

    2017-07-01

    Dengue virus consists of 10 different constituent proteins and are classified into 4 major serotypes (DEN 1 - DEN 4). This study was designed to perform clustering against 30 protein sequences of dengue virus taken from Virus Pathogen Database and Analysis Resource (VIPR) using Regularized Markov Clustering (R-MCL) algorithm and then we analyze the result. By using Python program 3.4, R-MCL algorithm produces 8 clusters with more than one centroid in several clusters. The number of centroid shows the density level of interaction. Protein interactions that are connected in a tissue, form a complex protein that serves as a specific biological process unit. The analysis of result shows the R-MCL clustering produces clusters of dengue virus family based on the similarity role of their constituent protein, regardless of serotypes.

  4. The stress protein BAG3 stabilizes Mcl-1 protein and promotes survival of cancer cells and resistance to antagonist ABT-737.

    Science.gov (United States)

    Boiani, Mariana; Daniel, Cristina; Liu, Xueyuan; Hogarty, Michael D; Marnett, Lawrence J

    2013-03-08

    Members of the Bcl-2 family of proteins are important inhibitors of apoptosis in human cancer and are targets for novel anticancer agents such as the Bcl-2 antagonists, ABT-263 (Navitoclax), and its analog ABT-737. Unlike Bcl-2, Mcl-1 is not antagonized by ABT-263 or ABT-737 and is considered to be a major factor in resistance. Also, Mcl-1 exhibits differential regulation when compared with other Bcl-2 family members and is a target for anticancer drug discovery. Here, we demonstrate that BAG3, an Hsp70 co-chaperone, protects Mcl-1 from proteasomal degradation, thereby promoting its antiapoptotic activity. Using neuroblastoma cell lines, with a defined Bcl-2 family dependence, we found that BAG3 expression correlated with Mcl-1 dependence and ABT-737 resistance. RNA silencing of BAG3 led to a marked reduction in Mcl-1 protein levels and overcame ABT-737 resistance in Mcl-1-dependent cells. In ABT-737-resistant cells, Mcl-1 co-immunoprecipitated with BAG3, and loss of Mcl-1 after BAG3 silencing was prevented by proteasome inhibition. BAG3 and Mcl-1 were co-expressed in a panel of diverse cancer cell lines resistant to ABT-737. Silencing BAG3 reduced Mcl-1 protein levels and overcame ABT-737 resistance in several of the cell lines, including triple-negative breast cancer (MDA-MB231) and androgen receptor-negative prostate cancer (PC3) cells. These studies identify BAG3-mediated Mcl-1 stabilization as a potential target for cancer drug discovery.

  5. The Stress Protein BAG3 Stabilizes Mcl-1 Protein and Promotes Survival of Cancer Cells and Resistance to Antagonist ABT-737*

    Science.gov (United States)

    Boiani, Mariana; Daniel, Cristina; Liu, Xueyuan; Hogarty, Michael D.; Marnett, Lawrence J.

    2013-01-01

    Members of the Bcl-2 family of proteins are important inhibitors of apoptosis in human cancer and are targets for novel anticancer agents such as the Bcl-2 antagonists, ABT-263 (Navitoclax), and its analog ABT-737. Unlike Bcl-2, Mcl-1 is not antagonized by ABT-263 or ABT-737 and is considered to be a major factor in resistance. Also, Mcl-1 exhibits differential regulation when compared with other Bcl-2 family members and is a target for anticancer drug discovery. Here, we demonstrate that BAG3, an Hsp70 co-chaperone, protects Mcl-1 from proteasomal degradation, thereby promoting its antiapoptotic activity. Using neuroblastoma cell lines, with a defined Bcl-2 family dependence, we found that BAG3 expression correlated with Mcl-1 dependence and ABT-737 resistance. RNA silencing of BAG3 led to a marked reduction in Mcl-1 protein levels and overcame ABT-737 resistance in Mcl-1-dependent cells. In ABT-737-resistant cells, Mcl-1 co-immunoprecipitated with BAG3, and loss of Mcl-1 after BAG3 silencing was prevented by proteasome inhibition. BAG3 and Mcl-1 were co-expressed in a panel of diverse cancer cell lines resistant to ABT-737. Silencing BAG3 reduced Mcl-1 protein levels and overcame ABT-737 resistance in several of the cell lines, including triple-negative breast cancer (MDA-MB231) and androgen receptor-negative prostate cancer (PC3) cells. These studies identify BAG3-mediated Mcl-1 stabilization as a potential target for cancer drug discovery. PMID:23341456

  6. BAG3-mediated Mcl-1 stabilization contributes to drug resistance via interaction with USP9X in ovarian cancer.

    Science.gov (United States)

    Habata, Shutaro; Iwasaki, Masahiro; Sugio, Asuka; Suzuki, Miwa; Tamate, Masato; Satohisa, Seiro; Tanaka, Ryoichi; Saito, Tsuyoshi

    2016-07-01

    Paclitaxel in combination with carboplatin improves survival among patients with susceptible ovarian cancers, but no strategy has been established against resistant ovarian cancers. BAG3 (Bcl-2-associated athanogene 3) is one of six BAG family proteins, which are involved in such cellular processes as proliferation, migration and apoptosis. In addition, expression of BAG3 with Mcl-1, a Bcl-2 family protein, reportedly associates with resistance to chemotherapy. Our aim in this study was to evaluate the functional role of BAG3 and Mcl-1 in ovarian cancer chemoresistance and explore possible new targets for treatment. We found that combined expression of BAG3 and Mcl-1 was significantly associated with a poor prognosis in ovarian cancer patients. In vitro, BAG3 knockdown in ES2 clear ovarian cancer cells significantly increased the efficacy of paclitaxel in combination with the Mcl-1 antagonist MIM1, with or without the Bcl-2 family antagonist ABT737. Moreover, BAG3 was found to positively regulate Mcl-1 levels by binding to and inhibiting USP9X. Our data show that BAG3 and Mcl-1 are key mediators of resistance to chemotherapy in ovarian cancer. In BAG3 knockdown ES2 clear ovarian cancer cells, combination with ABT737 and MIM1 enhanced the efficacy of paclitaxel. These results suggest that inhibiting BAG3 in addition to anti-apoptotic Bcl-2 family proteins may be a useful therapeutic strategy for the treatment of chemoresistant ovarian cancers.

  7. Reducing stigma in healthcare and law enforcement: a novel approach to service provision for street level sex workers.

    Science.gov (United States)

    Bodkin, Kate; Delahunty-Pike, Alannah; O'Shea, Tim

    2015-04-09

    Providing services for street level sex workers requires a multidisciplinary approach, addressing both health and safety concerns typical of their age and gender and those that arise specific to their line of work. Despite being a diverse population, studies have identified some specific health needs for sex workers including addictions treatment, mental health. Additionally, studies have shown a higher risk of physical and sexual assault for this population. The Persons at Risk program (PAR) in London, Ontario, Canada was started in 2005 to address the specific needs of street level sex workers by using a harm-reduction model for policing and healthcare provision. This qualitative study evaluated this model of care in terms of improving access to healthcare and essential police services for street level sex workers. A total of 14 semi-structured interviews were conducted with current and former female street level sex workers enrolled in the PAR program. In addition, 3 semi-structured interviews were conducted with health and law enforcement professionals. The research team then analyzed and coded the transcripts using qualitative description to identify key themes in the data. Results indicated that participants represent a vulnerable population with increased safety concerns and healthcare needs relating to addictions, mental health and infectious disease. Despite this, participants reported avoiding healthcare workers and police officers in the past because of fear of stigma or repercussions. All participants identified the harm reduction approach of the PAR program as being essential to their continued engagement with the program. Other important aspects included flexible hours, the location of the clinic, streamlined access to mental health and addictions treatment and the female gender of the police and healthcare worker. The PAR program provides sex workers access to much needed primary healthcare that is flexible and without judgment. In addition, they are

  8. Disentangling the roles of safety climate and safety culture: Multi-level effects on the relationship between supervisor enforcement and safety compliance.

    Science.gov (United States)

    Petitta, Laura; Probst, Tahira M; Barbaranelli, Claudio; Ghezzi, Valerio

    2017-02-01

    Despite increasing attention to contextual effects on the relationship between supervisor enforcement and employee safety compliance, no study has yet explored the conjoint influence exerted simultaneously by organizational safety climate and safety culture. The present study seeks to address this literature shortcoming. We first begin by briefly discussing the theoretical distinctions between safety climate and culture and the rationale for examining these together. Next, using survey data collected from 1342 employees in 32 Italian organizations, we found that employee-level supervisor enforcement, organizational-level safety climate, and autocratic, bureaucratic, and technocratic safety culture dimensions all predicted individual-level safety compliance behaviors. However, the cross-level moderating effect of safety climate was bounded by certain safety culture dimensions, such that safety climate moderated the supervisor enforcement-compliance relationship only under the clan-patronage culture dimension. Additionally, the autocratic and bureaucratic culture dimensions attenuated the relationship between supervisor enforcement and compliance. Finally, when testing the effects of technocratic safety culture and cooperative safety culture, neither safety culture nor climate moderated the relationship between supervisor enforcement and safety compliance. The results suggest a complex relationship between organizational safety culture and safety climate, indicating that organizations with particular safety cultures may be more likely to develop more (or less) positive safety climates. Moreover, employee safety compliance is a function of supervisor safety leadership, as well as the safety climate and safety culture dimensions prevalent within the organization. Copyright © 2016 Elsevier Ltd. All rights reserved.

  9. Targeting Mcl-1 for Radiosensitization of Pancreatic Cancers

    Directory of Open Access Journals (Sweden)

    Dongping Wei

    2015-02-01

    Full Text Available In order to identify targets whose inhibition may enhance the efficacy of chemoradiation in pancreatic cancer, we previously conducted an RNAi library screen of 8,800 genes. We identified Mcl-1 (myeloid cell leukemia-1, an anti-apoptotic member of the Bcl-2 family, as a target for sensitizing pancreatic cancer cells to chemoradiation. In the present study we investigated Mcl-1 inhibition by either genetic or pharmacological approaches as a radiosensitizing strategy in pancreatic cancer cells. Mcl-1 depletion by siRNA produced significant radiosensitization in BxPC-3 and Panc-1 cells in association with Caspase-3 activation and PARP cleavage, but only minimal radiosensitization in MiaPaCa-2 cells. We next tested the ability of the recently identified, selective, small molecule inhibitor of Mcl-1, UMI77, to radiosensitize in pancreatic cancer cells. UMI77 caused dissociation of Mcl-1 from the pro-apoptotic protein Bak and produced significant radiosensitization in BxPC-3 and Panc-1 cells, but minimal radiosensitization in MiaPaCa-2 cells. Radiosensitization by UMI77 was associated with Caspase-3 activation and PARP cleavage. Importantly, UMI77 did not radiosensitize normal small intestinal cells. In contrast, ABT-737, an established inhibitor of Bcl-2, Bcl-XL, and Bcl-w, failed to radiosensitize pancreatic cancer cells suggesting the unique importance of Mcl-1 relative to other Bcl-2 family members to radiation survival in pancreatic cancer cells. Taken together, these results validate Mcl-1 as a target for radiosensitization of pancreatic cancer cells and demonstrate the ability of small molecules which bind the canonical BH3 groove of Mcl-1, causing displacement of Mcl-1 from Bak, to selectively radiosensitize pancreatic cancer cells.

  10. Creating a Learning Organization in Law Enforcement: Maturity Levels for Police Oversight Agencies

    Science.gov (United States)

    Filstad, Cathrine; Gottschalk, Petter

    2010-01-01

    Purpose: The purpose of this paper is to conceptualize a stage model for maturity levels for police oversight agencies. Design/methodology/approach: The paper is based on a literature review covering police oversight organizations and stages of growth models. Findings: As a conceptual paper, the main findings are related to the appropriateness of…

  11. Effectiveness of enforcement levels of speed limit and drink driving laws and associated factors – Exploratory empirical analysis using a bivariate ordered probit model

    Directory of Open Access Journals (Sweden)

    Behram Wali

    2017-06-01

    Full Text Available The contemporary traffic safety research comprises little information on quantifying the simultaneous association between drink driving and speeding among fatally injured drivers. Potential correlation between driver's drink driving and speeding behavior poses a substantial methodological concern which needs investigation. This study therefore focused on investigating the simultaneous impact of socioeconomic factors, fatalities, vehicle ownership, health services and highway agency road safety policies on enforcement levels of speed limit and drink driving laws. The effectiveness of enforcement levels of speed limit and drink driving laws has been investigated through development of bivariate ordered probit model using data extricated from WHO's global status report on road safety in 2013. The consistent and intuitive parameter estimates along with statistically significant correlation between response outcomes validates the statistical supremacy of bivariate ordered probit model. The results revealed that fatalities per thousand registered vehicles, hospital beds per hundred thousand population and road safety policies are associated with a likely medium or high effectiveness of enforcement levels of speed limit and drink driving laws, respectively. Also, the model encapsulates the effect of several other agency related variables and socio-economic status on the response outcomes. Marginal effects are reported for analyzing the impact of such factors on intermediate categories of response outcomes. The results of this study are expected to provide necessary insights to elemental enforcement programs. Also, marginal effects of explanatory variables may provide useful directions for formulating effective policy countermeasures for overcoming driver's speeding and drink driving behavior.

  12. Explorative data analysis of MCL reveals gene expression networks implicated in survival and prognosis supported by explorative CGH analysis

    International Nuclear Information System (INIS)

    Blenk, Steffen; Engelmann, Julia C; Pinkert, Stefan; Weniger, Markus; Schultz, Jörg; Rosenwald, Andreas; Müller-Hermelink, Hans K; Müller, Tobias; Dandekar, Thomas

    2008-01-01

    Mantle cell lymphoma (MCL) is an incurable B cell lymphoma and accounts for 6% of all non-Hodgkin's lymphomas. On the genetic level, MCL is characterized by the hallmark translocation t(11;14) that is present in most cases with few exceptions. Both gene expression and comparative genomic hybridization (CGH) data vary considerably between patients with implications for their prognosis. We compare patients over and below the median of survival. Exploratory principal component analysis of gene expression data showed that the second principal component correlates well with patient survival. Explorative analysis of CGH data shows the same correlation. On chromosome 7 and 9 specific genes and bands are delineated which improve prognosis prediction independent of the previously described proliferation signature. We identify a compact survival predictor of seven genes for MCL patients. After extensive re-annotation using GEPAT, we established protein networks correlating with prognosis. Well known genes (CDC2, CCND1) and further proliferation markers (WEE1, CDC25, aurora kinases, BUB1, PCNA, E2F1) form a tight interaction network, but also non-proliferative genes (SOCS1, TUBA1B CEBPB) are shown to be associated with prognosis. Furthermore we show that aggressive MCL implicates a gene network shift to higher expressed genes in late cell cycle states and refine the set of non-proliferative genes implicated with bad prognosis in MCL. The results from explorative data analysis of gene expression and CGH data are complementary to each other. Including further tests such as Wilcoxon rank test we point both to proliferative and non-proliferative gene networks implicated in inferior prognosis of MCL and identify suitable markers both in gene expression and CGH data

  13. Voting over law enforcement: Mission impossible

    OpenAIRE

    İnal , Hakan

    2015-01-01

    Median voter theorem has been used in many economic environments including law enforcement. Assumptions of the median voter theorem, however, are generally violated in lawenforcement models. Moreover, it is impossible to have agents with "opposite equilibrium preferences" over enforcement levels in law enforcement models. These limitations on the use of preferences over law enforcement raises questions about the robustness and validity of law enforcement models.

  14. Bax/Mcl-1 balance affects neutrophil survival in intermittent hypoxia and obstructive sleep apnea: effects of p38MAPK and ERK1/2 signaling.

    Science.gov (United States)

    Dyugovskaya, Larissa; Polyakov, Andrey; Cohen-Kaplan, Victoria; Lavie, Peretz; Lavie, Lena

    2012-10-22

    Prolonged neutrophil survival is evident in various cardiovascular and respiratory morbidities, in hypoxic conditions in-vitro and in patients with obstructive sleep apnea (OSA) characterized by nightly intermittent hypoxia (IH). This may lead to persistent inflammation, tissue injury and dysfunction. We therefore investigated by a translational approach the potential contribution of the intrinsic stress-induced mitochondrial pathway in extending neutrophil survival under IH conditions. Thus, neutrophils of healthy individuals treated with IH in-vitro and neutrophils of OSA patients undergoing nightly IH episodes in-vivo were investigated. Specifically, the balance between pro-apoptotic Bax and anti-apoptotic Mcl-1 protein expression, and the potential involvement of p38MAPK and ERK1/2 signaling pathways in the control of Mcl-1 expression were investigated. Purified neutrophils were exposed to IH and compared to normoxia and to sustained hypoxia (SH) using a BioSpherix-OxyCycler C42 system. Bax and Mcl-1 levels, and p38MAPK and ERK1/2 phosphorylation were determined by western blotting. Also, Bax/Mcl-1 expression and Bax translocation to the mitochondria were assessed by confocal microscopy in pre-apoptotic neutrophils, before the appearance of apoptotic morphology. Co-localization of Bax and mitochondria was quantified by LSM 510 CarlZeiss MicroImaging using Manders Overlap Coefficient. A paired two-tailed t test, with Bonferroni correction for multiple comparisons, was used for statistical analysis. Compared to normoxia, IH and SH up-regulated the anti-apoptotic Mcl-1 by about 2-fold, down-regulated the pro-apoptotic Bax by 41% and 27%, respectively, and inhibited Bax co-localization with mitochondria before visible morphological signs of apoptosis were noted. IH induced ERK1/2 and p38MAPKs phosphorylation, whereas SH induced only p38MAPK phosphorylation. Accordingly, both ERK and p38MAPK inhibitors attenuated the IH-induced Mcl-1 increase. In SH, only p38MAPK

  15. FLAG-induced remission in a patient with acute mast cell leukemia (MCL exhibiting t(7;10(q22;q26 and KIT D816H

    Directory of Open Access Journals (Sweden)

    Peter Valent

    2014-01-01

    Full Text Available Mast cell leukemia (MCL is a life-threatening disease associated with high mortality and drug-resistance. Only few patients survive more than 12 months. We report on a 55-year-old female patient with acute MCL diagnosed in May 2012. The disease was characterized by a rapid increase in white blood cells and mast cells (MC in the peripheral blood, and a rapid increase of serum tryptase levels. The KIT D816H mutation was detected in the blood and bone marrow (BM. Induction chemotherapy with high-dose ARA-C and fludarabine (FLAG was administered. Unexpectedly, the patient entered a hematologic remission with almost complete disappearance of neoplastic MC and a decrease of serum tryptase levels to normal range after 2 cycles of FLAG. Consecutively, the patient was prepared for allogeneic stem cell transplantation. However, shortly after the third cycle of FLAG, tryptase levels increased again, immature MC appeared in the blood, and the patient died from cerebral bleeding. Together, this case shows that intensive chemotherapy regimens, like FLAG, may induce remission in acute MCL. However, treatment responses are short-lived and the overall outcome remains dismal in these patients. We propose to separate this acute type of MCL from more subacute or chronic variants of MCL.

  16. A Maltose-Binding Protein Fusion Construct Yields a Robust Crystallography Platform for MCL1.

    Directory of Open Access Journals (Sweden)

    Matthew C Clifton

    Full Text Available Crystallization of a maltose-binding protein MCL1 fusion has yielded a robust crystallography platform that generated the first apo MCL1 crystal structure, as well as five ligand-bound structures. The ability to obtain fragment-bound structures advances structure-based drug design efforts that, despite considerable effort, had previously been intractable by crystallography. In the ligand-independent crystal form we identify inhibitor binding modes not observed in earlier crystallographic systems. This MBP-MCL1 construct dramatically improves the structural understanding of well-validated MCL1 ligands, and will likely catalyze the structure-based optimization of high affinity MCL1 inhibitors.

  17. Levels of Organisation in agent-based modelling for renewable resources management. Agricultural water management collective rules enforcement in the French Drome River Valley Case Study

    International Nuclear Information System (INIS)

    Abrami, G.

    2004-11-01

    Levels of Organisation in agent-based modelling for renewable resources management. Agricultural water management collective rules enforcement in the French Dr me River Valley Case Study. In the context of Agent-Based Modelling for participative renewable resources management, this thesis is concerned with representing multiple tangled levels of organisation of a system. The Agent-Group-Role (AGR) formalism is borrowed from computer science research. It has been conceptually specified to handle levels of organisation, and behaviours within levels of organisation. A design methodology dedicated to AGR modelling has been developed, together with an implementation of the formalism over a multi-agent platform. AGR models of agricultural water management in the French Dr me River Valley have been built and tested. This experiment demonstrates the AGR formalism ability to (1) clarify usually implicit hypothesis on action modes, scales or viewpoints (2) facilitate the definition of scenarios with various collective rules, and various rules in enforcement behaviours (3) generate bricks for generic irrigated catchment models. (author)

  18. Law Enforcement Locations

    Data.gov (United States)

    Kansas Data Access and Support Center — Law Enforcement Locations in Kansas Any location where sworn officers of a law enforcement agency are regularly based or stationed. Law enforcement agencies "are...

  19. Adsorption of 1,2,3-Trichloropropane (TCP) to meet a MCL of 5 ppt.

    Science.gov (United States)

    Babcock, Roger W; Harada, Bryce K; Lamichhane, Krishna M; Tsubota, Korey T

    2018-02-01

    1,2,3-Trichloropropane (TCP) is a groundwater contaminant in the drinking water aquifers in Hawaii and some other states. Granular activated carbon (GAC) has been used for 30 years to treat approximately 60 million gallons per day of TCP-contaminated groundwater in Hawaii. The State of Hawaii's current maximum contaminant level (MCL) for TCP is 600 ng/L (ppt), and consideration is being given to lower the MCL to 5 ppt. There is no EPA MCL for TCP. A study was conducted to determine if any GAC could meet a 5 ppt MCL for TCP, and if so, how many bedvolumes (BVs) could be treated prior to breakthrough. Constant Diffusivity-Rapid Small-Scale Column Tests (CD-RSSCTs) were performed to evaluate GAC adsorption of TCP. Three different groundwaters and six different GACs were utilized. The RSSCTs with the currently-utilized GAC were predictive of the performance of the GAC contactors (50,000 BVs to breakthrough). Any of the six GACs could meet a MCL of 5 ppt and some could do so for 150,000 or more BVs. No single GAC was optimal for all three well sites, indicating effects of subtle undefined differences in the water matrix and/or GAC physiochemical properties. The coal-based direct-activated carbon currently being used is the least optimal for all three well sites with respect to meeting a potential new TCP MCL of 5 ppt. The most effective GACs for Kunia were the Calgon coal-based GAC and the Siemens enhanced coconut shell GAC, while the most effective for Waipahu were the Siemens regular and enhanced coconut shell GACs, and the most effective for Mililani was the Calgon coal-based GAC. Choosing just one GAC for use at all three well sites (rather than the optimal for each site) would result in a reduction of treatment run time of 1 year at one well site (63% reduction). Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. Pre-apoptotic response to therapeutic DNA damage involves protein modulation of Mcl-1, Hdm2 and Flt3 in acute myeloid leukemia cells

    Directory of Open Access Journals (Sweden)

    Hovland Randi

    2007-05-01

    Full Text Available Abstract Background Acute myeloid leukemia (AML cells are characterized by non-mutated TP53, high levels of Hdm2, and frequent mutation of the Flt3 receptor tyrosine kinase. The juxtamembrane mutation of FLT3 is the strongest independent marker for disease relapse and is associated with elevated Bcl-2 protein and p53 hyper-phosphorylation in AML. DNA damage forms the basic mechanism of cancer cell eradication in current therapy of AML. Hdm2 and pro-apoptotic Bcl-2 members are among the most intensely induced genes immediately after chemotherapy and Hdm2 is proposed a role in receptor tyrosine kinase regulation. Thus we examined the DNA damage related modulation of these proteins in relation to FLT3 mutational status and induction of apoptosis. Results Within one hour after exposure to ionizing radiation (IR, the AML cells (NB4, MV4-11, HL-60, primary AML cells showed an increase in Flt3 protein independent of mRNA levels, while the Hdm2 protein decreased. The FLT3 mutant MV4-11 cells were resistant to IR accompanied by presence of both Mcl-1 and Hdm2 protein three hours after IR. In contrast, the FLT3 wild type NB4 cells responded to IR with apoptosis and pre-apoptotic Mcl-1 down regulation. Daunorubicin (DNR induced continuing down regulation of Hdm2 and Mcl-1 in both cell lines followed by apoptosis. Conclusion Both IR and DNR treatment resulted in concerted protein modulations of Mcl-1, Hdm2 and Flt3. Cell death induction was associated with persistent attenuation of Mcl-1 and Hdm2. These observations suggest that defining the pathway(s modulating Flt3, Hdm2 and Mcl-1 may propose new strategies to optimize therapy for the relapse prone FLT3 mutated AML patients.

  1. Certification/enforcement analysis

    Energy Technology Data Exchange (ETDEWEB)

    None

    1980-06-01

    Industry compliance with minimum energy efficiency standards will be assured through a two-part program approach of certification and enforcement activities. The technical support document (TSD) presents the analyses upon which the proposed rule for assuring that consumer product comply with applicable energy efficiency standards is based. Much of the TSD is based upon support provided DOE by Vitro Laboratories. The OAO Corporation provided additional support in the development of the sampling plan incorporated in the proposed rule. Vitro's recommended approach to appliance certification and enforcement, developed after consideration of various program options, benefits, and impacts, establishes the C/E program framework, general criteria, and procedures for assuring a specified level of energy efficiency performance of covered consumer products. The results of the OAO analysis are given in Volume II of the TSD.

  2. miR-193b Modulates Resistance to Doxorubicin in Human Breast Cancer Cells by Downregulating MCL-1

    Directory of Open Access Journals (Sweden)

    Jingpei Long

    2015-01-01

    Full Text Available MicroRNAs (miRNAs family, which is involved in cancer development, proliferation, apoptosis, and drug resistance, is a group of noncoding RNAs that modulate the expression of oncogenes and antioncogenes. Doxorubicin is an active cytotoxic agent for breast cancer treatment, but the acquisition of doxorubicin resistance is a common and critical limitation to cancer therapy. The aim of this study was to investigate whether miR-193b mediated the resistance of breast cancer cells to doxorubicin by targeting myeloid cell leukemia-1 (MCL-1. In this study, we found that miR-193b levels were significantly lower in doxorubicin-resistant MCF-7 (MCF-7/DOXR cells than in the parental MCF-7 cells. We observed that exogenous miR-193b significantly suppressed the ability of MCF-7/DOXR cells to resist doxorubicin. It demonstrated that miR-193b directly targeted MCL-1 3′-UTR (3′-Untranslated Regions. Further studies indicated that miR-193b sensitized MCF-7/DOXR cells to doxorubicin through a mechanism involving the downregulation of MCL-1. Together, our findings provide evidence that the modulation of miR-193b may represent a novel therapeutic target for the treatment of breast cancer.

  3. Downregulation of miR-29a/b/c in placenta accreta inhibits apoptosis of implantation site intermediate trophoblast cells by targeting MCL1.

    Science.gov (United States)

    Gu, Yongzhong; Bian, Yuehong; Xu, Xiaofei; Wang, Xietong; Zuo, Changting; Meng, Jinlai; Li, Hongyan; Zhao, Shigang; Ning, Yunnan; Cao, Yongzhi; Huang, Tao; Yan, Junhao; Chen, Zi-Jiang

    2016-12-01

    Placenta accreta is defined as abnormal adhesion of placental villi to the uterine myometrium. Although this condition has become more common as a result of the increasing rate of cesarean sections, the underlying causative mechanism(s) remain elusive. Because microRNA-29a/b/c (miR-29a/b/c) have been shown to play important roles in placental development, this study evaluated the roles of these microRNAs in placenta accreta. Expression of miR-29a/b/c and myeloid cell leukemia-1 (MCL1) were quantified in patient tissues and HTR8/SVneo trophoblast cells using the real-time quantitative polymerase chain reaction. Western blotting was used to analyze expression of the MCL1 protein in HTR8/SVneo trophoblast cells with altered expression of miR-29a/b/c. To determine their role in apoptosis, miR-29a/b/c were overexpressed in HTR-8/SVneo cells, and levels of apoptosis were analyzed by flow cytometry. Luciferase activity assays were used to determine whether MCL1 is a target gene of miR-29a/b/c. Expression of miR-29a/b/c was significantly lower in creta sites compared to noncreta sites (p = 0.018, 0.041, and 0.022, respectively), but expression of MCL1 was upregulated in creta sites (p = 0.039). MCL1 expression was significantly downregulated in HTR-8/SVneo cells overexpressing miR-29a/b/c (p = 0.002, 0.008, and 0.013, respectively). Luciferase activity assays revealed that miR-29a/b/c directly target the 3' untranslated region of MCL1 in 293T cells. Over-expression of miR-29a/b/c induced apoptosis in the HTR-8/SVneo trophoblast cell line. Moreover, histopathological evaluation revealed that the number of implantation site intermediate trophoblast (ISIT) cells was increased in creta sites and that these cells were positive for MCL1. Our results demonstrate that in placenta accreta, miR-29a/b/c inhibits apoptosis of ISIT cells by targeting MCL1. These findings provide new insights into the pathogenesis of placenta accreta. Copyright © 2016 Elsevier Ltd. All rights

  4. Drug Enforcement Administration

    Science.gov (United States)

    ... de informacin confidencial --> DEA NEWS The Drug Enforcement Administration and Discovery Education name grand winner of Operation ... JUN 15 (Washington) The United States Drug Enforcement Administration, DEA Educational Foundation and Discovery Education awarded Porter ...

  5. Is intra-articular pathology associated with MCL edema on MR imaging of the non-traumatic knee?

    International Nuclear Information System (INIS)

    Blankenbaker, Donna G.; De Smet, Arthur A.; Fine, Jason P.

    2005-01-01

    Edema surrounding the medial collateral ligament (MCL) is seen on MR imaging in patients with MCL injuries and in patients with radiographic osteoarthritis in the non-traumatic knee. Because we noted MCL edema in patients without prior trauma or osteoarthritis, we studied the association between intra-articular pathology and MCL edema in patients without knee trauma. We evaluated the MR examinations of 247 consecutive patients (121 male, 126 female with a mean age of 44 years) without recent trauma for the presence of edema surrounding the MCL, meniscal and ACL tears, medial meniscal extrusion, medial compartment chondromalacia, and osteoarthritis. The percentages of patients illustrating MCL edema with and without each type of pathology were compared using Fisher's exact test to determine if there was a statistically significant association. We found MCL edema in 60% of 247 patients. MCL edema was present in 67% of patients with medial meniscal tears, 35% with lateral meniscal tears, 100% with meniscal extrusion of 3 mm or more, 78% with femoral chondromalacia, 82% with tibial chondromalacia, and 50% with osteoarthritis. The percentage of patients with edema increased with the severity of the chondromalacia. These associations were all statistically significant (p <0.02). The mean age of those with MCL edema was 49.7 years compared with 34.9 years without MCL edema (p <0.001). Patient gender and ACL tear did not correlate with MCL edema. Nine (4%) of the 247 patients had MCL edema without intra-articular pathology. None of these 9 patients had MCL tenderness or joint laxity on physical examination. We confirmed that MCL edema is associated with osteoarthritis, but is also associated with meniscal tears, meniscal extrusion, and chondromalacia. In addition, MCL edema can be seen in patients without intra-articular pathology, recent trauma or MCL abnormality on physical examination. (orig.)

  6. Is intra-articular pathology associated with MCL edema on MR imaging of the non-traumatic knee?

    Energy Technology Data Exchange (ETDEWEB)

    Blankenbaker, Donna G.; De Smet, Arthur A. [University of Wisconsin Medical School, Division of Musculoskeletal Imaging, Department of Radiology, Madison (United States); Fine, Jason P. [University of Wisconsin, Department of Statistics, Madison (United States); University of Wisconsin, Department of Biostatistics and Informatics, Madison (United States)

    2005-08-01

    Edema surrounding the medial collateral ligament (MCL) is seen on MR imaging in patients with MCL injuries and in patients with radiographic osteoarthritis in the non-traumatic knee. Because we noted MCL edema in patients without prior trauma or osteoarthritis, we studied the association between intra-articular pathology and MCL edema in patients without knee trauma. We evaluated the MR examinations of 247 consecutive patients (121 male, 126 female with a mean age of 44 years) without recent trauma for the presence of edema surrounding the MCL, meniscal and ACL tears, medial meniscal extrusion, medial compartment chondromalacia, and osteoarthritis. The percentages of patients illustrating MCL edema with and without each type of pathology were compared using Fisher's exact test to determine if there was a statistically significant association. We found MCL edema in 60% of 247 patients. MCL edema was present in 67% of patients with medial meniscal tears, 35% with lateral meniscal tears, 100% with meniscal extrusion of 3 mm or more, 78% with femoral chondromalacia, 82% with tibial chondromalacia, and 50% with osteoarthritis. The percentage of patients with edema increased with the severity of the chondromalacia. These associations were all statistically significant (p <0.02). The mean age of those with MCL edema was 49.7 years compared with 34.9 years without MCL edema (p <0.001). Patient gender and ACL tear did not correlate with MCL edema. Nine (4%) of the 247 patients had MCL edema without intra-articular pathology. None of these 9 patients had MCL tenderness or joint laxity on physical examination. We confirmed that MCL edema is associated with osteoarthritis, but is also associated with meniscal tears, meniscal extrusion, and chondromalacia. In addition, MCL edema can be seen in patients without intra-articular pathology, recent trauma or MCL abnormality on physical examination. (orig.)

  7. Split Dirac cones in HgTe/CdTe quantum wells due to symmetry-enforced level anticrossing at interfaces

    Science.gov (United States)

    Tarasenko, S. A.; Durnev, M. V.; Nestoklon, M. O.; Ivchenko, E. L.; Luo, Jun-Wei; Zunger, Alex

    2015-02-01

    HgTe is a band-inverted compound which forms a two-dimensional topological insulator if sandwiched between CdTe barriers for a HgTe layer thickness above the critical value. We describe the fine structure of Dirac states in the HgTe/CdTe quantum wells of critical and close-to-critical thicknesses and show that the necessary creation of interfaces brings in another important physical effect: the opening of a significant anticrossing gap between the tips of the Dirac cones. The level repulsion driven by the natural interface inversion asymmetry of zinc-blende heterostructures considerably modifies the electron states and dispersion but preserves the topological transition at the critical thickness. By combining symmetry analysis, atomistic calculations, and extended k .p theory with interface terms, we obtain a quantitative description of the energy spectrum and extract the interface mixing coefficient. We discuss how the fingerprints of the predicted zero-magnetic-field splitting of the Dirac cones could be detected experimentally by studying magnetotransport phenomena, cyclotron resonance, Raman scattering, and THz radiation absorption.

  8. 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...

  9. Speed enforcement in Norway

    DEFF Research Database (Denmark)

    Elvik, Rune

    2015-01-01

    and the police. This model makes predictions both about how drivers will adapt to changes in the amount of enforcement (the more enforcement, the less violations) as well as how the police will adapt to changes in the rate of violations (the less violations, the less enforcement). The paper attempts to test...... in the amount of enforcement. The predictions of the game-theoretic model were supported, although the results were not statistically significant in the model of how the police adapt enforcement to changes in the rate of violations....

  10. The combination of reduced MCL-1 and standard chemotherapeutics is tolerable in mice.

    Science.gov (United States)

    Brinkmann, Kerstin; Grabow, Stephanie; Hyland, Craig D; Teh, Charis E; Alexander, Warren S; Herold, Marco J; Strasser, Andreas

    2017-12-01

    A common therapeutic strategy to combat human cancer is the use of combinations of drugs, each targeting different cellular processes or vulnerabilities. Recent studies suggest that addition of an MCL-1 inhibitor to such anticancer drug treatments could be an attractive therapeutic strategy. Thus, it is of great interest to understand whether combinations of conventional anticancer drugs with an MCL-1 inhibitor will be tolerable and efficacious. In order to mimic the combination of MCL-1 inhibition with other cancer therapeutics, we treated Mcl-1 +/- heterozygous mice, which have a ~50% reduction in MCL-1 protein in their cells, with a broad range of chemotherapeutic drugs. Careful monitoring of treated mice revealed that a wide range of chemotherapeutic drugs had no significant effect on the general well-being of Mcl-1 +/- mice with no overt damage to a broad range of tissues, including the haematopoietic compartment, heart, liver and kidney. These results indicate that MCL-1 inhibition may represent a tolerable strategy in cancer therapy, even when combined with select cytotoxic drugs.

  11. Camptothecin and khat (Catha edulis Forsk. induced distinct cell death phenotypes involving modulation of c-FLIPL, Mcl-1, procaspase-8 and mitochondrial function in acute myeloid leukemia cell lines

    Directory of Open Access Journals (Sweden)

    Fossan Kjell O

    2009-11-01

    Full Text Available Abstract Background An organic extract of the recreational herb khat (Catha edulis Forsk. triggers cell death in various leukemia cell lines in vitro. The chemotherapeutics camptothecin, a plant alkaloid topoisomerase I inhibitor, was tested side-by-side with khat in a panel of acute myeloid leukemia cell lines to elucidate mechanisms of toxicity. Results Khat had a profound effect on MOLM-13 cells inducing mitochondrial damage, chromatin margination and morphological features of autophagy. The effects of khat on mitochondrial ultrastructure in MOLM-13 correlated with strongly impaired routine respiration, an effect neither found in the khat-resistant MV-4-11 cells nor in camptothecin treated cells. Enforced expression of anti-apoptotic Bcl-2 protein provided protection against camptothecin-induced cell death and partly against khat toxicity. Khat-induced cell death in MOLM-13 cells included reduced levels of anti-apoptotic Mcl-1 protein, while both khat and camptothecin induced c-FLIPL cleavage and procaspase-8 activation. Conclusion Khat activated a distinct cell death pathway in sensitive leukemic cells as compared to camptothecin, involving mitochondrial damage and morphological features of autophagy. This suggests that khat should be further explored in the search for novel experimental therapeutics.

  12. Bax/Mcl-1 balance affects neutrophil survival in intermittent hypoxia and obstructive sleep apnea: effects of p38MAPK and ERK1/2 signaling

    Directory of Open Access Journals (Sweden)

    Dyugovskaya Larissa

    2012-10-01

    Full Text Available Abstract Background Prolonged neutrophil survival is evident in various cardiovascular and respiratory morbidities, in hypoxic conditions in-vitro and in patients with obstructive sleep apnea (OSA characterized by nightly intermittent hypoxia (IH. This may lead to persistent inflammation, tissue injury and dysfunction. We therefore investigated by a translational approach the potential contribution of the intrinsic stress-induced mitochondrial pathway in extending neutrophil survival under IH conditions. Thus, neutrophils of healthy individuals treated with IH in-vitro and neutrophils of OSA patients undergoing nightly IH episodes in-vivo were investigated. Specifically, the balance between pro-apoptotic Bax and anti-apoptotic Mcl-1 protein expression, and the potential involvement of p38MAPK and ERK1/2 signaling pathways in the control of Mcl-1 expression were investigated. Methods Purified neutrophils were exposed to IH and compared to normoxia and to sustained hypoxia (SH using a BioSpherix-OxyCycler C42 system. Bax and Mcl-1 levels, and p38MAPK and ERK1/2 phosphorylation were determined by western blotting. Also, Bax/Mcl-1 expression and Bax translocation to the mitochondria were assessed by confocal microscopy in pre-apoptotic neutrophils, before the appearance of apoptotic morphology. Co-localization of Bax and mitochondria was quantified by LSM 510 CarlZeiss MicroImaging using Manders Overlap Coefficient. A paired two-tailed t test, with Bonferroni correction for multiple comparisons, was used for statistical analysis. Results Compared to normoxia, IH and SH up-regulated the anti-apoptotic Mcl-1 by about 2-fold, down-regulated the pro-apoptotic Bax by 41% and 27%, respectively, and inhibited Bax co-localization with mitochondria before visible morphological signs of apoptosis were noted. IH induced ERK1/2 and p38MAPKs phosphorylation, whereas SH induced only p38MAPK phosphorylation. Accordingly, both ERK and p38MAPK inhibitors attenuated

  13. Cafestol overcomes ABT-737 resistance in Mcl-1-overexpressed renal carcinoma Caki cells through downregulation of Mcl-1 expression and upregulation of Bim expression.

    Science.gov (United States)

    Woo, S M; Min, K-J; Seo, B R; Nam, J-O; Choi, K S; Yoo, Y H; Kwon, T K

    2014-11-06

    Although ABT-737, a small-molecule Bcl-2/Bcl-xL inhibitor, has recently emerged as a novel cancer therapeutic agent, ABT-737-induced apoptosis is often blocked in several types of cancer cells with elevated expression of Mcl-1. Cafestol, one of the major compounds in coffee beans, has been reported to have anti-carcinogenic activity and tumor cell growth-inhibitory activity, and we examined whether cafestol could overcome resistance against ABT-737 in Mcl-1-overexpressed human renal carcinoma Caki cells. ABT-737 alone had no effect on apoptosis, but cafestol markedly enhanced ABT-737-mediated apoptosis in Mcl-1-overexpressed Caki cells, human glioma U251MG cells, and human breast carcinoma MDA-MB231 cells. By contrast, co-treatment with ABT-737 and cafestol did not induce apoptosis in normal human skin fibroblast. Furthermore, combined treatment with cafestol and ABT-737 markedly reduced tumor growth compared with either drug alone in xenograft models. We found that cafestol inhibited Mcl-1 protein expression, which is important for ABT-737 resistance, through promotion of protein degradation. Moreover, cafestol increased Bim expression, and siRNA-mediated suppression of Bim expression reduced the apoptosis induced by cafestol plus ABT-737. Taken together, cafestol may be effectively used to enhance ABT-737 sensitivity in cancer therapy via downregulation of Mcl-1 expression and upregulation of Bim expression.

  14. Weight enforcement and evasion : Oregon case study: final report.

    Science.gov (United States)

    2002-03-01

    This study examines the incidence of overweight trucks and its relation to regulatory enforcement activity. Addressed are questions of scale operations in relation to weight violations and the effectiveness of enforcement levels, automated preclearan...

  15. Enforcement and judicial review

    International Nuclear Information System (INIS)

    Anon.

    1991-01-01

    The 1990 Amendments to the enforcement provisions of the Clean Air Act generally give the Administrator and the courts broader powers to enforce the substantive provisions of the Act. The changes include wider applicability of civil sanctions, increased criminal penalties, broader emergency powers, broader inspection powers, and increased citizen involvement in enforcement and administrative decisionmaking. Another significant change is the addition of an administrative penalty scheme that would allow EPA to use streamlined procedures to assess administrative penalties of up to $200,000 (or more, in some cases). Furthermore, the Amendments extend the prohibition against entering into government contracts with violators to other facilities owned or operated by the convicted person. This chapter summarizes the statutory enforcement provisions of the Clean Air Act. It covers the new civil and criminal enforcement provisions, the new administrative penalty scheme, and the new provisions allowing broader public involvement in enforcement proceedings

  16. Environmental Enforcement Districts

    Data.gov (United States)

    Vermont Center for Geographic Information — Current statewide map of the geographic territories of Environmental Enforcement Officers. Part of a dataset that contains administrative boundaries for Vermont's...

  17. Significant NRC Enforcement Actions

    Data.gov (United States)

    Nuclear Regulatory Commission — This dataset provides a list of Nuclear Regulartory Commission (NRC) issued significant enforcement actions. These actions, referred to as "escalated", are issued by...

  18. EPA Administrative Enforcement Dockets

    Data.gov (United States)

    U.S. Environmental Protection Agency — The EPA Administrative Enforcement Dockets database contains the electronic dockets for administrative penalty cases filed by EPA Regions and Headquarters. Visitors...

  19. RNA silencing of Mcl-1 enhances ABT-737-mediated apoptosis in melanoma: role for a caspase-8-dependent pathway.

    Science.gov (United States)

    Keuling, Angela M; Felton, Kathleen E A; Parker, Arabesque A M; Akbari, Majid; Andrew, Susan E; Tron, Victor A

    2009-08-17

    Malignant melanoma is resistant to almost all conventional forms of chemotherapy. Recent evidence suggests that anti-apoptotic proteins of the Bcl-2 family are overexpressed in melanoma and may contribute to melanoma's striking resistance to apoptosis. ABT-737, a small-molecule inhibitor of Bcl-2, Bcl-xl and Bcl-w, has demonstrated efficacy in several forms of leukemia, lymphoma as well as solid tumors. However, overexpression of Mcl-1, a frequent observance in melanoma, is known to confer ABT-737 resistance. Here we report that knockdown of Mcl-1 greatly reduces cell viability in combination with ABT-737 in six different melanoma cell lines. We demonstrate that the cytotoxic effect of this combination treatment is due to apoptotic cell death involving not only caspase-9 activation but also activation of caspase-8, caspase-10 and Bid, which are normally associated with the extrinsic pathway of apoptosis. Caspase-8 (and caspase-10) activation is abrogated by inhibition of caspase-9 but not by inhibitors of the death receptor pathways. Furthermore, while caspase-8/-10 activity is required for the full induction of cell death with treatment, the death receptor pathways are not. Finally, we demonstrate that basal levels of caspase-8 and Bid correlate with treatment sensitivity. Our findings suggest that the combination of ABT-737 and Mcl-1 knockdown represents a promising, new treatment strategy for malignant melanoma. We also report a death receptor-independent role for extrinsic pathway proteins in treatment response and suggest that caspase-8 and Bid may represent potential markers of treatment sensitivity.

  20. RNA silencing of Mcl-1 enhances ABT-737-mediated apoptosis in melanoma: role for a caspase-8-dependent pathway.

    Directory of Open Access Journals (Sweden)

    Angela M Keuling

    Full Text Available BACKGROUND: Malignant melanoma is resistant to almost all conventional forms of chemotherapy. Recent evidence suggests that anti-apoptotic proteins of the Bcl-2 family are overexpressed in melanoma and may contribute to melanoma's striking resistance to apoptosis. ABT-737, a small-molecule inhibitor of Bcl-2, Bcl-xl and Bcl-w, has demonstrated efficacy in several forms of leukemia, lymphoma as well as solid tumors. However, overexpression of Mcl-1, a frequent observance in melanoma, is known to confer ABT-737 resistance. METHODOLOGY/PRINCIPAL FINDINGS: Here we report that knockdown of Mcl-1 greatly reduces cell viability in combination with ABT-737 in six different melanoma cell lines. We demonstrate that the cytotoxic effect of this combination treatment is due to apoptotic cell death involving not only caspase-9 activation but also activation of caspase-8, caspase-10 and Bid, which are normally associated with the extrinsic pathway of apoptosis. Caspase-8 (and caspase-10 activation is abrogated by inhibition of caspase-9 but not by inhibitors of the death receptor pathways. Furthermore, while caspase-8/-10 activity is required for the full induction of cell death with treatment, the death receptor pathways are not. Finally, we demonstrate that basal levels of caspase-8 and Bid correlate with treatment sensitivity. CONCLUSIONS/SIGNIFICANCE: Our findings suggest that the combination of ABT-737 and Mcl-1 knockdown represents a promising, new treatment strategy for malignant melanoma. We also report a death receptor-independent role for extrinsic pathway proteins in treatment response and suggest that caspase-8 and Bid may represent potential markers of treatment sensitivity.

  1. Noxa/Mcl-1 Balance Regulates Susceptibility of Cells to Camptothecin-Induced Apoptosis

    Directory of Open Access Journals (Sweden)

    Yide Mei

    2007-10-01

    Full Text Available Although camptothecin (CPT has been reported to induce apoptosis in various cancer cells, the molecular details of this regulation remain largely unknown. In this study, we demonstrate that 131-113-only protein Noxa is upregulated during CPT-induced apoptosis, which is independent of p53. In addition, we show that phosphatidylinositol 3-kinase (PI3K/Akt signaling pathway is responsible for Noxa's induction. Luciferase assay, cAMP response element binding protein (CREB knockdown experiments further demonstrate that CREB is involved in the transcriptional upregulation of Noxa. Moreover, blocking Noxa expression using specific small interfering ribonucleic acid (siRNA significantly reduces the apoptosis in response to CPT, indicating that Noxa is an essential mediator for CPT-induced apoptosis. Interestingly, antiapoptotic Mcl-1 was also upregulated through PI3K/Akt signaling pathway upon CPT treatment. Using immunoprecipitation assay, Noxa was found to interact with Mcl-1 in the presence or absence of CPT. Knockdown of Mcl-1 expression by short hairpin ribonucleic acid (shRNA was shown to potentiate CPT-induced apoptosis. Consistently, ectopic overexpression of Mcl-1 rescued cells from apoptosis induced by CPT. Cells coexpressing Noxa, Mcl-1 at different ratio correlates well with the extent of apoptosis, suggesting that the balance between Noxa, Mcl-1 may determine the susceptibility of HeLa cells to CPT-induced apoptosis.

  2. Noxa/Mcl-1 Balance Regulates Susceptibility of Cells to Camptothecin-Induced Apoptosis1

    Science.gov (United States)

    Mei, Yide; Xie, Chongwei; Xie, Wei; Tian, Xu; Li, Mei; Wu, Mian

    2007-01-01

    Although camptothecin (CPT) has been reported to induce apoptosis in various cancer cells, the molecular details of this regulation remain largely unknown. In this study, we demonstrate that BH3-only protein Noxa is upregulated during CPT-induced apoptosis, which is independent of p53. In addition, we show that phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway is responsible for Noxa's induction. Luciferase assay and cAMP response element binding protein (CREB) knockdown experiments further demonstrate that CREB is involved in the transcriptional upregulation of Noxa. Moreover, blocking Noxa expression using specific small interfering ribonucleic acid (siRNA) significantly reduces the apoptosis in response to CPT, indicating that Noxa is an essential mediator for CPT-induced apoptosis. Interestingly, antiapoptotic Mcl-1 was also upregulated through PI3K/Akt signaling pathway upon CPT treatment. Using immunoprecipitation assay, Noxa was found to interact with Mcl-1 in the presence or absence of CPT. Knockdown of Mcl-1 expression by short hairpin ribonucleic acid (shRNA) was shown to potentiate CPT-induced apoptosis. Consistently, ectopic overexpression of Mcl-1 rescued cells from apoptosis induced by CPT. Cells coexpressing Noxa and Mcl-1 at different ratio correlates well with the extent of apoptosis, suggesting that the balance between Noxa and Mcl-1 may determine the susceptibility of HeLa cells to CPT-induced apoptosis. PMID:17971907

  3. Financial Reporting Enforcement

    DEFF Research Database (Denmark)

    Olsen, Carsten

    the auditors’ auditing efforts, which are made in conjunction with the impact of the enforcement of auditors and limitations on the auditors’ liability. However, research indicates that strict enforcement is a prerequisite for ensuring compliance with accounting regulations (Hail and Leuz 2006, Daske et al...

  4. Anxiolytic-like and antidepressant-like activities of MCL0129 (1-[(S)-2-(4-fluorophenyl)-2-(4-isopropylpiperadin-1-yl)ethyl]-4-[4-(2-methoxynaphthalen-1-yl)butyl]piperazine), a novel and potent nonpeptide antagonist of the melanocortin-4 receptor.

    Science.gov (United States)

    Chaki, Shigeyuki; Hirota, Shiho; Funakoshi, Takeo; Suzuki, Yoshiko; Suetake, Sayoko; Okubo, Taketoshi; Ishii, Takaaki; Nakazato, Atsuro; Okuyama, Shigeru

    2003-02-01

    We investigated the effects of a novel melanocortin-4 (MC4) receptor antagonist,1-[(S)-2-(4-fluorophenyl)-2-(4-isopropylpiperadin-1-yl)ethyl]-4-[4-(2-methoxynaphthalen-1-yl)butyl]piperazine (MCL0129) on anxiety and depression in various rodent models. MCL0129 inhibited [(125)I][Nle(4)-D-Phe(7)]-alpha-melanocyte-stimulating hormone (alpha-MSH) binding to MC4 receptor with a K(i) value of 7.9 nM, without showing affinity for MC1 and MC3 receptors. MCL0129 at 1 microM had no apparent affinity for other receptors, transporters, and ion channels related to anxiety and depression except for a moderate affinity for the sigma(1) receptor, serotonin transporter, and alpha(1)-adrenoceptor, which means that MCL0129 is selective for the MC4 receptor. MCL0129 attenuated the alpha-MSH-increased cAMP formation in COS-1 cells expressing the MC4 receptor, whereas MCL0129 did not affect basal cAMP levels, thereby indicating that MCL0129 acts as an antagonist at the MC4 receptor. Swim stress markedly induced anxiogenic-like effects in both the light/dark exploration task in mice and the elevated plus-maze task in rats, and MCL0129 reversed the stress-induced anxiogenic-like effects. Under nonstress conditions, MCL0129 prolonged time spent in the light area in the light/dark exploration task and suppressed marble-burying behavior. MCL0129 shortened immobility time in the forced swim test and reduced the number of escape failures in inescapable shocks in the learned helplessness test, thus indicating an antidepressant potential. In contrast, MCL0129 had negligible effects on spontaneous locomotor activity, Rotarod performance, and hexobarbital-induced anesthesia. These observations indicate that MCL0129 is a potent and selective MC4 antagonist with anxiolytic- and antidepressant-like activities in various rodent models. MC4 receptor antagonists may prove effective for treating subjects with stress-related disorders such as depression and/or anxiety.

  5. 32 CFR 637.7 - Drug enforcement activities.

    Science.gov (United States)

    2010-07-01

    .... Provost marshals and U.S. Army law enforcement supervisors at all levels will ensure that active drug... National Defense Department of Defense (Continued) DEPARTMENT OF THE ARMY (CONTINUED) LAW ENFORCEMENT AND... important nature of the drug enforcement effort. (a) MPI and DAC detectives/investigators will conduct...

  6. PI3K and Bcl-2 inhibition primes glioblastoma cells to apoptosis through downregulation of Mcl-1 and Phospho-BAD.

    Science.gov (United States)

    Pareja, Fresia; Macleod, David; Shu, Chang; Crary, John F; Canoll, Peter D; Ross, Alonzo H; Siegelin, Markus D

    2014-07-01

    Glioblastoma multiforme (GBM) is a highly malignant human brain neoplasm with limited therapeutic options. GBMs display a deregulated apoptotic pathway with high levels of the antiapoptotic Bcl-2 family of proteins and overt activity of the phosphatidylinositol 3-kinase (PI3K) signaling pathway. Therefore, combined interference of the PI3K pathway and the Bcl-2 family of proteins is a reasonable therapeutic strategy. ABT-263 (Navitoclax), an orally available small-molecule Bcl-2 inhibitor, and GDC-0941, a PI3K inhibitor, were used to treat established glioblastoma and glioblastoma neurosphere cells, alone or in combination. Although GDC-0941 alone had a modest effect on cell viability, treatment with ABT-263 displayed a marked reduction of cell viability and induction of apoptotic cell death. Moreover, combinatorial therapy using ABT-263 and GDC-0941 showed an enhanced effect, with a further decrease in cellular viability. Furthermore, combination treatment abrogated the ability of stem cell-like glioma cells to form neurospheres. ABT-263 and GDC-0941, in combination, resulted in a consistent and significant increase of Annexin V positive cells and loss of mitochondrial membrane potential compared with either monotherapy. The combination treatment led to enhanced cleavage of both initiator and effector caspases. Mechanistically, GDC-0941 depleted pAKT (Serine 473) levels and suppressed Mcl-1 protein levels, lowering the threshold for the cytotoxic actions of ABT-263. GDC-0941 decreased Mcl-1 in a posttranslational manner and significantly decreased the half-life of Mcl-1 protein. Ectopic expression of human Mcl-1 mitigated apoptotic cell death induced by the drug combination. Furthermore, GDC-0941 modulated the phosphorylation status of BAD, thereby further enhancing ABT-263-mediated cell death. Combination therapy with ABT-263 and GDC-0941 has novel therapeutic potential by specifically targeting aberrantly active, deregulated pathways in GBM, overcoming

  7. Regulation of antiapoptotic MCL-1 function by gossypol: mechanistic insights from in vitro reconstituted systems.

    Science.gov (United States)

    Etxebarria, Aitor; Landeta, Olatz; Antonsson, Bruno; Basañez, Gorka

    2008-12-01

    Small-molecule drugs that induce apoptosis in tumor cells by activation of the BCL-2-regulated mitochondrial outer membrane permeabilization (MOMP) pathway hold promise for rational anticancer therapies. Accumulating evidence indicates that the natural product gossypol and its derivatives can kill tumor cells by targeting antiapoptotic BCL-2 family members in such a manner as to trigger MOMP. However, due to the inherent complexity of the cellular apoptotic network, the precise mechanisms by which interactions between gossypol and individual BCL-2 family members lead to MOMP remain poorly understood. Here, we used simplified systems bearing physiological relevance to examine the impact of gossypol on the function of MCL-1, a key determinant for survival of various human malignancies that has become a highly attractive target for anticancer drug design. First, using a reconstituted liposomal system that recapitulates basic aspects of the BCL-2-regulated MOMP pathway, we demonstrate that MCL-1 inhibits BAX permeabilizing function via a "dual-interaction" mechanism, while submicromolar concentrations of gossypol reverse MCL-1-mediated inhibition of functional BAX activation. Solution-based studies showed that gossypol competes with BAX/BID BH3 ligands for binding to MCL-1 hydrophobic groove, thereby providing with a mechanistic explanation for how gossypol restores BAX permeabilizing function in the presence of MCL-1. By contrast, no evidence was found indicating that gossypol transforms MCL-1 into a BAX-like pore-forming molecule. Altogether, our findings validate MCL-1 as a direct target of gossypol, and highlight that making this antiapoptotic protein unable to inhibit BAX-driven MOMP may represent one important mechanism by which gossypol exerts its cytotoxic effect in selected cancer cells.

  8. Constitutionality of enforcement of claims by private enforcement agents

    Directory of Open Access Journals (Sweden)

    Bodiroga Nikola

    2014-01-01

    Full Text Available The main focus of this paper is legal status of private enforcement agents in Serbia. The 2011 Serbian Law on Enforcement and Security has introduced private enforcement agents as legal professionals in charge mainly for carrying out of the enforcement. Special enforcement procedure for collection of utilities and similar claims has become exclusive competence of private enforcement agents. Since enforcement procedure has always been regarded as a set of coercive measures against enforcement debtor, it became questionable whether this coercion could be exercised by private enforcement agents. It has been argued by legal scholars that enforcement of civil judgments and other enforcement deeds belongs only to the state authority. The author tackles this issue from the standpoint of decisions of constitutional courts and jurisprudence of European Court of Human Rights.

  9. Compliance and Enforcement Actions (CEA) -

    Data.gov (United States)

    Department of Transportation — Compliance and Enforcement Actions application provides process assistance / improvements for conducting investigation and enforcement activities. The Compliance and...

  10. Enforcement Information System

    Data.gov (United States)

    Department of Transportation — EIS is an automated management information system that tracks the FAA’s enforcement actions on a nationwide basis. EIS is the FAA’s primary database for tracking...

  11. Chemotherapeutic drugs sensitize human renal cell carcinoma cells to ABT-737 by a mechanism involving the Noxa-dependent inactivation of Mcl-1 or A1

    Directory of Open Access Journals (Sweden)

    Zantl Niko

    2010-06-01

    Full Text Available Abstract Background Human renal cell carcinoma (RCC is very resistant to chemotherapy. ABT-737 is a novel inhibitor of anti-apoptotic proteins of the Bcl-2 family that has shown promise in various preclinical tumour models. Results We here report a strong over-additive pro-apoptotic effect of ABT-737 and etoposide, vinblastine or paclitaxel but not 5-fluorouracil in cell lines from human RCC. ABT-737 showed very little activity as a single agent but killed RCC cells potently when anti-apoptotic Mcl-1 or, unexpectedly, A1 was targeted by RNAi. This potent augmentation required endogenous Noxa protein since RNAi directed against Noxa but not against Bim or Puma reduced apoptosis induction by the combination of ABT-737 and etoposide or vinblastine. At the level of mitochondria, etoposide-treatment had a similar sensitizing activity and allowed for ABT-737-induced release of cytochrome c. Conclusions Chemotherapeutic drugs can overcome protection afforded by Mcl-1 and A1 through endogenous Noxa protein in RCC cells, and the combination of such drugs with ABT-737 may be a promising strategy in RCC. Strikingly, A1 emerged in RCC cell lines as a protein of similar importance as the well-established Mcl-1 in protection against apoptosis in these cells.

  12. Use of the MCL dialog language for autonomous multi-channel analyzer automation

    International Nuclear Information System (INIS)

    Gyunter, Z.; Lebner, M.; Mikhaehlis, B.; Shvenkner, V.; Shul'tts, K.-Kh.

    1985-01-01

    The structure and software of a time-of-flight multichannel analyzer are considered. The analyzer is a subsystem of the measuring module of the SPN-1 polarized neutron spectrometer used in experiments at the IBR-2 reactor. The analyzer operates having several structures differing from one another by a timing coder. The MCL (MULTI-CONTROL-LANGUAGE) system is developed for control of the spectrometer. The system ensures the computer-user conversation and interfacing the computer and the experimental equipment. The MCL language is similar to that of the BASIC or the BAMBI. It has modular structure. The language interpreter and operating system have about 2 kbyte memory. The considered analyser is successfully used already during 6 months. The number of detector inputs of the analyser increased. Expenditures for alternations of programs are negligible due to modular structure of the system. Realization of new commads does not require comprehensive knowledge of the MCL language

  13. The effect of N-nitrosodimethylamine (NDMA) on Bax and Mcl-1 expression in human neutrophils.

    Science.gov (United States)

    Jablonski, Jakub; Jablonska, Ewa; Leonik, Agnieszka

    2011-12-01

    In the present study we examined a role of pro-apoptotic Bax and anti-apoptotic Mcl-1 proteins, participating in the regulation of intrinsic apoptosis pathway in human neutrophils (PMNs) exposed to N-nitrosodimethylamine (NDMA), the environmental xenobiotic. For the purpose comparison, the same studies were conducted in autologous peripheral blood mononuclear cells (PBMCs). The production of cytochrome c by PMNs was also determined. A deficit of anti-apoptotic Mcl-1 and overexpression of the pro-apoptotic protein Bax suggest that the apoptosis process in human neutrophils exposed to NDMA is dependent on changes in the expression of these proteins. PMNs were more sensitive to NDMA than PBMCs.

  14. 40 CFR 141.209 - Special notice for nitrate exceedances above MCL by non-community water systems (NCWS), where...

    Science.gov (United States)

    2010-07-01

    ... Water Violations § 141.209 Special notice for nitrate exceedances above MCL by non-community water... 40 Protection of Environment 22 2010-07-01 2010-07-01 false Special notice for nitrate exceedances above MCL by non-community water systems (NCWS), where granted permission by the primacy agency under Â...

  15. Why Border Enforcement Backfired.

    Science.gov (United States)

    Massey, Douglas S; Durand, Jorge; Pren, Karen A

    2016-03-01

    In this article we undertake a systematic analysis of why border enforcement backfired as a strategy of immigration control in the United States. We argue theoretically that border enforcement emerged as a policy response to a moral panic about the perceived threat of Latino immigration to the United States propounded by self-interested bureaucrats, politicians, and pundits who sought to mobilize political and material resources for their own benefit. The end result was a self-perpetuating cycle of rising enforcement and increased apprehensions that resulted in the militarization of the border in a way that was disconnected from the actual size of the undocumented flow. Using an instrumental variable approach, we show how border militarization affected the behavior of unauthorized migrants and border outcomes to transform undocumented Mexican migration from a circular flow of male workers going to three states into an eleven-million person population of settled families living in 50 states.

  16. Mcl-1 is essential for germinal center formation and B cell memory

    NARCIS (Netherlands)

    Vikstrom, Ingela; Carotta, Sebastian; Lüthje, Katja; Peperzak, Victor; Jost, Philipp J.; Glaser, Stefan; Busslinger, Meinrad; Bouillet, Philippe; Strasser, Andreas; Nutt, Stephen L.; Tarlinton, David M.

    2010-01-01

    Lymphocyte survival during immune responses is controlled by the relative expression of pro- and anti-apoptotic molecules, regulating the magnitude, quality, and duration of the response. We investigated the consequences of deleting genes encoding the anti-apoptotic molecules Mcl1 and Bcl2l1

  17. Drug Enforcement Administration.

    Science.gov (United States)

    Department of Justice, Washington, DC.

    This fact sheet contains information relating to drug abuse and abusers; drug traffic legislation; law enforcement; and descriptions of commonly used narcotics, stimulants, depressants, and hallucinogens. Also included is a short but explicit listing of audiovisual aids, an annotated bibliography, and drug identification pictures. The booklet…

  18. Circumvention of Mcl-1-dependent drug resistance by simultaneous Chk1 and MEK1/2 inhibition in human multiple myeloma cells.

    Science.gov (United States)

    Pei, Xin-Yan; Dai, Yun; Felthousen, Jessica; Chen, Shuang; Takabatake, Yukie; Zhou, Liang; Youssefian, Leena E; Sanderson, Michael W; Bodie, Wesley W; Kramer, Lora B; Orlowski, Robert Z; Grant, Steven

    2014-01-01

    The anti-apoptotic protein Mcl-1 plays a major role in multiple myeloma (MM) cell survival as well as bortezomib- and microenvironmental forms of drug resistance in this disease. Consequently, there is a critical need for strategies capable of targeting Mcl-1-dependent drug resistance in MM. The present results indicate that a regimen combining Chk1 with MEK1/2 inhibitors effectively kills cells displaying multiple forms of drug resistance stemming from Mcl-1 up-regulation in association with direct transcriptional Mcl-1 down-regulation and indirect disabling of Mcl-1 anti-apoptotic function through Bim up-regulation and increased Bim/Mcl-1 binding. These actions release Bak from Mcl-1, accompanied by Bak/Bax activation. Analogous events were observed in both drug-naïve and acquired bortezomib-resistant MM cells displaying increased Mcl-1 but diminished Bim expression, or cells ectopically expressing Mcl-1. Moreover, concomitant Chk1 and MEK1/2 inhibition blocked Mcl-1 up-regulation induced by IL-6/IGF-1 or co-culture with stromal cells, effectively overcoming microenvironment-related drug resistance. Finally, this regimen down-regulated Mcl-1 and robustly killed primary CD138+ MM cells, but not normal hematopoietic cells. Together, these findings provide novel evidence that this targeted combination strategy could be effective in the setting of multiple forms of Mcl-1-related drug resistance in MM.

  19. Circumvention of Mcl-1-dependent drug resistance by simultaneous Chk1 and MEK1/2 inhibition in human multiple myeloma cells.

    Directory of Open Access Journals (Sweden)

    Xin-Yan Pei

    Full Text Available The anti-apoptotic protein Mcl-1 plays a major role in multiple myeloma (MM cell survival as well as bortezomib- and microenvironmental forms of drug resistance in this disease. Consequently, there is a critical need for strategies capable of targeting Mcl-1-dependent drug resistance in MM. The present results indicate that a regimen combining Chk1 with MEK1/2 inhibitors effectively kills cells displaying multiple forms of drug resistance stemming from Mcl-1 up-regulation in association with direct transcriptional Mcl-1 down-regulation and indirect disabling of Mcl-1 anti-apoptotic function through Bim up-regulation and increased Bim/Mcl-1 binding. These actions release Bak from Mcl-1, accompanied by Bak/Bax activation. Analogous events were observed in both drug-naïve and acquired bortezomib-resistant MM cells displaying increased Mcl-1 but diminished Bim expression, or cells ectopically expressing Mcl-1. Moreover, concomitant Chk1 and MEK1/2 inhibition blocked Mcl-1 up-regulation induced by IL-6/IGF-1 or co-culture with stromal cells, effectively overcoming microenvironment-related drug resistance. Finally, this regimen down-regulated Mcl-1 and robustly killed primary CD138+ MM cells, but not normal hematopoietic cells. Together, these findings provide novel evidence that this targeted combination strategy could be effective in the setting of multiple forms of Mcl-1-related drug resistance in MM.

  20. BAG3 upregulates Mcl-1 through downregulation of miR-29b to induce anticancer drug resistance in ovarian cancer.

    Science.gov (United States)

    Sugio, Asuka; Iwasaki, Masahiro; Habata, Shutaro; Mariya, Tasuku; Suzuki, Miwa; Osogami, Hiroyuki; Tamate, Masato; Tanaka, Ryoichi; Saito, Tsuyoshi

    2014-09-01

    Ovarian cancer is the leading cause of death from gynecologic cancer, reflecting its often late diagnosis and its chemoresistance. We identified a set of microRNAs whose expression is altered upon BAG3 knockdown. Our primary objective was to examine the relationships between BAG3, miR-29b and Mcl-1, an antiapoptotic Bcl-2 family protein, in ovarian cancer cells. Ovarian cancer cells were cultured and their responsiveness to paclitaxel was tested. Microarray analysis was performed to identify microRNAs differentially expressed in ES2 BAG3 knockdown ovarian cancer cells and their control cells. Primary ovarian cancer tissues were obtained from 56 patients operated on for ovarian cancer. The patients' clinical and pathological data were obtained from their medical records. BAG3 knockdown increased the chemosensitivity to paclitaxel of ES2 ovarian clear cell carcinoma cells to a greater degree than AMOC2 serous adenocarcinoma cells. qRT-PCR analysis showed that miR-29b expression was significantly upregulated in primary cancer tissue expressing low levels of BAG3, as compared to tissue expressing high levels. Moreover, levels of miR-29b correlated significantly with progression-free survival. Upregulation of miR-29b also reduced levels of Mcl-1 and sensitized ES2 cells to low-dose paclitaxel. BAG3 knockdown appears to downregulate expression of Mcl-1 through upregulation of miR-29b, thereby increasing the chemosensitivity of ovarian clear cell carcinoma cells. This suggests that BAG3 is a key determinant of the responsiveness of ovarian cancer cells, especially clear cell carcinoma, to paclitaxel and that BAG3 may be a useful therapeutic target for the treatment of ovarian cancer. Copyright © 2014 Elsevier Inc. All rights reserved.

  1. p32, a novel binding partner of Mcl-1, positively regulates mitochondrial Ca{sup 2+} uptake and apoptosis

    Energy Technology Data Exchange (ETDEWEB)

    Xiao, Kang [Division of Life Science, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong (China); Wang, Yinyin; Chang, Zhijie [School of Medicine, Tsinghua University, Beijing (China); Lao, Yuanzhi, E-mail: laurence_ylao@163.com [School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai (China); Chang, Donald C., E-mail: bochang@ust.hk [Division of Life Science, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong (China)

    2014-08-22

    Highlights: • p32 binds to Mcl-1. • p32 affects apoptosis. • p32 and Mcl-1 regulate mitochondrial Ca{sup 2+}. - Abstract: Mcl-1 is a major anti-apoptotic Bcl-2 family protein. It is well known that Mcl-1 can interact with certain pro-apoptotic Bcl-2 family proteins in normal cells to neutralize their pro-apoptotic functions, thus prevent apoptosis. In addition, it was recently found that Mcl-1 can also inhibit mitochondrial calcium uptake. The detailed mechanism, however, is still not clear. Based on Yeast Two-Hybrid screening and co-immunoprecipitation, we identified a mitochondrial protein p32 (C1qbp) as a novel binding partner of Mcl-1. We found that p32 had a number of interesting properties: (1) p32 can positively regulate UV-induced apoptosis in HeLa cells. (2) Over-expressing p32 could significantly promote mitochondrial calcium uptake, while silencing p32 by siRNA suppressed it. (3) In p32 knockdown cells, Ruthenium Red treatment (an inhibitor of mitochondrial calcium uniporter) showed no further suppressive effect on mitochondrial calcium uptake. In addition, in Ruthenium Red treated cells, Mcl-1 also failed to suppress mitochondrial calcium uptake. Taken together, our findings suggest that p32 is part of the putative mitochondrial uniporter that facilitates mitochondrial calcium uptake. By binding to p32, Mcl-1 can interfere with the uniporter function, thus inhibit the mitochondrial Ca{sup 2+} uploading. This may provide a novel mechanism to explain the anti-apoptotic function of Mcl-1.

  2. Differential properties of human ACL and MCL stem cells may be responsible for their differential healing capacity

    Directory of Open Access Journals (Sweden)

    Fu Freddie H

    2011-06-01

    Full Text Available Abstract Background The human anterior cruciate ligament (hACL and medial collateral ligament (hMCL of the knee joint are frequently injured, especially in athletic settings. It has been known that, while injuries to the MCL typically heal with conservative treatment, ACL injuries usually do not heal. As adult stem cells repair injured tissues through proliferation and differentiation, we hypothesized that the hACL and hMCL contain stem cells exhibiting unique properties that could be responsible for the differential healing capacity of the two ligaments. Methods To test the above hypothesis, we derived ligament stem cells from normal hACL and hMCL samples from the same adult donors using tissue culture techniques and characterized their properties using immunocytochemistry, RT-PCR, and flow cytometry. Results We found that both hACL stem cells (hACL-SCs and hMCL stem cells (hMCL-SCs formed colonies in culture and expressed stem cell markers nucleostemin and stage-specific embryonic antigen-4 (SSEA-4. Moreover, both hACL-SCs and hMCL-SCs expressed CD surface markers for mesenchymal stem cells, including CD44 and CD90, but not those markers for vascular cells, CD31, CD34, CD45, and CD146. However, hACL-SCs differed from hMCL-SCs in that the size and number of hACL-SC colonies in culture were much smaller and grew more slowly than hMCL-SC colonies. Moreover, fewer hACL-SCs in cell colonies expressed stem cell markers STRO-1 and octamer-binding transcription factor-4 (Oct-4 than hMCL-SCs. Finally, hACL-SCs had less multi-differentiation potential than hMCL-SCs, evidenced by differing extents of adipogenesis, chondrogenesis, and osteogenesis in the respective induction media. Conclusions This study shows for the first time that hACL-SCs are intrinsically different from hMCL-SCs. We suggest that the differences in their properties contribute to the known disparity in healing capabilities between the two ligaments.

  3. Powerful subjects of tax law enforcement

    Directory of Open Access Journals (Sweden)

    Igor Dementyev

    2017-01-01

    Full Text Available УДК 342.6The subject. Competence of government bodies and their officials in the sphere of application of the tax law is considered in the article.The purpose of research is to determine the ratio of tax enforcement and application of the tax law, as well as the relationship between the concepts “party of tax enforcement” and “participant of tax legal relations”.Main results and scope of their application. The circle of participants of tax legal relations is broader than the circle of parties of tax law enforcement. The participants of tax legal relations are simultaneously the subjects of tax law, because they realize their tax status when enter into the tax relationships. The tax and customs authorities are the undoubted parties of the tax law enforcement.Although the financial authorities at all levels of government are not mentioned by article 9 of the Tax Code of the Russian Federation as participants of tax relations, they are parties of tax enforcement, because they make the agreement for deferment or installment payment of regional and local taxes.Scope of application. Clarification of participants of tax legal relations and determination of their mutual responsibility is essential to effective law enforcement.Conclusion. It was concluded that the scope tax law enforcement is tax proceedings, not administrative proceedings, civil (arbitration proceedings or enforcement proceedings.The application of the tax law is carried out not only in the form of tax relations, but also in relations of other branches of law.

  4. Enforcement handbook: Enforcement of DOE nuclear safety requirements

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1995-06-01

    This Handbook provides detailed guidance and procedures to implement the General Statement of DOE Enforcement Policy (Enforcement Policy or Policy). A copy of this Enforcement Policy is included for ready reference in Appendix D. The guidance provided in this Handbook is qualified, however, by the admonishment to exercise discretion in determining the proper disposition of each potential enforcement action. As discussed in subsequent chapters, the Enforcement and Investigation Staff will apply a number of factors in assessing each potential enforcement situation. Enforcement sanctions are imposed in accordance with the Enforcement Policy for the purpose of promoting public and worker health and safety in the performance of activities at DOE facilities by DOE contractors (and their subcontractors and suppliers) who are indemnified under the Price-Anderson Amendments Act. These indemnified contractors, and their suppliers and subcontractors, will be referred to in this Handbook collectively as DOE contractors. It should be remembered that the purpose of the Department`s enforcement policy is to improve nuclear safety for the workers and the public, and this goal should be the prime consideration in exercising enforcement discretion.

  5. Enforcement handbook: Enforcement of DOE nuclear safety requirements

    International Nuclear Information System (INIS)

    1995-06-01

    This Handbook provides detailed guidance and procedures to implement the General Statement of DOE Enforcement Policy (Enforcement Policy or Policy). A copy of this Enforcement Policy is included for ready reference in Appendix D. The guidance provided in this Handbook is qualified, however, by the admonishment to exercise discretion in determining the proper disposition of each potential enforcement action. As discussed in subsequent chapters, the Enforcement and Investigation Staff will apply a number of factors in assessing each potential enforcement situation. Enforcement sanctions are imposed in accordance with the Enforcement Policy for the purpose of promoting public and worker health and safety in the performance of activities at DOE facilities by DOE contractors (and their subcontractors and suppliers) who are indemnified under the Price-Anderson Amendments Act. These indemnified contractors, and their suppliers and subcontractors, will be referred to in this Handbook collectively as DOE contractors. It should be remembered that the purpose of the Department's enforcement policy is to improve nuclear safety for the workers and the public, and this goal should be the prime consideration in exercising enforcement discretion

  6. Deciphering the Mechanism of Alternative Cleavage and Polyadenylation in Mantle Cell Lymphoma (MCL)

    Science.gov (United States)

    2015-12-01

    event. The discovery that transformed and rapidly proliferating cells use alternative cleavage and polyadenylation ( APA ) to shorten the 3´UTR of their... APA . However, the mechanism that APA is still unknown. The goal of this project is to identify the mechanism of cyclin D1 APA regulation in cancer...for APA in MCL. In addition, by using RNA Seq. CFIm25 has been identified as an important global regulator of shortening of cyclin D1 mRNA and other

  7. NOX4-mediated ROS production induces apoptotic cell death via down-regulation of c-FLIP and Mcl-1 expression in combined treatment with thioridazine and curcumin.

    Science.gov (United States)

    Seo, Seung Un; Kim, Tae Hwan; Kim, Dong Eun; Min, Kyoung-Jin; Kwon, Taeg Kyu

    2017-10-01

    Thioridazine is known to have anti-tumor effects by inhibiting PI3K/Akt signaling, which is an important signaling pathway in cell survival. However, thioridazine alone does not induce apoptosis in head and neck squamous cell carcinoma (AMC-HN4), human breast carcinoma (MDA-MB231), and human glioma (U87MG) cells. Therefore, we investigated whether combined treatment with thioridazine and curcumin induces apoptosis. Combined treatment with thioridazine and curcumin markedly induced apoptosis in cancer cells without inducing apoptosis in human normal mesangial cells and human normal umbilical vein cells (EA.hy926). We found that combined treatment with thioridazine and curcumin had synergistic effects in AMC-HN4 cells. Among apoptosis-related proteins, thioridazine plus curcumin induced down-regulation of c-FLIP and Mcl-1 expression at the post-translational levels in a proteasome-dependent manner. Augmentation of proteasome activity was related to the up-regulation of proteasome subunit alpha 5 (PSMA5) expression in curcumin plus thioridazine-treated cells. Combined treatment with curcumin and thioridazine produced intracellular ROS in a NOX4-dependent manner, and ROS-mediated activation of Nrf2/ARE signaling played a critical role in the up-regulation of PSMA5 expression. Furthermore, ectopic expression of c-FLIP and Mcl-1 inhibited apoptosis in thioridazine and curcumin-treated cells. Therefore, we demonstrated that thioridazine plus curcumin induces proteasome activity by up-regulating PSMA5 expression via NOX4-mediated ROS production and that down-regulation of c-FLIP and Mcl-1 expression post-translationally is involved in apoptosis. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  8. NOX4-mediated ROS production induces apoptotic cell death via down-regulation of c-FLIP and Mcl-1 expression in combined treatment with thioridazine and curcumin

    Directory of Open Access Journals (Sweden)

    Seung Un Seo

    2017-10-01

    Full Text Available Thioridazine is known to have anti-tumor effects by inhibiting PI3K/Akt signaling, which is an important signaling pathway in cell survival. However, thioridazine alone does not induce apoptosis in head and neck squamous cell carcinoma (AMC-HN4, human breast carcinoma (MDA-MB231, and human glioma (U87MG cells. Therefore, we investigated whether combined treatment with thioridazine and curcumin induces apoptosis. Combined treatment with thioridazine and curcumin markedly induced apoptosis in cancer cells without inducing apoptosis in human normal mesangial cells and human normal umbilical vein cells (EA.hy926. We found that combined treatment with thioridazine and curcumin had synergistic effects in AMC-HN4 cells. Among apoptosis-related proteins, thioridazine plus curcumin induced down-regulation of c-FLIP and Mcl-1 expression at the post-translational levels in a proteasome-dependent manner. Augmentation of proteasome activity was related to the up-regulation of proteasome subunit alpha 5 (PSMA5 expression in curcumin plus thioridazine-treated cells. Combined treatment with curcumin and thioridazine produced intracellular ROS in a NOX4-dependent manner, and ROS-mediated activation of Nrf2/ARE signaling played a critical role in the up-regulation of PSMA5 expression. Furthermore, ectopic expression of c-FLIP and Mcl-1 inhibited apoptosis in thioridazine and curcumin-treated cells. Therefore, we demonstrated that thioridazine plus curcumin induces proteasome activity by up-regulating PSMA5 expression via NOX4-mediated ROS production and that down-regulation of c-FLIP and Mcl-1 expression post-translationally is involved in apoptosis.

  9. c-FLIP and the NOXA/Mcl-1 axis participate in the synergistic effect of pemetrexed plus cisplatin in human choroidal melanoma cells.

    Science.gov (United States)

    Zhao, Xiaofei; Kong, Feng; Wang, Lei; Zhang, Han

    2017-01-01

    Choroidal melanoma is the most common primary malignant intraocular tumor, and very few effective therapies are available to treat it. Our study aimed to understand whether pemetrexed plus cisplatin exerts a beneficial synergistic effect in human choroidal melanoma cells and to delineate the underlying molecular mechanism. To accomplish these aims, we treated choroidal melanoma cells with pemetrexed and cisplatin and assessed cell survival with SRB and MTT assays. Proteins were detected using western blotting analysis. NOXA and CHOP were knocked down with siRNA. We found that pemetrexed or cisplatin alone inhibited survival and induced apoptosis in human choroidal melanoma cells. Furthermore, the expression levels of c-FLIP, an anti-apoptotic protein in the extrinsic apoptosis pathway, and Mcl-1, an anti-apoptotic protein in the intrinsic apoptosis pathway, were decreased by pemetrexed or cisplatin respectively, while the expression of a pro-apoptotic protein in the intrinsic apoptosis pathway, NOXA, was up-regulated. Moreover, pemetrexed or cisplatin alone increased the protein expression of the endoplasmic reticulum stress markers IRE1α, Bip and CHOP. Silencing CHOP expression reduced NOXA expression. These findings suggest that the pemetrexed or cisplatin induced intrinsic apoptosis via activation of the ER stress response. Importantly, combining the two compounds more strongly induced apoptosis. Following the cotreatment, CHOP and NOXA expression increased, while c-FLIP and Mcl-1 expression decreased, and these effects were more pronounced than when using either compound alone. This result suggests that pemetrexed and cisplatin synergistically activate ER stress response-induced apoptosis in choroidal melanoma cells. To summarize, the c-FLIP and NOXA/Mcl-1 axis participated in the synergistic effect of pemetrexed plus cisplatin in human choroidal melanoma cells. Intrinsic apoptosis was induced via activation of the ER stress response. Our study provides

  10. Fragment-based discovery of potent inhibitors of the anti-apoptotic MCL-1 protein.

    Science.gov (United States)

    Petros, Andrew M; Swann, Steven L; Song, Danying; Swinger, Kerren; Park, Chang; Zhang, Haichao; Wendt, Michael D; Kunzer, Aaron R; Souers, Andrew J; Sun, Chaohong

    2014-03-15

    Apoptosis is regulated by the BCL-2 family of proteins, which is comprised of both pro-death and pro-survival members. Evasion of apoptosis is a hallmark of malignant cells. One way in which cancer cells achieve this evasion is thru overexpression of the pro-survival members of the BCL-2 family. Overexpression of MCL-1, a pro-survival protein, has been shown to be a resistance factor for Navitoclax, a potent inhibitor of BCL-2 and BCL-XL. Here we describe the use of fragment screening methods and structural biology to drive the discovery of novel MCL-1 inhibitors from two distinct structural classes. Specifically, cores derived from a biphenyl sulfonamide and salicylic acid were uncovered in an NMR-based fragment screen and elaborated using high throughput analog synthesis. This culminated in the discovery of selective and potent inhibitors of MCL-1 that may serve as promising leads for medicinal chemistry optimization efforts. Copyright © 2014 Elsevier Ltd. All rights reserved.

  11. Protein sequences clustering of herpes virus by using Tribe Markov clustering (Tribe-MCL)

    Science.gov (United States)

    Bustamam, A.; Siswantining, T.; Febriyani, N. L.; Novitasari, I. D.; Cahyaningrum, R. D.

    2017-07-01

    The herpes virus can be found anywhere and one of the important characteristics is its ability to cause acute and chronic infection at certain times so as a result of the infection allows severe complications occurred. The herpes virus is composed of DNA containing protein and wrapped by glycoproteins. In this work, the Herpes viruses family is classified and analyzed by clustering their protein-sequence using Tribe Markov Clustering (Tribe-MCL) algorithm. Tribe-MCL is an efficient clustering method based on the theory of Markov chains, to classify protein families from protein sequences using pre-computed sequence similarity information. We implement the Tribe-MCL algorithm using an open source program of R. We select 24 protein sequences of Herpes virus obtained from NCBI database. The dataset consists of three types of glycoprotein B, F, and H. Each type has eight herpes virus that infected humans. Based on our simulation using different inflation factor r=1.5, 2, 3 we find a various number of the clusters results. The greater the inflation factor the greater the number of their clusters. Each protein will grouped together in the same type of protein.

  12. Strategies for Automated Control of the Bioproduction of Mcl-PHA Biopolymers

    Directory of Open Access Journals (Sweden)

    P. Hrnčiřík

    2017-10-01

    Full Text Available Medium-chain-length polyhydroxyalkanoates (mcl-PHAs are polyesters synthesized by numerous bacteria as storage material. Despite being promising candidates for biodegradable materials of industrial interest and environmental value, their usage is still rather limited because of high production costs. One of the areas with considerable potential for further improvements is control of the production process. This paper deals with the experimental work related to the design of control strategies for mcl-PHA biopolymer production process (Pseudomonas putida KT2442 fed-batch cultivations. For this bioprocess, a set of five control strategies (two main and three auxiliary strategies have been proposed, together with the proper sequence of their switching during the fed-batch part of the production process. The application of these strategies with octanoic acid as a sole carbon source resulted in intracellular PHA content (max. mass fraction 65 % of mcl-PHA in cell dry mass (g g–1 and PHA productivity (max. 0.89 g L–1 h–1 comparable to the best results reported in the literature for this type of strain and carbon substrate.

  13. Virtual screening for potential inhibitors of Mcl-1 conformations sampled by normal modes, molecular dynamics, and nuclear magnetic resonance

    Directory of Open Access Journals (Sweden)

    Glantz-Gashai Y

    2017-06-01

    Full Text Available Yitav Glantz-Gashai,* Tomer Meirson,* Eli Reuveni, Abraham O Samson Faculty of Medicine in the Galilee, Bar Ilan University, Safed, Israel *These authors contributed equally to this work Abstract: Myeloid cell leukemia-1 (Mcl-1 is often overexpressed in human cancer and is an important target for developing antineoplastic drugs. In this study, a data set containing 2.3 million lead-like molecules and a data set of all the US Food and Drug Administration (FDA-approved drugs are virtually screened for potential Mcl-1 ligands using Protein Data Bank (PDB ID 2MHS. The potential Mcl-1 ligands are evaluated and computationally docked on to three conformation ensembles generated by normal mode analysis (NMA, molecular dynamics (MD, and nuclear magnetic resonance (NMR, respectively. The evaluated potential Mcl-1 ligands are then compared with their clinical use. Remarkably, half of the top 30 potential drugs are used clinically to treat cancer, thus partially validating our virtual screen. The partial validation also favors the idea that the other half of the top 30 potential drugs could be used in the treatment of cancer. The normal mode-, MD-, and NMR-based conformation greatly expand the conformational sampling used herein for in silico identification of potential Mcl-1 inhibitors. Keywords: virtual screening, Mcl-1, molecular dynamics, NMR, normal modes

  14. HTLV-1 tax stabilizes MCL-1 via TRAF6-dependent K63-linked polyubiquitination to promote cell survival and transformation.

    Directory of Open Access Journals (Sweden)

    Young Bong Choi

    2014-10-01

    Full Text Available The human T-cell leukemia virus type 1 (HTLV-1 Tax protein hijacks the host ubiquitin machinery to activate IκB kinases (IKKs and NF-κB and promote cell survival; however, the key ubiquitinated factors downstream of Tax involved in cell transformation are unknown. Using mass spectrometry, we undertook an unbiased proteome-wide quantitative survey of cellular proteins modified by ubiquitin in the presence of Tax or a Tax mutant impaired in IKK activation. Tax induced the ubiquitination of 22 cellular proteins, including the anti-apoptotic BCL-2 family member MCL-1, in an IKK-dependent manner. Tax was found to promote the nondegradative lysine 63 (K63-linked polyubiquitination of MCL-1 that was dependent on the E3 ubiquitin ligase TRAF6 and the IKK complex. Tax interacted with and activated TRAF6, and triggered its mitochondrial localization, where it conjugated four carboxyl-terminal lysine residues of MCL-1 with K63-linked polyubiquitin chains, which stabilized and protected MCL-1 from genotoxic stress-induced degradation. TRAF6 and MCL-1 played essential roles in the survival of HTLV-1 transformed cells and the immortalization of primary T cells by HTLV-1. Therefore, K63-linked polyubiquitination represents a novel regulatory mechanism controlling MCL-1 stability that has been usurped by a viral oncogene to precipitate cell survival and transformation.

  15. HTLV-1 Tax Stabilizes MCL-1 via TRAF6-Dependent K63-Linked Polyubiquitination to Promote Cell Survival and Transformation

    Science.gov (United States)

    Choi, Young Bong; Harhaj, Edward William

    2014-01-01

    The human T-cell leukemia virus type 1 (HTLV-1) Tax protein hijacks the host ubiquitin machinery to activate IκB kinases (IKKs) and NF-κB and promote cell survival; however, the key ubiquitinated factors downstream of Tax involved in cell transformation are unknown. Using mass spectrometry, we undertook an unbiased proteome-wide quantitative survey of cellular proteins modified by ubiquitin in the presence of Tax or a Tax mutant impaired in IKK activation. Tax induced the ubiquitination of 22 cellular proteins, including the anti-apoptotic BCL-2 family member MCL-1, in an IKK-dependent manner. Tax was found to promote the nondegradative lysine 63 (K63)-linked polyubiquitination of MCL-1 that was dependent on the E3 ubiquitin ligase TRAF6 and the IKK complex. Tax interacted with and activated TRAF6, and triggered its mitochondrial localization, where it conjugated four carboxyl-terminal lysine residues of MCL-1 with K63-linked polyubiquitin chains, which stabilized and protected MCL-1 from genotoxic stress-induced degradation. TRAF6 and MCL-1 played essential roles in the survival of HTLV-1 transformed cells and the immortalization of primary T cells by HTLV-1. Therefore, K63-linked polyubiquitination represents a novel regulatory mechanism controlling MCL-1 stability that has been usurped by a viral oncogene to precipitate cell survival and transformation. PMID:25340740

  16. ENFORCEMENT OF MORTGAGE CONTRACT

    Directory of Open Access Journals (Sweden)

    Alisa A. BELU

    2016-07-01

    Full Text Available A chattel mortgage contract is the expression of a real guarantee that gives the creditor precedence over other creditors, in addition to the general pledge upon the belongings of the debtor. It refers to the sale of mortgaged movable assets, exclusively or prioritized in favor of the mortgaging creditor, in case the debtor does not comply with his / her commitments, under the signed mortgage contract. Beginning from this purpose, shared by both sides (as the chattel mortgage contract is synallagmatic, in case the debtor is unable to fulfill his / her commitments, the sides reach a situation of enforcement of the signed chattel mortgage contract. Given the legal status of the chattel mortgage contract [Art. 2387-2477 Noul Cod Civil , Universul Juridic, Bucureşti, 2016, ISBN 978-606-673-792-0], the principle of binding force of the contract and the principle according to which signed legal conventions will entail legal effects, the Romanian law maker developed the proper legal framework for the enforcement of the chattel mortgage contract. [art. 622 si urm. Noul Cod de Procedură Civilă, ed. Hamangiu, Bucureşti, 2016, ISBN 978-606-27-0459-9].

  17. Bim and Mcl-1 exert key roles in regulating JAK2V617F cell survival

    International Nuclear Information System (INIS)

    Rubert, Joëlle; Qian, Zhiyan; Andraos, Rita; Guthy, Daniel A; Radimerski, Thomas

    2011-01-01

    The JAK2 V617F mutation plays a major role in the pathogenesis of myeloproliferative neoplasms and is found in the vast majority of patients suffering from polycythemia vera and in roughly every second patient suffering from essential thrombocythemia or from primary myelofibrosis. The V617F mutation is thought to provide hematopoietic stem cells and myeloid progenitors with a survival and proliferation advantage. It has previously been shown that activated JAK2 promotes cell survival by upregulating the anti-apoptotic STAT5 target gene Bcl-xL. In this study, we have investigated the role of additional apoptotic players, the pro-apoptotic protein Bim as well as the anti-apoptotic protein Mcl-1. Pharmacological inhibition of JAK2/STAT5 signaling in JAK2 V617F mutant SET-2 and MB-02 cells was used to study effects on signaling, cell proliferation and apoptosis by Western blot analysis, WST-1 proliferation assays and flow cytometry. Cells were transfected with siRNA oligos to deplete candidate pro- and anti-apoptotic proteins. Co-immunoprecipitation assays were performed to assess the impact of JAK2 inhibition on complexes of pro- and anti-apoptotic proteins. Treatment of JAK2 V617F mutant cell lines with a JAK2 inhibitor was found to trigger Bim activation. Furthermore, Bim depletion by RNAi suppressed JAK2 inhibitor-induced cell death. Bim activation following JAK2 inhibition led to enhanced sequestration of Mcl-1, besides Bcl-xL. Importantly, Mcl-1 depletion by RNAi was sufficient to compromise JAK2 V617F mutant cell viability and sensitized the cells to JAK2 inhibition. We conclude that Bim and Mcl-1 have key opposing roles in regulating JAK2 V617F cell survival and propose that inactivation of aberrant JAK2 signaling leads to changes in Bim complexes that trigger cell death. Thus, further preclinical evaluation of combinations of JAK2 inhibitors with Bcl-2 family antagonists that also tackle Mcl-1, besides Bcl-xL, is warranted to assess the therapeutic potential

  18. Differential effects of suppressors on hazardous sound pressure levels generated by AR-15 rifles: Considerations for recreational shooters, law enforcement, and the military.

    Science.gov (United States)

    Lobarinas, Edward; Scott, Ryan; Spankovich, Christopher; Le Prell, Colleen G

    2016-01-01

    Firearm discharges produce hazardous levels of impulse noise that can lead to permanent hearing loss. In the present study, we evaluated the effects of suppression, ammunition, and barrel length on AR-15 rifles. Sound levels were measured left/right of a user's head, and 1-m left of the muzzle, per MIL-STD-1474-D, under both unsuppressed and suppressed conditions. Nine commercially available AR-15 rifles and 14 suppressors were used. Suppressors significantly decreased peak dB SPL at the 1-m location and the left ear location. However, under most rifle/ammunition conditions, levels remained above 140 dB peak SPL near a user's right ear. In a subset of conditions, subsonic ammunition produced values near or below 140 dB peak SPL. Overall suppression ranged from 7-32 dB across conditions. These data indicate that (1) suppressors reduce discharge levels to 140 dB peak SPL or below in only a subset of AR-15 conditions, (2) shorter barrel length and use of muzzle brake devices can substantially increase exposure level for the user, and (3) there are significant left/right ear sound pressure differences under suppressed conditions as a function of the AR-15 direct impingement design that must be considered during sound measurements to fully evaluate overall efficacy.

  19. Immigration Enforcement Actions - Annual Report

    Data.gov (United States)

    Department of Homeland Security — Each year, the Department of Homeland Security (DHS) undertakes immigration enforcement actions involving hundreds of thousands of foreign nationals. These actions...

  20. Effect of oxaliplatin on the survival rate of human Y79 cells after down-regulation of Mcl-1

    Directory of Open Access Journals (Sweden)

    Lu Zhou

    2017-12-01

    Full Text Available AIM: To study the effect of oxaliplatin on the survival rate of Y79 after down-regulation of Mcl-1 by SiRNA. METHODS: Y79 cells were cultured in RPMI1640. The cultured cells were stimulated with 0.25μmol/L of oxaliplatin. The expression of Mcl-1 protein was detected by Western blot after 6, 16 and 24h respectively. Cells in logarithmic phase were collected and used for single-cell suspension. Then they were transfected with empty plasmid, Mcl-1-homo-991, Mcl-1-homo-1114 and Mcl-1-homo-1235. After 6h, fluorescence microscope was used to observe the transfection efficiency and the optimal one was selected. The cells were divided into Group A and transfected with empty plasmids. The cells transfected with Mcl-1 were divided into Group B and Group C. Group A and Group C were treated with 0.25μmol/L oxaliplatin for stimulating induction, and the apoptotic rate was compared after 24h.RESULTS: The expression of Mcl-1 in Y79 stimulated by oxaliplatin was the most after 24h of culture. Mcl-1-homo-991 significantly inhibited the expression of Mcl-1 in Y79 after transfection. There was no significant difference in the apoptosis rate in Group A(11.1%±1.2%and in the control group(6.1%±0.6%(P>0.05. The apoptotic rate of Group C(49.2%±2.7%was significantly higher than that of Group B(20.8%±1.9%. At the same time, the apoptotic rates of these two groups were significantly higher than those of Group A and control group, the difference was statistically significant(PCONCLUSION:Downregulation of Mcl-1 by siRNA can reduce the drug resistance of Y79, thereby enhancing the apoptosis of Y79, and reducing the survival rate of Y79.

  1. Stable and Enforceable

    DEFF Research Database (Denmark)

    Hallett, Andrew Hughes; Hougaard Jensen, Svend E.

    2011-01-01

    Since the great financial crash, the need for new fiscal rules to prevent unsustainable fiscal policies is universally recognised. In practice such rules, including those in the Stability and Growth Pact, have proved to be impossible to enforce. Thus, to avoid unsustainable fiscal policies...... reappearing, and to prevent monetary policy from being undermined by undisciplined governments, there is a need for a framework capable of imposing fiscal discipline. This paper considers an intertemporal assignment, where fiscal policy focuses on long-term objectives and monetary policy on short...... which the debt targeting regime should operate. Making these factors explicit would both improve the credibility of planned fiscal policies and reduce risk premia on borrowing costs. We finally show how Europe’s competitiveness pact, and debt restructuring operations, can be used to maximise...

  2. TRAIL and proteasome inhibitors combination induces a robust apoptosis in human malignant pleural mesothelioma cells through Mcl-1 and Akt protein cleavages

    International Nuclear Information System (INIS)

    Yuan, Bao-Zhu; Chapman, Joshua; Ding, Min; Wang, Junzhi; Jiang, Binghua; Rojanasakul, Yon; Reynolds, Steven H

    2013-01-01

    Malignant pleural mesothelioma (MPM) is an aggressive malignancy closely associated with asbestos exposure and extremely resistant to current treatments. It exhibits a steady increase in incidence, thus necessitating an urgent development of effective new treatments. Proteasome inhibitors (PIs) and TNFα-Related Apoptosis Inducing Ligand (TRAIL), have emerged as promising new anti-MPM agents. To develop effective new treatments, the proapoptotic effects of PIs, MG132 or Bortezomib, and TRAIL were investigated in MPM cell lines NCI-H2052, NCI-H2452 and NCI-H28, which represent three major histological types of human MPM. Treatment with 0.5-1 μM MG132 alone or 30 ng/mL Bortezomib alone induced a limited apoptosis in MPM cells associated with the elevated Mcl-1 protein level and hyperactive PI3K/Akt signaling. However, whereas 10–20 ng/ml TRAIL alone induced a limited apoptosis as well, TRAIL and PI combination triggered a robust apoptosis in all three MPM cell lines. The robust proapoptotic activity was found to be the consequence of a positive feedback mechanism-governed amplification of caspase activation and cleavage of both Mcl-1 and Akt proteins, and exhibited a relative selectivity in MPM cells than in non-tumorigenic Met-5A mesothelial cells. The combinatorial treatment using TRAIL and PI may represent an effective new treatment for MPMs

  3. Oversight and enforcement at DOE

    International Nuclear Information System (INIS)

    Fergus, I.E., Christopher, R.K.

    1996-01-01

    This paper addresses recent changes to the independent oversight and enforcement programs within the U.S. Department of Energy (DOE) and applications to criticality safety. DOE's Office of Oversight (Oversight hereafter), in the Office of Environment, Safety, and Health (EH), independently evaluates whether management systems ensure adequate protection of the worker, public, and environment. Oversight has adopted a new approach to performing evaluations based on the guiding principles for safety management identified by the Secretary of Energy. The principles Oversight evaluates are line management responsibility for safety and health, comprehensive requirements, and competence commensurate with responsibilities. Recently, the DOE codified the implementation of integrated safety management, further expounding on these basic guiding principles and Oversight's role. The Office of Enforcement and Investigations in EH (Enforcement hereafter) is responsible for enforcement, and relevant documents describe its role. This paper briefly discusses criticality safety aspects of the twin initiatives of Oversight and Enforcement

  4. Quota enforcement in resource industries

    DEFF Research Database (Denmark)

    Hansen, Lars Gårn; Jensen, Frank; Nøstbakken, Linda

    cant non-compliance and exogenous constraints on nes and enforcement budget. We propose a new enforcement system based on self-reporting of excess extraction and explicit di erentiation of inspection rates based on compliance history. In particular, we use state-dependent enforcement to induce rms...... to self-report excess extraction. We show that such system increases the e ectiveness of quota management by allowing the regulator to implement a wider range of aggregate extraction targets than under traditional enforcement, while ensuring an ecient allocation of aggregate extraction. In addition......Quotas or permits are frequently used in the management of renewable resources and emissions. However, in many industries there is concern about the basic e ectiveness of quotas due to non-compliance. We develop an enforcement model of a quota-regulated resource and focus on a situation with signi...

  5. Assessing the efficiency of priorities for traffic law enforcement in Norway

    DEFF Research Database (Denmark)

    Elvik, Rune; Sogge, Céline Vallet; Lager, Lasse

    2012-01-01

    attributable to them; and (3) an optimal level of enforcement is selected, i.e. the marginal benefits of enforcement in terms of preventing accidents equal the marginal costs of enforcement. The efficiency of current traffic law enforcement in Norway is assessed in terms of these criteria. It is found......This paper assesses the efficiency of priorities for traffic law enforcement in Norway. Priorities are regarded as efficient if: (1) enforcement ensures a sufficient level of deterrence to keep down the rate of violations; (2) selection of target violations for enforcement is based on the risk...... low. Cost-benefit analyses show that substantially increasing the amount of police enforcement is cost-effective....

  6. Loss of a Single Mcl-1 Allele Inhibits MYC-Driven Lymphomagenesis by Sensitizing Pro-B Cells to Apoptosis

    Directory of Open Access Journals (Sweden)

    Stephanie Grabow

    2016-03-01

    Full Text Available MCL-1 is critical for progenitor cell survival during emergency hematopoiesis, but its role in sustaining cells undergoing transformation and in lymphomagenesis is only poorly understood. We investigated the importance of MCL-1 in the survival of B lymphoid progenitors undergoing MYC-driven transformation and its functional interactions with pro-apoptotic BIM and PUMA and the tumor suppressor p53 in lymphoma development. Loss of one Mcl-1 allele almost abrogated MYC-driven-lymphoma development owing to a reduction in lymphoma initiating pre-B cells. Although loss of the p53 target PUMA had minor impact, loss of one p53 allele substantially accelerated lymphoma development when MCL-1 was limiting, most likely because p53 loss also causes defects in non-apoptotic tumor suppressive processes. Remarkably, loss of BIM restored the survival of lymphoma initiating cells and rate of tumor development. Thus, MCL-1 has a major role in lymphoma initiating pro-B cells to oppose BIM, which is upregulated in response to oncogenic stress.

  7. The Cost of Enforcing Building Energy Codes: Phase 1

    Energy Technology Data Exchange (ETDEWEB)

    Williams, Alison [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Vine, Ed [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Price, Sarah [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Sturges, Andrew [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Rosenquist, Greg [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)

    2013-04-01

    The purpose of this literature review is to summarize key findings regarding the costs associated with enforcing building energy code compliance—primarily focusing on costs borne by local government. The review takes into consideration over 150 documents that discuss, to some extent, code enforcement. This review emphasizes those documents that specifically focus on costs associated with energy code enforcement. Given the low rates of building energy code compliance that have been reported in existing studies, as well as the many barriers to both energy code compliance and enforcement, this study seeks to identify the costs of initiatives to improve compliance and enforcement. Costs are reported primarily as presented in the original source. Some costs are given on a per home or per building basis, and others are provided for jurisdictions of a certain size. This literature review gives an overview of state-based compliance rates, barriers to code enforcement, and U.S. Department of Energy (DOE) and key stakeholder involvement in improving compliance with building energy codes. In addition, the processes and costs associated with compliance and enforcement of building energy codes are presented. The second phase of this study, which will be presented in a different report, will consist of surveying 34 experts in the building industry at the national and state or local levels in order to obtain additional cost information, building on the findings from the first phase, as well as recommendations for where to most effectively spend money on compliance and enforcement.

  8. Verification of Security Policy Enforcement in Enterprise Systems

    Science.gov (United States)

    Gupta, Puneet; Stoller, Scott D.

    Many security requirements for enterprise systems can be expressed in a natural way as high-level access control policies. A high-level policy may refer to abstract information resources, independent of where the information is stored; it controls both direct and indirect accesses to the information; it may refer to the context of a request, i.e., the request’s path through the system; and its enforcement point and enforcement mechanism may be unspecified. Enforcement of a high-level policy may depend on the system architecture and the configurations of a variety of security mechanisms, such as firewalls, host login permissions, file permissions, DBMS access control, and application-specific security mechanisms. This paper presents a framework in which all of these can be conveniently and formally expressed, a method to verify that a high-level policy is enforced, and an algorithm to determine a trusted computing base for each resource.

  9. HSIP Law Enforcement Locations in New Mexico

    Data.gov (United States)

    Earth Data Analysis Center, University of New Mexico — Law Enforcement Locations Any location where sworn officers of a law enforcement agency are regularly based or stationed. Law Enforcement agencies "are publicly...

  10. 75 FR 60485 - NRC Enforcement Policy Revision

    Science.gov (United States)

    2010-09-30

    ... NUCLEAR REGULATORY COMMISSION [NRC-2008-0497] NRC Enforcement Policy Revision AGENCY: Nuclear Regulatory Commission. ACTION: Policy statement. SUMMARY: The Nuclear Regulatory Commission (NRC or Commission) is publishing a major revision to its Enforcement Policy (Enforcement Policy or Policy) to...

  11. Enforcement actions: Significant actions resolved

    International Nuclear Information System (INIS)

    1990-05-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (January--March 1990) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. Also included are a number of enforcement actions that had been previously resolved but not published in this NUREG. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

  12. Enforcement actions: Significant actions resolved

    International Nuclear Information System (INIS)

    1989-06-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (January--March 1989) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. Also included are a number of enforcement actions that had been previously resolved but not published in this NUREG. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

  13. Loss of FBXW7 and accumulation of MCL1 and PLK1 promote paclitaxel resistance in breast cancer.

    Science.gov (United States)

    Gasca, Jessica; Flores, Maria Luz; Giráldez, Servando; Ruiz-Borrego, Manuel; Tortolero, María; Romero, Francisco; Japón, Miguel A; Sáez, Carmen

    2016-08-16

    FBXW7 is a component of SCF (complex of SKP1, CUL1 and F-box-protein)-type ubiquitin ligases that targets several oncoproteins for ubiquitination and degradation by the proteasome. FBXW7 regulates cellular apoptosis by targeting MCL1 for ubiquitination. Recently, we identified PLK1 as a new substrate of FBXW7 modulating the intra-S-phase DNA-damage checkpoint. Taxanes are frequently used in breast cancer treatments, but the acquisition of resistance makes these treatments ineffective. We investigated the role of FBXW7 and their substrates MCL1 and PLK1 in regulating the apoptotic response to paclitaxel treatment in breast cancer cells and their expression in breast cancer tissues. Paclitaxel-sensitive MDA-MB-468 and a paclitaxel-resistant MDA-MB-468R subclone were used to study the role of FBXW7 and substrates in paclitaxel-induced apoptosis. Forced expression of FBXW7 or downregulation of MCL1 or PLK1 restored sensitivity to paclitaxel in MDA-MB-468R cells. By contrary, FBXW7-silenced MDA-MB-468 cells became resistant to paclitaxel. The expression of FBXW7 and substrates were studied in 296 invasive carcinomas by immunohistochemistry and disease-free survival was analyzed in a subset of patients treated with paclitaxel. In breast cancer tissues, loss of FBXW7 correlated with adverse prognosis markers and loss of FBXW7 and MCL1 or PLK1 accumulation were associated with diminished disease-free survival in paclitaxel-treated patients. We conclude that FBXW7 regulates the response to paclitaxel by targeting MCL1 and PLK1 in breast cancer cells and thus targeting these substrates may be a valuable adjunct for paclitaxel treatment. Also, FBXW7, MCL1 and PLK1 may be relevant predictive markers of tumor progression and response to paclitaxel treatment.

  14. Antitrust Enforcement and Marginal Deterrence

    NARCIS (Netherlands)

    Houba, H.E.D.; Motchenkova, E.; Wen, Q.

    2011-01-01

    Abstract: We study antitrust enforcement in which the fine must obey four legal principles: punishments should fit the crime, proportionality, bankruptcy considerations, and minimum fines. We integrate these legal principles into an infinitely-repeated oligopoly model. Bankruptcy considerations

  15. Conservation Law Enforcement Program Standardization

    National Research Council Canada - National Science Library

    Rogers, Stan

    2004-01-01

    The ultimate goal of standardization is to develop a safe and effective program that is recognized within the USAF, DoD, and by other Federal and state law enforcement agencies, and the general public...

  16. Quota enforcement in resource industries

    DEFF Research Database (Denmark)

    Hansen, Lars Gårn; Jensen, Frank; Nøstbakken, Linda

    2014-01-01

    -compliance and exogenous constraints on fines and enforcement budget. We propose a new enforcement system based on self-reporting of excess extraction and explicit differentiation of inspection rates depending on compliance history. We use differentiated inspections to induce firms to self-report excess extraction....... This system increases the effectiveness of the quota by allowing the regulator to implement a wider range of aggregate extraction targets than under traditional enforcement, while ensuring an efficient allocation of extraction. In addition, inspection costs can be reduced without reductions in welfare.......Quotas are frequently used in the management of renewable resources and emissions. However, in many industries there is concern about their basic effectiveness due to non-compliance. We develop an enforcement model of a quota-regulated resource and focus on a situation with significant non...

  17. Enforcement actions: Significant actions resolved

    International Nuclear Information System (INIS)

    1994-03-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (October - December 1993) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

  18. Financial Private Regulation and Enforcement

    OpenAIRE

    MILLER, Geoffrey

    2011-01-01

    This paper has been delivered within the context of the research project "Transnational Private Regulatory Regimes: Constitutional foundations and governance design". This paper considers the topic of private regulation and enforcement for internationally active financial services firms. The paper documents the following types of regulation and enforcement that involve significant private input: house rules, contracts, internal compliance, management-based regulation, private standard-sett...

  19. Enforcement actions: Significant actions resolved

    International Nuclear Information System (INIS)

    1992-11-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (July - September 1992) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

  20. On the Enforcement of Specific Performance in Civil Law Countries

    DEFF Research Database (Denmark)

    Lando, Henrik; Rose, Caspar

    2003-01-01

    requires actions to beundertaken, and we relate this to costs of enforcement. We arguethat it is administratively costly to run a system of enforcementthat renders specific performance attractive to the aggrieved party,and that the Civil Law countries have (like Common Law countries)chosen not to incur...... these costs of enforcement. This is especiallyclear in the case of Denmark, where specific performance of actionshas been abandoned as a legal remedy.At the normative level, we argue that enforcement costs providesan additional rationale, over and above the rationales of the theoryof efficient breach...

  1. MCL Plays an Anti-Inflammatory Role in Mycobacterium tuberculosis-Induced Immune Response by Inhibiting NF-κB and NLRP3 Inflammasome Activation

    Directory of Open Access Journals (Sweden)

    Qingwen Zhang

    2017-01-01

    Full Text Available Mycobacterium tuberculosis (Mtb remains a significant menace to global health as it induces granulomatous lung lesions and systemic inflammatory responses during active tuberculosis (TB. Micheliolide (MCL, a sesquiterpene lactone, was recently reported to have a function of relieving LPS-induced inflammatory response, but the regulative role of MCL on the immunopathology of TB still remains unknown. In this experiment, we examined the inhibitory effect of MCL on Mtb-induced inflammatory response in mouse macrophage-like cell line Raw264.7 by downregulating the activation of nuclear factor kappa B (NF-κB and NLRP3 inflammasome. Evidences showed that MCL decreased the secretion of Mtb-induced inflammatory cytokines (IL-1β and TNF-α in a dose-dependent manner. Meanwhile, MCL dramatically suppressed Mtb-induced activation of iNOS and COX2 as well as subsequent production of NO. Furthermore, MCL inhibited Mtb-induced phosphorylation of Akt (Ser 473 in Raw264.7. According to our results, MCL plays an important role in modulating Mtb-induced inflammatory response through PI3K/Akt/NF-κB pathway and subsequently downregulating the activation of NLRP3 inflammasome. Therefore, MCL may represent as a potential drug candidate in the adjuvant treatment of TB by regulating host immune response.

  2. Recent Trends in Antitrust Enforcement

    Directory of Open Access Journals (Sweden)

    Mario Siragusa

    2015-10-01

    Full Text Available This article intends to discuss a selection of the most relevant features of the most recent trends in antitrust enforcement. Firstly, anticompetitive signalling will be addressed: its assessment depends on the kind of information provided. Where such information is of public knowledge or is very well known by the market participants, signalling should not be deemed as anticompetitive. Secondly, the Power Cable case has raised for the first time various problematic issues, such as the possibility to impose parental liability on a purely financial investor, even where the presumed direct infringer would have been able to pay the fine. This appears to be irreconcilable with the objectives for which the case law on parental liability has been elaborated. Thirdly, as to the concept of restriction of competition by object, it is argued that the Intel case does not disavow the principles established in Cartes Bancaires. Indeed, the finding of a violation and the different methodology applied in the first case are only due to its specific factual circumstances. Finally, the nouvelle vague of the case law on the anticompetitive abuse of rights has led to two opposite approaches, one at the EU and the other at the Italian level. The first one, based on the finding of objective circumstances, is perfectly consistent with existing EU case law, while the second, exclusively focused on the exclusionary intent, seems to be in sharp contrast with it. The hope is that the Court of Justice will intervene to resolve this contradiction.

  3. A Combination of Targeted Therapy with Chemotherapy Backbone Induces Response in a Treatment-Resistant Triple-Negative MCL1-Amplified Metastatic Breast Cancer Patient

    Directory of Open Access Journals (Sweden)

    Siraj M. Ali

    2016-02-01

    Full Text Available After failure of anthracycline- and platinum-based therapy, no effective therapies exist for management of metastatic triple-negative breast cancer (TNBC. We report a case of metastatic TNBC harboring MCL1 amplification, as identified by comprehensive genomic profiling in the course of clinical care. MCL1 is an antiapoptotic gene in the BCL2 family, and MCL1 amplification is common in TNBC (at least 20%. A personalized dose-reduced regimen centered on a combination of sorafenib and vorinostat was implemented, based on preclinical evidence demonstrating treatment synergy in the setting of MCL1 amplification. Although hospice care was being considered before treatment initiation, the personalized regimen yielded 6 additional months of life for this patient. Further rigorous studies are needed to confirm that this regimen or derivatives thereof can benefit the MCL1-amplified subset of TNBC patients.

  4. Wnt modulates MCL1 to control cell survival in triple negative breast cancer

    International Nuclear Information System (INIS)

    Yang, Lixin; Zhang, Hang; Zheng, Shu; Liu, Zheng; Ann, David; Yen, Yun; Perez, Aldwin Apollo; Fujie, Sayuri; Warden, Charles; Li, Jie; Wang, Yafan; Yung, Bryan; Chen, Yun-Ru; Liu, Xiyong

    2014-01-01

    Triple negative breast cancer (TNBC) has higher rates of recurrence and distant metastasis, and poorer outcome as compared to non-TNBC. Aberrant activation of WNT signaling has been detected in TNBC, which might be important for triggering oncogenic conversion of breast epithelial cell. Therefore, we directed our focus on identifying the WNT ligand and its underlying mechanism in TNBC cells. We performed large-scale analysis of public microarray data to screen the WNT ligands and the clinical significance of the responsible ligand in TNBC. WNT5B was identified and its overexpression in TNBC was confirmed by immunohistochemistry staining, Western blot and ELISA. ShRNA was used to knockdown WNT5B expression (shWNT5B). Cellular functional alteration with shWNT5B treatment was determined by using wound healing assay, mammosphere assay; while cell cycle and apoptosis were examined by flowcytometry. Mitochondrial morphology was photographed by electron microscope. Biological change of mitochondria was detected by RT-PCR and oxygen consumption assay. Activation of WNT pathway and its downstream targets were evaluated by liciferase assay, immunohistochemistry staining and immunoblot analysis. Statistical methods used in the experiments besides microarray analysis was two-tailed t-test. WNT5B was elevated both in the tumor and the patients’ serum. Suppression of WNT5B remarkably impaired cell growth, migration and mammosphere formation. Additionally, G0/G1 cell cycle arrest and caspase-independent apoptosis was observed. Study of the possible mechanism indicated that these effects occurred through suppression of mitochondrial biogenesis, as evidenced by reduced mitochondrial DNA (MtDNA) and compromised oxidative phosphorylation (OXPHOS). In Vivo and in vitro data uncovered that WNT5B modulated mitochondrial physiology was mediated by MCL1, which was regulated by WNT/β-catenin responsive gene, Myc. Clinic data analysis revealed that both WNT5B and MCL1 are associated with

  5. State enforcement of federal standards: Implications for interstate pollution

    Energy Technology Data Exchange (ETDEWEB)

    Hutchinson, Emma; Kennedy, Peter W. [Department of Economics, University of Victoria, Victoria, BC V8W 2Y2 (Canada)

    2008-08-15

    This paper explores the relationship between interstate air pollution and the division of power between federal and state agencies in setting and enforcing standards. In the context of the US Clean Air Act we argue that the EPA is able to monitor the adoption of technology-based standards more closely than it can monitor state-level enforcement, and that this causes an effective division of control between federal and state agencies. Our analysis offers three main insights into the interstate pollution problem in this setting. First, states have an incentive to enforce standards less stringently on firms located close to downwind borders, and this leads to excessive interstate pollution in equilibrium. Second, there can arise an inherent substitutability in the regulatory problem between strict standards and compliance effort, and this creates a strategic linkage between the federal policy on standards and state policies on enforcement. In particular, a tighter federal standard can induce less selective enforcement but can also lead to less enforcement overall. Third, states will attempt to neutralize the impact of location-based federal standards (that specifically target interstate pollution) in a way that actually exacerbates the underlying enforcement problem. (author)

  6. Prospects of development of the court decrees enforcement system

    Directory of Open Access Journals (Sweden)

    Kristina Sergeyevna Morkovskaya

    2015-06-01

    Full Text Available Objective the relevance of the topic the insufficient level of its scientific elaboration predetermined the research objectives which consist in the analysis of the institution of enforcement proceedings the identification of key challenges trends and ways to improve the current system of court decrees enforcement. Methods the methodological basis of the undertaken research is scientific method of cognition in conjunction with certain specific scientific methods the laws of formal logic historical method comparative legal method and systematic analysis of theoretical works studied in this work. Results the emerging trends in the enforcement proceedings reform in the country cannot be considered to be satisfactory in general although some initiatives seem quite appropriate in case of the proper performance. If you the situation cannot be rectified with the execution of judicial decrees basing on own experience only it is necessary to pay attention to foreign practices and to provide citizens with the right to an effective judicial protection. Of all approaches to reforming of the enforcement institution analyzed in the article the preferred for the Russian legal reality is modernization of the existing nonjudicial system of enforcement through civil procedural means. Scientific novelty at present neither the civil procedure nor the general theory of law has not developed a unified understanding of the civil procedural tools for improving the efficiency of enforcement proceedings. Practical value the main provisions and conclusions of the article can be used in research and teaching when viewing the issues of the effectiveness of enforcement proceedings. nbsp

  7. 29 CFR 42.6 - Enforcement strategy.

    Science.gov (United States)

    2010-07-01

    ... 29 Labor 1 2010-07-01 2010-07-01 true Enforcement strategy. 42.6 Section 42.6 Labor Office of the Secretary of Labor COORDINATED ENFORCEMENT § 42.6 Enforcement strategy. (a) Each Regional Farm Labor... enforcement strategy for each protective statute pursuant to § 42.20(c)(3). The National Committee shall...

  8. The effect of repeated measurements and working memory on the most comfortable level in the ANL test.

    Science.gov (United States)

    Brännström, K Jonas; Olsen, Steen Østergaard; Holm, Lucas; Kastberg, Tobias; Ibertsson, Tina

    2014-11-01

    To study the effect of a large number of repetitions on the most comfortable level (MCL) when doing the acceptable noise level (ANL) test, and explore if MCL variability is related to central cognitive processes. Twelve MCL repetitions were measured within the ANL test using interleaved methodology during one session using a non-semantic version. Phonological (PWM) and visuospatial working memory (VSWM) was measured. Thirty-two normal-hearing adults. Repeated measures ANOVA, intraclass correlations, and the coefficient of repeatability (CR) were used to assess the repeatability. Repeated measures ANOVA and CR indicated poor agreement between the two first repetitions. After excluding the first repetition, analyses showed that the MCL in the ANL test is reliable. A negative association was found between PWM and MCL variability indicating that subjects with higher PWM show less variability. The findings suggest that, after excluding the first repetition, the MCL in the ANL test is reliable. A single repetition of the MCL in the ANL test should be avoided. If an interleaved methodology is used, a single ANL repetition should be added prior to the actual testing. The findings also suggest that MCL variability is associated to PWM but not VSWM.

  9. Optimization and calculation of the MCl-ZnCl2 (M = Li, Na, K) phase diagrams

    International Nuclear Information System (INIS)

    Romero-Serrano, Antonio; Hernandez-Ramirez, Aurelio; Cruz-Ramirez, Alejandro; Hallen-Lopez, Manuel; Zeifert, Beatriz

    2010-01-01

    An earlier structural model for binary silicate melts and glasses is extended to zinc chloride-alkali metal chloride systems. The evaluation of the available thermodynamic and phase diagrams data for the MCl-ZnCl 2 (M = Li, Na, K) binary systems have been carried out using the structural model for the liquid phase. This thermodynamic model is based on the assumption that each alkali chloride produces the depolymerization of ZnCl 2 network with a characteristic free-energy change. A least-squares optimization program permits all available thermodynamic and phase diagram data to be optimized simultaneously. In this manner, data for these binary systems have been analysed and represented with a small number of parameters.

  10. The role of glucocorticoid receptor phosphorylation in Mcl-1 and NOXA gene expression

    Directory of Open Access Journals (Sweden)

    Demonacos Constantinos

    2010-02-01

    Full Text Available Abstract Background The cyclin-dependent kinase (CDK and mitogen-activated protein kinase (MAPK mediated phosphorylation of glucocorticoid receptor (GR exerts opposite effects on GR transcriptional activity and affects other posttranslational modifications within this protein. The major phosphorylation site of human GR targeted by MAPK family is the serine 226 and multiple kinase complexes phosphorylate receptor at the serine 211 residue. We hypothesize that GR posttranslational modifications are involved in the determination of the cellular fate in human lymphoblastic leukemia cells. We investigated whether UV signalling through alternative GR phosphorylation determined the cell type specificity of glucocorticoids (GCs mediated apoptosis. Results We have identified putative Glucocorticoid Response Elements (GREs within the promoter regulatory regions of the Bcl-2 family members NOXA and Mcl-1 indicating that they are direct GR transcriptional targets. These genes were differentially regulated in CEM-C7-14, CEM-C1-15 and A549 cells by glucocorticoids and JNK pathway. In addition, our results revealed that the S211 phosphorylation was dominant in CEM-C7-14, whereas the opposite was the case in CEM-C1-15 where prevalence of S226 GR phosphorylation was observed. Furthermore, multiple GR isoforms with cell line specific patterns were identified in CEM-C7-14 cells compared to CEM-C1-15 and A549 cell lines with the same antibodies. Conclusions GR phosphorylation status kinetics, and site specificity as well as isoform variability differ in CEM-C7-14, CEM-C1-15, and A549 cells. The positive or negative response to GCs induced apoptosis in these cell lines is a consequence of the variable equilibrium of NOXA and Mcl-1 gene expression potentially mediated by alternatively phosphorylated GR, as well as the balance of MAPK/CDK pathways controlling GR phosphorylation pattern. Our results provide molecular base and valuable knowledge for improving the GC

  11. Performance-Driven Interface Contract Enforcement for Scientific Components

    Energy Technology Data Exchange (ETDEWEB)

    Dahlgren, Tamara Lynn [Univ. of California, Davis, CA (United States)

    2008-01-01

    Performance-driven interface contract enforcement research aims to improve the quality of programs built from plug-and-play scientific components. Interface contracts make the obligations on the caller and all implementations of the specified methods explicit. Runtime contract enforcement is a well-known technique for enhancing testing and debugging. However, checking all of the associated constraints during deployment is generally considered too costly from a performance stand point. Previous solutions enforced subsets of constraints without explicit consideration of their performance implications. Hence, this research measures the impacts of different interface contract sampling strategies and compares results with new techniques driven by execution time estimates. Results from three studies indicate automatically adjusting the level of checking based on performance constraints improves the likelihood of detecting contract violations under certain circumstances. Specifically, performance-driven enforcement is better suited to programs exercising constraints whose costs are at most moderately expensive relative to normal program execution.

  12. Enforcement actions: Significant actions resolved

    International Nuclear Information System (INIS)

    1993-09-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (April--June 1993) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

  13. Enforcement actions: Significant actions resolved

    International Nuclear Information System (INIS)

    1991-05-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (January--March 1991) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

  14. Enforcement actions: Significant actions resolved

    International Nuclear Information System (INIS)

    1991-02-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (October--December 1990) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

  15. Enforcement actions: Significant actions resolved

    International Nuclear Information System (INIS)

    1990-03-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (October--December 1989) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

  16. Enforcement actions: Significant actions resolved

    International Nuclear Information System (INIS)

    1990-11-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (July--September 1990) and includes copies of letters, notices, and orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

  17. Enforcement actions: Significant actions resolved

    International Nuclear Information System (INIS)

    1992-08-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (April--June 1992) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

  18. Enforcement actions: Significant actions resolved

    International Nuclear Information System (INIS)

    1990-09-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (April--June 1990) and includes copies of letters, notices, and orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

  19. Enforcement actions: Significant actions resolved

    International Nuclear Information System (INIS)

    1993-06-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (January--March 1993) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

  20. Enforcement actions: Significant actions resolved

    International Nuclear Information System (INIS)

    1992-05-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (January--March 1992) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

  1. Enforcement actions: Significant actions resolved

    International Nuclear Information System (INIS)

    1993-12-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (July--September 1993) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

  2. Enforcement actions: Significant actions resolved

    International Nuclear Information System (INIS)

    1993-03-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (October--December 1992) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

  3. Enforcement actions: Significant actions resolved

    International Nuclear Information System (INIS)

    1991-07-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (April-June 1991) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

  4. Enforcement actions: Significant actions resolved

    International Nuclear Information System (INIS)

    1991-11-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (July--September 1991) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

  5. Enforcement actions: Significant actions resolved

    International Nuclear Information System (INIS)

    1992-03-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (October--December 1991) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

  6. Enforcement actions: Significant actions resolved

    International Nuclear Information System (INIS)

    1989-12-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (July--September 1989) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

  7. Optimal enforcement of competition law

    NARCIS (Netherlands)

    Motchenkova, E.

    2005-01-01

    Despite the recent theoretical developments in the field of antitrust law enforcement, much still needs to be done in order to prevent collusion and price-fixing in the major indiustries. Although penalties were recently increased considerably and new instruments of cartel deterrence such as

  8. The Impact of Financial Reporting Enforcement and IFRS Adoption on Executive Compensation

    DEFF Research Database (Denmark)

    Banghøj, Jesper; Marton, Jan; Plenborg, Thomas

    This study examines whether both IFRS adoption and the level of financial reporting enforcement impact the contractual usefulness of financial statements, as reflected in payperformance sensitivity. Using a sample of 8,440 executive year observations from 522 firms in 16 European countries we find....... This suggests that the impact of enforcement on pay‐performance sensitivity vanishes after the implementation of IFRS. These results indicate that IFRS dominate enforcement when it comes to the contractual usefulness of financial statements. The findings should be of interest to both enforcement authorities...... that when earnings are based on local GAAP, the payperformance sensitivity is positive and significant only when the level of enforcement is high. When earnings are based on IFRS, we find that the pay‐performance sensitivity is (equally) positive and significant across different levels of enforcement...

  9. Activation of mitochondrial apoptosis pathways in cutaneous squamous cell carcinoma cells by diclofenac/hyaluronic acid is related to upregulation of Bad as well as downregulation of Mcl-1 and Bcl-w.

    Science.gov (United States)

    Rodust, Paul M; Fecker, Lothar F; Stockfleth, Eggert; Eberle, Jürgen

    2012-07-01

    Actinic keratosis (AK) is characterized by high prevalence and the risk to proceed to squamous cell carcinoma (SCC). Cyclooxygenase-2 (COX-2)-mediated prostaglandin E2 (PGE (2) ) synthesis has been reported in AK and SCC, and the COX inhibitor diclofenac in hyaluronic acid (diclofenac/HA) was approved for AK therapy. Its mode of action, however, remained to be unravelled. In the present study, diclofenac resulted in reduced PGE (2) levels in apoptosis-sensitive cutaneous SCC cell lines (SCL-II, SCC-12, SCC-13) whereas no PGE (2) and no COX-2 expression was detectable in a SCC cell line resistant to apoptosis induction (SCL-I). Activation of mitochondrial apoptosis pathways was evident in SCC cells owing to loss of the mitochondrial membrane potential and release of the mitochondrial factors cytochrome c and apoptosis-inducing factor. Characteristic proapoptotic changes at the level of Bcl-2 proteins occurred in sensitive cells, as upregulation of Bad and downregulation of Mcl-1 and Bcl-w. In contrast, Bad was already high, and Mcl-1 and Bcl-w were already low in resistant SCL-I, even without treatment, which may be explained by the lack of PGE (2) . An antiapoptotic downregulation of proapoptotic Bcl-2 proteins Noxa and Puma was, however, also seen in SCL-I, suggesting here pathways independent of COX-2. The regulations of Mcl-1 and Bad were also reproduced in SCC cells by the more selective COX-2 inhibitor celecoxib, thus further underlining the specific role of COX-2. The findings illuminate the mode of action of diclofenac/HA in SCC cells as well as principles of their resistance, which may allow further adaptation and improvement of the new therapy. © 2012 John Wiley & Sons A/S.

  10. Public education and enforcement research study (PEERS).

    Science.gov (United States)

    2013-08-01

    In 2001, the Federal Railroad Administration (FRA) and the Illinois Commerce Commission (ICC) established the Public Education and Enforcement Research Study (PEERS) to test the effectiveness of various education and enforcement (E&E) techniques to i...

  11. GAMING LAW ENFORCEMENT AND CRIMINAL JUSTICE PROBLEMS,

    Science.gov (United States)

    and techniques of gaming as they apply to the study of law enforcement problems in general, and to show how gaming may assist in identifying and overcoming some of the major pitfalls in law enforcement planning. (Author)

  12. 20 CFR 655.50 - Enforcement process.

    Science.gov (United States)

    2010-04-01

    ... 20 Employees' Benefits 3 2010-04-01 2010-04-01 false Enforcement process. 655.50 Section 655.50... FOREIGN WORKERS IN THE UNITED STATES Labor Certification Process and Enforcement of Attestations for... Workers) § 655.50 Enforcement process. (a) Authority of the WHD Administrator. The WHD Administrator shall...

  13. 78 FR 69133 - Drug Enforcement Administration

    Science.gov (United States)

    2013-11-18

    ... DEPARTMENT OF JUSTICE Drug Enforcement Administration Manufacturer of Controlled Substances..., California 94085, made application by renewal to the Drug Enforcement Administration (DEA) to be registered... Diversion Control, Drug Enforcement Administration. [FR Doc. 2013-27486 Filed 11-15-13; 8:45 am] BILLING...

  14. 76 FR 76192 - NRC Enforcement Policy

    Science.gov (United States)

    2011-12-06

    ... NUCLEAR REGULATORY COMMISSION [NRC-2011-0273] NRC Enforcement Policy AGENCY: Nuclear Regulatory Commission. ACTION: Proposed enforcement policy revision; request for comment. SUMMARY: The U.S. Nuclear... licensees, vendors, and contractors), on proposed revisions to the NRC's Enforcement Policy (the Policy) and...

  15. Employee perceptions of protected area law enforcement

    Science.gov (United States)

    Christopher J. Wynveen; Robert D. Bixler; William E. Hammitt

    2006-01-01

    It is widely accepted that criminal activity negatively impacts visitors? recreation experiences in the nation?s parks and forests (Fletcher 1983). To further understand how law enforcement can effectively manage criminal activity in protected areas, this study was designed to describe law enforcement and non-law enforcement rangers? perceptions of a range of law...

  16. 50 CFR 600.740 - Enforcement policy.

    Science.gov (United States)

    2010-10-01

    ... 50 Wildlife and Fisheries 8 2010-10-01 2010-10-01 false Enforcement policy. 600.740 Section 600... § 600.740 Enforcement policy. (a) The Magnuson-Stevens Act provides four basic enforcement remedies for... and its catch. (4) Criminal prosecution of the owner or operator for some offenses. It shall be the...

  17. 12 CFR 411.410 - Enforcement.

    Science.gov (United States)

    2010-01-01

    ... 12 Banks and Banking 4 2010-01-01 2010-01-01 false Enforcement. 411.410 Section 411.410 Banks and Banking EXPORT-IMPORT BANK OF THE UNITED STATES NEW RESTRICTIONS ON LOBBYING Penalties and Enforcement § 411.410 Enforcement. The head of each agency shall take such actions as are necessary to ensure that...

  18. 75 FR 69573 - Export Enforcement Coordination Center

    Science.gov (United States)

    2010-11-15

    ... Export Enforcement Coordination Center By the authority vested in me as President by the Constitution and... enforcement of United States export control laws and enhanced intelligence exchange in support of such enforcement efforts, it is hereby ordered as follows: Section 1. Policy. Export controls are critical to...

  19. Differences in TRAIL-induced changes of Mcl-1 expression among distinct human colon epithelial cell lines

    Czech Academy of Sciences Publication Activity Database

    Vaculová, Alena; Hofmanová, Jiřina; Zatloukalová, Jiřina; Kozubík, Alois

    2009-01-01

    Roč. 315, č. 19 (2009), s. 3259-3266 ISSN 0014-4827 R&D Projects: GA ČR(CZ) GA524/07/1178; GA ČR(CZ) GA301/07/1557; GA AV ČR(CZ) 1QS500040507 Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : TRAIL * Mcl-1 * apoptosis Subject RIV: BO - Biophysics Impact factor: 3.589, year: 2009

  20. TOFA (5-tetradecyl-oxy-2-furoic acid) reduces fatty acid synthesis, inhibits expression of AR, neuropilin-1 and Mcl-1 and kills prostate cancer cells independent of p53 status.

    Science.gov (United States)

    Guseva, Natalya V; Rokhlin, Oskar W; Glover, Rebecca A; Cohen, Michael B

    2011-07-01

    A key player in prostate cancer development and progression is the androgen receptor (AR). Tumor-associated lipogenesis can protect cancer cells from carcinogenic- and therapeutic-associated treatments. Increased synthesis of fatty acids and cholesterol is regulated by androgens through induction of several genes in androgen-responsive cancer cells. Acetyl-CoA-carboxylase-α (ACCA) is a key enzyme in the regulation of fatty acids synthesis. Here we show that AR binds in vivo to intron regions of human ACCA gene. We also show that the level of ACCA protein in LNCaP depends on AR expression and that DHT treatment increases ACCA expression and fatty acid synthesis. Inhibition of ACCA by TOFA (5-tetradecyl-oxy-2-furoic acid) decreases fatty acid synthesis and induces caspase activation and cell death in most PCa cell lines. Our data suggest that TOFA can kill cells via the mitochondrial pathway since we found cytochrome c release after TOFA treatment in androgen sensitive cell lines. The results also imply that the pro-apoptotic effect of TOFA may be mediated via a decrease of neuropilin-1(NRP1) and Mcl-1expression. We have previously reported that Mcl-1 is under AR regulation and plays an important role in resistance to drug-induced apoptosis in prostate cancer cells, and NRP1 is known to regulate Mcl-1 expression. Here, we show for the first time that NRP1 expression is under AR control. Taken together, our data suggest that TOFA is a potent cell death inducing agent in prostate cancer cells.

  1. 3-Bromopyruvate induces apoptosis in breast cancer cells by downregulating Mcl-1 through the PI3K/Akt signaling pathway.

    Science.gov (United States)

    Liu, Zhe; Zhang, Yuan-Yuan; Zhang, Qian-Wen; Zhao, Su-Rong; Wu, Cheng-Zhu; Cheng, Xiu; Jiang, Chen-Chen; Jiang, Zhi-Wen; Liu, Hao

    2014-04-01

    The hexokinase inhibitor 3-bromopyruvate (3-BrPA) can inhibit glycolysis in tumor cells to reduce ATP production, resulting in apoptosis. However, as 3-BrPA is an alkylating agent, its cytotoxic action may be induced by other molecular mechanisms. The results presented here reveal that 3-BrPA-induced apoptosis is caspase independent. Further, 3-BrPA induces the generation of reactive oxygen species in MDA-MB-231 cells, leading to mitochondria-mediated apoptosis. These results suggest that caspase-independent apoptosis may be induced by the generation of reactive oxygen species. In this study, we also demonstrated that 3-BrPA induces apoptosis through the downregulation of myeloid cell leukemia-1 (Mcl-1) in MDA-MB-231 breast cancer cells. The results of Mcl-1 knockdown indicate that Mcl-1 plays an important role in 3-BrPA-induced apoptosis. Further, the upregulation of Mcl-1 expression in 3-BrPA-treated MDA-MB-231 cells significantly increases cell viability. In addition, 3-BrPA treatment resulted in the downregulation of p-Akt, suggesting that 3-BrPA may downregulate Mcl-1 through the phosphoinositide-3-kinase/Akt pathway. These findings indicate that 3-BrPA induces apoptosis in breast cancer cells by downregulating Mcl-1 through the phosphoinositide-3-kinase/Akt signaling pathway.

  2. PDGF upregulates Mcl-1 through activation of β-catenin and HIF-1α-dependent signaling in human prostate cancer cells.

    Directory of Open Access Journals (Sweden)

    Shareen Iqbal

    Full Text Available BACKGROUND: Aberrant platelet derived growth factor (PDGF signaling has been associated with prostate cancer (PCa progression. However, its role in the regulation of PCa cell growth and survival has not been well characterized. METHODOLOGY/PRINCIPAL FINDINGS: Using experimental models that closely mimic clinical pathophysiology of PCa progression, we demonstrated that PDGF is a survival factor in PCa cells through upregulation of myeloid cell leukemia-1 (Mcl-1. PDGF treatment induced rapid nuclear translocation of β-catenin, presumably mediated by c-Abl and p68 signaling. Intriguingly, PDGF promoted formation of a nuclear transcriptional complex consisting of β-catenin and hypoxia-inducible factor (HIF-1α, and its binding to Mcl-1 promoter. Deletion of a putative hypoxia response element (HRE within the Mcl-1 promoter attenuated PDGF effects on Mcl-1 expression. Blockade of PDGF receptor (PDGFR signaling with a pharmacological inhibitor AG-17 abrogated PDGF induction of Mcl-1, and induced apoptosis in metastatic PCa cells. CONCLUSIONS/SIGNIFICANCE: Our study elucidated a crucial survival mechanism in PCa cells, indicating that interruption of the PDGF-Mcl-1 survival signal may provide a novel strategy for treating PCa metastasis.

  3. The law enforcement agencies in Turkey

    International Nuclear Information System (INIS)

    Aygun, A.

    2001-01-01

    activities, if there is any indicator related to drug smuggling during the inspection. The main task of the General Directorate of Customs Enforcement is to prevent, prosecute and investigate any act of smuggling not only in customs areas (border crossing) but also all over Turkey as well as to be responsible for carrying out the task of the customs procedure partially in customs area. General Directorate of Customs Enforcement implements the task with regard to the prevention, prosecution and investigation of violation of customs legislation, i.e. combating all kinds of smuggling and illegal activities. As far as organizational structure of GDCE is concerned, it has Center and District units. In the Center, under the General Director, three Deputy General Directors exist. There are five Heads of Departments linked to the concerned Deputy General Director. One of them is related with anti-smuggling and anti-narcotics activities as Head of Department of Investigation Intelligence and Prosecution of Anti-Smuggling and Anti-Narcotics. Four Directorates have fulfilled their activities in this Department. The role of Directorate of Anti-Smuggling is to coordinate districts units activities related with combating commercial fraud. That of anti-narcotics is responsible for directing and monitoring of the activities on fighting drugs smuggling done by regional units. The directorate of criminal laboratory is in the stage of being set up. The aim of this directorate is to determine whether or not any suspected material is drugs, and whether any suspected document used in customs procedure is genuine of false. The Directorate of Data Processing and Assessment has: performed the data processing affairs; collected information on seizure case, suspected persons and vehicles; analyzed and distributed information and intelligence. At the regional level, GDCE has 18 district headquarters. There are also many units linked to Regional Headquarters. Especially, after the fall of the Soviet

  4. Enforcing the climate regime: Game theory and the Marrakesh Accords

    Energy Technology Data Exchange (ETDEWEB)

    Hovi, Jon

    2002-07-01

    The article reviews basic insights about compliance and ''hard'' enforcement that can be derived from various non-cooperative equilibrium concepts and evaluates the Marrakesh Accords in light of these insights. Five different notions of equilibrium are considered - the Nash equilibrium, the sub game perfect equilibrium, the re negotiation proof equilibrium, the coalition proof equilibrium and the perfect Bayesian equilibrium. These various types of equilibrium have number of implications for effective enforcement: 1. Consequences of non-compliance should be more than proportionate. 2. To be credible punishment needs to take place in the Pareto frontier, rather than by reversion to some suboptimal state. 3. An effective enforcement system must be able to curb collective as well as individual incentives to cheat. 4. A fully transparent enforcement regime could in fact turn out to be detrimental for compliance levels. It is concluded that constructing an effective system for ''hard'' enforcement of the Kyoto Protocol is a formidable task that has only partially been accomplished by the Marrakesh Accords. A possible explanation is that the design of a compliance system for the climate regime involved a careful balancing of the desire to minimise non-compliance against other important considerations. (Author)

  5. Enforcing the climate regime: Game theory and the Marrakesh Accords

    International Nuclear Information System (INIS)

    Hovi, Jon

    2002-01-01

    The article reviews basic insights about compliance and ''hard'' enforcement that can be derived from various non-cooperative equilibrium concepts and evaluates the Marrakesh Accords in light of these insights. Five different notions of equilibrium are considered - the Nash equilibrium, the sub game perfect equilibrium, the re negotiation proof equilibrium, the coalition proof equilibrium and the perfect Bayesian equilibrium. These various types of equilibrium have number of implications for effective enforcement: 1. Consequences of non-compliance should be more than proportionate. 2. To be credible punishment needs to take place in the Pareto frontier, rather than by reversion to some suboptimal state. 3. An effective enforcement system must be able to curb collective as well as individual incentives to cheat. 4. A fully transparent enforcement regime could in fact turn out to be detrimental for compliance levels. It is concluded that constructing an effective system for ''hard'' enforcement of the Kyoto Protocol is a formidable task that has only partially been accomplished by the Marrakesh Accords. A possible explanation is that the design of a compliance system for the climate regime involved a careful balancing of the desire to minimise non-compliance against other important considerations. (Author)

  6. Forensic Speaker Recognition Law Enforcement and Counter-Terrorism

    CERN Document Server

    Patil, Hemant

    2012-01-01

    Forensic Speaker Recognition: Law Enforcement and Counter-Terrorism is an anthology of the research findings of 35 speaker recognition experts from around the world. The volume provides a multidimensional view of the complex science involved in determining whether a suspect’s voice truly matches forensic speech samples, collected by law enforcement and counter-terrorism agencies, that are associated with the commission of a terrorist act or other crimes. While addressing such topics as the challenges of forensic case work, handling speech signal degradation, analyzing features of speaker recognition to optimize voice verification system performance, and designing voice applications that meet the practical needs of law enforcement and counter-terrorism agencies, this material all sounds a common theme: how the rigors of forensic utility are demanding new levels of excellence in all aspects of speaker recognition. The contributors are among the most eminent scientists in speech engineering and signal process...

  7. The efficiency of private enforcement of publik law claims in Estonia. Riiginõuete sissenõudmise efektiivsus Eestis

    Directory of Open Access Journals (Sweden)

    Indrek Saar

    2016-08-01

    Full Text Available In Estonia, since 2001 the function of the enforcement of public law claims, such as fines or taxes, has been transferred to freelance bailiffs. The intention was to create profit motives for private enforcers to increase the effectiveness of the enforcement system. In this paper it is shown that the remuneration scheme for bailiffs that is currently applied tends to lead to inefficiently low level of enforced public law claims. Through quantitative calculations it is illustrated that there might exist alternatives that significantly increase the economic efficiency of the enforcement system.

  8. Restraint use law enforcement intervention in Latino communities.

    Science.gov (United States)

    Schaechter, Judy; Uhlhorn, Susan B

    2011-11-01

    Motor vehicle crashes are the leading cause of death for U.S. Latinos aged 1 to 35 years. Restraint use is an effective means of prevention of motor vehicle crash injury. Effective interventions to raise restraint use include the following: legislation, law enforcement, education, and equipment distribution. The effects of law enforcement interventions in Latino immigrant communities are understudied. We measured the community-level effect of a combined intervention that included warnings and citations phase enforcement in Latino communities. We designed and implemented in two of three Latino-majority communities a multicomponent intervention consisting of a community awareness campaign, restraint use education with equipment distribution, and a two-staged law enforcement intervention. Restraint use observations were conducted in all three communities at baseline, after the warnings phase and again after the citations phase of the intervention were completed. The combined intervention of community awareness, education, child passenger restraint distribution, and law enforcement focused on educational traffic stops with incentives and warnings was associated with a significant increase in both driver and child passenger restraint use in one intervention community, but only driver restraint increased to a level of significance in the other intervention community; significant increase was also noted among nonintervention drivers. The citations phase of the intervention did not result in a significant increase in restraint use and was complicated by interruptions due to unlicensed drivers. The combined effort of community awareness, education, equipment distribution and law enforcement intervention that included incentives and warnings may be effective at increasing seat belt use in Latino communities without the need for citations.

  9. AMPK-mediated up-regulation of mTORC2 and MCL-1 compromises the anti-cancer effects of aspirin

    Science.gov (United States)

    Hua, Hui; Yin, Yancun; Wang, Jiao; Luo, Ting; Jiang, Yangfu

    2016-01-01

    AMP-activated protein kinase (AMPK) is an important energy sensor that may inhibit cell proliferation or promote cell survival during stresses. Besides cyclooxygenase, AMPK is another target of the nonsteroid anti-inflammatory agent aspirin. Preclinical and clinical investigations demonstrate that aspirin can inhibit several types of cancer such as colorectal adenomas and hepatocellular carcinoma (HCC). However, little is known about the cellular response to aspirin that may lead to aspirin resistance. Here, we show that aspirin induces the expression of MCL-1 in HepG2 and SW480 cells through AMPK-mTOR-Akt/ERK axis. Treatment of HepG2 and SW480 cells with aspirin leads to increased MCL-1 expression, Akt and ERK1/2 phosphorylation. Inhibition of Akt/MEK abrogates the induction of MCL-1 by aspirin. Aspirin activates AMPK, which in turn up-regulates mTORC2 activity, Akt, ERK1/2 phosphorylation and MCL-1 expression. MCL-1 knockdown sensitizes cancer cells to aspirin-induced apoptosis. Combination of aspirin and AMPK, Akt or MEK inhibitor results in more significant inhibition of cell proliferation and induction of apoptosis than single agent. Moreover, sorafenib blocks aspirin-induced MCL-1 up-regulation. Combination of aspirin and sorafenib leads to much more cell death and less cell proliferation than each drug alone. Treatment of HCC and colon cancer xenografts with both aspirin and sorafenib results in more significant tumor suppression than single agent. These data demonstrate that AMPK-mediated up-regulation of mTORC2 and MCL-1 may compromise the anticancer effects of aspirin. Combination of aspirin and sorafenib may be an effective regimen to treat HCC and colon cancer. PMID:26918349

  10. MicroRNA hsa-miR-29b potentiates etoposide toxicity in HeLa cells via down-regulation of Mcl-1.

    Science.gov (United States)

    Kollinerová, S; Dostál, Z; Modrianský, M

    2017-04-01

    Etoposide is commonly used as a monotherapy or in combination with other drugs for cancer treatments. In order to increase the drug efficacy, ceaseless search for novel combinations of drugs and supporting molecules is under way. MiRNAs are natural candidates for facilitating drug effect in various cell types. We used several systems to evaluate the effect of miR-29 family on etoposide toxicity in HeLa cells. We show that miR-29b significantly increases etoposide toxicity in HeLa cells. Because Mcl-1 protein has been recognized as a miR-29 family target, we evaluated downregulation of Mcl-1 protein splicing variant expression induced by miR-29 precursors and confirmed a key role of Mcl-1 protein in enhancing etoposide toxicity. Despite downregulation of Mcl-1 by all three miR-29 family members, only miR-29b significantly enhanced etoposide toxicity. We hypothesized that this difference may be linked to the change in Mcl-1L/Mcl-1S ratio induced by miR-29b. We hypothesized that the change could be due to miR-29b nuclear shuttling. Using specifically modified miR-29b sequences with enhanced cytosolic and nuclear localization we show that there is a difference, albeit statistically non-significant. In conclusion, we show that miR-29b has the synergistic effect with etoposide treatment in the HeLa cells and that this effect is linked to Mcl-1 protein expression and nuclear shuttling of miR-29b. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. Perceived local enforcement, personal beliefs,and underage drinking: an assessment of moderating and main effects.

    Science.gov (United States)

    Lipperman-Kreda, Sharon; Paschall, Mallie J; Grube, Joel W

    2009-01-01

    Strategies to enforce underage drinking laws are aimed at reducing youth access to alcohol from commercial and social sources and deterring its possession and use. However, the processes through which enforcement strategies may affect underage drinking are not well understood. This study examined three possible processes by which perceived enforcement of underage drinking laws and personal beliefs (perceived alcohol availability, perceived harm, and personal disapproval of alcohol use) may influence alcohol use among adolescents. Survey data were obtained from 20,747 adolescents (48.3% males) in 115 school districts who participated in the 2006 Oregon Healthy Teens survey. Linear regression analyses were conducted to examine possible interactive and main effects of perceived enforcement and personal beliefs on past-30-day alcohol use. Analyses were adjusted for clustering of observations within school districts and included student demographics and age of alcohol use initiation as covariates. Statistically significant interaction effects on past-30-day alcohol use were found for perceived police enforcement and the three personal beliefs variables, indicating weaker associations between personal beliefs and past-30-day alcohol use at higher levels of perceived enforcement. Main effects of perceived enforcement and personal beliefs variables were also observed in the presence of interaction effects. Evidence for a moderating effect of perceived local enforcement on the relationships between personal beliefs and drinking behaviors suggests that the combination of individually focused prevention programs and local enforcement of underage drinking laws may have the greatest impact on underage drinking.

  12. Accounting for enforcement costs in the spatial allocation of marine zones.

    Science.gov (United States)

    Davis, Katrina; Kragt, Marit; Gelcich, Stefan; Schilizzi, Steven; Pannell, David

    2015-02-01

    Marine fish stocks are in many cases extracted above sustainable levels, but they may be protected through restricted-use zoning systems. The effectiveness of these systems typically depends on support from coastal fishing communities. High management costs including those of enforcement may, however, deter fishers from supporting marine management. We incorporated enforcement costs into a spatial optimization model that identified how conservation targets can be met while maximizing fishers' revenue. Our model identified the optimal allocation of the study area among different zones: no-take, territorial user rights for fisheries (TURFs), or open access. The analysis demonstrated that enforcing no-take and TURF zones incurs a cost, but results in higher species abundance by preventing poaching and overfishing. We analyzed how different enforcement scenarios affected fishers' revenue. Fisher revenue was approximately 50% higher when territorial user rights were enforced than when they were not. The model preferentially allocated area to the enforced-TURF zone over other zones, demonstrating that the financial benefits of enforcement (derived from higher species abundance) exceeded the costs. These findings were robust to increases in enforcement costs but sensitive to changes in species' market price. We also found that revenue under the existing zoning regime in the study area was 13-30% lower than under an optimal solution. Our results highlight the importance of accounting for both the benefits and costs of enforcement in marine conservation, particularly when incurred by fishers. © 2014 Society for Conservation Biology.

  13. Enforcement and Compliance History Online | US EPA

    Science.gov (United States)

    ECHO, Enforcement and Compliance History Online, provides compliance and enforcement information for approximately 800,000 EPA-regulated facilities nationwide. ECHO includes permit, inspection, violation, enforcement action, and penalty information about facilities regulated under the Clean Air Act (CAA) Stationary Source Program, Clean Water Act (CWA) National Pollutant Elimination Discharge System (NPDES), and/or Resource Conservation and Recovery Act (RCRA). Information also is provided on surrounding demographics when available.

  14. OSHA Enforcement, Industrial Compliance and Workplace Injuries

    OpenAIRE

    Ann P. Bartel; Lacy Glenn Thomas

    1982-01-01

    This paper develops and tests a three-equation simultaneous model of OSHA enforcement behavior, industrial compliance and workplace injuries. The enforcement equation is based on the assumption that OSHA acts as a political institution that gains support through the transfer of wealth from firms to employees; the empirical results are largely consistent with this notion. Contrary to previous work, we find that OSHA enforcement efforts have, indeed, had a statistically significant impact on in...

  15. Immigration Enforcement Actions: Fiscal Year 2012

    Data.gov (United States)

    Department of Homeland Security — Each year, the Department of Homeland Security (DHS) undertakes immigration enforcement actions involving hundreds of thousands of foreign nationals. These actions...

  16. Public healthcare interests require strict competition enforcement.

    Science.gov (United States)

    Loozen, Edith M H

    2015-07-01

    Several countries have introduced competition in their health systems in order to maintain the supply of high quality health care in a cost-effective manner. The introduction of competition triggers competition enforcement. Since healthcare is characterized by specific market failures, many favor healthcare-specific competition enforcement in order not only to account for the competition interest, but also for the healthcare interests. The question is whether healthcare systems based on competition can succeed when competition enforcement deviates from standard practice. This paper analyzes whether healthcare-specific competition enforcement is theoretically sound and practically effective. This is exemplified by the Dutch system that is based on regulated competition and thus crucially depends on getting competition enforcement right. Governments are responsible for correcting market failures. Markets are responsible for maximizing the public healthcare interests. By securing sufficient competitive pressure, competition enforcement makes sure they do. When interpreted according to welfare-economics, competition law takes into account both costs and benefits specific market behavior may have for healthcare. Competition agencies and judiciary are not legitimized to deviate from standard evidentiary requirements. Dutch case law shows that healthcare-specific enforcement favors the healthcare undertakings concerned, but to the detriment of public health care. Healthcare-specific competition enforcement is conceptually flawed and counterproductive. In order for healthcare systems based on competition to succeed, competition enforcement should be strict. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  17. Immigration Enforcement Actions: Fiscal Year 2004

    Data.gov (United States)

    Department of Homeland Security — Each year, the Department of Homeland Security (DHS) undertakes immigration enforcement actions involving hundreds of thousands of foreign nationals. These actions...

  18. Immigration Enforcement Actions: Fiscal Year 2007

    Data.gov (United States)

    Department of Homeland Security — Each year, the Department of Homeland Security (DHS) undertakes immigration enforcement actions involving hundreds of thousands of foreign nationals. These actions...

  19. EPA Enforcement and Compliance History Online

    Data.gov (United States)

    U.S. Environmental Protection Agency — The Environmental Protection Agency's Enforcement and Compliance History Online (ECHO) website provides customizable and downloadable information about environmental...

  20. 50 CFR 17.107 - Facilitating enforcement.

    Science.gov (United States)

    2010-10-01

    ... WILDLIFE AND PLANTS (CONTINUED) ENDANGERED AND THREATENED WILDLIFE AND PLANTS (CONTINUED) Manatee Protection Areas § 17.107 Facilitating enforcement. Water vehicles operating in manatee sanctuary or refuge...

  1. Immigration Enforcement Actions: Fiscal Year 2008

    Data.gov (United States)

    Department of Homeland Security — Each year, the Department of Homeland Security (DHS) undertakes immigration enforcement actions involving hundreds of thousands of foreign nationals. These actions...

  2. Immigration Enforcement Actions: Fiscal Year 2010

    Data.gov (United States)

    Department of Homeland Security — Each year, the Department of Homeland Security (DHS) undertakes immigration enforcement actions involving hundreds of thousands of foreign nationals. These actions...

  3. Immigration Enforcement Actions: Fiscal Year 2011

    Data.gov (United States)

    Department of Homeland Security — Each year, the Department of Homeland Security (DHS) undertakes immigration enforcement actions involving hundreds of thousands of foreign nationals. These actions...

  4. Immigration Enforcement Actions: Fiscal Year 2006

    Data.gov (United States)

    Department of Homeland Security — Each year, the Department of Homeland Security (DHS) undertakes immigration enforcement actions involving hundreds of thousands of foreign nationals. These actions...

  5. Immigration Enforcement Actions: Fiscal Year 2009

    Data.gov (United States)

    Department of Homeland Security — Each year, the Department of Homeland Security (DHS) undertakes immigration enforcement actions involving hundreds of thousands of foreign nationals. These actions...

  6. Immigration Enforcement Actions: Fiscal Year 2005

    Data.gov (United States)

    Department of Homeland Security — Each year, the Department of Homeland Security (DHS) undertakes immigration enforcement actions involving hundreds of thousands of foreign nationals. These actions...

  7. Ectopic overexpression of LAPTM5 results in lysosomal targeting and induces Mcl-1 down-regulation, Bak activation, and mitochondria-dependent apoptosis in human HeLa cells.

    Directory of Open Access Journals (Sweden)

    Do Youn Jun

    Full Text Available Human lysosomal-associated protein multispanning membrane 5 (LAPTM5 was identified by an ordered differential display-polymerase chain reaction (ODD-PCR as an up-regulated cDNA fragment during 12-O-tetradecanoylphorbol 13-acetate (TPA-induced differentiation of U937 cells into monocytes/macrophages. After TPA-treatment, the levels of LAPTM5 mRNA and protein increased and reached a maximum at 18-36 h. In healthy human tissues, LAPTM5 mRNA was expressed at high levels in hematopoietic cells and tissues, at low levels in the lung and fetal liver, and was not detected in other non-hematopoietic tissues. LAPTM5 mRNA was detected in immature malignant cells of myeloid lineage, such as K562, HL-60, U937, and THP-1 cells, and in unstimulated peripheral T cells, but was absent or barely detectable in lymphoid malignant or non-hematopoietic malignant cells. The LAPTM5 level in HL-60 cells increased more significantly during TPA-induced monocyte/macrophage differentiation than during DMSO-induced granulocyte differentiation. Ectopic expression of GFP-LAPTM5 or LAPTM5 in HeLa cells exhibited the localization of LAPTM5 to the lysosome. In HeLa cells overexpressing LAPTM5, the Mcl-1 and Bid levels declined markedly and apoptosis was induced via Bak activation, Δψm loss, activation of caspase-9, -8 and -3, and PARP degradation without accompanying necrosis. However, these LAPTM5-induced apoptotic events except for the decline of Bid level were completely abrogated by concomitant overexpression of Mcl-1. The pan-caspase inhibitor (z-VAD-fmk could suppress the LAPTM5-induced apoptotic sub-G1 peak by ~40% but failed to block the induced Δψm loss, whereas the broad-range inhibitor of cathepsins (Cathepsin Inhibitor I could suppress the LAPTM5-induced apoptotic sub-G1 peak and Δψm loss, by ~22% and ~23%, respectively, suggesting that the LAPTM5-mediated Δψm loss was exerted at least in part in a cathepsin-dependent manner. Together, these results

  8. Ectopic overexpression of LAPTM5 results in lysosomal targeting and induces Mcl-1 down-regulation, Bak activation, and mitochondria-dependent apoptosis in human HeLa cells

    Science.gov (United States)

    Jun, Do Youn; Kim, Hyejin; Jang, Won Young; Lee, Ji Young; Fukui, Kiyoshi; Kim, Young Ho

    2017-01-01

    Human lysosomal-associated protein multispanning membrane 5 (LAPTM5) was identified by an ordered differential display-polymerase chain reaction (ODD-PCR) as an up-regulated cDNA fragment during 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced differentiation of U937 cells into monocytes/macrophages. After TPA-treatment, the levels of LAPTM5 mRNA and protein increased and reached a maximum at 18–36 h. In healthy human tissues, LAPTM5 mRNA was expressed at high levels in hematopoietic cells and tissues, at low levels in the lung and fetal liver, and was not detected in other non-hematopoietic tissues. LAPTM5 mRNA was detected in immature malignant cells of myeloid lineage, such as K562, HL-60, U937, and THP-1 cells, and in unstimulated peripheral T cells, but was absent or barely detectable in lymphoid malignant or non-hematopoietic malignant cells. The LAPTM5 level in HL-60 cells increased more significantly during TPA-induced monocyte/macrophage differentiation than during DMSO-induced granulocyte differentiation. Ectopic expression of GFP-LAPTM5 or LAPTM5 in HeLa cells exhibited the localization of LAPTM5 to the lysosome. In HeLa cells overexpressing LAPTM5, the Mcl-1 and Bid levels declined markedly and apoptosis was induced via Bak activation, Δψm loss, activation of caspase-9, -8 and -3, and PARP degradation without accompanying necrosis. However, these LAPTM5-induced apoptotic events except for the decline of Bid level were completely abrogated by concomitant overexpression of Mcl-1. The pan-caspase inhibitor (z-VAD-fmk) could suppress the LAPTM5-induced apoptotic sub-G1 peak by ~40% but failed to block the induced Δψm loss, whereas the broad-range inhibitor of cathepsins (Cathepsin Inhibitor I) could suppress the LAPTM5-induced apoptotic sub-G1 peak and Δψm loss, by ~22% and ~23%, respectively, suggesting that the LAPTM5-mediated Δψm loss was exerted at least in part in a cathepsin-dependent manner. Together, these results demonstrate that

  9. PIK3CA mutations enable targeting of a breast tumor dependency through mTOR-mediated MCL-1 translation

    OpenAIRE

    Anderson, Grace R.; Wardell, Suzanne E.; Cakir, Merve; Crawford, Lorin; Leeds, Jim C.; Nussbaum, Daniel P.; Shankar, Pallavi S.; Soderquist, Ryan S.; Stein, Elizabeth M.; Tingley, Jennifer P.; Winter, Peter S.; Zieser-Misenheimer, Elizabeth K.; Alley, Holly M.; Yllanes, Alexander; Haney, Victoria

    2016-01-01

    Therapies that efficiently induce apoptosis are likely to be required for durable clinical responses in patients with solid tumors. Using a pharmacological screening approach, we discovered that the combined inhibition of BCL-XL and the mTOR/4E-BP axis results in selective and synergistic induction of apoptosis in cellular and animal models of PIK3CA mutant breast cancers, including triple negative tumors. Mechanistically, inhibition of mTOR/4E-BP suppresses MCL-1 protein translation only in ...

  10. MicroRNA 17-5p regulates autophagy in Mycobacterium tuberculosis-infected macrophages by targeting Mcl-1 and STAT3.

    Science.gov (United States)

    Kumar, Ranjeet; Sahu, Sanjaya Kumar; Kumar, Manish; Jana, Kuladip; Gupta, Pushpa; Gupta, Umesh D; Kundu, Manikuntala; Basu, Joyoti

    2016-05-01

    Autophagy plays a crucial role in the control of bacterial burden during Mycobacterium tuberculosis infection. MicroRNAs (miRNAs) are small non-coding RNAs that regulate immune signalling and inflammation in response to challenge by pathogens. Appreciating the potential of host-directed therapies designed to control autophagy during mycobacterial infection, we focused on the role of miRNAs in regulating M. tuberculosis-induced autophagy in macrophages. Here, we demonstrate that M. tuberculosis infection leads to downregulation of miR-17 and concomitant upregulation of its targets Mcl-1 and STAT3, a transcriptional activator of Mcl-1. Forced expression of miR-17 reduces expression of Mcl-1 and STAT3 and also the interaction between Mcl-1 and Beclin-1. This is directly linked to enhanced autophagy, because Mcl-1 overexpression attenuates the effects of miR-17. At the same time, transfection with a kinase-inactive mutant of protein kinase C δ (PKCδ) (an activator of STAT3) augments M. tuberculosis-induced autophagy, and miR-17 overexpression diminishes phosphorylation of PKCδ, suggesting that an miR-17/PKC δ/STAT3 axis regulates autophagy during M. tuberculosis infection. © 2015 John Wiley & Sons Ltd.

  11. Genetic variants of NOXA and MCL1 modify the risk of HPV16-associated squamous cell carcinoma of the head and neck

    International Nuclear Information System (INIS)

    Zhou, Ziyuan; Sturgis, Erich M; Liu, Zhensheng; Wang, Li-E; Wei, Qingyi; Li, Guojun

    2012-01-01

    The cooperation between phorbol 12-myristate 13-acetate induced protein 1 (NOXA) and myeloid cell leukemia 1 (MCL1) is critical in the intrinsic apoptotic pathway. Human papillomavirus 16 (HPV16), by inducing p53 and pRb-E2F degradation, may play an essential role in development of squamous cell carcinoma of the head and neck (SCCHN) through NOXA-MCL1 axis-mediated apoptosis. Therefore, genetic variants of NOXA and MCL1 may modify the SCCHN risk associated with HPV16 seropositivity. HPV16 serology was obtained by immunoadsorption assay. Four functional SNPs in the promoter of NOXA (rs9957673, rs4558496) and MCL1 (rs9803935, rs3738485) were genotyped for 380 cases and 335 frequency-matched cancer-free controls of non-Hispanic whites. Associations between the four polymorphisms and SCCHN risk were not significant, while we observed a significantly joint effect on SCCHN risk between the polymorphisms and HPV16 seropositivity. Notably, this effect modification was particularly pronounced for oropharyngeal cancer in subgroups including never smokers, never drinkers and younger subjects. Our results suggested that polymorphisms of NOXA and MCL1 may modify the risk of HPV16-associated oropharyngeal cancer. The further identification of population subgroups at higher risk provides evidence that HPV-targeting treatment may help benefit SCCHN. However, larger studies are needed to validate our findings

  12. BAG3-dependent expression of Mcl-1 confers resistance of mutant KRAS colon cancer cells to the HSP90 inhibitor AUY922.

    Science.gov (United States)

    Wang, Chun Yan; Guo, Su Tang; Croft, Amanda; Yan, Xu Guang; Jin, Lei; Zhang, Xu Dong; Jiang, Chen Chen

    2018-02-01

    Past studies have shown that mutant KRAS colon cancer cells are susceptible to apoptosis induced by the HSP90 inhibitor AUY922. Nevertheless, intrinsic and acquired resistance remains an obstacle for the potential application of the inhibitor in the treatment of the disease. Here we report that Mcl-1 is important for survival of colon cancer cells in the presence of AUY922. Mcl-1 was upregulated in mutant KRAS colon cancer cells selected for resistance to AUY922-induced apoptosis. This was due to its increased stability mediated by Bcl-2-associated athanogene domain 3 (BAG3), which was also increased in resistant colon cancer cells by heat shock factor 1 (HSF1) as a result of chronic endoplasmic reticulum (ER) stress. Functional investigations demonstrated that inhibition of Mcl-1, BAG3, or HSF1 triggered apoptosis in resistant colon cancer cells, and rendered AUY922-naïve colon cancer cells more sensitive to the inhibitor. Together, these results identify that the HSF1-BAG3-Mcl-1 signal axis is critical for protection of mutant KRAS colon cancer cells from AUY922-induced apoptosis, with potential implications for targeting HSF1/BAG3/Mcl-1 to improve the efficacy of AUY922 in the treatment of colon cancer. © 2017 Wiley Periodicals, Inc.

  13. Notification: Audit of EPA's Office of Criminal Enforcement, Forensics and Training's Law Enforcement Availability Pay Reporting

    Science.gov (United States)

    Project #OA-FY18-0075, November 30, 2017. The EPA OIG plans to begin preliminary research on the EPA Office of Criminal Enforcement, Forensics and Training's (OCEFT's) law enforcement availability pay (LEAP) reporting.

  14. How to Enforce European Law

    DEFF Research Database (Denmark)

    Rasmussen, Morten

    2017-01-01

    This article explores the well known saga of the European Court of Justice’s introduction of direct effect of Council directives on basis of new comprehensive archival research. The expansion of the doctrine of direct effect to include directives was part of a drive of the Legal Service of the Eu......This article explores the well known saga of the European Court of Justice’s introduction of direct effect of Council directives on basis of new comprehensive archival research. The expansion of the doctrine of direct effect to include directives was part of a drive of the Legal Service...... of the European Commission and the ECJ to strengthen the enforcement of European law. This threatened the deeper balance of competences between the European Community and its member states and consequently led to a sharp response from the national parliaments and courts. The force of these responses and the deep...

  15. Distributed Enforcement of Service Choreographies

    Directory of Open Access Journals (Sweden)

    Marco Autili

    2015-02-01

    Full Text Available Modern service-oriented systems are often built by reusing, and composing together, existing services distributed over the Internet. Service choreography is a possible form of service composition whose goal is to specify the interactions among participant services from a global perspective. In this paper, we formalize a method for the distributed and automated enforcement of service choreographies, and prove its correctness with respect to the realization of the specified choreography. The formalized method is implemented as part of a model-based tool chain released to support the development of choreography-based systems within the EU CHOReOS project. We illustrate our method at work on a distributed social proximity network scenario.

  16. FLASH knockdown sensitizes cells to Fas-mediated apoptosis via down-regulation of the anti-apoptotic proteins, MCL-1 and Cflip short.

    Directory of Open Access Journals (Sweden)

    Song Chen

    Full Text Available FLASH (FLICE-associated huge protein or CASP8AP2 is a large multifunctional protein that is involved in many cellular processes associated with cell death and survival. It has been reported to promote apoptosis, but we show here that depletion of FLASH in HT1080 cells by siRNA interference can also accelerate the process. As shown previously, depletion of FLASH halts growth by down-regulating histone biosynthesis and arrests the cell cycle in S-phase. FLASH knockdown followed by stimulating the cells with Fas ligand or anti-Fas antibodies was found to be associated with a more rapid cleavage of PARP, accelerated activation of caspase-8 and the executioner caspase-3 and rapid progression to cellular disintegration. As is the case for most anti-apoptotic proteins, FLASH was degraded soon after the onset of apoptosis. Depletion of FLASH also resulted in the reduced intracellular levels of the anti-apoptotic proteins, MCL-1 and the short isoform of cFLIP. FLASH knockdown in HT1080 mutant cells defective in p53 did not significantly accelerate Fas mediated apoptosis indicating that the effect was dependent on functional p53. Collectively, these results suggest that under some circumstances, FLASH suppresses apoptosis.

  17. Enforcement, Integration, and the Future of Immigration Federalism

    Directory of Open Access Journals (Sweden)

    Cristina Rodriguez

    2017-06-01

    immigrants with different legal statuses. While this essay remains largely (though not entirely agnostic on these questions, it offers four basic principles to frame any future federalism agenda. First, when it comes to enforcement federalism, the federal government ought to acknowledge the reasons that localities might resist federal enforcement efforts, at least as a matter of politics, and if only to ensure that federal policy is subjected to accountability checks by competing, external pressures. Second, whatever the value of resistance to enforcement, a federalism agenda should include efforts by all levels of government to identify a manageable equilibrium that reconciles the federal government’s constitutional and statutory responsibilities for maintaining an enforcement regime with the local politics of immigration and the lived realities of immigrant communities. Third, when it comes to integration federalism, the problem of illegal immigration must be solved, and only the federal government can do so decisively. Federalism can only mediate the political conflict over status and help set the terms for its ultimate resolution. And yet, the structural reasons that have given rise to integration federalism should re-enforce the country’s commitment to locally driven integration policy, supported by a national-level commitment to information sharing, coordination, and resource support. Finally, because both enforcement and integration policy require systemic flexibility, it is important not to confuse arguments on the merits of immigration policy with structural claims. In other words, scholars, advocates, or policymakers should exercise humility and circumspection when developing conversation-stopping claims that a certain intergovernmental relation is required by law, especially in a context as charged as immigration policy.

  18. 17 CFR 39.6 - Enforceability.

    Science.gov (United States)

    2010-04-01

    ... 17 Commodity and Securities Exchanges 1 2010-04-01 2010-04-01 false Enforceability. 39.6 Section 39.6 Commodity and Securities Exchanges COMMODITY FUTURES TRADING COMMISSION DERIVATIVES CLEARING ORGANIZATIONS § 39.6 Enforceability. An agreement, contract or transaction submitted to a derivatives clearing...

  19. 12 CFR 564.7 - Enforcement.

    Science.gov (United States)

    2010-01-01

    ... 12 Banks and Banking 5 2010-01-01 2010-01-01 false Enforcement. 564.7 Section 564.7 Banks and Banking OFFICE OF THRIFT SUPERVISION, DEPARTMENT OF THE TREASURY APPRAISALS § 564.7 Enforcement. Institutions and institution-affiliated parties, including staff appraisers and fee appraisers, who violate...

  20. Effective speed management through automatic enforcement.

    NARCIS (Netherlands)

    Oei, H.-l.

    1994-01-01

    This paper analyses several aspects of the Dutch experience of speed enforcement, and presents the results of some speed management experiments in The Netherlands, using automatic warning of speeders and enforcement of speeding. Traditional approaches to manage speed there have not resulted in

  1. 76 FR 4369 - Special Law Enforcement Commissions

    Science.gov (United States)

    2011-01-25

    ...This notice announces the online publication of the Interim Special Law Enforcement Commission Policy, Rules and Procedures, the Interim Special Law Enforcement Commission Protocols and the Interim Domestic Violence Waiver that will be used by the Office of Justice Services following passage of the Tribal Law and Order Act of 2010. The documents are published on the Indian Affairs Web site.

  2. 76 FR 54986 - NRC Enforcement Policy

    Science.gov (United States)

    2011-09-06

    ... NUCLEAR REGULATORY COMMISSION 10 CFR Chapter I [NRC-2011-0209] NRC Enforcement Policy AGENCY: Nuclear Regulatory Commission. ACTION: Proposed enforcement policy revision; request for comment. SUMMARY: The U.S. Nuclear Regulatory Commission (NRC or the Commission) is soliciting comments from interested...

  3. 78 FR 5838 - NRC Enforcement Policy

    Science.gov (United States)

    2013-01-28

    ... NUCLEAR REGULATORY COMMISSION [NRC-2013-0014] NRC Enforcement Policy AGENCY: Nuclear Regulatory Commission. ACTION: Policy revision; issuance and request for comments. SUMMARY: The U.S. Nuclear Regulatory... Nuclear Regulatory Commission Enforcement Policy,'' December 30, 2009 (ADAMS Accession No. ML093200520);(2...

  4. 17 CFR 8.05 - Enforcement staff.

    Science.gov (United States)

    2010-04-01

    ... 17 Commodity and Securities Exchanges 1 2010-04-01 2010-04-01 false Enforcement staff. 8.05... staff. (a) Each exchange shall establish an adequate enforcement staff which shall be authorized by the... staff shall consist of employees of the exchange and/or persons hired on a contract basis. It may not...

  5. Law Enforcement School Programs. Fact Sheet

    Science.gov (United States)

    Arkansas Safe Schools Initiative Division, 2010

    2010-01-01

    The school shooting incidents during the decade of the 1990's prompted an increase of law enforcement presence in schools. The School Violence Resource Center (SVRC) at the Criminal Justice Institute (CJI) University of Arkansas System undertook a project to determine what programs law enforcement agencies currently provide in their local schools…

  6. Immigration Enforcement Within the United States

    Science.gov (United States)

    2006-04-06

    Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Policy Issues...Remained in the United States, (Washington: Center for Immigration Studies, May 2002). Immigration Enforcement Within the United States Introduction ...interior enforcement lack a border component. For example, fugitive taskforces, investigations of alien slavery and sweatshops , and employer sanctions do

  7. 5 CFR 1201.85 - Enforcing subpoenas.

    Science.gov (United States)

    2010-01-01

    ....85 Administrative Personnel MERIT SYSTEMS PROTECTION BOARD ORGANIZATION AND PROCEDURES PRACTICES AND... in the foreign country. (b) Upon application by the Special Counsel, the Board may seek court enforcement of a subpoena issued by the Special Counsel in the same manner in which it seeks enforcement of...

  8. 29 CFR 502.15 - Enforcement.

    Science.gov (United States)

    2010-07-01

    ... 29 Labor 3 2010-07-01 2010-07-01 false Enforcement. 502.15 Section 502.15 Labor Regulations Relating to Labor (Continued) WAGE AND HOUR DIVISION, DEPARTMENT OF LABOR REGULATIONS ENFORCEMENT OF CONTRACTUAL OBLIGATIONS FOR TEMPORARY ALIEN AGRICULTURAL WORKERS ADMITTED UNDER SECTION 218 OF THE IMMIGRATION...

  9. 29 CFR 501.15 - Enforcement.

    Science.gov (United States)

    2010-07-01

    ... 29 Labor 3 2010-07-01 2010-07-01 false Enforcement. 501.15 Section 501.15 Labor Regulations Relating to Labor (Continued) WAGE AND HOUR DIVISION, DEPARTMENT OF LABOR REGULATIONS ENFORCEMENT OF CONTRACTUAL OBLIGATIONS FOR TEMPORARY ALIEN AGRICULTURAL WORKERS ADMITTED UNDER SECTION 218 OF THE IMMIGRATION...

  10. 77 FR 12865 - Enforcement Actions Summary

    Science.gov (United States)

    2012-03-02

    ...] Enforcement Actions Summary AGENCY: Transportation Security Administration, DHS. ACTION: Notice of availability. SUMMARY: The Transportation Security Administration (TSA) is providing notice that it has issued an annual summary of all enforcement actions taken by TSA under the authority granted in the...

  11. 78 FR 11216 - Enforcement Actions Summary

    Science.gov (United States)

    2013-02-15

    ...] Enforcement Actions Summary AGENCY: Transportation Security Administration, DHS. ACTION: Notice of availability. SUMMARY: The Transportation Security Administration (TSA) is providing notice that it has issued an annual summary of all enforcement actions taken by TSA under the authority granted in the...

  12. 76 FR 9357 - Enforcement Actions Summary

    Science.gov (United States)

    2011-02-17

    ...] Enforcement Actions Summary AGENCY: Transportation Security Administration, DHS. ACTION: Notice of Availability. SUMMARY: The Transportation Security Administration (TSA) is providing notice that it has issued an annual summary of all enforcement actions taken by TSA under the authority granted in the...

  13. Assessment of the NRC Enforcement Program

    International Nuclear Information System (INIS)

    Lieberman, J.; Coblentz, L.

    1995-04-01

    On May 12, 1994, the Executive Director for Operations (EDO) established a Review Team composed of senior NRC managers to re-examine the NRC enforcement program. A copy of the Review Team's charter is enclosed as Appendix A. This report presents the Team's assessment. The purpose of this review effort are: (1) to perform an assessment of the NRC's enforcement program to determine whether the defined purposes of the enforcement program are appropriate; (2) to determine whether the NRC's enforcement practices and procedures for issuing enforcement actions are consistent with those purposes; and (3) to provide recommendations on any changes the Review Team believes advisable. In accordance with its charter, the Review Team considered the following principal issues in conducting its assessment of the enforcement program: the balance between providing deterrence and incentives (both positive and negative) for the identification and correction of violations; the appropriateness of NRC sanctions; whether the commission should seek statutory authority to increase the amount of civil penalties; whether the NRC should use different enforcement policies and practices for different licensees (e.g., materials licensees in contrast to power reactors or large fuel facilities); and whether the commission should establish open enforcement conferences as the normal practice

  14. Hsp90 inhibitor 17-AAG sensitizes Bcl-2 inhibitor (-)-gossypol by suppressing ERK-mediated protective autophagy and Mcl-1 accumulation in hepatocellular carcinoma cells.

    Science.gov (United States)

    Wang, Bin; Chen, Linfeng; Ni, Zhenhong; Dai, Xufang; Qin, Liyan; Wu, Yaran; Li, Xinzhe; Xu, Liang; Lian, Jiqin; He, Fengtian

    2014-11-01

    Natural BH3-memitic (-)-gossypol shows promising antitumor efficacy in several kinds of cancer. However, our previous studies have demonstrated that protective autophagy decreases the drug sensitivities of Bcl-2 inhibitors in hepatocellular carcinoma (HCC) cells. In the present study, we are the first to report that Hsp90 inhibitor 17-AAG enhanced (-)-gossypol-induced apoptosis via suppressing (-)-gossypol-triggered protective autophagy and Mcl-1 accumulation. The suppression effect of 17-AAG on autophagy was mediated by inhibiting ERK-mediated Bcl-2 phosphorylation while was not related to Beclin1 or LC3 protein instability. Meanwhile, 17-AAG downregulated (-)-gossypol-triggered Mcl-1 accumulation by suppressing Mcl-1(Thr163) phosphorylation and promoting protein degradation. Collectively, our study indicates that Hsp90 plays an important role in tumor maintenance and inhibition of Hsp90 may become a new strategy for sensitizing Bcl-2-targeted chemotherapies in HCC cells. Copyright © 2014 Elsevier Inc. All rights reserved.

  15. Optimization of Water/Oil/Surfactant System for Preparation of Medium-Chain-Length Poly-3-Hydroxyalkanoates (mcl-PHA)-Incorporated Nanoparticles via Nanoemulsion Templating Technique.

    Science.gov (United States)

    Ishak, K A; Annuar, M Suffian M; Ahmad, N

    2017-12-01

    Polymeric nanoparticles gain a widespread interest in food and pharmaceutical industries as delivery systems that encapsulate, protect, and release lipophilic compounds such as omega-3 fatty acids, fat-soluble vitamins, carotenoids, carvedilol, cyclosporine, and ketoprofen. In this study, medium-chain-length poly-3-hydroxyalkanoate (mcl-PHA)-incorporated nanoparticle was developed via facile organic solvent-free nanoemulsion templating technique. The water content (W/surfactant-to-oil (S/O)), S/O, and Cremophor EL-to-Span 80 (Cremo/Sp80) ratios were first optimized using response surface methodology (RSM) to obtain nanoemulsion template prior to incorporation of mcl-PHA. Their effects on nanoemulsion formation were investigated. The mcl-PHA-incorporated nanoparticle system showed a good preservation capability of β-carotene and extended storage stability.

  16. Spectroscopic study of divalent copper complexes forming in the systems CuCl2-MCl (M= Na, K, Rb, Cs)

    International Nuclear Information System (INIS)

    Utorov, N.P.; Bakshi, Yu.M.; Bazov, V.P.; Gel'bshtejn, A.I.

    1982-01-01

    The structure of complex ions formed in salt systems CuCl 2 -MCl depending on the nature of cation of alkali metal chloride at different mole ratios (n=MCl/CuCl 2 ) is studied. The data obtained using the methods of oscillation and electron spectroscopy enable to consider that during the melting of CuCl 2 and CsCl at n 4 2- ions, have the symmetry Csub(2v) at n=1. π-bonding, which is realized with participation of of Cl - p-orbitals and Cu 2+ d-orbitals plays a very important role in the formation of dimers and polymer chains. π-conjugated systems are characterized by the spectrum of charge transfer in the visible region. Charge transfer promotes metal reduction in the excited state which is adequate to the change of electron configuration of copper from d 9 for d 10 . It results in the decrease of acceptor and increase of dative ability of copper cation in the composition of salt complex. Big (n >= 2) additions of CsCl lead to the formation of separate stable ions of CuCl 4 2- type with the symmetry Dsub(2d)

  17. 45 CFR 150.203 - Circumstances requiring CMS enforcement.

    Science.gov (United States)

    2010-10-01

    ... 45 Public Welfare 1 2010-10-01 2010-10-01 false Circumstances requiring CMS enforcement. 150.203... CARE ACCESS CMS ENFORCEMENT IN GROUP AND INDIVIDUAL INSURANCE MARKETS CMS Enforcement Processes for... requiring CMS enforcement. CMS enforces HIPAA requirements to the extent warranted (as determined by CMS) in...

  18. General statement of policy and procedures for NRC enforcement actions: Enforcement policy. Revision 1

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1998-05-01

    This document includes the US Nuclear Regulatory Commission`s (NRC`s or Commission`s) revised General Statement of Policy and Procedure for Enforcement Actions (Enforcement Policy) as it was published in the Federal Register on May 13, 1998 (63 ER 26630). The Enforcement Policy is a general statement of policy explaining the NRC`s policies and procedures in initiating enforcement actions, and of the presiding officers and the Commission in reviewing these actions. This policy statement is applicable to enforcement matters involving the radiological health and safety of the public, including employees` health and safety, the common defense and security, and the environment.

  19. General statement of policy and procedures for NRC enforcement actions: Enforcement policy. Revision 1

    International Nuclear Information System (INIS)

    1998-05-01

    This document includes the US Nuclear Regulatory Commission's (NRC's or Commission's) revised General Statement of Policy and Procedure for Enforcement Actions (Enforcement Policy) as it was published in the Federal Register on May 13, 1998 (63 ER 26630). The Enforcement Policy is a general statement of policy explaining the NRC's policies and procedures in initiating enforcement actions, and of the presiding officers and the Commission in reviewing these actions. This policy statement is applicable to enforcement matters involving the radiological health and safety of the public, including employees' health and safety, the common defense and security, and the environment

  20. Investigation into qualitative discourses of the occupational safety and health inspectors in order to promote enforcement.

    Science.gov (United States)

    Niskanen, Toivo

    2015-01-01

    The aim of this study is to conduct an ex-post evaluation of the OSH Enforcement Act. The focus of the study was to collate the views of occupational safety and health (OSH) inspectors on how the OSH Enforcement Act and the practices of the governmental OSH inspectorate operate from an effectiveness perspective. The questionnaire included open questions addressed to OSH inspectors. The results indicated that there is a tension between the quantitative performance targets, e.g., the number of inspections and the effectiveness of the practical enforcement work. Harmonizing the enforcement practices should be implemented at two levels: OSH local agencies and individual inspectors. OSH inspectors believe that developing the professional skills of OSH inspectors and the monitoring of OSH management systems are important ways of promoting the effectiveness of OSH enforcement.

  1. Ki-67 as a prognostic marker in mantle cell lymphoma-consensus guidelines of the pathology panel of the European MCL Network

    DEFF Research Database (Denmark)

    Klapper, W.; Hoster, E.; Determann, O.

    2009-01-01

    powerful prognostic biomarker. The pathology panel of the European MCL Network evaluated methods to assess the Ki-67 index including stringent counting, digital image analysis, and estimation by eyeballing. Counting of 2 x 500 lymphoma cells is the gold standard to assess the Ki-67 index since this value...... has been shown to predict survival in prospective randomized trials of the European MCL Network. Estimation by eyeballing and digital image analysis showed a poor concordance with the gold standard (concordance correlation coefficients [CCC] between 0.29 and 0.61 for eyeballing and CCC of 0.24 and 0...

  2. Post-Crackdown Effectiveness of Field-Based Forest Law Enforcement in the Brazilian Amazon

    Science.gov (United States)

    Börner, Jan; Kis-Katos, Krisztina; Hargrave, Jorge; König, Konstantin

    2015-01-01

    Regulatory enforcement of forest conservation laws is often dismissed as an ineffective approach to reducing tropical forest loss. Yet, effective enforcement is often a precondition for alternative conservation measures, such as payments for environmental services, to achieve desired outcomes. Fair and efficient policies to reducing emissions from deforestation and forest degradation (REDD) will thus crucially depend on understanding the determinants and requirements of enforcement effectiveness. Among potential REDD candidate countries, Brazil is considered to possess the most advanced deforestation monitoring and enforcement infrastructure. This study explores a unique dataset of over 15 thousand point coordinates of enforcement missions in the Brazilian Amazon during 2009 and 2010, after major reductions of deforestation in the region. We study whether local deforestation patterns have been affected by field-based enforcement and to what extent these effects vary across administrative boundaries. Spatial matching and regression techniques are applied at different spatial resolutions. We find that field-based enforcement operations have not been universally effective in deterring deforestation during our observation period. Inspections have been most effective in reducing large-scale deforestation in the states of Mato Grosso and Pará, where average conservation effects were 4.0 and 9.9 hectares per inspection, respectively. Despite regional and actor-specific heterogeneity in inspection effectiveness, field-based law enforcement is highly cost-effective on average and might be enhanced by closer collaboration between national and state-level authorities. PMID:25875656

  3. Examining the spatial distribution of law enforcement encounters among people who inject drugs after implementation of Mexico's drug policy reform.

    Science.gov (United States)

    Gaines, Tommi L; Beletsky, Leo; Arredondo, Jaime; Werb, Daniel; Rangel, Gudelia; Vera, Alicia; Brouwer, Kimberly

    2015-04-01

    In 2009, Mexico decriminalized the possession of small amounts of illicit drugs for personal use in order to refocus law enforcement resources on drug dealers and traffickers. This study examines the spatial distribution of law enforcement encounters reported by people who inject drugs (PWID) in Tijuana, Mexico to identify concentrated areas of policing activity after implementation of the new drug policy. Mapping the physical location of law enforcement encounters provided by PWID (n = 461) recruited through targeted sampling, we identified hotspots of extra-judicial encounters (e.g., physical/sexual abuse, syringe confiscation, and money extortion by law enforcement) and routine authorized encounters (e.g., being arrested or stopped but not arrested) using point density maps and the Getis-Ord Gi* statistic calculated at the neighborhood-level. Approximately half of the participants encountered law enforcement more than once in a calendar year and nearly one third of these encounters did not result in arrest but involved harassment or abuse by law enforcement. Statistically significant hotspots of law enforcement encounters were identified in a limited number of neighborhoods located in areas with known drug markets. At the local-level, law enforcement activities continue to target drug users despite a national drug policy that emphasizes drug treatment diversion rather than punitive enforcement. There is a need for law enforcement training and improved monitoring of policing tactics to better align policing with public health goals.

  4. Abandoned Uranium Mine (AUM) Priority Mines with Enforcement Actions, Navajo Nation, 2016, US EPA Region 9

    Data.gov (United States)

    U.S. Environmental Protection Agency — There are 13 mines total that have enforcement actions and are classified as priority mines. USEPA and NNEPA prioritized 46 mines based on gamma radiation levels,...

  5. Evaluation of Personal Chemical Vapor Protection for Patrol and Tactical Law Enforcement

    National Research Council Canada - National Science Library

    Fedele, Paul D; Lake, William L; Arca, Victor J; Marshall, Stephen M; Mitchell, David B

    2002-01-01

    ... functions in law enforcement. Various Level C, impermeable and charcoal impregnated, vapor-absorptive, air-permeable protective clothing ensembles, worn with the MSA Millenium respiratory protective mask/butyl hood, and seven-mil...

  6. Restricted rights : Obstacles in enforcing labour rights of EU mobile workers in the German and Dutch construction sector

    NARCIS (Netherlands)

    Wagner, Ines; Berntsen, Lisa

    2016-01-01

    There is considerable evidence that employers are violating the labour rights of EU mobile workers. However there is disagreement as to whether the enforcement problem is caused by poor EU-level or weak national-level possibilities for overseeing and sanctioning companies and enforcing regulation.

  7. A law enforcement perspective of electricity deregulation

    International Nuclear Information System (INIS)

    Horowitz, Ira

    2006-01-01

    In April 2004, the California Attorney General's (AG) office issued a white paper that provided a 'law enforcement perspective of the California energy crisis.' To complete this special issue's coverage, I summarize three aspects of that paper: notably, the deficiencies in market oversight and enforcement that left the deregulated market prone to potential abuse, the principal modus operandi that some market agents used to exploit those deficiencies without fear of retribution, and the AG's 'recommendations for improving enforcement and protecting consumers in deregulated energy markets.'. (author)

  8. A law enforcement perspective of electricity deregulation

    Energy Technology Data Exchange (ETDEWEB)

    Horowitz, Ira [Warrington College of Business, University of Florida, Gainesville, FL 32611-7169 (United States)

    2006-05-15

    In April 2004, the California Attorney General's (AG) office issued a white paper that provided a 'law enforcement perspective of the California energy crisis.' To complete this special issue's coverage, I summarize three aspects of that paper: notably, the deficiencies in market oversight and enforcement that left the deregulated market prone to potential abuse, the principal modus operandi that some market agents used to exploit those deficiencies without fear of retribution, and the AG's 'recommendations for improving enforcement and protecting consumers in deregulated energy markets.'. (author)

  9. Effective enforcement of the forest practices code

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1995-12-31

    The British Columbia Forest Practices Code establishes a scheme to guide and direct forest harvesting and other forest uses in concert with other related acts. The Code is made up of the Forest Practices Code of British Columbia Act, regulations, standards, and guidebooks. This document provides information on Code enforcement. It reviews the roles of the three provincial resource ministries and the Attorney General in enforcing the code, the various activities undertaken to ensure compliance (including inspections, investigations, and responses to noncompliance), and the role of the public in helping to enforce the Code. The appendix contains a list of Ministry of Forests office locations and telephone numbers.

  10. Implementing the ban on smoking in Israeli pubs: measuring airborne nicotine and enforcement by local authorities.

    Science.gov (United States)

    Satran, Carmit; Drach-Zahavy, Anat; Hammond, S Katharine; Baron-Epel, Orna

    2014-06-01

    In 2007 an amendment to the law restricting smoking in pubs and bars (P&Bs) was enacted in Israel. However, a year after the ban only slight decreases in airborne smoke in P&Bs in one city have been reported. We aimed to assess levels of airborne nicotine in Israeli P&Bs and to measure ifself-reported enforcement of the law by local officials was associated with levels of airborne nicotine in P&Bs. Airborne nicotine levels were measured in 72 P&Bs in 29 towns in Israel; this consisted of 90% of eligible towns. In addition, 73 local authority officials were interviewed in 25 of these towns. The officials were asked to assess the local authority's level of enforcement of the law banning smoking in P&Bs. The association of levels of airborne nicotine with the levels of enforcement of the law was calculated. Data were collected during 2009-2010 and analyzed in 2010-2011. Levels of airborne nicotine were comparatively high in P&Bs. No association was detected between levels of nicotine and the P&Bs' characteristics. In the larger towns, levels of airborne nicotine were higher. In 16% of towns the local authority officials reported high levels of law enforcement. Generally, levels of reported enforcement by local authorities were low and did not predict levels of airborne nicotine in the P&Bs. Self-reported local authorities' law enforcement was not associated with levels of airborne nicotine in P&Bs in these towns. There is a need to develop ways to increase law enforcement by the local authorities or other agencies.

  11. BCL-x{sub L}/MCL-1 inhibition and RARγ antagonism work cooperatively in human HL60 leukemia cells

    Energy Technology Data Exchange (ETDEWEB)

    Perri, Mariarita; Yap, Jeremy L.; Yu, Jianshi [Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N Pine Street, Baltimore, MD 21201 (United States); Cione, Erika [Department of Pharmacy, Health and Nutritional Sciences, Ed. Polifunzionale, University of Calabria, 87036 Rende, CS (Italy); Fletcher, Steven [Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N Pine Street, Baltimore, MD 21201 (United States); Kane, Maureen A., E-mail: mkane@rx.umaryland.edu [Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N Pine Street, Baltimore, MD 21201 (United States)

    2014-10-01

    The acute promyelocytic leukemia (APL) subtype of acute myeloid leukemia (AML) is characterized by chromosomal translocations that result in fusion proteins, including the promyelocytic leukemia–retinoic acid receptor, alpha fusion protein (PML–RARα). All-trans retinoic acid (atRA) treatment is the standard drug treatment for APL yielding cure rates >80% by activating transcription and proteasomal degradation of retinoic acid receptor, alpha (RARα). Whereas combination therapy with As{sub 2}O{sub 3} has increased survival further, patients that experience relapse and are refractory to atRA and/or As{sub 2}O{sub 3} is a clinically significant problem. BCL-2 family proteins regulate apoptosis and over-expression of anti-apoptotic B-cell leukemia/lymphoma 2 (BCL-2) family proteins has been associated with chemotherapeutic resistance in APL including impairment of the ability of atRA to induce growth arrest and differentiation. Here we investigated the novel BH3 domain mimetic, JY-1-106, which antagonizes the anti-apoptotic BCL-2 family members B-cell lymphoma-extra large (BCL-x{sub L}) and myeloid cell leukemia-1 (MCL-1) alone and in combination with retinoids including atRA, AM580 (RARα agonist), and SR11253 (RARγ antagonist). JY-1-106 reduced cell viability in HL-60 cells alone and in combination with retinoids. The combination of JY-1-106 and SR11253 had the greatest impact on cell viability by stimulating apoptosis. These studies indicate that dual BCL-x{sub L}/MCL-1 inhibitors and retinoids could work cooperatively in leukemia treatment. - Highlights: • Novel Bcl-x{sub L}/Mcl-1 inhibitor JY-1-106 reduces HL60 cell viability. • JY-1-106 is investigated in combination with retinoic acid, AM580, and SR11253. • AM580 is an RARα agonist; SR11253 is an RARγ antagonist. • Combined use of JY-1-106/SR11253 exhibited the greatest cell viability reduction. • JY-1-106 alone or in combination with retinoids induces apoptosis.

  12. Interactions of Transgender Latina Women with Law Enforcement

    OpenAIRE

    Galvan, Frank H.; Bazargan, Mohzen

    2012-01-01

    A new report, funded by the Williams Institute, reveals high levels of reported harassment and assault of Latina transgender women by law enforcement agencies and highlights steps that police departments should take to improve relations with the transgender community.    The report, “Interactions of Latina Transgender Women with Law Enforcement” is based on interviews with 220 Latina transgender women from the Los Angeles area. BIENESTAR, a non-profit social service organization comm...

  13. Nuclear topography of the 1q21 genomic region and MCl-1 protein levels associated with pathophysiology of multiple myeloma

    Czech Academy of Sciences Publication Activity Database

    Legartová, Soňa; Krejčí, Jana; Harničarová, Andrea; Hájek, R.; Kozubek, Stanislav; Bártová, Eva

    2009-01-01

    Roč. 56, č. 5 (2009), s. 404-413 ISSN 0028-2685 R&D Projects: GA MŠk(CZ) LC06027; GA AV ČR(CZ) 1QS500040508 Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : multiple myeloma * 1q21 * DNA-FISH Subject RIV: BO - Biophysics Impact factor: 1.192, year: 2009

  14. Loss in MCL-1 function sensitizes non-Hodgkin's lymphoma cell lines to the BCL-2-selective inhibitor venetoclax (ABT-199)

    International Nuclear Information System (INIS)

    Phillips, D C; Xiao, Y; Lam, L T; Litvinovich, E; Roberts-Rapp, L; Souers, A J; Leverson, J D

    2015-01-01

    As a population, non-Hodgkin's lymphoma (NHL) cell lines positive for the t(14;18) translocation and/or possessing elevated BCL2 copy number (CN; BCL2 High ) are exquisitely sensitive to navitoclax or the B-cell lymphoma protein-2 (BCL-2)-selective inhibitor venetoclax. Despite this, some BCL2 High cell lines remain resistant to either agent. Here we show that the MCL-1-specific inhibitor A-1210477 sensitizes these cell lines to navitoclax. Chemical segregation of this synergy with the BCL-2-selective inhibitor venetoclax or BCL-X L -selective inhibitor A-1155463 indicated that MCL-1 and BCL-2 are the two key anti-apoptotic targets for sensitization. Similarly, the CDK inhibitor flavopiridol downregulated MCL-1 expression and synergized with venetoclax in BCL2 High NHL cell lines to a similar extent as A-1210477. A-1210477 also synergized with navitoclax in the majority of BCL2 Low NHL cell lines. However, chemical segregation with venetoclax or A-1155463 revealed that synergy was driven by BCL-X L inhibition in this population. Collectively these data emphasize that BCL2 status is predictive of venetoclax potency in NHL not only as a single agent, but also in the adjuvant setting with anti-tumorigenic agents that inhibit MCL-1 function. These studies also potentially identify a patient population (BCL2 Low ) that could benefit from BCL-X L (navitoclax)-driven combination therapy

  15. Exposure to the viral by-product dsRNA or Coxsackievirus B5 triggers pancreatic beta cell apoptosis via a Bim / Mcl-1 imbalance.

    Directory of Open Access Journals (Sweden)

    Maikel L Colli

    2011-09-01

    Full Text Available The rise in type 1 diabetes (T1D incidence in recent decades is probably related to modifications in environmental factors. Viruses are among the putative environmental triggers of T1D. The mechanisms regulating beta cell responses to viruses, however, remain to be defined. We have presently clarified the signaling pathways leading to beta cell apoptosis following exposure to the viral mimetic double-stranded RNA (dsRNA and a diabetogenic enterovirus (Coxsackievirus B5. Internal dsRNA induces cell death via the intrinsic mitochondrial pathway. In this process, activation of the dsRNA-dependent protein kinase (PKR promotes eIF2α phosphorylation and protein synthesis inhibition, leading to downregulation of the antiapoptotic Bcl-2 protein myeloid cell leukemia sequence 1 (Mcl-1. Mcl-1 decrease results in the release of the BH3-only protein Bim, which activates the mitochondrial pathway of apoptosis. Indeed, Bim knockdown prevented both dsRNA- and Coxsackievirus B5-induced beta cell death, and counteracted the proapoptotic effects of Mcl-1 silencing. These observations indicate that the balance between Mcl-1 and Bim is a key factor regulating beta cell survival during diabetogenic viral infections.

  16. Trust in Security-Policy Enforcement Mechanisms

    National Research Council Canada - National Science Library

    Schneider, Fred B; Morrisett, Greg

    2006-01-01

    .... but provides the strong security guarantees of modern languages such as Java. A second avenue of language-based work explored a general class of policy enforcement mechanism based on in-line reference monitors (IRM...

  17. Flow enforcement algorithms for ATM networks

    DEFF Research Database (Denmark)

    Dittmann, Lars; Jacobsen, Søren B.; Moth, Klaus

    1991-01-01

    Four measurement algorithms for flow enforcement in asynchronous transfer mode (ATM) networks are presented. The algorithms are the leaky bucket, the rectangular sliding window, the triangular sliding window, and the exponentially weighted moving average. A comparison, based partly on teletraffic...

  18. Anticorruption expertise of law-enforcement acts

    Directory of Open Access Journals (Sweden)

    Sergey B. Polyakov

    2015-12-01

    Full Text Available Objective to substantiate public necessity to define the subject methodological and organizational capabilities of anticorruption expertise of law enforcement acts. Methods universal dialecticmaterialistic method was used to study the needs in anticorruption expertise of law enforcement acts in the mechanism of legal regulation based on it general scientific and special formal legal and comparative legal methods of research used for the definition of subjectmatter of the proposed expertise. Results the value of anticorruption expertise of law enforcement was shown corruption factors and corruption indicators enabling legislation were identified ways of conducting such examinations were proposed. Scientific novelty the article examines the need and the subject proposes methods of a new type of anticorruption expertise. Practical significance the conditions of corruption are defined which are created in law enforcement activities and methods for their detection are proposed. nbsp

  19. Risk sharing relations and enforcement mechanisms

    NARCIS (Netherlands)

    Barr, A.; Dekker, M.; Fafchamps, M.

    2008-01-01

    We investigate whether the set of available enforcement mechanisms affects the formation of risk sharing relations by applying dyadic regression analysis to data from a specifically designed behavioural experiment, two surveys and a genealogical mapping exercise. During the experiment participants

  20. 49 CFR 212.115 - Enforcement actions.

    Science.gov (United States)

    2010-10-01

    ..., DEPARTMENT OF TRANSPORTATION STATE SAFETY PARTICIPATION REGULATIONS State/Federal Roles § 212.115 Enforcement... assess and compromise penalties, to issue emergency orders and compliance orders, institute or cause to...

  1. Enforcement and Compliance History Online (ECHO) Facilities

    Data.gov (United States)

    U.S. Environmental Protection Agency — ECHO provides integrated compliance and enforcement information for about 800,000 regulated facilities nationwide. Its features range from simple to advanced,...

  2. DNR Division of Enforcement Officer Patrol Areas

    Data.gov (United States)

    Minnesota Department of Natural Resources — This theme shows the DNR Division of Enforcement Office Patrol Areas as of January 1, 2003. Patrol areas were defined and verified by Patrol Officers during the fall...

  3. System analysis of automated speed enforcement implementation.

    Science.gov (United States)

    2016-04-01

    Speeding is a major factor in a large proportion of traffic crashes, injuries, and fatalities in the United States. Automated Speed Enforcement (ASE) is one of many approaches shown to be effective in reducing speeding violations and crashes. However...

  4. Optimization and calculation of the MCl-ZnCl{sub 2} (M = Li, Na, K) phase diagrams

    Energy Technology Data Exchange (ETDEWEB)

    Romero-Serrano, Antonio, E-mail: romeroipn@hotmail.com [Metallurgy and Materials Department, Instituto Politecnico Nacional-ESIQIE, Apdo. P. 118-431, 07051 Mexico, D.F. (Mexico); Hernandez-Ramirez, Aurelio, E-mail: aurelioh@hotmail.com [Metallurgy and Materials Department, Instituto Politecnico Nacional-ESIQIE, Apdo. P. 118-431, 07051 Mexico, D.F. (Mexico); Cruz-Ramirez, Alejandro, E-mail: alcruzr@ipn.mx [Metallurgy and Materials Department, Instituto Politecnico Nacional-ESIQIE, Apdo. P. 118-431, 07051 Mexico, D.F. (Mexico); Hallen-Lopez, Manuel, E-mail: j_hallen@yahoo.com [Metallurgy and Materials Department, Instituto Politecnico Nacional-ESIQIE, Apdo. P. 118-431, 07051 Mexico, D.F. (Mexico); Zeifert, Beatriz, E-mail: bzeifert@yahoo.com [Metallurgy and Materials Department, Instituto Politecnico Nacional-ESIQIE, Apdo. P. 118-431, 07051 Mexico, D.F. (Mexico)

    2010-10-20

    An earlier structural model for binary silicate melts and glasses is extended to zinc chloride-alkali metal chloride systems. The evaluation of the available thermodynamic and phase diagrams data for the MCl-ZnCl{sub 2} (M = Li, Na, K) binary systems have been carried out using the structural model for the liquid phase. This thermodynamic model is based on the assumption that each alkali chloride produces the depolymerization of ZnCl{sub 2} network with a characteristic free-energy change. A least-squares optimization program permits all available thermodynamic and phase diagram data to be optimized simultaneously. In this manner, data for these binary systems have been analysed and represented with a small number of parameters.

  5. MCL and mincle: C-type lectin receptors that sense damaged self and pathogen associated molecular patterns

    Directory of Open Access Journals (Sweden)

    Mark B Richardson

    2014-06-01

    Full Text Available MCL (macrophage C-type lectin and mincle (macrophage inducible C-type lectin comprise part of an extensive repertoire of pattern recognition receptors with the ability to sense damage associated and pathogen associated molecular patterns. In this review we cover the discovery and molecular characterization of these C-type lectin receptors, and highlight recent advances in the understanding of their roles in orchestrating the response of the immune system to bacterial and fungal infection, and damaged self. We also discuss the identification and structure-activity relationships of activating ligands, particularly trehalose dimycolate (TDM and related mycobacterial glycolipids, which have significant potential in the development of TH1/TH17 vaccination strategies.

  6. 39 CFR 7.7 - Enforcement.

    Science.gov (United States)

    2010-07-01

    ... 39 Postal Service 1 2010-07-01 2010-07-01 false Enforcement. 7.7 Section 7.7 Postal Service UNITED STATES POSTAL SERVICE THE BOARD OF GOVERNORS OF THE U.S. POSTAL SERVICE PUBLIC OBSERVATION (ARTICLE VII) § 7.7 Enforcement. (a) Under 5 U.S.C. 552b(g), any person may bring a proceeding in the United States...

  7. The Legality and Validity of Administrative Enforcement

    Directory of Open Access Journals (Sweden)

    Sergei V. Iarkovoi

    2018-01-01

    Full Text Available The article discusses the concept and content of the validity of adopted by the executive authorities and other bodies of public administration legal acts and committed by them legal actions as an important characteristic of law enforcement by these bodies. The Author concludes that the validity of the administrative law enforcement is not an independent requirement for it, and acts as an integral part of its legal requirements.

  8. Citizen enforcement and the smoking gun

    International Nuclear Information System (INIS)

    Unterberger, G.L.

    1991-01-01

    This article addresses the provisions for private citizens to bring lawsuits in federal court against regulated parties violating federal air pollution-control laws and the steps that operators of facilities subject to air pollution-control laws need to take to help avoid significant enforcement liabilities. The topics of the article include a look at citizen enforcement since 1970, the 1990 amendments to the Clean Air Act, construction and management with these regulations

  9. miR-146a down-regulation alleviates H2O2-induced cytotoxicity of PC12 cells by regulating MCL1/JAK/STAT pathway : miR-146a down-regulation relieves H2O2-induced PC12 cells cytotoxicity by MCL1/JAK/STAT.

    Science.gov (United States)

    Yang, Xuecheng; Mao, Xin; Ding, Xuemei; Guan, Fengju; Jia, Yuefeng; Luo, Lei; Li, Bin; Tan, Hailin; Cao, Caixia

    2018-02-26

    Oxidative stress and miRNAs have been confirmed to play an important role in neurological diseases. The study aimed to explore the underlying effect and mechanisms of miR-146a in H 2 O 2 -induced injury of PC12 cells. Here, PC12 cells were stimulated with 200 μM of H 2 O 2 to construct oxidative injury model. Cell injury was evaluated on the basis of the changes in cell viability, migration, invasion, apoptosis, and DNA damage. Results revealed that miR-146a expression was up-regulated in H 2 O 2 -induced PC12 cells. Functional analysis showed that down-regulation of miR-146a alleviated H 2 O 2 -induced cytotoxicity in PC12 cells. Dual-luciferase reporter and western blot assay verified that MCL1 was a direct target gene of miR-146a. Moreover, anti-miR-146a-mediated suppression on cell cytotoxicity was abated following MCL1 knockdown in H 2 O 2 -induced PC12 cells. Furthermore, MCL1 activated JAK/STAT signaling pathway and MCL1 overexpression attenuated H 2 O 2 -induced cytotoxicity in PC12 cells by JAK/STAT signaling pathway. In conclusion, this study suggested that suppression of miR-146a abated H 2 O 2 -induced cytotoxicity in PC12 cells via regulating MCL1/JAK/STAT pathway.

  10. Long-term follow-up of MCL patients treated with single-agent ibrutinib: updated safety and efficacy results.

    Science.gov (United States)

    Wang, Michael L; Blum, Kristie A; Martin, Peter; Goy, Andre; Auer, Rebecca; Kahl, Brad S; Jurczak, Wojciech; Advani, Ranjana H; Romaguera, Jorge E; Williams, Michael E; Barrientos, Jacqueline C; Chmielowska, Ewa; Radford, John; Stilgenbauer, Stephan; Dreyling, Martin; Jedrzejczak, Wieslaw Wiktor; Johnson, Peter; Spurgeon, Stephen E; Zhang, Liang; Baher, Linda; Cheng, Mei; Lee, Dana; Beaupre, Darrin M; Rule, Simon

    2015-08-06

    Ibrutinib, an oral inhibitor of Bruton tyrosine kinase, is approved for patients with mantle cell lymphoma (MCL) who have received one prior therapy. We report the updated safety and efficacy results from the multicenter, open-label phase 2 registration trial of ibrutinib (median 26.7-month follow-up). Patients (N = 111) received oral ibrutinib 560 mg once daily, and those with stable disease or better could enter a long-term extension study. The primary end point was overall response rate (ORR). The median patient age was 68 years (range, 40-84), with a median of 3 prior therapies (range, 1-5). The median treatment duration was 8.3 months; 46% of patients were treated for >12 months, and 22% were treated for ≥2 years. The ORR was 67% (23% complete response), with a median duration of response of 17.5 months. The 24-month progression-free survival and overall survival rates were 31% (95% confidence interval [CI], 22.3-40.4) and 47% (95% CI, 37.1-56.9), respectively. The most common adverse events (AEs) in >30% of patients included diarrhea (54%), fatigue (50%), nausea (33%), and dyspnea (32%). The most frequent grade ≥3 infections included pneumonia (8%), urinary tract infection (4%), and cellulitis (3%). Grade ≥3 bleeding events in ≥2% of patients were hematuria (2%) and subdural hematoma (2%). Common all-grade hematologic AEs were thrombocytopenia (22%), neutropenia (19%), and anemia (18%). The prevalence of infection, diarrhea, and bleeding was highest for the first 6 months of therapy and less thereafter. With longer follow-up, ibrutinib continues to demonstrate durable responses and favorable safety in relapsed/refractory MCL. The trial is registered to www.ClinicalTrials.gov as #NCT01236391. © 2015 by The American Society of Hematology.

  11. Law enforcement suicide: a national analysis.

    Science.gov (United States)

    Violanti, John M; Robinson, Cynthia F; Shen, Rui

    2013-01-01

    Previous research suggests that there is an elevated risk of suicide among workers within law enforcement occupations. The present study examined the proportionate mortality for suicide in law enforcement in comparison to the US working population during 1999, 2003-2004, and 2007, based on Centers for Disease Control and Prevention's National Institute for Occupational Safety and Health National Occupational Mortality Surveillance data. We analyzed data for all law enforcement occupations and focused on two specific law enforcement occupational categories-detectives/criminal investigators/ police and corrections officers. Suicides were also explored by race, gender and ethnicity. The results of the study showed proportionate mortality ratios (PMRs) for suicide were significantly high for all races and sexes combined (all law enforcement--PMR = 169, 95% CI = 150-191, p law enforcement combined category, and a similarly high PMR was found among Hispanic detectives/criminal investigators/police (PMR = 388, p < 0.01, 95% CI = 168-765). There were small numbers of deaths among female and African American officers. The results included significantly increased risk for suicide among detectives/criminal investigators/police and corrections officers, which suggests that additional study could provide better data to inform us for preventive action.

  12. Strengthened enforcement enhances marine sanctuary performance

    Directory of Open Access Journals (Sweden)

    Brendan P. Kelaher

    2015-01-01

    Full Text Available Marine sanctuaries are areas where the extraction of biota is not permitted. Although most marine sanctuaries have a positive influence on biotic communities, not all sanctuaries are meeting their conservation objectives. Amidst possible explanations (e.g., size, age and isolation, insufficient enforcement is often speculated to be a key driver of marine sanctuary underperformance. Despite this, there are few studies directly linking quantitative enforcement data to changes in biotic communities within marine sanctuaries. Here, we used an asymmetrical-BACI experimental design from 2006–2012 to test whether new enforcement initiatives enhanced abundances of target fishes and threatened species in an existing large sub-tropical marine sanctuary relative to areas open to fishing. Implementation of the new enforcement initiatives in 2010 was associated with a 201% increase in annual fine rate and a significant increase in target fish and elasmobranch abundance, as well as sightings of a critically-endangered shark, in the marine sanctuary relative to areas open to fishing. Overall, these results demonstrate that strengthening enforcement can have a rapid positive influence on target fish and perhaps threatened species in a subtropical marine sanctuary. From this, we contend that increased enforcement guided by risk-based compliance planning and operations may be a useful first step for improving underperforming marine sanctuaries.

  13. miR-22 and miR-29a Are Members of the Androgen Receptor Cistrome Modulating LAMC1 and Mcl-1 in Prostate Cancer.

    Science.gov (United States)

    Pasqualini, Lorenza; Bu, Huajie; Puhr, Martin; Narisu, Narisu; Rainer, Johannes; Schlick, Bettina; Schäfer, Georg; Angelova, Mihaela; Trajanoski, Zlatko; Börno, Stefan T; Schweiger, Michal R; Fuchsberger, Christian; Klocker, Helmut

    2015-07-01

    The normal prostate as well as early stages and advanced prostate cancer (PCa) require a functional androgen receptor (AR) for growth and survival. The recent discovery of microRNAs (miRNAs) as novel effector molecules of AR disclosed the existence of an intricate network between AR, miRNAs and downstream target genes. In this study DUCaP cells, characterized by high content of wild-type AR and robust AR transcriptional activity, were chosen as the main experimental model. By integrative analysis of chromatin immunoprecipitation-sequencing (ChIP-seq) and microarray expression profiling data, miRNAs putatively bound and significantly regulated by AR were identified. A direct AR regulation of miR-22, miR-29a, and miR-17-92 cluster along with their host genes was confirmed. Interestingly, endogenous levels of miR-22 and miR-29a were found to be reduced in PCa cells expressing AR. In primary tumor samples, miR-22 and miR-29a were less abundant in the cancerous tissue compared with the benign counterpart. This specific expression pattern was associated with a differential DNA methylation of the genomic AR binding sites. The identification of laminin gamma 1 (LAMC1) and myeloid cell leukemia 1 (MCL1) as direct targets of miR-22 and miR-29a, respectively, suggested a tumor-suppressive role of these miRNAs. Indeed, transfection of miRNA mimics in PCa cells induced apoptosis and diminished cell migration and viability. Collectively, these data provide additional information regarding the complex regulatory machinery that guides miRNAs activity in PCa, highlighting an important contribution of miRNAs in the AR signaling.

  14. Peer punishment promotes enforcement of bad social norms.

    Science.gov (United States)

    Abbink, Klaus; Gangadharan, Lata; Handfield, Toby; Thrasher, John

    2017-09-20

    Social norms are an important element in explaining how humans achieve very high levels of cooperative activity. It is widely observed that, when norms can be enforced by peer punishment, groups are able to resolve social dilemmas in prosocial, cooperative ways. Here we show that punishment can also encourage participation in destructive behaviours that are harmful to group welfare, and that this phenomenon is mediated by a social norm. In a variation of a public goods game, in which the return to investment is negative for both group and individual, we find that the opportunity to punish led to higher levels of contribution, thereby harming collective payoffs. A second experiment confirmed that, independently of whether punishment is available, a majority of subjects regard the efficient behaviour of non-contribution as socially inappropriate. The results show that simply providing a punishment opportunity does not guarantee that punishment will be used for socially beneficial ends, because the social norms that influence punishment behaviour may themselves be destructive.Punishment by peers can enforce social norms, such as contributing to a public good. Here, Abbink and colleagues show that individuals will enforce norms even when contributions reduce the net benefit of the group, resulting in the maintenance of wasteful contributions.

  15. 7 CFR 501.14 - Non-Federal law enforcement.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 6 2010-01-01 2010-01-01 false Non-Federal law enforcement. 501.14 Section 501.14...-Federal law enforcement. Research Center special policemen may be deputized by State or local law... State or local law enforcement agency, the facilities or services of such State or local law enforcement...

  16. 43 CFR 422.3 - Reclamation law enforcement policy.

    Science.gov (United States)

    2010-10-01

    ... 43 Public Lands: Interior 1 2010-10-01 2010-10-01 false Reclamation law enforcement policy. 422.3 Section 422.3 Public Lands: Interior Regulations Relating to Public Lands BUREAU OF RECLAMATION, DEPARTMENT OF THE INTERIOR LAW ENFORCEMENT AUTHORITY AT BUREAU OF RECLAMATION PROJECTS § 422.3 Reclamation law enforcement policy. The law enforcement...

  17. 33 CFR 88.11 - Law enforcement vessels.

    Science.gov (United States)

    2010-07-01

    ... NAVIGATION RULES ANNEX V: PILOT RULES § 88.11 Law enforcement vessels. (a) Law enforcement vessels may display a flashing blue light when engaged in direct law enforcement or public safety activities. This... lights. (b) The blue light described in this section may be displayed by law enforcement vessels of the...

  18. Determination of the photolysis rate coefficient of monochlorodimethyl sulfide (MClDMS) in the atmosphere and its implications for the enhancement of SO2 production from the DMS + Cl2 reaction.

    Science.gov (United States)

    Copeland, G; Lee, E P F; Williams, R G; Archibald, A T; Shallcross, D E; Dyke, J M

    2014-01-01

    In this work, the photolysis rate coefficient of CH3SCH2Cl (MClDMS) in the lower atmosphere has been determined and has been used in a marine boundary layer (MBL) box model to determine the enhancement of SO2 production arising from the reaction DMS + Cl2. Absorption cross sections measured in the 28000-34000 cm(-1) region have been used to determine photolysis rate coefficients of MClDMS in the troposphere at 10 solar zenith angles (SZAs). These have been used to determine the lifetimes of MClDMS in the troposphere. At 0° SZA, a photolysis lifetime of 3-4 h has been obtained. The results show that the photolysis lifetime of MClDMS is significantly smaller than the lifetimes with respect to reaction with OH (≈ 4.6 days) and with Cl atoms (≈ 1.2 days). It has also been shown, using experimentally derived dissociation energies with supporting quantum-chemical calculations, that the dominant photodissocation route of MClDMS is dissociation of the C-S bond to give CH3S and CH2Cl. MBL box modeling calculations show that buildup of MClDMS at night from the Cl2 + DMS reaction leads to enhanced SO2 production during the day. The extra SO2 arises from photolysis of MClDMS to give CH3S and CH2Cl, followed by subsequent oxidation of CH3S.

  19. Deregulated expression of A1, Bcl-2, Bcl-xL, and Mcl-1 antiapoptotic proteins and Bid, Bad, and Bax proapoptotic genes in polycythemia vera patients

    Directory of Open Access Journals (Sweden)

    Elainy Patricia Lino Gasparotto

    2011-12-01

    Full Text Available Apoptosis deregulation might have a role in the pathophysiology of polycythemia vera (PV. This study evaluated Bcl-2 molecule expression in CD34+ cells and leukocytes in 12 PV patients. Gene expression was investigated by real time PCR using SybrGreen Quantitect kit and protein expression was evaluated by western-blotting. JAK2 V617F mutation was detected according to Baxter et al (2005. CD34+ cells from PV patients presented higher levels of A1 and Mcl-1 expression (median: 22.6 and 5.2, respectively in comparison with controls (0.9 and 0.5, p=0.004 and p=0.020; while Bcl-2 and Bcl-xL expression decreased in PV patients (0.18 and 1.19 compared with controls (1.39 and 2.01, p=0.006 and p=0.020. CD34+ cells in PV patients showed an elevated Bid expression (14.4 in comparison with healthy subjects (1.0; p=0.002. Patients' leukocytes showed an A1 augmentation (7.41, p=0.001 and a reduced expression of Bax (0.19; p=0.040 and Bad (0.2; p=0.030. There was no correlation between JAK2 V617F allele burden and molecular expression. PV patients showed alterations in Bcl-2 members' expression, which may interfere with control of apoptotic machinery and contribute to disease pathogenesis.A desregulação da apoptose parece participar da fisiopatologia da policitemia vera (PV. Este estudo avaliou a expressão das moléculas da família Bcl-2 em células hematopoéticas CD34 + e leucócitos de 12 pacientes com PV. Foram realizados: a quantificação da expressão gênica por PCR em tempo real utilizando kit Sybrgreen Quantitect, avaliação da expressão de proteínas por western-blot e detecção da mutação JAK2 V617F segundo Baxter et al. (2005. Células CD34 + dos pacientes com PV apresentaram maior expressão de A1 e Mcl-1 (mediana: 22,6 e 5,2, respectivamente em comparação com controles (0,9 e 0,5, p = 0,004 e p = 0,020 e expressão de Bcl-2 e Bcl-xL diminuída nestes pacientes (0,18 e 1,19 em relação aos controles (1,39 e 2,01, p = 0,006 e p = 0

  20. Hunting, law enforcement, and African primate conservation.

    Science.gov (United States)

    N'Goran, Paul K; Boesch, Christophe; Mundry, Roger; N'Goran, Eliezer K; Herbinger, Ilka; Yapi, Fabrice A; Kühl, Hjalmar S

    2012-06-01

    Primates are regularly hunted for bushmeat in tropical forests, and systematic ecological monitoring can help determine the effect hunting has on these and other hunted species. Monitoring can also be used to inform law enforcement and managers of where hunting is concentrated. We evaluated the effects of law enforcement informed by monitoring data on density and spatial distribution of 8 monkey species in Taï National Park, Côte d'Ivoire. We conducted intensive surveys of monkeys and looked for signs of human activity throughout the park. We also gathered information on the activities of law-enforcement personnel related to hunting and evaluated the relative effects of hunting, forest cover and proximity to rivers, and conservation effort on primate distribution and density. The effects of hunting on monkeys varied among species. Red colobus monkeys (Procolobus badius) were most affected and Campbell's monkeys (Cercopithecus campbelli) were least affected by hunting. Density of monkeys irrespective of species was up to 100 times higher near a research station and tourism site in the southwestern section of the park, where there is little hunting, than in the southeastern part of the park. The results of our monitoring guided law-enforcement patrols toward zones with the most hunting activity. Such systematic coordination of ecological monitoring and law enforcement may be applicable at other sites. ©2012 Society for Conservation Biology.

  1. 25 CFR 12.33 - Are Indian country law enforcement officers paid less than other law enforcement officers?

    Science.gov (United States)

    2010-04-01

    ... 25 Indians 1 2010-04-01 2010-04-01 false Are Indian country law enforcement officers paid less than other law enforcement officers? 12.33 Section 12.33 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR LAW AND ORDER INDIAN COUNTRY LAW ENFORCEMENT Qualifications and Training Requirements § 12.33 Are Indian country law enforcement...

  2. Some reactions of hydrotris(3,5-dimethylpyrazolyl)-borato trichloroactinides(IV), MCl/sub 3/(HBL/sub 3/). THF (M=Th/sup IV/, U/sup IV/; L=3,5-dimethylpyrazolyl, THF=tetrahydrofuran)

    Energy Technology Data Exchange (ETDEWEB)

    Marcalo, J; Marques, N; Pires de Matos, A; Bagnall, K W

    1986-08-01

    The thorium(IV) and uranium(IV) compounds MCl/sub 2/(Cp)(HBL/sub 3/) (Cp=eta/sup 5/-C/sub 5/H/sub 5/), MCl/sub 2/(N(SiMe/sub 3/)/sub 2/)(HBL/sub 3/) and M(NPh/sub 2/)/sub 3/(HBL/sub 3/) have been prepared from MCl/sub 3/(HBL/sub 3/).THF. IR, near-IR-visible, /sup 1/H NMR and /sup 11/B NMR spectra are reported for these compounds.

  3. Law Enforcement of Cyber Terorism in Indonesia

    Directory of Open Access Journals (Sweden)

    Sri Ayu Astuti

    2015-12-01

    Full Text Available Cyber terrorism is one of the category of crimes that cross border organized and has been established as an extraordinary crime. This crime is becoming a serious threat to countries in the world. In this regard, the Government's attitude of firmness needed to enforce cyber laws against the freedom development in social media. The development of the immeasurable it in the country of Indonesia required the limitations by doing legal liability over the behavior of law which deviates towards the use of technology tools. Strict law enforcement efforts as a clear attitude to stop actively moving massive terrorism, by enacting the provisions of the law on information and electronic transactions as well as the law of terrorism effectively. How To Cite: Astuti, S. (2015. Law Enforcement of Cyber Terorism in Indonesia. Rechtsidee, 2(2, 157-178. doi:http://dx.doi.org/10.21070/jihr.v2i2.82

  4. A Review on Regulatory Enforcement Policy

    International Nuclear Information System (INIS)

    Lim, Ji Han; Lee, Kyung Joo; Choi, Young Sung

    2017-01-01

    This paper examine the meaning and principle of enforcement through examples from other countries. Regulatory enforcement is the last stage of safety regulation and how it is exercised when one failing to meet regulatory requirements can have significant ripple effect across the industry. Thus, right philosophy and principle should be established. It is not recommended to emphasize neither deterrence approach nor behavior modification approach. This should be also taken into consideration when setting up the principle and system of regulatory enforcement. In the process of Vienna Declaration, Europe and the U.S showed the fundamental differences in their approaches to safety regulation. Considering this, it is required to remain cautious at all times on what to be improved in the aspect of internal consistency within our system and also in the aspect of procedure.

  5. Institutional Design of Enforcement in the EU: The Case of Financial Markets

    Directory of Open Access Journals (Sweden)

    Miroslava Scholten

    2014-12-01

    Full Text Available Enforcement of EU law has become increasingly ‘Europeanized’. But how is and can it be organized in the integrated legal order of the EU to promote effective enforcement? In light of the recent institutional and substantive changes in the area of EU financial markets regulation, this article identifies four models (S, M, L, and XL models of enforcement of EU law. It discusses the possibilities and challenges to effective enforcement of each of such models and the major trade-offs which policy-makers face at the EU and national levels when designing enforcement frameworks, namely centralization vs. decentralization (an institutional perspective and harmonization vs. differentiation (substantive and procedural perspectives. It argues that at least a minimum degree of institutional centralization is necessary to promote the uniform enforcement and implementation of EU policies in a Union with 28 legal systems. The more specific details, such as specific institutional shape of centralized bodies (should it be a network, an agency or an EU institution? and of the distribution of functions between the national and EU level are better addressed on a case-by-case basis in light of the political, economic, and social characteristics of the sector at stake.

  6. NRC program of inspection and enforcement

    International Nuclear Information System (INIS)

    LeDoux, J.C.; Rehfuss, C.

    1978-01-01

    The Nuclear Regulatory Commission (NRC) regulates civilian uses of nuclear materials to ensure the protection of the public health and safety and the environment. The Office of Inspection and Enforcement (IE) develops and implements the inspection, investigation, and enforcement programs for the NRC. The IE conducts inspection programs for reactors under construction and in operation, nuclear industry vendors, fuel facilities and users of nuclear materials, and all aspects of the safeguarding of facilities and materials. Recently the IE began implementing a program that will place inspectors on site at nuclear power reactors and will provide for national appraisal of licensee performance and for an evaluation of the effectiveness of the inspection programs

  7. Concurrent Inhibition of Pim and FLT3 Kinases Enhances Apoptosis of FLT3-ITD Acute Myeloid Leukemia Cells through Increased Mcl-1 Proteasomal Degradation.

    Science.gov (United States)

    Kapoor, Shivani; Natarajan, Karthika; Baldwin, Patrick R; Doshi, Kshama A; Lapidus, Rena G; Mathias, Trevor J; Scarpa, Mario; Trotta, Rossana; Davila, Eduardo; Kraus, Manfred; Huszar, Dennis; Tron, Adriana E; Perrotti, Danilo; Baer, Maria R

    2018-01-01

    Purpose: fms -like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) is present in 30% of acute myeloid leukemia (AML), and these patients have short disease-free survival. FLT3 inhibitors have limited and transient clinical activity, and concurrent treatment with inhibitors of parallel or downstream signaling may improve responses. The oncogenic serine/threonine kinase Pim-1 is upregulated downstream of FLT3-ITD and also promotes its signaling in a positive feedback loop, suggesting benefit of combined Pim and FLT3 inhibition. Experimental Design: Combinations of clinically active Pim and FLT3 inhibitors were studied in vitro and in vivo Results: Concurrent treatment with the pan-Pim inhibitor AZD1208 and FLT3 inhibitors at clinically applicable concentrations abrogated in vitro growth of FLT3-ITD, but not wild-type FLT3 (FLT3-WT), cell lines. AZD1208 cotreatment increased FLT3 inhibitor-induced apoptosis of FLT3-ITD, but not FLT3-WT, cells measured by sub-G 1 fraction, annexin V labeling, mitochondrial membrane potential, and PARP and caspase-3 cleavage. Concurrent treatment with AZD1208 and the FLT3 inhibitor quizartinib decreased growth of MV4-11 cells, with FLT3-ITD, in mouse xenografts, and prolonged survival, enhanced apoptosis of FLT3-ITD primary AML blasts, but not FLT3-WT blasts or remission marrow cells, and decreased FLT3-ITD AML blast colony formation. Mechanistically, AZD1208 and quizartinib cotreatment decreased expression of the antiapoptotic protein Mcl-1. Decrease in Mcl-1 protein expression was abrogated by treatment with the proteasome inhibitor MG132, and was preceded by downregulation of the Mcl-1 deubiquitinase USP9X, a novel mechanism of Mcl-1 regulation in AML. Conclusions: The data support clinical testing of Pim and FLT3 inhibitor combination therapy for FLT3-ITD AML. Clin Cancer Res; 24(1); 234-47. ©2017 AACR . ©2017 American Association for Cancer Research.

  8. Growth kinetics, effect of carbon substrate in biosynthesis of mcl-PHA by Pseudomonas putida Bet001.

    Science.gov (United States)

    Gumel, A M; Annuar, M S M; Heidelberg, T

    2014-01-01

    Growth associated biosynthesis of medium chain length poly-3-hydroxyalkanoates (mcl-PHA) in Pseudomonas putida Bet001 isolated from palm oil mill effluent was studied. Models with substrate inhibition terms described well the kinetics of its growth. Selected fatty acids (C8:0 to C18:1) and ammonium were used as carbon and nitrogen sources during growth and PHA biosynthesis, resulting in PHA accumulation of about 50 to 69% (w/w) and PHA yields ranging from 10.12 g L(-1) to 15.45 g L(-1), respectively. The monomer composition of the PHA ranges from C4 to C14, and was strongly influenced by the type of carbon substrate fed. Interestingly, an odd carbon chain length (C7) monomer was also detected when C18:1 was fed. Polymer showed melting temperature (T m) of 42.0 (± 0.2) °C, glass transition temperature (T g) of -1.0 (± 0.2) °C and endothermic melting enthalpy of fusion (ΔHf) of 110.3 (± 0.1) J g(-1). The molecular weight (M w) range of the polymer was relatively narrow between 55 to 77 kDa.

  9. Growth kinetics, effect of carbon substrate in biosynthesis of mcl-PHA by Pseudomonas putida Bet001

    Directory of Open Access Journals (Sweden)

    A.M. Gumel

    2014-06-01

    Full Text Available Growth associated biosynthesis of medium chain length poly-3-hydroxyalkanoates (mcl-PHA in Pseudomonas putida Bet001 isolated from palm oil mill effluent was studied. Models with substrate inhibition terms described well the kinetics of its growth. Selected fatty acids (C8:0 to C18:1 and ammonium were used as carbon and nitrogen sources during growth and PHA biosynthesis, resulting in PHA accumulation of about 50 to 69% (w/w and PHA yields ranging from 10.12 g L-1 to 15.45 g L-1, respectively. The monomer composition of the PHA ranges from C4 to C14, and was strongly influenced by the type of carbon substrate fed. Interestingly, an odd carbon chain length (C7 monomer was also detected when C18:1 was fed. Polymer showed melting temperature (Tm of 42.0 (± 0.2 °C, glass transition temperature (Tg of -1.0 (± 0.2 °C and endothermic melting enthalpy of fusion (ΔHf of 110.3 (± 0.1 J g-1. The molecular weight (Mw range of the polymer was relatively narrow between 55 to 77 kDa.

  10. 17 CFR 37.9 - Enforceability.

    Science.gov (United States)

    2010-04-01

    ... 17 Commodity and Securities Exchanges 1 2010-04-01 2010-04-01 false Enforceability. 37.9 Section 37.9 Commodity and Securities Exchanges COMMODITY FUTURES TRADING COMMISSION DERIVATIVES TRANSACTION... pursuant to the rules of, a registered derivatives transaction execution facility shall not be void...

  11. 7 CFR 3016.43 - Enforcement.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 15 2010-01-01 2010-01-01 false Enforcement. 3016.43 Section 3016.43 Agriculture Regulations of the Department of Agriculture (Continued) OFFICE OF THE CHIEF FINANCIAL OFFICER, DEPARTMENT OF AGRICULTURE UNIFORM ADMINISTRATIVE REQUIREMENTS FOR GRANTS AND COOPERATIVE AGREEMENTS TO STATE AND LOCAL...

  12. Commercial Court and Enforcement Assessment Tool

    OpenAIRE

    Ebeid, Omniah; Gramckow, Heike

    2016-01-01

    An effective and efficient justice system is essential for sustained economic growth. In a well-functioning, independent, and efficient justice system, decisions are taken within a reasonable time and are predictably and effectively enforced, and individual rights, including property rights, are adequately protected. Among other objectives, the efficiency of the judicial system is importan...

  13. 18 CFR 1b.21 - Enforcement hotline.

    Science.gov (United States)

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Enforcement hotline. 1b.21 Section 1b.21 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION... shall be treated as non-public by the Commission and its staff, consistent with the provisions of...

  14. Intimate Partner Violence within Law Enforcement Families

    Science.gov (United States)

    Anderson, Anita S.; Lo, Celia C.

    2011-01-01

    Using data from the Baltimore Police Stress and Domestic Violence study, the authors examined how exposure to stressful events on the job affects law enforcement employees' physical aggression toward domestic partners, evaluating the role of negative emotions and authoritarian spillover in mediating the impact of such task-related stress. The…

  15. 30 CFR 903.843 - Federal enforcement.

    Science.gov (United States)

    2010-07-01

    ... request, to a designated Arizona State agency with jurisdiction over mining. ... Mineral Resources OFFICE OF SURFACE MINING RECLAMATION AND ENFORCEMENT, DEPARTMENT OF THE INTERIOR PROGRAMS FOR THE CONDUCT OF SURFACE MINING OPERATIONS WITHIN EACH STATE ARIZONA § 903.843 Federal...

  16. 8 CFR 270.2 - Enforcement procedures.

    Science.gov (United States)

    2010-01-01

    ... Aliens and Nationality DEPARTMENT OF HOMELAND SECURITY IMMIGRATION REGULATIONS PENALTIES FOR DOCUMENT FRAUD § 270.2 Enforcement procedures. (a) Procedures for the filing of complaints. Any person or entity... charges for document fraud committed by refugees at the time of entry. The Service shall not issue a...

  17. 31 CFR 31.218 - Enforcement.

    Science.gov (United States)

    2010-07-01

    ... 31 Money and Finance: Treasury 1 2010-07-01 2010-07-01 false Enforcement. 31.218 Section 31.218 Money and Finance: Treasury Office of the Secretary of the Treasury TROUBLED ASSET RELIEF PROGRAM... more of the following sanctions: (1) Rejection of work tainted by an organizational conflict of...

  18. 7 CFR 1145.3 - Enforcement.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 9 2010-01-01 2009-01-01 true Enforcement. 1145.3 Section 1145.3 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements... contracts and based on the results of the investigation will take appropriate action. ...

  19. Intergroup Bias in Parliamentary Rule Enforcement

    DEFF Research Database (Denmark)

    Hjorth, Frederik Georg

    2016-01-01

    Political actors are often assigned roles requiring them to enforce rules without giving in-groups special treatment. But are such institutional roles likely to be successful? Here, I exploit a special case of exogenously assigned intergroup relations: debates in the Danish Parliament, in which P...... of clear rules, complete observability, and a tradition of parliamentary cooperation....

  20. 30 CFR 933.843 - Federal enforcement.

    Science.gov (United States)

    2010-07-01

    ... PROGRAMS FOR THE CONDUCT OF SURFACE MINING OPERATIONS WITHIN EACH STATE NORTH CAROLINA § 933.843 Federal... violations on surface coal mining and reclamation operations. (b) OSM will furnish a copy of each enforcement action and order to show cause issued pursuant to this part to the North Carolina Department of Natural...

  1. 16 CFR 1602.1 - Enforcement policy.

    Science.gov (United States)

    2010-01-01

    ... 16 Commercial Practices 2 2010-01-01 2010-01-01 false Enforcement policy. 1602.1 Section 1602.1 Commercial Practices CONSUMER PRODUCT SAFETY COMMISSION FLAMMABLE FABRICS ACT REGULATIONS STATEMENTS OF..., set aside, or repealed by the Consumer Product Safety Commission, by any court of competent...

  2. 12 CFR 370.11 - Enforcement mechanisms.

    Science.gov (United States)

    2010-01-01

    ... TEMPORARY LIQUIDITY GUARANTEE PROGRAM § 370.11 Enforcement mechanisms. (a) Termination of Participation. If... participate in the temporary liquidity guarantee program, the FDIC will inform the entity that it will no longer be provided the protections of the temporary liquidity guarantee program. (1) Termination of...

  3. Price-Anderson Nuclear Safety Enforcement Program. 1996 Annual report

    International Nuclear Information System (INIS)

    1996-01-01

    This first annual report on DOE's Price Anderson Amendments Act enforcement program covers the activities, accomplishments, and planning for calendar year 1996. It also includes the infrastructure development activities of 1995. It encompasses the activities of the headquarters' Office of Enforcement in the Office of Environment, Safety and Health (EH) and Investigation and the coordinators and technical advisors in DOE's Field and Program Offices and other EH Offices. This report includes an overview of the enforcement program; noncompliances, investigations, and enforcement actions; summary of significant enforcement actions; examples where enforcement action was deferred; and changes and improvements to the program

  4. Assessing peak aerobic capacity in Dutch law enforcement officers

    Directory of Open Access Journals (Sweden)

    Harriet Wittink

    2015-06-01

    Full Text Available Objectives: To cross-validate the existing peak rate of oxygen consumption (VO2peak prediction equations in Dutch law enforcement officers and to determine whether these prediction equations can be used to predict VO2peak for groups and in a single individual. A further objective was to report normative absolute and relative VO2peak values of a sample of law enforcement officers in the Netherlands. Material and Methods: The peak rate of oxygen consumption (ml×kg–1×min–1 was measured using a maximal incremental bicycle test in 1530 subjects, including 1068 male and 461 female police officers. Validity of the prediction equations for groups was assessed by comparing predicted VO2peak with measured VO2peak using paired t-tests. For individual differences limits of agreement (LoA were calculated. Equations were considered valid for individuals when the difference between measured and predicted VO2peak did not exceed ±1 metabolic equivalent (MET in 95% of individuals. Results: None of the equations met the validity criterion of 95% of individuals having ±1 MET difference or less than the measured value. Limits of agreement (LoAs were large in all predictions. At the individual level, none of the equations were valid predictors of VO2peak (ml×kg–1×min–1. Normative values for Dutch law enforcement officers were presented. Conclusions: Substantial differences between measured and predicted VO2peak (ml×kg–1×min–1 were found. Most tested equations were invalid predictors of VO2peak at group level and all were invalid at individual levels.

  5. Hypoxic human cancer cells are sensitized to BH-3 mimetic–induced apoptosis via downregulation of the Bcl-2 protein Mcl-1

    Science.gov (United States)

    Harrison, Luke R.E.; Micha, Dimitra; Brandenburg, Martin; Simpson, Kathryn L.; Morrow, Christopher J.; Denneny, Olive; Hodgkinson, Cassandra; Yunus, Zaira; Dempsey, Clare; Roberts, Darren; Blackhall, Fiona; Makin, Guy; Dive, Caroline

    2011-01-01

    Solid tumors contain hypoxic regions in which cancer cells are often resistant to chemotherapy-induced apoptotic cell death. Therapeutic strategies that specifically target hypoxic cells and promote apoptosis are particularly appealing, as few normal tissues experience hypoxia. We have found that the compound ABT-737, a Bcl-2 homology domain 3 (BH-3) mimetic, promotes apoptotic cell death in human colorectal carcinoma and small cell lung cancer cell lines exposed to hypoxia. This hypoxic induction of apoptosis was mediated through downregulation of myeloid cell leukemia sequence 1 (Mcl-1), a Bcl-2 family protein that serves as a biomarker for ABT-737 resistance. Downregulation of Mcl-1 in hypoxia was independent of hypoxia-inducible factor 1 (HIF-1) activity and was consistent with decreased global protein translation. In addition, ABT-737 induced apoptosis deep within tumor spheroids, consistent with an optimal hypoxic oxygen tension being necessary to promote ABT-737–induced cell death. Tumor xenografts in ABT-737–treated mice also displayed significantly more apoptotic cells within hypoxic regions relative to normoxic regions. Synergies between ABT-737 and other cytotoxic drugs were maintained in hypoxia, suggesting that this drug may be useful in combination with chemotherapeutic agents. Taken together, these findings suggest that Mcl-1–sparing BH-3 mimetics may induce apoptosis in hypoxic tumor cells that are resistant to other chemotherapeutic agents and may have a role in combinatorial chemotherapeutic regimens for treatment of solid tumors. PMID:21393866

  6. Informed consent: Enforcing pharmaceutical companies' obligations abroad.

    Science.gov (United States)

    Lee, Stacey B

    2010-06-15

    The past several years have seen an evolution in the obligations of pharmaceutical companies conducting clinical trials abroad. Key players, such as international human rights organizations, multinational pharmaceutical companies, the United States government and courts, and the media, have played a significant role in defining these obligations. This article examines how such obligations have developed through the lens of past, present, and future recommendations for informed consent protections. In doing so, this article suggests that, no matter how robust obligations appear, they will continue to fall short of providing meaningful protection until they are accompanied by a substantive enforcement mechanism that holds multinational pharmaceutical companies accountable for their conduct. Issues of national sovereignty, particularly in the United States, will continue to prevent meaningful enforcement by an international tribunal or through one universally adopted code of ethics. This article argues that, rather than continuing to pursue an untenable international approach, the Alien Torts Statute (ATS) offers a viable enforcement mechanism, at least for US-based pharmaceutical companies. Recent federal appellate court precedent interpreting the ATS provides the mechanism for granting victims redress and enforcing accountability of sponsors (usually pharmaceutical companies and research and academic institutions) for informed consent misconduct. Substantive human rights protections are vital in order to ensure that every person can realize the "right to health." This article concludes that by building on the federal appellate court's ATS analysis, which grants foreign trial participants the right to pursue claims of human rights violations in US courts, a mechanism can be created for enforcing not only substantive informed consent, but also human rights protections.

  7. Regulatory inspection of nuclear facilities and enforcement by the regulatory body. Safety guide

    International Nuclear Information System (INIS)

    2002-01-01

    The purpose of this Safety Guide is to provide recommendations for regulatory bodies on the inspection of nuclear facilities, regulatory enforcement and related matters. The objective is to provide the regulatory body with a high level of confidence that operators have the processes in place to ensure compliance and that they do comply with legal requirements, including meeting the safety objectives and requirements of the regulatory body. However, in the event of non-compliance, the regulatory body should take appropriate enforcement action. This Safety Guide covers regulatory inspection and enforcement in relation to nuclear facilities such as: enrichment and fuel manufacturing plants; nuclear power plants; other reactors such as research reactors and critical assemblies; spent fuel reprocessing plants; and facilities for radioactive waste management, such as treatment, storage and disposal facilities. This Safety Guide also covers issues relating to the decommissioning of nuclear facilities, the closure of waste disposal facilities and site rehabilitation. Section 2 sets out the objectives of regulatory inspection and enforcement. Section 3 covers the management of regulatory inspections. Section 4 covers the performance of regulatory inspections, including internal guidance, planning and preparation, methods of inspection and reports of inspections. Section 5 deals with regulatory enforcement actions. Section 6 covers the assessment of regulatory inspections and enforcement activities. The Appendix provides further details on inspection areas for nuclear facilities

  8. Third party objection and action against enforcement: Request for exclusion

    Directory of Open Access Journals (Sweden)

    Salma Marija

    2014-01-01

    Full Text Available This paper deals with a right of a third party to prevent enforcement on the basis of a claim and evidence that rights or assets seized in enforcement proceeding belong to him (third party and not to the enforcement debtor. In most of jurisdictions that were subject of analysis of this paper, this right of a third party is exercised by filing an objection to the court conducting enforcement proceedings. The claim of the third party is directed towards the enforcement creditor as well as against the enforcement debtor. In the event the claim of the third party is being contested, the court instructs the third party to initiate litigation proceedings for determining whether the third party is entitled to exclusion of such rights or assets from enforcement, especially if such third party holds property rights or some other rights over the assets that are being subject to enforcement proceedings. In majority of analyzed jurisdictions, enforcement proceedings are being suspended provided the third party, in the objection being filed makes prima facie likely, on the basis of credible evidence, that his assets were seized in the enforcement proceedings. However, according to the law of the Republic of Serbia, a credible objection of a third party does not result in suspension of enforcement proceedings, something that is being criticized in this paper. As a result of this provision of the law, a bona fide third party is forced to endure the enforcement although his claim has been made likely and subsequently confirmed in the litigation proceedings. The author, in particular, points to the legal consequences of mala fide enforcement creditor that knew that the assets that are being subject of the enforcement proceedings do not belong to the enforcement debtor. The author is of the opinion that, in such cases, the enforcement creditor should be obliged to pay to the third party damages that such party suffered as a result of enforcement proceedings being

  9. Appendix F. Developmental enforcement algorithm definition document : predictive braking enforcement algorithm definition document.

    Science.gov (United States)

    2012-05-01

    The purpose of this document is to fully define and describe the logic flow and mathematical equations for a predictive braking enforcement algorithm intended for implementation in a Positive Train Control (PTC) system.

  10. EPA Enforcement and Compliance History Online: EPA Enforcement Action Data Set

    Data.gov (United States)

    U.S. Environmental Protection Agency — The Enforcement and Compliance History Online (ECHO) data sets have been compiled for access to larger sets of national data to ensure that ECHO meets your data...

  11. Thermal-work strain in law enforcement personnel during chemical, biological, radiological, and nuclear (CBRN) training

    Science.gov (United States)

    Yokota, M; Karis, A J; Tharion, W J

    2014-01-01

    Background: Thermal safety standards for the use of chemical, biological, radiological, and nuclear (CBRN) ensembles have been established for various US occupations, but not for law enforcement personnel. Objectives: We examined thermal strain levels of 30 male US law enforcement personnel who participated in CBRN field training in Arizona, Florida, and Massachusetts. Methods: Physiological responses were examined using unobtrusive heart rate (HR) monitors and a simple thermoregulatory model to predict core temperature (Tc) using HR and environment. Results: Thermal strain levels varied by environments, activity levels, and type of CBRN ensemble. Arizona and Florida volunteers working in hot-dry and hot-humid environment indicated high heat strain (predicted max Tc>38.5°C). The cool environment of Massachusetts reduced thermal strain although thermal strains were occasionally moderate. Conclusions: The non-invasive method of using physiological monitoring and thermoregulatory modeling could improve law enforcement mission to reduce the risk of heat illness or injury. PMID:24999847

  12. 48 CFR 1322.406 - Administration and enforcement.

    Science.gov (United States)

    2010-10-01

    ... 48 Federal Acquisition Regulations System 5 2010-10-01 2010-10-01 false Administration and enforcement. 1322.406 Section 1322.406 Federal Acquisition Regulations System DEPARTMENT OF COMMERCE... Involving Construction 1322.406 Administration and enforcement. ...

  13. 48 CFR 1222.406 - Administration and enforcement.

    Science.gov (United States)

    2010-10-01

    ... 48 Federal Acquisition Regulations System 5 2010-10-01 2010-10-01 false Administration and enforcement. 1222.406 Section 1222.406 Federal Acquisition Regulations System DEPARTMENT OF TRANSPORTATION... Involving Construction 1222.406 Administration and enforcement. ...

  14. 40 CFR 205.57 - Selective enforcement auditing requirements.

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 24 2010-07-01 2010-07-01 false Selective enforcement auditing requirements. 205.57 Section 205.57 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) NOISE... Selective enforcement auditing requirements. ...

  15. 40 CFR 204.57 - Selective enforcement auditing.

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 24 2010-07-01 2010-07-01 false Selective enforcement auditing. 204.57 Section 204.57 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) NOISE ABATEMENT... enforcement auditing. ...

  16. 40 CFR 205.160 - Selective enforcement auditing (SEA) requirements.

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 24 2010-07-01 2010-07-01 false Selective enforcement auditing (SEA) requirements. 205.160 Section 205.160 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED... Selective enforcement auditing (SEA) requirements. ...

  17. Child Support Enforcement Annual Data Reports Form 157 - YR 2013

    Data.gov (United States)

    U.S. Department of Health & Human Services — The Office of Child Support Enforcement's Annual Data Report from State agencies administering child support enforcement plans under Title IV-D of the Social...

  18. Child Support Enforcement Annual Data Report Form 157

    Data.gov (United States)

    U.S. Department of Health & Human Services — The Office of Child Support Enforcement's Annual Data Report from State agencies administering child support enforcement plans under Title IV-D of the Social...

  19. Fusing Intelligence With Law Enforcement Information: An Analytic Imperative

    National Research Council Canada - National Science Library

    Thornlow, Christopher C

    2005-01-01

    ... and Law Enforcement Communities to fuse and analyze foreign threat intelligence with domestic law enforcement information in a timely fashion to provide adequate indications and warning of such an...

  20. Law Enforcement Strategies for Preventing Rail Trespassing Risk Factors.

    Science.gov (United States)

    2016-03-01

    The Volpe Center has investigated law enforcement methods that have successfully prevented trespassing along the railroad right of way. The types of law enforcement strategies currently being used and procedures followed in the field are documented, ...

  1. Law Enforcement Support Office (LESO) 1999 National Conference

    National Research Council Canada - National Science Library

    Lytle, Michael

    1999-01-01

    The Law Enforcement Support Office (LESO) national conference was a three-day forum to inform and update federal, state and local law enforcement agents, of the DoD role supporting the National Drug Control Strategy...

  2. A novel small molecule FL118 that selectively inhibits survivin, Mcl-1, XIAP and cIAP2 in a p53-independent manner, shows superior antitumor activity.

    Directory of Open Access Journals (Sweden)

    Xiang Ling

    Full Text Available Drug/radiation resistance to treatment and tumor relapse are major obstacles in identifying a cure for cancer. Development of novel agents that address these challenges would therefore be of the upmost importance in the fight against cancer. In this regard, studies show that the antiapoptotic protein survivin is a central molecule involved in both hurdles. Using cancer cell-based survivin-reporter systems (US 7,569,221 B2 via high throughput screening (HTS of compound libraries, followed by in vitro and in vivo analyses of HTS-derived hit-lead compounds, we identified a novel anticancer compound (designated FL118. FL118 shows structural similarity to irinotecan. However, while the inhibition of DNA topoisomerase 1 activity by FL118 was no better than the active form of irinotecan, SN-38 at 1 µM, FL118 effectively inhibited cancer cell growth at less than nM levels in a p53 status-independent manner. Moreover, FL118 selectively inhibited survivin promoter activity and gene expression also in a p53 status-independent manner. Although the survivin promoter-reporter system was used for the identification of FL118, our studies revealed that FL118 not only inhibits survivin expression but also selectively and independently inhibits three additional cancer-associated survival genes (Mcl-1, XIAP and cIAP2 in a p53 status-independent manner, while showing no inhibitory effects on control genes. Genetic silencing or overexpression of FL118 targets demonstrated a role for these targets in FL118's effects. Follow-up in vivo studies revealed that FL118 exhibits superior antitumor efficacy in human tumor xenograft models in comparison with irinotecan, topotecan, doxorubicin, 5-FU, gemcitabine, docetaxel, oxaliplatin, cytoxan and cisplatin, and a majority of mice treated with FL118 showed tumor regression with a weekly × 4 schedule. FL118 induced favorable body-weight-loss profiles (temporary and reversible and was able to eliminate large tumors. Together

  3. 29 CFR 1952.122 - Level of Federal enforcement.

    Science.gov (United States)

    2010-07-01

    ...)) will not be initiated with regard to Federal occupational safety and health standards in issues covered... Labor Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION... determination that Washington is operational in the issues covered by the Washington occupational safety and...

  4. 29 CFR 1952.382 - Level of Federal enforcement.

    Science.gov (United States)

    2010-07-01

    ...)) will not be initiated with regard to Federal occupational safety and health standards in issues covered... Labor Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION... determination that Puerto Rico is operational in the issues covered by the Puerto Rico occupational safety and...

  5. 29 CFR 1952.172 - Level of Federal enforcement.

    Science.gov (United States)

    2010-07-01

    ..., and Ron Rinaldi, Director, California Department of Industrial Relations, effective October 5, 1989... access of the shore). (iii) All afloat marine ship building and repair from the foot of the gangway. (iv) All ship building and repair in graving docks or dry docks. (v) All ship repairing done in marine...

  6. 29 CFR 1952.165 - Level of Federal enforcement.

    Science.gov (United States)

    2010-07-01

    ... issues covered under the Iowa plan. This determination also relinquishes concurrent Federal OSHA... proceedings in contested cases under section 10; to institute proceedings to correct imminent dangers under... accordance with section 18(e), final approval relinquishes Federal OSHA authority only with regard to...

  7. 29 CFR 1952.215 - Level of Federal enforcement.

    Science.gov (United States)

    2010-07-01

    ... OSHA authority to issue citations for violations of such standards under sections 5(a)(2) and 9 of the... proceedings in contested cases under section 10; to institute proceedings to correct imminent dangers under... accordance with section 18(e), final approval relinquishes Federal OSHA authority only with regard to...

  8. 29 CFR 1952.244 - Level of Federal enforcement.

    Science.gov (United States)

    2010-07-01

    ... OSHA authority to issue citations for violation of such standards under sections 5(a)(2) and 9 of the... proceedings in contested cases under section 10; to institute proceedings to correct imminent dangers under.... (b) In accordance with section 18(e), final approval relinquishes Federal OSHA authority only with...

  9. 29 CFR 1952.225 - Level of Federal enforcement.

    Science.gov (United States)

    2010-07-01

    ... OSHA authority to issue citations for violations of such standards under sections 5(a)(2) and 9 of the... proceedings in contested cases under section 10; to institute proceedings to correct imminent dangers under... accordance with section 18(e), final approval relinquishes Federal OSHA authority only with regard to...

  10. 29 CFR 1952.265 - Level of Federal enforcement.

    Science.gov (United States)

    2010-07-01

    ... employees, as in the case of temporary emergency standards promulgated under section 6(c) of the Act (29 U.S... Michigan plan under sections 18(e) and (f) of the Act (29 U.S.C. 667(e) and (f)). Federal OSHA will also... engaged in USPS mail operations. The OSHA Regional Administrator will make a prompt recommendation for the...

  11. 29 CFR 1952.314 - Level of Federal enforcement.

    Science.gov (United States)

    2010-07-01

    ... to issues covered under the Hawaii plan. This determination also relinquishes concurrent Federal OSHA... proceedings in contested cases under section 10; to institute proceedings to correct imminent dangers under.... (b) In accordance with section 18(e), final approval relinquishes Federal OSHA authority only with...

  12. 29 CFR 1952.355 - Level of Federal enforcement.

    Science.gov (United States)

    2010-07-01

    ... OSHA authority to issue citations for violation of such standards under sections 5(a)(2) and 9 of the... proceedings in contested cases under section 10; to institute proceedings to correct imminent dangers under... accordance with section 18(e), final approval relinquishes Federal OSHA authority only with regard to...

  13. 29 CFR 1952.235 - Level of Federal enforcement.

    Science.gov (United States)

    2010-07-01

    ... OSHA authority to issue citations for violations of such standards under sections 5(a)(2) and 9 of the... proceedings in contested cases under section 10; to institute proceedings to correct imminent dangers under... accordance with section 18(e), final approval relinquishes Federal OSHA authority only with regard to...

  14. 29 CFR 1952.95 - Level of Federal enforcement.

    Science.gov (United States)

    2010-07-01

    ... under the South Carolina plan. This determination also relinquishes concurrent Federal OSHA authority to... cases under section 10; to institute proceedings to correct imminent dangers under section 13; and to... with section 18(e), final approval relinquishes Federal OSHA authority only with regard to occupational...

  15. 29 CFR 1952.205 - Level of Federal enforcement.

    Science.gov (United States)

    2010-07-01

    ... OSHA authority to issue citations for violations of such standards under sections 5(a)(2) and 9 of the... proceedings in contested cases under section 10; to institute proceedings to correct imminent dangers under... accordance with section 18(e), final approval relinquishes Federal OSHA authority only with regard to...

  16. 29 CFR 1952.345 - Level of Federal enforcement.

    Science.gov (United States)

    2010-07-01

    ... OSHA authority to issue citations for violations of such standards under sections 5(a)(2) and 9 of the... proceedings in contested cases under section 10; to institute proceedings to correct imminent dangers under... accordance with section 18(e), final approval relinquishes Federal OSHA authority only with regard to...

  17. 29 CFR 1952.375 - Level of Federal Enforcement.

    Science.gov (United States)

    2010-07-01

    ... OSHA authority to issue citations for violations of such standards under section 5(a)(2) and 9 of the... proceedings in contested cases under section 10; to institute proceedings to correct imminent dangers under... accordance with section 18(e), final approval relinquishes Federal OSHA authority only with regard to...

  18. 29 CFR 1952.325 - Level of Federal enforcement.

    Science.gov (United States)

    2010-07-01

    ... OSHA authority to issue citations for violations of such standards under sections 5 (a)(2) and 9 of the... proceedings in contested cases under section 10; to institute proceedings to correct imminent dangers under... accordance with section 18(e), final approval relinquishes Federal OSHA authority only with regard to...

  19. 29 CFR 1952.105 - Level of Federal enforcement.

    Science.gov (United States)

    2010-07-01

    ... concurrent Federal OSHA authority to issue citations for violations of such standards under Sections 5(a)(2... proceedings in contested cases under Section 10; to institute proceedings to correct imminent dangers under...), final approval relinquishes Federal OSHA authority with regard to occupational safety and health issues...

  20. 29 CFR 1952.115 - Level of Federal enforcement.

    Science.gov (United States)

    2010-07-01

    ... issues covered under the Utah plan. This determination also relinquishes concurrent Federal OSHA... proceedings in contested cases under section 10; to institute proceedings to correct imminent dangers under... accordance with section 18(e), final approval relinquishes Federal OSHA authority only with regard to...

  1. 29 CFR 1952.295 - Level of Federal enforcement.

    Science.gov (United States)

    2010-07-01

    ... OSHA authority to issue citations for violations of such standards under section 5(a)(2) and 9 of the... proceedings in contested cases under section 10; to institute proceedings to correct imminent dangers under.... (b)(1) In accordance with section 18(e), final approval relinquishes Federal OSHA authority only with...

  2. 29 CFR 1952.272 - Level of Federal enforcement.

    Science.gov (United States)

    2010-07-01

    ... case of temporary emergency standards promulgated under section 6(c) of the Act (29 U.S.C. 665(c)), in... sections 18(e) and (f) of the Act (29 U.S.C. 667(e) and (f)). Federal OSHA will also retain authority for... operations. The OSHA Regional Administrator will make a prompt recommendation for the resumption of the...

  3. A Comparison of Military and Law Enforcement Body Armour

    OpenAIRE

    Robin Orr; Ben Schram; Rodney Pope

    2018-01-01

    Law-enforcement officers increasingly wear body armour for protection; wearing body armour is common practice in military populations. Law-enforcement and military occupational demands are vastly different and military-styled body armour may not be suitable for law-enforcement. This study investigated differences between selected military body armour (MBA: 6.4 kg) and law-enforcement body armour (LEBA: 2.1 kg) in impacts on postural sway, vertical jump, agility, a functional movement screen (...

  4. Enforcement of entailment constraints in distributed service-based business processes.

    Science.gov (United States)

    Hummer, Waldemar; Gaubatz, Patrick; Strembeck, Mark; Zdun, Uwe; Dustdar, Schahram

    2013-11-01

    A distributed business process is executed in a distributed computing environment. The service-oriented architecture (SOA) paradigm is a popular option for the integration of software services and execution of distributed business processes. Entailment constraints, such as mutual exclusion and binding constraints, are important means to control process execution. Mutually exclusive tasks result from the division of powerful rights and responsibilities to prevent fraud and abuse. In contrast, binding constraints define that a subject who performed one task must also perform the corresponding bound task(s). We aim to provide a model-driven approach for the specification and enforcement of task-based entailment constraints in distributed service-based business processes. Based on a generic metamodel, we define a domain-specific language (DSL) that maps the different modeling-level artifacts to the implementation-level. The DSL integrates elements from role-based access control (RBAC) with the tasks that are performed in a business process. Process definitions are annotated using the DSL, and our software platform uses automated model transformations to produce executable WS-BPEL specifications which enforce the entailment constraints. We evaluate the impact of constraint enforcement on runtime performance for five selected service-based processes from existing literature. Our evaluation demonstrates that the approach correctly enforces task-based entailment constraints at runtime. The performance experiments illustrate that the runtime enforcement operates with an overhead that scales well up to the order of several ten thousand logged invocations. Using our DSL annotations, the user-defined process definition remains declarative and clean of security enforcement code. Our approach decouples the concerns of (non-technical) domain experts from technical details of entailment constraint enforcement. The developed framework integrates seamlessly with WS-BPEL and the Web

  5. 10 CFR 431.383 - Enforcement process for electric motors.

    Science.gov (United States)

    2010-01-01

    ... 10 Energy 3 2010-01-01 2010-01-01 false Enforcement process for electric motors. 431.383 Section... COMMERCIAL AND INDUSTRIAL EQUIPMENT Enforcement § 431.383 Enforcement process for electric motors. (a) Test... motor sold by a particular manufacturer or private labeler, which indicates that the electric motor may...

  6. 45 CFR 164.412 - Law enforcement delay.

    Science.gov (United States)

    2010-10-01

    ... 45 Public Welfare 1 2010-10-01 2010-10-01 false Law enforcement delay. 164.412 Section 164.412 Public Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES ADMINISTRATIVE DATA STANDARDS AND RELATED... § 164.412 Law enforcement delay. If a law enforcement official states to a covered entity or business...

  7. 49 CFR 1542.217 - Law enforcement personnel.

    Science.gov (United States)

    2010-10-01

    ... 49 Transportation 9 2010-10-01 2010-10-01 false Law enforcement personnel. 1542.217 Section 1542... Law enforcement personnel. (a) Each airport operator must ensure that law enforcement personnel used... the criminal laws of the State and local jurisdictions in which the airport is located— (1) A crime...

  8. 49 CFR 1546.211 - Law enforcement personnel.

    Science.gov (United States)

    2010-10-01

    ... 49 Transportation 9 2010-10-01 2010-10-01 false Law enforcement personnel. 1546.211 Section 1546... § 1546.211 Law enforcement personnel. (a) At airports within the United States not governed by part 1542...) When using a screening system required by § 1546.101(a), (b), or (c), provide for law enforcement...

  9. 49 CFR 1544.217 - Law enforcement personnel.

    Science.gov (United States)

    2010-10-01

    ... 49 Transportation 9 2010-10-01 2010-10-01 false Law enforcement personnel. 1544.217 Section 1544... AND COMMERCIAL OPERATORS Operations § 1544.217 Law enforcement personnel. (a) The following applies to... for law enforcement personnel meeting the qualifications and standards specified in §§ 1542.215 and...

  10. Hybrid static-runtime information flow and declassification enforcement

    NARCIS (Netherlands)

    Pontes Soares Rocha, B.; Conti, M.; Etalle, S.; Crispo, B.

    2013-01-01

    There are different paradigms for enforcing information flow and declassification policies. These approaches can be divided into static analyzers and runtime enforcers. Each class has its own strengths and weaknesses, each being able to enforce a different set of policies. In this paper we introduce

  11. Hybrid static-runtime information flow and declassification enforcement

    NARCIS (Netherlands)

    Rocha, Bruno P.S.; Conti, Mauro; Etalle, Sandro; Crispo, Bruno

    There are different paradigms for enforcing information flow and declassification policies. These approaches can be divided into static analyzers and runtime enforcers. Each class has its own strengths and weaknesses, each being able to enforce a different set of policies. In this paper, we

  12. 32 CFR 634.33 - Training of law enforcement personnel.

    Science.gov (United States)

    2010-07-01

    ... 32 National Defense 4 2010-07-01 2010-07-01 true Training of law enforcement personnel. 634.33 Section 634.33 National Defense Department of Defense (Continued) DEPARTMENT OF THE ARMY (CONTINUED) LAW ENFORCEMENT AND CRIMINAL INVESTIGATIONS MOTOR VEHICLE TRAFFIC SUPERVISION Traffic Supervision § 634.33 Training of law enforcement personnel. (a) A...

  13. 32 CFR 806b.8 - Obtaining law enforcement records.

    Science.gov (United States)

    2010-07-01

    ... 32 National Defense 6 2010-07-01 2010-07-01 false Obtaining law enforcement records. 806b.8 Section 806b.8 National Defense Department of Defense (Continued) DEPARTMENT OF THE AIR FORCE ADMINISTRATION PRIVACY ACT PROGRAM Obtaining Law Enforcement Records and Confidentiality Promises § 806b.8 Obtaining law enforcement records. The Commander, Air...

  14. 20 CFR 401.155 - Law enforcement purposes.

    Science.gov (United States)

    2010-04-01

    ... 20 Employees' Benefits 2 2010-04-01 2010-04-01 false Law enforcement purposes. 401.155 Section 401... INFORMATION Disclosure of Official Records and Information § 401.155 Law enforcement purposes. (a) General. The Privacy Act allows us to disclose information for law enforcement purposes under certain...

  15. 21 CFR 1309.26 - Exemption of law enforcement officials.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 9 2010-04-01 2010-04-01 false Exemption of law enforcement officials. 1309.26 Section 1309.26 Food and Drugs DRUG ENFORCEMENT ADMINISTRATION, DEPARTMENT OF JUSTICE REGISTRATION OF MANUFACTURERS, DISTRIBUTORS, IMPORTERS AND EXPORTERS OF LIST I CHEMICALS Requirements for Registration § 1309.26 Exemption of law enforcement...

  16. 21 CFR 1301.24 - Exemption of law enforcement officials.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 9 2010-04-01 2010-04-01 false Exemption of law enforcement officials. 1301.24 Section 1301.24 Food and Drugs DRUG ENFORCEMENT ADMINISTRATION, DEPARTMENT OF JUSTICE REGISTRATION OF MANUFACTURERS, DISTRIBUTORS, AND DISPENSERS OF CONTROLLED SUBSTANCES Exceptions to Registration and Fees § 1301.24 Exemption of law enforcement...

  17. 25 CFR 11.1003 - Law enforcement officer's duties.

    Science.gov (United States)

    2010-04-01

    ... 25 Indians 1 2010-04-01 2010-04-01 false Law enforcement officer's duties. 11.1003 Section 11.1003 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR LAW AND ORDER COURTS OF INDIAN OFFENSES AND LAW AND ORDER CODE Juvenile Offender Procedure § 11.1003 Law enforcement officer's duties. A law enforcement officer who takes a minor into...

  18. 46 CFR 4.03-55 - Law enforcement officer.

    Science.gov (United States)

    2010-10-01

    ... 46 Shipping 1 2010-10-01 2010-10-01 false Law enforcement officer. 4.03-55 Section 4.03-55 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY PROCEDURES APPLICABLE TO THE PUBLIC MARINE CASUALTIES AND INVESTIGATIONS Definitions § 4.03-55 Law enforcement officer. Law enforcement officer means a Coast Guard commissioned, warrant or petty officer...

  19. 78 FR 44165 - Nuclear Regulatory Commission Enforcement Policy

    Science.gov (United States)

    2013-07-23

    ... NUCLEAR REGULATORY COMMISSION [NRC-2013-0159] Nuclear Regulatory Commission Enforcement Policy AGENCY: Nuclear Regulatory Commission. ACTION: Enforcement policy; request for comment. SUMMARY: The U.S... Policy. In SRM-SECY-12-0047, ``Revisions to the Nuclear Regulatory Commission Enforcement Policy,'' dated...

  20. 10 CFR 431.198 - Enforcement testing for distribution transformers.

    Science.gov (United States)

    2010-01-01

    ... 10 Energy 3 2010-01-01 2010-01-01 false Enforcement testing for distribution transformers. 431.198... COMMERCIAL AND INDUSTRIAL EQUIPMENT Distribution Transformers Compliance and Enforcement § 431.198 Enforcement testing for distribution transformers. (a) Test notice. Upon receiving information in writing...

  1. 20 CFR 638.805 - Security and law enforcement.

    Science.gov (United States)

    2010-04-01

    ... 20 Employees' Benefits 3 2010-04-01 2010-04-01 false Security and law enforcement. 638.805 Section... and law enforcement. (a) The Job Corps Director shall provide guidelines to protect the security of... jurisdiction with the appropriate State and locality with respect to criminal law enforcement as long as a...

  2. 50 CFR 10.22 - Law enforcement offices.

    Science.gov (United States)

    2010-10-01

    ... 50 Wildlife and Fisheries 1 2010-10-01 2010-10-01 false Law enforcement offices. 10.22 Section 10... GENERAL PROVISIONS Addresses § 10.22 Law enforcement offices. Service law enforcement offices and their areas of responsibility follow. Mail should be addressed: “Assistant Regional Director, Division of Law...

  3. 45 CFR 5.68 - Exemption seven: Law enforcement.

    Science.gov (United States)

    2010-10-01

    ... 45 Public Welfare 1 2010-10-01 2010-10-01 false Exemption seven: Law enforcement. 5.68 Section 5... INFORMATION REGULATIONS Reasons for Withholding Some Records § 5.68 Exemption seven: Law enforcement. We are not required to disclose information or records that the government has compiled for law enforcement...

  4. 77 FR 32901 - State Enforcement of Household Goods Consumer Protection

    Science.gov (United States)

    2012-06-04

    ... enforce certain consumer protection provisions of Title 49 of the United States Code (U.S.C.) and related... bring civil actions in the U.S. district courts to enforce the consumer protection provisions that apply..., 386, and 387 State Enforcement of Household Goods Consumer Protection AGENCY: Federal Motor Carrier...

  5. 24 CFR 125.401 - Private Enforcement Initiative.

    Science.gov (United States)

    2010-04-01

    ... 24 Housing and Urban Development 1 2010-04-01 2010-04-01 false Private Enforcement Initiative. 125... FAIR HOUSING FAIR HOUSING INITIATIVES PROGRAM § 125.401 Private Enforcement Initiative. (a) The Private Enforcement Initiative provides funding on a single-year or multi-year basis, to investigate violations and...

  6. 32 CFR 634.26 - Traffic law enforcement principles.

    Science.gov (United States)

    2010-07-01

    ... 32 National Defense 4 2010-07-01 2010-07-01 true Traffic law enforcement principles. 634.26 Section 634.26 National Defense Department of Defense (Continued) DEPARTMENT OF THE ARMY (CONTINUED) LAW... law enforcement principles. (a) Traffic law enforcement should motivate drivers to operate vehicles...

  7. Forensic imaging tools for law enforcement

    Energy Technology Data Exchange (ETDEWEB)

    SMITHPETER,COLIN L.; SANDISON,DAVID R.; VARGO,TIMOTHY D.

    2000-01-01

    Conventional methods of gathering forensic evidence at crime scenes are encumbered by difficulties that limit local law enforcement efforts to apprehend offenders and bring them to justice. Working with a local law-enforcement agency, Sandia National Laboratories has developed a prototype multispectral imaging system that can speed up the investigative search task and provide additional and more accurate evidence. The system, called the Criminalistics Light-imaging Unit (CLU), has demonstrated the capabilities of locating fluorescing evidence at crime scenes under normal lighting conditions and of imaging other types of evidence, such as untreated fingerprints, by direct white-light reflectance. CLU employs state of the art technology that provides for viewing and recording of the entire search process on videotape. This report describes the work performed by Sandia to design, build, evaluate, and commercialize CLU.

  8. Nuclear forensics in law enforcement applications

    International Nuclear Information System (INIS)

    Grant, P.M.; Moody, K.J.; Hutcheon, I.D.; Phinney, D.L.; Whipple, R.E.; Haas, J.S.; Alcaraz, A.; Andrews, J.E.; Klunder, G.L.; Russo, R.E.

    1998-01-01

    Over the past several years, the Livermore Forensic Science Center has conducted analyses of nuclear-related samples in conjunction with domestic and international criminal investigations. Law enforcement officials have sought conventional and nuclear-forensic analyses of questioned specimens that have typically consisted of miscellaneous metal species or actinide salts. The investigated activities have included nuclear smuggling and the proliferation of alleged fissionable materials, nonradioactive hoaxes such as 'Red Mercury', and the interdiction of illegal laboratories engaged in methamphetamine synthesis. (author)

  9. Social Background, Cooperative Behavior, and Norm Enforcement

    OpenAIRE

    Kocher, Martin; Martinsson, Peter; Visser, Martine

    2009-01-01

    Studies have shown that there are differences in cooperative behavior across countries. Furthermore, differences in the use of and the reaction to the introduction of a norm enforcement mechanism have recently been documented in cross-cultural studies. We present data that prove that stark differences in both dimensions can exist even within the same town. For this end, we created a unique data set, based on one-shot public goods experiments conducted in South Africa. Most of our group differ...

  10. Digital Rights Enforcement for Pervasive Computing Applications

    OpenAIRE

    Dahlem, Dominik

    2005-01-01

    Increasingly, application software is expanding from the desktop into mobile application environments, such as handset devices and embedded systems which are more limited in resources and volatile in their network connectivity. An integrated architecture that can protect intellectual property for both types of environments should offer the promise of reduced software maintenance costs. Software licensing is an existing mechanism by which specific license agreements are enforced be...

  11. Volunteer Flying Organizations: Law Enforcements Untapped Resource

    Science.gov (United States)

    2016-12-01

    World War II, women in the United States turned manpower into woman power as housewives across the nation took manufacturing jobs building bombers...delineates responsibilities for the entire volunteer organization. Safety -first Flying Culture CHP CHP’s first- class safety program uses the most...civilian pilots to augment law enforcement based aviation operations. This thesis uses recommendations of the Public Safety Aviation Accreditation

  12. Forensic drug intelligence: an important tool in law enforcement.

    Science.gov (United States)

    Esseiva, Pierrre; Ioset, Sylvain; Anglada, Frédéric; Gasté, Laëtitia; Ribaux, Olivier; Margot, Pierre; Gallusser, Alain; Biedermann, Alex; Specht, Yves; Ottinger, Edmond

    2007-04-11

    Organised criminality is a great concern for national/international security. The demonstration of complex crimes is increasingly dependant on knowledge distributed within law-enforcement agencies and scientific disciplines. This separation of knowledge creates difficulties in reconstructing and prosecuting such crimes. Basic interdisciplinary research in drug intelligence combined with crime analysis, forensic intelligence, and traditional law enforcement investigation is leading to important advances in crime investigation support. Laboratory results constitute one highly dependable source of information that is both reliable and testable. Their operational use can support investigation and even provide undetected connections or organisation of structure. The foremost difficulties encountered by drug analysts are not principally of a chemical or analytical nature, but methodologies to extract parameters or features that are deemed to be crucial for handling and contextualising drug profiling data. An organised memory has been developed in order to provide accurate, timely, useful and meaningful information for linking spatially and temporally distinct events on a national and international level (including cross-border phenomena). Literature has already pointed out that forensic case data are amenable for use in an intelligence perspective if data and knowledge of specialised actors are appropriately organised, shared and processed. As a particular form of forensic case data, the authors' research focuses on parameters obtained through the systematic physical and chemical profiling of samples of illicit drugs. The procedure is used to infer and characterise links between samples that originate from the same and different seizures. The discussion will not, however, focus on how samples are actually analysed and compared as substantial literature on this topic already exists. Rather, attention is primarily drawn to an active and close collaboration between

  13. Internal Security Cooperation under Functional Expectations: Initial Law Enforcement Europeanization - Case of Finland and Estonia

    Directory of Open Access Journals (Sweden)

    Ramon Loik

    2016-03-01

    Full Text Available Law enforcement cooperation as a central part of the EU internal security policy to combat cross-border organised crime and terrorism needs to be more effective by adopting specific provisions and tools. This paper argues that functional expectations require removal of barriers and construction of a common security area, but sometimes better cooperation in practice does not fit, as Europeanization of law enforcement still lacks understanding of objectives, values and principles for improving international trust, consensus, sincere cooperation and effective national coordination. The level of Europeanization of law enforcement could be evaluated as based on the level of implementation of the EU provisions on police cooperation related to practical enforcement, factors promoting or hindering law enforcement and changes in discursive practices due to EU provisions and professional socialisation processes. Some aspects of observed inertia characterizes the slow process of transition or tendencies for absorption in which resilience meets the necessary degree of flexibility allowing for some mutual learning and cooperation, but the result is expectedly a form of accommodation of needful policy requirements in the lack of substantial change perspective.

  14. Metformin combined with aspirin significantly inhibit pancreatic cancer cell growth in vitro and in vivo by suppressing anti-apoptotic proteins Mcl-1 and Bcl-2

    Science.gov (United States)

    Yue, Wen; Zheng, Xi; Lin, Yong; Yang, Chung S.; Xu, Qing; Carpizo, Darren; Huang, Huarong; DiPaola, Robert S.; Tan, Xiang-Lin

    2015-01-01

    Metformin and aspirin have been studied extensively as cancer preventive or therapeutic agents. However, the effects of their combination on pancreatic cancer cells have not been investigated. Herein, we evaluated the effects of metformin and aspirin, alone or in combination, on cell viability, migration, and apoptosis as well as the molecular changes in mTOR, STAT3 and apoptotic signaling pathways in PANC-1 and BxPC3 cells. Metformin and aspirin, at relatively low concentrations, demonstrated synergistically inhibitory effects on cell viability. Compared to the untreated control or individual drug, the combination of metformin and aspirin significantly inhibited cell migration and colony formation of both PANC-1 and BxPC-3 cells. Metformin combined with aspirin significantly inhibited the phosphorylation of mTOR and STAT3, and induced apoptosis as measured by caspase-3 and PARP cleavage. Remarkably, metformin combined with aspirin significantly downregulated the anti-apoptotic proteins Mcl-1 and Bcl-2, and upregulated the pro-apoptotic proteins Bim and Puma, as well as interrupted their interactions. The downregulation of Mcl-1 and Bcl-2 was independent of AMPK or STAT3 pathway but partially through mTOR signaling and proteasome degradation. In a PANC-1 xenograft mouse model, we demonstrated that the combination of metformin and aspirin significantly inhibited tumor growth and downregulated the protein expression of Mcl-1 and Bcl-2 in tumors. Taken together, the combination of metformin and aspirin significantly inhibited pancreatic cancer cell growth in vitro and in vivo by regulating the pro- and anti-apoptotic Bcl-2 family members, supporting the continued investigation of this two drug combination as chemopreventive or chemotherapeutic agents for pancreatic cancer. PMID:26056043

  15. The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized

    OpenAIRE

    van Delft, Mark F.; Wei, Andrew H.; Mason, Kylie D.; Vandenberg, Cassandra J.; Chen, Lin; Czabotar, Peter E.; Willis, Simon N.; Scott, Clare L.; Day, Catherine L.; Cory, Suzanne; Adams, Jerry M.; Roberts, Andrew W.; Huang, David C.S.

    2006-01-01

    Since apoptosis is impaired in malignant cells overexpressing pro-survival Bcl-2 proteins, drugs mimicking their natural antagonists, BH3-only proteins, might overcome chemoresistance. Of seven putative BH3 mimetics tested, only ABT-737 triggered Bax/Bak-mediated apoptosis. Despite its high affinity for Bcl-2, Bcl-xL and Bcl-w, many cell types proved refractory to ABT-737. We show that this resistance reflects its inability to target another pro-survival relative, Mcl-1. Down-regulation of Mc...

  16. Regulation of occupational health and safety in the semiconductor industry: enforcement problems and solutions.

    Science.gov (United States)

    Watterson, Andrew

    2006-01-01

    Reports of high incidences of occupational illnesses in the semiconductor industry should have triggered global investigations and rigorous inspection of the industry. Yet semiconductor plants remain essentially unregulated. Health and safety standards are inadequate and enforcement is lax. Roles for stakeholders in laying down good practice, monitoring, and regulating are proposed, and obstacles are described. Effective regulation has advantages for the industry as well as workers. Conditions for best practice include education at all levels, protection and support for labor inspectors, government commitment to enforcing laws, recognition of the right of workers to organize, and recognition of their rights.

  17. Enforcement actions: significant actions resolved. Quarterly progress report, July-September 1983. Volume 2, No.3

    International Nuclear Information System (INIS)

    1983-11-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (July-September 1983) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions ad licensees' responses. This and future issues will include cases involving Severity Level III violations for which no civil penalty was assessed. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, in the interest of promoting public health and safety as well as common defense and security

  18. Social Norms and the Enforcement of Laws

    OpenAIRE

    Daron Acemoglu; Matthew O. Jackson

    2014-01-01

    We examine the interplay between social norms and the enforcement of laws. Agents choose a behavior (e.g., tax evasion, production of low-quality products, corruption, substance abuse, etc.) and then are randomly matched with another agent. An agent's payoff decreases with the mismatch between her behavior and her partner's, as well as average behavior in society. A law is an upper bound (cap) on behavior and a law-breaker, when detected, pays a fine and has her behavior forced down to the le...

  19. Computational infrastructure for law enforcement. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Lades, M.; Kunz, C.; Strikos, I.

    1997-02-01

    This project planned to demonstrate the leverage of enhanced computational infrastructure for law enforcement by demonstrating the face recognition capability at LLNL. The project implemented a face finder module extending the segmentation capabilities of the current face recognition so it was capable of processing different image formats and sizes and create the pilot of a network-accessible image database for the demonstration of face recognition capabilities. The project was funded at $40k (2 man-months) for a feasibility study. It investigated several essential components of a networked face recognition system which could help identify, apprehend, and convict criminals.

  20. Powerful subjects of tax law enforcement

    OpenAIRE

    Igor Dementyev

    2017-01-01

    УДК 342.6The subject. Competence of government bodies and their officials in the sphere of application of the tax law is considered in the article.The purpose of research is to determine the ratio of tax enforcement and application of the tax law, as well as the relationship between the concepts “party of tax enforcement” and “participant of tax legal relations”.Main results and scope of their application. The circle of participants of tax legal relations is broader than the circle of parties...

  1. Radiological response training for law enforcement personnel

    International Nuclear Information System (INIS)

    Maixner, R.D.

    1983-01-01

    A specialized training course for Nevada's law enforcement personnel has been conducted by Reynolds Electrical and Engineering Co., Inc. for the US Department of Energy since February 1981. This course is designed for those persons who are first to arrive at a transportation accident scene. The course provides a basic understanding of radiation protection, the prevention of contamination spread from the accident site, use of radiation detection equipment, and decontamination procedures. The Department of Energy's Nevada Operations Office provides the training at no cost to Nevada agencies. Each agency selects its attendees. Details of the course are given

  2. US statutes for enforcement by security inspectors

    Energy Technology Data Exchange (ETDEWEB)

    Cadwell, J.J.; Ruger, C.J.

    1995-12-01

    This document is one of a three volume set. BNL 52201 is titled `Selected Text of Atomic Energy Act Executive Orders and Other Laws of General Interest to Safeguards and Security Executives`, and it contains detailed information for use by executives. BNL 52202 is titled `U.S. Statutes of General Interest to Safeguards and Security Officers`, and contains less detail than BNL 52201. It is intended for use by officers. BNL 52203 is titled `U.S. Statutes for Enforcement by Security Inspectors`, and it contains statutes to be applied by uniformed security inspectors.

  3. Alcohol policy enforcement and changes in student drinking rates in a statewide public college system: a follow-up study

    Directory of Open Access Journals (Sweden)

    Harris Sion K

    2010-08-01

    Full Text Available Abstract Background Heavy alcohol use among U.S. college students is a major contributor to young adult morbidity and mortality. The aim of this study was to examine whether college alcohol policy enforcement levels predict changes in student drinking and related behaviors in a state system of public colleges and universities, following a system-wide change to a stricter policy. Methods Students and administrators at 11 Massachusetts public colleges/universities completed surveys in 1999 (N of students = 1252, one year after the policy change, and again in 2001 (N = 1074. We calculated policy enforcement scores for each school based on the reports of deans of students, campus security chiefs, and students, and examined the correlations between perceived enforcement levels and the change in student drinking rates over the subsequent two year period, after weighting the 2001 data to adjust for demographic changes in the student body. Results Overall rates of any past-30-days drinking, heavy episodic drinking, and usual heavy drinking among past-30-days drinkers were all lower in 2001 compared to 1999. School-level analyses (N = 11 found deans' baseline reports of stricter enforcement were strongly correlated with subsequent declines in heavy episodic drinking (Pearson's r = -0.73, p = 0.011. Moreover, consistently high enforcement levels across time, as reported by deans, were associated with greater declines in heavy episodic drinking. Such relationships were not found for students' and security chiefs' reports of enforcement. Marijuana use did not rise during this period of decline in heavy drinking. Conclusions Study findings suggest that stronger enforcement of a stricter alcohol policy may be associated with reductions in student heavy drinking rates over time. An aggressive enforcement stance by deans may be an important element of an effective college alcohol policy.

  4. Preparing the National Capital Region to Conduct a Multijurisdictional and Interdisciplinary Law Enforcement Investigation

    Science.gov (United States)

    2013-09-01

    stalk the weak and defenseless? What if a Mumbai-style terrorist attack were to occur? Is the NCR law enforcement (LE) community prepared to...task forces for street level crimes (e.g., gangs , drugs, firearms), they rarely work together on investigations that would require dozens, or even

  5. Commercial-vehicle enforcement: a guide for law-enforcement managers

    International Nuclear Information System (INIS)

    1987-01-01

    The purpose of the document is to provide a resource for law enforcement agencies to evaluate their programs, and to promote the uniform application of concepts already shown to be effective in other jurisdictions, which identify and address commercial-vehicle traffic safety needs

  6. REGULATION AND ENFORCEMENT OF COMPETITION POLICY

    Directory of Open Access Journals (Sweden)

    Liviana Andreea Niminet

    2014-12-01

    Full Text Available Competition policy starts by shaping a legislative framework. This is aimed to establish boundaries for conducting competition and also sets limits of licit and illicit demarcation, for competitive and anticompetitive practices. The Romanian Competition Law has a divalent approach and it aims to provide specific behavioral conditions in order to stimulate and protect free-market competition, with the ultimate goal of developing a balanced, efficient and competitive economy. Our country’s Competition policy is based on punishing the behavior. There are three such types of anti-competitive behavior, namely: agreements between undertakings, abuse of dominant position and mergers and other concentrations between undertakings. Recent Practice proved that this “enforcement-conduct-punishment” structure is not necessary the best way to address competition and it is high time for authorities to switch both regulation and enforcement of competition from the “classical perspective” towards concepts like “competition advocacy” and “soft power” and give competition policy a new, reshaped face.

  7. Sex Trafficking, Law Enforcement and Perpetrator Accountability

    Directory of Open Access Journals (Sweden)

    Holly Burkhalter

    2012-06-01

    Full Text Available In theory, everyone – except for criminals involved in their exploitation - agrees that children must not be in the sex industry and further, that those who prey on them must be prosecuted and punished. Virtually every country in the world has adopted national laws prohibiting the commercial sexual exploitation of children. International law is clear on this point, as well. Yet, when governments – and NGOs working with them – take action to extract children from commercial sex venues, common ground on protecting children from abuse can quickly erode with concerns about the efficacy of police intervention, the possibility of collateral harm to consenting adult sex workers or a decrease in access to HIV-prevention and related health services. The author argues that healing this divide must come through the reform of local police – and that, without the participation of law enforcement, there can be no long-term protection for children vulnerable to trafficking and related exploitation. In this article, human rights practitioner Holly Burkhalter argues that healing this divide must be accomplished through the reform of local police – and that human rights advocates, local governments and others seeking to combat trafficking cannot achieve long-term, sustainable protection for children without the involvement of law enforcement.

  8. Enforcement of evaluation by achievement analysis system

    International Nuclear Information System (INIS)

    Konishi, Yasutoshi; Sonoyama, Minoru; Suzuki, Atsushi

    2004-02-01

    Japan Nuclear Cycle Development Institute (JNC) has developed FBR achievement analysis system by the last fiscal year and has enforced the investigation of its functional expansion. That system is based on the AHP (Analytic Hierarchy Process) to do comparative evaluation multilaterally between proposed concepts of FBR cycle or between FBR cycle and other power source systems. This fiscal year, we enforced achievement analysis for 22 cases of proposed concepts of FBR cycle and between FBR cycle and other power source systems (LWR, thermal power generation, hydraulic power generation, etc.). The evaluation items related with technical feasibility and social acceptability were included in addition to those of economy, resource utilization effectiveness, environmental burden reduction, nuclear proliferation resistance and safety. Also, we investigated social changes that could happen in our country in the future, and we drew 4 future scenarios combining likely changes, then we investigated classifications of weight that seem to be adequate under each scenario with its calculation logic. In establishing points of view or structure of evaluation, and in the process of drawing scenarios, we collected comments from experts in OR (Operations Research) field and energy field. (author)

  9. Secondary harm mitigation: A more humanitarian framework for international drug law enforcement.

    Science.gov (United States)

    Blaustein, Jarrett; McLay, Miki; McCulloch, Jude

    2017-08-01

    This article introduces the concept of 'secondary harm mitigation' as a framework for improving the humanitarian credentials of international drug law enforcement agencies. The concept is rooted in a critical analysis of the compatibility of the harm reduction philosophy with Australia's international drug law enforcement practices. On a utilitarian level, the net benefits of international drug law enforcement are determined to be, at best inconclusive, arguably counterproductive and in most cases, incalculable. On a humanitarian level, international drug law enforcement is also determined to be problematic from a criminological standpoint because it generates secondary harms and it is indifferent to the vulnerability of individuals who participate in illicit drug trafficking. Accordingly, the article concludes that a philosophy of harm reduction grounded in the public health perspective is inadequate for mitigating secondary harms arising from Australia's efforts to combat international illicit drug trafficking. A tentative list of secondary harm mitigation principles is presented and the article argues that secondary harm mitigation should replace supply reduction as a core tenet of Australia's National Drug Strategy. The article also concludes that secondary harm mitigation may provide a viable framework for stimulating a productive dialogue between those who advocate prohibition and those who call for decriminalisation at the global level. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Civil Enforcement Case Report Data Dictionary | ECHO | US ...

    Science.gov (United States)

    ECHO, Enforcement and Compliance History Online, provides compliance and enforcement information for approximately 800,000 EPA-regulated facilities nationwide. ECHO includes permit, inspection, violation, enforcement action, and penalty information about facilities regulated under the Clean Air Act (CAA) Stationary Source Program, Clean Water Act (CWA) National Pollutant Elimination Discharge System (NPDES), and/or Resource Conservation and Recovery Act (RCRA). Information also is provided on surrounding demographics when available.

  11. Sharing Powers Within Exclusive Competences: Rethinking EU Antitrust Law Enforcement

    OpenAIRE

    Van Cleynenbreugel, Pieter

    2016-01-01

    Although the establishment of competition rules forms part of the EU’s exclusive competences, the application and enforcement of those rules has always been shared consistently between the EU and its Member States.The sharing of enforcement powers is conceptualised traditionally as a delegation of the exercise of exclusively conferred competences. The Court of Justice of the European Union’s case law in the context of EU antitrust law enforcement nevertheless raises profound questions as to t...

  12. Labor Law Enforcement in California, 1970-2000

    OpenAIRE

    Bar-Cohen, Limor; Carrillo, Deana Milam

    2002-01-01

    This chapter examines the record of two state agencies within the California Department of Industrial Relations, the Division of Labor Standards Enforcement (DLSE) and the California Occupational Safety and Health Program (Cal/OSHA), over the 1970-2000 period. Although the data available on the performance of these agencies are severely limited - in most cases consisting only of enforcement activity measures, without any valid measures of enforcement outcomes, it is possible to draw some conc...

  13. NRC Enforcement Policy Review, July 1995-July 1997

    International Nuclear Information System (INIS)

    Lieberman, J.; Pedersen, R.M.

    1998-04-01

    On June 30, 1995, the Nuclear Regulatory Commission (NRC) issued a complete revision of its General Statement of Policy and Procedure for Enforcement Action (Enforcement Policy) (60 FR 34381). In approving the 1995 revision to the Enforcement Policy, the Commission directed the staff to perform a review of its implementation of the Policy after approximately 2 years of experience and to consider public comments. This report represents the results of that review

  14. Privacy Enforcement in a Cost-Effective Smart Grid

    DEFF Research Database (Denmark)

    Mikkelsen, Søren Aagaard

    In this technical report we present the current state of the research conducted during the first part of the PhD period. The PhD thesis “Privacy Enforcement in a Cost-Effective Smart Grid” focuses on ensuring privacy when generating market for energy service providers that develop web services...... for the residential domain in the envisaged smart grid. The PhD project is funded and associated to the EU project “Energy Demand Aware Open Services for Smart Grid Intelligent Automation” (Smart HG) and therefore introduces the project on a system-level. Based on this, we present some of the integration, security...... and privacy challenges that emerge when designing a system architecture and infrastructure. The resulting architecture is a consumer-centric and agent-based design and uses open Internet-based communication protocols for enabling interoperability while being cost-effective. Finally, the PhD report present...

  15. Deterring Spoilers: Peace Enforcement Operations and Political Settlements to Conflict

    National Research Council Canada - National Science Library

    Manseau, Nicole C

    2008-01-01

    .... In Somalia, Operation Restore Hope provided a strong peace enforcement operation, but ultimately failed to deter spoilers to United Nations negotiations for a political settlement to the conflict...

  16. Understanding Law Enforcement Support to National Security Problems and Prospects

    National Research Council Canada - National Science Library

    Davies, Jeffrey S

    2008-01-01

    This paper explores law enforcement as an element of national power, defines its contributions, limitations, and challenges, and provides recommendations to maximize interagency competencies and unity...

  17. Enforcing Transferable Permit Systems in the Presence of Market Power

    International Nuclear Information System (INIS)

    Chavez, C.A.; Stanlund, J.K.

    2003-01-01

    We derive an enforcement strategy for a transferable permit system in the presence of market power that achieves complete compliance in a cost-effective manner. We show that the presence of a firm with market influence makes designing an enforcement strategy more difficult than enforcing a perfectly competitive system. We also re-consider the suggestion that a firm with market influence should be allocated permits so that it chooses to not participate in the permit market. When enforcement and its costs are taken into account, that suggestion does not hold except in a very special case

  18. Community involvement works where enforcement fails: conservation success through community-based management of Amazon river turtle nests

    Directory of Open Access Journals (Sweden)

    Darren Norris

    2018-06-01

    Full Text Available Law enforcement is widely regarded as a cornerstone to effective natural resource management. Practical guidelines for the optimal use of enforcement measures are lacking particularly in areas protected under sustainable and/or mixed use management regimes and where legal institution are weak. Focusing on the yellow-spotted river turtles (Podocnemis unifilis along 33 km of river that runs between two sustainable–use reserves in the Brazilian Amazon as an illustrative example, we show that two years of patrols to enforce lawful protection regulations had no effect on nest harvesting. In contrast, during one year when community-based management approaches were enacted harvest levels dropped nearly threefold to a rate (26% that is likely sufficient for river turtle population recovery. Our findings support previous studies that show how community participation, if appropriately implemented, can facilitate effective natural resource management where law enforcement is limited or ineffective.

  19. Dynamic Enforcement of the Strict Integrity Policy

    Institute of Scientific and Technical Information of China (English)

    ZHANGXiangfeng; LIANGHongliang; SUNYufang

    2005-01-01

    The Strict integrity policy (SIP) in Biba's integrity model is widely used in protecting information integrity, but the static integrity labels of both subjects and objects increase compatibility cost of applications and might prevent some operations that are indeed harmless.In order to improve compatibility, Dynamic enforcement of the Strict integrity policy (DESIP) is put forward. The current integrity label attribute of a subject in SIP is replaced with two attributes in DESIP, which are used to confine dynamically the range of objects a subject could be allowed to access. The new rules of access control in DESIP are given for each kind of access mode (observe,modify and invoke) together with the proofs of their valid-ity. Comparison between SIP and DESIP shows that after a sequence of operations, a subject controlled by DESIP tends to behave in a similar way as it is controlled by SIP and DESIP is more compatible than SIP.

  20. [The protection of health in law enforcement].

    Science.gov (United States)

    Pira, Enrico

    2014-01-01

    Herein the question of health protection/safety and well being in the Law Enforcement is introduced and includes examples of some particular risk conditions that may be multiple and polymorphous. Not only the "traditional" sources are involved in these risks, like chemical, physical and biological agents, but other issues emerge in these "new scenarios" connected to risk factors involving organization and/or psychosocial elements. From this, we may deduce that there is a specific need for all the operators involved in prevention/care in this particular sector to be well versed on the highest possible updated specialized knowledge along with having a complete and thorough mastery of the best practices in Occupational Medicine to face this task in the correct manner:

  1. Technical Review of Law Enforcement Standards and Guides Relative to Incident Management

    Energy Technology Data Exchange (ETDEWEB)

    Stenner, Robert D.; Salter, R.; Stanton, J. R.; Fisher, D.

    2009-03-24

    In an effort to locate potential law enforcement-related standards that support incident management, a team from the Pacific Northwest National Laboratory (PNNL) contacted representatives from the National Institute of Standards-Office of Law Enforcement Standards (NIST-OLES), National Institute of Justice (NIJ), Federal Bureau of Investigation (FBI), Secret Service, ASTM International committees that have a law enforcement focus, and a variety of individuals from local and regional law enforcement organizations. Discussions were held with various state and local law enforcement organizations. The NIJ has published several specific equipment-related law enforcement standards that were included in the review, but it appears that law enforcement program and process-type standards are developed principally by organizations that operate at the state and local level. Input is provided from state regulations and codes and from external non-government organizations (NGOs) that provide national standards. The standards that are adopted from external organizations or developed independently by state authorities are available for use by local law enforcement agencies on a voluntary basis. The extent to which they are used depends on the respective jurisdictions involved. In some instances, use of state and local disseminated standards is mandatory, but in most cases, use is voluntary. Usually, the extent to which these standards are used appears to depend on whether or not jurisdictions receive certification from a “governing” entity due to their use and compliance with the standards. In some cases, these certification-based standards are used in principal but without certification or other compliance monitoring. In general, these standards appear to be routinely used for qualification, selection for employment, and training. In these standards, the term “Peace Officer” is frequently used to refer to law enforcement personnel. This technical review of national law

  2. Curcumin significantly enhances dual PI3K/Akt and mTOR inhibitor NVP-BEZ235-induced apoptosis in human renal carcinoma Caki cells through down-regulation of p53-dependent Bcl-2 expression and inhibition of Mcl-1 protein stability.

    Directory of Open Access Journals (Sweden)

    Bo Ram Seo

    Full Text Available The PI3K/Akt and mTOR signaling pathways are important for cell survival and growth, and they are highly activated in cancer cells compared with normal cells. Therefore, these signaling pathways are targets for inducing cancer cell death. The dual PI3K/Akt and mTOR inhibitor NVP-BEZ235 completely inhibited both signaling pathways. However, NVP-BEZ235 had no effect on cell death in human renal carcinoma Caki cells. We tested whether combined treatment with natural compounds and NVP-BEZ235 could induce cell death. Among several chemopreventive agents, curcumin, a natural biologically active compound that is extracted from the rhizomes of Curcuma species, markedly induced apoptosis in NVP-BEZ235-treated cells. Co-treatment with curcumin and NVP-BEZ235 led to the down-regulation of Mcl-1 protein expression but not mRNA expression. Ectopic expression of Mcl-1 completely inhibited curcumin plus NVP-NEZ235-induced apoptosis. Furthermore, the down-regulation of Bcl-2 was involved in curcumin plus NVP-BEZ235-induced apoptosis. Curcumin or NVP-BEZ235 alone did not change Bcl-2 mRNA or protein expression, but co-treatment reduced Bcl-2 mRNA and protein expression. Combined treatment with NVP-BEZ235 and curcumin reduced Bcl-2 expression in wild-type p53 HCT116 human colon carcinoma cells but not p53-null HCT116 cells. Moreover, Bcl-2 expression was completely reversed by treatment with pifithrin-α, a p53-specific inhibitor. Ectopic expression of Bcl-2 also inhibited apoptosis in NVP-BE235 plus curcumin-treated cells. In contrast, NVP-BEZ235 combined with curcumin did not have a synergistic effect on normal human skin fibroblasts and normal human mesangial cells. Taken together, combined treatment with NVP-BEZ235 and curcumin induces apoptosis through p53-dependent Bcl-2 mRNA down-regulation at the transcriptional level and Mcl-1 protein down-regulation at the post-transcriptional level.

  3. 48 CFR 822.406 - Administration and enforcement.

    Science.gov (United States)

    2010-10-01

    ... 48 Federal Acquisition Regulations System 5 2010-10-01 2010-10-01 false Administration and enforcement. 822.406 Section 822.406 Federal Acquisition Regulations System DEPARTMENT OF VETERANS AFFAIRS... Involving Construction 822.406 Administration and enforcement. ...

  4. 40 CFR 205.171 - Selective enforcement auditing (SEA) requirements.

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 24 2010-07-01 2010-07-01 false Selective enforcement auditing (SEA) requirements. 205.171 Section 205.171 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED... § 205.171 Selective enforcement auditing (SEA) requirements. ...

  5. Improving Law Enforcement Cross Cultural Competencies through Continued Education

    Science.gov (United States)

    Sereni-Massinger, Christine; Wood, Nancy

    2016-01-01

    Over the last thirty years Community Oriented Policing (COP) has spawned advancements in creating community partnerships with law enforcement agencies. Agencies that focus on such partnerships have served to reduce crime and resolve conflict. However, community opinions towards law enforcement have become increasingly negative due to recent civil…

  6. 49 CFR 1542.215 - Law enforcement support.

    Science.gov (United States)

    2010-10-01

    ... 49 Transportation 9 2010-10-01 2010-10-01 false Law enforcement support. 1542.215 Section 1542.215..., DEPARTMENT OF HOMELAND SECURITY CIVIL AVIATION SECURITY AIRPORT SECURITY Operations § 1542.215 Law... program under § 1542.103(a) or (b) must provide: (1) Law enforcement personnel in the number and manner...

  7. 29 CFR 1614.503 - Enforcement of final Commission decisions.

    Science.gov (United States)

    2010-07-01

    ... ADEA, the Equal Pay Act or the Rehabilitation Act and to seek judicial review of the agency's refusal... 1614.503 Labor Regulations Relating to Labor (Continued) EQUAL EMPLOYMENT OPPORTUNITY COMMISSION FEDERAL SECTOR EQUAL EMPLOYMENT OPPORTUNITY Remedies and Enforcement § 1614.503 Enforcement of final...

  8. 12 CFR 268.503 - Enforcement of final EEOC decisions.

    Science.gov (United States)

    2010-01-01

    ... the decision pursuant to title VII, the ADEA, the Equal Pay Act or the Rehabilitation Act and to seek... RESERVE SYSTEM RULES REGARDING EQUAL OPPORTUNITY Remedies and Enforcement § 268.503 Enforcement of final... Procedures Act, 5 U.S.C. 701 et seq., and the mandamus statute, 28 U.S.C. 1361, or to commence de novo...

  9. 40 CFR 63.313 - Implementation and enforcement.

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 9 2010-07-01 2010-07-01 false Implementation and enforcement. 63.313 Section 63.313 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS... Standards for Coke Oven Batteries § 63.313 Implementation and enforcement. (a) This subpart can be...

  10. The Convention on the Recognition and Enforcement of Foreign ...

    African Journals Online (AJOL)

    The Convention on the Recognition and Enforcement of Foreign Arbitral Awards, often referred to as the New York Convention, has established itself as a regulatory and enforcement instrument which is crucial to international trade. This is evident from the fact that more than 150 countries have so far ratified the convention.

  11. 19 CFR Appendix A to Part 210 - Adjudication and Enforcement

    Science.gov (United States)

    2010-04-01

    ... 19 Customs Duties 3 2010-04-01 2010-04-01 false Adjudication and Enforcement A Appendix A to Part 210 Customs Duties UNITED STATES INTERNATIONAL TRADE COMMISSION INVESTIGATIONS OF UNFAIR PRACTICES IN IMPORT TRADE ADJUDICATION AND ENFORCEMENT Pt. 210, App. A Appendix A to Part 210—Adjudication and...

  12. The effect of enforcement on speed behaviour : a literature review.

    NARCIS (Netherlands)

    Oei, H.-l.

    1998-01-01

    The objective of this literature study is to give an overview of research on speed enforcement and its effect on speed behaviour and safety. This study will be used to find new strategies and tactics to enhance the efficiency and effectiveness of speed enforcement by the police in terms of behaviour

  13. 28 CFR 0.29j - Law enforcement authority.

    Science.gov (United States)

    2010-07-01

    ... 28 Judicial Administration 1 2010-07-01 2010-07-01 false Law enforcement authority. 0.29j Section 0.29j Judicial Administration DEPARTMENT OF JUSTICE ORGANIZATION OF THE DEPARTMENT OF JUSTICE 4-Office of the Inspector General § 0.29j Law enforcement authority. Subject to guidelines promulgated by the Attorney General, Special Agents of the Offic...

  14. 49 CFR 1542.221 - Records of law enforcement response.

    Science.gov (United States)

    2010-10-01

    ... 49 Transportation 9 2010-10-01 2010-10-01 false Records of law enforcement response. 1542.221 Section 1542.221 Transportation Other Regulations Relating to Transportation (Continued) TRANSPORTATION SECURITY ADMINISTRATION, DEPARTMENT OF HOMELAND SECURITY CIVIL AVIATION SECURITY AIRPORT SECURITY Operations § 1542.221 Records of law enforcement...

  15. Randomized Trial of Law Enforcement Training on Autism Spectrum Disorders

    Science.gov (United States)

    Teagardin, Jill; Dixon, Dennis R.; Smith, Marlena N.; Granpeesheh, Doreen

    2012-01-01

    The core symptoms of autism spectrum disorders (ASD) are likely to affect interactions between law enforcement officers and persons with ASD. If law enforcement officers are not trained to identify and appropriately respond to persons with ASD, it is possible that officers may exacerbate a situation, resulting in unnecessary trauma, injury, or…

  16. 36 CFR 1270.50 - Consultation with law enforcement agencies.

    Science.gov (United States)

    2010-07-01

    ... 36 Parks, Forests, and Public Property 3 2010-07-01 2010-07-01 false Consultation with law enforcement agencies. 1270.50 Section 1270.50 Parks, Forests, and Public Property NATIONAL ARCHIVES AND RECORDS ADMINISTRATION PRESIDENTIAL RECORDS PRESIDENTIAL RECORDS Presidential Records Compiled for Law Enforcement Purposes § 1270.50 Consultation with...

  17. Constitutional Basis for the Enforcement of ''Executive'' Policies that ...

    African Journals Online (AJOL)

    Although "executive" policies remain an important governance tool, there appears to be confusion on the status and possible basis for their judicial enforcement in South Africa. The aim of this article is to critically reflect on the status and possible constitutional basis for the enforceability of "executive" policies that give effect ...

  18. Legal Enforcement of Social Rights: Enabling Conditions and Impact Assessment

    NARCIS (Netherlands)

    S. Gloppen (Siri)

    2009-01-01

    textabstractThis article commends the concise and useful analysis of courts and the legal enforcement of economic, social and cultural rights given in Christian Courtis’ book, Courts and the Legal Enforcement of Economic, Social and Cultural Rights: Comparative Experiences of Justiciability. Yet, in

  19. Enforcing Competition Rules in South Africa: Thieves at the Dinner ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    2013-03-01

    Mar 1, 2013 ... Describing and analyzing competition law in South Africa, this book promotes a deeper understanding of the development of this foundational economic law within its specific national, social and economic context. Enforcing Competition Rules in South Africa draws strongly on case law and enforcement ...

  20. A Case for Criminal Enforcement of Federal Environmental Laws

    Science.gov (United States)

    1989-02-19

    enforcement scheme can actually contribute to improper disposal. Szasz , Corporations. Organized Crime. and the Disposal of Hazardous Waste: An...the Syndicate Control Mystiaue, 1 Nat’l Envtl. Enforcement J. 3 (Dec. 1986). 150. See Szasz , supra note 79. 151. United States v. MacDonald & Watson

  1. When is public enforcement of insider trading regulations effective?

    NARCIS (Netherlands)

    Wielhouwer, J.L.

    2013-01-01

    In this paper we investigate when public enforcement of insider trading regulations reduces the amount of insider trading. We model a game between a potentially self-interested regulator enforcing insider trading laws and a trader who may be trading on inside information. We show that equilibrium

  2. 12 CFR 403.11 - Enforcement and investigation procedures.

    Science.gov (United States)

    2010-01-01

    ... 12 Banks and Banking 4 2010-01-01 2010-01-01 false Enforcement and investigation procedures. 403.11 Section 403.11 Banks and Banking EXPORT-IMPORT BANK OF THE UNITED STATES CLASSIFICATION, DECLASSIFICATION, AND SAFEGUARDING OF NATIONAL SECURITY INFORMATION § 403.11 Enforcement and investigation...

  3. 25 CFR 11.909 - Law enforcement records.

    Science.gov (United States)

    2010-04-01

    ... BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR LAW AND ORDER COURTS OF INDIAN OFFENSES AND LAW AND ORDER CODE Children's Court § 11.909 Law enforcement records. (a) Law enforcement records and files... minor's parents or guardian, the presenting officer, or others by order of the children's court. ...

  4. 24 CFR 125.201 - Administrative Enforcement Initiative.

    Science.gov (United States)

    2010-04-01

    ... Initiative. 125.201 Section 125.201 Housing and Urban Development Regulations Relating to Housing and Urban... FAIR HOUSING FAIR HOUSING INITIATIVES PROGRAM § 125.201 Administrative Enforcement Initiative. The Administrative Enforcement Initiative provides funding to State and local fair housing agencies administering...

  5. Practical Run-Time Norm Enforcement with Bounded Lookahead

    NARCIS (Netherlands)

    Alechina, Natasha; Bulling, Nils; Dastani, Mehdi; Logan, Brian

    2015-01-01

    Norms have been widely proposed as a means of coordinating and controlling the behaviour of agents in a multi-agent system. A key challenge in normative MAS is norm enforcement: how and when to restrict the agents’ behaviour in order to obtain a desirable outcome? Even if a norm can be enforced

  6. Decentralized enforcement, sequential bargaining, and the clean development mechanism

    Energy Technology Data Exchange (ETDEWEB)

    Hovi, Jon

    2001-07-01

    While there is a vast literature both on international bargaining and on how international agreements can be enforced, very little work has been done on how bargaining and enforcement interact. An important exception is Fearon (1998), who models international cooperation as a two-stage process in which the bargaining process is constrained by a need for decentralized enforcement (meaning that the agreement must be enforced by the parties themselves rather than a third party, such as a court). Using the Clean Development Mechanism as an example, the present paper proposes a different model of this kind of interaction. The model follows Fearon's in so far as we both use the infinitely repeated Prisoners' Dilemma to capture the enforcement phase of the game. However, while Fearon depicts the bargaining stage as a War of Attrition, the present model sees that stage as a sequential bargaining game of the Staahl-Rubinstein type. The implications of the present model are compared both to those of the Staahl-Rubinstein model and to those of the Fearon model. A surprising conclusion is that a need for decentralized enforcement tends to make the bargaining outcome more symmetrical than otherwise. Thus, the impact of bargaining power is actually smaller when the resulting agreement must be enforced by the parties themselves than it is if enforcement is taken care of by a third party. (author)

  7. Attitude of Nigerian courts to the enforcement of foreign judgments ...

    African Journals Online (AJOL)

    ... serious need of reform. The study therefore called on the Nigerian Minister of Justice to do the needful so that the position of the law as it pertains to the enforcement of foreign judgment in Nigeria will be well settled and devoid of ambiguity. Keywords: Foreign Judgment, Enforcement, Registration, Recognition, Commerce ...

  8. 15 CFR 922.103 - Management and enforcement.

    Science.gov (United States)

    2010-01-01

    ... provisions of any grant or cooperative agreement. NOAA may act to deputize enforcement agents of the American Samoa Government (ASG) to enforce the regulations in this subpart in accordance with existing law. If NOAA chooses to exercise this provision, a memorandum of understanding shall be executed between NOAA...

  9. Task force on compliance and enforcement. Final report. Volume 2

    Energy Technology Data Exchange (ETDEWEB)

    1978-03-01

    Recommendations for measures to strengthen the FEA enforcement program in the area of petroleum price regulation are presented. Results of task force efforts are presented in report and recommendations sections concerned with pending cases, compliance program organization, enforcement powers, compliance strategy, and audit staffing and techniques. (JRD)

  10. The lanthanoid(III) chloride oxoselenates(IV) MCl[SeO3] (M = Sm - Lu) with HoCl[TeO3]- or B-type structure

    International Nuclear Information System (INIS)

    Lipp, C.; Schleid, T.

    2008-01-01

    The B-type lanthanoid(III) chloride oxoselenates(IV) MCl[SeO 3 ] (M = Sm - Lu) crystallize in the orthorhombic space group Pnma (no. 62) with Z = 4 in the structure type of HoCl[TeO 3 ]. Their lattice constants are decreasing following the lanthanoid contraction from a = 730.01(7), b = 707.90(7), c 895.64(9) pm for SmCl[SeO 3 ] to a = 714.63(7), b = 681.76(7), c = 864.05(9) pm for LuCl[SeO 3 ]. In contrast to NdCl[SeO 3 ], the only representative of the A-type structure, where the coordination numbers of the Nd 3+ cations are 7+2 and 8, the B-type structure is dominated by pentagonal bipyramids [MO 5 Cl 2 ] 9- (CN(M 3+ ) = 7), which are connected via trans-oriented O..O edges to ∞ 1 {[MO 4/2 e O 1/1 t Cl 2/1 t ] 5- } chains (e = edge-sharing, t = terminal) running parallel to the [010] direction. Their inclination relative to each other allows for an alternating interconnection of these chains via Cl - and ψ 1 -tetrahedral [SeO 3 ] 2- anions to form a three-dimensional structure. The distances within the [SeO 3 ] 2- groups are in the normal range (d(Se-O) = 165 - 172 pm), while those of the O 2- and Cl - anions to the central M 3+ cation diminish in dependence of the increasing atomic number (d(M-O) = 226 - 244 pm / 216 - 232 pm, d(M-Cl) 277 - 278 pm / 266 - 270 pm, M = Sm / Lu). For the synthesis of the chloride oxoselenates(IV) MCl[SeO 3 ] the respective lanthanoid sesquioxide (M 2 O 3 ) and selenium dioxide (SeO 2 ) were reacted with either an eutectic mixture of RbCl and LiCl or with the corresponding lanthanoid trichloride (MCl 3 ) in evacuated silica ampoules for either five weeks at 500 C or one week at 850 C. (orig.)

  11. High-dose myeloablative versus conventional low-dose radioimmunotherapy (RIT) of mantle cell lymphoma (MCL) with the chimeric anti-CD20 antibody C2B8

    International Nuclear Information System (INIS)

    Behr, T.M.; Gotthardt, M.; Schipperm, M.L.; Gratz, S.; Behe, M.P.; Brittinger, G.; Woermann, B.; Becker, W.

    2002-01-01

    CD20 has been used as target molecule for low-dose as well as high-dose, myeloablative RIT of B-cell NHL. MCL is an especially aggressive, prognostically unfavorable form of B-cell NHL. The aim of this study was to investigate whether high-dose, myeloablative RIT with the 131 I-labeled chimeric anti-CD20 antibody C2B8 (rituxan, Mabthera, Roche) may be therapeutically more effective than conventional low-dose therapy in MCL. A total of twelve patients with chemorefractory or relapsed mantle cell lymphoma were studied so far (all of them having relapsed after high-dose chemotherapy, seven of them combined with 12 Gy TBI). A diagnostic-dosimetric study was performed with 10 mCi of 131 I-C2B8 at a protein dose of 2.5 mg/kg. In case of splenic pooling, the protein dose was increased until a more 'favorable' biodistribution was obtained. Therapy was performed with conventional (30-75 mCi; n=4) or myeloablative activities (261-515 mCi; n=8) of 131 I-C2B8 at the previously optimized protein dose, aiming at whole-body doses of ≤ 0.8 Gy (for low-dose RIT) or lung doses of ≤ 27 Gy (for high-dose RIT). Clinical follow-up was obtained for up to 42 months. Overall, in 11 patients the 2.5 mg/kg protein dose was used, whereas in one patient with marked splenomegaly, 10 mg/kg were necessary to overcome the splenic antigenic sink. In the high-dose patients, non-hematologic toxicity was restricted to mild to moderate nausea, fever, transient bilirubin or liver enzyme elevations. Despite thyroid blocking, 6/8 high-dose (in contrast to 0/4 low-dose) patients developed hypothyroidism, requiring thyroxine substitution at 6-18 months after RIT. The response rate in the low-dose arm was only 1(PR)/4, whereas 7/8 high-dose patients experienced complete and the remainder a partial remission. 6 high-dose patients are still in CR (one of them relapsed locally at 3 months, one systemically at 26 months after RIT), and 7 are still alive for up to 42+ months. In contrast to low-dose therapy

  12. DOE enforcement program roles and responsibilities: DOE handbook

    International Nuclear Information System (INIS)

    1995-08-01

    The Price-Anderson Act provides indemnification to DOE contractors who manage and conduct nuclear activities in the DOE complex. The government acts as an insurer for these contractors against any findings of liability from the nuclear activities of the contractor within the scope of its contract. 10 CFR Part 820 establishes the legal framework for implementing DOE's Nuclear Safety Enforcement Program. Integration with other DOE organizations and programs would assure that the enforcement process properly considers the actual or potential safety significance of a violation when determining an appropriate enforcement sanction. Achieving a proactive contractor compliance assurance rather than a heavy enforcement hand, will require a foundation of cooperation and teamwork across DOE organizations. This handbook identifies the areas of interface for the DOE Enforcement Program and provides guidance on roles and responsibilities for the key DOE organizational areas. It complements DOE-HDBK-1087-95 and 1089-95

  13. Drivers' perceived legitimacy of enforcement practices for sleep-related crashes: What are the associated factors?

    Science.gov (United States)

    Watling, Christopher N

    2018-02-01

    The purpose of traffic law enforcement is to deter risky driving behaviours. The aim of this study was to examine the individual factors of demographic, personality constructs, and attitudes for their association with perceived legitimacy of traffic law enforcement of sleep-related crashes. In total, 293 drivers completed a survey that assessed perceived legitimacy of enforcement and attitudes towards sleepy driving, as well as individual factors of demographic, personality and risk taking factors. The results demonstrate that younger drivers, drivers with higher levels of extraversion, and those with tolerant attitudes towards sleepy driving were less likely to agree that it is legitimate to charge someone if they crash due to sleepiness. The attitudes towards sleepy driving variable had the largest association with perceived legitimacy. Thus, the factors associated with perceived legitimacy of traffic law enforcement of sleep-related crashes are multifaceted. Overall, the findings have relevance with attitudinal and behaviour change programs, particularly with younger drivers. Copyright © 2017 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.

  14. Enforcement/certification program for appliance efficiency standards. Task II, report

    Energy Technology Data Exchange (ETDEWEB)

    1979-09-28

    The research and analysis program at Vitro Labs. in support of the appliance certification and enforcement program provides Vitro's recommended approach to appliance certification and enforcement (C/E). The approach established the C/E program framework, general criteria, and procedures for assuring a specified level of energy-efficiency performance for 13 categories of consumer products (furnaces, humidifiers, dehumidifiers, dishwashers, television, clothes washers, freezers, air conditioners, stoves, refrigerators, water heaters). Section 2 summarizes the recommended approach. Section 3 contains detailed evaluations and comparisons for four independent alternative approaches considered (minimal government intevention, strong certification control, strong enforcement audit, and mixed certification/enforcement). The fifth C/E approach (strong remedy/deterrent) involves the remedies available to the government should non-compliance be discovered and could affect the choice among the approaches, but this approach has not been evaluated. Section 4 summarizes the analysis methodology used to select the recommended approach. Additional information is provided in 6 appendices.

  15. The pressure-temperature phase diagram of pressure induced organic superconductors β-(BDA-TTP){2}MCl{4} (M = Ga, Fe)

    Science.gov (United States)

    Choi, E. S.; Graf, D.; Brooks, J. S.; Yamada, J.; Tokumoto, M.

    2004-04-01

    We investigate the pressure-temperature phase diagram of β -(BDA-TTP){2}MCl{4} (M=Ga, Fe), which shows a metal-insulator (MI) transition around 120 K at ambient pressure. By applying pressure, the insulating phase is suppressed. When the pressure is higher than 5.5 kbar, the superconducting phase appears in both salts with Tc ˜ 3 K for M=Ga and 2.2 K for M=Fe. We also observed Shubnikov-de Haas (SdH) oscillations at high magnetic field in both salts, where the SdH frequencies are found to be very similar each other. Key words. organic superconductor, pressure, phase diagram.

  16. Solubilities, densities and refractive indices for the ternary systems ethylene glycol + MCl + H2O (M = Na, K, Rb, Cs) at (15 and 35) deg. C

    International Nuclear Information System (INIS)

    Zhou Yanhong; Li Shuni; Zhai Quanguo; Jiang Yucheng; Hu Mancheng

    2010-01-01

    The solubilities, densities and refractive indices data for the four ternary systems ethylene glycol + MCl + H 2 O (M = Na, K, Rb, Cs) at different temperatures were measured, with mass fractions of ethylene glycol in the range of 0 to 1.0. In all cases, the presence of ethylene glycol significantly reduces the solubility of the salts in aqueous solution. The experimental data of density, refractive index and solubility of saturated solutions for these systems were correlated using polynomial equations as a function of the mass fraction of ethylene glycol. On the other hand, the refractive index and density of unsaturated solutions was also determined for the four ternary systems with varied unsaturated salt concentrations. Values for both the properties were correlated with the salt concentrations and proportions of ethylene glycol in the solutions.

  17. Growth and optical, magnetic and transport properties of (C4H9NH3)2MCl4 organic-inorganic hybrid films (M = Cu, Sn)

    Science.gov (United States)

    Aruta, C.; Licci, F.; Zappettini, A.; Bolzoni, F.; Rastelli, F.; Ferro, P.; Besagni, T.

    2005-10-01

    Films of (C4H9NH3)2MCl4 (M=Cu and Sn) organic-inorganic hybrid perovskites have been deposited in-situ by a single-source thermal ablation technique on glassy, crystalline and polymeric substrates. Independently of the substrate, the films were well crystallized, c-axis oriented and with a narrow rocking curve of the (0010) reflection (full width at half maximum photoluminescence spectra of typical (C4H9NH3)2SnCl4 films at 12 K had a broad yellow band, which did not correspond to any significant peak in the absorption spectrum. The films were semiconducting down to 250 K or, in the case of the best samples, down to 200 K and became insulating at lower temperature. The resistivity of the best films was (5±1) 104 Ω cm at 300 K, and the energy gap was 1.11 eV.

  18. Donor Acceptor Bond in [NPCl2]3—MCl3 Adducts, a DFT Study and Comparison of Results with Experimental X-Ray Data

    Directory of Open Access Journals (Sweden)

    Alireza Akbari

    2012-01-01

    Full Text Available Molecular structures of [PCl2N]3-MCl3 adducts, M=B, Al, Ga, In, Tl, have been studied employing HF, B3LYP*, B3LYP , PW91, BLYP, OLYP, BP and LDA methods using DZP basis set (as defined in Amsterdam Density Functional, ADF, package. Some aspects of adduct formation like considering the difference between Front and Back dihedral angles and also ring puckering showed that the [PCl2N]3-AlCl3 is the most stable adduct comparing the others. Based on the comparison between the X-ray and theoretical geometrical parameters of [NPCl2]3(AlCl3 and [NPCl2]3(GaCl3, the LDA method and BP, PW91 and OLYP functionals combined with DZP basis set were found to yield the most satisfactory agreement. Results showed that with surprise, the LDA(DZP method has the maximum matching with experimental data, comparing the others.

  19. Vibrational spectroscopy at very high pressures. Part 28. Raman and far-infrared spectra of some complex chlorides A2MCl6 under hydrostatic pressure

    DEFF Research Database (Denmark)

    Adams, David M.; Berg, Rolf W.; Williams, Alan D.

    1981-01-01

    Raman and far-IR mode frequency shifts with pressure have been observed under hydrostatic conditions in a gasketed diamond anvil cell (d.a.c.). Using compressibilities calculated from unit cell constants and lattice energies, Grüneisen parameters gammai have been obtained for all observed modes...... pressure curves for K2SnCl6 and [(CH3)4N]2MCl6 (M=Sn, Te, Pt) are discussed in relation to their structures. Shifts of nu-tilde i with temperature for K2ReCl6 and K2PtCl6 are analyzed into explicit and implicit anharmonic contributions. The Journal of Chemical Physics is copyrighted by The American...

  20. Synthesis, characterization and spectroscopic studies of the dihydrobis(1,2,3-benzotriazolylborate anion and its complexes with MCl2·py2

    Directory of Open Access Journals (Sweden)

    KHWAJA S. SIDDIQI

    2006-11-01

    Full Text Available The preparation of sodium dihydrobis(1,2,3-benzotriazolylborate was realised by refluxing one mole of sodium borohydride with two moles of 1,2,3-benzotriazole in toluene over a period of 12 h. Its complexes with MCl2·py2 [whereM=Mn(II, Fe(II, Co(II, Ni(II, Cu(II and py=pyridine] were characterized by elemental analysis as well as magnetic, spectroscopic and conductivity measurements. On the basis of these studies, it is proposed that the geometry of all the complexes is octahedral. The ligand field parameters 10 Dq, B and b show extensive overlap between the M–L orbital. The molar conductance of 10-3 M solutions of the complexes in DMSO suggest them to be non-ionic in nature.

  1. New approach towards the polyol route to fabricate MFe2O4 magnetic nanoparticles: The use of MCl2 and Fe(acac)3 as chemical precursors

    International Nuclear Information System (INIS)

    Solano, Eduardo; Yáñez, Ramón; Ricart, Susagna; Ros, Josep

    2015-01-01

    A new more efficient approach of the polyol route to generate MFe 2 O 4 (M=Mn, Fe, Co, Ni, Cu, Zn) nanoparticles in triethylene glycol (TREG) is presented. The selected thermal procedure is based on the Fe metalorganic precursor (iron(III) acetylacetonate) decomposition in presence of an inorganic transition metal chloride salt (MCl 2 , M=Mn, Fe, Co, Ni, Cu, Zn) to produce high quality polar dispersible nanoparticles with lower production cost. In addition, the nanoparticles are stabilized by ionic (from the Cl − ) and steric (TREG as capping ligand) effects inducing into the nanoparticles an extraordinary stability in different polar solvents. As result of this optimized methodology, the colloidal polar dispersible nanoparticles present a size around 10 nm with an adequate size dispersion demonstrated by analyzing transmission electron microscopy (TEM) images. X-ray powder diffraction (XRPD) results corroborate the absence of secondary phases and the high crystalline degree obtained for the spinel structure, fact proved by using synchrotron X-ray diffraction. The high magnetic performance at low and room temperature of the nanoparticles studied by magnetometry proves the high internal crystal order of the spinel. Parallel to this, the influence of the heating ramp and annealing time in the thermal procedure were also investigated for the CuFe 2 O 4 case, where a relationship between these two parameters and the final size and their associated diameter distribution was found, allowing a possible size control of the final ferrite magnetic nanoparticles synthesized. - Highlights: • An optimized one-pot methodology is presented to produce pure MFe 2 O 4 nanoparticles. • MCl 2 and Fe(acac) 3 precursors in TREG are used for a more efficient process. • Polar dispersible nanoparticles are obtained with high physicochemical properties. • The influence of the temperature ramp and rate on the final size is studied

  2. 75 FR 652 - Energy Conservation Program: Certification, Compliance, and Enforcement Requirements for Certain...

    Science.gov (United States)

    2010-01-05

    ...; Comment Request; Certification, Compliance, and Enforcement Requirements for Consumer Products and Certain...: Certification, Compliance, and Enforcement Requirements for Certain Consumer Products and Commercial and... certification, compliance, and enforcement requirements for various consumer products and commercial and...

  3. National Enforcement Initiative: Preventing Animal Waste from Contaminating Surface and Ground Water

    Science.gov (United States)

    This page describes EPA's goal in preventing animal waste from contaminating surface and ground Water. It is an EPA National Enforcement Initiative. Both enforcement cases, and a map of enforcement actions are provided.

  4. NF-κB activation fails to protect cells to TNFα-induced apoptosis in the absence of Bcl-xL, but not Mcl-1, Bcl-2 or Bcl-w.

    Science.gov (United States)

    Casanelles, Elisenda; Gozzelino, Raffaella; Marqués-Fernández, Fernando; Iglesias-Guimarais, Victoria; Garcia-Belinchón, Mercè; Sánchez-Osuna, María; Solé, Carme; Moubarak, Rana S; Comella, Joan X; Yuste, Victor J

    2013-05-01

    TNFα can promote either cell survival or cell death. The activation of NF-κB plays a central role in cell survival while its inhibition makes TNFα-triggered cytotoxicity possible. Here, we report that the overexpression of a non-degradable mutant of the inhibitor of NF-κB (super-repressor (SR)-IκBα) sensitizes HeLa cells towards TNFα-induced apoptosis, involving caspases activation and cytocrome C release from the mitochondria. Interestingly, we describe that the specific knockdown of Bcl-xL, but not that of Bcl-2, Bcl-w or Mcl-1, renders cells sensitive to TNFα-induced apoptosis. This cytotoxic effect occurs without altering the activation of NF-κB. Then, the activation of the NF-κB pathway is not sufficient to protect Bcl-xL-downregulated cells from TNFα-induced cell death, meaning that TNFα is not able to promote cell survival in the absence of Bcl-xL. In addition, Bcl-xL silencing does not potentiate the cytotoxicity afforded by the cytokine in SR-IκBα-overexpressing cells. This indicates that TNFα-induced apoptosis in SR-IκBα-overexpressing cells relies on the protein levels of Bcl-xL. We have corroborated these findings using RD and DU-145 cells, which also become sensitive to TNFα-induced apoptosis after Bcl-xL knockdown despite that NF-κB remains activated. Altogether, our results point out that the impairment of the anti-apoptotic function of Bcl-xL should make cells sensitive towards external insults circumventing the TNFα-triggered NF-κB-mediated cytoprotective effect. Hence, the specific inhibition of Bcl-xL could be envisaged as a promising alternative strategy against NF-κB-dependent highly chemoresistant proliferative malignancies. Copyright © 2013 Elsevier B.V. All rights reserved.

  5. TIC10/ONC201 synergizes with Bcl-2/Bcl-xL inhibition in glioblastoma by suppression of Mcl-1 and its binding partners in vitro and in vivo.

    Science.gov (United States)

    Karpel-Massler, Georg; Bâ, Maïmouna; Shu, Chang; Halatsch, Marc-Eric; Westhoff, Mike-Andrew; Bruce, Jeffrey N; Canoll, Peter; Siegelin, Markus D

    2015-11-03

    Glioblastoma is the most frequent primary brain tumor in adults. Current therapeutic options are sparse and the prognosis of patients suffering from this disease is grim. Abundance in intratumoral heterogeneity among different deregulated signaling pathways is a hallmark of glioblastoma and likely accounts for its recurrence and resistance to treatment. Glioblastomas harbor a plethora of deregulated pathways driving tumor formation and growth. In this study, we show that TIC10/ONC201, a promising compound that is currently in planned clinical development, along with Bcl-2/Bcl-xL inhibition by ABT263 yields a strong synergistic antiproliferative effect on pediatric, adult, proneural glioblastoma and glioma stem-like cells. On the molecular level, treatment with TIC10/ONC201 results in a posttranslational decrease of the anti-apoptotic Bcl-2 family member, myeloid cell leukemia 1 (Mcl-1), through modulation of the chaperone Bag3 and the deubiquitinase Usp9X. Consistently, the combination treatment of TIC10/ONC201 and ABT263 required the presence of functional BAX and BAK to drive intrinsic apoptosis, but is surprisingly independent of the extrinsic apoptotic pathway. Moreover, the expression of Noxa protein was required for efficient apoptosis induction by TIC10/ONC201 and ABT263. Importantly, the drug combination of TIC10/ONC201 and the BH3-mimetic, ABT263, led to a regression of tumors in vivo, without any notable toxicity and side effects. Overall, TIC10/ONC201 along with Bcl-2/Bcl-xL inhibition holds significant promise as a novel potential approach for the treatment of recalcitrant tumors such as glioblastoma.

  6. Effect of drug law enforcement on drug market violence: a systematic review.

    Science.gov (United States)

    Werb, Dan; Rowell, Greg; Guyatt, Gordon; Kerr, Thomas; Montaner, Julio; Wood, Evan

    2011-03-01

    Violence is amongst the primary concerns of communities around the world and research has demonstrated links between violence and the illicit drug trade, particularly in urban settings. Given the growing emphasis on evidence-based policy-making, and the ongoing severe drug market violence in Mexico and other settings, we conducted a systematic review to examine the impacts of drug law enforcement on drug market violence. We conducted a systematic review using Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) guidelines. Specifically, we undertook a search of English language electronic databases (Academic Search Complete, PubMed, PsycINFO, EMBASE, Web of Science, Sociological Abstracts, Social Service Abstracts, PAIS International and Lexis-Nexis), the Internet (Google, Google Scholar), and article reference lists, from database inception to January 24, 2011. Overall, 15 studies were identified that evaluated the impact of drug law enforcement on drug market violence, including 11 (73%) longitudinal analyses using linear regression, 2 (13%) mathematical drug market models, and 2 (13%) qualitative studies. Fourteen (93%) studies reported an adverse impact of drug law enforcement on levels of violence. Ten of the 11 (91%) studies employing longitudinal qualitative analyses found a significant association between drug law enforcement and drug market violence. Our findings suggest that increasing drug law enforcement is unlikely to reduce drug market violence. Instead, the existing evidence base suggests that gun violence and high homicide rates may be an inevitable consequence of drug prohibition and that disrupting drug markets can paradoxically increase violence. In this context, and since drug prohibition has not meaningfully reduced drug supply, alternative regulatory models will be required if drug supply and drug market violence are to be meaningfully reduced. Copyright © 2011 Elsevier B.V. All rights reserved.

  7. Lip-reading enhancement for law enforcement

    Science.gov (United States)

    Theobald, Barry J.; Harvey, Richard; Cox, Stephen J.; Lewis, Colin; Owen, Gari P.

    2006-09-01

    Accurate lip-reading techniques would be of enormous benefit for agencies involved in counter-terrorism and other law-enforcement areas. Unfortunately, there are very few skilled lip-readers, and it is apparently a difficult skill to transmit, so the area is under-resourced. In this paper we investigate the possibility of making the lip-reading task more amenable to a wider range of operators by enhancing lip movements in video sequences using active appearance models. These are generative, parametric models commonly used to track faces in images and video sequences. The parametric nature of the model allows a face in an image to be encoded in terms of a few tens of parameters, while the generative nature allows faces to be re-synthesised using the parameters. The aim of this study is to determine if exaggerating lip-motions in video sequences by amplifying the parameters of the model improves lip-reading ability. We also present results of lip-reading tests undertaken by experienced (but non-expert) adult subjects who claim to use lip-reading in their speech recognition process. The results, which are comparisons of word error-rates on unprocessed and processed video, are mixed. We find that there appears to be the potential to improve the word error rate but, for the method to improve the intelligibility there is need for more sophisticated tracking and visual modelling. Our technique can also act as an expression or visual gesture amplifier and so has applications to animation and the presentation of information via avatars or synthetic humans.

  8. Competitiveness levels in cattle herd farms

    Directory of Open Access Journals (Sweden)

    Pedro Rocha Marques

    2015-03-01

    Full Text Available The aim of this experiment was to identify improvement demands for farms with different levels of competitiveness in the west of Rio Grande do Sul state, Brazil. A total of 63 owners of large farms were interviewed (farms with an area greater than 900ha by applying a semi-structured questionnaire, guided by four drivers: technology (TEC, management (MAN, market relations (MR and the institutional environment (IE.It was used the Statistical Analysis System 9.2 software to perform the cluster analysis and identify farmers' characteristics. Three random clusters with different levels of competitiveness were observed: low competitiveness level (LCL, middle competitiveness level (MCL and high competitiveness level (HCL. The 29 variables (sub factors were evaluated in the cluster analysis according to level of impact on competitiveness, being classified into variables of high, medium or low impact. Stratification was carried out, ranking demands for improvements from aspects attributed by experts in relation to sub factors. The farmers with low competitiveness level (LTL had an unfavorable status for MAN, while the farmers belonging to clusters MCL and HCL have, respectively, favorable and neutral status for the same driver. The management characteristics determined the level of competitiveness of the farms surveyed

  9. Analysis of Environmental Law Enforcement Mechanism Based on Economic Principle

    Science.gov (United States)

    Cao, Hongjun; Shao, Haohao; Cai, Xuesen

    2017-11-01

    Strengthening and improving the environmental law enforcement mechanism is an important way to protect the ecological environment. This paper is based on economical principles, we did analysis of the marginal management costs by using Pigou means and the marginal transaction costs by using Coase means vary with the quantity growth of pollutant discharge Enterprises. We analyzed all this information, then we got the conclusion as follows. In the process of strengthening the environmental law enforcement mechanism, firstly, we should fully mobilize all aspects of environmental law enforcement, such as legislative bodies and law enforcement agencies, public welfare organizations, television, newspapers, enterprises, people and so on, they need to form a reasonable and organic structure system; then we should use various management means, such as government regulation, legal sanctions, fines, persuasion and denounce, they also need to form an organic structural system.

  10. Operational Design for Peace Enforcement: Lessons for the Operational Staff

    National Research Council Canada - National Science Library

    Neumann, Michael

    2004-01-01

    U.S. involvement in Somalia serves as a useful case study of the unique challenges an operational staff may face when applying operational design to the planning and execution of a peace enforcement operation. U.S...

  11. Child Support Enforcement Annual Data Report Form 34A - 2007

    Data.gov (United States)

    U.S. Department of Health & Human Services — This dataset contains annual data on collections received and distributed by State agencies administering the Child Support Enforcement program under title IV-D of...

  12. Enforcement and Effectiveness of Consumer Law in the Czech Republic

    Czech Academy of Sciences Publication Activity Database

    Pauknerová, Monika; Skalská, H.

    2017-01-01

    Roč. 7, č. 4 (2017), s. 243-254 ISSN 1805-8396 Institutional support: RVO:68378122 Keywords : consumer law * enforcement * alternative dispute resolution Subject RIV: AG - Legal Sciences OBOR OECD: Law

  13. Spatial service delivery system for smart licensing & enforcement management

    Science.gov (United States)

    Wahap, N. A.; Ismail, N. M.; Nor, N. M.; Ahmad, N.; Omar, M. F.; Termizi, A. A. A.; Zainal, D.; Noordin, N. M.; Mansor, S.

    2016-06-01

    Spatial information has introduced a new sense of urgency for a better understanding of the public needs in term of what, when and where they need services and through which devices, platform or physical locations they need them. The objective of this project is to value- add existing license management process for business premises which comes under the responsibility of Local Authority (PBT). Manipulation of geospatial and tracing technology via mobile platform allows enforcement officers to work in real-time, use a standardized system, improve service delivery, and optimize operation management. This paper will augment the scope and capabilities of proposed concept namely, Smart Licensing/Enforcement Management (SLEm). It will review the current licensing and enforcement practice of selected PBT in comparison to the enhanced method. As a result, the new enhanced system is expected to offer a total solution for licensing/enforcement management whilst increasing efficiency and transparency for smart city management and governance.

  14. 49 CFR 244.21 - Compliance and Enforcement.

    Science.gov (United States)

    2010-10-01

    ... Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION, DEPARTMENT OF TRANSPORTATION REGULATIONS ON SAFETY INTEGRATION PLANS GOVERNING RAILROAD CONSOLIDATIONS, MERGERS, AND ACQUISITIONS OF CONTROL Safety Integration Plans § 244.21 Compliance and Enforcement. (a...

  15. Child Support Enforcement Annual Data Report Form 34A - 2006

    Data.gov (United States)

    U.S. Department of Health & Human Services — This dataset contains annual data on collections received and distributed by State agencies administering the Child Support Enforcement program under title IV-D of...

  16. recognition and enforcement of foreign arbitral awards in civil

    African Journals Online (AJOL)

    eliasn

    (CPC), rules on the recognition and enforcement of foreign judgments ..... copy of the judgment to be executed; and a certificate signed by the President or ...... Convention has been praised as: “the single most important pillar on which the.

  17. 78 FR 21826 - Defense Support of Civilian Law Enforcement Agencies

    Science.gov (United States)

    2013-04-12

    ... enforcement officials with respect to audits and investigations conducted, supervised, monitored, or initiated... that are undertaken primarily for a military or foreign affairs purpose. (B) Audits and investigations... acting as undercover agents, informants, investigators, or interrogators. (7) Forensic investigations or...

  18. Sharing Law Enforcement and Intelligence Information: The Congressional Role

    National Research Council Canada - National Science Library

    Best Jr., Richard A

    2007-01-01

    Almost all assessments of the attacks of September 11, 2001, have concluded that U.S. intelligence and law enforcement agencies had failed to share information that might have provided advance warning of the plot...

  19. Public education and enforcement research study : Macomb, Illinois : analysis

    Science.gov (United States)

    2011-03-01

    The Public Education and Enforcement Research Study (PEERS) was a collaborative effort between the Federal Railroad Administration, the Illinois Commerce Commission, and local communities in the State of Illinois. This project was designed to promote...

  20. Pesticides and Asbestos Programs and Enforcement Branch Case Tracking System

    Science.gov (United States)

    Tracks the entire life cycle of a regulated site from initial inspection through site response to enforcement actions. Separate site action history is maintained for each statute under which the site is regulated.

  1. Deporting the American Dream: Immigration Enforcement and Latino Foreclosures

    Directory of Open Access Journals (Sweden)

    Jacob S. Rugh

    2016-12-01

    Full Text Available Over the past decade, Latinos have been buffeted by two major forces: a record number of immigrant deportations and the housing foreclosure crisis. Yet, prior work has not assessed the link between the two. We hypothesize that deportations exacerbate rates of foreclosure among Latinos by removing income earners from owner-occupied households. We employ a quasi-experimental approach that leverages variation in county applications for 287(g immigration enforcement agreements with Immigration and Customs Enforcement and data on foreclosure filings from 2005–2012. These models uncover a substantial association of enforcement with Hispanic foreclosure rates. The association is stronger in counties with more immigrant detentions and a larger share of undocumented persons in owner-occupied homes. The results imply that local immigration enforcement plays an important role in understanding why Latinos experienced foreclosures most often. The reduced home ownership and wealth that result illustrate how legal status and deportation perpetuate the racial stratification of Latinos.

  2. Criminality or monopoly? Informal immigration enforcement in South Africa

    NARCIS (Netherlands)

    Vigneswaran, D.; Araia, T.; Hoag, C.; Tshabalala, X.

    2010-01-01

    Zimbabwean displacement has significant implications for the evolution of state forms in Southern Africa. In South Africa, Zimbabwean migrants' claims to residence confront exclusionary immigration laws. The South African government officials who are responsible for enforcing these laws have helped

  3. Privacy Impact Assessment for the Enforcement Action Response System

    Science.gov (United States)

    The Enforcement Action Response System collects waste transaction information, and liability determination information. Learn how this data is collected, how it will be used, access to the data, the purpose of data collection, and record retention policies

  4. Privacy Impact Assessment for the Enforcement Superfund Tracking System

    Science.gov (United States)

    This Enforcement Superfund Tracking System (ESTS) collects publicly available information from the California Secretary of State on businesses. Learn how this data is collected, how it will be used, access to the data, and the purpose of data collection.

  5. Price-Anderson Nuclear Safety Enforcement Program. 1997 annual report

    International Nuclear Information System (INIS)

    1998-01-01

    This report summarizes activities in the Department of Energy's Price-Anderson Amendments Act (PAAA) Enforcement Program in calendar year 1997 and highlights improvements planned for 1998. The DOE Enforcement Program involves the Office of Enforcement and Investigation in the DOE Headquarters Office of Environment, Safety and Health, as well as numerous PAAA Coordinators and technical advisors in DOE Field and Program Offices. The DOE Enforcement Program issued 13 Notices of Violation (NOV's) in 1997 for cases involving significant or potentially significant nuclear safety violations. Six of these included civil penalties totaling $440,000. Highlights of these actions include: (1) Brookhaven National Laboratory Radiological Control Violations / Associated Universities, Inc.; (2) Bioassay Program Violations at Mound / EG ampersand G, Inc.; (3) Savannah River Crane Operator Uptake / Westinghouse Savannah River Company; (4) Waste Calciner Worker Uptake / Lockheed-Martin Idaho Technologies Company; and (5) Reactor Scram and Records Destruction at Sandia / Sandia Corporation (Lockheed-Martin). Sandia / Sandia Corporation (Lockheed-Martin)

  6. 24 CFR 115.305 - Special enforcement effort (SEE) funds.

    Science.gov (United States)

    2010-04-01

    ... enforced a subpoena or made use of its prompt judicial action authority within the past year; (2) The... the most recent three years, or is currently engaged in, at least one major fair housing systemic...

  7. Enforcement of Intellectual Property, Pollution Abatement, and Directed Technical Change

    OpenAIRE

    Schaefer, Andreas

    2017-01-01

    We theoretically investigate the interaction between endogenous enforcement of intellectual property rights (IPRs) and tax-financed pollution abatement measures. IPRs affect dirty and clean intermediates alike such that higher IPR enforcement may promote the transition to the clean technology, if this technology is productive enough. If the green technology is relatively unproductive, higher IPRs promote the dirty technology while pollution is increasing. As households are due to subsistence ...

  8. Overview of the recognition and enforcement of international commercial arbitration

    Directory of Open Access Journals (Sweden)

    Sergey Kravtsov

    2017-01-01

    Full Text Available The subject. This informational article is devoted to the peculiarities of recognition and enforcement of international commercial arbitration awards according to different countries’ legislation and international legal regulation.The purpose of the article is to identify legal patterns of recognition and enforcement of international commercial arbitration awards in different countries.Methodology. The study is based on comparative law and formal law methods, analysis and synthesis.Results, scope of application. Enforcement of arbitral awards in foreign countries is ensured and guaranteed by multilateral conventions, bilateral treaties and national legislation. The New York Convention 1958 in a certain way limits the scope of legal protection of arbitral awards and leaves the procedure for recognition and enforcement of arbitral awards for consideration of the state court. The author analyses of differentiation of the recognition and enforcement regime of so-called "domestic" and "foreign" solutions of international commercial arbitration in terms of doctrinal approaches and practice of foreign countries. Special attention is given to the analysis of foreign arbitral awards of recognition and enforcement procedures is given to a denial of recognition and enforcement of foreign arbitral awards and their reasons. In spite of the explicit grounds for refusal of recognition and enforcement of foreign arbitral awards in New York Convention 1958, some countries try to establish certain exceptions to the rule in the national legislation. Results may be applicable in improvement of international legal regulation.Conclusions. The courts of the countries – participants of the New York Convention 1958 cannot cancel the foreign arbitral award or revise it substantially. The refutation of this award is possible only in the court of the state in whose territory the relevant arbitral award was made, and such court is not formally bound by the rules of the

  9. 25 CFR 11.1103 - Law enforcement officer's duties.

    Science.gov (United States)

    2010-04-01

    ... 25 Indians 1 2010-04-01 2010-04-01 false Law enforcement officer's duties. 11.1103 Section 11.1103 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR LAW AND ORDER COURTS OF INDIAN OFFENSES AND LAW AND ORDER CODE Minor-in-Need-of-Care Procedure § 11.1103 Law enforcement officer's duties. Upon taking a minor into custody the officer...

  10. An empirical investigation of compliance and enforcement problems

    DEFF Research Database (Denmark)

    Kronbak, Lone Grønbæk; Jensen, Frank

    2011-01-01

    contributes to the literature by investigating compliance and enforcement in the empirical case of a mixed trawl fishery targeting Norway lobster in Kattegat and Skagerrak located north of Denmark with help from a simulated model. The paper presents results from two simulation models of the case study: one....... Another conclusion from the case study is that only small welfare effects are obtained by increasing enforcement efforts to reduce non-compliance....

  11. U.S. Environmental Protection Agency Office of Enforcement and Compliance Assurance New Mapping Tool for Enforcement Cases

    Data.gov (United States)

    U.S. Environmental Protection Agency — The new mapping tool shows facilities in the United States where the EPA concluded formal environmental enforcement actions between October 1, 2008 and September 30,...

  12. Assessing the Effectiveness of Competition Law Enforcement Policy in Relation to Cartels

    Directory of Open Access Journals (Sweden)

    Priit Mändmaa

    2014-11-01

    Full Text Available Despite the high fines for cartel infringements it is claimed that the current competition law enforcement lacks deterrent effect for the avoidance of cartel infringements and is procedurally fragile. This article analyses the current competition law enforcement policy in relation to cartels. More specifically, the article assesses the effectiveness of the policy in deterring the formation of cartels and pursuing the goals of competition law by analysing the theory of deterrence, case law, procedural norms, imposed fines and academic literature. The main conclusions are that wrong targets are aimed at under the deterrence principle, the proceedings are of a criminal law nature and require a separation of powers, and that the current level of fines does not pose a threat on the economy and continually fail to deter price-fixing.

  13. Optimisation of the enforcement of energy regulations and the use of SIA building standards; Optimierung Energievollzug und Anwendung der SIA-Normen Gebaeude

    Energy Technology Data Exchange (ETDEWEB)

    Dettli, R.; Baur, M.; Signer, B. [Econcept AG, Zuerich (Switzerland); Renaud, P.; Wermeille, Ch. [Planair, Bureau d' ingenieurs SIA, La Sagne (Switzerland)

    2003-07-01

    This report for the Swiss Federal Office of Energy (SFOE) presents the results of a study made on the effectiveness of the enforcement of energy legislation and the value of standards in planning and building activities. The reasons for deficiencies in the enforcement of regulations are examined and suggestions are made for improving the situation. Enforcement problems are discussed, including, for example, the partly insufficient capacities at the building authority level. Detailed measures are proposed at the federal and cantonal level and better training and know-how for building professionals is recommended. Those responsible for enforcement - usually the local authorities - are advised to improve the communication of their supervisory activities. Certain improvements to legislation are proposed and professional institutions are motivated to improve quality management and the know-how of their members. The report is completed with a comprehensive list of literature on the subject.

  14. Automatic analysis of online image data for law enforcement agencies by concept detection and instance search

    Science.gov (United States)

    de Boer, Maaike H. T.; Bouma, Henri; Kruithof, Maarten C.; ter Haar, Frank B.; Fischer, Noëlle M.; Hagendoorn, Laurens K.; Joosten, Bart; Raaijmakers, Stephan

    2017-10-01

    The information available on-line and off-line, from open as well as from private sources, is growing at an exponential rate and places an increasing demand on the limited resources of Law Enforcement Agencies (LEAs). The absence of appropriate tools and techniques to collect, process, and analyze the volumes of complex and heterogeneous data has created a severe information overload. If a solution is not found, the impact on law enforcement will be dramatic, e.g. because important evidence is missed or the investigation time is too long. Furthermore, there is an uneven level of capabilities to deal with the large volumes of complex and heterogeneous data that come from multiple open and private sources at national level across the EU, which hinders cooperation and information sharing. Consequently, there is a pertinent need to develop tools, systems and processes which expedite online investigations. In this paper, we describe a suite of analysis tools to identify and localize generic concepts, instances of objects and logos in images, which constitutes a significant portion of everyday law enforcement data. We describe how incremental learning based on only a few examples and large-scale indexing are addressed in both concept detection and instance search. Our search technology allows querying of the database by visual examples and by keywords. Our tools are packaged in a Docker container to guarantee easy deployment on a system and our tools exploit possibilities provided by open source toolboxes, contributing to the technical autonomy of LEAs.

  15. Tobacco outlet density, retailer cigarette sales without ID checks and enforcement of underage tobacco laws: associations with youths' cigarette smoking and beliefs.

    Science.gov (United States)

    Lipperman-Kreda, Sharon; Grube, Joel W; Friend, Karen B; Mair, Christina

    2016-03-01

    To estimate the relationships of tobacco outlet density, cigarette sales without ID checks and local enforcement of underage tobacco laws with youth's life-time cigarette smoking, perceived availability of tobacco and perceived enforcement of underage tobacco laws and changes over time. The study involved: (a) three annual telephone surveys, (b) two annual purchase surveys in 2000 tobacco outlets and (c) interviews with key informants from local law enforcement agencies. Analyses were multi-level models (city, individual, time). A sample of 50 mid-sized non-contiguous cities in California, USA. A total of 1478 youths (aged 13-16 at wave 1, 52.2% male); 1061 participated in all waves. Measures at the individual level included life-time cigarette smoking, perceived availability and perceived enforcement. City-level measures included tobacco outlet density, cigarette sales without ID checks and compliance checks. Outlet density was associated positively with life-time smoking [OR = 1.12, P Sales rate without checking IDs was related to greater perceived availability (β = 0.01, P sales without ID checks and enforcement levels may influence beliefs about access to cigarettes and enforcement of underage tobacco sales laws. © 2015 Society for the Study of Addiction.

  16. 49 CFR 26.105 - What enforcement actions apply in FAA programs?

    Science.gov (United States)

    2010-10-01

    ... 49 Transportation 1 2010-10-01 2010-10-01 false What enforcement actions apply in FAA programs? 26... Enforcement § 26.105 What enforcement actions apply in FAA programs? (a) Compliance with all requirements of this part by airport sponsors and other recipients of FAA financial assistance is enforced through the...

  17. 27 CFR 478.134 - Sale of firearms to law enforcement officers.

    Science.gov (United States)

    2010-04-01

    ... AMMUNITION Records § 478.134 Sale of firearms to law enforcement officers. (a) Law enforcement officers... complete Form 4473 or Form 5300.35. The law enforcement officer purchasing the firearm may purchase a...) In Federal law enforcement offices, the supervisor in charge of the office to which the Federal...

  18. 49 CFR 26.103 - What enforcement actions apply in FHWA and FTA programs?

    Science.gov (United States)

    2010-10-01

    ... 49 Transportation 1 2010-10-01 2010-10-01 false What enforcement actions apply in FHWA and FTA... Enforcement § 26.103 What enforcement actions apply in FHWA and FTA programs? The provisions of this section apply to enforcement actions under FHWA and FTA programs: (a) Noncompliance complaints. Any person who...

  19. Law enforcement attitudes toward overdose prevention and response

    Science.gov (United States)

    Green, Traci C.; Zaller, Nickolas; Palacios, Wilson R.; Bowman, Sarah E.; Ray, Madeline; Heimer, Robert; Case, Patricia

    2014-01-01

    Background Law enforcement is often the first to respond to medical emergencies in the community, including overdose. Due to the nature of their job, officers have also witnessed first-hand the changing demographic of drug users and devastating effects on their community associated with the epidemic of nonmedical prescription opioid use in the United States. Despite this seminal role, little data exist on law enforcement attitudes toward overdose prevention and response. Methods We conducted key informant interviews as part of a 12-week Rapid Assessment and Response (RAR) process that aimed to better understand and prevent nonmedical prescription opioid use and overdose deaths in locations in Connecticut and Rhode Island experiencing overdose “outbreaks.” Interviews with 13 law enforcement officials across three study sites were analyzed to uncover themes on overdose prevention and naloxone. Results Findings indicated support for law enforcement involvement in overdose prevention. Hesitancy around naloxone administration by laypersons was evident. Interview themes highlighted officers’ feelings of futility and frustration with their current overdose response options, the lack of accessible local drug treatment, the cycle of addiction, and the pervasiveness of easily accessible prescription opioid medications in their communities. Overdose prevention and response, which for some officers included law enforcement-administered naloxone, were viewed as components of community policing and good police-community relations. Conclusion Emerging trends, such as existing law enforcement medical interventions and Good Samaritan Laws, suggest the need for broader law enforcement engagement around this pressing public health crisis, even in suburban and small town locations, to promote public safety. PMID:24051061

  20. Nonfatal Injuries to Law Enforcement Officers: A Rise in Assaults.

    Science.gov (United States)

    Tiesman, Hope M; Gwilliam, Melody; Konda, Srinivas; Rojek, Jeff; Marsh, Suzanne

    2018-04-01

    Limited studies exist that describe nonfatal work-related injuries to law enforcement officers. The aim of this study is to provide national estimates and trends of nonfatal injuries to law enforcement officers from 2003 through 2014. Nonfatal injuries were obtained from the National Electronic Injury Surveillance System-Occupational Supplement. Data were obtained for injuries treated in U.S. emergency departments from 2003 to 2014. Nonfatal injury rates were calculated using denominators from the Current Population Survey. Negative binomial regression was used to analyze temporal trends. Data were analyzed in 2016-2017. Between 2003 and 2014, an estimated 669,100 law enforcement officers were treated in U.S. emergency departments for nonfatal injuries. The overall rate of 635 per 10,000 full-time equivalents was three times higher than all other U.S. workers rate (213 per 10,000 full-time equivalents). The three leading injury events were assaults and violent acts (35%), bodily reactions and exertion (15%), and transportation incidents (14%). Injury rates were highest for the youngest officers, aged 21-24 years. Male and female law enforcement officers had similar nonfatal injury rates. Rates for most injuries remained stable; however, rates for assault-related injuries grew among law enforcement officers between 2003 and 2011. National Electronic Injury Surveillance System-Occupational Supplement data demonstrate a significant upward trend in assault injuries among U.S. law enforcement officers and this warrants further investigation. Police-citizen interactions are dynamic social encounters and evidence-based policing is vital to the health and safety of both police and civilians. The law enforcement community should energize efforts toward the study of how policing tactics impact both officer and citizen injuries. Published by Elsevier Inc.

  1. Law enforcement attitudes toward overdose prevention and response.

    Science.gov (United States)

    Green, Traci C; Zaller, Nickolas; Palacios, Wilson R; Bowman, Sarah E; Ray, Madeline; Heimer, Robert; Case, Patricia

    2013-12-01

    Law enforcement is often the first to respond to medical emergencies in the community, including overdose. Due to the nature of their job, officers have also witnessed first-hand the changing demographic of drug users and devastating effects on their community associated with the epidemic of nonmedical prescription opioid use in the United States. Despite this seminal role, little data exist on law enforcement attitudes toward overdose prevention and response. We conducted key informant interviews as part of a 12-week Rapid Assessment and Response (RAR) process that aimed to better understand and prevent nonmedical prescription opioid use and overdose deaths in locations in Connecticut and Rhode Island experiencing overdose "outbreaks." Interviews with 13 law enforcement officials across three study sites were analyzed to uncover themes on overdose prevention and naloxone. Findings indicated support for law enforcement involvement in overdose prevention. Hesitancy around naloxone administration by laypersons was evident. Interview themes highlighted officers' feelings of futility and frustration with their current overdose response options, the lack of accessible local drug treatment, the cycle of addiction, and the pervasiveness of easily accessible prescription opioid medications in their communities. Overdose prevention and response, which for some officers included law enforcement-administered naloxone, were viewed as components of community policing and good police-community relations. Emerging trends, such as existing law enforcement medical interventions and Good Samaritan Laws, suggest the need for broader law enforcement engagement around this pressing public health crisis, even in suburban and small town locations, to promote public safety. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  2. The diversity of the EU approach to law enforcement: Towards a coherent model inspired by a law and economics approach

    NARCIS (Netherlands)

    M.G. Faure (Michael); F. Weber (Franziska)

    2017-01-01

    textabstractTraditionally in the division of labor between the European level and the Member States it was, roughly, the European legislature that set the norms and the Member States that took care of enforcing these norms. In various policy areas, an implementation deficit has been observed, which

  3. Cross sections of the 36Ar(d,α)34mCl, 40Ar(d,α)38Cl, and 40Ar(d,p)41Ar nuclear reactions below 8.4 MeV.

    Science.gov (United States)

    Engle, J W; Severin, G W; Barnhart, T E; Knutson, L D; Nickles, R J

    2012-02-01

    We have measured the cross section for production of the medically interesting isotope (34m)Cl, along with (38)Cl and (41)Ar, using deuteron bombardments of (36)Ar and (40)Ar below 8.4 MeV. ALICE/ASH analytical codes were employed to determine the shape of nuclear excitation functions, and experiments were performed using the University of Wisconsin tandem electrostatic accelerator to irradiate thin targets of argon gas. Copyright © 2011 Elsevier Ltd. All rights reserved.

  4. Sorafenib blocks tumour growth, angiogenesis and metastatic potential in preclinical models of osteosarcoma through a mechanism potentially involving the inhibition of ERK1/2, MCL-1 and ezrin pathways

    Directory of Open Access Journals (Sweden)

    Ferrari Stefano

    2009-12-01

    Full Text Available Abstract Background Osteosarcoma (OS is the most common primary bone tumour in children and young adults. Despite improved prognosis, metastatic or relapsed OS remains largely incurable and no significant improvement has been observed in the last 20 years. Therefore, the search for alternative agents in OS is mandatory. Results We investigated phospho-ERK 1/2, MCL-1, and phospho-Ezrin/Radixin/Moesin (P-ERM as potential therapeutic targets in OS. Activation of these pathways was shown by immunohistochemistry in about 70% of cases and in all OS cell lines analyzed. Mutational analysis revealed no activating mutations in KRAS whereas BRAF gene was found to be mutated in 4/30 OS samples from patients. Based on these results we tested the multi-kinase inhibitor sorafenib (BAY 43-9006 in preclinical models of OS. Sorafenib inhibited OS cell line proliferation, induced apoptosis and downregulated P-ERK1/2, MCL-1, and P-ERM in a dose-dependent manner. The dephosphorylation of ERM was not due to ERK inhibition. The downregulation of MCL-1 led to an increase in apoptosis in OS cell lines. In chick embryo chorioallantoic membranes, OS supernatants induced angiogenesis, which was blocked by sorafenib and it was also shown that sorafenib reduced VEGF and MMP2 production. In addition, sorafenib treatment dramatically reduced tumour volume of OS xenografts and lung metastasis in SCID mice. Conclusion In conclusion, ERK1/2, MCL-1 and ERM pathways are shown to be active in OS. Sorafenib is able to inhibit their signal transduction, both in vitro and in vivo, displaying anti-tumoural activity, anti-angiogenic effects, and reducing metastatic colony formation in lungs. These data support the testing of sorafenib as a potential therapeutic option in metastatic or relapsed OS patients unresponsive to standard treatments.

  5. Cross Sections of the 36Ar(d,α)34mCl, 40Ar(d,α)38Cl and 40Ar(d,p)41Ar Nuclear Reactions below 8.4 MeV

    Science.gov (United States)

    Engle, J W; Severin, G W; Barnhart, T E; Knutson, L D; Nickles, R J

    2011-01-01

    We have measured the cross section for production of the medically interesting isotope 34mCl, along with 38Cl and 41Ar, using deuteron bombardments of 36Ar and 40Ar below 8.4 MeV. ALICE/ASH analytical codes were employed to determine the shape of nuclear excitation functions, and experiments were performed using the University of Wisconsin tandem electrostatic accelerator to irradiate thin targets of argon gas. PMID:22041299

  6. Law enforcement attitudes towards naloxone following opioid overdose training.

    Science.gov (United States)

    Purviance, Donna; Ray, Bradley; Tracy, Abigail; Southard, Erik

    2017-01-01

    Opioid intoxication and overdoses are life-threatening emergencies requiring rapid treatment. One response to this has been to train law enforcement to detect the signs of an opioid overdose and train them to administer naloxone to reverse the effects. Although not a new concept, few studies have attempted to examine this policy. At 4 different locations in Indiana, law enforcement personnel were trained to detect the signs of an opioid-related overdose and how to administer naloxone to reverse the effects of the overdose. Pre and post surveys were administered at each location (N = 97). To examine changes in attitudes following training, the authors included items from the Opioid Overdose Attitudes Scale (OOAS), which measures respondents' competency, concerns, and readiness to administer naloxone. Among the full sample, naloxone training resulted in significant increases in competency, concerns, and readiness. Examining changes in attitudes by each location revealed that the training had the greatest effect on competency to administer naloxone and in easing concerns that law enforcement personal might have in administering naloxone. This study adds to others in showing that law enforcement personnel are receptive to naloxone training and that the OOAS is able to capture these attitudes. This study advances this literature by examining pre-post changes across multiple locations. As the distribution of naloxone continues to proliferate, this study and the OOAS may be valuable towards the development of an evidence-based training model for law enforcement.

  7. Individual psychological features of law enforcement officers convicted of crimes

    Directory of Open Access Journals (Sweden)

    Lyutykh V.A.

    2016-06-01

    Full Text Available The relevance of this topic is caused by a significant number of crimes committed by law enforcement officers and the necessity of active prevention. The aim of the study was to determine the individual psychological characteristics of law enforcement officers convicted of intentional crimes. The hypothesis was suggested that the main difference of individual psychological characteristics of law enforcement officers convicted of intentional crimes from individual psychological characteristics of law-abiding law enforcement officers is the difference between the principal values of the person both the main motives of activity adopted by an individual and the structure and the hierarchy of these values. This article describes the progress and results of empirical research conducted on the materials of psychodiagnostic examination of: employees who have been convicted of intentional crimes; law-abiding employees; people entering an internal affairs agency. Test subjects - men 18-46 years old, 90 people. Recommendations for practical psychologist of internal affairs agencies on detection of individual psychological personality features typical for law enforcement officers convicted of intentional crimes are formulated based on the obtained results.

  8. Remote data entry and retrieval for law enforcement

    Science.gov (United States)

    Kwasowsky, Bohdan R.; Capraro, Gerard T.; Berdan, Gerald B.; Capraro, Christopher T.

    1997-02-01

    Law enforcement personnel need to capture and retrieve quality multimedia data in `real time' while in the field. This is not done today, for the most part. Most law enforcement officers gather data on handwritten forms and retrieve data via voice communications or fax. This approach is time consuming, costly, prone to errors, and may require months before some data are entered into a usable law enforcement database. With advances in the computing and communications industries, it is now possible to communicate with anyone using a laptop computer or personal digital assistant (PDA), given a phone line, an RF modem, or cellular capability. Many law enforcement officers have access to laptop computers within their vehicles and can stay in touch with their command center and/or retrieve data from local, state, or federal databases. However, this same capability is not available once they leave the vehicle or if the officer is on a beat, motorcycle, or horseback. This paper investigates the issues and reviews the state of the art for integrating a PDA into the gathering and retrieving of multimedia data for law enforcement.

  9. New approach towards the polyol route to fabricate MFe2O4 magnetic nanoparticles: The use of MCl2 and Fe(acac)3 as chemical precursors

    Science.gov (United States)

    Solano, Eduardo; Yáñez, Ramón; Ricart, Susagna; Ros, Josep

    2015-05-01

    A new more efficient approach of the polyol route to generate MFe2O4 (M=Mn, Fe, Co, Ni, Cu, Zn) nanoparticles in triethylene glycol (TREG) is presented. The selected thermal procedure is based on the Fe metalorganic precursor (iron(III) acetylacetonate) decomposition in presence of an inorganic transition metal chloride salt (MCl2, M=Mn, Fe, Co, Ni, Cu, Zn) to produce high quality polar dispersible nanoparticles with lower production cost. In addition, the nanoparticles are stabilized by ionic (from the Cl-) and steric (TREG as capping ligand) effects inducing into the nanoparticles an extraordinary stability in different polar solvents. As result of this optimized methodology, the colloidal polar dispersible nanoparticles present a size around 10 nm with an adequate size dispersion demonstrated by analyzing transmission electron microscopy (TEM) images. X-ray powder diffraction (XRPD) results corroborate the absence of secondary phases and the high crystalline degree obtained for the spinel structure, fact proved by using synchrotron X-ray diffraction. The high magnetic performance at low and room temperature of the nanoparticles studied by magnetometry proves the high internal crystal order of the spinel. Parallel to this, the influence of the heating ramp and annealing time in the thermal procedure were also investigated for the CuFe2O4 case, where a relationship between these two parameters and the final size and their associated diameter distribution was found, allowing a possible size control of the final ferrite magnetic nanoparticles synthesized.

  10. The corruption process of a law enforcement officer: a paradigm of occupational stress and deviancy.

    Science.gov (United States)

    McCafferty, F L; Souryal, S; McCafferty, M A

    1998-01-01

    The public does not want all laws enforced. In the closed society of law enforcement institutions, police discretion, the conspiracy of silence, the lack of an administration with integrity, and susceptible law enforcement officers contribute to the development of corruption from occupational deviance. Corruption in law enforcement agencies may have similar roots in business, law, medicine, and other professions. Understanding the law enforcement corruption paradigm may therefore be helpful in correcting and curbing corruption in other professions.

  11. Survey and Certification - Enforcement - 2567 Report

    Data.gov (United States)

    U.S. Department of Health & Human Services — This website provides high level results of the surveys conducted by the State Agencies captured by the ASPEN system. It provides deficiency information for Nursing...

  12. The Law Enforcement of Journalism Profession in The Context of Press Freedom

    Directory of Open Access Journals (Sweden)

    Sri Ayu Astuti

    2014-06-01

    Full Text Available Law No. 40 of 1999 on Press is a manifestation of respect for the legal protection of press workers . Press in their role contributes to the intellectual level of the nation, through the information submitted in news publications, as well as bringing stipulated by the 1945 Constitution of Republic of Indonesia on freedom of thought and speech as Human Rights. However, in carrying out their journalistic duties, the Press should have responsibilities in the news process, and must not violate the ethics of his profession. Press that violates profession intentionally or unintentionally in the writing and publication of news in the public sphere, will still do the law enforcement process for any misuse of the meaning of freedom of speech and thought that harm others. Enforcement of this law, in line with the revocation of the right of immunity of profession issued by the Constitutional Court, which means the Press as a Professional must do the job with the precautionary principle, not by carelessness due to the trapped arrogance of jobs, and injuring other people's human rights, even doing work profession with not commendable behavior. How To Cite: Astuti, S. (2014. The Law Enforcement of Journalism Profession in The Context of Press Freedom. Rechtsidee, 1(2, 175-190. doi:http://dx.doi.org/10.21070/jihr.v1i2.97

  13. Use of force by law enforcement: an evaluation of safetyand injury.

    Science.gov (United States)

    Strote, Jared; Verzemnieks, Erik; Walsh, Mimi; Hutson, H Range

    2010-11-01

    Little is known about the frequency and types of injuries sustained from law enforcement use of force (UOF). The purpose of this study was to examine injury patterns and subject conditions after law enforcement UOF under real-life conditions. A retrospective cohort design was used to examine every UOF by a single police department from January through December, 2006. Data were collected from law enforcement UOF forms as well as medical records and included conditions surrounding the UOF, medical histories, and data from emergency department (ED) evaluations and hospital admissions. Of 888 individuals subjected to force during the study period, 86.9% were men and the average body mass index was 25.8. Ages ranged from 10 to 77 years; juveniles comprised 5.6%. Of the types of force used by police, 73.7% were blows with arms or legs; 15.9% were Taser, 4.6% were capsicum spray, 1.7% were K-9, 0.7% were impact weapons, and 0.2% were firearms. Of the 630 (70.9%) with medical records, 78.7% had a substance abuse or psychiatric history. ED evaluations occurred for 187 (21.1% of) incidents. When laboratory workup occurred, 75.5% had positive urine toxicology and 45.9% had positive ethanol levels. Admission occurred in 15.5% (29) of ED presentations (3.3% of all subjects); of these, 9 (31.0%) were for UOF-related injury. Two subjects in the study died: one as a result of firearm injury and one by suicide after UOF; both were declared dead on scene. Significant injuries related to law enforcement UOF in one city were rare and the only deaths were related to firearm use. A large percentage of those subjected to UOF had diagnoses of substance abuse and/or psychiatric conditions, and most hospital admissions were for problems unrelated to the UOF.

  14. Finding solid ground: law enforcement, key populations and their health and rights in South Africa.

    Science.gov (United States)

    Scheibe, Andrew; Howell, Simon; Müller, Alexandra; Katumba, Munyaradzi; Langen, Bram; Artz, Lillian; Marks, Monique

    2016-01-01

    Sex workers, people who use drugs, men who have sex with men, women who have sex with women and transgender people in South Africa frequently experience high levels of stigma, abuse and discrimination. Evidence suggests that such abuse is sometimes committed by police officers, meaning that those charged with protection are perpetrators. This reinforces cycles of violence, increases the risk of HIV infection, undermines HIV prevention and treatment interventions and violates the constitutional prescriptions that the police are mandated to protect. This paper explores how relationship building can create positive outcomes while taking into account the challenges associated with reforming police strategies in relation to key populations, and vice versa. We argue that relationships between law enforcement agencies and key populations need to be re-examined and reconstituted to enable appropriate responses and services. The antagonistic positioning, "othering" and blame assignment frequently seen in interactions between law enforcement officials and key populations can negatively influence both, albeit for different reasons. In addressing these concerns, we argue that mediation based on consensual dialogue is required, and can be harnessed through a process that highlights points of familiarity that are often shared, but not understood, by both parties. Rather than laying blame, we argue that substantive changes need to be owned and executed by all role-players, informed by a common language that is cognisant of differing perspectives. Relational approaches can be used to identify programmes that align goals that are part of law enforcement, human rights and public health despite not always being seen as such. Law enforcement champions and representatives of key populations need to be identified and supported to promote interventions that are mutually reinforcing, and address perceived differences by highlighting commonality. Creating opportunities to share experiences

  15. When Reputation Enforces Evolutionary Cooperation in Unreliable MANETs.

    Science.gov (United States)

    Tang, Changbing; Li, Ang; Li, Xiang

    2015-10-01

    In self-organized mobile ad hoc networks (MANETs), network functions rely on cooperation of self-interested nodes, where a challenge is to enforce their mutual cooperation. In this paper, we study cooperative packet forwarding in a one-hop unreliable channel which results from loss of packets and noisy observation of transmissions. We propose an indirect reciprocity framework based on evolutionary game theory, and enforce cooperation of packet forwarding strategies in both structured and unstructured MANETs. Furthermore, we analyze the evolutionary dynamics of cooperative strategies and derive the threshold of benefit-to-cost ratio to guarantee the convergence of cooperation. The numerical simulations verify that the proposed evolutionary game theoretic solution enforces cooperation when the benefit-to-cost ratio of the altruistic exceeds the critical condition. In addition, the network throughput performance of our proposed strategy in structured MANETs is measured, which is in close agreement with that of the full cooperative strategy.

  16. Expedited enforcement of UST regulations in New Mexico

    International Nuclear Information System (INIS)

    Sutton-Mendoza, S.A.

    1993-01-01

    New Mexico is the first state to implement an expedited enforcement program to enhance compliance with the Underground Storage Tank Regulations (USTR). UST field inspectors conduct inspections at UST facilities to ensure compliance with the USTR. If the inspector detects a violation, a field Notice of Violation is issued to the owner/operator and a penalty assessed. Prior to expedited enforcement 14% of the violations were corrected. Since implementing the program the Underground Storage Tank Bureau has conducted 592 inspections, issued 181 field Notices of Violation and 52% of those cited have complied. As a result of the enforcement program 85% of the facilities inspected are in compliance with USTR. This program has been successful in gaining compliance with USTR, specifically the release detection requirements. The UST Bureau has significantly increased compliance with the Regulations; and thereby reduced the threats to New Mexico's environment posed by petroleum products and hazardous substances released from underground storage tanks

  17. Personal characteristics of a law enforcement unit of special purpose

    Directory of Open Access Journals (Sweden)

    Vasilenko T.G.

    2017-07-01

    Full Text Available The relevance of the study of the personal characteristics of law enforcement officers due to a significant number of crimes of an aggressive nature, committed by employees of internal Affairs bodies, and the need to develop preventive measures. The purpose of this research is to study peculiarities of the manifestation of progressive and inhibiting aggression personality factors in the structure of law enforcement officers, whose activities directly associated with aggression in the performance of official duties. The study involved 149 employees of special forces of law enforcement are male aged 18 to 35 years. Used a wide battery of psychodiagnostic methods aimed at a comprehensive study of the individual respondents. the data Obtained were analyzed using the method of correlation pleiades. According to the results, was discovered a unique picture of the relationship among personality structures and interaction progressive and deterrent aggression factors with the prevalence of progressive on inhibitory factors in the studied structure.

  18. A Critical Review of OSHA Heat Enforcement Cases: Lessons Learned.

    Science.gov (United States)

    Arbury, Sheila; Lindsley, Matthew; Hodgson, Michael

    2016-04-01

    The aim of the study was to review the Occupational Safety and Health Administration's (OSHA) 2012 to 2013 heat enforcement cases, using identified essential elements of heat illness prevention to evaluate employers' programs and make recommendations to better protect workers from heat illness. (1) Identify essential elements of heat illness prevention; (2) develop data collection tool; and (3) analyze OSHA 2012 to 2013 heat enforcement cases. OSHA's database contains 84 heat enforcement cases in 2012 to 2013. Employer heat illness prevention programs were lacking in essential elements such as providing water and shade; adjusting the work/rest proportion to allow for workload and effective temperature; and acclimatizing and training workers. In this set of investigations, most employers failed to implement common elements of illness prevention programs. Over 80% clearly did not rely on national standard approaches to heat illness prevention.

  19. Medical support for law enforcement-extended operations incidents.

    Science.gov (United States)

    Levy, Matthew J; Tang, Nelson

    2014-01-01

    As the complexity and frequency of law enforcement-extended operations incidents continue to increase, so do the opportunities for adverse health and well-being impacts on the responding officers. These types of clinical encounters have not been well characterized nor have the medical response strategies which have been developed to effectively manage these encounters been well described. The purpose of this article is to provide a descriptive epidemiology of the clinical encounters reported during extended law enforcement operations, as well as to describe a best practices approach for their effective management. This study retrospectively examined the clinical encounters of the Maryland State Police (MSP) Tactical Medical Unit (TMU) during law enforcement extended operations incidents lasting 8 or more hours. In addition, a qualitative analysis was performed on clinical data collected by federal law enforcement agencies during their extended operations. Forty-four percent of missions (455/1,047) supported by the MSP TMU lasted 8 or more hours. Twenty-six percent of these missions (117/455) resulted in at least one patient encounter. Nineteen percent of patient chief complaints (45/238) were related to heat illness/ dehydration. Fifteen percent of encounters (36/238) were for musculoskeletal injury/pain. Eight percent of patients (19/238) had nonspecific sick call (minor illness) complaints. The next most common occurring complaints were cold-related injuries, headache, sinus congestion, and wound/laceration, each of which accounted for 7 percent of patients (16/238), respectively. Analysis of federal law enforcement agencies' response to such events yielded similar clinical encounters. A wide range of health problems are reported by extended law enforcement operations personnel. Timely and effective treatment of these problems can help ensure that the broader operations mission is not compromised. An appropriate operational strategy for managing health complaints

  20. The carrot or the stick? Evaluation of education and enforcement as management tools for human-wildlife conflicts.

    Directory of Open Access Journals (Sweden)

    Sharon Baruch-Mordo

    Full Text Available Evidence-based decision-making is critical for implementing conservation actions, especially for human-wildlife conflicts, which have been increasing worldwide. Conservation practitioners recognize that long-term solutions should include altering human behaviors, and public education and enforcement of wildlife-related laws are two management actions frequently implemented, but with little empirical evidence evaluating their success. We used a system where human-black bear conflicts were common, to experimentally test the efficacy of education and enforcement in altering human behavior to better secure attractants (garbage from bears. We conducted 3 experiments in Aspen CO, USA to evaluate: 1 on-site education in communal dwellings and construction sites, 2 Bear Aware educational campaign in residential neighborhoods, and 3 elevated law enforcement at two levels in the core business area of Aspen. We measured human behaviors as the response including: violation of local wildlife ordinances, garbage availability to bears, and change in use of bear-resistance refuse containers. As implemented, we found little support for education, or enforcement in the form of daily patrolling in changing human behavior, but found more support for proactive enforcement, i.e., dispensing warning notices. More broadly we demonstrated the value of gathering evidence before and after implementing conservation actions, and the dangers of measuring responses in the absence of ecological knowledge. We recommend development of more effective educational methods, application of proactive enforcement, and continued evaluation of tools by directly measuring change in human behavior. We provide empirical evidence adding to the conservation managers' toolbox, informing policy makers, and promoting solutions to human-wildlife conflicts.

  1. Enforcement of UK merchant shipping legislation: in 2 volumes

    OpenAIRE

    Jurgens, Ulrich

    2009-01-01

    The basis of this thesis is an investigation of Maritime and Coastguard Agency (MCA) administrative and criminal enforcement files, relating to UK detentions and prosecutions. It would appear that this is the first time that such an analysis has been made.The thesis is divided into four parts of which Part B and C form the heart of the work. These two consider administrative (Part B) and criminal (Part C) enforcement measures and discusses their legal basis. But before these subjects are deal...

  2. On financing the internal enforcement of illegal immigration policies.

    Science.gov (United States)

    Bucci, G A; Tenorio, R

    1996-02-01

    "We introduce a government budget constraint into an illegal immigration model, and show that the effect of increasing internal enforcement of immigration laws on the host country's disposable national income depends on the mix of employer fines and income taxation used to finance the added enforcement. These issues are addressed under alternative assumptions about (a) the ability of host country employers to discern between legal and illegal workers, and (b) host country labor market conditions. Empirical evidence for the United States indicates that the employer sanctions program may have had a negative impact on disposable national income." excerpt

  3. The Continuing Role For Antitrust Enforcement In the Electricity Sector

    OpenAIRE

    William Stallings

    2013-01-01

    William Stallings discusses some of the recent enforcement actions in the electricity sector, a highly regulated sector, where government has played an important role in enforcing competition policy. The recent “New York Capacity†cases involving a power generator and its financial services firm, includes the use of a derivative agreement to bypass merger regulation and restrain trade. As Stalling notes, this is an example of a novel liability theory used by the Antitrust Division of...

  4. The impact of local immigration enforcement policies on the health of immigrant hispanics/latinos in the United States.

    Science.gov (United States)

    Rhodes, Scott D; Mann, Lilli; Simán, Florence M; Song, Eunyoung; Alonzo, Jorge; Downs, Mario; Lawlor, Emma; Martinez, Omar; Sun, Christina J; O'Brien, Mary Claire; Reboussin, Beth A; Hall, Mark A

    2015-02-01

    We sought to understand how local immigration enforcement policies affect the utilization of health services among immigrant Hispanics/Latinos in North Carolina. In 2012, we analyzed vital records data to determine whether local implementation of section 287(g) of the Immigration and Nationality Act and the Secure Communities program, which authorizes local law enforcement agencies to enforce federal immigration laws, affected the prenatal care utilization of Hispanics/Latinas. We also conducted 6 focus groups and 17 interviews with Hispanic/Latino persons across North Carolina to explore the impact of immigration policies on their utilization of health services. We found no significant differences in utilization of prenatal care before and after implementation of section 287(g), but we did find that, in individual-level analysis, Hispanic/Latina mothers sought prenatal care later and had inadequate care when compared with non-Hispanic/Latina mothers. Participants reported profound mistrust of health services, avoiding health services, and sacrificing their health and the health of their family members. Fear of immigration enforcement policies is generalized across counties. Interventions are needed to increase immigrant Hispanics/Latinos' understanding of their rights and eligibility to utilize health services. Policy-level initiatives are also needed (e.g., driver's licenses) to help undocumented persons access and utilize these services.

  5. Problems of Soviet procedural law enforcement in 1930s.

    Directory of Open Access Journals (Sweden)

    Alexander Kodintsev

    2017-01-01

    Full Text Available УДК 340.158The subject. Features of the organization of justice and the quality of procedural law enforcement in the USSR in the 1930s.The purpose. The determination of historical patterns of judicial enforcement in the USSR in the 1930s and the identification of the causes of the ineffectiveness of the proceedings in this period.Methodology. The author uses historical legal method, formal legal interpretation of statutes, the method of analysis of judicial statistics.Results, scope of application. After the criminal law campaigns of the early 1930s the judg-ment in the Soviet Union was in a disturbed condition. The Soviet civil process was almost absolutely eliminated. Tens thousands materials of court cases were lost throughout the Union every year. The courts were extremely busy.The courts used accusatory approach. The petitions of the accused were almost never solved. Prisoners were not handed copies of the indictments.During the terror of the old evils of the judicial system worsened, the destruction of the judicial process began. The timeframe for completing cases increased. Almost half of criminal cases in case of complaint (appeal has been revised by the higher courts. The courts again applied the simplified procedure.At the end of the 1930s the procedural regulation of the judicial work was the duty of People's Commissariat of Justice of the USSR and of the Supreme Court of the USSR. USSR Supreme Court continued to take decisions in litigation in the plenums. The Boards of Su-preme Court examines cases influencing law of practice.The quality of judgment by the Supreme Courts of the Republics of Soviet Union in the late 1930s did not change significantly in comparison with the previous period. This was due to constant staff turnover and low level of qualification of judges. The Supreme Courts of the Republics had no Plenum, so they could influence law of practice by the rulings of of the Boards. These rulings were extremely ignorant

  6. 40 CFR 80.81 - Enforcement exemptions for California gasoline.

    Science.gov (United States)

    2010-07-01

    ... gasoline. 80.81 Section 80.81 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) REGULATION OF FUELS AND FUEL ADDITIVES Reformulated Gasoline § 80.81 Enforcement exemptions for California gasoline. (a)(1) The requirements of subparts D, E, F, and J of this part are...

  7. Law enforcement tools available at the Savannah River Site

    Energy Technology Data Exchange (ETDEWEB)

    Hofstetter, K.J.

    2000-03-29

    A number of nuclear technologies developed and applied at the Savannah River Site in support of nuclear weapons material production and environmental remediation can be applied to problems in law enforcement. Techniques and equipment for high-sensitivity analyses of samples are available to identify and quantify trace elements and establish origins and histories of forensic evidence removed from crime scenes. While some of theses capabilities are available at local crime laboratories, state-of-the-art equipment and breakthroughs in analytical techniques are continually being developed at DOE laboratories. Extensive experience with the handling of radioactive samples at the DOE labs minimizes the chances of cross-contamination of evidence received from law enforcement. In addition to high-sensitivity analyses, many of the field techniques developed for use in a nuclear facility can assist law enforcement personnel in detecting illicit materials and operations, in retrieving of pertinent evidence and in surveying crime scenes. Some of these tools include chemical sniffers, hand-held detectors, thermal imaging, etc. In addition, mobile laboratories can be deployed to a crime scene to provide field screening of potential evidence. A variety of portable sensors can be deployed on vehicle, aerial, surface or submersible platforms to assist in the location of pertinent evidence or illicit operations. Several specific nuclear technologies available to law enforcement and their potential uses are discussed.

  8. 22 CFR 103.7 - Initiation of administrative enforcement proceedings.

    Science.gov (United States)

    2010-04-01

    ... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Initiation of administrative enforcement proceedings. 103.7 Section 103.7 Foreign Relations DEPARTMENT OF STATE ECONOMIC AND OTHER FUNCTIONS... papers and documentary evidence must be submitted in English. (h) Waiver. The failure of the respondent...

  9. 40 CFR 35.6760 - Enforcement and termination for convenience.

    Science.gov (United States)

    2010-07-01

    ... convenience. 35.6760 Section 35.6760 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY GRANTS AND... Enforcement and termination for convenience. The recipient must comply with all terms and conditions in the... termination for convenience described in 40 CFR 31.43 and 31.44. ...

  10. Consumption risk sharing with private information and limited enforcement

    Czech Academy of Sciences Publication Activity Database

    Broer, T.; Kapička, Marek; Klein, P.

    2017-01-01

    Roč. 23, January (2017), s. 170-190 ISSN 1094-2025 Institutional support: Progres-Q24 Keywords : consumption insurance * private information * limited enforcement Subject RIV: AH - Economic s OBOR OECD: Economic Theory Impact factor: 1.053, year: 2016

  11. Consumption risk sharing with private information and limited enforcement

    Czech Academy of Sciences Publication Activity Database

    Broer, T.; Kapička, Marek; Klein, P.

    2017-01-01

    Roč. 23, January (2017), s. 170-190 ISSN 1094-2025 Institutional support: RVO:67985998 Keywords : consumption insurance * private information * limited enforcement Subject RIV: AH - Economic s OBOR OECD: Economic Theory Impact factor: 1.053, year: 2016

  12. Assessing peak aerobic capacity in Dutch law enforcement officers

    NARCIS (Netherlands)

    Wittink, Harriet; Takken, Tim; de Groot, Janke; Reneman, Michiel; Peters, Roelof; Vanhees, Luc

    2015-01-01

    Objectives: To cross-validate the existing peak rate of oxygen consumption (VO2peak) prediction equations in Dutch law enforcement officers and to determine whether these prediction equations can be used to predict VO2peak for groups and in a single individual. A further objective was to report

  13. A Key Management Method for Cryptographically Enforced Access Control

    NARCIS (Netherlands)

    Zych, Anna; Petkovic, Milan; Jonker, Willem; Fernández-Medina, Eduardo; Yagüe, Mariemma I.

    Cryptographic enforcement of access control mechanisms relies on encrypting protected data with the keys stored by authorized users. This approach poses the problem of the distribution of secret keys. In this paper, a key management scheme is presented where each user stores a single key and is

  14. Efficient key management for cryptographically enforced access control

    NARCIS (Netherlands)

    Zych, Anna; Petkovic, Milan; Jonker, Willem

    Cryptographic enforcement of access control mechanisms relies on encrypting protected data with the keys stored by authorized users. This approach poses the problem of the distribution of secret keys. In this paper, a key management scheme is presented where each user stores a single key and is

  15. Communication Error Management in Law Enforcement Interactions : a receiver's perspective

    NARCIS (Netherlands)

    Oostinga, Miriam; Giebels, Ellen; Taylor, Paul Jonathon

    2018-01-01

    Two experiments explore the effect of law enforcement officers’ communication errors and their response strategies on a suspect’s trust in the officer; established rapport and hostility; and, the amount and quality of information shared. Students were questioned online by an exam board member about

  16. Event Composition Model: Achieving Naturalness in Runtime Enforcement

    NARCIS (Netherlands)

    Malakuti Khah Olun Abadi, Somayeh

    2011-01-01

    Runtime enforcement techniques are introduced in the literature to cope with the failures that occur while software is being executed in its target environment. These techniques may also offer diagnosis and recovery actions to respectively identify the causes of the failures and to heal them. Since

  17. Immigration Enforcement Practices Harm Refugee Children and Citizen-Children

    Science.gov (United States)

    Zayas, Luis H.

    2018-01-01

    Aggressive immigration enforcement hurts the very youngest children. Refugee and U.S.-born children of undocumented immigrants experience many childhood adversities, compromising their development and health. Refugee children flee traumatizing violence in their home countries, face grueling migrations, and are harmed further by being held in…

  18. 24 CFR 7.42 - Enforcement of EEOC final decisions.

    Science.gov (United States)

    2010-04-01

    ... action for enforcement of the decision pursuant to title VII, the ADEA, the Equal Pay Act or the Rehabilitation Act and to seek judicial review of the Department's refusal to implement the ordered relief in... Urban Development EQUAL EMPLOYMENT OPPORTUNITY; POLICY, PROCEDURES AND PROGRAMS Equal Employment...

  19. 40 CFR 70.11 - Requirements for enforcement authority.

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 15 2010-07-01 2010-07-01 false Requirements for enforcement authority. 70.11 Section 70.11 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR...) Burden of proof. The burden of proof and degree of knowledge or intent required under State law for...

  20. 40 CFR 281.41 - Requirements for enforcement authority.

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 26 2010-07-01 2010-07-01 false Requirements for enforcement authority. 281.41 Section 281.41 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) SOLID... for each day of violation. (b) The burden of proof and degree of knowledge or intent required under...