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Sample records for achieving target bp

  1. Comparing Science Achievement Constructs: Targeted and Achieved

    ERIC Educational Resources Information Center

    Ferrara, Steve; Duncan, Teresa

    2011-01-01

    This article illustrates how test specifications based solely on academic content standards, without attention to other cognitive skills and item response demands, can fall short of their targeted constructs. First, the authors inductively describe the science achievement construct represented by a statewide sixth-grade science proficiency test.…

  2. JS ISH-ISN-3 OPTIMAL TARGETS FOR BP CONTROL IN CKD.

    PubMed

    Wheeler, David

    2016-09-01

    Hypertension is the most prevalent complication of chronic kidney disease (CKD). Lowering high blood pressure slows progressive loss of kidney function and may also reduce the associated risk of cardiovascular complications, a common cause of premature death in CKD patients.Current International Guidelines produced by Kidney Disease: Improving Global Outcomes (KDIGO) acknowledges that no single BP target is optimal for all CKD patients, and encourages individualization of treatment depending on age, the severity of albuminuria and comorbidities. When published in 2012, the available evidence indicated that in CKD patients without albuminuria, the target BP should be ≤140 mmHg systolic and ≤90 mmHg diastolic. However, in most patients with an albumin excretion rate of ≥30 mg/24 h (i.e., those with both micro- and macroalbuminuria), a lower target of ≤130 mmHg systolic and ≤80 mmHg diastolic was suggested. In achieving BP control, the value of lifestyle changes and the need for multiple pharmacological agents was acknowledged. Use of agents that block the renin-angiotensin-aldosterone system was recommended or suggested in all patients with an albumin excretion rate of ≥30 mg/24 h. Recommendations are almost identical in CKD patients with and without diabetes.Recent data from SPRINT (which included CKD patients) and other clinical trials has led nephrologists to ask whether targets lower than those recommend by KDIGO are appropriate and the guidelines are currently undergoing an update. Controversies remain around discontinuation of ACE/ARB in patients with stage 4-5 CKD and dual renin-angiotensin-aldosterone system blockade.

  3. RNA-binding protein IGF2BP3 targeting of oncogenic transcripts promotes hematopoietic progenitor proliferation

    PubMed Central

    Palanichamy, Jayanth Kumar; Tran, Tiffany M.; Howard, Jonathan M.; Contreras, Jorge R.; Fernando, Thilini R.; Sterne-Weiler, Timothy; Katzman, Sol; Toloue, Masoud; Yan, Weihong; Sanford, Jeremy R.; Rao, Dinesh S.

    2016-01-01

    Posttranscriptional control of gene expression is important for defining both normal and pathological cellular phenotypes. In vitro, RNA-binding proteins (RBPs) have recently been shown to play important roles in posttranscriptional regulation; however, the contribution of RBPs to cell specification is not well understood. Here, we determined that the RBP insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) is specifically overexpressed in mixed lineage leukemia–rearranged (MLL-rearranged) B-acute lymphoblastic leukemia (B-ALL), which constitutes a subtype of this malignancy associated with poor prognosis and high risk of relapse. IGF2BP3 was required for the survival of B-ALL cell lines, as knockdown led to decreased proliferation and increased apoptosis. Enforced expression of IGF2BP3 provided murine BM cells with a strong survival advantage, led to proliferation of hematopoietic stem and progenitor cells, and skewed hematopoietic development to the B cell/myeloid lineage. Cross-link immunoprecipitation and high throughput sequencing uncovered the IGF2BP3-regulated transcriptome, which includes oncogenes MYC and CDK6 as direct targets. IGF2BP3 regulated transcripts via targeting elements within 3′ untranslated regions (3′UTR), and enforced IGF2BP3 expression in mice resulted in enhanced expression of Myc and Cdk6 in BM. Together, our data suggest that IGF2BP3-mediated targeting of oncogenic transcripts may represent a critical pathogenetic mechanism in MLL-rearranged B-ALL and support IGF2BP3 and its cognate RNA-binding partners as potential therapeutic targets in this disease. PMID:26974154

  4. RNA-binding protein IGF2BP3 targeting of oncogenic transcripts promotes hematopoietic progenitor proliferation.

    PubMed

    Palanichamy, Jayanth Kumar; Tran, Tiffany M; Howard, Jonathan M; Contreras, Jorge R; Fernando, Thilini R; Sterne-Weiler, Timothy; Katzman, Sol; Toloue, Masoud; Yan, Weihong; Basso, Giuseppe; Pigazzi, Martina; Sanford, Jeremy R; Rao, Dinesh S

    2016-04-01

    Posttranscriptional control of gene expression is important for defining both normal and pathological cellular phenotypes. In vitro, RNA-binding proteins (RBPs) have recently been shown to play important roles in posttranscriptional regulation; however, the contribution of RBPs to cell specification is not well understood. Here, we determined that the RBP insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) is specifically overexpressed in mixed lineage leukemia-rearranged (MLL-rearranged) B-acute lymphoblastic leukemia (B-ALL), which constitutes a subtype of this malignancy associated with poor prognosis and high risk of relapse. IGF2BP3 was required for the survival of B-ALL cell lines, as knockdown led to decreased proliferation and increased apoptosis. Enforced expression of IGF2BP3 provided murine BM cells with a strong survival advantage, led to proliferation of hematopoietic stem and progenitor cells, and skewed hematopoietic development to the B cell/myeloid lineage. Cross-link immunoprecipitation and high throughput sequencing uncovered the IGF2BP3-regulated transcriptome, which includes oncogenes MYC and CDK6 as direct targets. IGF2BP3 regulated transcripts via targeting elements within 3' untranslated regions (3'UTR), and enforced IGF2BP3 expression in mice resulted in enhanced expression of Myc and Cdk6 in BM. Together, our data suggest that IGF2BP3-mediated targeting of oncogenic transcripts may represent a critical pathogenetic mechanism in MLL-rearranged B-ALL and support IGF2BP3 and its cognate RNA-binding partners as potential therapeutic targets in this disease.

  5. Joint Targeting: Achieving Effects in an Uncertain Environment

    DTIC Science & Technology

    2007-06-01

    evolved into the first Joint Target Group , which possessed the single point responsibility for the collection and analysis of all intelligence data...Office of Air Force History, 1986) 21-22. 7 Targeting Group did not always achieve success. The nomination of major industrial production...East Command assumed responsibility for targeting in Korea and established the General Headquarters Target Group . The General Headquarters Target

  6. Cost Implications in Achieving Alternative Water Quality Targets

    NASA Astrophysics Data System (ADS)

    Schleich, Joachim; White, David; Stephenson, Kurt

    1996-04-01

    Excessive nutrient loading poses significant water quality problems in many water bodies across the country. An important question that must be addressed when nutrient reduction policies are devised is where nutrient reduction targets will be applied within the watershed. This paper examines the cost implications of establishing three possible nutrient reduction targets in different locations along the Fox-Wolf River basin in northeast Wisconsin. A linear programming model calculates the total cost of achieving a 50% phosphorus load reduction target established in various locations throughout the basin. Two strategies establish phosphorus reduction targets for each of the 41 subwatersheds, and the third approach establishes a single 50% target reduction at Green Bay for the entire watershed. The results indicate that achieving target phosphorus reductions at the subwatershed level is over 4 times more expensive than achieving the same percentage phosphorus reduction for the watershed as a whole.

  7. Synergies and trade-offs in achieving global biodiversity targets.

    PubMed

    Di Marco, Moreno; Butchart, Stuart H M; Visconti, Piero; Buchanan, Graeme M; Ficetola, Gentile F; Rondinini, Carlo

    2016-02-01

    After their failure to achieve a significant reduction in the global rate of biodiversity loss by 2010, world governments adopted 20 new ambitious Aichi biodiversity targets to be met by 2020. Efforts to achieve one particular target can contribute to achieving others, but different targets may sometimes require conflicting solutions. Consequently, lack of strategic thinking might result, once again, in a failure to achieve global commitments to biodiversity conservation. We illustrate this dilemma by focusing on Aichi Target 11. This target requires an expansion of terrestrial protected area coverage, which could also contribute to reducing the loss of natural habitats (Target 5), reducing human-induced species decline and extinction (Target 12), and maintaining global carbon stocks (Target 15). We considered the potential impact of expanding protected areas to mitigate global deforestation and the consequences for the distribution of suitable habitat for >10,000 species of forest vertebrates (amphibians, birds, and mammals). We first identified places where deforestation might have the highest impact on remaining forests and then identified places where deforestation might have the highest impact on forest vertebrates (considering aggregate suitable habitat for species). Expanding protected areas toward locations with the highest deforestation rates (Target 5) or the highest potential loss of aggregate species' suitable habitat (Target 12) resulted in partially different protected area network configurations (overlapping with each other by about 73%). Moreover, the latter approach contributed to safeguarding about 30% more global carbon stocks than the former. Further investigation of synergies and trade-offs between targets would shed light on these and other complex interactions, such as the interaction between reducing overexploitation of natural resources (Targets 6, 7), controlling invasive alien species (Target 9), and preventing extinctions of native

  8. Targeting 24 bp within Telomere Repeat Sequences with Tandem Tetramer Pyrrole-Imidazole Polyamide Probes.

    PubMed

    Kawamoto, Yusuke; Sasaki, Asuka; Chandran, Anandhakumar; Hashiya, Kaori; Ide, Satoru; Bando, Toshikazu; Maeshima, Kazuhiro; Sugiyama, Hiroshi

    2016-10-03

    Synthetic molecules that bind sequence-specifically to DNA have been developed for varied biological applications, including anticancer activity, regulation of gene expression, and visualization of specific genomic regions. Increasing the number of base pairs targeted by synthetic molecules strengthens their sequence specificity. Our group has been working on the development of pyrrole-imidazole polyamides that bind to the minor groove of DNA in a sequence-specific manner without causing denaturation. Recently, we reported a simple synthetic method of fluorescent tandem dimer polyamide probes composed of two hairpin moieties with a linking hinge, which bound to 12 bp in human telomeric repeats (5'-(TTAGGG)n-3') and could be used to specifically visualize telomeres in chemically fixed cells under mild conditions. We also performed structural optimization and extension of the target base pairs to allow more specific stain-ing of telomeres. In the present study, we synthesized tandem tetramer polyamides composed of four hairpin moieties, targeting 24 bp in telomeric repeats, the longest reported binding site for synthetic, non-nucleic-acid-based, sequence-specific DNA-binding molecules. The novel tandem tetramers bound with a nanomolar dissociation constant to 24 bp sequences made up of four telomeric repeats. Fluorescently labeled tandem tetramer polyamide probes could visualize human telomeres in chemically fixed cells with lower background signals than polyamide probes reported previously, suggesting that they had higher specificity for telomeres. Furthermore, high-throughput sequencing of human genomic DNA pulled down by the biotin-labeled tandem tetramer polyamide probe confirmed its effective binding to telomeric repeats in the complex chromatinized genome.

  9. Targeting of C-Terminal Binding Protein (CtBP) by ARF Results in p53-Independent Apoptosis

    PubMed Central

    Paliwal, Seema; Pande, Sandhya; Kovi, Ramesh C.; Sharpless, Norman E.; Bardeesy, Nabeel; Grossman, Steven R.

    2006-01-01

    ARF encodes a potent tumor suppressor that antagonizes MDM2, a negative regulator of p53. ARF also suppresses the proliferation of cells lacking p53, and loss of ARF in p53-null mice, compared with ARF or p53 singly null mice, results in a broadened tumor spectrum and decreased tumor latency. To investigate the mechanism of p53-independent tumor suppression by ARF, potential interacting proteins were identified by yeast two-hybrid screen. The antiapoptotic transcriptional corepressor C-terminal binding protein 2 (CtBP2) was identified, and ARF interactions with both CtBP1 and CtBP2 were confirmed in vitro and in vivo. Interaction with ARF resulted in proteasome-dependent CtBP degradation. Both ARF-induced CtBP degradation and CtBP small interfering RNA led to p53-independent apoptosis in colon cancer cells. ARF induction of apoptosis was dependent on its ability to interact with CtBP, and reversal of ARF-induced CtBP depletion by CtBP overexpression abrogated ARF-induced apoptosis. CtBP proteins represent putative targets for p53-independent tumor suppression by ARF. PMID:16508011

  10. SY 07-3 WHICH BP LEVELS ARE ADEQUATE TARGETS FOR THE MANAGEMENT OF DIABETIC HYPERTENSIVE PATIENTS IN ASIA?

    PubMed

    Eguchi, Kazuo

    2016-09-01

    In patients with type 2 diabetes, prevention of future cardiovascular disease is an ultimate goal in the management. Coexistence of diabetes and hypertension enhances cardiovascular risk, and antihypertensive therapy has been shown to be very effective method in reducing micro- and macrovascular complications of type 2 diabetes. However, the optimal target BP levels are still under debate. Most of the international guidelines have raised the target clinic BP from 130/80 mmHg to 140/90 mmHg, but the Japanese Society of Hypertension 2014 guideline kept the target BP level as below 130/80 mmHg. However, individualized BP-lowering treatment should be considered in patients with type 2 diabetes: in high-risk individuals such as those with a history of stroke or retinopathy, aggressive antihypertensive therapy targeting below 130 mmHg should be applied even when the initial SBP level is <140 mmHg. Recently, we performed studies concerning the BP target levels of clinic and home BP in patients with type 2 diabetes. In this session, we will show the preliminary results of these target levels and discuss how we should manage hypertension in patients with type 2 diabetes.

  11. Multiple-site mutations of phage Bp7 endolysin improves its activities against target bacteria.

    PubMed

    Zhang, Can; Wang, Yuanchao; Sun, Huzhi; Ren, Huiying

    2015-10-01

    The widespread use of antibiotics has caused serious drug resistance. Bacteria that were once easily treatable are now extremely difficult to treat. Endolysin can be used as an alternative to antibiotics for the treatment of drug-resistant bacteria. To analyze the antibacterial activity of the endolysin of phage Bp7 (Bp7e), a 489-bp DNA fragment of endolysin Bp7e was PCR-amplified from a phage Bp7 genome and cloned, and then a pET28a-Bp7e prokaryotic expression vector was constructed. Two amino acids were mutated (L99A, M102E) to construct pET28a-Bp7Δe, with pET28a-Bp7e as a template. Phylogenetic analysis suggested that BP7e belongs to a T4-like phage endolysin group. Bp7e and its mutant Bp7Δe were expressed in Escherichia coli BL21(DE3) as soluble proteins. They were purified by affinity chromatography, and then their antibacterial activities were analyzed. The results demonstrated that the recombinant proteins Bp7e and Bp7Δe showed obvious antibacterial activity against Micrococcus lysodeikticus but no activity against Staphylococcus aureus. In the presence of malic acid, Bp7e and Bp7Δe exhibited an effect on most E. coli strains which could be lysed by phage Bp7, but no effect on Salmonella paratyphi or Pseudomonas aeruginosa. Moreover, Bp7Δe with double-site mutations showed stronger antibacterial activity and a broader lysis range than Bp7e.

  12. Survey and Rapid Detection of Bordetella pertussis in Clinical Samples Targeting the BP485 in China

    PubMed Central

    Liu, Wei; Xu, Yinghua; Dong, Derong; Li, Huan; Zhao, Xiangna; Li, Lili; Zhang, Ying; Wei, Xiao; Wang, Xuesong; Huang, Simo; Zeng, Ming; Huang, Liuyu; Zhang, Shumin; Yuan, Jing

    2015-01-01

    Bordetella pertussis is an important human respiratory pathogen. Here, we describe a loop-mediated isothermal amplification (LAMP) method for the rapid detection of B. pertussis in clinical samples based on a visual test. The LAMP assay detected the BP485 target sequence within 60 min with a detection limit of 1.3 pg/μl, a 10-fold increase in sensitivity compared with conventional PCR. All 31 non-pertussis respiratory pathogens tested were negative for LAMP detection, indicating the high specificity of the primers for B. pertussis. To evaluate the application of the LAMP assay to clinical diagnosis, of 105 sputum and nasopharyngeal samples collected from the patients with suspected respiratory infections in China, a total of 12 B. pertussis isolates were identified from 33 positive samples detected by LAMP-based surveillance targeting BP485. Strikingly, a 4.5 months old baby and her mother were found to be infected with B. pertussis at the same time. All isolates belonged to different B. pertussis multilocus sequence typing groups with different alleles of the virulence-related genes including four alleles of ptxA, six of prn, four of tcfA, two of fim2, and three of fim3. The diversity of B. pertussis carrying toxin genes in clinical strains indicates a rapid and continuing evolution of B. pertussis. This combined with its high prevalence will make it difficult to control. In conclusion, we have developed a visual detection LAMP assay, which could be a useful tool for rapid B. pertussis detection, especially in situations where resources are poor and in point-of-care tests. PMID:25798436

  13. MicroRNA Let-7b inhibits keratinocyte migration in cutaneous wound healing by targeting IGF2BP2.

    PubMed

    Wu, Yan; Zhong, Julia Li; Hou, Ning; Sun, Yaolan; Ma, Benting; Nisar, Muhammad Farrukh; Teng, Yan; Tan, Zhaoli; Chen, Keping; Wang, Youliang; Yang, Xiao

    2017-02-01

    Wound healing is a complex process which involves proliferation and migration of keratinocyte for closure of epidermal injuries. A member of microRNA family, let-7b, has been expressed in mammalian skin, but its exact role in keratinocyte migration is still not in knowledge. Here, we showed that let-7b regulates keratinocyte migration by targeting the insulin-like growth factor IGF2BP2. Overexpression of let-7b led to reduced HaCaT cell migration, while knockdown of let-7b resulted in enhanced migration. Furthermore, let-7b was decreased during wound healing in wild-type mice, which led us to construct the transgenic mice with overexpression of let-7b in skin. The re-epithelialization of epidermis of let-7b transgenic mice was reduced during wound healing. Using bioinformatics prediction software and a reporter gene assay, we found that IGF2BP2 was a target of let-7b, which contributes to keratinocyte migration. Introduction of an expression vector of IGF2BP2 also rescued let-7b-induced migration deficiency, which confirms that IGF2BP2 is an important target for let-7b regulation. Our findings suggest that let-7b significantly delayed the re-epithelialization possibly due to reduction of keratinocyte migration and restraints IGF2BP2 during skin wound healing.

  14. What would it take to achieve the Paris temperature targets?

    NASA Astrophysics Data System (ADS)

    Sanderson, Benjamin M.; O'Neill, Brian C.; Tebaldi, Claudia

    2016-07-01

    The 2015 Paris Agreement aims to limit warming to 2 or 1.5°C above preindustrial level, although combined Intended Nationally Determined Contributions (INDCs) are likely insufficient to achieve these targets. We propose a set of idealized emission pathways consistent with the targets. If countries reduce emissions in line with their INDCs, the 2°C threshold could be avoided only if net zero greenhouse gas emissions (GHGEs) are achieved by 2085 and late century negative emissions are considerably in excess of those assumed in Representative Concentration Pathway (RCP) 2.6 (net -5 Gt CO2/yr, compared with -1.5 Gt CO2/yr in RCP2.6). More aggressive near-term reductions would allow 2°C to be avoided with less end-of-century carbon removal capacity. A 10% cut in GHGEs by 2030 (relative to 2015) could likely achieve 2°C with RCP2.6 level negative emissions. The 1.5°C target requires GHGEs to be reduced by almost a third by 2030 and net zero by 2050, while a 50 year overshoot of 1.5°C allows net zero GHGEs by 2060.

  15. MAP kinase p38 is a novel target of CacyBP/SIP phosphatase.

    PubMed

    Topolska-Woś, Agnieszka M; Rosińska, Sara; Filipek, Anna

    2017-03-10

    Mitogen-activated protein (MAP) kinases are important players in cellular signaling pathways. Recently, it has been shown that CacyBP/SIP serves as a phosphatase for one of the MAP kinases, ERK1/2. Through dephosphorylation of this kinase CacyBP/SIP modulates the transcriptional activity of Elk-1 and the activity of the CREB-BDNF pathway. In this work, using NB2a cell lysate and recombinant proteins, we show that CacyBP/SIP binds and dephosphorylates another member of the MAP kinase family, p38. Analysis of recombinant full-length CacyBP/SIP and its three major domains, N-terminal, middle CS and C-terminal SGS, indicates that the middle CS domain is responsible for p38 dephosphorylation. Moreover, we show that CacyBP/SIP might be implicated in response to oxidative stress. Dephosphorylation of phospho-p38 by CacyBP/SIP in NB2a cells treated with hydrogen peroxide is much more effective than in control ones. In conclusion, involvement of CacyBP/SIP in the regulation of p38 kinase activity, in addition to that of ERK1/2, might point to the function of CacyBP/SIP in pro-survival and pro-apoptotic pathways.

  16. CtBP1 associates metabolic syndrome and breast carcinogenesis targeting multiple miRNAs

    PubMed Central

    De Luca, Paola; Dalton, Guillermo N.; Scalise, Georgina D.; Moiola, Cristian P.; Porretti, Juliana; Massillo, Cintia; Kordon, Edith; Gardner, Kevin; Zalazar, Florencia; Flumian, Carolina; Todaro, Laura; Vazquez, Elba S.; Meiss, Roberto; De Siervi, Adriana

    2016-01-01

    Metabolic syndrome (MeS) has been identified as a risk factor for breast cancer. C-terminal binding protein 1 (CtBP1) is a co-repressor of tumor suppressor genes that is activated by low NAD+/NADH ratio. High fat diet (HFD) increases intracellular NADH. We investigated the effect of CtBP1 hyperactivation by HFD intake on mouse breast carcinogenesis. We generated a MeS-like disease in female mice by chronically feeding animals with HFD. MeS increased postnatal mammary gland development and generated prominent duct patterns with markedly increased CtBP1 and Cyclin D1 expression. CtBP1 induced breast cancer cells proliferation. Serum from animals with MeS enriched the stem-like/progenitor cell population from breast cancer cells. CtBP1 increased breast tumor growth in MeS mice modulating multiple genes and miRNA expression implicated in cell proliferation, progenitor cells phenotype, epithelial to mesenchymal transition, mammary development and cell communication in the xenografts. These results define a novel function for CtBP1 in breast carcinogenesis. PMID:26933806

  17. Ikaros and its interacting partner CtBP target the metalloprotease ADAMTS10 to modulate pituitary cell function.

    PubMed

    Shen, Zhongyi; Asa, Sylvia L; Ezzat, Shereen

    2017-01-05

    We have previously described the expression and up-regulation of the C-terminal Binding Protein (CtBP) in response to pituitary hypoxia. This co-repressor interacts with the hematopoietic factor Ikaros to target several components implicated in cellular growth and apoptotic pathways. To identify common transcriptional pituitary targets we performed promoter arrays using Ikaros and CtBP chromatin immunoprecipitated (ChIP) DNA from pituitary AtT20 cells. This approach yielded a finite list of gene targets common to both transcription factors. Of these, the metalloprotease ADAMTS10 emerged as a validated target. We show the ability of Ikaros to bind the ADAMTS10 promoter, influence its transfected activity, and induce endogenous gene expression. ADAMTS10 is expressed in primary pituitary cells and is down-regulated in Ikaros null mice. Further, knockdown of ADAMTS10 in AtT20 cells recapitulates the impact of Ikaros deficiency on POMC/ACTH hormone expression. These results uncover a novel role for the metalloprotease ADAMTS10 in the pituitary. Additionally, they position this metalloprotease as a potential functional integrator of the Ikaros-CtBP chromatin remodeling network.

  18. Comparison of PCR assays targeting the multi-copy targets B1 gene and 529 bp repetitive element for detection of Toxoplasma gondii in swine muscle.

    PubMed

    Veronesi, Fabrizia; Santoro, Azzurra; Milardi, Giovanni Luigi; Diaferia, Manuela; Branciari, Raffaella; Miraglia, Dino; Cioffi, Attilia; Gabrielli, Simona; Ranucci, David

    2017-05-01

    The comparison of the sensitivities of two molecular assays designed to target the multi-copy sequences of the Toxoplasma gondii genomic B1 region and 529 bp-RE respectively, in detecting T. gondii in swine muscle was assessed. Diaphragm pillars were obtained from 498 slaughtered pigs managed in intensive farms in Central Italy. Genomic DNA was extracted from the tissues and T. gondii-B1 and 529 bp-RE sequences were amplified by specific PCR protocols. Toxoplasma gondii DNA was detected in 165 samples (33.13%). There was a good correlation (κ = 0.77) between the results obtained targeting the two different genetic markers, however the 529 bp RE-PCR assay overall detected a significantly higher (P < 0.05) number of T. gondii-positive samples (150 samples) than the B1-PCR protocol (134). Our results show that: i) standardized B1 and 529 bp-RE PCRs applied to muscle tissues can detect a high rate of T. gondii-infection; ii) a multi-target PCR approach is recommended for the accurate diagnosis of infection in swine and can also be used in food testing.

  19. Integrating epidemiology, psychology, and economics to achieve HPV vaccination targets.

    PubMed

    Basu, Sanjay; Chapman, Gretchen B; Galvani, Alison P

    2008-12-02

    Human papillomavirus (HPV) vaccines provide an opportunity to reduce the incidence of cervical cancer. Optimization of cervical cancer prevention programs requires anticipation of the degree to which the public will adhere to vaccination recommendations. To compare vaccination levels driven by public perceptions with levels that are optimal for maximizing the community's overall utility, we develop an epidemiological game-theoretic model of HPV vaccination. The model is parameterized with survey data on actual perceptions regarding cervical cancer, genital warts, and HPV vaccination collected from parents of vaccine-eligible children in the United States. The results suggest that perceptions of survey respondents generate vaccination levels far lower than those that maximize overall health-related utility for the population. Vaccination goals may be achieved by addressing concerns about vaccine risk, particularly those related to sexual activity among adolescent vaccine recipients. In addition, cost subsidizations and shifts in federal coverage plans may compensate for perceived and real costs of HPV vaccination to achieve public health vaccination targets.

  20. Likelihood of achieving air quality targets under model uncertainties.

    PubMed

    Digar, Antara; Cohan, Daniel S; Cox, Dennis D; Kim, Byeong-Uk; Boylan, James W

    2011-01-01

    Regulatory attainment demonstrations in the United States typically apply a bright-line test to predict whether a control strategy is sufficient to attain an air quality standard. Photochemical models are the best tools available to project future pollutant levels and are a critical part of regulatory attainment demonstrations. However, because photochemical models are uncertain and future meteorology is unknowable, future pollutant levels cannot be predicted perfectly and attainment cannot be guaranteed. This paper introduces a computationally efficient methodology for estimating the likelihood that an emission control strategy will achieve an air quality objective in light of uncertainties in photochemical model input parameters (e.g., uncertain emission and reaction rates, deposition velocities, and boundary conditions). The method incorporates Monte Carlo simulations of a reduced form model representing pollutant-precursor response under parametric uncertainty to probabilistically predict the improvement in air quality due to emission control. The method is applied to recent 8-h ozone attainment modeling for Atlanta, Georgia, to assess the likelihood that additional controls would achieve fixed (well-defined) or flexible (due to meteorological variability and uncertain emission trends) targets of air pollution reduction. The results show that in certain instances ranking of the predicted effectiveness of control strategies may differ between probabilistic and deterministic analyses.

  1. GHG emission reductions and costs to achieve Kyoto target.

    PubMed

    Chen, Wen-ying

    2003-07-01

    Emission projection and marginal abatement cost curves (MACs) are the central components of any assessment of future carbon market, such as CDM (clean development mechanism) potentials, carbon quota price etc. However, they are products of very complex, dynamic systems driven by forces like population growth, economic development, resource endowments, technology progress and so on. The modeling approaches for emission projection and MACs evaluation were summarized, and some major models and their results were compared. Accordingly, reduction and cost requirements to achieve the Kyoto target were estimated. It is concluded that Annex I Parties' total reduction requirements range from 503-1304 MtC with USA participation and decrease significantly to 140-612 MtC after USA's withdrawal. Total costs vary from 21-77 BUSD with USA and from 5-36 BUSD without USA if only domestic reduction actions are taken. The costs would sharply reduce while considering the three flexible mechanisms defined in the Kyoto Protocol with domestic actions' share in the all mitigation strategies drops to only 0-16% .

  2. Healthy latrine development model to achieve MDGs target

    NASA Astrophysics Data System (ADS)

    Soedjono, Eddy S.; Arumsari, Nurvita

    2014-03-01

    A case happened in Pungging sub-district was one example of low level healthy habits of East Java inhabitants. According to the data of Mojokerto district Health Service until the end of 2010, there are 219 families (or about 8% of total families in Pungging sub-district) which do not have their own latrine. Moreover, if we observe closely to their prosperity level, the percentage of disadvantaged families and prosperous level I is still adequately high about 29,54% of the total number of families in Pungging sub-district. Accordingly, comprehensive studies related to basic sanitation requirement need to be done, not only in the matter of quantity but also in the matter of quality. Furthermore, further studies on people's knowledge and understanding on healthy sanitation also needed in the effort to understand people's demand to own latrine (willingness to pay) and ability to pay. Consequently, the design of healthy latrine which agrees with people's demand and ability is needed in order to achieve the target of Open Defecation Free (ODF) in 2015. The research methodology includes literary study, data collection, data analysis, and healthy latrine design. Out of 75 respondents, only 32% of them who attended counselling program on healthy latrine and only 48% of them who have knowledge on healthy latrine, but in reality 96% of respondents stated that healthy latrine is important. Healthy latrine, according to the respondents, is a place of defecation (BAB) which has components like latrine bowl or septic tank. Estimation on WTP distribution which is divided in two categories; low category with range of willingness to pay from IDR 0 to IDR 200,000 is IDR 90,048,000. On the other hand, high category with range of willingness to pay more than IDR 1,000,000 is IDR 749,964,768. Estimation on respondents' ATP in the area of study on the sanitation maintenance service is from IDR 7,000 to IDR 30,000.

  3. Resveratrol induces apoptosis by directly targeting Ras-GTPase activating protein SH3 domain binding protein 1 (G3BP1)

    PubMed Central

    Oi, Naomi; Yuan, Jian; Malakhova, Margarita; Luo, Kuntian; Li, Yunhui; Ryu, Joohyun; Zhang, Lei; Bode, Ann M.; Xu, Zengguang; Li, Yan; Lou, Zhenkun; Dong, Zigang

    2014-01-01

    Resveratrol possesses a strong anticancer activity exhibited as the induction of apoptosis through p53 activation. However, the molecular mechanism and direct target(s) of resveratrol-induced p53 activation remain elusive. Here, the Ras-GTPase activating protein SH3 domain binding protein 1 (G3BP1) was identified as a potential target of resveratrol, and in vitro binding assay results using resveratrol (RSVL)-conjugated Sepharose 4B beads confirmed their direct binding. Depletion of G3BP1 significantly diminishes resveratrol-induced p53 expression and apoptosis. We also found that G3BP1 negatively regulates p53 expression by interacting with ubiquitin-specific protease 10 (USP10), a deubiquitinating enzyme of p53. Disruption of the interaction of p53 with USP10 by G3BP1 interference leads to suppression of p53 deubiquitination. Resveratrol, on the other hand, directly binds to G3BP1 and prevents the G3BP1/USP10 interaction, resulting in enhanced USP10-mediated deubiquitination of p53 and consequently increased p53 expression. These findings disclose a novel mechanism of resveratrol-induced p53 activation and resveratrol-induced apoptosis by direct targeting of G3BP1. PMID:24998844

  4. Novel feline autoimmune blistering disease resembling bullous pemphigoid in humans: IgG autoantibodies target the NC16A ectodomain of type XVII collagen (BP180/BPAG2).

    PubMed

    Olivry, T; Chan, L S; Xu, L; Chace, P; Dunston, S M; Fahey, M; Marinkovich, M P

    1999-07-01

    In humans and dogs, bullous pemphigoid (BP) is an autoimmune blistering disease associated with the production of basement membrane autoantibodies that target the 180-kd type XVII collagen (BP180, BPAG2) and/or the 230-kd plakin epidermal isoform BPAG1e (BP230). In two adult cats, an acquired dermatosis and stomatitis was diagnosed as BP subsequent to the fulfillment of the following criteria: 1) presence of cutaneous vesicles, erosions, and ulcers; 2) histologic demonstration of subepidermal vesiculation with inflammatory cells, including eosinophils; 3) in vivo deposition of IgG autoantibodies at the epidermal basement membrane zone; and 4) serum IgG autoantibodies targeting a 180-kd epidermal protein identified as type XVII collagen. In both cats, the antigenic epitopes targeted by IgG autoantibodies were shown to be situated in the NC16A ectodomain of type XVII collagen, a situation similar to that of humans and dogs with BP. Feline BP therefore can be considered a clinical, histopathologic, and immunologic homologue of BP in humans and dogs.

  5. Structural Insights into Membrane Targeting by the Flagellar Calcium-binding Protein (FCaBP) a Myristoylated and Palmitoylated Calcium Sensor in Trypanosoma cruzi

    SciTech Connect

    J Wingard; J Ladner; M Vanarotti; A Fisher; H Robinson; K Buchanan; D Engman; J Ames

    2011-12-31

    The flagellar calcium-binding protein (FCaBP) of the protozoan Trypanosoma cruzi is targeted to the flagellar membrane where it regulates flagellar function and assembly. As a first step toward understanding the Ca{sup 2+}-induced conformational changes important for membrane-targeting, we report here the x-ray crystal structure of FCaBP in the Ca{sup 2+}-free state determined at 2.2{angstrom} resolution. The first 17 residues from the N terminus appear unstructured and solvent-exposed. Residues implicated in membrane targeting (Lys-19, Lys-22, and Lys-25) are flanked by an exposed N-terminal helix (residues 26-37), forming a patch of positive charge on the protein surface that may interact electrostatically with flagellar membrane targets. The four EF-hands in FCaBP each adopt a 'closed conformation' similar to that seen in Ca{sup 2+}-free calmodulin. The overall fold of FCaBP is closest to that of grancalcin and other members of the penta EF-hand superfamily. Unlike the dimeric penta EF-hand proteins, FCaBP lacks a fifth EF-hand and is monomeric. The unstructured N-terminal region of FCaBP suggests that its covalently attached myristoyl group at the N terminus may be solvent-exposed, in contrast to the highly sequestered myristoyl group seen in recoverin and GCAP1. NMR analysis demonstrates that the myristoyl group attached to FCaBP is indeed solvent-exposed in both the Ca{sup 2+}-free and Ca{sup 2+}-bound states, and myristoylation has no effect on protein structure and folding stability. We propose that exposed acyl groups at the N terminus may anchor FCaBP to the flagellar membrane and that Ca{sup 2+}-induced conformational changes may control its binding to membrane-bound protein targets..

  6. Targeting the latent reservoir to achieve functional HIV cure

    PubMed Central

    Cary, Daniele C.; Peterlin, B. Matija

    2016-01-01

    While highly active anti-retroviral therapy has greatly improved the lives of HIV-infected individuals, current treatments are unable to completely eradicate the virus. This is due to the presence of HIV latently infected cells which harbor transcriptionally silent HIV. Latent HIV does not replicate or produce viral proteins, thereby preventing efficient targeting by anti-retroviral drugs. Strategies to target the HIV latent reservoir include viral reactivation, enhancing host defense mechanisms, keeping latent HIV silent, and using gene therapy techniques to knock out or reactivate latent HIV. While research into each of these areas has yielded promising results, currently no one mechanism eradicates latent HIV. Instead, combinations of these approaches should be considered for a potential HIV functional cure. PMID:27303638

  7. Inhibition of GLI1 Expression by Targeting the CRD-BP-GLI1 mRNA Interaction Using a Specific Oligonucleotide.

    PubMed

    Mehmood, Kashif; Akhtar, Daud; Mackedenski, Sebastian; Wang, Chuyi; Lee, Chow H

    2016-06-01

    The stabilization of glioma-associated oncogene 1 (GLI1) mRNA by coding region determinant binding protein (CRD-BP) through the Wnt/β-catenin signaling pathway is implicated in the proliferation of colorectal cancer and basal cell carcinoma. Here, we set out to characterize the physical interaction between CRD-BP and GLI1 mRNA so as to find inhibitors for such interaction. Studies using CRD-BP variants with a point mutation in the GXXG motif at each KH domain showed that KH1 and KH2 domain are critical for the binding of GLI1 RNA. The smallest region of GLI1 RNA binding to CRD-BP was mapped to nucleotides (nts) 320-380. A 37-nt S1 RNA sense oligonucleotide, containing two distinct stem-loops present in nts 320-380 of GLI1 RNA, was found to be effective in blocking CRD-BP-GLI1 RNA interaction. Studies using various competitor RNAs with modifications to S1 RNA oligonucleotide further displayed that both the sequences and the structure of the two stem-loops are important for CRD-BP-GLI1 RNA binding. The role of the two-stem-loop motif in influencing CRD-BP-RNA interaction was further investigated in cells. The 2'-O-methyl derivative of the S1 RNA oligonucleotide significantly decreased GLI1, c-myc, and CD44 mRNA levels, in a panel of colon and breast cancer cells. The results from this study demonstrate the potential importance of the two-stem-loop motif as a target region for the inhibition of the CRD-BP-GLI1 RNA interaction and Hedgehog signaling pathway. Such results pave the way for the development of novel inhibitors that act by destabilizing the CRD-BP-GLI1 mRNA interaction.

  8. Identification of Targets of CUG-BP, Elav-Like Family Member 1 (CELF1) Regulation in Embryonic Heart Muscle

    PubMed Central

    Coram, Ryan J.; Ladd, Andrea N.

    2016-01-01

    CUG-BP, Elav-like family member 1 (CELF1) is a highly conserved RNA binding protein that regulates pre-mRNA alternative splicing, polyadenylation, mRNA stability, and translation. In the heart, CELF1 is expressed in the myocardium, where its levels are tightly regulated during development. CELF1 levels peak in the heart during embryogenesis, and aberrant up-regulation of CELF1 in the adult heart has been implicated in cardiac pathogenesis in myotonic dystrophy type 1, as well as in diabetic cardiomyopathy. Either inhibition of CELF activity or over-expression of CELF1 in heart muscle causes cardiomyopathy in transgenic mice. Nonetheless, many of the cardiac targets of CELF1 regulation remain unknown. In this study, to identify cardiac targets of CELF1 we performed cross-linking immunoprecipitation (CLIP) for CELF1 from embryonic day 8 chicken hearts. We identified a previously unannotated exon in MYH7B as a novel target of CELF1-mediated regulation. We demonstrated that knockdown of CELF1 in primary chicken embryonic cardiomyocytes leads to increased inclusion of this exon and decreased MYH7B levels. We also investigated global changes in the transcriptome of primary embryonic cardiomyocytes following CELF1 knockdown in a published RNA-seq dataset. Pathway and network analyses identified strong associations between CELF1 and regulation of cell cycle and translation. Important regulatory proteins, including both RNA binding proteins and a cardiac transcription factor, were affected by loss of CELF1. Together, these data suggest that CELF1 is a key regulator of cardiomyocyte gene expression. PMID:26866591

  9. Detection of Toxoplasma gondii in faeces of privately owned cats using two PCR assays targeting the B1 gene and the 529-bp repetitive element.

    PubMed

    Veronesi, Fabrizia; Santoro, Azzurra; Milardi, Giovanni L; Diaferia, Manuela; Morganti, Giulia; Ranucci, David; Gabrielli, Simona

    2017-03-01

    Toxoplasma gondii infection is a worldwide parasitic zoonosis with a high-health risk for humans. The key epidemiological role played by felids is related to oocyst shedding. The present study compared two amplification protocols for the molecular diagnosis of Toxoplasma infection in owned cats. A total of 78 owned cats referred to an Italian university-teaching hospital and exposed to various T. gondii-associated risk factors were sampled for blood and faeces. Faecal specimens were processed by flotation and tested using 2 copro-PCRs targeting the widely used B1 gene and the 529-bp repetitive element (RE). The sera were tested by the indirect immunofluorescent antibody test (IFAT) for the detection of immunoglobulins against T. gondii. Sixteen faeces (20.52%) tested positive for T. gondii DNA; 12 samples were positive only at B1-PCR, two at 529-bp RE-PCR and two at both genetic targets (overall agreement = 82.11%). The amplicons obtained were sequenced, and the Basic Local Alignment Search Tool analysis showed a high homology with the T. gondii strains available in reference databases. Two stool samples were microscopically positive for T. gondii-like oocysts and also tested positive by both B1 and 529-bp RE-PCRs. Thirty-three (42.3%) sera tested positive for antibodies; of which, seven were found to have T. gondii DNA-positive results using the B1 genetic target (overall agreement = 57.77%). The amplification sets targeting B1 and 529-bp RE showed substantially different yields. Further research is needed to better understand the significance and the sensitivities of using these multi-copy-targeted molecular methods from cat faeces before being used for routine diagnosis.

  10. 4E-BP is a target of the GCN2-ATF4 pathway during Drosophila development and aging.

    PubMed

    Kang, Min-Ji; Vasudevan, Deepika; Kang, Kwonyoon; Kim, Kyunggon; Park, Jung-Eun; Zhang, Nan; Zeng, Xiaomei; Neubert, Thomas A; Marr, Michael T; Ryoo, Hyung Don

    2017-01-02

    Reduced amino acid availability attenuates mRNA translation in cells and helps to extend lifespan in model organisms. The amino acid deprivation-activated kinase GCN2 mediates this response in part by phosphorylating eIF2α. In addition, the cap-dependent translational inhibitor 4E-BP is transcriptionally induced to extend lifespan in Drosophila melanogaster, but through an unclear mechanism. Here, we show that GCN2 and its downstream transcription factor, ATF4, mediate 4E-BP induction, and GCN2 is required for lifespan extension in response to dietary restriction of amino acids. The 4E-BP intron contains ATF4-binding sites that not only respond to stress but also show inherent ATF4 activity during normal development. Analysis of the newly synthesized proteome through metabolic labeling combined with click chemistry shows that certain stress-responsive proteins are resistant to inhibition by 4E-BP, and gcn2 mutant flies have reduced levels of stress-responsive protein synthesis. These results indicate that GCN2 and ATF4 are important regulators of 4E-BP transcription during normal development and aging.

  11. Achieving target hematocrit in dialysis patients: new concepts in iron management.

    PubMed

    Nissenson, A R

    1997-12-01

    The management of anemia in dialysis patients involves a comprehensive understanding of the role of erythropoietin deficiency and of the importance of adequate available iron. It is clear that iron and recombinant human erythropoietin (rHuEPO) in concert allow the clinician to achieve a given target hematocrit in dialysis patients. By first repleting and then maintaining iron stores, and with an appreciation of the concept of functional iron deficiency, the nephrologist can achieve target hematocrits with the lowest necessary dose of rHuEPO. Iron repletion and maintenance is difficult to achieve with oral iron, and parenteral iron is needed in most cases. New protocols for ongoing parenteral maintenance therapy with iron dextran or iron gluconate, a form of iron likely to be available soon in the United States, should lead to achievement of target hematocrits in a greater number of patients and be cost-effective in improving patient outcomes.

  12. The likelihood of achieving quantified road safety targets: a binary logistic regression model for possible factors.

    PubMed

    Sze, N N; Wong, S C; Lee, C Y

    2014-12-01

    In past several decades, many countries have set quantified road safety targets to motivate transport authorities to develop systematic road safety strategies and measures and facilitate the achievement of continuous road safety improvement. Studies have been conducted to evaluate the association between the setting of quantified road safety targets and road fatality reduction, in both the short and long run, by comparing road fatalities before and after the implementation of a quantified road safety target. However, not much work has been done to evaluate whether the quantified road safety targets are actually achieved. In this study, we used a binary logistic regression model to examine the factors - including vehicle ownership, fatality rate, and national income, in addition to level of ambition and duration of target - that contribute to a target's success. We analyzed 55 quantified road safety targets set by 29 countries from 1981 to 2009, and the results indicate that targets that are in progress and with lower level of ambitions had a higher likelihood of eventually being achieved. Moreover, possible interaction effects on the association between level of ambition and the likelihood of success are also revealed.

  13. Antisense oligodeoxynucleotides targeted to MAG mRNA profoundly alter BP and PLP mRNA expression in differentiating oligodendrocytes: a caution.

    PubMed

    Laszkiewicz, I; Wiggins, R C; Konat, G W

    1999-09-01

    The applicability of antisense technology to suppress the expression of myelin associated glycoprotein (MAG) in cultured oligodendrocytes was evaluated. Differentiating oligodendrocyte precursor cells obtained by the shake-off method were exposed to nine unmodified antisense oligodeoxynucleotides (ODNs) targeted to the first seven exons of MAG mRNA. After four days, steady-state levels of MAG, proteolipid protein (PLP) and basic protein (BP) mRNAs were determined by Northern blot analysis. Only ODN annealing to 599-618 nt of the MAG mRNA (the junction of exon 5 and 6) resulted in a significant, 75% decrease in the MAG mRNA level. Unexpectedly, six other anti-MAG ODNs which had no significant effect on the MAG message, greatly increased the level of BP mRNA. The highest upregulation of approximately 12 fold was observed with ODN annealing to 139-168 nt (junction of exon 3 and 4). On the other hand, the 997-1016 ODN decreased the levels of BP and PLP messages by 70-80%. The 599-618 ODN also decreased the PLP mRNA by 85%. The results demonstrate that antisense ODNs targeted to one gene may profoundly alter the expression of other genes, and hence, complicate functional analysis of the targeted protein.

  14. A report on the Zimbabwe Antiretroviral Therapy (ART) programme progress towards achieving MGD6 target 6B: achievement and challenges.

    PubMed

    Apollo, T; Takarinda, K; Mugurungi, O; Chakanyuka, C; Simbini, T; Harries, A D

    2010-01-01

    Zimbabwe's target to achieve Universal Access to treatment for HIV and AIDS, was severely affected by a decade long economic recession that threatened to reverse all the country's social and economic indicators. Despite these challenges, by September 2010, 282,916 adults and children (47.7% of those in need of treatment) were on treatment at 509 sites countrywide since national scale up started. ART services are predominantly offered through the public sector, with the private sector being an untapped potential resource for ART services for the future. Challenges of skilled and adequately trained human resources have hindered progress towards service availability. Providing access to children in particular has been constrained by lack of clinical mentorship for health workers, weak systems for support supervision, and inadequate HIV diagnostic services especially for children under 18 months and challenges with follow up of the HIV-exposed infants. Though the country has not met its target of Universal Access by 2010, significant progress has been made with over a 30-fold increase in service availability.

  15. Blood pressure (BP) assessment-from BP level to BP variability.

    PubMed

    Feber, Janusz; Litwin, Mieczyslaw

    2016-07-01

    The assessment of blood pressure (BP) can be challenging in children, especially in very young individuals, due to their variable body size and lack of cooperation. In the absence of data relating BP with cardiovascular outcomes in children, there is a need to convert absolute BP values (in mmHg) into age-, gender- and height appropriate BP percentiles or Z-scores in order to compare a patient's BP with the BP of healthy children of the same age, but also of children of different ages. Traditionally, the interpretation of BP has been based mainly on the assessment of the BP level obtained by office, home or 24-h BP monitoring. Recent studies suggest that it is not only BP level (i.e. average BP) but also BP variability that is clinically important for the development of target organ damage, including the progression of chronic kidney disease. In this review we describe current methods to evaluate of BP level, outline available methods for BP variability assessment and discuss the clinical consequences of BP variability, including its potential role in the management of hypertension.

  16. A method to achieve rapid localised deep heating in a laser irradiated solid density target

    NASA Astrophysics Data System (ADS)

    Schmitz, H.; Robinson, A. P. L.

    2016-09-01

    Rapid heating of small buried regions by laser generated fast electrons may be useful for applications such as extreme ultraviolet (XUV) radiation sources or as drivers for shock experiments. In non-structured targets, the heating profile possesses a global maximum near the front surface. This paper presents a new target design that uses resistive guiding to concentrate the fast electron current density at a finite depth inside the target. The choice of geometry uses principles of non-imaging optics. A global temperature maximum at depths up to 50 μ m into the target is achieved. Although theoretical calculations suggest that small source sizes should perform better than large ones, simulations show that a large angular spread at high intensities results in significant losses of the fast electrons to the sides. A systematic parameter scan suggests an optimal laser intensity. A ratio of 1.6 is demonstrated between the maximum ion temperature and the ion temperature at the front surface.

  17. Quantitative Guidance for Stove Usage and Performance to Achieve Health and Environmental Targets

    PubMed Central

    Chiang, Ranyee A.

    2015-01-01

    Background Displacing the use of polluting and inefficient cookstoves in developing countries is necessary to achieve the potential health and environmental benefits sought through clean cooking solutions. Yet little quantitative context has been provided on how much displacement of traditional technologies is needed to achieve targets for household air pollutant concentrations or fuel savings. Objectives This paper provides instructive guidance on the usage of cooking technologies required to achieve health and environmental improvements. Methods We evaluated different scenarios of displacement of traditional stoves with use of higher performing technologies. The air quality and fuel consumption impacts were estimated for these scenarios using a single-zone box model of indoor air quality and ratios of thermal efficiency. Results Stove performance and usage should be considered together, as lower performing stoves can result in similar or greater benefits than a higher performing stove if the lower performing stove has considerably higher displacement of the baseline stove. Based on the indoor air quality model, there are multiple performance–usage scenarios for achieving modest indoor air quality improvements. To meet World Health Organization guidance levels, however, three-stone fire and basic charcoal stove usage must be nearly eliminated to achieve the particulate matter target (< 1–3 hr/week), and substantially limited to meet the carbon monoxide guideline (< 7–9 hr/week). Conclusions Moderate health gains may be achieved with various performance–usage scenarios. The greatest benefits are estimated to be achieved by near-complete displacement of traditional stoves with clean technologies, emphasizing the need to shift in the long term to near exclusive use of clean fuels and stoves. The performance–usage scenarios are also provided as a tool to guide technology selection and prioritize behavior change opportunities to maximize impact. Citation

  18. Achieving CO2 reductions in Colombia: Effects of carbon taxes and abatement targets

    SciTech Connect

    Calderón, Silvia; Alvarez, Andres Camilo; Loboguerrero, Ana Maria; Arango, Santiago; Calvin, Katherine; Kober, Tom; Daenzer, Kathryn; Fisher-Vanden, Karen

    2015-06-03

    In this paper we investigate CO2 emission scenarios for Colombia and the effects of implementing carbon taxes and abatement targets on the energy system. By comparing baseline and policy scenario results from two integrated assessment partial equilibrium models TIAM-ECN and GCAM and two general equilibrium models Phoenix and MEG4C, we provide an indication of future developments and dynamics in the Colombian energy system. Currently, the carbon intensity of the energy system in Colombia is low compared to other countries in Latin America. However, this trend may change given the projected rapid growth of the economy and the potential increase in the use of carbon-based technologies. Climate policy in Colombia is under development and has yet to consider economic instruments such as taxes and abatement targets. This paper shows how taxes or abatement targets can achieve significant CO2 reductions in Colombia. Though abatement may be achieved through different pathways, taxes and targets promote the entry of cleaner energy sources into the market and reduce final energy demand through energy efficiency improvements and other demand-side responses. The electric power sector plays an important role in achieving CO2 emission reductions in Colombia, through the increase of hydropower, the introduction of wind technologies, and the deployment of biomass, coal and natural gas with CO2 capture and storage (CCS). Uncertainty over the prevailing mitigation pathway reinforces the importance of climate policy to guide sectors toward low-carbon technologies. This paper also assesses the economy-wide implications of mitigation policies such as potential losses in GDP and consumption. As a result, an assessment of the legal, institutional, social and environmental barriers to economy-wide mitigation policies is critical yet beyond the scope of this paper.

  19. Achieving CO2 reductions in Colombia: Effects of carbon taxes and abatement targets

    DOE PAGES

    Calderón, Silvia; Alvarez, Andres Camilo; Loboguerrero, Ana Maria; ...

    2015-06-03

    In this paper we investigate CO2 emission scenarios for Colombia and the effects of implementing carbon taxes and abatement targets on the energy system. By comparing baseline and policy scenario results from two integrated assessment partial equilibrium models TIAM-ECN and GCAM and two general equilibrium models Phoenix and MEG4C, we provide an indication of future developments and dynamics in the Colombian energy system. Currently, the carbon intensity of the energy system in Colombia is low compared to other countries in Latin America. However, this trend may change given the projected rapid growth of the economy and the potential increase inmore » the use of carbon-based technologies. Climate policy in Colombia is under development and has yet to consider economic instruments such as taxes and abatement targets. This paper shows how taxes or abatement targets can achieve significant CO2 reductions in Colombia. Though abatement may be achieved through different pathways, taxes and targets promote the entry of cleaner energy sources into the market and reduce final energy demand through energy efficiency improvements and other demand-side responses. The electric power sector plays an important role in achieving CO2 emission reductions in Colombia, through the increase of hydropower, the introduction of wind technologies, and the deployment of biomass, coal and natural gas with CO2 capture and storage (CCS). Uncertainty over the prevailing mitigation pathway reinforces the importance of climate policy to guide sectors toward low-carbon technologies. This paper also assesses the economy-wide implications of mitigation policies such as potential losses in GDP and consumption. As a result, an assessment of the legal, institutional, social and environmental barriers to economy-wide mitigation policies is critical yet beyond the scope of this paper.« less

  20. Achieving targeted and quantifiable alteration of mRNA splicing with Morpholino oligos

    SciTech Connect

    Morcos, Paul A. . E-mail: pmorcos@gene-tools.com

    2007-06-29

    This work represents the first guide for using steric-block antisense oligos as tools for effective and targeted modification of RNA splicing. Comparison of several steric-block oligo types shows the properties of Morpholinos provide significant advantages over other potential splice-blocking oligos. The procedures and complications of designing effective splice-blocking Morpholino oligos are described. The design process requires complete pre-mRNA sequence for defining suitable targets, which usually generate specific predictable messengers. To validate the targeting procedure, the level and nature of transcript alteration is characterized by RT-PCR analysis of splice modification in a {beta}-globin splice model system. An oligo-walking study reveals that while U1 and U2 small nuclear RiboNucleoProtein (snRNP) binding sites are the most effective targets for blocking splicing, inclusion of these sites is not required to achieve effective splice modifications. The most effective targeting strategy employs simultaneously blocking snRNP binding sites and splice-junctions. The work presented here continues to be the basis for most of the successful Morpholino oligos designed for the worldwide research community to block RNA splicing.

  1. Achieving Target Pressures with Combined Surgery: Primary Patchless Ahmed Valve Combined with Phacoemulsification vs Primary Phacotrabeculectomy

    PubMed Central

    Sánchez-Noguera, Carmen C; Cárdenas-Gómez, Lorena; Castañeda-Diez, Rafael; Thomas, Ravi; Gil-Carrasco, Félix

    2015-01-01

    ABSTRACT Purpose: To evaluate the ability of phacoemulsification combined with either primary trabeculectomy (PT) or primary Ahmed glaucoma valve implantation (PAVI) to achieve target intraocular pressures (TIOP) in adults with primary open angle glaucoma. Materials and methods: Chart review of 214 adult patients operated between January 2002 and June 2008 with a minimum follow-up of 6 months. Group 1 comprised 181 eyes of 166 patients undergoing PT while group 2 included 50 eyes of 49 patients in combination with primary AVI. Target lOPs were pre-determined for each patient and success was defined as an IOP at or lower than target with or without medications. An IOP above target, loss of light perception or need for additional procedures to lower IOP were considered a failure. Results: Mean preoperative IOP was 17.2 mm Hg in group 1 and 17.3 in group 2. Mean postoperative IOPs were 10.2 and 9.2 on day 1, 12.2 and 11.6 at year 1, and 10.7 in both groups at year 5. Survival rates in groups 1 and 2 were 96.7 vs 96% at 6 months, 89 vs 96% at 12 months, 83.5 vs 96% at 24 months and 79.4 vs 89.1% at 36, 48 and 72 months. Transient bleb leaks were more frequent in group 1 (26 eyes, 14.4 vs 0%, p = 0.001) and transient choroidal detachments were more frequent in group 2 (7 eyes, 3.9 vs 6 eyes, 12%, p = 0.038). Conclusion: Midterm results for achieving target pressures using combined phacoemulsification with either PT or PAVI are comparable. The profile of complications is different for the two procedures. How to cite this article: Albis-Donado O, Sánchez-Noguera CC, Cárdenas-Gómez L, Castañeda-Diez R, Thomas R, Gil-Carrasco F. Achieving Target Pressures with Combined Surgery: Primary Patchless Ahmed Valve Combined with Phacoemulsification vs Primary Phacotrabeculectomy. J Curr Glaucoma Pract 2015;9(1):6-11. PMID:26997825

  2. Achieving cultural appropriateness in health promotion programs: targeted and tailored approaches.

    PubMed

    Kreuter, Matthew W; Lukwago, Susan N; Bucholtz, R D Dawn C; Clark, Eddie M; Sanders-Thompson, Vetta

    2003-04-01

    It is a truism of health education that programs and interventions will be more effective when they are culturally appropriate for the populations they serve. In practice, however, the strategies used to achieve cultural appropriateness vary widely. This article briefly describes five strategies commonly used to target programs to culturally defined groups. It then explains how a sixth approach, cultural tailoring, might extend these strategies and enhance our ability to develop effective programs for cultural groups. The authors illustrate this new approach with an example of cultural tailoring forcancer prevention in a population of lower income urban African American women.

  3. G3BP1, G3BP2 and CAPRIN1 are required for translation of interferon stimulated mRNAs and are targeted by a dengue virus non-coding RNA.

    PubMed

    Bidet, Katell; Dadlani, Dhivya; Garcia-Blanco, Mariano A

    2014-07-01

    Viral RNA-host protein interactions are critical for replication of flaviviruses, a genus of positive-strand RNA viruses comprising major vector-borne human pathogens including dengue viruses (DENV). We examined three conserved host RNA-binding proteins (RBPs) G3BP1, G3BP2 and CAPRIN1 in dengue virus (DENV-2) infection and found them to be novel regulators of the interferon (IFN) response against DENV-2. The three RBPs were required for the accumulation of the protein products of several interferon stimulated genes (ISGs), and for efficient translation of PKR and IFITM2 mRNAs. This identifies G3BP1, G3BP2 and CAPRIN1 as novel regulators of the antiviral state. Their antiviral activity was antagonized by the abundant DENV-2 non-coding subgenomic flaviviral RNA (sfRNA), which bound to G3BP1, G3BP2 and CAPRIN1, inhibited their activity and lead to profound inhibition of ISG mRNA translation. This work describes a new and unexpected level of regulation for interferon stimulated gene expression and presents the first mechanism of action for an sfRNA as a molecular sponge of anti-viral effectors in human cells.

  4. G3BP1, G3BP2 and CAPRIN1 Are Required for Translation of Interferon Stimulated mRNAs and Are Targeted by a Dengue Virus Non-coding RNA

    PubMed Central

    Bidet, Katell; Dadlani, Dhivya; Garcia-Blanco, Mariano A.

    2014-01-01

    Viral RNA-host protein interactions are critical for replication of flaviviruses, a genus of positive-strand RNA viruses comprising major vector-borne human pathogens including dengue viruses (DENV). We examined three conserved host RNA-binding proteins (RBPs) G3BP1, G3BP2 and CAPRIN1 in dengue virus (DENV-2) infection and found them to be novel regulators of the interferon (IFN) response against DENV-2. The three RBPs were required for the accumulation of the protein products of several interferon stimulated genes (ISGs), and for efficient translation of PKR and IFITM2 mRNAs. This identifies G3BP1, G3BP2 and CAPRIN1 as novel regulators of the antiviral state. Their antiviral activity was antagonized by the abundant DENV-2 non-coding subgenomic flaviviral RNA (sfRNA), which bound to G3BP1, G3BP2 and CAPRIN1, inhibited their activity and lead to profound inhibition of ISG mRNA translation. This work describes a new and unexpected level of regulation for interferon stimulated gene expression and presents the first mechanism of action for an sfRNA as a molecular sponge of anti-viral effectors in human cells. PMID:24992036

  5. The Immature Fiber Mutant Phenotype of Cotton (Gossypium hirsutum) Is Linked to a 22-bp Frame-Shift Deletion in a Mitochondria Targeted Pentatricopeptide Repeat Gene

    PubMed Central

    Thyssen, Gregory N.; Fang, David D.; Zeng, Linghe; Song, Xianliang; Delhom, Christopher D.; Condon, Tracy L.; Li, Ping; Kim, Hee Jin

    2016-01-01

    Cotton seed trichomes are the most important source of natural fibers globally. The major fiber thickness properties influence the price of the raw material, and the quality of the finished product. The recessive immature fiber (im) gene reduces the degree of fiber cell wall thickening by a process that was previously shown to involve mitochondrial function in allotetraploid Gossypium hirsutum. Here, we present the fine genetic mapping of the im locus, gene expression analysis of annotated proteins near the locus, and association analysis of the linked markers. Mapping-by-sequencing identified a 22-bp deletion in a pentatricopeptide repeat (PPR) gene that is completely linked to the immature fiber phenotype in 2837 F2 plants, and is absent from all 163 cultivated varieties tested, although other closely linked marker polymorphisms are prevalent in the diversity panel. This frame-shift mutation results in a transcript with two long open reading frames: one containing the N-terminal transit peptide that targets mitochondria, the other containing only the RNA-binding PPR domains, suggesting that a functional PPR protein cannot be targeted to mitochondria in the im mutant. Taken together, these results suggest that PPR gene Gh_A03G0489 is involved in the cotton fiber wall thickening process, and is a promising candidate gene at the im locus. Our findings expand our understanding of the molecular mechanisms that modulate cotton fiber fineness and maturity, and may facilitate the development of cotton varieties with superior fiber attributes. PMID:27172184

  6. HDAC4 as a potential therapeutic target in neurodegenerative diseases: a summary of recent achievements

    PubMed Central

    Mielcarek, Michal; Zielonka, Daniel; Carnemolla, Alisia; Marcinkowski, Jerzy T.; Guidez, Fabien

    2015-01-01

    For the past decade protein acetylation has been shown to be a crucial post-transcriptional modification involved in the regulation of protein functions. Histone acetyltransferases (HATs) mediate acetylation of histones which results in the nucleosomal relaxation associated with gene expression. The reverse reaction, histone deacetylation, is mediated by histone deacetylases (HDACs) leading to chromatin condensation followed by transcriptional repression. HDACs are divided into distinct classes: I, IIa, IIb, III, and IV, on the basis of size and sequence homology, as well as formation of distinct repressor complexes. Implications of HDACs in many diseases, such as cancer, heart failure, and neurodegeneration, have identified these molecules as unique and attractive therapeutic targets. The emergence of HDAC4 among the members of class IIa family as a major player in synaptic plasticity raises important questions about its functions in the brain. The characterization of HDAC4 specific substrates and molecular partners in the brain will not only provide a better understanding of HDAC4 biological functions but also might help to develop new therapeutic strategies to target numerous malignancies. In this review we highlight and summarize recent achievements in understanding the biological role of HDAC4 in neurodegenerative processes. PMID:25759639

  7. Achieving cholesterol targets by individualizing starting doses of statin according to baseline low-density lipoprotein cholesterol and coronary artery disease risk category: The CANadians Achieve Cholesterol Targets Fast with Atorvastatin Stratified Titration (CanACTFAST) study

    PubMed Central

    Ur, Ehud; Langer, Anatoly; Rabkin, Simon W; Calciu, Cristina-Dana; Leiter, Lawrence A

    2010-01-01

    BACKGROUND: Despite an increasing body of evidence on the benefit of lowering elevated levels of low-density lipoprotein cholesterol (LDL-C), there is still considerable concern that patients are not achieving target LDL-C levels. OBJECTIVE: The CANadians Achieve Cholesterol Targets Fast with Atorvastatin Stratified Titration (CanACTFAST) trial tested whether an algorithm-based statin dosing approach would enable patients to achieve LDL-C and total cholesterol/high-density lipoprotein cholesterol (TC/HDL-C) ratio targets quickly. METHODS: Subjects requiring statin therapy, but with an LDL-C level of 5.7 mmol/L or lower, and triglycerides of 6.8 mmol/L or lower at screening participated in the 12-week study, which had two open-label, six-week phases: a treatment period during which patients received 10 mg, 20 mg, 40 mg or 80 mg of atorvastatin based on an algorithm incorporating baseline LDL-C value and cardiovascular risk; and patients who achieved both LDL-C and TC/HDL-C ratio targets at six weeks continued on the same atorvastatin dose. Patients who did not achieve both targets received dose uptitration using a single-step titration regimen. The primary efficacy outcome was the proportion of patients achieving target LDL-C levels after 12 weeks. RESULTS: Of 2016 subjects screened at 88 Canadian sites, 1258 were assigned to a study drug (1101 were statin-free and 157 were statin-treated at baseline). The proportion of subjects who achieved LDL-C targets after 12 weeks of treatment was 86% (95% CI 84% to 88%) for statin-free patients and 54% (95% CI 46% to 61%) for statin-treated patients. Overall, 1003 subjects (80%; 95% CI 78% to 82%) achieved both lipid targets. CONCLUSIONS: Algorithm-based statin dosing enables patients to achieve LDL-C and TC/HDL-C ratio targets quickly, with either no titration or a single titration. PMID:20151053

  8. Determination of contrast media administration to achieve a targeted contrast enhancement in CT

    NASA Astrophysics Data System (ADS)

    Sahbaee, Pooyan; Li, Yuan; Segars, Paul; Marin, Daniele; Nelson, Rendon; Samei, Ehsan

    2015-03-01

    Contrast enhancement is a key component of CT imaging and offer opportunities for optimization. The design and optimization of new techniques however requires orchestration with the scan parameters and further a methodology to relate contrast enhancement and injection function. In this study, we used such a methodology to develop a method, analytical inverse method, to predict the required injection function to achieve a desired contrast enhancement in a given organ by incorporation of a physiologically based compartmental model. The method was evaluated across 32 different target contrast enhancement functions for aorta, kidney, stomach, small intestine, and liver. The results exhibited that the analytical inverse method offers accurate performance with error in the range of 10% deviation between the predicted and desired organ enhancement curves. However, this method is incapable of predicting the injection function based on the liver enhancement. The findings of this study can be useful in optimizing contrast medium injection function as well as the scan timing to provide more consistency in the way that the contrast enhanced CT examinations are performed. To our knowledge, this work is one of the first attempts to predict the contrast material injection function for a desired organ enhancement curve.

  9. On achieving the state's household recycling target: A case study of Northern New Jersey, USA

    SciTech Connect

    Otegbeye, M.; Abdel-Malek, L.; Hsieh, H.N.; Meegoda, J.N.

    2009-02-15

    In recent times, the State of New Jersey (USA) has been making attempts at promoting recycling as an environmentally friendly means of attaining self-sufficiency at waste disposal, and the state has put in place a 50% recycling target for its municipal solid waste stream. While the environmental benefits of recycling are obvious, a recycling program must be cost effective to ensure its long-term sustainability. In this paper, a linear programming model is developed to examine the current state of recycling in selected counties in Northern New Jersey and assess the needs to achieve the state's recycling goal in these areas. The optimum quantities of waste to be sent to the different waste facilities, which include landfills, incinerators, transfer stations, recycling and composting plants, are determined by the model. The study shows that for these counties, the gap between the current waste practices where the recycling rate stands at 32% and the state's goal can be bridged by more efficient utilization of existing facilities and reasonable investment in expanding those for recycling activities.

  10. Overexpression of miR-214-3p in Esophageal Squamous Cancer Cells Enhances Sensitivity to Cisplatin by Targeting Survivin Directly and Indirectly Through CUG-BP1

    PubMed Central

    Phatak, Pornima; Byrnes, Kimberly A.; Mansour, Daniel; Liu, Lan; Cao, Shan; Li, Ruiyun; Rao, Jaladanki N.; Turner, Douglas J.; Wang, Jian-Ying; Donahue, James M.

    2015-01-01

    Based on its marked overexpression in multiple malignancies and its roles in promoting cell survival and proliferation, survivin is an attractive candidate for targeted therapy. Towards this end, a detailed understanding of the mechanisms regulating survivin expression in different cancer cells will be critical. We have previously shown that the RNA-binding protein (RBP) CUG-BP1 is overexpressed in esophageal cancer cells and post-transcriptionally regulates survivin in these cells. The objective of this study was to investigate the role of microRNAs (miRs) in regulating survivin expression in esophageal cancer cells. Using miR expression profiling analysis, we found that miR-214-3p is one of the most markedly downregulated miRs in two esophageal squamous cancer cell lines compared to esophageal epithelial cells. Interestingly, using miR target prediction programs, both survivin and CUG-BP1 mRNA were found to contain potential binding sites for miR-214-3p. Forced expression of miR-214-3p in esophageal cancer cells leads to a decrease in the mRNA and protein levels of both survivin and CUG-BP1. This effect is due to decreased mRNA stability of both targets. By contrast, silencing miR-214-3p in esophageal epithelial cells leads to an increase in both survivin and CUG-BP1 mRNA and protein. To determine whether the observed effect of miR-214-3p on survivin expression was direct, mediated through CUG-BP1, or both, binding studies utilizing biotin pull-down assays and heterologous luciferase reporter constructs were performed. These demonstrated that the mRNA of survivin and CUG-BP1 each contain two functional miR-214-3p binding sites as confirmed by mutational analysis. Finally, forced expression of miR-214-3p enhances the sensitivity of esophageal cancer cells to Cisplatin-induced apoptosis. This effect is abrogated with rescue expression of survivin or CUG-BP1. These findings suggest that miR-214-3p acts as a tumor suppressor and that its downregulation contributes to

  11. Prenatal Transmission of Syphilis and Human Immunodeficiency Virus in Brazil: Achieving Regional Targets for Elimination

    PubMed Central

    Cerda, Rodrigo; Perez, Freddy; Domingues, Rosa Maria S.M.; Luz, Paula M.; Grinsztejn, Beatriz; Veloso, Valdilea G.; Caffe, Sonja; Francke, Jordan A.; Freedberg, Kenneth A.; Ciaranello, Andrea L.

    2015-01-01

    Background. The Pan-American Health Organization has called for reducing (1) human immunodeficiency virus (HIV) mother-to-child transmission (MTCT) to ≤0.30 infections/1000 live births (LB), (2) HIV MTCT risk to ≤2.0%, and (3) congenital syphilis (CS) incidence to ≤0.50/1000 LB in the Americas by 2015. Methods. Using published Brazilian data in a mathematical model, we simulated a cohort of pregnant women from antenatal care (ANC) through birth. We investigated 2 scenarios: “current access” (89.1% receive one ANC syphilis test and 41.1% receive 2; 81.7% receive one ANC HIV test and 18.9% receive birth testing; if diagnosed, 81.0% are treated for syphilis and 87.5% are treated for HIV) and “ideal access” (95% of women undergo 2 HIV and syphilis screenings; 95% receive appropriate treatment). We conducted univariate and multivariate sensitivity analyses on key inputs. Results. With current access, we projected 2.95 CS cases/1000 LB, 0.29 HIV infections/1000 LB, 7.1% HIV MTCT risk, and 11.11 intrauterine fetal demises (IUFD)/1000 pregnancies, with significant regional variation. With ideal access, we projected improved outcomes: 1.00 CS cases/1000 LB, 0.10 HIV infections/1000 LB, HIV MTCT risk of 2.4%, and 10.65 IUFD/1000 pregnancies. Increased testing drove the greatest improvements. Even with ideal access, only HIV infections/1000 LB met elimination goals. Achieving all targets required testing and treatment >95% and reductions in prevalence and incidence of HIV and syphilis. Conclusions. Increasing access to care and HIV and syphilis antenatal testing will substantially reduce HIV and syphilis MTCT in Brazil. In addition, regionally tailored interventions reducing syphilis incidence and prevalence and supporting HIV treatment adherence are necessary to completely meet elimination goals. PMID:26180825

  12. Substantial Targeting Advantage Achieved by Pulmonary Administration of Colistin Methanesulfonate in a Large-Animal Model.

    PubMed

    Landersdorfer, Cornelia B; Nguyen, Tri-Hung; Lieu, Linh Thuy; Nguyen, Gary; Bischof, Robert J; Meeusen, Els N; Li, Jian; Nation, Roger L; McIntosh, Michelle P

    2017-01-01

    Colistin, administered as its inactive prodrug colistin methanesulfonate (CMS), is often used in multidrug-resistant Gram-negative pulmonary infections. The CMS and colistin pharmacokinetics in plasma and epithelial lining fluid (ELF) following intravenous and pulmonary dosing have not been evaluated in a large-animal model with pulmonary architecture similar to that of humans. Six merino sheep (34 to 43 kg body weight) received an intravenous or pulmonary dose of 4 to 8 mg/kg CMS (sodium) or 2 to 3 mg/kg colistin (sulfate) in a 4-way crossover study. Pulmonary dosing was achieved via jet nebulization through an endotracheal tube cuff. CMS and colistin were quantified in plasma and bronchoalveolar lavage fluid (BALF) samples by high-performance liquid chromatography (HPLC). ELF concentrations were calculated via the urea method. CMS and colistin were comodeled in S-ADAPT. Following intravenous CMS or colistin administration, no concentrations were quantifiable in BALF samples. Elimination clearance was 1.97 liters/h (4% interindividual variability) for CMS (other than conversion to colistin) and 1.08 liters/h (25%) for colistin. On average, 18% of a CMS dose was converted to colistin. Following pulmonary delivery, colistin was not quantifiable in plasma and CMS was detected in only one sheep. Average ELF concentrations (standard deviations [SD]) of formed colistin were 400 (243), 384 (187), and 184 (190) mg/liter at 1, 4, and 24 h after pulmonary CMS administration. The population pharmacokinetic model described well CMS and colistin in plasma and ELF following intravenous and pulmonary administration. Pulmonary dosing provided high ELF and low plasma colistin concentrations, representing a substantial targeting advantage over intravenous administration. Predictions from the pharmacokinetic model indicate that sheep are an advantageous model for translational research.

  13. ED 03-2 HOME BLOOD PRESSURE MONITORING IS BETTER THAN OFFICE BP AND AMBULATORY BP: UPDATE.

    PubMed

    Kario, Kazuomi

    2016-09-01

    Out-of-office blood pressure (BP) measured by home BP monitoring (HBPM) or ambulatory BP monitoring (ABPM) was demonstrated to be superior to office BP for the prediction of cardiovascular events. The ABPM is superior to HBPM for detecting the all the BP-related risks throughout 24-hr, and the self-measured HBPM underestimates the risk of daytime stress hypertension and nocturnal hypertension. However, ABPM cannot always be provided in clinical practice, and home BP monitoring can be superior to ABPM as part of a home BP-guided antihypertension strategy in clinical practice. In clinical practice, we should use both ABPM and HBPM considering these device properties. We have developed the new ABPM device which is alternatively used as self-measure HBPM (Kario. Prog Cardiovasc Dis 2016, in press).The importance of on-treatment HBPM for the cardiovascular prognosis of hypertensive individuals was recently revealed in the largest real-world prospective study held to date, the Home blood pressure measurement with Olmesartan Naive patients to Establish Standard Target blood pressure (HONEST) study. That study of more than 21 000 hypertensive patients used HBPM, and the results demonstrated that when morning home systolic BP was well-controlled during the 2-year follow-up at < 125 mmHg, there was no increase in cardiovascular events even among the patients whose office systolic BP was ≥150 mmHg, compared with those with office systolic BP < 130 mmHg and morning home systolic BP < 125 mmHg. On the other hand, even when the office systolic BP of the HONEST study's hypertensive patients was well controlled at < 130 mmHg, the hazard ratio of cardiovascular events was 2.5 in the masked uncontrolled hypertension patients with morning systolic BP ≥145 mmHg compared with the well-controlled patients with morning systolic BP < 125 mmHg (Kario, et al. Hypertension 2014;64:989-996). The threshold of on-treatment morning BP for a significant increase in

  14. Clinical Outcomes according to the Achievement of Target Low Density Lipoprotein-Cholesterol in Patients with Acute Myocardial Infarction

    PubMed Central

    Ahn, Taehoon; Lee, Kyounghoon; Kang, Woong Chol; Han, Seung Hwan; Ahn, Youngkeun; Jeong, Myung Ho

    2017-01-01

    Background and Objectives The clinical outcome of patient with an acute myocardial infarction (AMI) undergoing percutaneous coronary intervention (PCI), with or without achievement of target low density lipoprotein-cholesterol (LDL-C), has little known information. This study investigated if target LDL-C level (below 70 mg/dL) achievements in patients with AMI showed better clinical outcomes or not. Subjects and Methods Between May 2008 and September 2012, this study enrolled 13473 AMI patients in a large-scale, prospective, multicenter Korean Myocardial Infarction (KorMI) registry. 12720 patients survived and 6746 patients completed a 1-year clinical follow up. Among them 3315 patients received serial lipid profile follow-ups. Propensity score matching was applied to adjust for differences in clinical baseline and angiographic characteristics, producing a total of 1292 patients (646 target LDL-C achievers vs. 646 non-achievers). The primary end point was the composite of a 1-year major adverse cardiac event (MACE) including cardiac death, recurrent myocardial infarction (MI), target lesion revascularization (TLR) and coronary artery bypass grafting. Results After propensity score matching, baseline clinical and angiographic characteristics were similar between the two groups. Clinical outcomes of the propensity score matched patients who showed no significant differences in cardiac death (0.5% vs. 0.5%, p=1.000), recurrent MI (1.1% vs. 0.8%, p=0.562), TLR (5.0% vs. 4.5%, p=0.649), MACEs (6.5% vs. 5.9%, p=0.644) and stent thrombosis (2.5% vs. 1.9%, p=0.560). Conclusion In this propensity-matched comparison, AMI patients undergoing PCI with a target LDL-C (below 70 mg/dL) achievement did not show better clinical outcomes. PMID:28154588

  15. Communicating Non-Targeted Effects of Ionizing Radiation to Achieve Adaptive Homeostasis in Tissues

    SciTech Connect

    Morgan, William F.

    2011-06-04

    Non-targeted effects, i.e., those responses in cells or tissues that were not subject to energy deposition events after localized exposure to ionizing radiaton, are well-established. While they are not universal phenotype, when they do occur they can be associated with subsequent tissue or whole body responses. Here it is argued that non-targeted effects are a tissue level response to restore equilibrium within an organ system, and thus restores tissue homeostasis. This "adaptive homeostasis" has evolved in response to a variety of environmental and other such stresses an individual is exposed to in their lifetime. These non-targeted effects are not likely to impact significantly on estimates of potential risks associated with radiation exposure because they are presumably "built into" current risk estimates. However, they could have implications for radiation carcinogenesis, by driving processes in targeted and non-targeted cells that could eliminate transformed cells or transform cells from a normal phenotype to a phenotype associated with malignancy within a tissue.

  16. Targeted therapies in non-small cell lung carcinoma: what have we achieved so far?

    PubMed Central

    Houhou, Wissam

    2013-01-01

    The search for innovative therapeutic agents in non-small cell lung cancer (NSCLC) has witnessed a swift evolution. The number of targeted drugs that can improve patient outcomes with an acceptable safety profile is steadily increasing. In this review, we highlight current drugs that have already been approved or are under evaluation for the treatment of patients with NSCLC, either in monotherapy or combined therapy for both the first- and second-line settings. Experience with drugs targeting the vascular endothelial growth factor and its receptor, as well as the epidermal growth factor receptor is summarized. Moreover, we provide an overview of more novel targets in NSCLC and initial experience with the respective therapeutic agents. PMID:23858333

  17. [Update of planning tables of cholesterol-lowering therapy orientated to achieve LDL therapeutic targets].

    PubMed

    Masana, Luis; Plana, Núria

    2015-01-01

    This is the third update of a planning-table for use in cholesterol-lowering therapy, so as to obtain LDLc objectives. This is an easy to use laptop tool to help choose the best statin or combination therapy (statin plus ezetimibe) depending on the current LDL concentration of the patient, and the LDLc objective to achieve. It is based on a colour code that indicates the drugs that are efficient enough to help patients to achieve their LDL goal. Along with the table, recommendations are given for the best strategy in order to implement the optimal therapy in a maximum of two clinical encounters.

  18. Narrowing the Field: Achieve Engagement Outcomes Faster by Targeting Potential Alumni Leaders

    ERIC Educational Resources Information Center

    Coolman, Jason

    2013-01-01

    Traditional alumni relations programs are about prompting graduates to do something--anything--for or with the institution. In this article, the author proposes something different: an outcome-oriented alumni relations programming model, which the author calls "strategic advancement," that focuses on smaller, targeted sets of graduates…

  19. Aliskiren in Patients Failing to Achieve Blood Pressure Targets With Angiotensin Converting Enzyme Inhibitors or Angiotensin Receptor Blockers

    PubMed Central

    Hawkins, Elizabeth B.; Ling, Hua; Burns, Tammy L.; Mooss, Aryan N.; Hilleman, Daniel E.

    2012-01-01

    Background To assess the efficacy of aliskiren in patients failing to reach blood pressure (BP) goals with angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB). Methods A total of 107 patients who failed to reach BP goals on ACEI or ARB were switched to aliskiren. Changes in BP were determined during maximal ACEI, ARB, or aliskiren therapy. Results Mean reduction in sBP and dBP with ACEI was 8.5 ± 6.3 mmHg and 6.0 ± 4.7 mmHg, respectively. Mean reduction in sBP and dBP with ARB was 8.3 ± 6.7 mmHg and 5.0 ± 5.2 mmHg, respectively. Mean reduction in sBP and dBP with aliskiren 150 mg/d was 6.7 ± 5.4 mmHg and 5.4 ± 4.8 mmHg, respectively. Mean reduction in sBP and dBP with aliskiren 300 mg/d was 8.6 ± 6.3 mmHg and 6.0 ± 4.9 mmHg, respectively. BP reductions between ACEI, ARB, and aliskiren were not significantly different. Conclusions Aliskiren is ineffective in patients failing ACEI or ARB therapy. Given the label changes restricting the use of aliskiren in combination with ACEI and ARB, excess cost compared to ACEI and ARB, and a paucity of outcome data, there is a limited role for aliskiren in practice.

  20. Can China achieve the WHO global targets for TB control by 2035?

    PubMed

    Huynh, Grace H

    2016-03-01

    To reach the ambitious WHO TB global targets by 2035, it is likely that China will need a comprehensive strategy that builds on its existing high-quality directly observed treatment, short-course program. This will require optimizing the use of existing tools within a changing health system landscape. In addition, new tools are needed to identify and treat TB in high-risk groups and in older people, who are a growing driver of disease incidence. Lastly, strategies are needed to address the proximate risk factors and social determinants that underlie trends in TB burden.

  1. Targeting CD47: the achievements and concerns of current studies on cancer immunotherapy.

    PubMed

    Huang, Yuting; Ma, Yuchi; Gao, Peng; Yao, Zhi

    2017-02-01

    Targeting CD47 is in the spotlight of cancer immunotherapy. Blocking CD47 triggers the recognition and elimination of cancer cells by the innate immunity. There are three CD47 antagonists in phase I clinical trials, but their potential efficacies are highly controversial. We raise our concern that NOD-based xenograft hosts tend to overestimate, while syngeneic mouse models could substantially underestimate the efficacy of anti-CD47 therapy. Such discrepancy may be resulted from specific reagent that alters CD47 clustering, and the highly variable avidities of interspecies and intraspecies CD47-SIRPα interaction. This problem can be addressed by alternative animal models for better recapitulation of human CD47-SIRPα interaction. Both fragment crystallizable (Fc) fragment-dependent effects, like antibody-dependent cell-mediated cytotoxicity (ADCC), and Fc-independent CD47 intrinsic functions are involved in anti-CD47 therapy. The latter may be SIRPα-dependent or SIRPα-independent, such as the case of calreticulin. It has not reached a consensus which of the factors predominate the process, but the answer to this question will determine the optimal pharmaceutical and clinical design of CD47 targeting strategies.

  2. Targeting CD47: the achievements and concerns of current studies on cancer immunotherapy

    PubMed Central

    Huang, Yuting; Ma, Yuchi

    2017-01-01

    Targeting CD47 is in the spotlight of cancer immunotherapy. Blocking CD47 triggers the recognition and elimination of cancer cells by the innate immunity. There are three CD47 antagonists in phase I clinical trials, but their potential efficacies are highly controversial. We raise our concern that NOD-based xenograft hosts tend to overestimate, while syngeneic mouse models could substantially underestimate the efficacy of anti-CD47 therapy. Such discrepancy may be resulted from specific reagent that alters CD47 clustering, and the highly variable avidities of interspecies and intraspecies CD47-SIRPα interaction. This problem can be addressed by alternative animal models for better recapitulation of human CD47-SIRPα interaction. Both fragment crystallizable (Fc) fragment-dependent effects, like antibody-dependent cell-mediated cytotoxicity (ADCC), and Fc-independent CD47 intrinsic functions are involved in anti-CD47 therapy. The latter may be SIRPα-dependent or SIRPα-independent, such as the case of calreticulin. It has not reached a consensus which of the factors predominate the process, but the answer to this question will determine the optimal pharmaceutical and clinical design of CD47 targeting strategies. PMID:28275508

  3. Targeted immunotherapy of cancer with CAR T cells: achievements and challenges.

    PubMed

    Lipowska-Bhalla, Grazyna; Gilham, David E; Hawkins, Robert E; Rothwell, Dominic G

    2012-07-01

    The adoptive transfer of chimeric antigen receptor (CAR)-expressing T cells is a relatively new but promising approach in the field of cancer immunotherapy. This therapeutic strategy is based on the genetic reprogramming of T cells with an artificial immune receptor that redirects them against targets on malignant cells and enables their destruction by exerting T cell effector functions. There has been an explosion of interest in the use of CAR T cells as an immunotherapy for cancer. In the pre-clinical setting, there has been a considerable focus upon optimizing the structural and signaling potency of the CAR while advances in bio-processing technology now mean that the clinical testing of these gene-modified T cells has become a reality. This review will summarize the concept of CAR-based immunotherapy and recent clinical trial activity and will further discuss some of the likely future challenges facing CAR-modified T cell therapies.

  4. Trade-offs of different land and bioenergy policies on the path to achieving climate targets

    SciTech Connect

    Calvin, Katherine V.; Wise, Marshall A.; Kyle, G. Page; Patel, Pralit L.; Clarke, Leon E.; Edmonds, James A.

    2013-10-16

    Many papers have shown that bioenergy and land-use are potentially important elements in a strategy to limit anthropogenic climate change. But, significant expansion of bioenergy production can have a large terrestrial footprint. In this paper, we test the implications for land use, the global energy system, carbon cycle, and carbon prices of meeting a specific climate target, using a single fossil fuel and industrial sector policy instrument—the carbon tax, but with five alternative bioenergy and land-use policy architectures. We find that the policies we examined have differing effects on the different segments of the economy. Comprehensive land policies can reduce land-use change emissions, increasing allowable emissions in the energy system, but have implications for the cost of food. Bioenergy taxes and constraints, on the other hand, have little effect on food prices, but can result in increased carbon and energy prices.

  5. The Knowledge Base for Achieving the Sustainable Development Goal Targets on Water Supply, Sanitation and Hygiene

    PubMed Central

    Hutton, Guy; Chase, Claire

    2016-01-01

    Safe drinking water, sanitation, and hygiene (WASH) are fundamental to an improved standard of living. Globally, 91% of households used improved drinking water sources in 2015, while for improved sanitation it is 68%. Wealth disparities are stark, with rural populations, slum dwellers and marginalized groups lagging significantly behind. Service coverage is significantly lower when considering the new water and sanitation targets under the sustainable development goals (SDGs) which aspire to a higher standard of ‘safely managed’ water and sanitation. Lack of access to WASH can have an economic impact as much as 7% of Gross Domestic Product, not including the social and environmental consequences. Research points to significant health and socio-economic consequences of poor nutritional status, child growth and school performance caused by inadequate WASH. Groundwater over-extraction and pollution of surface water bodies have serious impacts on water resource availability and biodiversity, while climate change exacerbates the health risks of water insecurity. A significant literature documents the beneficial impacts of WASH interventions, and a growing number of impact evaluation studies assess how interventions are optimally financed, implemented and sustained. Many innovations in behavior change and service delivery offer potential for scaling up services to meet the SDGs. PMID:27240389

  6. The Knowledge Base for Achieving the Sustainable Development Goal Targets on Water Supply, Sanitation and Hygiene.

    PubMed

    Hutton, Guy; Chase, Claire

    2016-05-27

    Safe drinking water, sanitation, and hygiene (WASH) are fundamental to an improved standard of living. Globally, 91% of households used improved drinking water sources in 2015, while for improved sanitation it is 68%. Wealth disparities are stark, with rural populations, slum dwellers and marginalized groups lagging significantly behind. Service coverage is significantly lower when considering the new water and sanitation targets under the sustainable development goals (SDGs) which aspire to a higher standard of 'safely managed' water and sanitation. Lack of access to WASH can have an economic impact as much as 7% of Gross Domestic Product, not including the social and environmental consequences. Research points to significant health and socio-economic consequences of poor nutritional status, child growth and school performance caused by inadequate WASH. Groundwater over-extraction and pollution of surface water bodies have serious impacts on water resource availability and biodiversity, while climate change exacerbates the health risks of water insecurity. A significant literature documents the beneficial impacts of WASH interventions, and a growing number of impact evaluation studies assess how interventions are optimally financed, implemented and sustained. Many innovations in behavior change and service delivery offer potential for scaling up services to meet the SDGs.

  7. Physiological geroscience: targeting function to increase healthspan and achieve optimal longevity.

    PubMed

    Seals, Douglas R; Justice, Jamie N; LaRocca, Thomas J

    2016-04-15

    Most nations of the world are undergoing rapid and dramatic population ageing, which presents great socio-economic challenges, as well as opportunities, for individuals, families, governments and societies. The prevailing biomedical strategy for reducing the healthcare impact of population ageing has been 'compression of morbidity' and, more recently, to increase healthspan, both of which seek to extend the healthy period of life and delay the development of chronic diseases and disability until a brief period at the end of life. Indeed, a recently established field within biological ageing research, 'geroscience', is focused on healthspan extension. Superimposed on this background are new attitudes and demand for 'optimal longevity' - living long, but with good health and quality of life. A key obstacle to achieving optimal longevity is the progressive decline in physiological function that occurs with ageing, which causes functional limitations (e.g. reduced mobility) and increases the risk of chronic diseases, disability and mortality. Current efforts to increase healthspan centre on slowing the fundamental biological processes of ageing such as inflammation/oxidative stress, increased senescence, mitochondrial dysfunction, impaired proteostasis and reduced stress resistance. We propose that optimization of physiological function throughout the lifespan should be a major emphasis of any contemporary biomedical policy addressing global ageing. Effective strategies should delay, reduce in magnitude or abolish reductions in function with ageing (primary prevention) and/or improve function or slow further declines in older adults with already impaired function (secondary prevention). Healthy lifestyle practices featuring regular physical activity and ideal energy intake/diet composition represent first-line function-preserving strategies, with pharmacological agents, including existing and new pharmaceuticals and novel 'nutraceutical' compounds, serving as potential

  8. The Socioeconomic Benefit to Individuals of Achieving the 2020 Targets for Five Preventive Chemotherapy Neglected Tropical Diseases

    PubMed Central

    Luyendijk, Marianne; Fitzpatrick, Christopher; Niessen, Louis; Stolk, Wilma A.; Tediosi, Fabrizio; Rijnsburger, Adriana J.; Bakker, Roel; Hontelez, Jan A. C.; Richardus, Jan H.; Jacobson, Julie; de Vlas, Sake J.; Severens, Johan L.

    2017-01-01

    Background Lymphatic filariasis (LF), onchocerciasis, schistosomiasis, soil-transmitted helminths (STH) and trachoma represent the five most prevalent neglected tropical diseases (NTDs). They can be controlled or eliminated by means of safe and cost-effective interventions delivered through programs of Mass Drug Administration (MDA)—also named Preventive Chemotherapy (PCT). The WHO defined targets for NTD control/elimination by 2020, reinforced by the 2012 London Declaration, which, if achieved, would result in dramatic health gains. We estimated the potential economic benefit of achieving these targets, focusing specifically on productivity and out-of-pocket payments. Methods Productivity loss was calculated by combining disease frequency with productivity loss from the disease, from the perspective of affected individuals. Productivity gain was calculated by deducting the total loss expected in the target achievement scenario from the loss in a counterfactual scenario where it was assumed the pre-intervention situation in 1990 regarding NTDs would continue unabated until 2030. Economic benefits from out-of-pocket payments (OPPs) were calculated similarly. Benefits are reported in 2005 US$ (purchasing power parity-adjusted and discounted at 3% per annum from 2010). Sensitivity analyses were used to assess the influence of changes in input parameters. Results The economic benefit from productivity gain was estimated to be I$251 billion in 2011–2020 and I$313 billion in 2021–2030, considerably greater than the total OPPs averted of I$0.72 billion and I$0.96 billion in the same periods. The net benefit is expected to be US$ 27.4 and US$ 42.8 for every dollar invested during the same periods. Impact varies between NTDs and regions, since it is determined by disease prevalence and extent of disease-related productivity loss. Conclusion Achieving the PCT-NTD targets for 2020 will yield significant economic benefits to affected individuals. Despite large

  9. Down-Regulation of miR-129-5p and the let-7 Family in Neuroendocrine Tumors and Metastases Leads to Up-Regulation of Their Targets Egr1, G3bp1, Hmga2 and Bach1

    PubMed Central

    Døssing, Kristina B. V.; Binderup, Tina; Kaczkowski, Bogumil; Jacobsen, Anders; Rossing, Maria; Winther, Ole; Federspiel, Birgitte; Knigge, Ulrich; Kjær, Andreas; Friis-Hansen, Lennart

    2014-01-01

    Expression of miRNAs in Neuroendocrine Neoplasms (NEN) is poorly characterized. We therefore wanted to examine the miRNA expression in Neuroendocrine Tumors (NETs), and identify their targets and importance in NET carcinogenesis. miRNA expression in six NEN primary tumors, six NEN metastases and four normal intestinal tissues was characterized using miRNA arrays, and validated by in-situ hybridization and qPCR. Among the down-regulated miRNAs miR-129-5p and the let-7f/let-7 family, were selected for further characterization. Transfection of miR-129-5p inhibited growth of a pulmonary and an intestinal carcinoid cell line. Analysis of mRNA expression changes identified EGR1 and G3BP1 as miR-129-5p targets. They were validated by luciferase assay and western blotting, and found robustly expressed in NETs by immunohistochemistry. Knockdown of EGR1 and G3BP1 mimicked the growth inhibition induced by miR-129-5p. let-7 overexpression inhibited growth of carcinoid cell lines, and let-7 inhibition increased protein content of the transcription factor BACH1 and its targets MMP1 and HMGA2, all known to promote bone metastases. Immunohistochemistry analysis revealed that let-7 targets are highly expressed in NETs and metastases. We found down-regulation of miR-129-5p and the let-7 family, and identified new neuroendocrine specific targets for these miRNAs, which contributes to the growth and metastatic potential of these tumors. PMID:25546138

  10. A Pharmacist-Staffed, Virtual Gout Management Clinic for Achieving Target Serum Uric Acid Levels: A Randomized Clinical Trial

    PubMed Central

    Goldfien, Robert; Pressman, Alice; Jacobson, Alice; Ng, Michele; Avins, Andrew

    2016-01-01

    Context: Relatively few patients with gout receive appropriate treatment. Objective: To determine whether a pharmacist-staffed gout management program is more effective than usual care in achieving target serum uric acid (sUA) levels in gout patients. Design: A parallel-group, randomized controlled trial of a pharmacist-staffed, telephone-based program for managing hyperuricemia vs usual care. Trial duration was 26 weeks. Main Outcome Measures: Primary outcome measure was achieving sUA levels at or below 6 mg/dL at the 26-week visit. Secondary outcome was mean change in sUA levels in the control and intervention groups. Participants were adults with recurrent gout and sUA levels above 6.0 mg/dL. Participants were randomly assigned to management by a clinical pharmacist following protocol or to monitoring of sUA levels but management of their gout by their usual treating physician. Results: Of 102 patients who met eligibility criteria, 77 subjects obtained a baseline sUA measurement and were entered into the trial. Among 37 participants in the intervention group, 13 (35%) had sUA levels at or below 6.0 mg/dL at 26 weeks, compared with 5 (13%) of 40 participants in the control group (risk ratio = 2.8, 95% confidence interval [CI] = 1.1 to 7.1, p = 0.03). The mean change in sUA levels among controls was +0.1 mg/dL compared with −1.5 mg/dL in the intervention group (sUA difference = −1.6, 95% CI = −0.9 to −2.4, p < 0.001). Conclusions: A structured pharmacist-staffed program was more effective than usual care for achieving target sUA levels. These results suggest a structured program could greatly improve gout management. PMID:27352414

  11. Different systolic blood pressure targets for people with history of stroke or transient ischaemic attack: PAST-BP (Prevention After Stroke—Blood Pressure) randomised controlled trial

    PubMed Central

    McManus, Richard J; Roalfe, Andrea; Fletcher, Kate; Taylor, Clare J; Martin, Una; Virdee, Satnam; Greenfield, Sheila; Hobbs, F D Richard

    2016-01-01

    Objective To assess whether using intensive blood pressure targets leads to lower blood pressure in a community population of people with prevalent cerebrovascular disease. Design Open label randomised controlled trial. Setting 99 general practices in England, with participants recruited in 2009-11. Participants People with a history of stroke or transient ischaemic attack whose systolic blood pressure was 125 mm Hg or above. Interventions Intensive systolic blood pressure target (<130 mm Hg or 10 mm Hg reduction from baseline if this was <140 mm Hg) or standard target (<140 mm Hg). Apart from the different target, patients in both arms were actively managed in the same way with regular reviews by the primary care team. Main outcome measure Change in systolic blood pressure between baseline and 12 months. Results 529 patients (mean age 72) were enrolled, 266 to the intensive target arm and 263 to the standard target arm, of whom 379 were included in the primary analysis (182 (68%) intensive arm; 197 (75%) standard arm). 84 patients withdrew from the study during the follow-up period (52 intensive arm; 32 standard arm). Mean systolic blood pressure dropped by 16.1 mm Hg to 127.4 mm Hg in the intensive target arm and by 12.8 mm Hg to 129.4 mm Hg in the standard arm (difference between groups 2.9 (95% confidence interval 0.2 to 5.7) mm Hg; P=0.03). Conclusions Aiming for target below 130 mm Hg rather than 140 mm Hg for systolic blood pressure in people with cerebrovascular disease in primary care led to a small additional reduction in blood pressure. Active management of systolic blood pressure in this population using a <140 mm Hg target led to a clinically important reduction in blood pressure. Trial registration Current Controlled Trials ISRCTN29062286. PMID:26919870

  12. Targeting Clusters, Achieving Excellence.

    ERIC Educational Resources Information Center

    Rosenfeld, Stuart; Jacobs, Jim; Liston, Cynthia

    2003-01-01

    Suggests that groups, or clusters, of industries form partnerships with community colleges in order to positively impact economic development. Asserts that a cluster-oriented community college system requires innovation, specialized resources and expertise, knowledge of trends, and links to industry. Offers suggestions for developing such a…

  13. Efficacy of a liquid low-energy formula diet in achieving preoperative target weight loss before bariatric surgery.

    PubMed

    Nielsen, Lone V; Nielsen, Mette S; Schmidt, Julie B; Pedersen, Sue D; Sjödin, Anders

    2016-01-01

    A preoperative weight loss of 8 % is a prerequisite to undergo bariatric surgery (BS) in Denmark. The aim of the present study was to evaluate the efficacy of a 7- or an 11-week low-energy diet (LCD) for achieving preoperative target weight before BS. A total of thirty obese patients (BMI 46·0 (sd 4·4) kg/m(2)) followed an LCD (Cambridge Weight Plan(®), 4184 kJ/d (1000 kcal/d)) for 7 or 11 weeks as preparation for BS. Anthropometric measurements including body composition (dual-energy X-ray absorptiometry), blood parameters and blood pressure were assessed at weeks 0, 7 and 11. At week 7, the majority of patients (77 %) had reached their target weight, and this was achieved after 5·4 (sem 0·3) weeks. Mean weight loss was 9·3 (sem 0·5) % (P < 0·01) and consisted of 41·6 % fat-free mass (FFM) and 58·4 % fat mass. The weight loss was accompanied by a decrease in systolic and diastolic blood pressure (7·1 (sem 2·3) and 7·3 (sem 1·8) mmHg, respectively, all P < 0·01) as well as an improved metabolic profile (8·2 (sem 1·8) % decrease in fasting glucose (P < 0·01), 28·6 (sem 6·4) % decrease in fasting insulin (P < 0·01), 23·1 (sem 2·2) % decrease in LDL (P < 0·01), and 9·7 (sem 4·7) % decrease in TAG (P < 0·05)). Weight, FFM and fat mass continued to decrease from week 7 to 11 (all P < 0·01), whereas no additional improvements was observed in the metabolic parameters. Severely obese patients can safely achieve preoperative target weight on an LCD within 7 weeks as part of preparation for BS. However, the considerable reduction in FFM in severely obese subjects needs further investigation.

  14. Left ventricular hypertrophy by electrocardiogram as a predictor of success in home blood pressure control: HOMED-BP study.

    PubMed

    Tanabe, Ayumi; Asayama, Kei; Hanazawa, Tomohiro; Watabe, Daisuke; Nomura, Kyoko; Okamura, Tomonori; Ohkubo, Takayoshi; Imai, Yutaka

    2017-01-12

    Few studies have focused on the effect of organ damage on achievement of long-term home blood pressure (BP) control. Based on the nationwide home BP-based trial data, we aimed to investigate the factors associated with home BP control, in particular, left ventricular hypertrophy (LVH) using the electrocardiogram in patients who started antihypertensive drug treatment. According to the trial protocol, we defined BP as controlled when systolic home BP reached specified targets (125-134 mm Hg in usual control (UC), n=1261; <125 mm Hg in tight control (TC), n=1288). At baseline, before drug treatment started, the mean Sokolow-Lyon voltage was 2.57±0.87 mV, and the mean Cornell product was 1573±705 mm·ms. The numbers of patients who achieved the target BP level in the UC and TC groups were 892 (70.7%) and 576 (44.7%), respectively. In both the UC and TC groups, systolic home BP at baseline was significantly lower in patients who achieved target levels than in those who did not achieve target levels (P<0.0001). Sokolow-Lyon voltage was significantly lower in patients who achieved target levels than in those who did not (P⩽0.0055). The Cornell product levels in each group were similar (P⩾0.12), although significantly different between patients who did or did not achieve the target level when the UC and TC groups were combined for analysis (P=0.031). Sokolow-Lyon voltage was significantly associated with achievement of home BP control in the multivariable-adjusted model (odds ratio, 1.13; 95% confidence intervals, 1.02-1.26; P=0.015), but Cornell product was not (P=0.13). These results indicate the difficulty of sufficient antihypertensive treatment when untreated patients had target organ damage, that is, LVH diagnosed by Sokolow-Lyon voltage.Hypertension Research advance online publication, 12 January 2017; doi:10.1038/hr.2016.176.

  15. Target Achievement Control Test: evaluating real-time myoelectric pattern-recognition control of multifunctional upper-limb prostheses.

    PubMed

    Simon, Ann M; Hargrove, Levi J; Lock, Blair A; Kuiken, Todd A

    2011-01-01

    Despite high classification accuracies (~95%) of myoelectric control systems based on pattern recognition, how well offline measures translate to real-time closed-loop control is unclear. Recently, a real-time virtual test analyzed how well subjects completed arm motions using a multiple-degree of freedom (DOF) classifier. Although this test provided real-time performance metrics, the required task was oversimplified: motion speeds were normalized and unintended movements were ignored. We included these considerations in a new, more challenging virtual test called the Target Achievement Control Test (TAC Test). Five subjects with transradial amputation attempted to move a virtual arm into a target posture using myoelectric pattern recognition, performing the test with various classifier (1- vs 3-DOF) and task complexities (one vs three required motions per posture). We found no significant difference in classification accuracy between the 1- and 3-DOF classifiers (97.2% +/- 2.0% and 94.1% +/- 3.1%, respectively; p = 0.14). Subjects completed 31% fewer trials in significantly more time using the 3-DOF classifier and took 3.6 +/- 0.8 times longer to reach a three-motion posture compared with a one-motion posture. These results highlight the need for closed-loop performance measures and demonstrate that the TAC Test is a useful and more challenging tool to test real-time pattern-recognition performance.

  16. [Molecular mechanisms in the resistance of CML stem cells to tyrosine kinase inhibitors and novel targets for achieving a cure].

    PubMed

    Tanaka, Hirokazu; Hirase, Chikara; Matsumura, Itaru

    2015-02-01

    Tyrosine kinase inhibitors (TKIs) have dramatically improved the clinical outcomes of patients with chronic myeloid leukemia (CML) in the chronic phase. However, even if these patients achieve and maintain marked molecular responses such as a complete molecular response (BCR-ABL/ABL≤0.032% by international scale), discontinuation of TKI treatment results in early molecular relapse in most cases. Although several factors such as the Sokal score and the duration of TKI treatment have been identified as being related to treatment-free remission (TFR), identification of more definite factors or clinical conditions that would enable us to select patients who can maintain TFR is required. Relapse after TKI discontinuation is considered to be attributable to CML stem cells surviving even in patients who maintain marked molecular responses. A number of in vitro experiments have shown that TKI by itself cannot kill CML stem cells. Also, CML stem cells are resistant to TKI in a manner dependent on self-renewal factors (Hh, Wnt/β-catenin), cell cycle regulators (PML), metabotropic factors (FOXO3, Alox5), and adhesion molecules (CXCR4). In addition, surface markers specific for CML stem cells such as IL-1RAP and CD26 have been identified. New therapeutic strategies targeting these molecules in combination with TKI hold promise of achieving a more effective strategy for curing CML.

  17. Primary care of patients with high cardiovascular risk : Blood pressure, lipid and diabetic target levels and their achievement in Hungary.

    PubMed

    Szigethy, Endre; Jancsó, Zoltán; Móczár, Csaba; Ilyés, István; Kovács, Eszter; Róbert Kolozsvári, László; Rurik, Imre

    2013-07-01

    Cardiovascular diseases are responsible for the majority of premature deaths in Hungary as well. Most of them could be prevented with healthy lifestyle of patients and adequate drug prescription of primary care physicians. Earlier European surveys found wide differences between the practices and achievements of different countries in this field. The study was based on and designed according to the framework of previous European Action on Secondary and Primary Prevention by Intervention to Reduce Events (EUROASPIRE) studies and aimed presenting Hungarian results and comparing with the achievements of other countries and previous Hungarian surveys. Among rural and urban settings, 679 patients under continuous care (236 diabetics, 218 with dyslipidaemia, and 225 with hypertension) were consecutively selected by 20 experienced general practitioners. The mean age of patients was 60.3 years (men) and 64.0 years (women). Among diabetics, less than 7 % of glycated hemoglobin (HbA1c) values were found in 42.5 % patients, while only 11.4 % patients had fasting plasma sugar less than 6.0 mmol/L. Of the patients treated for dyslipidaemia, the target level of triglyceride was reached by 40.6 %, recommended total cholesterol by 14.2 % and the HDL-cholesterol by 71.8 %. The therapeutic control of total and HDL-cholesterol was better in men, although women had better triglyceride values. The achievement among patients with hypertension was 42.0 %. Significantly higher blood pressure was measured by patients who were treated with not recommended combinations of antihypertensive medication. A remarkable improvement could be observed in Hungary in the field of secondary prevention. It was greater among patients with hypertension and dyslipidaemia and smaller in diabetes care. Compared to the results of published European surveys, Hungary occupies a good position, but further improvement is still required.

  18. Elevated BP after AKI.

    PubMed

    Hsu, Chi-yuan; Hsu, Raymond K; Yang, Jingrong; Ordonez, Juan D; Zheng, Sijie; Go, Alan S

    2016-03-01

    The connection between AKI and BP elevation is unclear. We conducted a retrospective cohort study to evaluate whether AKI in the hospital is independently associated with BP elevation during the first 2 years after discharge among previously normotensive adults. We studied adult members of Kaiser Permanente Northern California, a large integrated health care delivery system, who were hospitalized between 2008 and 2011, had available preadmission serum creatinine and BP measures, and were not known to be hypertensive or have BP>140/90 mmHg. Among 43,611 eligible patients, 2451 experienced AKI defined using observed changes in serum creatinine concentration measured during hospitalization. Survivors of AKI were more likely than those without AKI to have elevated BP--defined as documented BP>140/90 mmHg measured during an ambulatory, nonemergency department visit--during follow-up (46.1% versus 41.2% at 730 days; P<0.001). This difference was evident within the first 180 days (30.6% versus 23.1%; P<0.001). In multivariable models, AKI was independently associated with a 22% (95% confidence interval, 12% to 33%) increase in the odds of developing elevated BP during follow-up, with higher adjusted odds with more severe AKI. Results were similar in sensitivity analyses when elevated BP was defined as having at least two BP readings of >140/90 mmHg or those with evidence of CKD were excluded. We conclude that AKI is an independent risk factor for subsequent development of elevated BP. Preventing AKI during a hospitalization may have clinical and public health benefits beyond the immediate hospitalization.

  19. The effects of telmisartan alone or with hydrochlorothiazide on morning and 24-h ambulatory BP control: results from a practice-based study (SURGE 2).

    PubMed

    Parati, Gianfranco; Bilo, Grzegorz; Redon, Josep

    2013-04-01

    Observational studies have shown that 24-h and morning ambulatory blood pressure (BP) control is low. This large-scale, practice-based study evaluated the effects of telmisartan 40 or 80 mg alone or in combination with hydrochlorothiazide (HCTZ) 12.5 mg on these BP parameters over 8 weeks; treatment was adjusted if clinic BP remained ≥140/90 mm Hg. A total of 863 patients were evaluated (baseline mean clinic BP, morning and 24-h ambulatory BP: 155±15/93±10 mm Hg, 137±15/83±11 mm Hg, 133±14/79±10 mm Hg, respectively; 68% were previously treated at baseline). Telmisartan with/without HCTZ significantly reduced the mean morning ambulatory BP (-8.2/-4.9 mm Hg), daytime ambulatory BP (-8.0/-4.7 mm Hg), 24-h ambulatory BP (-7.9/-4.7 mm Hg) and clinic BP (-22.3/-13.2 mm Hg) (all P<0.001) in previously untreated and in treated patients who switched to telmisartan and telmisartan/HCTZ. After treatment with telmisartan with/without HCTZ, the morning ambulatory BP control increased from 36.5 to 64.4%; daytime ambulatory BP control increased from 40.8 to 67.6%; 53.0% of patients achieved 24-h ambulatory BP <125/80 mm Hg and 62% achieved <130/80 mm Hg targets. Only 0.8% (7/863) reported an adverse event. In summary, telmisartan and telmisartan/HCTZ increased smooth 24-h BP control in daily management of hypertension.

  20. Elevated BP after AKI

    PubMed Central

    Hsu, Raymond K.; Yang, Jingrong; Ordonez, Juan D.; Zheng, Sijie; Go, Alan S.

    2016-01-01

    The connection between AKI and BP elevation is unclear. We conducted a retrospective cohort study to evaluate whether AKI in the hospital is independently associated with BP elevation during the first 2 years after discharge among previously normotensive adults. We studied adult members of Kaiser Permanente Northern California, a large integrated health care delivery system, who were hospitalized between 2008 and 2011, had available preadmission serum creatinine and BP measures, and were not known to be hypertensive or have BP>140/90 mmHg. Among 43,611 eligible patients, 2451 experienced AKI defined using observed changes in serum creatinine concentration measured during hospitalization. Survivors of AKI were more likely than those without AKI to have elevated BP—defined as documented BP>140/90 mmHg measured during an ambulatory, nonemergency department visit—during follow-up (46.1% versus 41.2% at 730 days; P<0.001). This difference was evident within the first 180 days (30.6% versus 23.1%; P<0.001). In multivariable models, AKI was independently associated with a 22% (95% confidence interval, 12% to 33%) increase in the odds of developing elevated BP during follow-up, with higher adjusted odds with more severe AKI. Results were similar in sensitivity analyses when elevated BP was defined as having at least two BP readings of >140/90 mmHg or those with evidence of CKD were excluded. We conclude that AKI is an independent risk factor for subsequent development of elevated BP. Preventing AKI during a hospitalization may have clinical and public health benefits beyond the immediate hospitalization. PMID:26134154

  1. Population Pharmacokinetics of Colistin Methanesulfonate in Rats: Achieving Sustained Lung Concentrations of Colistin for Targeting Respiratory Infections

    PubMed Central

    W. S. Yapa, Shalini; Li, Jian; Porter, Christopher J. H.; Nation, Roger L.

    2013-01-01

    Colistin methanesulfonate (CMS), the inactive prodrug of colistin, is administered by inhalation for the management of respiratory infections. However, limited pharmacokinetic data are available for CMS and colistin following pulmonary delivery. This study investigates the pharmacokinetics of CMS and colistin following intravenous (i.v.) and intratracheal (i.t.) administration in rats and determines the targeting advantage after direct delivery into the lungs. In addition to plasma, bronchoalveolar lavage (BAL) fluid was collected to quantify drug concentrations in lung epithelial lining fluid (ELF). The resulting data were analyzed using a population modeling approach in S-ADAPT. A three-compartment model described the disposition of both compounds in plasma following i.v. administration. The estimated mean clearance from the central compartment was 0.122 liters/h for CMS and 0.0657 liters/h for colistin. Conversion of CMS to colistin from all three compartments was required to fit the plasma data. The fraction of the i.v. dose converted to colistin in the systemic circulation was 0.0255. Two BAL fluid compartments were required to reflect drug kinetics in the ELF after i.t. dosing. A slow conversion of CMS (mean conversion time [MCTCMS] = 3.48 h) in the lungs contributed to high and sustained concentrations of colistin in ELF. The fraction of the CMS dose converted to colistin in ELF (fm,ELF = 0.226) was higher than the corresponding fractional conversion in plasma after i.v. administration. In conclusion, pulmonary administration of CMS achieves high and sustained exposures of colistin in lungs for targeting respiratory infections. PMID:23917323

  2. Lives saved by tuberculosis control and prospects for achieving the 2015 global target for reducing tuberculosis mortality

    PubMed Central

    Floyd, Katherine; Korenromp, Eline L; Sismanidis, Charalambos; Bierrenbach, Ana L; Williams, Brian G; Atun, Rifat; Raviglione, Mario

    2011-01-01

    Abstract Objective To assess whether the global target of halving tuberculosis (TB) mortality between 1990 and 2015 can be achieved and to conduct the first global assessment of the lives saved by the DOTS/Stop TB Strategy of the World Health Organization (WHO). Methods Mortality from TB since 1990 was estimated for 213 countries using established methods endorsed by WHO. Mortality trends were estimated separately for people with and without human immunodeficiency virus (HIV) infection in accordance with the International classification of diseases. Lives saved by the DOTS/Stop TB Strategy were estimated with respect to the performance of TB control in 1995, the year that DOTS was introduced. Findings TB mortality among HIV-negative (HIV−) people fell from 30 to 20 per 100 000 population (36%) between 1990 and 2009 and could be halved by 2015. The overall decline (when including HIV-positive [HIV+] people, who comprise 12% of all TB cases) was 19%. Between 1995 and 2009, 49 million TB patients were treated under the DOTS/Stop TB Strategy. This saved 4.6–6.3 million lives, including those of 0.23–0.28 million children and 1.4–1.7 million women of childbearing age. A further 1 million lives could be saved annually by 2015. Conclusion Improvements in TB care and control since 1995 have greatly reduced TB mortality, saved millions of lives and brought within reach the global target of halving TB deaths by 2015 relative to 1990. Intensified efforts to reduce deaths among HIV+ TB cases are needed, especially in sub-Saharan Africa. PMID:21836756

  3. Can we bet on negative emissions to achieve the 2°C target even under strong carbon cycle feedbacks?

    NASA Astrophysics Data System (ADS)

    Tanaka, K.; Yamagata, Y.; Yokohata, T.; Emori, S.; Hanaoka, T.

    2015-12-01

    tentative results point to a key policy message: do not rely on negative emissions to achieve the 2°C target. It would make more sense to gear climate mitigation actions toward the stabilization target without betting on negative emissions because negative emissions might create large overshoot in case of strong feedbacks.

  4. Analysis of the first therapeutic-target-achieving time of warfarin therapy and associated factors in patients with pulmonary embolism

    PubMed Central

    Gong, Xiaowei; Wang, Haiyan; Yuan, Yadong

    2016-01-01

    The present study aimed to investigate the factors affecting the first therapeutic-target-achieving (TTA) time of warfarin therapy in patients with acute pulmonary embolism (PTE). Between January 2008 and June 2013, patients with PTE confirmed by transpulmonary arterial enhanced computed tomographic pulmonary angiography or pulmonary ventilation perfusion scanning were included in the present study. Data collected included demographic information, history of tobacco and alcohol intake, basic diseases (stable and unstable hypertension, diabetes, heart failure, cancer/cerebral infarction, old myocardial infarction and atrial fibrillation), liver and kidney function, the haemoglobin and platelet count of the blood, international normalized ratio monitoring, warfarin dosage adjustment and medication combinations. Dynamic changes in international normalized ratio, anticoagulant efficacy, and adverse events within 90 days were monitored and analyzed. Univariate analysis demonstrated that the following factors affect the first TTA time: Initial dose, body mass index (BMI), liver function, heart failure, and the administration of levofloxacin, cephalosporins, and blood circulation-activating drugs. Logistic regression analysis revealed that the following were independent factors of the first TTA time: Initial dose, BMI, liver function, heart failure and levofloxacin. Therefore, the results of the present study demonstrated that various factors may affect the first TTA time of warfarin therapy, including the initial dose, BMI, liver function, heart function and concomitant medication. PMID:27698722

  5. Gracilaria lemaneiformis polysaccharide as integrin-targeting surface decorator of selenium nanoparticles to achieve enhanced anticancer efficacy.

    PubMed

    Jiang, Wenting; Fu, Yuanting; Yang, Fang; Yang, Yufeng; Liu, Ting; Zheng, Wenjie; Zeng, Lilan; Chen, Tianfeng

    2014-08-27

    The poor permeability of glioma parenchyma represents a major limit for antiglioblastoma drug delivery. Gracilaria lemaneiformis polysaccharide (GLP), which has a high binding affinity to αvβ3 integrin overexpressed in glioma cells, was employed in the present study to functionalize selenium nanoparticles (SeNPs) to achieve antiglioblastoma efficacy. GLP-SeNPs showed satisfactory size distribution, high stability, and selectivity between cancer and normal cells. In U87 glioma cell membrane, which has a high integrin expression level, GLP-SeNPs exhibited significantly higher cellular uptake than unmodified SeNPs. As expected, U87 cells exhibited a greater uptake of GLP-SeNPs than C6 cells with low integrin expression level. Furthermore, the internalization of GLP-SeNPs was inhibited by cyclo-(Arg-Gly-Asp-Phe-Lys) peptides, suggesting that cellular uptake into U87 cells and C6 cells occurred via αvβ3 integrin-mediated endocytosis. For U87 cells, the cytotoxicity of SeNPs decorated by GLP was enhanced significantly because of the induction of various apoptosis signaling pathways. Internalized GLP-SeNPs triggered intracellular reactive oxygen species downregulation. Therefore, p53, MAPKs, and AKT pathways were activated to advance cell apoptosis. These findings suggest that surface decoration of nanomaterials with GLP could be an efficient strategy for design and preparation of glioblastoma targeting nanodrugs.

  6. Short training in focused cardiac ultrasound in an Internal Medicine department: what realistic skill targets could be achieved?

    PubMed

    Mozzini, Chiara; Garbin, Ulisse; Fratta Pasini, Anna Maria; Cominacini, Luciano

    2015-02-01

    The importance of focused cardiac ultrasound (FCU) in Internal Medicine care has been recognized by the American Society of Echocardiography. The aim of this study was to test what realistic skill targets could be achieved in FCU, with a relatively short training (theoretical and practical) of 9 h offered to Internal Medicine certification board attending students, and if the addition of further 9 h of training could significantly improve the level of competence. Kappa statistic was used to calculate the inter-observer agreement (trainees/tutor). The agreement between the trainees (who completed the entire training) and the tutor was, respectively, "substantial" (k = 0.71) for the identification of pericardial effusion, "moderate" (k = 0.56-0.54) for the identification of marked right ventricular and left ventricular enlargement, "substantial" (k = 0.77) for the assessment of global cardiac systolic function by visual inspection and "fair" (k = 0.35) for the assessment of size and respiratory change in the diameter of the inferior cave vein (IVC). 18 h training in FCU provided proficiency in obtaining adequate images from the parasternal window without providing the ability to correctly master the apical and subcostal windows. As concerns the interpretative skills, only pericardial effusion and visual estimation of global systolic function could be correctly identified, while ventricular enlargement and IVC prove to be more difficult to evaluate. This study supports incorporating FCU into Internal Medicine fellowship training programs, and should facilitate the design of other similar training courses.

  7. Interoperability of wearable cuffless BP measuring devices.

    PubMed

    Liu, Jing; Zhang, Yuan-Ting

    2014-01-01

    While a traditional cuff-based Blood Pressure (BP) measuring device can only take a snap shot of BP, real-time and continuous measurement of BP without an occluding cuff is preferred which usually use the pulse transit time (PTT) in combination with other physiological parameters to estimate or track BP over a certain period of time after an initial calibration. This article discusses some perspectives of interoperability of wearable medical devices, based on IEEE P1708 draft standard that focuses on the objective performance evaluation of wearable cuffless BP measuring devices. The ISO/IEEE 11073 family of standards, supporting the plug-and play feature, is intended to enable medical devices to interconnect and interoperate with other medical devices and with computerized healthcare information systems in a manner suitable for the clinical environment. In this paper, the possible adoption of ISO/IEEE 11073 for the interoperability of wearable cuffless BP devices is proposed. In the consideration of the difference of the continuous and cuffless BP measuring methods from the conventional ones, the existing device specialization standards of ISO/IEEE 11073 cannot be directly followed when designing the cuffless BP device. Specifically, this paper discusses how the domain information model (DIM), in which vital sign information is abstracted as objects, is used to structure the information about the device and that generated from the device. Though attention should also be paid to adopt the communication standards for other parts for the communication system, applying communication standards that enable plug-and-play feature allows achieving the interoperability of different cuffless BP measuring devices with possible different configurations.

  8. Large-scale survey of rates of achieving targets for blood glucose, blood pressure, and lipids and prevalence of complications in type 2 diabetes (JDDM 40)

    PubMed Central

    Yokoyama, Hiroki; Oishi, Mariko; Takamura, Hiroshi; Yamasaki, Katsuya; Shirabe, Shin-ichiro; Uchida, Daigaku; Sugimoto, Hidekatsu; Kurihara, Yoshio; Araki, Shin-ichi; Maegawa, Hiroshi

    2016-01-01

    Objective The fact that population with type 2 diabetes mellitus and bodyweight of patients are increasing but diabetes care is improving makes it important to explore the up-to-date rates of achieving treatment targets and prevalence of complications. We investigated the prevalence of microvascular/macrovascular complications and rates of achieving treatment targets through a large-scale multicenter-based cohort. Research design and methods A cross-sectional nationwide survey was performed on 9956 subjects with type 2 diabetes mellitus who consecutively attended primary care clinics. The prevalence of nephropathy, retinopathy, neuropathy, and macrovascular complications and rates of achieving targets of glycated hemoglobin (HbA1c) <7.0%, blood pressure <130/80 mm Hg, and lipids of low-density/high-density lipoprotein cholesterol <3.1/≥1.0 mmol/L and non-high-density lipoprotein cholesterol <3.8 mmol/L were investigated. Results The rates of achieving targets for HbA1c, blood pressure, and lipids were 52.9%, 46.8% and 65.5%, respectively. The prevalence of microvascular complications was ∼28% each, 6.4% of which had all microvascular complications, while that of macrovascular complications was 12.6%. With an increasing duration of diabetes, the rate of achieving target HbA1c decreased and the prevalence of each complication increased despite increased use of diabetes medication. The prevalence of each complication decreased according to the number achieving the 3 treatment targets and was lower in subjects without macrovascular complications than those with. Adjustments for considerable covariates exhibited that each complication was closely inter-related, and the achievement of each target was significantly associated with being free of each complication. Conclusions Almost half of the subjects examined did not meet the recommended targets. The risk of each complication was significantly affected by 1 on-target treatment (inversely) and the

  9. 78 FR 60270 - BP America Inc., BP Corporation North America Inc., BP America Production Company, and BP Energy...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-10-01

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF ENERGY Federal Energy Regulatory Commission BP America Inc., BP Corporation North America Inc., BP America Production Company, and BP Energy Company; Notice of Designation of Commission Staff as Non-Decisional With respect to an order issued by the Commission...

  10. A waveform detector that targets template–decorrelated signals and achieves its predicted performance, Part I: Demonstration with IMS data

    SciTech Connect

    Carmichael, Joshua Daniel

    2016-01-01

    Here, waveform correlation detectors used in seismic monitoring scan multichannel data to test two competing hypotheses: that data contain (1) a noisy, amplitude-scaled version of a template waveform, or, (2) only noise. In reality, seismic wavefields include signals triggered by non-target sources (background seismicity) and targets signals that are only partially correlated with the waveform template.

  11. Deficiency in Either 4E-BP1 or 4E-BP2 Augments Innate Antiviral Immune Responses

    PubMed Central

    Nehdi, Atef; Sean, Polen; Linares, Izzar; Colina, Rodney; Jaramillo, Maritza; Alain, Tommy

    2014-01-01

    Genetic deletion of both 4E-BP1 and 4E-BP2 was found to protect cells against viral infections. Here we demonstrate that the individual loss of either 4E-BP1 or 4E-BP2 in mouse embryonic fibroblasts (MEFs) is sufficient to confer viral resistance. shRNA-mediated silencing of 4E-BP1 or 4E-BP2 renders MEFs resistant to viruses, and compared to wild type cells, MEFs knockout for either 4E-BP1 or 4E-BP2 exhibit enhanced translation of Irf-7 and consequently increased innate immune response to viruses. Accordingly, the replication of vesicular stomatitis virus, encephalomyocarditis virus, influenza virus and Sindbis virus is markedly suppressed in these cells. Importantly, expression of either 4E-BP1 or 4E-BP2 in double knockout or respective single knockout cells diminishes their resistance to viral infection. Our data show that loss of 4E-BP1 or 4E-BP2 potentiates innate antiviral immunity. These results provide further evidence for translational control of innate immunity and support targeting translational effectors as an antiviral strategy. PMID:25531441

  12. The Relationship between Anxiety and Attitude of Students Learning Turkish as a Foreign Language and Their Achievement on Target Language

    ERIC Educational Resources Information Center

    Gocer, Ali

    2014-01-01

    The purpose of this study is to assess the anxiety connected with target language of the high school students learning Turkish as a foreign language. In this study, descriptive relational screening model was used. Two scales were used for collecting data. First scale was FLCAS-Foreign Language Classroom Anxiety Scale; it was developed by Horwitz…

  13. Targeting Cancer Protein Profiles with Split-Enzyme Reporter Fragments to Achieve Chemical Resolution for Molecular Imaging

    DTIC Science & Technology

    2012-08-01

    receptor-targeted peptides as outlined in Milestone 1. For these studies, we employed a peptide discovered through phage display screening...9L cells overexpressing TfR were stably transfected with pcDNA3.1-EGFR and selected using antibiotics . Western blotting was used to show the relative

  14. Effects of Achieving Target Measures in Rheumatoid Arthritis on Functional Status, Quality of Life, and Resource Utilization: Analysis of Clinical Practice Data

    PubMed Central

    Joo, Seongjung; Kawabata, Hugh; Al, Maiwenn J.; Allison, Paul D.; Rutten‐van Mölken, Maureen P. M. H.; Frits, Michelle L.; Iannaccone, Christine K.; Shadick, Nancy A.; Weinblatt, Michael E.

    2016-01-01

    Objective To evaluate associations between achieving guideline‐recommended targets of disease activity, defined by the Disease Activity Score in 28 joints using C‐reactive protein level (DAS28‐CRP) <2.6, the Simplified Disease Activity Index (SDAI) ≤3.3, or the Clinical Disease Activity Index (CDAI) ≤2.8, and other health outcomes in a longitudinal observational study. Methods Other defined thresholds included low disease activity (LDA), moderate (MDA), or severe disease activity (SDA). To control for intraclass correlation and estimate effects of independent variables on outcomes of the modified Health Assessment Questionnaire (M‐HAQ), the EuroQol 5‐domain (EQ‐5D; a quality‐of‐life measure), hospitalization, and durable medical equipment (DME) use, we employed mixed models for continuous outcomes and generalized estimating equations for binary outcomes. Results Among 1,297 subjects, achievement (versus nonachievement) of recommended disease targets was associated with enhanced physical functioning and lower health resource utilization. After controlling for baseline covariates, achievement of disease targets (versus LDA) was associated with significantly enhanced physical functioning based on SDAI ≤3.3 (ΔM‐HAQ −0.047; P = 0.0100) and CDAI ≤2.8 (−0.073; P = 0.0003) but not DAS28‐CRP <2.6 (−0.022; P = 0.1735). Target attainment was associated with significantly improved EQ‐5D (0.022–0.096; P < 0.0030 versus LDA, MDA, or SDA). Patients achieving guideline‐recommended disease targets were 36–45% less likely to be hospitalized (P < 0.0500) and 23–45% less likely to utilize DME (P < 0.0100). Conclusion Attaining recommended target disease‐activity measures was associated with enhanced physical functioning and health‐related quality of life. Some health outcomes were similar in subjects attaining guideline targets versus LDA. Achieving LDA is a worthy clinical objective in some patients. PMID:26238974

  15. The Potential for School-Based Interventions That Target Executive Function to Improve Academic Achievement: A Review

    ERIC Educational Resources Information Center

    Jacob, Robin; Parkinson, Julia

    2015-01-01

    This article systematically reviews what is known empirically about the association between executive function and student achievement in both reading and math and critically assesses the evidence for a causal association between the two. Using meta-analytic techniques, the review finds that there is a moderate unconditional association between…

  16. Enabling implementation of the Global Vaccine Action Plan: developing investment cases to achieve targets for measles and rubella prevention.

    PubMed

    Thompson, Kimberly M; Strebel, Peter M; Dabbagh, Alya; Cherian, Thomas; Cochi, Stephen L

    2013-04-18

    Global prevention and control of infectious diseases requires significant investment of financial and human resources and well-functioning leadership and management structures. The reality of competing demands for limited resources leads to trade-offs and questions about the relative value of specific investments. Developing investment cases can help to provide stakeholders with information about the benefits, costs, and risks associated with available options, including examination of social, political, governance, and ethical issues. We describe the process of developing investment cases for globally coordinated management of action plans for measles and rubella as tools for enabling the implementation of the Global Vaccine Action Plan (GVAP). We focus on considerations related to the timing of efforts to achieve measles and rubella goals independently and within the context of ongoing polio eradication efforts, other immunization priorities, and other efforts to control communicable diseases or child survival initiatives. Our analysis suggests that the interactions between the availability and sustainability of financial support, sufficient supplies of vaccines, capacity of vaccine delivery systems, and commitments at all levels will impact the feasibility and timing of achieving national, regional, and global goals. The timing of investments and achievements will determine the net financial and health benefits obtained. The methodology, framing, and assumptions used to characterize net benefits and uncertainties in the investment cases will impact estimates and perceptions about the value of prevention achieved overall by the GVAP. We suggest that appropriately valuing the benefits of investments of measles and rubella prevention will require the use of integrated dynamic disease, economic, risk, and decision analytic models in combination with consideration of qualitative factors, and that synthesizing information in the form of investment cases may help

  17. Kazakhstan can achieve ambitious HIV targets despite expected donor withdrawal by combining improved ART procurement mechanisms with allocative and implementation efficiencies

    PubMed Central

    Benedikt, Clemens; Bokazhanova, Aliya; Đurić, Predrag; Petrenko, Irina; Ganina, Lolita; Kelly, Sherrie L.; Stuart, Robyn M.; Kerr, Cliff C.; Vinichenko, Tatiana; Zhang, Shufang; Hamelmann, Christoph; Manova, Manoela; Masaki, Emiko; Wilson, David P.; Gray, Richard T.

    2017-01-01

    Background Despite a non-decreasing HIV epidemic, international donors are soon expected to withdraw funding from Kazakhstan. Here we analyze how allocative, implementation, and technical efficiencies could strengthen the national HIV response under assumptions of future budget levels. Methodology We used the Optima model to project future scenarios of the HIV epidemic in Kazakhstan that varied in future antiretroviral treatment unit costs and management expenditure—two areas identified for potential cost-reductions. We determined optimal allocations across HIV programs to satisfy either national targets or ambitious targets. For each scenario, we considered two cases of future HIV financing: the 2014 national budget maintained into the future and the 2014 budget without current international investment. Findings Kazakhstan can achieve its national HIV targets with the current budget by (1) optimally re-allocating resources across programs and (2) either securing a 35% [30%–39%] reduction in antiretroviral treatment drug costs or reducing management costs by 44% [36%–58%] of 2014 levels. Alternatively, a combination of antiretroviral treatment and management cost-reductions could be sufficient. Furthermore, Kazakhstan can achieve ambitious targets of halving new infections and AIDS-related deaths by 2020 compared to 2014 levels by attaining a 67% reduction in antiretroviral treatment costs, a 19% [14%–27%] reduction in management costs, and allocating resources optimally. Significance With Kazakhstan facing impending donor withdrawal, it is important for the HIV response to achieve more with available resources. This analysis can help to guide HIV response planners in directing available funding to achieve the greatest yield from investments. The key changes recommended were considered realistic by Kazakhstan country representatives. PMID:28207809

  18. Evaluation of the Specificity of BP3385 for Bordetella pertussis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    BP3385 has been proposed as a diagnostic PCR target for discriminating between Bordetella pertussis and other Bordetella species that also infect humans. Our results demonstrate this gene is also present in some strains of Bordetella hinzii and Bordetella bronchiseptica....

  19. City-specific vehicle emission control strategies to achieve stringent emission reduction targets in China's Yangtze River Delta region.

    PubMed

    Zhang, Shaojun; Wu, Ye; Zhao, Bin; Wu, Xiaomeng; Shu, Jiawei; Hao, Jiming

    2017-01-01

    The Yangtze River Delta (YRD) region is one of the most prosperous and densely populated regions in China and is facing tremendous pressure to mitigate vehicle emissions and improve air quality. Our assessment has revealed that mitigating vehicle emissions of NOx would be more difficult than reducing the emissions of other major vehicular pollutants (e.g., CO, HC and PM2.5) in the YRD region. Even in Shanghai, where the emission control implemented are more stringent than in Jiangsu and Zhejiang, we observed little to no reduction in NOx emissions from 2000 to 2010. Emission-reduction targets for HC, NOx and PM2.5 are determined using a response surface modeling tool for better air quality. We design city-specific emission control strategies for three vehicle-populated cities in the YRD region: Shanghai and Nanjing and Wuxi in Jiangsu. Our results indicate that even if stringent emission control consisting of the Euro 6/VI standards, the limitation of vehicle population and usage, and the scrappage of older vehicles is applied, Nanjing and Wuxi will not be able to meet the NOx emissions target by 2020. Therefore, additional control measures are proposed for Nanjing and Wuxi to further mitigate NOx emissions from heavy-duty diesel vehicles.

  20. Trends and implications for achieving VISION 2020 human resources for eye health targets in 16 countries of sub-Saharan Africa by the year 2020

    PubMed Central

    2014-01-01

    Background Development of human resources for eye health (HReH) is a major global eye health strategy to reduce the prevalence of avoidable visual impairment by the year 2020. Building on our previous analysis of current progress towards key HReH indicators and cataract surgery rates (CSRs), we predicted future indicator achievement among 16 countries of sub-Saharan Africa by 2020. Methods Surgical and HReH data were collected from national eye care programme coordinators on six practitioner cadres: ophthalmologists, cataract surgeons, ophthalmic clinical officers, ophthalmic nurses, optometrists and ‘mid-level refractionists’ and combined them with publicly available population data to calculate practitioner-to-population ratios and CSRs. Data on workforce entry and exit (2008 to 2010) was used to project practitioner population and CSR growth between 2011 and 2020 in relation to projected growth in the general population. Associations between indicator progress and the presence of a non-physician cataract surgeon cadre were also explored using Wilcoxon rank sum tests and Spearman rank correlations. Results In our 16-country sample, practitioner per million population ratios are predicted to increase slightly for surgeons (ophthalmologists/cataract surgeons, from 3.1 in 2011 to 3.4 in 2020) and ophthalmic nurses/clinical officers (5.8 to 6.8) but remain low for refractionists (including optometrists, at 3.6 in 2011 and 2020). Among countries that have not already achieved target indicators, however, practitioner growth will be insufficient for any additional countries to reach the surgeon and refractionist targets by year 2020. Without further strategy change and investment, even after 2020, surgeon growth is only expected to sufficiently outpace general population growth to reach the target in one country. For nurses, two additional countries will achieve the target while one will fall below it. In 2011, high surgeon practitioner ratios were associated with

  1. Nonspecific targeting of iron oxide nanoparticles to the liver, kidney and spleen: A novel approach to achieving specificity

    NASA Astrophysics Data System (ADS)

    Palihawadana Arachchige, Maheshika; Flack, Amanda; Chen, Xuequn; Li, Jing; Oupicky, David; Cheng, Y.-C. Norman; Shen, Yimin; Jena, Bhanu; Lawes, Gavin

    2013-03-01

    Recently, there has been significant interest in developing Fe3O4 nanoparticles for biomedical applications including targeted drug delivery and magnetic resonance imaging. One of the major problems in these applications is the undesirable filtration of these materials by the mononuclear phagocyte system. Preliminary magnetic resonance imaging and magnetization studies on hyaluronic acid coated nanoparticles injected intravenously into mice confirm that the nanoparticles accumulate in the liver, spleen, and kidneys. To identify whether certain specific proteins are responsible for nanoparticle accumulation in these organs, we exposed hyaluronic acid coated nanoparticles to proteins extracted from the liver, spleen, and kidneys, together with blood plasma proteins, then subsequently used gel electrophoresis and mass spectroscopy to identify the proteins binding to the nanoparticles. We find that the unwanted accumulation of nanoparticles in these organs can potentially be attributed to specific binding by a small number of proteins. By appropriately functionalizing the iron oxide nanoparticles, we expect that the nanoparticles uptake in the liver, spleen, and kidneys will be reduced.

  2. Nonspecific targeting of iron oxide nanoparticles to the liver, kidney and spleen: A novel approach to achieving specificity

    NASA Astrophysics Data System (ADS)

    Palihawadana Arachchige, Maheshika; Flack, Amanda; Chen, Xuequn; Li, Jing; Oupicky, David; Cheng, Y.-C. Norman; Shen, Yimin; Jena, Bhanu; Lawes, Gavin

    2012-10-01

    Recently there has been significant interest in developing Fe3O4 nanoparticles for biomedical applications including targeted drug delivery and magnetic resonance imaging. One of the major problems in applying these nanoparticles clinically is to minimize the undesirable filtration of these materials by the mononuclear phagocyte system. Preliminary MRI and magnetization studies on hyaluronic acid coated nanoparticles injected intravenously into mice confirm that the nanoparticles accumulate in the liver, spleen, and kidneys. To identify whether this nanoparticle accumulation are due to some certain specific proteins, we exposed hyaluronic acid coated nanoparticles to proteins extracted from these organs, together with blood plasma proteins, then used gel electrophoresis together with mass spectroscopy to identify the proteins binding to the nanoparticles. We find that the accumulation of nanoparticles in these organs can be due to specific binding by a small number of proteins. By appropriately functionalizing the Fe3O4 nanoparticles, possibly by blocking the binding sites of these specific proteins, we expect that the nanoparticles uptake in the liver, spleen, and kidneys will be reduced, which, in turn, could increase the concentration of nanoparticles at tumor sites.

  3. How to achieve the 2020 and 2030 emissions targets of China: Evidence from high, mid and low energy-consumption industrial sub-sectors

    NASA Astrophysics Data System (ADS)

    Wang, Juan; Zhao, Tao; Wang, Yanan

    2016-11-01

    Facing the challenge of meeting emissions reduction targets of China, this paper employed the logarithmic mean Divisia index (LMDI) method to study the changes of energy-related carbon emissions in high energy-consumption sectors (HES), mid energy-consumption sectors (MES) and low energy-consumption sectors (LES) from 1996 to 2012. The decomposition results revealed that the economic growth was the most significant factor to increase carbon emissions of three subgroups while the decrease in energy intensity was the dominant factor to reduce carbon emissions of MES and LES. Considering the important roles economic growth and energy intensity played in carbon emissions, three scenarios were set based on the different growth rates of these two factors to identify whether the emissions reduction targets of 40-45% in 2020 and 60-65% in 2030 can be achieved using the co-integration technique. It was indicated that the emissions targets both in 2020 and 2030 can be achieved by LES in the base scenario. In stark contrast to LES, the carbon intensity of HES reduced only 10.03% in 2020 and 14% in 2030 compared to the 2005 level. Therefore, more attentions should be focused on the economic activity and energy intensity of HES. Finally, according to the results obtained, policy implications were provided to further mitigate the carbon intensity of China's industrial sector.

  4. Using the soil and water assessment tool to estimate achievable water quality targets through implementation of beneficial management practices in an agricultural watershed.

    PubMed

    Yang, Qi; Benoy, Glenn A; Chow, Thien Lien; Daigle, Jean-Louis; Bourque, Charles P-A; Meng, Fan-Rui

    2012-01-01

    Runoff from crop production in agricultural watersheds can cause widespread soil loss and degradation of surface water quality. Beneficial management practices (BMPs) for soil conservation are often implemented as remedial measures because BMPs can reduce soil erosion and improve water quality. However, the efficacy of BMPs may be unknown because it can be affected by many factors, such as farming practices, land-use, soil type, topography, and climatic conditions. As such, it is difficult to estimate the impacts of BMPs on water quality through field experiments alone. In this research, the Soil and Water Assessment Tool was used to estimate achievable performance targets of water quality indicators (sediment and soluble P loadings) after implementation of combinations of selected BMPs in the Black Brook Watershed in northwestern New Brunswick, Canada. Four commonly used BMPs (flow diversion terraces [FDTs], fertilizer reductions, tillage methods, and crop rotations), were considered individually and in different combinations. At the watershed level, the best achievable sediment loading was 1.9 t ha(-1) yr(-1) (89% reduction compared with default scenario), with a BMP combination of crop rotation, FDT, and no-till. The best achievable soluble P loading was 0.5 kg ha(-1) yr(-1) (62% reduction), with a BMP combination of crop rotation and FDT and fertilizer reduction. Targets estimated through nonpoint source water quality modeling can be used to evaluate BMP implementation initiatives and provide milestones for the rehabilitation of streams and rivers in agricultural regions.

  5. Coated minispheres of salmon calcitonin target rat intestinal regions to achieve systemic bioavailability: Comparison between intestinal instillation and oral gavage.

    PubMed

    Aguirre, Tanira A S; Aversa, Vincenzo; Rosa, Mónica; Guterres, Sílvia S; Pohlmann, Adriana R; Coulter, Ivan; Brayden, David J

    2016-09-28

    Achieving oral peptide delivery is an elusive challenge. Emulsion-based minispheres of salmon calcitonin (sCT) were synthesized using single multiple pill (SmPill®) technology incorporating the permeation enhancers (PEs): sodium taurodeoxycholate (NaTDC), sodium caprate (C10), or coco-glucoside (CG), or the pH acidifier, citric acid (CA). Minispheres were coated with an outer layer of Eudragit® L30 D-55 (designed for jejunal release) or Surelease®/Pectin (designed for colonic release). The process was mild and in vitro biological activity of sCT was retained upon release from minispheres stored up to 4months. In vitro release profiles suggested that sCT was released from minispheres by diffusion through coatings due to swelling of gelatin and the polymeric matrix upon contact with PBS at pH6.8. X-ray analysis confirmed that coated minispheres dissolved at the intended intestinal region of rats following oral gavage. Uncoated minispheres at a dose of ~2000I.U.sCT/kg were administered to rats by intra-jejunal (i.j.) or intra-colonic (i.c.) instillation and caused hypocalcaemia. Notable sCT absolute bioavailability (F) values were: 5.5% from minispheres containing NaTDC (i.j), 17.3% with CG (i.c.) and 18.2% with C10 (i.c.). Coated minispheres administered by oral gavage at threefold higher doses also induced hypocalcaemia. A highly competitive F value of 2.7% was obtained for orally-administered sCT-minispheres containing CG (45μmol/kg) and coated with Eudragit®. In conclusion, the SmPill® technology is a potential dosage form for several peptides when formulated with PEs and coated for regional delivery. PK data from instillations over-estimates oral bioavailability and poorly predicts rank ordering of formulations.

  6. The mechanism of insulin-stimulated 4E-BP protein binding to mammalian target of rapamycin (mTOR) complex 1 and its contribution to mTOR complex 1 signaling.

    PubMed

    Rapley, Joseph; Oshiro, Noriko; Ortiz-Vega, Sara; Avruch, Joseph

    2011-11-04

    Insulin activation of mTOR complex 1 is accompanied by enhanced binding of substrates. We examined the mechanism and contribution of this enhancement to insulin activation of mTORC1 signaling in 293E and HeLa cells. In 293E, insulin increased the amount of mTORC1 retrieved by the transiently expressed nonphosphorylatable 4E-BP[5A] to an extent that varied inversely with the amount of PRAS40 bound to mTORC1. RNAi depletion of PRAS40 enhanced 4E-BP[5A] binding to ∼70% the extent of maximal insulin, and PRAS40 RNAi and insulin together did not increase 4E-BP[5A] binding beyond insulin alone, suggesting that removal of PRAS40 from mTORC1 is the predominant mechanism of an insulin-induced increase in substrate access. As regards the role of increased substrate access in mTORC1 signaling, RNAi depletion of PRAS40, although increasing 4E-BP[5A] binding, did not stimulate phosphorylation of endogenous mTORC1 substrates S6K1(Thr(389)) or 4E-BP (Thr(37)/Thr(46)), the latter already ∼70% of maximal in amino acid replete, serum-deprived 293E cells. In HeLa cells, insulin and PRAS40 RNAi also both enhanced the binding of 4E-BP[5A] to raptor but only insulin stimulated S6K1 and 4E-BP phosphorylation. Furthermore, Rheb overexpression in 293E activated mTORC1 signaling completely without causing PRAS40 release. In the presence of Rheb and insulin, PRAS40 release is abolished by Akt inhibition without diminishing mTORC1 signaling. In conclusion, dissociation of PRAS40 from mTORC1 and enhanced mTORC1 substrate binding results from Akt and mTORC1 activation and makes little or no contribution to mTORC1 signaling, which rather is determined by Rheb activation of mTOR catalytic activity, through mechanisms that remain to be fully elucidated.

  7. Achievement of recommended glucose and blood pressure targets in patients with type 2 diabetes and hypertension in clinical practice – study rationale and protocol of DIALOGUE

    PubMed Central

    2012-01-01

    Background Patients with type 2 diabetes have 2–4 times greater risk for cardiovascular morbidity and mortality than those without, and this is even further aggravated if they also suffer from hypertension. Unfortunately, less than one third of hypertensive diabetic patients meet blood pressure targets, and more than half fail to achieve target HbA1c values. Thus, appropriate blood pressure and glucose control are of utmost importance. Since treatment sometimes fails in clinical practice while clinical trials generally suggest good efficacy, data from daily clinical practice, especially with regard to the use of newly developed anti-diabetic and anti-hypertensive compounds in unselected patient populations, are essential. The DIALOGUE registry aims to close this important gap by evaluating different treatment approaches in hypertensive type 2 diabetic patients with respect to their effectiveness and tolerability and their impact on outcomes. In addition, DIALOGUE is the first registry to determine treatment success based on the new individualized treatment targets recommended by the ADA and the EASD. Methods DIALOGUE is a prospective observational German multicentre registry and will enrol 10,000 patients with both diabetes and hypertension in up to 700 sites. After a baseline visit, further documentations are scheduled at 6, 12 and 24 months. There are two co-primary objectives referring to the most recent guidelines for the treatment of diabetes and hypertension: 1) individual HbA1c goal achievement with respect to anti-diabetic pharmacotherapy and 2) individual blood pressure goal achievement with different antihypertensive treatments. Among the secondary objectives the rate of major cardio-vascular and cerebro-vascular events (MACCE) and the rate of hospitalizations are the most important. Conclusion The registry will be able to gain insights into the reasons for the obvious gap between the demonstrated efficacy and safety of anti-diabetic and anti

  8. NREL 2012 Achievement of Ethanol Cost Targets: Biochemical Ethanol Fermentation via Dilute-Acid Pretreatment and Enzymatic Hydrolysis of Corn Stover

    SciTech Connect

    Tao, L.; Schell, D.; Davis, R.; Tan, E.; Elander, R.; Bratis, A.

    2014-04-01

    For the DOE Bioenergy Technologies Office, the annual State of Technology (SOT) assessment is an essential activity for quantifying the benefits of biochemical platform research. This assessment has historically allowed the impact of research progress achieved through targeted Bioenergy Technologies Office funding to be quantified in terms of economic improvements within the context of a fully integrated cellulosic ethanol production process. As such, progress toward the ultimate 2012 goal of demonstrating cost-competitive cellulosic ethanol technology can be tracked. With an assumed feedstock cost for corn stover of $58.50/ton this target has historically been set at $1.41/gal ethanol for conversion costs only (exclusive of feedstock) and $2.15/gal total production cost (inclusive of feedstock) or minimum ethanol selling price (MESP). This year, fully integrated cellulosic ethanol production data generated by National Renewable Energy Laboratory (NREL) researchers in their Integrated Biorefinery Research Facility (IBRF) successfully demonstrated performance commensurate with both the FY 2012 SOT MESP target of $2.15/gal (2007$, $58.50/ton feedstock cost) and the conversion target of $1.41/gal through core research and process improvements in pretreatment, enzymatic hydrolysis, and fermentation.

  9. Association between the Achievement of Target Range CKD-MBD Markers and Mortality in Prevalent Hemodialysis Patients in Taiwan by Using the Kidney Disease: Improving Global Outcomes Clinical Guidelines

    PubMed Central

    Cheng, Ben-Chung; Lee, Chih-Hsiung; Chang, Wen-Xiu

    2016-01-01

    Background. This study evaluated the association between achieving target chronic kidney disease-mineral and bone disorder (CKD-MBD) marker levels and mortality in Taiwanese hemodialysis (HD) patients. Target levels were based on the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. Methods. We performed a retrospective medical record review of 1126 HD patients between 2009 and 2013. A logistic regression model was used to evaluate the relationship between achieving target marker levels and the risk for all-cause and cardiovascular (CV) mortality. Reference target ranges were 7.9 ≤ calcium (Ca) ≤ 9.9 mg/dL, 2.4 ≤ phosphate (P) ≤ 4.7 mg/dL, and 144 ≤ intact parathyroid hormone (iPTH) ≤ 648 pg/mL. Results. Achievement of target P levels was associated with a lower risk for all-cause mortality compared to achievement of either target Ca or iPTH levels. Achieving target P + iPTH levels (OR 1.32) was associated with a lower odds ratio for all-cause mortality compared to achieving target Ca + P (OR 1.66) and Ca + iPTH (OR 1.43) levels. Similar trends were observed for CV mortality risk. Conclusions. The present study demonstrated that achieving serum P levels within the KDIGO target range is the most important factor for lowering mortality in HD patients. PMID:28003998

  10. Impact of an acute coronary syndrome pathway in achieving target heart rate and utilization of evidence-based doses of beta-blockers.

    PubMed

    Irani, Farzan; Herial, Nabeel; Colyer, William R

    2012-11-01

    Beta-blockers remain a cornerstone of therapy in the management of acute coronary syndrome (ACS). The 2007 American College of Cardiology/American Heart Association unstable angina/non-ST elevation myocardial infarction guideline revisions recommend a target heart rate (HR) of 50-60 beats per minute (bpm). Despite improved trends toward utilization of beta-blockers therapy, beta-blockers continue to be underdosed. Guideline-based tools have been shown to improve adherence to evidence-based therapy in patients with ACS. Implementation of a standardized ACS pathway would lead to titration of beta-blockers to recommended dosages with improved HRs in eligible patients. The ACS clinical protocol was implemented at the University of Toledo Medical Center in May 2007. A retrospective study of 516 patients admitted during a comparable 6-month period, before and after the institution of the protocol, was conducted. The preprotocol and protocol group included 237 and 279 patients, respectively. Patient information extracted from the medical records included age, gender, HR on admission, blood pressure on admission, duration of hospital stay, preadmission use of beta-blocker, type of beta-blocker and dosage, discharge beta-blocker and dosage, peak troponin levels, and therapeutic intervention. A target HR of less than 60 bpm was achieved in 19% of the protocol group, as compared with 6% in the preprotocol group (P < 0.001). The protocol group had a significantly lower mean discharge HR than the preprotocol group (67 vs. 74 bpm; P < 0.001). The mean discharge dose of metoprolol in the protocol group was noted to be significantly higher (118 vs. 80 mg/d; P < 0.001). The institution of an ACS clinical pathway led to utilization of beta-blockers in significantly higher dosages, resulting in improved HR control and increased attainment of target HR.

  11. Lack of CaBP1/Caldendrin or CaBP2 Leads to Altered Ganglion Cell Responses

    PubMed Central

    Sinha, Raunak; Lee, Amy

    2016-01-01

    Calcium-binding proteins (CaBPs) form a subfamily of calmodulin-like proteins that were cloned from the retina. CaBP4 and CaBP5 have been shown to be important for normal visual function. Although CaBP1/caldendrin and CaBP2 have been shown to modulate various targets in vitro, it is not known whether they contribute to the transmission of light responses through the retina. Therefore, we generated mice that lack CaBP2 or CaBP1/caldendrin (Cabp2–/– and Cabp1–/–) to test whether these CaBPs are essential for normal retinal function. By immunohistochemistry, the overall morphology of Cabp1–/– and Cabp2–/– retinas and the number of synaptic ribbons appear normal; transmission electron microscopy shows normal tethered ribbon synapses and synaptic vesicles as in wild-type retinas. However, whole-cell patch clamp recordings showed that light responses of retinal ganglion cells of Cabp2–/– and Cabp1–/– mice differ in amplitude and kinetics from those of wild-type mice. We conclude that CaBP1/caldendrin and CaBP2 are not required for normal gross retinal and synapse morphology but are necessary for the proper transmission of light responses through the retina; like other CaBPs, CaBP1/caldendrin and CaBP2 likely act by modulating presynaptic Ca2+-dependent signaling mechanisms. PMID:27822497

  12. The potential role of CacyBP/SIP in tumorigenesis.

    PubMed

    Ning, Xiaoxuan; Chen, Yang; Wang, Xiaosu; Li, Qiaoneng; Sun, Shiren

    2016-08-01

    Calcyclin-binding protein/Siah-1-interacting protein (CacyBP/SIP) was initially described as a binding partner of S100A6 in the Ehrlich ascites tumor cells and later as a Siah-1-interacting protein. This 30 kDa protein includes three domains and is involved in cell proliferation, differentiation, cytoskeletal rearrangement, and transcriptional regulation via binding to various proteins. Studies have also shown that the CacyBP/SIP is a critical protein in tumorigenesis. But, its promotion or suppression of cancer progression may depend on the cell type. In this review, the biological characteristics and target proteins of CacyBP/SIP have been described. Moreover, the exact role of CacyBP/SIP in various cancers is discussed.

  13. The AP-1 site at -150 bp, but not the NF-kappa B site, is likely to represent the major target of protein kinase C in the interleukin 2 promoter

    PubMed Central

    1992-01-01

    Stimulation of T cells with antigen results in activation of several kinases, including protein kinase C (PKC), that may mediate the later induction of activation-related genes. We have examined the potential role of PKC in induction of the interleukin 2 (IL-2) gene in T cells stimulated through the T cell receptor/CD3 complex. We have previously shown that prolonged treatment of the untransformed T cell clone Ar-5 with phorbol esters results in downmodulation of the alpha and beta isozymes of PKC, and abrogates induction of IL-2 mRNA and protein. Here we show that phorbol ester treatment also abolishes induction of chloramphenicol acetyltransferase activity in Ar-5 cells transfected with a plasmid containing the IL-2 promoter linked to this reporter gene. The IL-2 promoter contains binding sites for nuclear factors including NFAT-1, Oct, NF-kappa B, and AP-1, which are all potentially sensitive to activation of PKC. We show that induction of a trimer of the NFAT and Oct sites is not sensitive to phorbol ester treatment, and that mutations in the NF-kappa B site have no effect on inducibility of the IL-2 promoter. In contrast, mutations in the AP-1 site located at - 150 bp almost completely abrogate induction of the IL-2 promoter, and appearance of an inducible nuclear factor binding to this site is sensitive to PKC depletion. Moreover, cotransfections with c-fos and c- jun expression plasmids markedly enhance induction of the IL-2 promoter in minimally stimulated T cells. Our results indicate that the AP-1 site at -150 bp represents a major, if not the only, site of PKC responsiveness in the IL-2 promoter. PMID:1740667

  14. Use pattern of maternal health services and determinants of skilled care during delivery in Southern Tanzania: implications for achievement of MDG-5 targets

    PubMed Central

    Mpembeni, Rose NM; Killewo, Japhet Z; Leshabari, Melkzedeck T; Massawe, Siriel N; Jahn, Albrecht; Mushi, Declare; Mwakipa, Hassan

    2007-01-01

    Background Almost two decades since the initiation of the Safe motherhood Initiative, Maternal Mortality is still soaring high in most developing countries. In 2000 WHO estimated a life time risk of a maternal death of 1 in 16 in Sub- Saharan Africa while it was only 1 in 2800 in developed countries. This huge discrepancy in the rate of maternal deaths is due to differences in access and use of maternal health care services. It is known that having a skilled attendant at every delivery can lead to marked reductions in maternal mortality. For this reason, the proportion of births attended by skilled health personnel is one of the indicators used to monitor progress towards the achievement of the MDG-5 of improving maternal health. Methods Cross sectional study which employed quantitative research methods. Results We interviewed 974 women who gave birth within one year prior to the survey. Although almost all (99.8%) attended ANC at least once during their last pregnancy, only 46.7% reported to deliver in a health facility and only 44.5% were assisted during delivery by a skilled attendant. Distance to the health facility (OR = 4.09 (2.72–6.16)), discussion with the male partner on place of delivery (OR = 2.37(1.75–3.22)), advise to deliver in a health facility during ANC (OR = 1.43 (1.25–2.63)) and knowledge of pregnancy risk factors (OR 2.95 (1.65–5.25)) showed significant association with use of skilled care at delivery even after controlling for confounding factors. Conclusion Use of skilled care during delivery in this district is below the target set by ICPD + of attaining 80% of deliveries attended by skilled personnel by 2005. We recommend the following in order to increase the pace towards achieving the MDG targets: to improve coverage of health facilities, raising awareness for both men and women on danger signs during pregnancy/delivery and strengthening counseling on facility delivery and individual birth preparedness. PMID:18053268

  15. How China achieved its 11th Five-Year Plan emissions reduction target: A structural decomposition analysis of industrial SO2 and chemical oxygen demand.

    PubMed

    Liu, Qiaoling; Wang, Qi

    2017-01-01

    To curb the increasing pollutant emissions that have accompanied rapid economic growth, China implemented a mandatory emissions control system since the 11th Five-Year Plan (FYP) period, and the emission reduction targets have been met and even exceeded. This article explores how China achieved its emissions reduction targets by systematically identifying the main emission reduction pathways, including both the environmental and economic factors, and evaluates the contribution of each factor using structure decomposition analysis. A study of the two key controlled pollutants, industrial sulfur dioxide (SO2) and chemical oxygen demand (COD), during the 11th FYP period showed that (i) changes in the end-of-pipe treatment and pollutant generation coefficient were the dominant contributors to emissions reduction. The power and metal smelting sectors played important roles in SO2 abatement, while the paper products and food products sectors were important in COD reduction; (ii) changes to the input coefficient increased overall emissions although there was a decrease in SO2 emissions in 2007-2010 mainly due to input structure improvements in the construction sector; (iii) the trade effect largely offset the domestic emission reduction effects, although the trade effect declined during the study period; (iv) domestic demand was the main factor increasing domestic emissions; domestic investment changes (especially in the construction sector) were the major contributor to increases in SO2 emissions, and final consumption changes (especially consumption in the food production sector) were the main contributor to the increase in COD emissions. The results yield important implications for China's pollution emissions control policies.

  16. Split vector systems for ultra-targeted gene delivery: a contrivance to achieve ethical assurance of somatic gene therapy in vivo.

    PubMed

    Tolmachov, Oleg E

    2014-08-01

    Tightly controlled spatial localisation of therapeutic gene delivery is essential to maximize the benefits of somatic gene therapy in vivo and to reduce its undesired effects on the 'bystander' cell populations, most importantly germline cells. Indeed, complete ethical assurance of somatic gene therapy can only be achieved with ultra-targeted gene delivery, which excludes the risk of inadvertent germline gene transfer. Thus, it is desired to supplement existing strategies of physical focusing and biological (cell-specific) targeting of gene delivery with an additional principle for the rigid control over spread of gene transfer within the body. In this paper I advance the concept of 'combinatorial' targeting of therapeutic gene transfer in vivo. I hypothesize that it is possible to engineer complex gene delivery vector systems consisting of several components, each one of them capable of independent spread within the human body but incapable of independent facilitation of gene transfer. As the gene delivery augmented by such split vector systems would be reliant on the simultaneous availability of all the vector system components at a predetermined body site, it is envisaged that higher order reaction kinetics required for the assembly of the functional gene transfer configuration would sharpen spatial localisation of gene transfer via curtailing the blurring effect of the vector spread within the body. A particular implementation of such split vector system could be obtained through supplementing a viral therapeutic gene vector with a separate auxiliary vector carrying a non-integrative and non-replicative form of a gene (e.g., mRNA) coding for a cellular receptor of the therapeutic vector component. Gene-transfer-enabling components of the vector system, which would be delivered separately from the vector component loaded with the therapeutic gene cargo, could also be cell-membrane-insertion-proficient receptors, elements of artificial transmembrane channels

  17. Variability in protein binding of teicoplanin and achievement of therapeutic drug monitoring targets in critically ill patients: lessons from the DALI Study.

    PubMed

    Roberts, J A; Stove, V; De Waele, J J; Sipinkoski, B; McWhinney, B; Ungerer, J P J; Akova, M; Bassetti, M; Dimopoulos, G; Kaukonen, K-M; Koulenti, D; Martin, C; Montravers, P; Rello, J; Rhodes, A; Starr, T; Wallis, S C; Lipman, J

    2014-05-01

    The aims of this study were to describe the variability in protein binding of teicoplanin in critically ill patients as well as the number of patients achieving therapeutic target concentrations. This report is part of the multinational pharmacokinetic DALI Study. Patients were sampled on a single day, with blood samples taken both at the midpoint and the end of the dosing interval. Total and unbound teicoplanin concentrations were assayed using validated chromatographic methods. The lower therapeutic range of teicoplanin was defined as total trough concentrations from 10 to 20 mg/L and the higher range as 10-30 mg/L. Thirteen critically ill patients were available for analysis. The following are the median (interquartile range) total and free concentrations (mg/L): midpoint, total 13.6 (11.2-26.0) and free 1.5 (0.7-2.5); trough, total 11.9 (10.2-22.7) and free 1.8 (0.6-2.6). The percentage free teicoplanin for the mid-dose and trough time points was 6.9% (4.5-15.6%) and 8.2% (5.5-16.4%), respectively. The correlation between total and free antibiotic concentrations was moderate for both the midpoint (ρ = 0.79, P = 0.0021) and trough (ρ = 0.63, P = 0.027). Only 42% and 58% of patients were in the lower and higher therapeutic ranges, respectively. In conclusion, use of standard dosing for teicoplanin leads to inappropriate concentrations in a high proportion of critically ill patients. Variability in teicoplanin protein binding is very high, placing significant doubt on the validity of total concentrations for therapeutic drug monitoring in critically ill patients.

  18. Achievement of a target dose of bisoprolol may not be a preferred option for attenuating pressure overload-induced cardiac hypertrophy and fibrosis

    PubMed Central

    Xiang, Shizhao; Zhang, Ning; Yang, Zheng; Bian, Zhouyan; Yuan, Yuan; Tang, Qizhu

    2016-01-01

    Bisoprolol is a drug that acts via the mechanism of specifically and selectively inhibiting the β1-adrenoreceptor in cardiac myocytes, and provides a pure reduction of heart rate without changing other cardiac parameters. It has long been clinically used to treat cerebrovascular and cardiovascular illnesses. However, there is little information available on whether the role of bisoprolol in the attenuation of ventricular remodeling is dependent upon the achievement of a target dose, and whether it must be used as a preferred option. The aim of the present study was to clarify the underlying benefits of bisoprolol in the attenuation of pressure overload-induced cardiac hypertrophy and fibrosis at different doses. C57BL/6J male mice, aged 6–8 weeks, were treated with saline or one of three different doses of bisoprolol (Biso: 2.5, 5 or 10 mg/kg/day) for 8 weeks from day 1 after aortic banding (AB). A number of mice underwent sham surgery and were treated with saline or bisoprolol. The mice were randomly assigned into the sham (n=24) and AB (n=62) groups. The results revealed that bisoprolol had a protective role against the cardiac hypertrophy, fibrosis and dysfunction caused by AB. This was determined on the basis of heart/body and lung/body weight ratios and heart weight/tibia length ratios, as well as echocardiographic and hemodynamic parameters, histological analysis, and the gene expression levels of hypertrophic and fibrotic markers. The present study revealed that administration of bisoprolol for a long time period may enhance its role in the prevention of cardiac hypertrophy and fibrosis induced by AB, whereas no statistically significant difference was observed between the middle- and high-doses. These observations indicated that the function of bisoprolol in protecting against cardiac hypertrophy, fibrosis and dysfunction is time-dependent. Furthermore, it is proposed that a middle dose of bisoprolol may be a better option for patients with

  19. Achievement of a target dose of bisoprolol may not be a preferred option for attenuating pressure overload-induced cardiac hypertrophy and fibrosis.

    PubMed

    Xiang, Shizhao; Zhang, Ning; Yang, Zheng; Bian, Zhouyan; Yuan, Yuan; Tang, Qizhu

    2016-10-01

    Bisoprolol is a drug that acts via the mechanism of specifically and selectively inhibiting the β1-adrenoreceptor in cardiac myocytes, and provides a pure reduction of heart rate without changing other cardiac parameters. It has long been clinically used to treat cerebrovascular and cardiovascular illnesses. However, there is little information available on whether the role of bisoprolol in the attenuation of ventricular remodeling is dependent upon the achievement of a target dose, and whether it must be used as a preferred option. The aim of the present study was to clarify the underlying benefits of bisoprolol in the attenuation of pressure overload-induced cardiac hypertrophy and fibrosis at different doses. C57BL/6J male mice, aged 6-8 weeks, were treated with saline or one of three different doses of bisoprolol (Biso: 2.5, 5 or 10 mg/kg/day) for 8 weeks from day 1 after aortic banding (AB). A number of mice underwent sham surgery and were treated with saline or bisoprolol. The mice were randomly assigned into the sham (n=24) and AB (n=62) groups. The results revealed that bisoprolol had a protective role against the cardiac hypertrophy, fibrosis and dysfunction caused by AB. This was determined on the basis of heart/body and lung/body weight ratios and heart weight/tibia length ratios, as well as echocardiographic and hemodynamic parameters, histological analysis, and the gene expression levels of hypertrophic and fibrotic markers. The present study revealed that administration of bisoprolol for a long time period may enhance its role in the prevention of cardiac hypertrophy and fibrosis induced by AB, whereas no statistically significant difference was observed between the middle- and high-doses. These observations indicated that the function of bisoprolol in protecting against cardiac hypertrophy, fibrosis and dysfunction is time-dependent. Furthermore, it is proposed that a middle dose of bisoprolol may be a better option for patients with cardiovascular

  20. Maximizing MST's inductive capability with a Bp programmable power supply

    NASA Astrophysics Data System (ADS)

    Chapman, B. E.; Holly, D. J.; Jacobson, C. M.; McCollam, K. J.; Morin, J. C.; Sarff, J. S.; Squitieri, A.

    2016-10-01

    A major goal of the MST program is the advancement of inductive control for the development of both the RFP's fusion potential and, synergistically, the predictive capability of fusion science. This entails programmable power supplies (PPS's) for the Bt and Bp circuits. A Bt PPS is already in place, allowing advanced RFP operation and the production of tokamak plasmas, and a Bp PPS prototype is under construction. To explore some of the new capabilities to be provided by the Bp PPS, the existing Bt PPS has been temporarily connected to the Bp circuit. One key result is new-found access to very low Ip (20 kA) and very low Lundquist number, S (104). At this low S, simulation of RFP plasmas with the MHD code NIMROD is readily achievable, and work toward validation of extended MHD models using NIMROD is underway with direct comparisons to these MST plasmas. The full Bp PPS will also provide higher Ip and S than presently possible, allowing MST to produce plasmas with S spanning as much as five orders of magnitude, a dramatic extension of MST's capability. In these initial tests, the PPS has also increased five-fold MST's Ip flattop duration, to about 100 ms. This, coupled with the recently demonstrated PPS ability to drive large-amplitude sinusoidal oscillations in Ip, will allow tests of extended-duration oscillating field current drive, the goal of which is ac sustainment of a quasi-dc plasma current. Work supported by US DOE.

  1. 'No delays achiever'.

    PubMed

    2007-05-01

    The latest version of the NHS Institute for Innovation and Improvement's 'no delays achiever', a web based tool created to help NHS organisations achieve the 18-week target for GP referrals to first treatment, is available at www.nodelaysachiever.nhs.uk.

  2. Achieved Blood Pressures in the Secondary Prevention of Small Subcortical Strokes (SPS3) Study: Challenges and Lessons Learned

    PubMed Central

    Pergola, Pablo E.; Szychowski, Jeff M.; Talbert, Robert; del Brutto, Oscar; Castellanos, Mar; Graves, John W.; Matamala, Gonzalo; Pretell, Edwin Javier; Yee, Jerry; Rebello, Rosario; Zhang, Yu; Benavente, Oscar R.

    2014-01-01

    BACKGROUND Lowering blood pressure (BP) after stroke remains a challenge, even in the context of clinical trials. The Secondary Prevention of Small Subcortical Strokes (SPS3) BP protocol, BP management during the study, and achieved BPs are described here. METHODS Patients with recent symptomatic lacunar stroke were randomized to 1 of 2 levels of systolic BP (SBP) targets: lower: <130mm Hg, or higher: 130–149mm Hg. SBP management over the course of the trial was examined by race/ethnicity and other baseline conditions. RESULTS Mean SBP decreased for both groups from baseline to the last follow-up, from 142.4 to 126.7mm Hg for the lower SBP target group and from 143.6 to 137.4mm Hg for the higher SBP target group. At baseline, participants in both groups used an average of 1.7±1.2 antihypertensive medications, which increased to a mean of 2.4±1.4 (lower group) and 1.8±1.4 (higher group) by the end-study visit. It took an average of 6 months for patients to reach their SBP target, sustained to the last follow-up. Black participants had the highest proportion of SBP ≥150mm Hg at both study entry (40%) and end-study visit (17%), as compared with whites (9%) and Hispanics (11%). CONCLUSIONS These results show that it is possible to safely lower BP even to a SBP goal <130mm Hg in a variety of patients and settings, including private and academic centers in multiple countries. This provides further support for protocol-driven care in lowering BP and consequently reducing the burden of stroke. PMID:24610884

  3. A strategic action plan for achieving uncompromising "treat to target" in individuals with insulin-dependent diabetes: a report by the Center for Insulin-Dependent Diabetes Access' Blue Ribbon Panel.

    PubMed

    Rudolf, Paul; Bartelme, Amanda

    2005-10-01

    The Center for Insulin-Dependent Diabetes Access, created by the Juvenile Diabetes Research Foundation International and funded by an unrestricted grant from The Medtronic Foundation, convened a Blue Ribbon Panel (the Panel) to identify barriers to achieving universal treatment-to-target in patients with insulin-dependent diabetes and to recommend solutions for addressing those barriers. The Panel was comprised of experts in diabetes care and included providers, academicians, researchers, payers, patient advocates, and policymakers. After reviewing the latest research on diabetes care, the Panel made six overall findings that identify barriers to achieving optimal diabetes care and made recommendations to address those barriers that are intended to achieve the goal of universal, uncompromising "Treat to Target" in insulin-dependent patients. The Panel's findings were: Finding 1: Improving care of patients with insulin-dependent diabetes depends on the public availability and ongoing collection of data that document patient characteristics, processes of care, health outcomes, the benefits and costs of new technologies, and the benefits and costs of different care models. Finding 2: Availability of new technologies and information systems for monitoring and treating insulin-dependent diabetes is critical to achieving recommended hemoglobin A1c levels. Finding 3: Increased reimbursement for new technologies and services provided by the "team" approach to medical management, such as coordinated non-face-to-face care and Internet communications, is imperative to achieving optimal diabetes care. Finding 4: Improving access to endocrinologists, certified diabetes educators, and adopting a chronic care or "team" approach to treating insulin-dependent diabetes are critical to achieving a "Treat to Target" objective. Finding 5: Primary care providers and individuals with insulin-dependent diabetes need to better understand the importance and impact of intensive insulin

  4. Segmentation of biological target volumes on multi-tracer PET images based on information fusion for achieving dose painting in radiotherapy.

    PubMed

    Lelandais, Benoît; Gardin, Isabelle; Mouchard, Laurent; Vera, Pierre; Ruan, Su

    2012-01-01

    Medical imaging plays an important role in radiotherapy. Dose painting consists in the application of a nonuniform dose prescription on a tumoral region, and is based on an efficient segmentation of biological target volumes (BTV). It is derived from PET images, that highlight tumoral regions of enhanced glucose metabolism (FDG), cell proliferation (FLT) and hypoxia (FMiso). In this paper, a framework based on Belief Function Theory is proposed for BTV segmentation and for creating 3D parametric images for dose painting. We propose to take advantage of neighboring voxels for BTV segmentation, and also multi-tracer PET images using information fusion to create parametric images. The performances of BTV segmentation was evaluated on an anthropomorphic phantom and compared with two other methods. Quantitative results show the good performances of our method. It has been applied to data of five patients suffering from lung cancer. Parametric images show promising results by highlighting areas where a high frequency or dose escalation could be planned.

  5. Differential gene expression and subcellular targeting of Arabidopsis glutathione S-transferase F8 is achieved through alternative transcription start sites.

    PubMed

    Thatcher, Louise F; Carrie, Chris; Andersson, Carol R; Sivasithamparam, Krishnapillai; Whelan, James; Singh, Karam B

    2007-09-28

    Glutathione S-transferases (GSTs) play major roles in the protection of plants from biotic and abiotic stresses through the detoxification of xenobiotics and toxic endogenous products. This report describes additional complexity in the regulation of the well characterized stress-responsive Arabidopsis thaliana GSTF8 promoter. This complexity results from the use of multiple transcription start sites (TSS) to give rise to alternate GSTF8 transcripts with the potential to produce two in-frame proteins differing only in their N-terminal sequence. In addition to the originally mapped TSS (Chen, W., Chao, G., and Singh, K. B. (1996) Plant J. 10, 955-966), a further nine TSS have been identified, with the majority clustered into a distinct group. The most 3' TSS gives rise to the major message (GSTF8-S) and the shorter form of the protein, whereas those originating from upstream TSS (GSTF8-L) are more weakly expressed and encode for the larger form of the protein. Differential tissue-specific and stress-responsive expression patterns were observed (e.g. GSTF8-L is more highly expressed in leaves compared with roots, whereas GSTF8-S expression has the opposite pattern and is much more stress-responsive). Analysis of GSTF8-L and GSTF8-S proteins demonstrated that GSTF8-L is solely targeted to plastids, whereas GSTF8-S is cytoplasmic. In silico analysis revealed potential conservation of GSTF8-S across a wide range of plants; in contrast, conservation of GSTF8-L was confined to the Brassicaceae. These studies demonstrate that alternate TSS of the GSTF8 promoter are used to confer differential tissue-specific and stress-responsive expression patterns as well as to target the same protein to two different subcellular localizations.

  6. Single peptide ligand-functionalized uniform hollow mesoporous silica nanoparticles achieving dual-targeting drug delivery to tumor cells and angiogenic blood vessel cells

    PubMed Central

    Liu, Yang; Chen, Qing; Xu, Ming; Guan, Guannan; Hu, Wen; Liang, Ying; Zhao, Xiuli; Qiao, Mingxi; Chen, Dawei; Liu, Hao

    2015-01-01

    Background The purpose of this study was to construct hollow mesoporous silica nanoparticles (HMSN) decorated with tLyp-1 peptide (tHMSN) for dual-targeting drug delivery to tumor cells and angiogenic blood vessel cells. Methods HMSN were synthesized de novo using a novel cationic surfactant-assisted selective etching strategy and were then modified with tLyp-1. Multiple methods, including transmission electron microscopy, X-ray photoelectron spectroscopy, thermogravimetric analysis, bicinchoninic acid assay, and nitrogen adsorption and desorption isotherms, were used to characterize the tHMSN. Doxorubicin were chosen as the model cargo, and the uptake of doxorubicin-loaded tHMSN into MDA-MB-231 cells and human umbilical vein endothelial cells (HUVECs), as models of tumor cells and tumor neovascular endothelial cells, respectively, were observed and detected by confocal laser scanning microscopy and flow cytometry. An in vitro pharmacodynamic study and a study of the mechanism via which the nanoparticles were endocytosed were also performed. Results HMSN with a highly uniform size and well oriented mesopores were synthesized. After tHMSN were characterized, enhanced uptake of the cargo carried by tHMSN into MDA-MB-231 cells and HUVECs compared with that of their unmodified counterparts was validated by confocal laser scanning microscopy and flow cytometry at the qualitative and quantitative levels, respectively. Further, the pharmacodynamic study suggested that, compared with their unmodified counterparts, doxorubicin-loaded tHMSN had an enhanced inhibitory effect on MDA-MB-231 cells and HUVECs in vitro. Finally, a preliminary study on the mechanism by which the nanoparticles were endocytosed indicated that the clathrin-mediated endocytosis pathway has a primary role in the transport of tHMSN into the cytoplasm. Conclusion tHMSN might serve as an effective active targeting nanocarrier strategy for anti-mammary cancer drug delivery. PMID:25834425

  7. Achieving net-zero emissions through the reframing of UK national targets in the post-Paris Agreement era

    NASA Astrophysics Data System (ADS)

    Pye, Steve; Li, Francis G. N.; Price, James; Fais, Birgit

    2017-03-01

    The Paris Agreement provides an international framework aimed at limiting average global temperature rise to well below 2 ∘C, implemented through actions determined at the national level. As the Agreement necessitates a 'net-zero' emissions energy system by 2100, decarbonization analyses in support of national climate policy should consider the post-2050 period. Focusing solely on mitigation objectives for 2030 or 2050 could lead to blindsiding of the challenge, inadequate ambition in the near term, and poor investment choices in energy infrastructure. Here we show, using the UK as an example, that even an ambitious climate policy is likely to fall short of the challenge of net-zero, and that analysis of the post-2050 period is therefore critical. We find that the analysis of detailed, longer-term national pathways that achieve net-zero is important for future reassessment of ambition under nationally determined contributions (NDCs).

  8. eIF4E/4E-BP dissociation and 4E-BP degradation in the first mitotic division of the sea urchin embryo.

    PubMed

    Salaün, Patrick; Pyronnet, Stéphane; Morales, Julia; Mulner-Lorillon, Odile; Bellé, Robert; Sonenberg, Nahum; Cormier, Patrick

    2003-03-15

    The mRNA's cap-binding protein eukaryotic translation initiation factor (eIF)4E is a major target for the regulation of translation initiation. eIF4E activity is controlled by a family of translation inhibitors, the eIF4E-binding proteins (4E-BPs). We have previously shown that a rapid dissociation of 4E-BP from eIF4E is related with the dramatic rise in protein synthesis that occurs following sea urchin fertilization. Here, we demonstrate that 4E-BP is destroyed shortly following fertilization and that 4E-BP degradation is sensitive to rapamycin, suggesting that proteolysis could be a novel means of regulating 4E-BP function. We also show that eIF4E/4E-BP dissociation following fertilization is sensitive to rapamycin. Furthermore, while rapamycin modestly affects global translation rates, the drug strongly inhibits cyclin B de novo synthesis and, consequently, precludes the completion of the first mitotic cleavage. These results demonstrate that, following sea urchin fertilization, cyclin B translation, and thus the onset of mitosis, are regulated by a rapamycin-sensitive pathway. These processes are effected at least in part through eIF4E/4E-BP complex dissociation and 4E-BP degradation.

  9. LGALS3BP — EDRN Public Portal

    Cancer.gov

    LGALS3BP is a secreted protein that binds to a human macrophage-associated lectin known as Mac-2 and also binds galectin 1. Elevated levels of LGALS3BP have been found in the serum of patients with cancer and in those infected by the human immunodeficiency virus (HIV).

  10. Genome-wide profiles of CtBP link metabolism with genome stability and epithelial reprogramming in breast cancer

    PubMed Central

    Di, Li-Jun; Byun, Jung S.; Wong, Madeline M.; Wakano, Clay; Taylor, Tara; Bilke, Sven; Baek, Songjoon; Hunter, Kent; Yang, Howard; Lee, Maxwell; Zvosec, Celia; Khramtsova, Galina; Cheng, Fan; Perou, Charles M.; Miller, C. Ryan; Raab, Rachel; Olopade, Olufunmilayo I.; Gardner, Kevin

    2013-01-01

    The C-terminal binding protein (CtBP) is a NADH-dependent transcriptional repressor that links carbohydrate metabolism to epigenetic regulation by recruiting diverse histone modifying complexes to chromatin. Here, global profiling of CtBP in breast cancer cells reveals that it drives epithelial to mesenchymal transition, stem cell pathways, and genome instability. CtBP expression induces mesenchymal and stem cell-like features while CtBP depletion or caloric restriction reverses gene repression and increases DNA repair. Multiple members of the CtBP-targeted gene network are selectively down-regulated in aggressive breast cancer subtypes. Differential expression of CtBP-targeted genes predicts poor clinical outcome in breast cancer patients, and elevated levels of CtBP in patient tumors predict shorter median survival. Finally, both CtBP promoter targeting and gene repression can be reversed by small molecule inhibition. These findings define broad roles for CtBP in breast cancer biology and suggest novel chromatin-based strategies for pharmacologic and metabolic intervention in cancer. PMID:23385593

  11. Overexpressed CacyBP/SIP leads to the suppression of growth in renal cell carcinoma

    SciTech Connect

    Sun, Shiren; Ning, Xiaoxuan; Liu, Jie; Liu, Lili; Chen, Yu; Han, Shuang; Zhang, Yanqi; Liang, Jie; Wu, Kaichun; Fan, Daiming . E-mail: fandaim@fmmu.edu.cn

    2007-05-18

    Calcyclin-binding protein/Siah-1-interacting protein (CacyBP/SIP), a target protein of S100, has been identified as a component of a novel ubiquitinylation complex leading to {beta}-catenin degradation, which was found to be related to the malignant phenotypes of gastric cancer. However, the roles of CacyBP/SIP in renal cell carcinoma still remain unclear. In the present study, we had analyzed the expression of the CacyBP/SIP protein in human renal cancer cells and clinical tissue samples. The possible roles of CacyBP/SIP in regulating the malignant phenotype of renal cancer cells were also investigated. The results demonstrated that the expression of CacyBP/SIP was markedly down-regulated in renal cell carcinoma tissues and cell lines. Ectopic overexpression of CacyBP/SIP in A498 cells inhibited the proliferation of this cell and delayed cell cycle progression significantly, which might be related to the down-regulation of Cyclin D1 through reducing {beta}-catenin protein. CacyBP/SIP also suppressed colony formation in soft agar and its tumorigenicity in nude mice. Taken together, our work showed that CacyBP/SIP, as a novel down-regulated gene in renal cell carcinoma, suppressed proliferation and tumorigenesis of renal cancer cells.

  12. Overexpressed CacyBP/SIP leads to the suppression of growth in renal cell carcinoma.

    PubMed

    Sun, Shiren; Ning, Xiaoxuan; Liu, Jie; Liu, Lili; Chen, Yu; Han, Shuang; Zhang, Yanqi; Liang, Jie; Wu, Kaichun; Fan, Daiming

    2007-05-18

    Calcyclin-binding protein/Siah-1-interacting protein (CacyBP/SIP), a target protein of S100, has been identified as a component of a novel ubiquitinylation complex leading to beta-catenin degradation, which was found to be related to the malignant phenotypes of gastric cancer. However, the roles of CacyBP/SIP in renal cell carcinoma still remain unclear. In the present study, we had analyzed the expression of the CacyBP/SIP protein in human renal cancer cells and clinical tissue samples. The possible roles of CacyBP/SIP in regulating the malignant phenotype of renal cancer cells were also investigated. The results demonstrated that the expression of CacyBP/SIP was markedly down-regulated in renal cell carcinoma tissues and cell lines. Ectopic overexpression of CacyBP/SIP in A498 cells inhibited the proliferation of this cell and delayed cell cycle progression significantly, which might be related to the down-regulation of Cyclin D1 through reducing beta-catenin protein. CacyBP/SIP also suppressed colony formation in soft agar and its tumorigenicity in nude mice. Taken together, our work showed that CacyBP/SIP, as a novel down-regulated gene in renal cell carcinoma, suppressed proliferation and tumorigenesis of renal cancer cells.

  13. CacyBP/SIP as a novel modulator of the thin filament.

    PubMed

    Jurewicz, Ewelina; Ostrowska, Zofia; Jozwiak, Jolanta; Redowicz, Maria Jolanta; Lesniak, Wieslawa; Moraczewska, Joanna; Filipek, Anna

    2013-03-01

    The CacyBP/SIP protein interacts with several targets, including actin. Since the majority of actin filaments are associated with tropomyosin, in this work we characterized binding of CacyBP/SIP to the actin-tropomyosin complex and examined the effects of CacyBP/SIP on actin filament functions. By using reconstituted filaments composed of actin and AEDANS-labeled tropomyosin, we observed that binding of CacyBP/SIP caused an increase in tropomyosin fluorescence intensity indicating the occurrence of conformational changes within the filament. We also found that CacyBP/SIP bound directly to tropomyosin and that these proteins did not compete with each other for binding to actin. Electron microscopy showed that in the absence of tropomyosin CacyBP/SIP destabilized actin filaments, but tropomyosin reversed this effect. Actin-activated myosin S1 ATPase activity assays, performed using a colorimetric method, indicated that CacyBP/SIP reduced ATPase activity and that the presence of tropomyosin enhanced this inhibitory effect. Thus, our results suggest that CacyBP/SIP, through its interaction with both actin and tropomyosin, regulates the organization and functional properties of the thin filament.

  14. Fuel and vehicle technology choices for passenger vehicles in achieving stringent CO2 targets: connections between transportation and other energy sectors.

    PubMed

    Grahn, M; Azar, C; Williander, M I; Anderson, J E; Mueller, S A; Wallington, T J

    2009-05-01

    The regionalized Global Energy Transition (GET-R 6.0) model has been modified to include a detailed description of light-duty vehicle options and used to investigate the potential impact of carbon capture and storage (CCS) and concentrating solar power (CSP) on cost-effective fuel/vehicle technologies in a carbon-constrained world. Total CO2 emissions were constrained to achieve stabilization at 400-550 ppm, by 2100, at lowesttotal system cost The dominantfuel/vehicle technologies varied significantly depending on CO2 constraint future cost of vehicle technologies, and availability of CCS and CSP. For many cases, no one technology dominated on a global scale. CCS provides relatively inexpensive low-CO2 electricity and heatwhich prolongs the use of traditional ICEVs. CSP displaces fossil fuel derived electricity, prolongs the use of traditional ICEVs, and promotes electrification of passenger vehicles. In all cases considered, CCS and CSP availability had a major impact on the lowest cost fuel/vehicle technologies, and alternative fuels are needed in response to expected dwindling oil and natural gas supply potential by the end of the century.

  15. Sleep-time blood pressure: prognostic value and relevance as a therapeutic target for cardiovascular risk reduction.

    PubMed

    Hermida, Ramón C; Ayala, Diana E; Fernández, José R; Mojón, Artemio

    2013-03-01

    showed that the asleep systolic BP mean was the most significant predictor of both total CVD events and major CVD events (a composite of CVD death, myocardial infarction, and stroke). Moreover, when the asleep BP mean was adjusted by the awake mean, only the former was a significant independent predictor of outcome in a Cox proportional-hazard model adjusted for sex, age, diabetes, anemia, and chronic kidney disease. Analyses of changes in ambulatory BP during follow-up revealed 17% reduction in CVD risk for each 5 mm Hg decrease in the asleep systolic BP mean (p < .001), independent of changes in any other clinic or ambulatory BP parameter. The increased event-free survival associated with the progressive reduction in the asleep systolic BP mean during follow-up was significant for subjects with either normal or elevated BP at baseline. The ABPM-derived asleep BP mean was the most significant prognostic marker of CVD morbidity and mortality. Most important, the progressive decrease in asleep BP mean, a novel therapeutic target that requires proper patient evaluation by ABPM and best achieved by ingestion of at least one hypertension medication at bedtime, was the most significant predictor of event-free survival.

  16. The adaptor 3BP2 is required for KIT receptor expression and human mast cell survival

    PubMed Central

    Ainsua-Enrich, Erola; Serrano-Candelas, Eva; Álvarez-Errico, Damiana; Picado, César; Sayós, Joan; Rivera, Juan; Martín, Margarita

    2015-01-01

    3BP2 is a cytoplasmic adaptor protein that acts as a positive regulator in mast cell FcεRI-dependent signaling. The KIT receptor whose ligand is the stem cell factor (SCF) is necessary for mast cell development, proliferation and survival as well as for optimal IgE-dependent signal. Activating mutations in KIT have been associated with several diseases including mastocytosis. In the present work, we found that 3BP2 silencing impairs KIT signaling pathways, thus affecting PI3K and MAP kinase pathways in human mast cells from HMC-1, LAD2 (human mast cell lines) and CD34+-derived mast cells. Unexpectedly, silencing of 3BP2 reduces KIT expression in normal human mast cells as well as in HMC-1 cells where KIT is mutated, thus increasing cellular apoptosis and caspase 3/7 activity. 3BP2 silencing reduces KIT transcription expression levels. Interestingly, 3BP2 silencing decreased MITF expression, a transcription factor involved in KIT expression. Reconstitution of 3BP2 in knockdown cells leads to reversal of KIT expression as well as survival phenotype. Accordingly MITF reconstitution enhances KIT expression levels in 3BP2 silenced cells. Moreover, downregulation of KIT expression by miRNA221 overexpression or the proteasome inhibitor bortezomib also reduced 3BP2 and MITF expression. Furthermore, KIT tyrosine activity inhibition reduced 3BP2 and MITF expression, demonstrating again a tight and reciprocal relationship between these molecules. Taken together, our results show that 3BP2 regulates human mast cell survival and participates in KIT-mediated signal transduction by directly controlling KIT receptor expression, suggesting its potential as a therapeutic target in mast cell-mediated inflammatory diseases and deregulated KIT disorders. PMID:25810396

  17. The millimetre spectrum of BP Cru

    NASA Astrophysics Data System (ADS)

    Pestalozzi, Michele; Hobbs, George; Torkelsson, Ulf

    2010-04-01

    In this experiment we attempt to detect the millimetre emission from the high-mass X-ray binary BP Cru. This object is composed of a hypergiant (Wray 977) and a slow spinning X-ray pulsar (GX301-2). The recent ATCA observations of centimeter emission (Pestalozzi et al. 2009, this was the first detection of radio emission towards BP Cru) suggested that radio emission consists of two components, a transient non-thermal one and a persistent thermal one, probably arising from the large stellar wind of Wray 977. As stellar winds often show a positive spectral index, we ask to observe BP Cru at 13 and 7 mm, where we expect fluxes of around 1 mJy. Any detection will allow us to probe the inner parts of the wind and characterise the structure of the stellar wind of BP Cru. For this detection experiment we require 11 hours of observations with ATCA.

  18. BP: synthesis and properties of boron phosphide

    NASA Astrophysics Data System (ADS)

    Woo, Katherine; Lee, Kathleen; Kovnir, Kirill

    2016-07-01

    Cubic boron phosphide, BP, is notorious for its difficult synthesis, thus preventing it from being a widely used material in spite of having numerous favorable technological properties. In the current work, three different methods of synthesis are developed and compared: from the high temperature reaction of elements, Sn flux assisted synthesis, and a solid state metathesis reaction. Structural and optical properties of the products synthesized from the three methods were thoroughly characterized. Solid state metathesis is shown to be the cleanest and most efficient method in terms of reaction temperature and time. Synthesis by Sn flux resulted in a novel Sn-doped BP compound. Undoped BP samples exhibit an optical bandgap of ∼2.2 eV while Sn-doped BP exhibits a significantly smaller bandgap of 1.74 eV. All synthesized samples show high stability in concentrated hydrochloric acid, saturated sodium hydroxide solutions, and fresh aqua regia.

  19. Reaching Grid Parity Using BP Solar Crystalline Silicon Technology: A Systems Class Application

    SciTech Connect

    Cunningham, Daniel W; Wohlgemuth, John; Carlson, David E; Clark, Roger F; Gleaton, Mark; Posbic, John P; Zahler, James

    2010-12-06

    The primary target market for this program was the residential and commercial PV markets, drawing on BP Solar's premium product and service offerings, brand and marketing strength, and unique routes to market. These two markets were chosen because: (1) in 2005 they represented more than 50% of the overall US PV market; (2) they are the two markets that will likely meet grid parity first; and (3) they are the two market segments in which product development can lead to the added value necessary to generate market growth before reaching grid parity. Federal investment in this program resulted in substantial progress toward the DOE TPP target, providing significant advancements in the following areas: (1) Lower component costs particularly the modules and inverters. (2) Increased availability and lower cost of silicon feedstock. (3) Product specifically developed for residential and commercial applications. (4) Reducing the cost of installation through optimization of the products. (5) Increased value of electricity in mid-term to drive volume increases, via the green grid technology. (6) Large scale manufacture of PV products in the US, generating increased US employment in manufacturing and installation. To achieve these goals BP Solar assembled a team that included suppliers of critical materials, automated equipment developers/manufacturers, inverter and other BOS manufacturers, a utility company, and University research groups. The program addressed all aspects of the crystalline silicon PV business from raw materials (particularly silicon feedstock) through installation of the system on the customers site. By involving the material and equipment vendors, we ensured that supplies of silicon feedstock and other PV specific materials like encapsulation materials (EVA and cover glass) will be available in the quantities required to meet the DOE goals of 5 to 10 GW of installed US PV by 2015 and at the prices necessary for PV systems to reach grid parity in 2015

  20. Effects of calcium channel blocker benidipine-based combination therapy on target blood pressure control and cardiovascular outcome: a sub-analysis of the COPE trial.

    PubMed

    Umemoto, Seiji; Ogihara, Toshio; Matsuzaki, Masunori; Rakugi, Hiromi; Ohashi, Yasuo; Saruta, Takao

    2017-04-01

    We compared three benidipine-based regimens-that is, benidipine plus angiotensin receptor blocker (ARB), β-blocker (BB) or thiazide-and found that the benidipine-BB combination was less beneficial in reducing the risk of stroke than the benidipine-thiazide combination. This sub-analysis sought to compare the effects of reaching a target blood pressure (BP) (<140/90 mm Hg) on the cardiovascular outcomes among the three benidipine-based treatment groups in the Combination Therapy of Hypertension to Prevent Cardiovascular Events trial. This sub-analysis included 3001 subjects to evaluate the achievement of target BP at a minimum of three points at 6-month intervals of clinical BP measurements during the study period. After randomization, the patients were categorized into two groups on the basis of achieved on-treatment target BP: a good control (GC) group achieving a BP⩾66.7% of the target and a poor control (PC) group with a BP <66.6% of the target. For each of the two control groups, outcomes were compared among the three treatment groups. The event rates for cardiovascular composite endpoints, stroke and hard cardiovascular events were higher in the PC group than the GC group (P=0.041, P=0.042 and P=0.038, respectively). Within the PC group, hazard ratios for the incidence of cardiovascular events were lower in the benidipine-thiazide group than in the benidipine-BB group (composite cardiovascular events: 2.04, P=0.033; stroke: 4.14, P=0.005; and hard cardiovascular events: 3.52, P=0.009). Within the GC group, the incidence of cardiovascular events was not different among the three treatment regimens. The benidipine-thiazide combination may provide better cardiovascular outcomes than the benidipine-BB combination even in patients with poor BP control.

  1. Predialysis systolic BP variability and outcomes in hemodialysis patients.

    PubMed

    Shafi, Tariq; Sozio, Stephen M; Bandeen-Roche, Karen J; Ephraim, Patti L; Luly, Jason R; St Peter, Wendy L; McDermott, Aidan; Scialla, Julia J; Crews, Deidra C; Tangri, Navdeep; Miskulin, Dana C; Michels, Wieneke M; Jaar, Bernard G; Herzog, Charles A; Zager, Philip G; Meyer, Klemens B; Wu, Albert W; Boulware, L Ebony

    2014-04-01

    BP variability (BPV) is an important predictor of outcomes in the general population, but its association with clinical outcomes in hemodialysis patients is not clear. We identified 11,291 patients starting dialysis in 2003-2008 and followed them through December 31, 2008 (median=22 months). Predialysis systolic BPV was assessed over monthly intervals. Outcomes included factors associated with BPV, mortality (all-cause and cardiovascular), and first cardiovascular event (cardiovascular death or hospitalization). Patients' mean age was 62 years, 55% of patients were men, and 58% of patients were white. Modifiable factors associated with higher BPV included obesity, higher calcium-phosphate product levels, and lower hemoglobin concentration; factors associated with lower BPV included greater fluid removal, achievement of prescribed dry weight during dialysis, higher hemoglobin concentration, and antihypertensive regimens without β-blockers or renin-angiotensin system blocking agents. In total, 3200 deaths occurred, including 1592 cardiovascular deaths. After adjustment for demographics, comorbidities, and clinical factors, higher predialysis BPV was associated with increased risk of all-cause mortality (hazard ratio [HR], 1.18; 95% confidence interval [95% CI] per 1 SD increase in BPV, 1.13 to 1.22), cardiovascular mortality (HR, 1.18; 95% CI, 1.12 to 1.24), and first cardiovascular event (HR, 1.11; 95% CI, 1.07 to 1.15). Results were similar when BPV was categorized in tertiles and patients were stratified by baseline systolic BP. In summary, predialysis systolic BPV is an important, potentially modifiable risk factor for death and cardiovascular outcomes in incident hemodialysis patients. Studies of BP management in dialysis patients should focus on both absolute BP and BPV.

  2. Translation control during prolonged mTORC1 inhibition mediated by 4E-BP3

    PubMed Central

    Tsukumo, Yoshinori; Alain, Tommy; Fonseca, Bruno D.; Nadon, Robert; Sonenberg, Nahum

    2016-01-01

    Targeting mTORC1 is a highly promising strategy in cancer therapy. Suppression of mTORC1 activity leads to rapid dephosphorylation of eIF4E-binding proteins (4E-BP1–3) and subsequent inhibition of mRNA translation. However, how the different 4E-BPs affect translation during prolonged use of mTOR inhibitors is not known. Here we show that the expression of 4E-BP3, but not that of 4E-BP1 or 4E-BP2, is transcriptionally induced during prolonged mTORC1 inhibition in vitro and in vivo. Mechanistically, our data reveal that 4E-BP3 expression is controlled by the transcription factor TFE3 through a cis-regulatory element in the EIF4EBP3 gene promoter. CRISPR/Cas9-mediated EIF4EBP3 gene disruption in human cancer cells mitigated the inhibition of translation and proliferation caused by prolonged treatment with mTOR inhibitors. Our findings show that 4E-BP3 is an important effector of mTORC1 and a robust predictive biomarker of therapeutic response to prolonged treatment with mTOR-targeting drugs in cancer. PMID:27319316

  3. Survey of the bp/tee genes from clinical group A streptococcus isolates in New Zealand - implications for vaccine development.

    PubMed

    Steemson, John D; Moreland, Nicole J; Williamson, Deborah; Morgan, Julie; Carter, Philip E; Proft, Thomas

    2014-12-01

    Group A streptococcus (GAS) is responsible for a wide range of diseases ranging from superficial infections, such as pharyngitis and impetigo, to life-threatening diseases, such as toxic shock syndrome and acute rheumatic fever (ARF). GAS pili are hair-like extensions protruding from the cell surface and consist of highly immunogenic structural proteins: the backbone pilin (BP) and one or two accessory pilins (AP1 and AP2). The protease-resistant BP builds the pilus shaft and has been recognized as the T-antigen, which forms the basis of a major serological typing scheme that is often used as a supplement to M typing. A previous sequence analysis of the bp gene (tee gene) in 39 GAS isolates revealed 15 different bp/tee types. In this study, we sequenced the bp/tee gene from 100 GAS isolates obtained from patients with pharyngitis, ARF or invasive disease in New Zealand. We found 20 new bp/tee alleles and four new bp/tee types/subtypes. No association between bp/tee type and clinical outcome was observed. We confirmed earlier reports that the emm type and tee type are associated strongly, but we also found exceptions, where multiple tee types could be found in certain M/emm type strains, such as M/emm89. We also reported, for the first time, the existence of a chimeric bp/tee allele, which was assigned into a new subclade (bp/tee3.1). A strong sequence conservation of the bp/tee gene was observed within the individual bp/tee types/subtypes (>97 % sequence identity), as well as between historical and contemporary New Zealand and international GAS strains. This temporal and geographical sequence stability provided further evidence for the potential use of the BP/T-antigen as a vaccine target.

  4. REPTOR and REPTOR-BP regulate organismal metabolism and transcription downstream of TORC1

    PubMed Central

    Tiebe, Marcel; Lutz, Marilena; De La Garza, Adriana; Buechling, Tina; Boutros, Michael; Teleman, Aurelio A.

    2015-01-01

    SUMMARY TORC1 regulates growth and metabolism in part by influencing transcriptional programs. We identify here REPTOR and REPTOR-BP as transcription factors downstream of TORC1, required for ~90% of the transcriptional induction that occurs upon TORC1 inhibition in Drosophila. Thus REPTOR and REPTOR-BP are major effectors of the transcriptional stress response induced upon TORC1 inhibition, analogous to the role of FOXO downstream of Akt. We find that when TORC1 is active, it phosphorylates REPTOR on Ser527 and Ser530, leading to REPTOR cytoplasmic retention. Upon TORC1 inhibition, REPTOR becomes dephosphorylated in a PP2A dependent manner, shuttles into the nucleus, joins its partner REPTOR-BP to bind target genes, and activates their transcription. In vivo functional analysis using knockout flies reveals that REPTOR and REPTOR-BP play critical roles in maintaining energy homeostasis and promoting animal survival upon nutrient restriction. PMID:25920570

  5. DB 01-3 TREATMENT TARGET OF SYSTOLIC BLOOD PRESSURE IN DIABETES MAY DIFFER ACCORDING TO ETHNICITY (PRO).

    PubMed

    Kario, Kazuomi

    2016-09-01

    Asians have specific characteristics of hypertension and related cardiovascular disease. Stroke is more common than coronary artery disease in Eastern Asian countries, while the coronary artery disease is more common than stroke in Western countries. The association slope between higher blood pressure (BP) and the risk of cardiovascular events is steeper in Asians than in Caucasians. This may partly explained by the recent result demonstrating that the morning BP surge in Asians is more extended (Hoshide, Kario, Parati et al. Hypertension 2016;68:54-61). Thus, 24-hr BP control including night-time and morning periods is especially important for Asian hypertensive patients (Kario. Essential manual of 24 hour blood pressure management. Wiley, UK, pp.1-158.2016).The existing direct evidence from Asian studies are limited than the accumulated evidence from Western countries. In the ACCORD BP trial which enrolled 4733 participants with type 2 diabetes and randomized them to a target systolic BP <120mmHg (intensive BP control) or <140mmHg (standard BP control). Despite the significant difference in the achieved systolic BP, there was no significant difference in the incidence of primary cardiovascular outcomes. Based on this evidence, the target systolic BP for diabetics has been revised from 130 mmHg to 140 mmHg in the majority of Western guidelines. However, in the ACCORD study, the intensive BP control was associated with significant reduction in both total stroke and nonfatal stroke. In addition, the ONTARGET study, which showed that in diabetic patients, the risk of stroke continued to decrease down to achieved SBP <115mmHg with no evidence of J curve.The new guidelines of the Japanese Society of Hypertension regarding the management of hypertension (JSH2014) were published in 2014 (Hypertens Res 2014;37:253-390). The JSH2014 guidelines use the systolic BP value 130 mmHg, a lower target clinic BP compared to the Western guidelines (140 mmHg), for hypertensive

  6. 3-Bromopyruvate: targets and outcomes.

    PubMed

    Shoshan, Maria C

    2012-02-01

    The pyruvate mimetic 3-bromopyruvate (3-BP) is generally presented as an inhibitor of glycolysis and has shown remarkable efficacy in not only preventing tumor growth, but even eradicating existant tumors in animal studies. We here review reported molecular targets of 3-BP and suggest that the very range of possible targets, which pertain to the altered energy metabolism of tumor cells, contributes both to the efficacy and the tumor specificity of the drug. Its in vivo efficacy is suggested to be due to a combination of glycolytic and mitochondrial targets, as well as to secondary effects affecting the tumor microenvironment. The cytotoxicity of 3-BP is less due to pyruvate mimicry than to alkylation of, e.g., key thiols. Alkylation of DNA/RNA has not been reported. More research is warranted to better understand the pharmacokinetics of 3-BP, and its potential toxic effects to normal cells, in particular those that are highly ATP-/mitochondrion-dependent.

  7. Benzo[a]pyrene (BP) DNA adduct formation in DNA repair-deficient p53 haploinsufficient [Xpa(-/-)p53(+/-)] and wild-type mice fed BP and BP plus chlorophyllin for 28 days.

    PubMed

    John, Kaarthik; Pratt, M Margaret; Beland, Frederick A; Churchwell, Mona I; McMullen, Gail; Olivero, Ofelia A; Pogribny, Igor P; Poirier, Miriam C

    2012-11-01

    We have evaluated DNA damage (DNA adduct formation) after feeding benzo[a]pyrene (BP) to wild-type (WT) and cancer-susceptible Xpa(-/-)p53(+/-) mice deficient in nucleotide excision repair and haploinsufficient for the tumor suppressor p53. DNA damage was evaluated by high-performance liquid chromatography/electrospray ionization tandem mass spectrometry (HPLC/ES-MS/MS), which measures r7,t8,t9-trihydroxy-c-10-(N (2)-deoxyguanosyl)-7,8,9,10-tetrahydrobenzo[a]pyrene (BPdG), and a chemiluminescence immunoassay (CIA), using anti-r7,t8-dihydroxy-t-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE)-DNA antiserum, which measures both BPdG and the other stable BP-DNA adducts. When mice were fed 100 ppm BP for 28 days, BP-induced DNA damage measured in esophagus, liver and lung was typically higher in Xpa(-/-)p53(+/-) mice, compared with WT mice. This result is consistent with the previously observed tumor susceptibility of Xpa(-/-)p53(+/-) mice. BPdG, the major DNA adduct associated with tumorigenicity, was the primary DNA adduct formed in esophagus (a target tissue in the mouse), whereas total BP-DNA adducts predominated in higher levels in the liver (a non-target tissue in the mouse). In an attempt to lower BP-induced DNA damage, we fed the WT and Xpa(-/-)p53(+/-) mice 0.3% chlorophyllin (CHL) in the BP-containing diet for 28 days. The addition of CHL resulted in an increase of BP-DNA adducts in esophagus, liver and lung of WT mice, a lowering of BPdG in esophagi of WT mice and livers of Xpa(-/-)p53(+/-) mice and an increase of BPdG in livers of WT mice. Therefore, the addition of CHL to a BP-containing diet showed a lack of consistent chemoprotective effect, indicating that oral CHL administration may not reduce PAH-DNA adduct levels consistently in human organs.

  8. R7BP modulates opiate analgesia and tolerance but not withdrawal.

    PubMed

    Terzi, Dimitra; Cao, Yan; Agrimaki, Ioanna; Martemyanov, Kirill A; Zachariou, Venetia

    2012-03-01

    The adaptor protein R7 family binding protein (R7BP) modulates G protein coupled receptor (GPCR) signaling and desensitization by controlling the function of regulator of G protein signaling (RGS) proteins. R7BP is expressed throughout the brain and appears to modulate the membrane localization and stability of three proteins that belong to R7 RGS family: RGS6, RGS7, and RGS9-2. RGS9-2 is a potent negative modulator of opiate and psychostimulant addiction and promotes the development of analgesic tolerance to morphine, whereas the role of RGS6 and RGS7 in addiction remains unknown. Recent studies revealed that functional deletion of R7BP reduces R7 protein activity by preventing their anchoring to the cell membrane and enhances GPCR responsiveness in the basal ganglia. Here, we take advantage of R7BP knockout mice in order to examine the way interventions in R7 proteins function throughout the brain affect opiate actions. Our results suggest that R7BP is a negative modulator of the analgesic and locomotor activating actions of morphine. We also report that R7BP contributes to the development of morphine tolerance. Finally, our data suggest that although prevention of R7BP actions enhances the analgesic responses to morphine, it does not affect the severity of somatic withdrawal signs. Our data suggest that interventions in R7BP actions enhance the analgesic effect of morphine and prevent tolerance, without affecting withdrawal, pointing to R7BP complexes as potential new targets for analgesic drugs.

  9. Tubulin binding protein, CacyBP/SIP, induces actin polymerization and may link actin and tubulin cytoskeletons.

    PubMed

    Schneider, Gabriela; Nieznanski, Krzysztof; Jozwiak, Jolanta; Slomnicki, Lukasz P; Redowicz, Maria J; Filipek, Anna

    2010-11-01

    CacyBP/SIP, originally identified as a S100A6 target, was shown to interact with some other S100 proteins as well as with Siah-1, Skp1, tubulin and ERK1/2 kinases (reviewed in Schneider and Filipek, Amino Acids, 2010). Here, we show that CacyBP/SIP interacts and co-localizes with actin in NB2a cells. Using a zero-length cross-linker we found that both proteins bound directly to each other. Co-sedimentation assays revealed that CacyBP/SIP induced G-actin polymerization and formation of unique circular actin filament bundles. The N-terminal fragment of CacyBP/SIP (residues 1-179) had similar effect on actin polymerization as the entire CacyBP/SIP protein, while the C-terminal one (residues 178-229) had not. To check the influence of CacyBP/SIP on cell morphology as well as on cell adhesion and migration, a stable NIH 3T3 cell line with an increased level of CacyBP/SIP was generated. We found that the adhesion and migration rates of the modified cells were changed in comparison with the control ones. Interestingly, the co-sedimentation and proximity ligation assays indicated that CacyBP/SIP could simultaneously interact with tubulin and actin, suggesting that CacyBP/SIP might link actin and tubulin cytoskeletons.

  10. CacyBP/SIP interacts with tubulin in neuroblastoma NB2a cells and induces formation of globular tubulin assemblies.

    PubMed

    Schneider, Gabriela; Nieznanski, Krzysztof; Kilanczyk, Ewa; Bieganowski, Paweł; Kuznicki, Jacek; Filipek, Anna

    2007-11-01

    CacyBP/SIP, originally identified as a S100A6 (calcyclin) target, was later shown to interact with some other members of the S100 family as well as with Siah-1 and Skp1 proteins. Recently, it has been shown that CacyBP/SIP is up-regulated during differentiation of cardiomyocytes. In this work we show that the level of CacyBP/SIP is higher in differentiated neuroblastoma NB2a cells than in undifferentiated ones and that in cells overexpressing CacyBP/SIP the level of GAP-43, a marker of differentiation, was increased. Since the process of differentiation is accompanied by an extensive rearrangement of microtubules, we examined whether CacyBP/SIP interacted with tubulin. By applying cross-linking experiments we found that these two proteins bind directly. The dissociation constant of the tubulin-CacyBP/SIP complex determined by the surface plasmon resonance technique is 1.57 x 10(-7 )M which suggests that the interaction is tight. The interaction and co-localization of CacyBP/SIP and tubulin was also demonstrated by co-immunoprecipitation, affinity chromatography and immunofluorescence methods. Light scattering measurements and electron microscopy studies revealed that CacyBP/SIP, but not its homologue, Sgt1, increased tubulin oligomerization. Altogether, our results suggest that CacyBP/SIP, via its interaction with tubulin, might contribute to the differentiation of neuroblastoma NB2a cells.

  11. Time to achieve target mean arterial pressure during resuscitation from experimental anaphylactic shock in an animal model. A comparison of adrenaline alone or in combination with different volume expanders.

    PubMed

    Tajima, K; Zheng, F; Collange, O; Barthel, G; Thornton, S N; Longrois, D; Levy, B; Audibert, G; Malinovsky, J M; Mertes, P M

    2013-11-01

    Anaphylactic shock is a rare, but potentially lethal complication, combining life-threatening circulatory failure and massive fluid shifts. Treatment guidelines rely on adrenaline and volume expansion by intravenous fluids, but there is no solid evidence for the choice of one specific type of fluid over another. Our purpose was to compare the time to achieve target mean arterial pressure upon resuscitation using adrenaline alone versus adrenaline with different resuscitation fluids in an animal model and to compare the tissue oxygen pressures (PtiO2) with the various strategies. Twenty-five ovalbumin-sensitised Brown Norway rats were allocated to five groups after anaphylactic shock induction: vehicle (CON), adrenaline alone (AD), or adrenaline with isotonic saline (AD+IS), hydroxyethyl starch (AD+HES) or hypertonic saline (AD+HS). Time to reach a target mean arterial pressure value of 75 mmHg, cardiac output, skeletal muscle PtiO2, lactate/pyruvate ratio and cumulative doses of adrenaline were recorded. Non-treated rats died within 15 minutes. The target mean arterial pressure value was reached faster with AD+HES (median: 10 minutes, range: 7.5 to 12.5 minutes) and AD+IS (median: 17.5 minutes, range: 5 to 25 minutes) versus adrenaline alone (median: 25 minutes, range: 20-30 minutes). There were also reduced adrenaline requirements in these groups. The skeletal muscle PtiO2 was restored only in the AD+HES group. Although direct extrapolation to humans should be made with caution, our results support the combined use of adrenaline and volume expansion for resuscitation from anaphylactic shock. When used with adrenaline the most effective fluid was hydroxyethyl starch, whereas hypertonic saline was the least effective.

  12. Benzo[a]pyrene (BP) DNA adduct formation in DNA repair–deficient p53 haploinsufficient [Xpa(−/−)p53(+/−)] and wild-type mice fed BP and BP plus chlorophyllin for 28 days

    PubMed Central

    Poirier, Miriam C.

    2012-01-01

    We have evaluated DNA damage (DNA adduct formation) after feeding benzo[a]pyrene (BP) to wild-type (WT) and cancer-susceptible Xpa(−/−)p53(+/−) mice deficient in nucleotide excision repair and haploinsufficient for the tumor suppressor p53. DNA damage was evaluated by high-performance liquid chromatography/electrospray ionization tandem mass spectrometry (HPLC/ES-MS/MS), which measures r7,t8,t9-trihydroxy-c-10-(N 2-deoxyguanosyl)-7,8,9,10-tetrahydrobenzo[a]pyrene (BPdG), and a chemiluminescence immunoassay (CIA), using anti-r7,t8-dihydroxy-t-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE)–DNA antiserum, which measures both BPdG and the other stable BP-DNA adducts. When mice were fed 100 ppm BP for 28 days, BP-induced DNA damage measured in esophagus, liver and lung was typically higher in Xpa(−/−)p53(+/−) mice, compared with WT mice. This result is consistent with the previously observed tumor susceptibility of Xpa(−/−)p53(+/−) mice. BPdG, the major DNA adduct associated with tumorigenicity, was the primary DNA adduct formed in esophagus (a target tissue in the mouse), whereas total BP-DNA adducts predominated in higher levels in the liver (a non-target tissue in the mouse). In an attempt to lower BP-induced DNA damage, we fed the WT and Xpa(−/−)p53(+/−) mice 0.3% chlorophyllin (CHL) in the BP-containing diet for 28 days. The addition of CHL resulted in an increase of BP–DNA adducts in esophagus, liver and lung of WT mice, a lowering of BPdG in esophagi of WT mice and livers of Xpa(−/−)p53(+/−) mice and an increase of BPdG in livers of WT mice. Therefore, the addition of CHL to a BP-containing diet showed a lack of consistent chemoprotective effect, indicating that oral CHL administration may not reduce PAH–DNA adduct levels consistently in human organs. PMID:22828138

  13. Licensing: BP, Lurgi unveil new butanediol process

    SciTech Connect

    Rotman, D.

    1995-07-26

    BP Chemicals and Lurgi (Frankfurt) say they have jointly developed a direct butane-to-1,4-butanediol process and are ready to license the technology. The companies-which began cooperating on the technology in early 1994-say the process, which is being marketed under the name Geminox, promises to be about 40% cheaper to operate than existing butandiol technologies.

  14. The CacyBP/SIP protein is sumoylated in neuroblastoma NB2a cells.

    PubMed

    Wasik, Urszula; Filipek, Anna

    2013-11-01

    The Calcyclin binding protein and Siah-1 interacting protein (CacyBP/SIP) protein is highly expressed in mammalian brain as well as in neuroblastoma NB2a cells and pheochromocytoma PC12 cells. This protein interacts with several targets such as cytoskeletal proteins or ERK1/2 kinase and seems to be involved in many cellular processes. In this work we examined a post-translational modification of CacyBP/SIP which might have an effect on its function. Since theoretical analysis of the amino acid sequence of CacyBP/SIP indicated several lysine residues which could potentially be sumoylated we checked experimentally whether this protein might be modified by SUMO attachment. We have shown that indeed CacyBP/SIP bound the E2 SUMO ligase, Ubc9, in neuroblastoma NB2a cell extract and was sumoylated in these cells. By fractionation of NB2a cell extract we have found that, contrary to the majority of SUMO-modified proteins, sumoylated CacyBP/SIP is present in the cytoplasmic and not in the nuclear fraction. We have also established that lysine 16 is the residue which undergoes sumoylation in the CacyBP/SIP protein.

  15. Arginine methylation of G3BP1 in response to Wnt3a regulates β-catenin mRNA

    PubMed Central

    Bikkavilli, Rama Kamesh; Malbon, Craig C.

    2011-01-01

    Wnt/β-catenin signaling is essential for normal mammalian development. Wnt3a activates the Wnt/β-catenin pathway through stabilization of β-catenin; a process in which the phosphoprotein Dishevelled figures prominently. Protein arginine methylation in signaling complexes containing Dishevelled was investigated. Mass spectrometry of a prominent arginine-methylated, Dishevelled-associated protein identified the Ras GTPase activating protein-binding protein 1 G3BP1. Stimulation of totipotent mouse embryonic F9 cells with Wnt3a provoked increased methylation of G3BP1. We show that G3BP1 is a novel Ctnnb1 mRNA binding protein. Methylation of G3BP1 constitutes a molecular switch that regulates Ctnnb1 mRNA in response to Wnt3a. Thus, the protein arginine methylation that targets G3BP1 acts as a novel regulator of Ctnnb1 mRNA. PMID:21652632

  16. RanBP3 Regulates Melanoma Cell Proliferation via Selective Control of Nuclear Export.

    PubMed

    Pathria, Gaurav; Garg, Bhavuk; Wagner, Christine; Garg, Kanika; Gschaider, Melanie; Jalili, Ahmad; Wagner, Stephan N

    2016-01-01

    Chromosome region maintenance 1-mediated nucleocytoplasmic transport has been shown as a potential anticancer target in various malignancies. However, the role of the most characterized chromosome region maintenance 1 cofactor ran binding protein 3 (RanBP3) in cancer cell biology has never been investigated. Utilizing a loss-of-function experimental setting in a vast collection of genetically varied melanoma cell lines, we observed the requirement of RanBP3 in melanoma cell proliferation and survival. Mechanistically, we suggest the reinstatement of transforming growth factor-β (TGF-β)-Smad2/3-p21(Cip1) tumor-suppressor axis as part of the RanBP3 silencing-associated antiproliferative program. Employing extensive nuclear export sequence analyses and immunofluorescence-based protein localization studies, we further present evidence suggesting the requirement of RanBP3 function for the nuclear exit of the weak nuclear export sequence-harboring extracellular signal-regulated kinase protein, although it is dispensable for general CRM1-mediated nuclear export of strong nuclear export sequence-harboring cargoes. Rendering mechanistic support to RanBP3 silencing-mediated apoptosis, consequent to extracellular signal-regulated kinase nuclear entrapment, we observed increased levels of cytoplasmically restricted nonphosphorylated/active proapoptotic Bcl-2-antagonist of cell death (BAD) protein. Last, we present evidence suggesting the frequently activated mitogen-activated protein kinase signaling in melanoma as a potential founding basis for a deregulated post-translational control of RanBP3 activity. Collectively, the presented data suggest RanBP3 as a potential target for therapeutic intervention in human melanoma.

  17. 2014 Eighth Joint National Committee Panel Recommendation for Blood Pressure Targets Revisited

    PubMed Central

    Bangalore, Sripal; Gong, Yan; Cooper-DeHoff, Rhonda M.; Pepine, Carl J.; Messerli, Franz H.

    2014-01-01

    BACKGROUND The 2014 Eighth Joint National Committee panel recommendations for management of high blood pressure (BP) recommend a systolic BP threshold for initiation of drug therapy and a therapeutic target of <150 mm Hg in those ≥60 years of age, a departure from prior recommendations of <140 mm Hg. However, it is not known whether this is an optimal choice, especially for the large population with coronary artery disease (CAD). OBJECTIVES This study sought to evaluate optimal BP in patients ≥60 years of age. METHODS Patients 60 years of age or older with CAD and baseline systolic BP >150 mm Hg randomized to a treatment strategy on the basis of either atenolol/hydrochlorothiazide or verapamil-SR (sustained release)/trandolapril in INVEST (INternational VErapamil SR Trandolapril STudy) were categorized into 3 groups on the basis of achieved on-treatment systolic BP: group 1, <140 mm Hg; group 2, 140 to <150 mm Hg; and group 3, ≥150 mm Hg. Primary outcome was first occurrence of all-cause death, nonfatal myocardial infarction (MI), or nonfatal stroke. Secondary outcomes were all-cause mortality, cardiovascular mortality, total MI, nonfatal MI, total stroke, nonfatal stroke, heart failure, or revascularization, tabulated separately. Outcomes for each group were compared in unadjusted and multiple propensity score–adjusted models. RESULTS Among 8,354 patients included in this analysis with an accumulated 22,308 patient-years of follow-up, 4,787 (57%) achieved systolic BP of <140 mm Hg (group 1), 1,747 (21%) achieved systolic BP of 140 to <150 mm Hg (group 2), and 1,820 (22%) achieved systolic BP of ≥150 mm Hg (group 3). In unadjusted models, group 1 had the lowest rates of the primary outcome (9.36% vs. 12.71% vs. 21.32%; p < 0.0001), all-cause mortality (7.92% vs. 10.07% vs. 16.81%; p < 0.0001), cardiovascular mortality (3.26% vs. 4.58% vs. 7.80%; p < 0.0001), MI (1.07% vs. 1.03% vs. 2.91%; p < 0.0001), total stroke (1.19% vs. 2.63% vs. 3.85%; p <0

  18. Biomechanical parameters of the BP-enriched bone cement.

    PubMed

    Matuszewski, Łukasz; Olchowik, Grażyna; Mazurkiewicz, Tomasz; Kowalczyk, Bartłomiej; Zdrojewska, Agata; Matuszewska, Anna; Ciszewski, Andrzej; Gospodarek, Małgorzata; Morawik, Iwona

    2014-05-01

    Bisphosphonates (BPs) are well-known substances with very efficient antiresorptive properties. Their beneficial actions are useful not only in achieving better bone mineral density but also in improving bone microarchitecture, strength and, consequently, its quality. Surgical cement, being a polymer composite, is required to be highly biocompatible and biotolerant. The goal of the presented study was to assess whether the enrichment of cement with pamidronate has changed its biomechanical properties. We compared the biomechanical parameters of clean bone cement and BP-enriched bone cement, which were both used formerly in our rat models. Biomechanical properties of BP-enriched bone cement are defined by two basic terms: stress and strain, which are caused by the influence of external force. In the investigatory process of the bone's biomechanical parameters, the compressive test and the three-point flexural tests were used. During the three-point flexural investigation, the sample was supported at both ends and loaded in the middle, resulting in a flexure. After a specific range of flexure, the sample was fractured. In obtained results, there were no significant differences in the values of the stress determined at the point of maximal load and the energy stored in the samples for proportional stress-strain limit (elastic region). There were also no significant differences in the density of the samples. The study shows that the enrichment of bisphosphonates causes yielding of the bone cement material. In the presented data, we conclude that use of pamidronate implanted in bone cement did not have a detrimental effect on its biomechanical properties. Therefore, the obtained results encouraged us to perform further in vivo experiments which assess the biomechanical properties of bones implanted with BP-enriched bone cement.

  19. DNA-Templated Aptamer Probe for Identification of Target Proteins.

    PubMed

    Bi, Wenjing; Bai, Xue; Gao, Fan; Lu, Congcong; Wang, Ye; Zhai, Guijin; Tian, Shanshan; Fan, Enguo; Zhang, Yukui; Zhang, Kai

    2017-04-04

    Using aptamers as molecular probes for biomarker discovery has attracted a great deal of attention in recent years. However, it is still a big challenge to accurately identify those protein markers that are targeted by aptamers under physiological conditions due to weak and noncovalent aptamer-protein interactions. Herein, we developed an aptamer based dual-probe using DNA-templated chemistry and photo-cross-linking technique for the identification of target proteins that are recognized by aptamers. In this system, the aptamer was modified by a single strand DNA as binding probe (BP), and another complementary DNA with a photoactive group and reporter group was modified as capture probe (CP). BP was first added to recruit the binding protein via aptamer recognition, and subsequently CP was added to let the cross-linker close to the target via DNA self-assembly, and then a covalent bond between CP and its binding protein was achieved via photo-cross-linking reaction. The captured protein can be detected or affinity enrichment using the tag, finally identified by MS. By use of lysozyme as a model substrate, we demonstrated that this multiple functionalized probe can be utilized for a successful labeling and enrichment of target protein even under a complicated and real environment. Thus, a novel method to precisely identify the aptamer-targeted proteins has been developed and it has a potential application for discovery of aptamer-based biomarkers.

  20. The Nedd4-binding partner 1 (N4BP1) protein is an inhibitor of the E3 ligase Itch.

    PubMed

    Oberst, Andrew; Malatesta, Martina; Aqeilan, Rami I; Rossi, Mario; Salomoni, Paolo; Murillas, Rodolfo; Sharma, Prashant; Kuehn, Michael R; Oren, Moshe; Croce, Carlo M; Bernassola, Francesca; Melino, Gerry

    2007-07-03

    Nedd4-binding partner-1 (N4BP1) has been identified as a protein interactor and a substrate of the homologous to E6AP C terminus (HECT) domain-containing E3 ubiquitin-protein ligase (E3), Nedd4. Here, we describe a previously unrecognized functional interaction between N4BP1 and Itch, a Nedd4 structurally related E3, which contains four WW domains, conferring substrate-binding activity. We show that N4BP1 association with the second WW domain (WW2) of Itch interferes with E3 binding to its substrates. In particular, we found that N4BP1 and p73 alpha, a target of Itch-mediated ubiquitin/proteasome proteolysis, share the same binding site. By competing with p73 alpha for binding to the WW2 domain, N4BP1 reduces the ability of Itch to recruit and ubiquitylate p73 alpha and inhibits Itch autoubiquitylation activity both in in vitro and in vivo ubiquitylation assays. Similarly, both c-Jun and p63 polyubiquitylation by Itch are inhibited by N4BP1. As a consequence, genetic and RNAi knockdown of N4BP1 diminish the steady-state protein levels and significantly impair the transcriptional activity of Itch substrates. Notably, stress-induced induction of c-Jun was impaired in N4BP1(-/-) cells. These results demonstrate that N4BP1 functions as a negative regulator of Itch. In addition, because inhibition of Itch by N4BP1 results in the stabilization of crucial cell death regulators such as p73 alpha and c-Jun, it is conceivable that N4BP1 may have a role in regulating tumor progression and the response of cancer cells to chemotherapy.

  1. Drosophila Longevity Assurance Conferred by Reduced Insulin Receptor Substrate Chico Partially Requires d4eBP

    PubMed Central

    Bai, Hua; Post, Stephanie; Kang, Ping; Tatar, Marc

    2015-01-01

    Mutations of the insulin/IGF signaling (IIS) pathway extend Drosophila lifespan. Based on genetic epistasis analyses, this longevity assurance is attributed to downstream effects of the FOXO transcription factor. However, as reported FOXO accounts for only a portion of the observed longevity benefit, suggesting there are additional outputs of IIS to mediate aging. One candidate is target of rapamycin complex 1 (TORC1). Reduced TORC1 activity is reported to slow aging, whereas reduced IIS is reported to repress TORC1 activity. The eukaryotic translation initiation factor 4E binding protein (4E-BP) is repressed by TORC1, and activated 4E-BP is reported to increase Drosophila lifespan. Here we use genetic epistasis analyses to test whether longevity assurance mutants of chico, the Drosophila insulin receptor substrate homolog, require Drosophila d4eBP to slow aging. In chico heterozygotes, which are robustly long-lived, d4eBP is required but not sufficient to slow aging. Remarkably, d4eBP is not required or sufficient for chico homozygotes to extend longevity. Likewise, chico heterozygote females partially require d4eBP to preserve age-dependent locomotion, and both chico genotypes require d4eBP to improve stress-resistance. Reproduction and most measures of growth affected by either chico genotype are always independent of d4eBP. In females, chico heterozygotes paradoxically produce more rather than less phosphorylated 4E-BP (p4E-BP). Altered IRS function within the IIS pathway of Drosophila appears to have partial, conditional capacity to regulate aging through an unconventional interaction with 4E-BP. PMID:26252766

  2. Drosophila Longevity Assurance Conferred by Reduced Insulin Receptor Substrate Chico Partially Requires d4eBP.

    PubMed

    Bai, Hua; Post, Stephanie; Kang, Ping; Tatar, Marc

    2015-01-01

    Mutations of the insulin/IGF signaling (IIS) pathway extend Drosophila lifespan. Based on genetic epistasis analyses, this longevity assurance is attributed to downstream effects of the FOXO transcription factor. However, as reported FOXO accounts for only a portion of the observed longevity benefit, suggesting there are additional outputs of IIS to mediate aging. One candidate is target of rapamycin complex 1 (TORC1). Reduced TORC1 activity is reported to slow aging, whereas reduced IIS is reported to repress TORC1 activity. The eukaryotic translation initiation factor 4E binding protein (4E-BP) is repressed by TORC1, and activated 4E-BP is reported to increase Drosophila lifespan. Here we use genetic epistasis analyses to test whether longevity assurance mutants of chico, the Drosophila insulin receptor substrate homolog, require Drosophila d4eBP to slow aging. In chico heterozygotes, which are robustly long-lived, d4eBP is required but not sufficient to slow aging. Remarkably, d4eBP is not required or sufficient for chico homozygotes to extend longevity. Likewise, chico heterozygote females partially require d4eBP to preserve age-dependent locomotion, and both chico genotypes require d4eBP to improve stress-resistance. Reproduction and most measures of growth affected by either chico genotype are always independent of d4eBP. In females, chico heterozygotes paradoxically produce more rather than less phosphorylated 4E-BP (p4E-BP). Altered IRS function within the IIS pathway of Drosophila appears to have partial, conditional capacity to regulate aging through an unconventional interaction with 4E-BP.

  3. PEP-1-FK506BP inhibits alkali burn-induced corneal inflammation on the rat model of corneal alkali injury

    PubMed Central

    Kim, Dae Won; Lee, Sung Ho; Shin, Min Jea; Kim, Kibom; Ku, Sae Kwang; Youn, Jong Kyu; Cho, Su Bin; Park, Jung Hwan; Lee, Chi Hern; Son, Ora; Sohn, Eun Jeong; Cho, Sung-Woo; Park, Jong Hoon; Kim, Hyun Ah; Han, Kyu Hyung; Park, Jinseu; Eum, Won Sik; Choi, Soo Young

    2015-01-01

    FK506 binding protein 12 (FK506BP) is a small peptide with a single FK506BP domain that is involved in suppression of immune response and reactive oxygen species. FK506BP has emerged as a potential drug target for several inflammatory diseases. Here, we examined the protective effects of directly applied cell permeable FK506BP (PEP-1-FK506BP) on corneal alkali burn injury (CAI). In the cornea, there was a significant decrease in the number of cells expressing pro-inflammation, apoptotic, and angiogenic factors such as TNF-α, COX-2, and VEGF. Both corneal opacity and corneal neovascularization (CNV) were significantly decreased in the PEP-1-FK506BP treated group. Our results showed that PEP-1-FK506BP can significantly inhibit alkali burn-induced corneal inflammation in rats, possibly by accelerating corneal wound healing and by reducing the production of angiogenic factors and inflammatory cytokines. These results suggest that PEP-1-FK506BP may be a potential therapeutic agent for CAI. [BMB Reports 2015; 48(11): 618-623] PMID:25817214

  4. Asiago spectroscopic classification of ASASSN-16bp

    NASA Astrophysics Data System (ADS)

    Tomasella, L.; Pastorello, A.; Benetti, S.; Cappellaro, E.; Elias-Rosa, N.; Ochner, P.; Tartaglia, L.; Terreran, G.; Turatto, M.

    2016-02-01

    The Asiago Transient Classification Program (Tomasella et al. 2014, AN, 335, 841) reports the spectroscopic classification of ASASSN-16bp ( = AT 2016adq), discovered by All Sky Automated Survey for SuperNovae ASAS-SN (see Shappee et al. 2014, ApJ, 788, 48 and http://www.astronomy.ohio-state.edu/~assassin/index.shtml ), in CGCG 336-041 (Atel #8666) The observation was performed with the Asiago 1.82 m Copernico Telescope (+AFOSC; range 340-820 nm; resolution 1.4 nm). Name | Discovery UT | Obs. Date UT |z | Type | Phase |Notes ASASSN-16bp | 20160209.61 | 20160211.11 |0.034194 | Ia | ~10d | (1) (1) Also known as SN2016adq in CGCG 336-041 (z=0.034194, d=145 Mpc, via NED).

  5. Tackling Targets.

    ERIC Educational Resources Information Center

    Further Education Unit, London (England).

    This document is designed to help British training and enterprise councils (TECs) and further education (FE) colleges develop and implement strategies for achieving the National Targets for Education and Training (NTET), which were developed by the Confederation of British Industry in 1992 and endorsed by the British government. The findings from…

  6. ME 02-2 BLOOD PRESSURE TARGETS IN CHRONIC KIDNEY DISEASES AFTER THE SPRINT TRIAL.

    PubMed

    Zanchetti, Alberto

    2016-09-01

    The question of BP targets of antihypertensive treatment has been debated in recent guidelines, and reopened by publication of SPRINT. Although interpretation of SPRINT is made difficult by a preferential effect of more intense BP lowering on heart failure rather than stroke and myocardial infarction, and by a different method of BP measurement, recent meta-analyses by my group have shown SBP reduction <130 mmHg can reduce risk of cardiovascular (CV) outcomes further, but absolute benefit is smaller than that achieved across the 140 mmHg cutoff, and treatment discontinuations for adverse events become greater.Even more difficult is answering the question of BP targets in CKD. In this condition risks of CV events and renal failure are both particularly elevated. Unfortunately, evidence available from trials is rather confusing. SPRINT has included a consistent number of hypertensive patients with CKD, and found a trend, albeit non-significant, toward a reduction of CV events and no effect on risk of renal failure by more intense BP lowering. When SPRINT results are analyzed together with those of other trials on CKV, it appears that the benefits of BP lowering on the risk of CV mortality and morbidity are, at best, lesser than in patients with normal renal function, and the response of renal function is quite variable from trial to trial, possibly depending on the nature of CKD (diabetic or non-diabetic, with or without proteinuria) and on the type of antihypertensive drugs used (renin-angiotensin system blockers or other classes). The issue of antihypertensive treatment in CKD needs to be investigated in greater depth and with precise questions.

  7. A central role for R7bp in the regulation of itch sensation.

    PubMed

    Pandey, Mritunjay; Zhang, Jian-Hua; Mishra, Santosh K; Adikaram, Poorni R; Harris, Benjamin; Kahler, John F; Loshakov, Anna; Sholevar, Roxanne; Genis, Allison; Kittock, Claire; Kabat, Juraj; Ganesan, Sundar; Neubig, Richard R; Hoon, Mark A; Simonds, William F

    2017-01-27

    Itch is a protective sensation producing a desire to scratch. Pathologic itch can be a chronic symptom of illnesses such as uremia, cholestatic liver disease, neuropathies and dermatitis, however current therapeutic options are limited. Many types of cell surface receptors, including those present on cells in the skin, on sensory neurons and on neurons in the spinal cord, have been implicated in itch signaling. The role of G protein signaling in the regulation of pruriception is poorly understood. We identify here 2 G protein signaling components whose mutation impairs itch sensation. R7bp (a.k.a. Rgs7bp) is a palmitoylated membrane anchoring protein expressed in neurons that facilitates Gαi/o -directed GTPase activating protein activity mediated by the Gβ5/R7-RGS complex. Knockout of R7bp diminishes scratching responses to multiple cutaneously applied and intrathecally-administered pruritogens in mice. Knock-in to mice of a GTPase activating protein-insensitive mutant of Gαo (Gnao1 G184S/+) produces a similar pruriceptive phenotype. The pruriceptive defect in R7bp knockout mice was rescued in double knockout mice also lacking Oprk1, encoding the G protein-coupled kappa-opioid receptor whose activation is known to inhibit itch sensation. In a model of atopic dermatitis (eczema), R7bp knockout mice showed diminished scratching behavior and enhanced sensitivity to kappa opioid agonists. Taken together, our results indicate that R7bp is a key regulator of itch sensation and suggest the potential targeting of R7bp-dependent GTPase activating protein activity as a novel therapeutic strategy for pathological itch.

  8. Ambulatory BP monitoring and clinic BP in predicting small-for-gestational-age infants during pregnancy.

    PubMed

    Eguchi, K; Ohmaru, T; Ohkuchi, A; Hirashima, C; Takahashi, K; Suzuki, H; Kario, K; Matsubara, S; Suzuki, Mitsuaki

    2016-01-01

    The significance of ambulatory blood pressure (ABP) monitoring during pregnancy has not been established. We performed a prospective study to elucidate whether ABP measures are associated with small-for-gestational-age birth weight (SGA). We studied 146 pregnant women who were seen for maternal medical checkups or suspected hypertension. ABP monitoring was performed for further assessment of hypertension. The outcome measure was SGA. The subjects were classified by their medical history and ABP as having preeclampsia or gestational hypertension (n=68 cases), chronic hypertension (n=48) or white-coat hypertension (n=30). There were 50 (34.2%) cases of SGA by the fetal growth reference standard. In multivariable logistic regression analyses adjusting for age, body mass index, the presence of prior pregnancy, current smoking habit and the use of antihypertensive medications, 24-h SBP (per 10 mm Hg (odds ratio (OR): 1.74; 95% confidence interval (CI): 1.28-2.38; P<0.001)) was more closely associated with SGA than clinic BP (OR: 1.40; 95% CI: 0.92-2.13; P=0.11). The results were essentially the same if 24-h BP was replaced by awake or sleep SBP. Ambulatory diastolic BP showed the same tendency. However, abnormal circadian rhythm was not associated with the outcome. In conclusion, ambulatory BP monitoring measures performed during pregnancy were more closely associated with SGA than clinic BP.

  9. UbcH7 regulates 53BP1 stability and DSB repair.

    PubMed

    Han, Xiangzi; Zhang, Lei; Chung, Jinsil; Mayca Pozo, Franklin; Tran, Amanda; Seachrist, Darcie D; Jacobberger, James W; Keri, Ruth A; Gilmore, Hannah; Zhang, Youwei

    2014-12-09

    DNA double-strand break (DSB) repair is not only key to genome stability but is also an important anticancer target. Through an shRNA library-based screening, we identified ubiquitin-conjugating enzyme H7 (UbcH7, also known as Ube2L3), a ubiquitin E2 enzyme, as a critical player in DSB repair. UbcH7 regulates both the steady-state and replicative stress-induced ubiquitination and proteasome-dependent degradation of the tumor suppressor p53-binding protein 1 (53BP1). Phosphorylation of 53BP1 at the N terminus is involved in the replicative stress-induced 53BP1 degradation. Depletion of UbcH7 stabilizes 53BP1, leading to inhibition of DSB end resection. Therefore, UbcH7-depleted cells display increased nonhomologous end-joining and reduced homologous recombination for DSB repair. Accordingly, UbcH7-depleted cells are sensitive to DNA damage likely because they mainly used the error-prone nonhomologous end-joining pathway to repair DSBs. Our studies reveal a novel layer of regulation of the DSB repair choice and propose an innovative approach to enhance the effect of radiotherapy or chemotherapy through stabilizing 53BP1.

  10. Smad3 promotes cancer progression by inhibiting E4BP4-mediated NK cell development

    PubMed Central

    Tang, Patrick Ming-Kuen; Zhou, Shuang; Meng, Xiao-Ming; Wang, Qing-Ming; Li, Chun-Jie; Lian, Guang-Yu; Huang, Xiao-Ru; Tang, Yong-Jiang; Guan, Xin-Yuan; Yan, Bryan Ping-Yen; To, Ka-Fai; Lan, Hui-Yao

    2017-01-01

    TGF-β is known to influence tumour progression. Here we report an additional role of Smad3 in the tumour microenvironment regulating cancer progression. Deletion or inhibition of Smad3 in the tumour microenvironment suppresses tumour growth, invasion and metastasis in two syngeneic mouse tumour models. Smad3−/− bone marrow gives rise to an expanded NK cell population with enhanced tumour-suppressive activities in vivo, and promotes differentiation of NK cells ex vivo. We identify E4BP4/NFIL3 as a direct Smad3 target gene critical for NK cell differentiation. Smad3 suppresses transcription of IFN-γ via E4BP4 in a T-bet independent manner. Therefore disruption of Smad3 enhances both the E4BP4-mediated NK cell differentiation and anti-cancer effector functions in vivo and in vitro. Furthermore, systemic treatment with a Smad3 inhibitor SIS3 effectively suppresses cancer progression. In summary, suppression of NK cell-mediated immunosurveillance via the Smad3-E4BP4 axis contributes to cancer progression. We propose targeting Smad3-dependent tumour microenvironment may represent an effective anti-cancer strategy. PMID:28262747

  11. Smad3 promotes cancer progression by inhibiting E4BP4-mediated NK cell development.

    PubMed

    Tang, Patrick Ming-Kuen; Zhou, Shuang; Meng, Xiao-Ming; Wang, Qing-Ming; Li, Chun-Jie; Lian, Guang-Yu; Huang, Xiao-Ru; Tang, Yong-Jiang; Guan, Xin-Yuan; Yan, Bryan Ping-Yen; To, Ka-Fai; Lan, Hui-Yao

    2017-03-06

    TGF-β is known to influence tumour progression. Here we report an additional role of Smad3 in the tumour microenvironment regulating cancer progression. Deletion or inhibition of Smad3 in the tumour microenvironment suppresses tumour growth, invasion and metastasis in two syngeneic mouse tumour models. Smad3(-/-) bone marrow gives rise to an expanded NK cell population with enhanced tumour-suppressive activities in vivo, and promotes differentiation of NK cells ex vivo. We identify E4BP4/NFIL3 as a direct Smad3 target gene critical for NK cell differentiation. Smad3 suppresses transcription of IFN-γ via E4BP4 in a T-bet independent manner. Therefore disruption of Smad3 enhances both the E4BP4-mediated NK cell differentiation and anti-cancer effector functions in vivo and in vitro. Furthermore, systemic treatment with a Smad3 inhibitor SIS3 effectively suppresses cancer progression. In summary, suppression of NK cell-mediated immunosurveillance via the Smad3-E4BP4 axis contributes to cancer progression. We propose targeting Smad3-dependent tumour microenvironment may represent an effective anti-cancer strategy.

  12. CacyBP/SIP protein promotes proliferation and G1/S transition of human pancreatic cancer cells.

    PubMed

    Chen, Xiong; Mo, Ping; Li, Xiaohua; Zheng, Peichan; Zhao, Lina; Xue, Zengfu; Ren, Gui; Han, Guohong; Wang, Xin; Fan, Daiming

    2011-10-01

    Calcyclin-binding protein or Siah-1-interacting protein (CacyBP/SIP), a component of the ubiquitin-mediated proteolysis, could participate in beta-catenin degradation, which was found to be related to the malignant phenotypes of pancreatic cancer previously. However, the role of CacyBP/SIP itself in pancreatic cancer has not been investigated. In the present study, CacyBP/SIP expression was assayed and manipulated to reveal the potential mechanism in pancreatic cancer carcinogenesis. Here, we show that CacyBP/SIP is over-expressed in pancreatic cancer cells. Down-regulation of CacyBP/SIP by small interference RNA (siRNA) severely suppresses the proliferation and tumorigenesis in pancreatic cancer. G1/S transition arrest induced by inhibition of CacyBP/SIP is at least partly mediated by down-regulation of Cyclin E and CDK2 as well as up-regulation of p27 and Rb. Collectively, CacyBP/SIP as an enhancer of pancreatic cancer malignance might develop into another possible therapeutic target.

  13. Age-dependent changes in neuronal distribution of CacyBP/SIP: comparison to tubulin and the tau protein.

    PubMed

    Filipek, Anna; Schneider, Gabriela; Mietelska, Anna; Figiel, Izabela; Niewiadomska, Grazyna

    2008-09-01

    CacyBP/SIP was originally identified as an S100A6 (calcyclin) target and later on as a Siah-1 interacting protein. Recently, we have shown that CacyBP/SIP interacts with tubulin, which suggests its involvement in the reorganization of microtubules. In this work we examined the localization of CacyBP/SIP in cultured neurons and in brain neurons of young and aged rats, and compared this localization with that of tubulin and the tau protein. We have found that in neurons of young rats CacyBP/SIP, tubulin and tau are present in the cytoplasm and in the neuronal processes, whereas in aged animals CacyBP/SIP and tau are mainly seen in the cytoplasm of the neuronal somata. In aged rats, these changes are also accompanied by a different localization pattern of tubulin. Thus, our results show that localization of CacyBP/SIP in brain neurons is similar to that observed for tau and tubulin, which points to the involvement of CacyBP/SIP in cytoskeletal physiology.

  14. An isocorydine derivative (d-ICD) inhibits drug resistance by downregulating IGF2BP3 expression in hepatocellular carcinoma

    PubMed Central

    Ge, Chao; Chen, Lijuan; Fang, Tao; Li, Hong; Tian, Hua; Liu, Junxi; Chen, Taoyang; Jiang, Guoping; Xie, Haiyang; Cui, Ying; Yao, Ming; Li, Jinjun

    2015-01-01

    In our previous studies, we reported that CD133+ cancer stem cells (CSCs) were chemoresistant in hepatocellular carcinoma (HCC) and that isocorydine treatment decreased the percentage of CD133+ CSCs. Here, we found that a derivative of isocorydine (d-ICD) inhibited HCC cell growth, particularly among the CD133+ subpopulation, and rendered HCC cells more sensitive to sorafenib treatment. d-ICD inhibited IGF2BP3 expression in a time-dependent manner, and IGF2BP3 expression negatively correlated with d-ICD-induced growth suppression. IGF2BP3 overexpression enriched the CD133+ CSC subpopulation in HCC, enhanced tumor sphere formation and suppressed the cytotoxic effects of sorafenib and doxorubicin. The expression of drug resistance-related genes, including ABCB1 and ABCG2, and the CSC marker CD133 expression was increased after IGF2BP3 overexpression. The significance of these observations was underscored by our findings that high IGF2BP3 expression predicted poor survival in a cohort of 236 patients with HCC and positively correlated with ABCG2 and CD133 expression in vivo. These results suggested that the d-ICD may inhibit HCC cells growth by IGF2BP3 decrease and that IGF2BP3 may serve as a therapeutic target for HCC. PMID:26327240

  15. Palmitoylation regulates plasma membrane–nuclear shuttling of R7BP, a novel membrane anchor for the RGS7 family

    PubMed Central

    Drenan, Ryan M.; Doupnik, Craig A.; Boyle, Maureen P.; Muglia, Louis J.; Huettner, James E.; Linder, Maurine E.; Blumer, Kendall J.

    2005-01-01

    The RGS7 (R7) family of RGS proteins bound to the divergent Gβ subunit Gβ5 is a crucial regulator of G protein–coupled receptor (GPCR) signaling in the visual and nervous systems. Here, we identify R7BP, a novel neuronally expressed protein that binds R7–Gβ5 complexes and shuttles them between the plasma membrane and nucleus. Regional expression of R7BP, Gβ5, and R7 isoforms in brain is highly coincident. R7BP is palmitoylated near its COOH terminus, which targets the protein to the plasma membrane. Depalmitoylation of R7BP translocates R7BP–R7–Gβ5 complexes from the plasma membrane to the nucleus. Compared with nonpalmitoylated R7BP, palmitoylated R7BP greatly augments the ability of RGS7 to attenuate GPCR-mediated G protein–regulated inward rectifying potassium channel activation. Thus, by controlling plasma membrane nuclear–shuttling of R7BP–R7–Gβ5 complexes, reversible palmitoylation of R7BP provides a novel mechanism that regulates GPCR signaling and potentially transduces signals directly from the plasma membrane to the nucleus. PMID:15897264

  16. CtBP1/BARS Gly172-->Glu mutant structure: impairing NAD(H)-binding and dimerization.

    PubMed

    Nardini, Marco; Valente, Carmen; Ricagno, Stefano; Luini, Alberto; Corda, Daniela; Bolognesi, Martino

    2009-03-27

    C-terminal binding proteins (CtBPs) are multi-functional proteins involved in nuclear transcriptional co-repression, Golgi membrane fission, and synaptic ribbon formation. Binding of NAD(H) to CtBPs promotes dimerization. CtBP dimers act as a scaffold for multimeric protein complex formation, thus bridging transcriptional repressors and their targets in the nucleus. Based on size-exclusion chromatography experiments and on the crystal structure of the NAD(H)-free G172E CtBP mutant, we show here that absence of NAD(H) induces flexibility/backbone conformational changes at the dimerization interface and at the CtBP interdomain region. The results presented shed first light on the correlation between NAD(H)-binding and functional CtBP dimerization.

  17. CtBP1/BARS Gly172 {yields} Glu mutant structure: Impairing NAD(H)-binding and dimerization

    SciTech Connect

    Nardini, Marco; Valente, Carmen; Ricagno, Stefano; Luini, Alberto; Corda, Daniela; Bolognesi, Martino

    2009-03-27

    C-terminal binding proteins (CtBPs) are multi-functional proteins involved in nuclear transcriptional co-repression, Golgi membrane fission, and synaptic ribbon formation. Binding of NAD(H) to CtBPs promotes dimerization. CtBP dimers act as a scaffold for multimeric protein complex formation, thus bridging transcriptional repressors and their targets in the nucleus. Based on size-exclusion chromatography experiments and on the crystal structure of the NAD(H)-free G172E CtBP mutant, we show here that absence of NAD(H) induces flexibility/backbone conformational changes at the dimerization interface and at the CtBP interdomain region. The results presented shed first light on the correlation between NAD(H)-binding and functional CtBP dimerization.

  18. Inhibition of 4E-BP1 Sensitizes U87 Glioblastoma Xenograft Tumors to Irradiation by Decreasing Hypoxia Tolerance

    SciTech Connect

    Dubois, Ludwig; Magagnin, Michael G.; Cleven, Arjen H.G.; Weppler, Sherry A.; Grenacher, Beat; Landuyt, Willy; Lieuwes, Natasja; Lambin, Philippe; Gorr, Thomas A.; Koritzinsky, Marianne

    2009-03-15

    Purpose: Eukaryotic initiation factor 4E (eIF4E) is an essential rate-limiting factor for cap-dependent translation in eukaryotic cells. Elevated eIF4E activity is common in many human tumors and is associated with disease progression. The growth-promoting effects of eIF4E are in turn negatively regulated by 4E-BP1. However, although 4E-BP1 harbors anti-growth activity, its expression is paradoxically elevated in some tumors. The aim of this study was to investigate the functional role of 4E-BP1 in the context of solid tumors. Methods and Materials: In vitro and in vivo growth properties, hypoxia tolerance, and response to radiation were assessed for HeLa and U87 cells, after stable expression of shRNA specific for 4E-BP1. Results: We found that loss of 4E-BP1 expression did not significantly alter in vitro growth but did accelerate the growth of U87 tumor xenografts, consistent with the growth-promoting function of deregulated eIF4E. However, cells lacking 4E-BP1 were significantly more sensitive to hypoxia-induced cell death in vitro. Furthermore, 4E-BP1 knockdown cells produced tumors more sensitive to radiation because of a reduction in the viable fraction of radioresistant hypoxic cells. Decreased hypoxia tolerance in the 4E-BP1 knockdown tumors was evident by increased cleaved caspase-3 levels and was associated with a reduction in adenosine triphosphate (ATP). Conclusions: Our results suggest that although tumors often demonstrate increases in cap-dependent translation, regulation of this activity is required to facilitate energy conservation, hypoxia tolerance, and tumor radioresistance. Furthermore, we suggest that targeting translational control may be an effective way to target hypoxic cells and radioresistance in metabolically hyperactive tumors.

  19. Recruitment of Histone Methyltransferase G9a Mediates Transcriptional Repression of Fgf21 Gene by E4BP4 Protein*

    PubMed Central

    Tong, Xin; Zhang, Deqiang; Buelow, Katie; Guha, Anirvan; Arthurs, Blake; Brady, Hugh J. M.; Yin, Lei

    2013-01-01

    The liver responds to fasting-refeeding cycles by reprogramming expression of metabolic genes. Fasting potently induces one of the key hepatic hormones, fibroblast growth factor 21 (FGF21), to promote lipolysis, fatty acid oxidation, and ketogenesis, whereas refeeding suppresses its expression. We previously reported that the basic leucine zipper transcription factor E4BP4 (E4 binding protein 4) represses Fgf21 expression and disrupts its circadian oscillations in cultured hepatocytes. However, the epigenetic mechanism for E4BP4-dependent suppression of Fgf21 has not yet been addressed. Here we present evidence that histone methyltransferase G9a mediates E4BP4-dependent repression of Fgf21 during refeeding by promoting repressive histone modification. We find that Fgf21 expression is up-regulated in E4bp4 knock-out mouse liver. We demonstrate that the G9a-specific inhibitor BIX01294 abolishes suppression of the Fgf21 promoter activity by E4BP4, whereas overexpression of E4bp4 leads to increased levels of dimethylation of histone 3 lysine 9 (H3K9me2) around the Fgf21 promoter region. Furthermore, we also show that E4BP4 interacts with G9a, and knockdown of G9a blocks repression of Fgf21 promoter activity and expression in cells overexpressing E4bp4. A G9a mutant lacking catalytic activity, due to deletion of the SET domain, fails to inhibit the Fgf21 promoter activity. Importantly, acute hepatic knockdown by adenoviral shRNA targeting G9a abolishes Fgf21 repression by refeeding, concomitant with decreased levels of H3K9me2 around the Fgf21 promoter region. In summary, we show that G9a mediates E4BP4-dependent suppression of hepatic Fgf21 by enhancing histone methylation (H3K9me2) of the Fgf21 promoter. PMID:23283977

  20. Characterizing the Coding Region Determinant-Binding Protein (CRD-BP)-Microphthalmia-associated Transcription Factor (MITF) mRNA interaction.

    PubMed

    Rensburg, Gerrit van; Mackedenski, Sebastian; Lee, Chow H

    2017-01-01

    Coding region determinant-binding protein (CRD-BP) binds to the 3'-UTR of microphthalmia-associated transcription factor (MITF) mRNA to prevent its targeted degradation by miR-340. Here, we aim to further understand the molecular interaction between CRD-BP and MITF RNA. Using point mutation in the GXXG motif of each KH domains, we showed that all four KH domains of CRD-BP are important for their physical association with MITF RNA. We mapped the CRD-BP-binding site in the 3'-UTR of MITF RNA from nts 1330-1740 and showed that the 49-nt fragment 1621-1669 is the minimal size MITF RNA for binding. Upon deletion of nts 1621-1669 within the nts1550-1740 of MITF RNA, there was a 3-fold increase in dissociation constant Kd, which further confirms the critical role sequences within nts 1621-1669 in binding to CRD-BP. Amongst the eight antisense oligonucleotides designed against MITF RNA 1550-1740, we found MHO-1 and MHO-7 as potent inhibitors of the CRD-BP-MITF RNA interaction. Using RNase protection and fluorescence polarization assays, we showed that both MHO-1 and MHO-7 have affinity for the MITF RNA, suggesting that both antisense oligonucleotides inhibited CRD-BP-MITF RNA interaction by directly binding to MITF RNA. The new molecular insights provided in this study have important implications for understanding the oncogenic function of CRD-BP and development of specific inhibitors against CRD-BP-MITF RNA interaction.

  1. Characterizing the Coding Region Determinant-Binding Protein (CRD-BP)-Microphthalmia-associated Transcription Factor (MITF) mRNA interaction

    PubMed Central

    2017-01-01

    Coding region determinant-binding protein (CRD-BP) binds to the 3’-UTR of microphthalmia-associated transcription factor (MITF) mRNA to prevent its targeted degradation by miR-340. Here, we aim to further understand the molecular interaction between CRD-BP and MITF RNA. Using point mutation in the GXXG motif of each KH domains, we showed that all four KH domains of CRD-BP are important for their physical association with MITF RNA. We mapped the CRD-BP-binding site in the 3’-UTR of MITF RNA from nts 1330–1740 and showed that the 49-nt fragment 1621–1669 is the minimal size MITF RNA for binding. Upon deletion of nts 1621–1669 within the nts1550-1740 of MITF RNA, there was a 3-fold increase in dissociation constant Kd, which further confirms the critical role sequences within nts 1621–1669 in binding to CRD-BP. Amongst the eight antisense oligonucleotides designed against MITF RNA 1550–1740, we found MHO-1 and MHO-7 as potent inhibitors of the CRD-BP-MITF RNA interaction. Using RNase protection and fluorescence polarization assays, we showed that both MHO-1 and MHO-7 have affinity for the MITF RNA, suggesting that both antisense oligonucleotides inhibited CRD-BP-MITF RNA interaction by directly binding to MITF RNA. The new molecular insights provided in this study have important implications for understanding the oncogenic function of CRD-BP and development of specific inhibitors against CRD-BP-MITF RNA interaction. PMID:28182633

  2. Graded Achievement, Tested Achievement, and Validity

    ERIC Educational Resources Information Center

    Brookhart, Susan M.

    2015-01-01

    Twenty-eight studies of grades, over a century, were reviewed using the argument-based approach to validity suggested by Kane as a theoretical framework. The review draws conclusions about the meaning of graded achievement, its relation to tested achievement, and changes in the construct of graded achievement over time. "Graded…

  3. BP Spill Sampling and Monitoring Data

    EPA Pesticide Factsheets

    This dataset analyzes waste from the the British Petroleum Deepwater Horizon Rig Explosion Emergency Response, providing opportunity to query data sets by metadata criteria and find resulting raw datasets in CSV format.The data query tool allows users to download EPA's air, water and sediment sampling and monitoring data that has been collected in response to the BP oil spill. All sampling and monitoring data that has been collected to date is available for download as raw structured data.The query tools enables CSV file creation to be refined based on the following search criteria: date range (between April 28, 2010 and 9/29/2010); location by zip, city, or county; media (solid waste, weathered oil, air, surface water, liquid waste, tar, sediment, water); substance categories (based on media selection) and substances (based on substance category selection).

  4. Nighttime home blood pressure and the risk of hypertensive target organ damage.

    PubMed

    Ishikawa, Joji; Hoshide, Satoshi; Eguchi, Kazuo; Ishikawa, Shizukiyo; Shimada, Kazuyuki; Kario, Kazuomi

    2012-10-01

    In ambulatory blood pressure (BP) monitoring, nighttime BP has a superior ability to predict hypertensive target organ damage than awake BP. We evaluated whether nighttime BP, assessed by a home BP monitor, was associated with hypertensive target organ damage. We measured clinic BP, out-of-clinic BP including nighttime home BP, and the urinary albumin:creatinine ratio (UACR) in 854 patients who had cardiovascular risk factors. Nighttime home BP was measured at 2:00, 3:00, and 4:00 am, in addition to clinic, awake ambulatory, nighttime ambulatory, and awake home BP. Nighttime home systolic BP (SBP) was slightly higher than nighttime ambulatory SBP (difference, 2.6 mm Hg; P<0.001). Clinic (r=0.186), awake ambulatory (r=0.173), nighttime ambulatory (r=0.194), awake home (r=0.298), and nighttime home (r=0.311) SBPs were all associated with log-transformed UACR (all P<0.001). The correlation coefficient for the relationship between nighttime home SBP and log-transformed UACR was significantly greater than that for the relationship between nighttime ambulatory SBP and log-transformed UACR (P<0.001). The goodness of fit of the association between SBP and UACR was improved by adding nighttime home SBP to the other SBPs (P<0.001). Nighttime home diastolic BP also improved the goodness-of-fit of the association between diastolic BP and UACR (P=0.001). Similar findings were observed for the left ventricular mass index in the subgroup (N=594). In conclusion, nighttime home BP is slightly different from (but comparable to) nighttime ambulatory BP. The addition of nighttime home BP to other BP measures improves the association of BP with hypertensive target organ damage.

  5. Polarized internal target apparatus

    DOEpatents

    Holt, R.J.

    1984-10-10

    A polarized internal target apparatus with a polarized gas target of improved polarization and density (achieved by mixing target gas atoms with a small amount of alkali metal gas atoms, and passing a high intensity polarized light source into the mixture to cause the alkali metal gas atoms to become polarized which interact in spin exchange collisions with target gas atoms yielding polarized target gas atoms) is described.

  6. Polarized internal target apparatus

    DOEpatents

    Holt, Roy J.

    1986-01-01

    A polarized internal target apparatus with a polarized gas target of improved polarization and density achieved by mixing target gas atoms with a small amount of alkali metal gas atoms, and passing a high intensity polarized light source into the mixture to cause the alkali metal gas atoms to become polarized which interact in spin exchange collisions with target gas atoms yielding polarized target gas atoms.

  7. Interaction with CCNH/CDK7 facilitates CtBP2 promoting esophageal squamous cell carcinoma (ESCC) metastasis via upregulating epithelial-mesenchymal transition (EMT) progression.

    PubMed

    Zhang, Jianguo; Zhu, Junya; Yang, Lei; Guan, Chengqi; Ni, Runzhou; Wang, Yuchan; Ji, Lili; Tian, Ye

    2015-09-01

    CtBP2, as a transcriptional corepressor of epithelial-specific genes, has been reported to promote tumor due to upregulating epithelial-mesenchymal transition (EMT) in cancer cells. CtBP2 was also demonstrated to contribute to the proliferation of esophageal squamous cell carcinoma (ESCC) cells through a negative transcriptional regulation of p16(INK4A). In this study, for the first time, we reported that CtBP2 expression, along with CCNH/CDK7, was higher in ESCC tissues with lymph node metastases than in those without lymph node metastases. Moreover, both CtBP2 and CCNH/CDK7 were positively correlated with E-cadherin, tumor grade, and tumor metastasis. However, the concrete mechanism of CtBP2's role in enhancing ESCC migration remains incompletely understood. We confirmed that CCNH/CDK7 could directly interact with CtBP2 in ESCC cells in vivo and in vitro. Furthermore, our data demonstrate for the first time that CtBP2 enhanced the migration of ESCC cells in a CCNH/CDK7-dependent manner. Our results indicated that CCNH/CDK7-CtBP2 axis may augment ESCC cell migration, and targeting the interaction of both may provide a novel therapeutic target of ESCC.

  8. RanBP9/TSSC3 complex cooperates to suppress anoikis resistance and metastasis via inhibiting Src-mediated Akt signaling in osteosarcoma

    PubMed Central

    Dai, Huanzi; Lv, Yang-Fan; Yan, Guang-Ning; Meng, Gang; Zhang, Xi; Guo, Qiao-Nan

    2016-01-01

    Suppression of anoikis is a prerequisite for tumor cell metastasis, which is correlated with chemoresistance and poor prognosis. We characterized a novel interaction between RanBP9 SPRY domain and TSSC3 PH domain by which RanBP9/TSSC3 complex exerts transcription and post-translation regulation in osteosarcoma. RanBP9/TSSC3 complex was inversely correlated with a highly anoikis-resistant phenotype in osteosarcoma cells and metastasis in human osteosarcoma. RanBP9 cooperated with TSSC3 to inhibit anchorage-independent growth and to promote anoikis in vitro and suppress lung metastasis in vivo. Moreover, RanBP9 SPRY domain was required for RanBP9/TSSC3 complex-mediated anoikis resistance. Mechanistically, RanBP9 formed a ternary complex with TSSC3 and Src to scaffold this interaction, which suppressed both Src and Src-dependent Akt pathway activations and facilitated mitochondrial-associated anoikis. Collectively, the newly identified RanBP9/TSSC3 complex cooperatively suppress metastasis via downregulation of Src-dependent Akt pathway to expedite mitochondrial-associated anoikis. This study provides a biological basis for exploring the therapeutic significance of dual targeting of RanBP9 and TSSC3 in osteosarcoma. PMID:28032865

  9. Protein phosphatase PPM1G regulates protein translation and cell growth by dephosphorylating 4E binding protein 1 (4E-BP1).

    PubMed

    Liu, Jianyu; Stevens, Payton D; Eshleman, Nichole E; Gao, Tianyan

    2013-08-09

    Protein translation initiation is a tightly controlled process responding to nutrient availability and mitogen stimulation. Serving as one of the most important negative regulators of protein translation, 4E binding protein 1 (4E-BP1) binds to translation initiation factor 4E and inhibits cap-dependent translation in a phosphorylation-dependent manner. Although it has been demonstrated previously that the phosphorylation of 4E-BP1 is controlled by mammalian target of rapamycin in the mammalian target of rapamycin complex 1, the mechanism underlying the dephosphorylation of 4E-BP1 remains elusive. Here, we report the identification of PPM1G as the phosphatase of 4E-BP1. A coimmunoprecipitation experiment reveals that PPM1G binds to 4E-BP1 in cells and that purified PPM1G dephosphorylates 4E-BP1 in vitro. Knockdown of PPM1G in 293E and colon cancer HCT116 cells results in an increase in the phosphorylation of 4E-BP1 at both the Thr-37/46 and Ser-65 sites. Furthermore, the time course of 4E-BP1 dephosphorylation induced by amino acid starvation or mammalian target of rapamycin inhibition is slowed down significantly in PPM1G knockdown cells. Functionally, the amount of 4E-BP1 bound to the cap-dependent translation initiation complex is decreased when the expression of PPM1G is depleted. As a result, the rate of cap-dependent translation, cell size, and protein content are increased in PPM1G knockdown cells. Taken together, our study has identified protein phosphatase PPM1G as a novel regulator of cap-dependent protein translation by negatively controlling the phosphorylation of 4E-BP1.

  10. Waste Sampling Data for BP Spill/Deepwater Horizon

    EPA Pesticide Factsheets

    The Deepwater Horizon oil spill (also referred to as the BP oil spill) began on 20 April 2010 in the Gulf of Mexico on the BP-operated Macondo Prospect. Following the explosion and sinking of the Deepwater Horizon oil rig, a sea-floor oil gusher flowed for 87 days, until it was capped on 15 July 2010.In response to the BP oil spill, EPA sampled air, water, sediment, and waste generated by the cleanup operations.

  11. Air Sampling Data for BP Spill/Deepwater Horizon

    EPA Pesticide Factsheets

    The Deepwater Horizon oil spill (also referred to as the BP oil spill) began on 20 April 2010 in the Gulf of Mexico on the BP-operated Macondo Prospect. Following the explosion and sinking of the Deepwater Horizon oil rig, a sea-floor oil gusher flowed for 87 days, until it was capped on 15 July 2010.In response to the BP oil spill, EPA sampled air, water, sediment, and waste generated by the cleanup operations.

  12. Air Monitoring Data for BP Spill/Deepwater Horizon

    EPA Pesticide Factsheets

    The Deepwater Horizon oil spill (also referred to as the BP oil spill) began on 20 April 2010 in the Gulf of Mexico on the BP-operated Macondo Prospect. Following the explosion and sinking of the Deepwater Horizon oil rig, a sea-floor oil gusher flowed for 87 days, until it was capped on 15 July 2010.In response to the BP oil spill, EPA sampled air, water, sediment, and waste generated by the cleanup operations.

  13. Surface Water Sampling Data for BP Spill/Deepwater Horizon

    EPA Pesticide Factsheets

    The Deepwater Horizon oil spill (also referred to as the BP oil spill) began on 20 April 2010 in the Gulf of Mexico on the BP-operated Macondo Prospect. Following the explosion and sinking of the Deepwater Horizon oil rig, a sea-floor oil gusher flowed for 87 days, until it was capped on 15 July 2010.In response to the BP oil spill, EPA sampled air, water, sediment, and waste generated by the cleanup operations.

  14. Sediment Sampling Data for BP Spill/Deepwater Horizon

    EPA Pesticide Factsheets

    The Deepwater Horizon oil spill (also referred to as the BP oil spill) began on 20 April 2010 in the Gulf of Mexico on the BP-operated Macondo Prospect. Following the explosion and sinking of the Deepwater Horizon oil rig, a sea-floor oil gusher flowed for 87 days, until it was capped on 15 July 2010.In response to the BP oil spill, EPA sampled air, water, sediment, and waste generated by the cleanup operations.

  15. Water Sampling Data for BP Spill/Deepwater Horizon

    EPA Pesticide Factsheets

    The Deepwater Horizon oil spill (also referred to as the BP oil spill) began on 20 April 2010 in the Gulf of Mexico on the BP-operated Macondo Prospect. Following the explosion and sinking of the Deepwater Horizon oil rig, a sea-floor oil gusher flowed for 87 days, until it was capped on 15 July 2010.In response to the BP oil spill, EPA sampled air, water, sediment, and waste generated by the cleanup operations.

  16. Assessing specific oligonucleotides and small molecule antibiotics for the ability to inhibit the CRD-BP-CD44 RNA interaction.

    PubMed

    King, Dustin T; Barnes, Mark; Thomsen, Dana; Lee, Chow H

    2014-01-01

    Studies on Coding Region Determinant-Binding Protein (CRD-BP) and its orthologs have confirmed their functional role in mRNA stability and localization. CRD-BP is present in extremely low levels in normal adult tissues, but it is over-expressed in many types of aggressive human cancers and in neonatal tissues. Although the exact role of CRD-BP in tumour progression is unclear, cumulative evidence suggests that its ability to physically associate with target mRNAs is an important criterion for its oncogenic role. CRD-BP has high affinity for the 3'UTR of the oncogenic CD44 mRNA and depletion of CRD-BP in cells led to destabilization of CD44 mRNA, decreased CD44 expression, reduced adhesion and disruption of invadopodia formation. Here, we further characterize the CRD-BP-CD44 RNA interaction and assess specific antisense oligonucleotides and small molecule antibiotics for their ability to inhibit the CRD-BP-CD44 RNA interaction. CRD-BP has a high affinity for binding to CD44 RNA nts 2862-3055 with a Kd of 645 nM. Out of ten antisense oligonucleotides spanning nts 2862-3055, only three antisense oligonucleotides (DD4, DD7 and DD10) were effective in competing with CRD-BP for binding to 32P-labeled CD44 RNA. The potency of DD4, DD7 and DD10 in inhibiting the CRD-BP-CD44 RNA interaction in vitro correlated with their ability to specifically reduce the steady-state level of CD44 mRNA in cells. The aminoglycoside antibiotics neomycin, paramomycin, kanamycin and streptomycin effectively inhibited the CRD-BP-CD44 RNA interaction in vitro. Assessing the potential inhibitory effect of aminoglycoside antibiotics including neomycin on the CRD-BP-CD44 mRNA interaction in cells proved difficult, likely due to their propensity to non-specifically bind nucleic acids. Our results have important implications for future studies in finding small molecules and nucleic acid-based inhibitors that interfere with protein-RNA interactions.

  17. Inhibition of HIF-1{alpha} activity by BP-1 ameliorates adjuvant induced arthritis in rats

    SciTech Connect

    Shankar, J.; Thippegowda, P.B.; Kanum, S.A.

    2009-09-18

    Rheumatoid arthritis (RA) is a chronic inflammatory, angiogenic disease. Inflamed synovitis is a hallmark of RA which is hypoxic in nature. Vascular endothelial growth factor (VEGF), one of the key regulators of angiogenesis, is overexpressed in the pathogenesis of RA. VEGF expression is regulated by hypoxia-inducible factor-1{alpha} (HIF-1{alpha}), a master regulator of homeostasis which plays a pivotal role in hypoxia-induced angiogenesis. In this study we show that synthetic benzophenone analogue, 2-benzoyl-phenoxy acetamide (BP-1) can act as a novel anti-arthritic agent in an experimental adjuvant induced arthritis (AIA) rat model by targeting VEGF and HIF-1{alpha}. BP-1 administered hypoxic endothelial cells and arthritic animals clearly showed down regulation of VEGF expression. Further, BP-1 inhibits nuclear translocation of HIF-1{alpha}, which in turn suppresses transcription of the VEGF gene. These results suggest a further possible clinical application of the BP-1 derivative as an anti-arthritic agent in association with conventional chemotherapeutic agents.

  18. Commensal Microbiota Contributes to Chronic Endocarditis in TAX1BP1 Deficient Mice

    PubMed Central

    Nakano, Satoko; Ikebe, Emi; Tsukamoto, Yoshiyuki; Wang, Yan; Matsumoto, Takashi; Mitsui, Takahiro; Yahiro, Takaaki; Inoue, Kunimitsu; Kawazato, Hiroaki; Yasuda, Aiko; Ito, Kanako; Yokoyama, Shigeo; Takahashi, Naohiko; Hori, Mitsuo; Shimada, Tatsuo; Moriyama, Masatsugu; Kubota, Toshiaki; Ono, Katsushige; Fujibuchi, Wataru; Jeang, Kuan-Teh; Iha, Hidekatsu; Nishizono, Akira

    2013-01-01

    Tax1-binding protein 1 (Tax1bp1) negatively regulates NF-κB by editing the ubiquitylation of target molecules by its catalytic partner A20. Genetically engineered TAX1BP1-deficient (KO) mice develop age-dependent inflammatory constitutions in multiple organs manifested as valvulitis or dermatitis and succumb to premature death. Laser capture dissection and gene expression microarray analysis on the mitral valves of TAX1BP1-KO mice (8 and 16 week old) revealed 588 gene transcription alterations from the wild type. SAA3 (serum amyloid A3), CHI3L1, HP, IL1B and SPP1/OPN were induced 1,180-, 361-, 187-, 122- and 101-fold respectively. WIF1 (Wnt inhibitory factor 1) exhibited 11-fold reduction. Intense Saa3 staining and significant I-κBα reduction were reconfirmed and massive infiltration of inflammatory lymphocytes and edema formation were seen in the area. Antibiotics-induced ‘germ free’ status or the additional MyD88 deficiency significantly ameliorated TAX1BP1-KO mice's inflammatory lesions. These pathological conditions, as we named ‘pseudo-infective endocarditis’ were boosted by the commensal microbiota who are usually harmless by their nature. This experimental outcome raises a novel mechanistic linkage between endothelial inflammation caused by the ubiquitin remodeling immune regulators and fatal cardiac dysfunction. PMID:24086273

  19. Evaluation of fungal- and photo-degradation as potential treatments for the removal of sunscreens BP3 and BP1.

    PubMed

    Gago-Ferrero, Pablo; Badia-Fabregat, Marina; Olivares, Alba; Piña, Benjamin; Blánquez, Paqui; Vicent, Teresa; Caminal, Gloria; Díaz-Cruz, M Silvia; Barceló, Damià

    2012-06-15

    Photodecomposition might be regarded as one of the most important abiotic factors affecting the fate of UV absorbing compounds in the environment and photocatalysis has been suggested as an effective method to degrade organic pollutants. However, UV filters transformation appears to be a complex process, barely addressed to date. The white rot fungus Trametes versicolor is considered as a promising alternative to conventional aerobic bacterial degradation, as it is able to metabolise a wide range of xenobiotics. This study focused on both degradation processes of two widely used UV filters, benzophenone-3 (BP3) and benzophenone-1 (BP1). Fungal treatment resulted in the degradation of more than 99% for both sunscreens in less than 24 h, whereas photodegradation was very inefficient, especially for BP3, which remained unaltered upon 24 h of simulated sunlight irradiation. Analysis of metabolic compounds generated showed BP1 as a minor by-product of BP3 degradation by T. versicolor while the main intermediate metabolites were glycoconjugate derivatives. BP1 and BP3 showed a weak, but significant estrogenic activity (EC50 values of 0.058 mg/L and 12.5 mg/L, respectively) when tested by recombinant yeast assay (RYA), being BP1 200-folds more estrogenic than BP3. Estrogenic activity was eliminated during T. versicolor degradation of both compounds, showing that none of the resulting metabolites possessed significant estrogenic activity at the concentrations produced. These results demonstrate the suitability of this method to degrade both sunscreen agents and to eliminate estrogenic activity.

  20. Trailer siting issues: BP Texas City.

    PubMed

    Kaszniak, Mark; Holmstrom, Donald

    2008-11-15

    On 23 March, 2005, a series of explosions and fires occurred at the BP Texas City refinery during the startup of an isomerization (ISOM) process unit. Fifteen workers were killed and about 180 others were injured. All of the fatalities were contract workers; the deaths and most of the serious injuries occurred in and around temporary office trailers that had been sited near a blowdown drum and stack open to the atmosphere as part of ongoing turnaround activities in an adjacent unit. Due to problems that developed during the ISOM startup, flammable hydrocarbon liquid overfilled the blowdown drum and stack which resulted in a geyser-like release out the top into the atmosphere. The flammable hydrocarbons fell to the ground releasing vapors that were likely ignited from a nearby idling diesel pickup truck. A total of 44 trailers were damaged by the blast pressure wave that propagated through the refinery when the vapor cloud exploded. Thirteen trailers were totally destroyed and workers were injured in trailers as far as 479ft away from the release. The focus of this paper will be on trailer siting issues, including: need for work/office trailers within process units, adequacy of risk analysis methods in API RP 752, and minimum safe distance requirements

  1. Signaling involved in PTTH-stimulated 4E-BP phosphorylation in prothoracic gland cells of Bombyx mori.

    PubMed

    Gu, Shi-Hong; Hsieh, Yun-Chih; Lin, Pei-Ling

    2017-01-01

    Our previous studies showed that adenosine 5'-monophosphate-activated protein kinase (AMPK)/the target of rapamycin (TOR) signaling is involved in prothoracicotropic hormone (PTTH)-stimulated ecdysteroidogenesis in Bombyx mori prothoracic glands (PGs). In the present study, we further investigated the signaling involved in PTTH-stimulated phosphorylation of 4E-BP. We found that 4E-BP phosphorylation stimulated by PTTH was partially reduced in Ca(2+)-free medium, indicating the involvement of Ca(2+). In addition, we found that a potent and specific inhibitor of phospholipase C (PLC), U73122, greatly inhibited 4E-BP phosphorylation. However, PTTH-stimulated 4E-BP phosphorylation was not attenuated by a protein kinase C (PKC) inhibitor (chelerythrine C). These results indicate that PLC, but not PKC, is involved in PTTH-stimulated 4E-BP phosphorylation. When PGs were treated with agents that directly elevate the intracellular Ca(2+) concentration (either A23187 or thapsigargin), a great increase in 4E-BP phosphorylation was observed. A23187-stimulated phosphorylation of 4E-BP was blocked by a chemical activator of AMPK (5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside, AICAR) and a phosphoinositide 3-kinase (PI3K) inhibitor (LY294002), but not by U0126, indicating involvement of AMPK and PI3K. Determination of AMPK phosphorylation showed that treatment with either A23187 or thapsigargin inhibited AMPK phosphorylation. Moreover, PTTH appeared to inhibit AMPK phosphorylation in a Ca(2+)-dependent manner. Altogether, these results indicate interconnections among Ca(2+) signaling, AMPK, and 4E-BP phosphorylation in PTTH-activated PGs of B. mori.

  2. Repurposing the CRISPR-Cas9 system for targeted DNA methylation

    PubMed Central

    Vojta, Aleksandar; Dobrinić, Paula; Tadić, Vanja; Bočkor, Luka; Korać, Petra; Julg, Boris; Klasić, Marija; Zoldoš, Vlatka

    2016-01-01

    Epigenetic studies relied so far on correlations between epigenetic marks and gene expression pattern. Technologies developed for epigenome editing now enable direct study of functional relevance of precise epigenetic modifications and gene regulation. The reversible nature of epigenetic modifications, including DNA methylation, has been already exploited in cancer therapy for remodeling the aberrant epigenetic landscape. However, this was achieved non-selectively using epigenetic inhibitors. Epigenetic editing at specific loci represents a novel approach that might selectively and heritably alter gene expression. Here, we developed a CRISPR-Cas9-based tool for specific DNA methylation consisting of deactivated Cas9 (dCas9) nuclease and catalytic domain of the DNA methyltransferase DNMT3A targeted by co–expression of a guide RNA to any 20 bp DNA sequence followed by the NGG trinucleotide. We demonstrated targeted CpG methylation in a ∼35 bp wide region by the fusion protein. We also showed that multiple guide RNAs could target the dCas9-DNMT3A construct to multiple adjacent sites, which enabled methylation of a larger part of the promoter. DNA methylation activity was specific for the targeted region and heritable across mitotic divisions. Finally, we demonstrated that directed DNA methylation of a wider promoter region of the target loci IL6ST and BACH2 decreased their expression. PMID:26969735

  3. Repurposing the CRISPR-Cas9 system for targeted DNA methylation.

    PubMed

    Vojta, Aleksandar; Dobrinić, Paula; Tadić, Vanja; Bočkor, Luka; Korać, Petra; Julg, Boris; Klasić, Marija; Zoldoš, Vlatka

    2016-07-08

    Epigenetic studies relied so far on correlations between epigenetic marks and gene expression pattern. Technologies developed for epigenome editing now enable direct study of functional relevance of precise epigenetic modifications and gene regulation. The reversible nature of epigenetic modifications, including DNA methylation, has been already exploited in cancer therapy for remodeling the aberrant epigenetic landscape. However, this was achieved non-selectively using epigenetic inhibitors. Epigenetic editing at specific loci represents a novel approach that might selectively and heritably alter gene expression. Here, we developed a CRISPR-Cas9-based tool for specific DNA methylation consisting of deactivated Cas9 (dCas9) nuclease and catalytic domain of the DNA methyltransferase DNMT3A targeted by co-expression of a guide RNA to any 20 bp DNA sequence followed by the NGG trinucleotide. We demonstrated targeted CpG methylation in a ∼35 bp wide region by the fusion protein. We also showed that multiple guide RNAs could target the dCas9-DNMT3A construct to multiple adjacent sites, which enabled methylation of a larger part of the promoter. DNA methylation activity was specific for the targeted region and heritable across mitotic divisions. Finally, we demonstrated that directed DNA methylation of a wider promoter region of the target loci IL6ST and BACH2 decreased their expression.

  4. Expanding the BP1-BP2 15q11.2 Microdeletion Phenotype: Tracheoesophageal Fistula and Congenital Cataracts.

    PubMed

    Wong, D; Johnson, S M; Young, D; Iwamoto, L; Sood, S; Slavin, T P

    2013-01-01

    The proximal q arm of chromosome 15 contains breakpoint regions BP1-BP5 with the classic deletion of BP1-BP3 best known to be associated with Prader-Willi and Angelman syndromes. The region is approximately 500 kb and microdeletions within the BP1-BP2 region have been reported in patients with developmental delay, behavioral abnormalities, and motor apraxia as well as dysmorphic features including hypertelorism, cleft or narrow palate, ear abnormalities, and recurrent upper airway infections. We report two patients with unique, never-before-reported 15q11.2 BP1-2 microdeletion syndrome findings, one with proximal esophageal atresia and distal tracheoesophageal fistula (type C) and one with congenital cataracts. Cataracts have been described in Prader-Willi syndrome but we could not find any description of cataracts in Angelman syndrome. Esophageal atresia and tracheoesophageal fistula have not been reported to our knowledge in either syndrome. A chance exists that both cases are sporadic birth defects; however, the findings of the concomitant microdeletion cannot be overlooked as a possible cause. Based on our review of the literature and the presentation of our patients, we recommend that esophageal atresia and distal tracheoesophageal fistula as well as congenital cataracts be included in the phenotypic spectrum of 15q11.2 BP1-2 microdeletion syndrome.

  5. Reaching recommended lipid and blood pressure targets with amlodipine/atorvastatin combination in patients with coronary heart disease.

    PubMed

    Dorval, Jean-Francois; Anderson, Todd; Buithieu, Jean; Chan, Sammy; Hutchison, Stuart; Huynh, Thao; Jobin, Jean; Lonn, Eva; Poirier, Paul; Title, Lawrence; Walling, Ann; Tran, Thang; Boudreau, Ghyslain; Charbonneau, Francois; Genest, Jacques

    2005-01-15

    The effects of combined atorvastatin and amlodipine on blood pressure (BP) and low-density lipoprotein (LDL) cholesterol levels were investigated in 134 patients with documented coronary heart disease treated for 1 year. BP at baseline was 128 +/- 15/79 +/- 9 mm Hg and was controlled by the treating physician; no calcium channel blockers were allowed. Baseline means for plasma cholesterol were 6.4 +/- 1.1 mmol/L (147 +/- 39 mg/dl), triglycerides 2.0 +/- 0.9 mmol/L (177 +/- 88 mg/dl), LDL cholesterol 4.4 +/- 1.0 mmol/L (170 +/- 39 mg/dl), and high-density lipoprotein cholesterol 1.2 +/- 0.3 mmol/L (46 +/- 12 mg/dl). Patients were all given atorvastatin 10 mg, then increased to 80 mg if the LDL cholesterol was <2.5 mmol/L (100 mg/dl). At 3 months, patients were randomized to amlodipine 10 mg or placebo. Plasma LDL cholesterol was decreased by 50%, and the LDL cholesterol target of <2.5 mmol/L was achieved in 81% of the patients. BP targets were achieved in 69% of the atorvastatin + placebo group, versus 96% in the atorvastatin + amlodipine group (p = 0.0002). With use of combination atorvastatin + amlodipine at doses ranging from 10 to 80 mg and 5 to 10 mg, respectively, recommended therapeutic goals were reached in most select subjects with coronary artery disease who were concomitantly receiving aspirin and antihypertensive therapy.

  6. Leader as achiever.

    PubMed

    Dienemann, Jacqueline

    2002-01-01

    This article examines one outcome of leadership: productive achievement. Without achievement one is judged to not truly be a leader. Thus, the ideal leader must be a visionary, a critical thinker, an expert, a communicator, a mentor, and an achiever of organizational goals. This article explores the organizational context that supports achievement, measures of quality nursing care, fiscal accountability, leadership development, rewards and punishments, and the educational content and teaching strategies to prepare graduates to be achievers.

  7. Magnetically attached sputter targets

    DOEpatents

    Makowiecki, D.M.; McKernan, M.A.

    1994-02-15

    An improved method and assembly for attaching sputtering targets to cathode assemblies of sputtering systems which includes a magnetically permeable material is described. The magnetically permeable material is imbedded in a target base that is brazed, welded, or soldered to the sputter target, or is mechanically retained in the target material. Target attachment to the cathode is achieved by virtue of the permanent magnets and/or the pole pieces in the cathode assembly that create magnetic flux lines adjacent to the backing plate, which strongly attract the magnetically permeable material in the target assembly. 11 figures.

  8. Magnetically attached sputter targets

    DOEpatents

    Makowiecki, Daniel M.; McKernan, Mark A.

    1994-01-01

    An improved method and assembly for attaching sputtering targets to cathode assemblies of sputtering systems which includes a magnetically permeable material. The magnetically permeable material is imbedded in a target base that is brazed, welded, or soldered to the sputter target, or is mechanically retained in the target material. Target attachment to the cathode is achieved by virtue of the permanent magnets and/or the pole pieces in the cathode assembly that create magnetic flux lines adjacent to the backing plate, which strongly attract the magnetically permeable material in the target assembly.

  9. Dufulin Activates HrBP1 to Produce Antiviral Responses in Tobacco

    PubMed Central

    Chen, Zhuo; Zeng, Mengjiao; Song, Baoan; Hou, Chengrui; Hu, Deyu; Li, Xiangyang; Wang, Zhenchao; Fan, Huitao; Bi, Liang; Liu, Jiaju; Yu, Dandan; Jin, Linhong; Yang, Song

    2012-01-01

    Background Dufulin is a new antiviral agent that is highly effective against plant viruses and acts by activating systemic acquired resistance (SAR) in plants. In recent years, it has been used widely to prevent and control tobacco and rice viral diseases in China. However, its targets and mechanism of action are still poorly understood. Methodology/Principal Findings Here, differential in-gel electrophoresis (DIGE) and classical two-dimensional electrophoresis (2-DE) techniques were combined with mass spectrometry (MS) to identify the target of Dufulin. More than 40 proteins were found to be differentially expressed (≥1.5 fold or ≤1.5 fold) upon Dufulin treatment in Nicotiana tabacum K326. Based on annotations in the Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) databases, these proteins were found to be related to disease resistance. Directed acyclic graph (DAG) analysis of the various pathways demonstrated harpin binding protein-1 (HrBP1) as the target of action of Dufulin. Additionally, western blotting, semi-quantitative reverse transcription polymerase chain reaction (RT-PCR), and real time PCR analyses were also conducted to identify the specific mechanism of action of Dufulin. Our results show that activation of HrBP1 triggers the salicylic acid (SA) signaling pathway and thereby produces antiviral responses in the plant host. A protective assay based on lesion counting further confirmed the antiviral activity of Dufulin. Conclusion This study identified HrBP1 as a target protein of Dufulin and that Dufulin can activate the SA signaling pathway to induce host plants to generate antiviral responses. PMID:22662252

  10. Possible enhancement of BP180 autoantibody production by herpes zoster.

    PubMed

    Kamiya, Koji; Aoyama, Yumi; Suzuki, Takahiro; Niwa, Haruo; Horio, Ai; Nishio, Eiichi; Tokura, Yoshiki

    2016-02-01

    Bullous pemphigoid (BP) is an autoimmune blistering disease caused by autoantibodies against type XVII collagen/BP180 (BP180). Although the mechanisms of autoantibody production remain to be elucidated, herpes virus infections have been identified as a possible triggering factor for pemphigus. We report a case of herpes zoster (HZ) having anti-BP180 serum antibodies. The patient developed sudden-onset, tense blisters and edematous erythema on the right anterior chest, shoulder and upper back. Histopathology showed remarkable degeneration of keratinocytes, acantholysis and blister formation with ballooning cells, indicating herpes virus infection. A polymerase chain reaction analysis of varicella zoster virus (VZV) was positive in crusts and effusions from the skin lesions, confirming the definitive diagnosis of HZ. Notably, we found that the patient had anti-BP180 serum antibodies in association with the occurrence of HZ. After successful treatment with valacyclovir hydrochloride for 7 days, the serum levels of anti-BP180 antibodies decreased in accordance with the improvement of skin lesions. These findings suggest that the production of anti-BP180 antibodies could be triggered by the reactivation of VZV.

  11. Cellular and Subcellular Localization of the RGS7/Gβ5/R7BP Complex in the Cerebellar Cortex

    PubMed Central

    Aguado, Carolina; Orlandi, Cesare; Fajardo-Serrano, Ana; Gil-Minguez, Mercedes; Martemyanov, Kirill A.; Luján, Rafael

    2016-01-01

    A member of regulator of G-protein signaling family, RGS7, is an essential modulator of signaling through GABAB receptors. RGS7 functions as a macromolecular complex with type 5 G protein β (Gβ5) and R7 binding protein (R7BP) to control the localization and function of the resultant heterotrimeric complexes. Here, we used co-immunoprecipitation, in situ hybridization, histoblot and immunohistochemical techniques at the light and electron microscopic level to advance understanding of RGS7-Gβ5-R7BP complexes in the central nervous system, focusing on distinct neuronal populations in the cerebellar cortex. Histoblot analysis showed that RGS7, Gβ5 and R7BP proteins were widely expressed in the brain, with mostly an overlapping pattern and showing a high expression level in the molecular layer of the cerebellar cortex. Co-immunoprecipitation experiments established that the RGS7/Gβ5 forms complexes with R7BP in the cerebellum. At the cellular level, RGS7 and R7BP mRNAs were expressed at the highest level in Purkinje cells (PCs) and Golgi cells, and at low levels in granule cells. Immunohistochemistry confirmed that labeling for RGS7, Gβ5 and R7BP were present in the three neuronal populations and concentrated in dendrites and spines. At the electron microscopic level, immunolabeling for RGS7, Gβ5 and R7BP proteins was found both at postsynaptic and presynaptic sites and showed similar distribution patterns. Immunoreactivity for the three proteins was mostly localized along the extrasynaptic plasma membrane of dendritic shafts and spines of PCs and to a lesser extent, in axon terminals (AT) establishing excitatory synapses. Quantitative analysis of immunogold particles for RGS7, Gβ5 and R7BP revealed that they are non-uniformly distributed along the surface of PCs, and show enrichment around excitatory synapses on dendritic spines. We further report that deletion of R7BP in mice reduced the targeting of both RGS7 and Gβ5 to the plasma membrane. Altogether, these

  12. How many clinic BP readings are needed to predict cardiovascular events as accurately as ambulatory BP monitoring?

    PubMed

    Eguchi, K; Hoshide, S; Shimada, K; Kario, K

    2014-12-01

    We tested the hypothesis that multiple clinic blood pressure (BP) readings over an extended baseline period would be as predictive as ambulatory BP (ABP) for cardiovascular disease (CVD). Clinic and ABP monitoring were performed in 457 hypertensive patients at baseline. Clinic BP was measured monthly and the means of the first 3, 5 and 10 clinic BP readings were taken as the multiple clinic BP readings. The subjects were followed up, and stroke, HARD CVD, and ALL CVD events were determined as outcomes. In multivariate Cox regression analyses, ambulatory systolic BP (SBP) best predicted three outcomes independently of baseline and multiple clinic SBP readings. The mean of 10 clinic SBP readings predicted stroke (hazards ratio (HR)=1.39, 95% confidence interval (CI)=1.02-1.90, P=0.04) and ALL CVD (HR=1.41, 95% CI=1.13-1.74, P=0.002) independently of baseline clinic SBP. Clinic SBPs by three and five readings were not associated with any CVD events, except that clinic SBP by three readings was associated with ALL CVD (P=0.015). Besides ABP values, the mean of the first 10 clinic SBP values was a significant predictor of stroke and ALL CVD events. It is important to take more than several clinic BP readings early after the baseline period for the risk stratification of future CVD events.

  13. Can aerobic exercise complement antihypertensive drugs to achieve blood pressure control in individuals with essential hypertension?

    PubMed

    Maruf, Fatai A; Salako, Babatunde L; Akinpelu, Aderonke O

    2014-06-01

    Achieving adequate blood pressure (BP) control with antihypertensive medication remains an elusive goal for many patients. The advances in knowledge of hypertension and the increasingly improved upon therapeutic strategies seem not to guarantee even sustainable control rates at the population level. In addition, patients who either discontinue their medications or are non-adherent to drug therapy run the risk of developing uncontrolled BP. Number of daily tablets more than two and number of daily drug administration at least three have been associated with poor adherence with drug therapy. However, BP control seems to go beyond adherence with drug therapy as there are other associated factors. Studies have demonstrated beneficial effect of aerobic exercise in the prevention and management of hypertension. It appears, however, that the majority of these studies failed to explore the possible additive or synergistic effect of aerobic exercise on antihypertensive drugs such that fewer drugs would be required to achieve BP control or that the BP control rate would be increased with the same number of drugs. This review presents the evidence for poor BP control in the general population, and the possible means and process of aerobic exercise complementing antihypertensive drug therapy in order to achieve higher BP control rates.

  14. The oncogenic triangle of HMGA2, LIN28B and IGF2BP1 antagonizes tumor-suppressive actions of the let-7 family

    PubMed Central

    Busch, Bianca; Bley, Nadine; Müller, Simon; Glaß, Markus; Misiak, Danny; Lederer, Marcell; Vetter, Martina; Strauß, Hans-Georg; Thomssen, Christoph; Hüttelmaier, Stefan

    2016-01-01

    The tumor-suppressive let-7 microRNA family targets various oncogene-encoding mRNAs. We identify the let-7 targets HMGA2, LIN28B and IGF2BP1 to form a let-7 antagonizing self-promoting oncogenic triangle. Surprisingly, 3′-end processing of IGF2BP1 mRNAs is unaltered in aggressive cancers and tumor-derived cells although IGF2BP1 synthesis was proposed to escape let-7 attack by APA-dependent (alternative polyadenylation) 3′ UTR shortening. However, the expression of the triangle factors is inversely correlated with let-7 levels and promoted by LIN28B impairing let-7 biogenesis. Moreover, IGF2BP1 enhances the expression of all triangle factors by recruiting the respective mRNAs in mRNPs lacking AGO proteins and let-7 miRNAs. This indicates that the downregulation of let-7, largely facilitated by LIN28B upregulation, and the protection of let-7 target mRNAs by IGF2BP1-directed shielding in mRNPs synergize in enhancing the expression of triangle factors. The oncogenic potential of this triangle was confirmed in ovarian cancer (OC)-derived ES-2 cells transduced with let-7 targeting decoys. In these, the depletion of HMGA2 only diminishes tumor cell growth under permissive conditions. The depletion of LIN28B and more prominently IGF2BP1 severely impairs tumor cell viability, self-renewal and 2D as well as 3D migration. In conclusion, this suggests the targeting of the HMGA2-LIN28B-IGF2BP1 triangle as a promising strategy in cancer treatment. PMID:26917013

  15. Targeted genome modification in mice using zinc-finger nucleases.

    PubMed

    Carbery, Iara D; Ji, Diana; Harrington, Anne; Brown, Victoria; Weinstein, Edward J; Liaw, Lucy; Cui, Xiaoxia

    2010-10-01

    Homologous recombination-based gene targeting using Mus musculus embryonic stem cells has greatly impacted biomedical research. This study presents a powerful new technology for more efficient and less time-consuming gene targeting in mice using embryonic injection of zinc-finger nucleases (ZFNs), which generate site-specific double strand breaks, leading to insertions or deletions via DNA repair by the nonhomologous end joining pathway. Three individual genes, multidrug resistant 1a (Mdr1a), jagged 1 (Jag1), and notch homolog 3 (Notch3), were targeted in FVB/N and C57BL/6 mice. Injection of ZFNs resulted in a range of specific gene deletions, from several nucleotides to >1000 bp in length, among 20-75% of live births. Modified alleles were efficiently transmitted through the germline, and animals homozygous for targeted modifications were obtained in as little as 4 months. In addition, the technology can be adapted to any genetic background, eliminating the need for generations of backcrossing to achieve congenic animals. We also validated the functional disruption of Mdr1a and demonstrated that the ZFN-mediated modifications lead to true knockouts. We conclude that ZFN technology is an efficient and convenient alternative to conventional gene targeting and will greatly facilitate the rapid creation of mouse models and functional genomics research.

  16. Targeted Genome Modification in Mice Using Zinc-Finger Nucleases

    PubMed Central

    Carbery, Iara D.; Ji, Diana; Harrington, Anne; Brown, Victoria; Weinstein, Edward J.; Liaw, Lucy; Cui, Xiaoxia

    2010-01-01

    Homologous recombination-based gene targeting using Mus musculus embryonic stem cells has greatly impacted biomedical research. This study presents a powerful new technology for more efficient and less time-consuming gene targeting in mice using embryonic injection of zinc-finger nucleases (ZFNs), which generate site-specific double strand breaks, leading to insertions or deletions via DNA repair by the nonhomologous end joining pathway. Three individual genes, multidrug resistant 1a (Mdr1a), jagged 1 (Jag1), and notch homolog 3 (Notch3), were targeted in FVB/N and C57BL/6 mice. Injection of ZFNs resulted in a range of specific gene deletions, from several nucleotides to >1000 bp in length, among 20–75% of live births. Modified alleles were efficiently transmitted through the germline, and animals homozygous for targeted modifications were obtained in as little as 4 months. In addition, the technology can be adapted to any genetic background, eliminating the need for generations of backcrossing to achieve congenic animals. We also validated the functional disruption of Mdr1a and demonstrated that the ZFN-mediated modifications lead to true knockouts. We conclude that ZFN technology is an efficient and convenient alternative to conventional gene targeting and will greatly facilitate the rapid creation of mouse models and functional genomics research. PMID:20628038

  17. Which Achievement Gap?

    ERIC Educational Resources Information Center

    Anderson, Sharon; Medrich, Elliott; Fowler, Donna

    2007-01-01

    From the halls of Congress to the local elementary school, conversations on education reform have tossed around the term "achievement gap" as though people all know precisely what that means. As it's commonly used, "achievement gap" refers to the differences in scores on state or national achievement tests between various…

  18. High expression and prognostic role of CAP1 and CtBP2 in breast carcinoma: associated with E-cadherin and cell proliferation.

    PubMed

    Liu, Xiancheng; Yao, Ninghua; Qian, Jing; Huang, Huiwei

    2014-03-01

    Overexpression of C-terminal binding protein-2 (CtBP2) has been noted to correlate with cancer metastasis in several human cancers including breast cancer. The aim of this study was to examine the effect of cyclase-associated protein 1 (CAP1) overexpression on CtBP2 expression and related mechanism in the metastasis of breast cancer. Immunohistochemical analysis was performed in 100 human breast carcinoma samples, and the data were correlated with clinicopathologic features. Furthermore, Western blot analysis was performed for CAP1 and CtBP2 in breast carcinoma samples and cell lines to evaluate their protein levels and molecular interaction. We found that the expression of CAP1 was positively related to CtBP2 expression (P<0.01); moreover, CAP1 expression was significantly correlated with histologic grade (P<0.01) and negatively related to E-cadherin expression (P<0.01). Meanwhile, CtBP2 expression obtained similar results. Kaplan-Meier survival analysis showed that overexpression of CAP1 and CtBP2 exhibited a significant correlation with poor prognosis in human breast cancer (P<0.01). While in vitro, we employed siRNA technique to knockdown CAP1 and CtBP2 expressions and observed their effects on MDA-MB-231 cells growth. CtBP2 depletion by siRNA-inhibited cell proliferation, resulted in increased E-cadherin levels. Moreover, knockdown of CAP1 resulted in decreased CtBP2 and increased E-cadherin expression. On the basis of these results, we suggested that CAP1's oncogenic abilities appear to be triggered at least in part by the modulation of CtBP2 and E-cadherin, which might serve as a future target for breast cancer.

  19. Multi-Functional Regulation of 4E-BP Gene Expression by the Ccr4-Not Complex

    PubMed Central

    Okada, Hirokazu; Schittenhelm, Ralf B.; Straessle, Anna; Hafen, Ernst

    2015-01-01

    The mechanistic target of rapamycin (mTOR) signaling pathway is highly conserved from yeast to humans. It senses various environmental cues to regulate cellular growth and homeostasis. Deregulation of the pathway has been implicated in many pathological conditions including cancer. Phosphorylation cascades through the pathway have been extensively studied but not much is known about the regulation of gene expression of the pathway components. Here, we report that the mRNA level of eukaryotic translation initiation factor (eIF) subunit 4E-binding protein (4E-BP) gene, one of the key mTOR signaling components, is regulated by the highly conserved Ccr4-Not complex. RNAi knockdown of Not1, a putative scaffold protein of this protein complex, increases the mRNA level of 4E-BP in Drosophila Kc cells. Examination of the gene expression mechanism using reporter swap constructs reveals that Not1 depletion increases reporter mRNAs with the 3’UTR of 4E-BP gene, but decreases the ones with the 4E-BP promoter region, suggesting that Ccr4-Not complex regulates both degradation and transcription of 4E-BP mRNA. These results indicate that the Ccr4-Not complex controls expression of a single gene at multiple levels and adjusts the magnitude of the total effect. Thus, our study reveals a novel regulatory mechanism of a key component of the mTOR signaling pathway at the level of gene expression. PMID:25793896

  20. Crystal Structures of the Human G3BP1 NTF2-Like Domain Visualize FxFG Nup Repeat Specificity

    PubMed Central

    Vognsen, Tina; Møller, Ingvar Runár; Kristensen, Ole

    2013-01-01

    Ras GTPase Activating Protein SH3 Domain Binding Protein (G3BP) is a potential anti-cancer drug target implicated in several cellular functions. We have used protein crystallography to solve crystal structures of the human G3BP1 NTF2-like domain both alone and in complex with an FxFG Nup repeat peptide. Despite high structural similarity, the FxFG binding site is located between two alpha helices in the G3BP1 NTF2-like domain and not at the dimer interface as observed for nuclear transport factor 2. ITC studies showed specificity towards the FxFG motif but not FG and GLFG motifs. The unliganded form of the G3BP1 NTF2-like domain was solved in two crystal forms to resolutions of 1.6 and 3.3 Å in space groups P212121 and P6322 based on two different constructs, residues 1–139 and 11–139, respectively. Crystal packing of the N-terminal residues against a symmetry related molecule in the P212121 crystal form might indicate a novel ligand binding site that, however, remains to be validated. The crystal structures give insight into the nuclear transportation mechanisms of G3BP and provide a basis for future structure based drug design. PMID:24324649

  1. Synaptic activity controls localization and function of CtBP1 via binding to Bassoon and Piccolo

    PubMed Central

    Ivanova, Daniela; Dirks, Anika; Montenegro-Venegas, Carolina; Schöne, Cornelia; Altrock, Wilko D; Marini, Claudia; Frischknecht, Renato; Schanze, Denny; Zenker, Martin; Gundelfinger, Eckart D; Fejtova, Anna

    2015-01-01

    Persistent experience-driven adaptation of brain function is associated with alterations in gene expression patterns, resulting in structural and functional neuronal remodeling. How synaptic activity—in particular presynaptic performance—is coupled to gene expression in nucleus remains incompletely understood. Here, we report on a role of CtBP1, a transcriptional co-repressor enriched in presynapses and nuclei, in the activity-driven reconfiguration of gene expression in neurons. We demonstrate that presynaptic and nuclear pools of CtBP1 are interconnected and that both synaptic retention and shuttling of CtBP1 between cytoplasm and nucleus are co-regulated by neuronal activity. Finally, we show that CtBP1 is targeted and/or anchored to presynapses by direct interaction with the active zone scaffolding proteins Bassoon and Piccolo. This association is regulated by neuronal activity via modulation of cellular NAD/NADH levels and restrains the size of the CtBP1 pool available for nuclear import, thus contributing to the control of activity-dependent gene expression. Our combined results reveal a mechanism for coupling activity-induced molecular rearrangements in the presynapse with reconfiguration of neuronal gene expression. PMID:25652077

  2. Randomized trial of guiding hypertension management using central aortic blood pressure compared with best-practice care: principal findings of the BP GUIDE study.

    PubMed

    Sharman, James E; Marwick, Thomas H; Gilroy, Deborah; Otahal, Petr; Abhayaratna, Walter P; Stowasser, Michael

    2013-12-01

    Arm cuff blood pressure (BP) may overestimate cardiovascular risk. Central aortic BP predicts mortality and could be a better method for patient management. We sought to determine the usefulness of central BP to guide hypertension management. This was a prospective, open-label, blinded-end point study in 286 patients with hypertension randomized to treatment decisions guided by best-practice usual care (n=142; using office, home, and 24-hour ambulatory BP) or, in addition, by central BP intervention (n=144; using SphygmoCor). Therapy was reviewed every 3 months for 12 months, and recommendations were provided to each patient and his/her doctor on antihypertensive medication titration. Outcome measures were as follows: medication quantity (daily defined dose), quality of life, and left ventricular mass (3-dimensional echocardiography). There was 92% compliance with recommendations on medication titration, and quality of life improved in both groups (post hoc P<0.05). For usual care, there was no change in daily defined dose (all P>0.10), but with intervention there was a significant stepwise decrease in daily defined dose from baseline to 3 months (P=0.008) and each subsequent visit (all P<0.001). Intervention was associated with cessation of medication in 23 (16%) patients versus 3 (2%) in usual care (P<0.001). Despite this, there were no differences between groups in left ventricular mass index, 24-hour ambulatory BP, home systolic BP, or aortic stiffness (all P>0.05). We conclude that guidance of hypertension management with central BP results in a significantly different therapeutic pathway than conventional cuff BP, with less use of medication to achieve BP control and no adverse effects on left ventricular mass, aortic stiffness, or quality of life.

  3. RMB Exchange Rate Forecast Approach Based on BP Neural Network

    NASA Astrophysics Data System (ADS)

    Ye, Sun

    RMB exchange rate system has reformed since July, 2005. This article chose RMB exchange rate data during a period from July, 2005 to September 2010 to establish BP neural network model to forecast RMB exchange rate in the future by using MATLAB software. The result showed that BP neural network is effective to forecast RMB exchange rate and also indicated that RMB exchange rate will continue to appreciate in the future.

  4. Black Phosphorus (BP) Nanodots for Potential Biomedical Applications.

    PubMed

    Lee, Hyun Uk; Park, So Young; Lee, Soon Chang; Choi, Saehae; Seo, Soonjoo; Kim, Hyeran; Won, Jonghan; Choi, Kyuseok; Kang, Kyoung Suk; Park, Hyun Gyu; Kim, Hee-Sik; An, Ha Rim; Jeong, Kwang-Hun; Lee, Young-Chul; Lee, Jouhahn

    2016-01-13

    Recently, the appeal of 2D black phosphorus (BP) has been rising due to its unique optical and electronic properties with a tunable band gap (≈0.3-1.5 eV). While numerous research efforts have recently been devoted to nano- and optoelectronic applications of BP, no attention has been paid to promising medical applications. In this article, the preparation of BP-nanodots of a few nm to <20 nm with an average diameter of ≈10 nm and height of ≈8.7 nm is reported by a modified ultrasonication-assisted solution method. Stable formation of nontoxic phosphates and phosphonates from BP crystals with exposure in water or air is observed. As for the BP-nanodot crystals' stability (ionization and persistence of fluorescent intensity) in aqueous solution, after 10 d, ≈80% at 1.5 mg mL(-1) are degraded (i.e., ionized) in phosphate buffered saline. They showed no or little cytotoxic cell-viability effects in vitro involving blue- and green-fluorescence cell imaging. Thus, BP-nanodots can be considered a promising agent for drug delivery or cellular tracking systems.

  5. Speech recognition method based on genetic vector quantization and BP neural network

    NASA Astrophysics Data System (ADS)

    Gao, Li'ai; Li, Lihua; Zhou, Jian; Zhao, Qiuxia

    2009-07-01

    Vector Quantization is one of popular codebook design methods for speech recognition at present. In the process of codebook design, traditional LBG algorithm owns the advantage of fast convergence, but it is easy to get the local optimal result and be influenced by initial codebook. According to the understanding that Genetic Algorithm has the capability of getting the global optimal result, this paper proposes a hybrid clustering method GA-L based on Genetic Algorithm and LBG algorithm to improve the codebook.. Then using genetic neural networks for speech recognition. consequently search a global optimization codebook of the training vector space. The experiments show that neural network identification method based on genetic algorithm can extricate from its local maximum value and the initial restrictions, it can show superior to the standard genetic algorithm and BP neural network algorithm from various sources, and the genetic BP neural networks has a higher recognition rate and the unique application advantages than the general BP neural network in the same GA-VQ codebook, it can achieve a win-win situation in the time and efficiency.

  6. Mitotic protein kinase CDK1 phosphorylation of mRNA translation regulator 4E-BP1 Ser83 may contribute to cell transformation

    PubMed Central

    Velásquez, Celestino; Cheng, Erdong; Shuda, Masahiro; Lee-Oesterreich, Paula J.; Pogge von Strandmann, Lisa; Gritsenko, Marina A.; Jacobs, Jon M.; Moore, Patrick S.; Chang, Yuan

    2016-01-01

    Mammalian target of rapamycin (mTOR)-directed eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) phosphorylation promotes cap-dependent translation and tumorigenesis. During mitosis, cyclin-dependent kinase 1 (CDK1) substitutes for mTOR and fully phosphorylates 4E-BP1 at canonical sites (T37, T46, S65, and T70) and the noncanonical S83 site, resulting in a mitosis-specific hyperphosphorylated δ isoform. Colocalization studies with a phospho-S83 specific antibody indicate that 4E-BP1 S83 phosphorylation accumulates at centrosomes during prophase, peaks at metaphase, and decreases through telophase. Although S83 phosphorylation of 4E-BP1 does not affect general cap-dependent translation, expression of an alanine substitution mutant 4E-BP1.S83A partially reverses rodent cell transformation induced by Merkel cell polyomavirus small T antigen viral oncoprotein. In contrast to inhibitory mTOR 4E-BP1 phosphorylation, these findings suggest that mitotic CDK1-directed phosphorylation of δ-4E-BP1 may yield a gain of function, distinct from translation regulation, that may be important in tumorigenesis and mitotic centrosome function. PMID:27402756

  7. A review of glycemic efficacy of liraglutide once daily in achieving glycated hemoglobin targets compared with exenatide twice daily, or sitagliptin once daily in the treatment of type 2 diabetes

    PubMed Central

    Alshali, Khalid Z.; Karawagh, Abdullah M.

    2016-01-01

    Incretin-based therapies such as glucagon-like peptide-1 (GLP-1) receptor agonists (RA) and dipeptidyl peptidase-4 (DPP-4) inhibitors have gained prominence in recent years for the treatment of type 2 diabetes (T2D). Such therapies offer the potential to stimulate endogenous insulin activity in proportion to circulating glucose levels; thereby, lowering the risk of hypoglycemic episodes. The synthetic GLP-1 RA exenatide, the human GLP-1 RA liraglutide, and the DPP-4 inhibitor sitagliptin are the first agents in their respective classes to be approved for the treatment of T2D and their efficacy and safety has been studied extensively in clinical trials. This article reviewed the efficacy of liraglutide once daily in achieving clinical guidelines-recommended glycated hemoglobin A1c levels in patients with T2D compared with exenatide twice daily, or sitagliptin once daily, based on published literature, with an aim to elucidate the preferred choice of incretin-related therapy in treating uncontrolled T2D. PMID:27464858

  8. MiR-980 is a memory suppressor microRNA that regulates the autism-susceptibility gene, A2bp1

    PubMed Central

    Guven-Ozkan, Tugba; Busto, Germain U.; Schutte, Soleil S.; Cervantes-Sandoval, Isaac; O’Dowd, Diane K.; Davis, Ronald L.

    2016-01-01

    SUMMARY MicroRNAs have been associated with many different biological functions but little is known about their roles in conditioned behavior. We demonstrate that Drosophila miR-980 is a memory suppressor gene functioning in multiple regions of the adult brain. Memory acquisition and stability were both increased by miR-980 inhibition. Whole cell recordings and functional imaging experiments indicated that miR-980 regulates neuronal excitability. We identified the autism susceptibility gene, A2bp1, as an mRNA target for miR-980. A2bp1 levels varied inversely with miR-980 expression; memory performance was directly related to A2bp1 levels. In addition, A2bp1 knockdown reversed the memory gains produced by miR-980 inhibition, consistent with A2bp1 being a downstream target of miR-980 responsible for the memory phenotypes. Our results indicate that miR-980 represses A2bp1 expression to tune the excitable state of neurons, and the overall state of excitability translates to memory impairment or improvement. PMID:26876166

  9. S100A6 binding protein and Siah-1 interacting protein (CacyBP/SIP): spotlight on properties and cellular function.

    PubMed

    Schneider, Gabriela; Filipek, Anna

    2011-10-01

    The CacyBP/SIP protein (S100A6 binding protein and Siah-1 interacting protein) was originally discovered in Ehrlich ascites tumor cells as a S100A6 (calcyclin) target (Filipek and Wojda in Biochem J 320:585-587, 1996; Filipek and Kuźnicki in J Neurochem 70(5):1793-1798, 1998) and later on as a Siah-1 interacting protein (Matsuzawa and Reed in Mol Cell 7(5):915-926, 2001). CacyBP/SIP binds several target proteins such as some calcium binding proteins of the S100 family (Filipek et al. in J Biol Chem 277(32):28848-28852, 2002), Skp1 (Matsuzawa and Reed in Mol Cell 7(5):915-926, 2001), tubulin (Schneider et al. in Biochim Biophys Acta 1773(11):1628-1636, 2007) and ERK1/2 (Kilanczyk et al. in Biochem Biophys Res Commun 380:54-59, 2009). Studies concerning distribution of CacyBP/SIP show that it is present in various tissues and that a particularly high level of CacyBP/SIP is observed in brain (Jastrzebska et al. in J Histochem Cytochem 48(9):1195-1202, 2000). Regarding the function of CacyBP/SIP, there are some reports suggesting its role in cellular processes such as ubiquitination, proliferation, differentiation, tumorigenesis, cytoskeletal rearrangement or regulation of transcription. This review describes the properties of CacyBP/SIP and summarizes all findings concerning its cellular function.

  10. Effect of hydrodynamics-based delivery of IL-18BP fusion gene on rat experimental autoimmune myocarditis.

    PubMed

    Chang, He; Wang, Yan; Li, Gang; Zhang, Le; Zhang, Guang Wei; Liao, Yan Chun; Hanawa, Haruo; Zou, Jun

    2014-11-01

    Interleukin-18 (IL-18) is a powerful and important cytokine in myocarditis. IL-18-binding protein (IL-18BP), a naturally occurring antagonist of IL-18, is presumed to play a vital regulatory function in IL-18-mediated immune responses. The purpose of this study was to evaluate the alterations of IL-18 and its related protein expressions and the effect of hydrodynamics-based delivery of the IL-18BP gene for treatment of rat experimental autoimmune myocarditis (EAM).Rats were immunized on Day 0 and killed on 2, 3 and 4 weeks to determine IL-18 and its related protein expression and target cells in EAM hearts. On Day 6, rats were injected with a recombinant plasmid encoding IL-18BP-Ig or SP-Ig. On Day 17, rats were detected with echocardiography and then be killed. IL-18BP gene therapy was effective in controlling EAM, as monitored by a decreased ratio of heart weight to body weight, reduced myocarditis areas, reduced expression of atrial natriuretic peptide, brain natriuretic peptide, IL-17, IFN-γ, IL-6 and IL-10. Furthermore, the effect of serum containing IL-18BP on the expression of immune-relevant genes in IL-1α-stimulated NC cells and splenocytes cultured from EAM rats was examined. The results showed that IL-18BP significantly suppressed the expression of IL-17 as well as other proinflammatory genes such as transforming growth factor-β, prostaglandin E2 synthase, cyclooxygenase-2 in IL-1α-stimulated NC cells, and IL-18BP also significantly suppressed the expression of IL-17, IL-17R, IL-21 and IL-17-related transcriptional factor retinoic acid-related orphan nuclear receptor, signal transducer and activator of transcription-3 and Foxp3 in IL-1α-stimulated splenocytes cultured from EAM rats. IL-18 and its related protein played an important role on the development of EAM. IL-18BP effectively prevented progression of EAM by blocking IL-17 and related inflammatory genes expression. This might be a possible mechanism of the amelioration of EAM by IL-18BP

  11. Vicarious Achievement Orientation.

    ERIC Educational Resources Information Center

    Leavitt, Harold J.; And Others

    This study tests hypotheses about achievement orientation, particularly vicarious achievement. Undergraduate students (N=437) completed multiple-choice questionnaires, indicating likely responses of one person to the success of another. The sex of succeeder and observer, closeness of relationship, and setting (medical school or graduate school of…

  12. Heritability of Creative Achievement

    ERIC Educational Resources Information Center

    Piffer, Davide; Hur, Yoon-Mi

    2014-01-01

    Although creative achievement is a subject of much attention to lay people, the origin of individual differences in creative accomplishments remain poorly understood. This study examined genetic and environmental influences on creative achievement in an adult sample of 338 twins (mean age = 26.3 years; SD = 6.6 years). Twins completed the Creative…

  13. Confronting the Achievement Gap

    ERIC Educational Resources Information Center

    Gardner, David

    2007-01-01

    This article talks about the large achievement gap between children of color and their white peers. The reasons for the achievement gap are varied. First, many urban minorities come from a background of poverty. One of the detrimental effects of growing up in poverty is receiving inadequate nourishment at a time when bodies and brains are rapidly…

  14. Achievement-Based Resourcing.

    ERIC Educational Resources Information Center

    Fletcher, Mike; And Others

    1992-01-01

    This collection of seven articles examines achievement-based resourcing (ABR), the concept that the funding of educational institutions should be linked to their success in promoting student achievement, with a focus on the application of ABR to postsecondary education in the United Kingdom. The articles include: (1) "Introduction" (Mick…

  15. States Address Achievement Gaps.

    ERIC Educational Resources Information Center

    Christie, Kathy

    2002-01-01

    Summarizes 2 state initiatives to address the achievement gap: North Carolina's report by the Advisory Commission on Raising Achievement and Closing Gaps, containing an 11-point strategy, and Kentucky's legislation putting in place 10 specific processes. The North Carolina report is available at www.dpi.state.nc.us.closingthegap; Kentucky's…

  16. Marine04 Marine radiocarbon age calibration, 26 ? 0 ka BP

    SciTech Connect

    Hughen, K; Baille, M; Bard, E; Beck, J; Bertrand, C; Blackwell, P; Buck, C; Burr, G; Cutler, K; Damon, P; Edwards, R; Fairbanks, R; Friedrich, M; Guilderson, T; Kromer, B; McCormac, F; Manning, S; Bronk-Ramsey, C; Reimer, P; Reimer, R; Remmele, S; Southon, J; Stuiver, M; Talamo, S; Taylor, F; der Plicht, J v; Weyhenmeyer, C

    2004-11-01

    New radiocarbon calibration curves, IntCal04 and Marine04, have been constructed and internationally ratified to replace the terrestrial and marine components of IntCal98. The new calibration datasets extend an additional 2000 years, from 0-26 ka cal BP (Before Present, 0 cal BP = AD 1950), and provide much higher resolution, greater precision and more detailed structure than IntCal98. For the Marine04 curve, dendrochronologically dated tree-ring samples, converted with a box-diffusion model to marine mixed-layer ages, cover the period from 0-10.5 ka cal BP. Beyond 10.5 ka cal BP, high-resolution marine data become available from foraminifera in varved sediments and U/Th-dated corals. The marine records are corrected with site-specific {sup 14}C reservoir age information to provide a single global marine mixed-layer calibration from 10.5-26.0 ka cal BP. A substantial enhancement relative to IntCal98 is the introduction of a random walk model, which takes into account the uncertainty in both the calendar age and the radiocarbon age to calculate the underlying calibration curve. The marine datasets and calibration curve for marine samples from the surface mixed layer (Marine04) are discussed here. The tree-ring datasets, sources of uncertainty, and regional offsets are presented in detail in a companion paper by Reimer et al.

  17. In situ SUMOylation analysis reveals a modulatory role of RanBP2 in the nuclear rim and PML bodies

    SciTech Connect

    Saitoh, Noriko . E-mail: hisa@gpo.kumamoto-u.ac.jp; Uchimura, Yasuhiro; Tachibana, Taro; Sugahara, Satoko; Saitoh, Hisato; Nakao, Mitsuyoshi . E-mail: mnakao@gpo.kumamoto-u.ac.jp

    2006-05-01

    SUMO modification plays a critical role in a number of cellular functions including nucleocytoplasmic transport, gene expression, cell cycle and formation of subnuclear structures such as promyelocytic leukemia (PML) bodies. In order to identify the sites where SUMOylation takes place in the cell, we developed an in situ SUMOylation assay using a semi-intact cell system and subsequently combined it with siRNA-based knockdown of nucleoporin RanBP2, also known as Nup358, which is one of the known SUMO E3 proteins. With the in situ SUMOylation assay, we found that both nuclear rim and PML bodies, besides mitotic apparatuses, are major targets for active SUMOylation. The ability to analyze possible SUMO conjugation sites would be a valuable tool to investigate where SUMO E3-like activities and/or SUMO substrates exist in the cell. Specific knockdown of RanBP2 completely abolished SUMOylation along the nuclear rim and dislocated RanGAP1 from the nuclear pore complexes. Interestingly, the loss of RanBP2 markedly reduced the number of PML bodies, in contrast to other, normal-appearing nuclear compartments including the nuclear lamina, nucleolus and chromatin, suggesting a novel link between RanBP2 and PML bodies. SUMOylation facilitated by RanBP2 at the nuclear rim may be a key step for the formation of a particular subnuclear organization. Our data imply that SUMO E3 proteins like RanBP2 facilitate spatio-temporal SUMOylation for certain nuclear structure and function.

  18. Achievability for telerobotic systems

    NASA Astrophysics Data System (ADS)

    Kress, Reid L.; Draper, John V.; Hamel, William R.

    2001-02-01

    Methods are needed to improve the capabilities of autonomous robots to perform tasks that are difficult for contemporary robots, and to identify those tasks that robots cannot perform. Additionally, in the realm of remote handling, methods are needed to assess which tasks and/or subtasks are candidates for automation. We are developing a new approach to understanding the capability of autonomous robotic systems. This approach uses formalized methods for determining the achievability of tasks for robots, that is, the likelihood that an autonomous robot or telerobot can successfully complete a particular task. Any autonomous system may be represented in achievability space by the volume describing that system's capabilities within the 3-axis space delineated by perception, cognition, and action. This volume may be thought of as a probability density with achievability decreasing as the distance from the centroid of the volume increases. Similarly, any task may be represented within achievability space. However, as tasks have more finite requirements for perception, cognition, and action, each may be represented as a point (or, more accurately, as a small sphere) within achievability space. Analysis of achievability can serve to identify, a priori, the survivability of robotic systems and the likelihood of mission success; it can be used to plan a mission or portions of a mission; it can be used to modify a mission plan to accommodate unpredicted occurrences; it can also serve to identify needs for modifications to robotic systems or tasks to improve achievability. .

  19. Preliminary Geological Findings on the BP-1 Simulant

    NASA Technical Reports Server (NTRS)

    Stoeser, D. B.; Rickman, D. L.; Wilson, S.

    2010-01-01

    A waste material from an aggregate producing quarry has been used to make an inexpensive lunar simulant called BP-1. The feedstock is the Black Point lava flow in northern Arizona. Although this is part of the San Francisco volcanic field, which is also the source of the JSC-1 series feedstock, BP-1 and JSC-1 are distinct. Chemically, the Black Point flow is an amygdaloidal nepheline-bearing basalt. The amygdules are filled with secondary minerals containing opaline silica, calcium carbonate, and ferric iron minerals. X-ray diffraction (XRD) detected approximately 3% quartz, which is in line with tests done by the Kennedy Space Center Industrial Hygiene Office. Users of this material should use appropriate protective equipment. XRD also showed the presence of significant halite and some bassanite. Both are interpreted to be evaporative residues due to recycling of wash water at the quarry. The size distribution of BP-1 may be superior to some other simulants for some applications.

  20. Preliminary Geological Findings on the BP-1 Simulant

    NASA Technical Reports Server (NTRS)

    Rickman, D. L.

    2010-01-01

    The following is a summation of information and discussion between Doug Stoeser of the USGS and Doug Rickman of NASA in February and March, 2010 pertaining to the BP-1 simulant. The analytical results and the bulk of the text are from communications from Dr. Stoeser. The BP-1 simulant is made from Black Point Basalt Flow, San Francisco Volcanic Field, northern Arizona. There is an aggregate (road metal) quarry on the northern margin of the flow towards the west end that was used as a Desert Research and Technology Studies (Desert RATS) analog test site. Silty material from this site was also used in laboratory tests and found to have geotechnical properties similar to the LHT-2M and Chenobi regolith simulants and is being proposed as a possible simulant for geotechnical use. It currently has the designation of BP-1 (Black Point 1). Figure

  1. 200-BP-5 operable unit treatability test report

    SciTech Connect

    1996-04-01

    The 200-BP-5 Operable Unit was established in response to recommendations presented in the 200 East Groundwater Aggregate Area Management Study Report (AAMSR) (DOE-RL 1993a). Recognizing different approaches to remediation, the groundwater AAMSR recommended separating groundwater from source and vadose zone operable units and subdividing 200 East Area groundwater into two operable units. The division between the 200-BP-5 and 200-PO-1 Operable Units was based principally on source operable unit boundaries and distribution of groundwater plumes derived from either B Plant or Plutonium/Uranium Extraction (PUREX) Plant liquid waste disposal sites.

  2. Feline Calicivirus Infection Disrupts Assembly of Cytoplasmic Stress Granules and Induces G3BP1 Cleavage

    PubMed Central

    Humoud, Majid N.; Doyle, Nicole; Royall, Elizabeth; Willcocks, Margaret M.; Sorgeloos, Frederic; van Kuppeveld, Frank; Roberts, Lisa O.; Goodfellow, Ian G.; Langereis, Martijn A.

    2016-01-01

    models to understand norovirus biology. Recent studies have suggested that the assembly of stress granules is central in orchestrating stress and antiviral responses to restrict viral replication. Overall, our study provides the first insight on how caliciviruses impair stress granule assembly by targeting the nucleating factor G3BP1 via the viral proteinase NS6Pro. This work provides new insights into host-pathogen interactions that regulate stress pathways during FCV infection. PMID:27147742

  3. BP-Broker use-cases in the UncertWeb framework

    NASA Astrophysics Data System (ADS)

    Roncella, Roberto; Bigagli, Lorenzo; Schulz, Michael; Stasch, Christoph; Proß, Benjamin; Jones, Richard; Santoro, Mattia

    2013-04-01

    The UncertWeb framework is a distributed, Web-based Information and Communication Technology (ICT) system to support scientific data modeling in presence of uncertainty. We designed and prototyped a core component of the UncertWeb framework: the Business Process Broker. The BP-Broker implements several functionalities, such as: discovery of available processes/BPs, preprocessing of a BP into its executable form (EBP), publication of EBPs and their execution through a workflow-engine. According to the Composition-as-a-Service (CaaS) approach, the BP-Broker supports discovery and chaining of modeling resources (and processing resources in general), providing the necessary interoperability services for creating, validating, editing, storing, publishing, and executing scientific workflows. The UncertWeb project targeted several scenarios, which were used to evaluate and test the BP-Broker. The scenarios cover the following environmental application domains: biodiversity and habitat change, land use and policy modeling, local air quality forecasting, and individual activity in the environment. This work reports on the study of a number of use-cases, by means of the BP-Broker, namely: - eHabitat use-case: implements a Monte Carlo simulation performed on a deterministic ecological model; an extended use-case supports inter-comparison of model outputs; - FERA use-case: is composed of a set of models for predicting land-use and crop yield response to climatic and economic change; - NILU use-case: is composed of a Probabilistic Air Quality Forecasting model for predicting concentrations of air pollutants; - Albatross use-case: includes two model services for simulating activity-travel patterns of individuals in time and space; - Overlay use-case: integrates the NILU scenario with the Albatross scenario to calculate the exposure to air pollutants of individuals. Our aim was to prove the feasibility of describing composite modeling processes with a high-level, abstract

  4. Culture and Achievement Motivation

    ERIC Educational Resources Information Center

    Maehr, Martin L.

    1974-01-01

    A framework is suggested for the cross-cultural study of motivation that stresses the importance of contextual conditions in eliciting achievement motivation and emphasizes cultural relativity in the definition of the concept. (EH)

  5. Achieving Salary Equity

    ERIC Educational Resources Information Center

    Nevill, Dorothy D.

    1975-01-01

    Three techniques are outlined for use by higher education institutions to achieve salary equity: salary prediction (using various statistical procedures), counterparting (comparing salaries of persons of similar rank), and grievance procedures. (JT)

  6. Pilot-scale treatability test plan for the 200-BP-5 operable unit

    SciTech Connect

    Not Available

    1994-08-01

    This document presents the treatability test plan for pilot-scale pump and treat testing at the 200-BP-5 Operable Unit. This treatability test plan has been prepared in response to an agreement between the U.S. Department of Energy (DOE), the U.S. Environmental Protection Agency (EPA), and the State of Washington Department of Ecology (Ecology), as documented in Hanford Federal Facility Agreement and Consent Order (Tri-Party Agreement, Ecology et al. 1989a) Change Control Form M-13-93-03 (Ecology et al. 1994) and a recent 200 NPL Agreement Change Control Form (Appendix A). The agreement also requires that, following completion of the activities described in this test plan, a 200-BP-5 Operable Unit Interim Remedial Measure (IRM) Proposed Plan be developed for use in preparing an Interim Action Record of Decision (ROD). The IRM Proposed Plan will be supported by the results of this treatability test plan, as well as by other 200-BP-5 Operable Unit activities (e.g., development of a qualitative risk assessment). Once issued, the Interim Action ROD will specify the interim action(s) for groundwater contamination at the 200-BP-5 Operable Unit. The treatability test approach is to conduct a pilot-scale pump and treat test for each of the two contaminant plumes associated with the 200-BP-5 Operable Unit. Primary contaminants of concern are {sup 99}Tc and {sup 60}Co for underwater affected by past discharges to the 216-BY Cribs, and {sup 90}Sr, {sup 239/240}Pu, and Cs for groundwater affected by past discharges to the 216-B-5 Reverse Well. The purpose of the pilot-scale treatability testing presented in this testplan is to provide the data basis for preparing an IRM Proposed Plan. To achieve this objective, treatability testing must: Assess the performance of groundwater pumping with respect to the ability to extract a significant amount of the primary contaminant mass present in the two contaminant plumes.

  7. Interaction of the eukaryotic initiation factor 4E with 4E-BP2 at a dynamic bipartite interface.

    PubMed

    Lukhele, Sabelo; Bah, Alaji; Lin, Hong; Sonenberg, Nahum; Forman-Kay, Julie D

    2013-12-03

    Cap-dependent translation initiation is regulated by the interaction of eukaryotic initiation factor 4E (eIF4E) with eIF4E binding proteins (4E-BPs). Whereas the binding of 4E-BP peptides containing the eIF4E-binding ⁵⁴YXXXXLΦ⁶⁰ motif has been studied, atomic-level characterization of the interaction of eIF4E with full-length 4E-BPs has been lacking. Here, we use isothermal titration calorimetry and nuclear magnetic resonance spectroscopy to characterize the dynamic, structural and binding properties of 4E-BP2. Although disordered, 4E-BP2 contains significant fluctuating secondary structure and binds eIF4E at an extensive bipartite interface including the canonical ⁵⁴YXXXXLΦ⁶⁰ and ⁷⁸IPGVT⁸² sites. Each of the two binding elements individually has submicromolar affinity and exchange on and off of the eIF4E surface within the context of the overall nanomolar complex. This dynamic interaction facilitates exposure of regulatory phosphorylation sites within the complex. The 4E-BP2 interface on eIF4E overlaps yet is more extensive than the eIF4G:eIF4E interface, suggesting that these key interactions may be differentially targeted for therapeutics.

  8. Residues Responsible for the Selectivity of α-Conotoxins for Ac-AChBP or nAChRs

    PubMed Central

    Lin, Bo; Xiang, Shihua; Li, Mengsen

    2016-01-01

    Nicotinic acetylcholine receptors (nAChRs) are targets for developing new drugs to treat severe pain, nicotine addiction, Alzheimer disease, epilepsy, etc. α-Conotoxins are biologically and chemically diverse. With 12–19 residues and two disulfides, they can be specifically selected for different nAChRs. Acetylcholine-binding proteins from Aplysia californica (Ac-AChBP) are homologous to the ligand-binding domains of nAChRs and pharmacologically similar. X-ray structures of the α-conotoxin in complex with Ac-AChBP in addition to computer modeling have helped to determine the binding site of the important residues of α-conotoxin and its affinity for nAChR subtypes. Here, we present the various α-conotoxin residues that are selective for Ac-AChBP or nAChRs by comparing the structures of α-conotoxins in complex with Ac-AChBP and by modeling α-conotoxins in complex with nAChRs. The knowledge of these binding sites will assist in the discovery and design of more potent and selective α-conotoxins as drug leads. PMID:27727162

  9. Molecular mechanism and functional role of brefeldin A-mediated ADP-ribosylation of CtBP1/BARS.

    PubMed

    Colanzi, Antonino; Grimaldi, Giovanna; Catara, Giuliana; Valente, Carmen; Cericola, Claudia; Liberali, Prisca; Ronci, Maurizio; Lalioti, Vasiliki S; Bruno, Agostino; Beccari, Andrea R; Urbani, Andrea; De Flora, Antonio; Nardini, Marco; Bolognesi, Martino; Luini, Alberto; Corda, Daniela

    2013-06-11

    ADP-ribosylation is a posttranslational modification that modulates the functions of many target proteins. We previously showed that the fungal toxin brefeldin A (BFA) induces the ADP-ribosylation of C-terminal-binding protein-1 short-form/BFA-ADP-ribosylation substrate (CtBP1-S/BARS), a bifunctional protein with roles in the nucleus as a transcription factor and in the cytosol as a regulator of membrane fission during intracellular trafficking and mitotic partitioning of the Golgi complex. Here, we report that ADP-ribosylation of CtBP1-S/BARS by BFA occurs via a nonconventional mechanism that comprises two steps: (i) synthesis of a BFA-ADP-ribose conjugate by the ADP-ribosyl cyclase CD38 and (ii) covalent binding of the BFA-ADP-ribose conjugate into the CtBP1-S/BARS NAD(+)-binding pocket. This results in the locking of CtBP1-S/BARS in a dimeric conformation, which prevents its binding to interactors known to be involved in membrane fission and, hence, in the inhibition of the fission machinery involved in mitotic Golgi partitioning. As this inhibition may lead to arrest of the cell cycle in G2, these findings provide a strategy for the design of pharmacological blockers of cell cycle in tumor cells that express high levels of CD38.

  10. Quasiparticle energies for cubic BN, BP, and BAs

    SciTech Connect

    Surh, M.P.; Louie, S.G.; Cohen, M.L. Materials Sciences Division, Lawrence Berkeley Laboratory, Berkeley, California 94720)

    1991-04-15

    Electronic excitation energies at the high-symmetry points {Gamma}, {ital X}, and {ital L} are obtained for zinc-blende-structure BN, BP, and BAs in the {ital GW} approximation using a model dielectric function. A model for the static screening matrix makes use of the {ital ab} {ital initio} ground-state charge density and either experimental values or empirical estimates for {epsilon}{sub {infinity}}, the electronic contribution to the macroscopic dielectric constant. Wave functions from an {ital ab} {ital initio} local-density-approximation calculation with norm-conserving pseudopotentials are employed along with the self-consistent quasiparticle spectrum to obtain the energy-dependent one-particle Green function {ital G}. The minimum band gaps are found to be 6.3, 1.9, and 1.6 eV for BN, BP, and BAs, respectively, in close agreement with existing measurements of 6.1 and 2.0 eV for BN and BP, respectively. The BN direct band gap is predicted to be 11.4 eV versus the experimental value of 14.5 eV, and the BP direct band gap is predicted to be 4.4 eV versus 5.0 eV from experiment.

  11. The binary Cepheid BP CIR - A test of evolutionary tracks

    NASA Astrophysics Data System (ADS)

    Evans, Nancy R.; Arellano Ferro, A.; Udalska, Joanna

    1992-05-01

    IUE spectra of the system containing the Cepheid BP Cir are used to derive the magnitude difference between the two stars (Δ V = 1.88 ± 0.3 mag) and the spectral type of the companion (B6.OV). This is the first system yet encountered for which the standard Seaton reddening law is inappropriate. For BP Cir, a stronger 2200 Å bump than the standard law is required. However, this does not affect the determination of the temperature of the hot star or the magnitude difference between the two stars, because those use the wavelength regions shorter than 1600 Å and longer than 2500 Å. The stars are very similar in mass. Possible pulsation in the first overtone mode implies that BP Cir B is evolved beyond the ZAMS but is still in the main sequence band. The best match to BP Cir A and B is with isochrones by Stothers and Chin (1991) with Inglesias and Rogers (1991) opacities and no core convective overshoot and Cepheid pulsation in the first overtone.

  12. The binary Cepheid BP Cir - A test of evolutionary tracks

    NASA Technical Reports Server (NTRS)

    Evans, Nancy R.; Ferro, A. A.; Udalska, Joanna

    1992-01-01

    IUE spectra of the system containing the Cepheid BP Cir are used to derive the magnitude difference between the two stars (Delta V = 1.88 +/- 0.3 mag) and the spectral type of the companion (B6.0V). This is the first system yet encountered for which the standard Seaton reddening law is inappropriate. For BP Cir, a stronger 2200-A bump than the standard law is required. However, this does not affect the determination of the temperature of the hot star or the magnitude difference between the two stars, because those use the wavelength regions shorter than 1600 A and longer than 2500 A. The stars are very similar in mass. Possible pulsation in the first overtone mode implies that BP Cir B is evolved beyond the ZAMS but is still in the main sequence band. The best match to BP Cir A and B is with isochrones by Stothers and Chin (1991) with Inglesias and Rogers (1991) opacities and no core convective overshoot and Cepheid pulsation in the first overtone.

  13. BP Piscium: its flaring disc imaged with SPHERE/ZIMPOL★

    NASA Astrophysics Data System (ADS)

    de Boer, J.; Girard, J. H.; Canovas, H.; Min, M.; Sitko, M.; Ginski, C.; Jeffers, S. V.; Mawet, D.; Milli, J.; Rodenhuis, M.; Snik, F.; Keller, C. U.

    2017-03-01

    Whether BP Piscium (BP Psc) is either a pre-main sequence T Tauri star at d ≈ 80 pc, or a post-main sequence G giant at d ≈ 300 pc is still not clear. As a first-ascent giant, it is the first to be observed with a molecular and dust disc. Alternatively, BP Psc would be among the nearest T Tauri stars with a protoplanetary disc (PPD). We investigate whether the disc geometry resembles typical PPDs, by comparing polarimetric images with radiative transfer models. Our Very Large Telescope/Spectro-Polarimetric High-contrast Exoplanet REsearch (SPHERE)/Zurich IMaging Polarimeter (ZIMPOL) observations allow us to perform polarimetric differential imaging, reference star differential imaging, and Richardson-Lucy deconvolution. We present the first visible light polarization and intensity images of the disc of BP Psc. Our deconvolution confirms the disc shape as detected before, mainly showing the southern side of the disc. In polarized intensity the disc is imaged at larger detail and also shows the northern side, giving it the typical shape of high-inclination flared discs. We explain the observed disc features by retrieving the large-scale geometry with MCMAX radiative transfer modelling, which yields a strongly flared model, atypical for discs of T Tauri stars.

  14. TopBP1-mediated DNA processing during mitosis.

    PubMed

    Gallina, Irene; Christiansen, Signe Korbo; Pedersen, Rune Troelsgaard; Lisby, Michael; Oestergaard, Vibe H

    2016-01-01

    Maintenance of genome integrity is crucial to avoid cancer and other genetic diseases. Thus faced with DNA damage, cells mount a DNA damage response to avoid genome instability. The DNA damage response is partially inhibited during mitosis presumably to avoid erroneous processing of the segregating chromosomes. Yet our recent study shows that TopBP1-mediated DNA processing during mitosis is highly important to reduce transmission of DNA damage to daughter cells. (1) Here we provide an overview of the DNA damage response and DNA repair during mitosis. One role of TopBP1 during mitosis is to stimulate unscheduled DNA synthesis at underreplicated regions. We speculated that such genomic regions are likely to hold stalled replication forks or post-replicative gaps, which become the substrate for DNA synthesis upon entry into mitosis. Thus, we addressed whether the translesion pathways for fork restart or post-replicative gap filling are required for unscheduled DNA synthesis in mitosis. Using genetics in the avian DT40 cell line, we provide evidence that unscheduled DNA synthesis in mitosis does not require the translesion synthesis scaffold factor Rev1 or PCNA ubiquitylation at K164, which serve to recruit translesion polymerases to stalled forks. In line with this finding, translesion polymerase η foci do not colocalize with TopBP1 or FANCD2 in mitosis. Taken together, we conclude that TopBP1 promotes unscheduled DNA synthesis in mitosis independently of the examined translesion polymerases.

  15. BP chief scientist nominated for senior energy role

    NASA Astrophysics Data System (ADS)

    Gwynne, Peter

    2014-01-01

    The Obama administration has nominated BP's chief scientist Ellen Williams to be director of the Advanced Research Projects Agency-Energy (ARPA-E), which was created in 2007 to fund "high-risk, high-reward" research into novel energy technologies that are too early for investment by the private sector.

  16. BP-1T, an antiangiogenic benzophenone-thiazole pharmacophore, counteracts HIF-1 signalling through p53/MDM2-mediated HIF-1α proteasomal degradation.

    PubMed

    Thirusangu, Prabhu; Vigneshwaran, V; Prashanth, T; Vijay Avin, B R; Malojirao, Vikas H; Rakesh, H; Khanum, Shaukath Ara; Mahmood, Riaz; Prabhakar, B T

    2017-02-01

    Hypoxia is a feature of all solid tumours, contributing to tumour progression. Activation of HIF-1α plays a critical role in promoting tumour angiogenesis and metastasis. Since its expression is positively correlated with poor prognosis for cancer patients, HIF-1α is one of the most convincing anticancer targets. BP-1T is a novel antiproliferative agent with promising antiangiogenic effects. In the present study, the molecular mechanism underlying cytotoxic/antiangiogenic effects of BP-1T on tumour/non-tumour angiogenesis was evaluated. Evidences show that BP-1T exhibits potent cytotoxicity with prolonged activity and effectively regressed neovessel formation both in reliable non-tumour and tumour angiogenic models. The expression of CoCl2-induced HIF-1α was inhibited by BP-1T in various p53 (WT)-expressing cancer cells, including A549, MCF-7 and DLA, but not in mutant p53-expressing SCC-9 cells. Mechanistically, BP-1T mediates the HIF-1α proteasomal degradation by activating p53/MDM2 pathway and thereby downregulated HIF-1α-dependent angiogenic genes such as VEGF-A, Flt-1, MMP-2 and MMP-9 under hypoxic condition of in vitro and in vivo solid tumour, eventually leading to abolition of migration and invasion. Based on these observations, we conclude that BP-1T acts on HIF-1α degradation through p53/MDM2 proteasome pathway.

  17. P-2 Years Targeted to Achieve Grade 3 Reading Proficiency

    ERIC Educational Resources Information Center

    Gewertz, Catherine

    2011-01-01

    In a bid to help more students read proficiently in 3rd grade--a skill considered critical to their future educational success--new laws and initiatives springing up around the country require educators to step up their efforts to identify and help struggling readers even before they enter kindergarten. It's not unusual for states or school…

  18. A translational study "case report" on the small molecule "energy blocker" 3-bromopyruvate (3BP) as a potent anticancer agent: from bench side to bedside.

    PubMed

    Ko, Y H; Verhoeven, H A; Lee, M J; Corbin, D J; Vogl, T J; Pedersen, P L

    2012-02-01

    The small alkylating molecule, 3-bromopyruvate (3BP), is a potent and specific anticancer agent. 3BP is different in its action from most currently available chemo-drugs. Thus, 3BP targets cancer cells' energy metabolism, both its high glycolysis ("Warburg Effect") and mitochondrial oxidative phosphorylation. This inhibits/ blocks total energy production leading to a depletion of energy reserves. Moreover, 3BP as an "Energy Blocker", is very rapid in killing such cells. This is in sharp contrast to most commonly used anticancer agents that usually take longer to show a noticeable effect. In addition, 3BP at its effective concentrations that kill cancer cells has little or no effect on normal cells. Therefore, 3BP can be considered a member, perhaps one of the first, of a new class of anticancer agents. Following 3BP's discovery as a novel anticancer agent in vitro in the Year 2000 (Published in Ko et al. Can Lett 173:83-91, 2001), and also as a highly effective and rapid anticancer agent in vivo shortly thereafter (Ko et al. Biochem Biophys Res Commun 324:269-275, 2004), its efficacy as a potent anticancer agent in humans was demonstrated. Here, based on translational research, we report results of a case study in a young adult cancer patient with fibrolamellar hepatocellular carcinoma. Thus, a bench side discovery in the Department of Biological Chemistry at Johns Hopkins University, School of Medicine was taken effectively to bedside treatment at Johann Wolfgang Goethe University Frankfurt/Main Hospital, Germany. The results obtained hold promise for 3BP as a future cancer therapeutic without apparent cyto-toxicity when formulated properly.

  19. Efficacy and tolerability of ezetimibe 10 mg/day coadministered with statins in patients with primary hypercholesterolemia who do not achieve target LDL-C while on statin monotherapy: A Canadian, multicentre, prospective study – the Ezetrol® Add-On Study

    PubMed Central

    Bissonnette, Stéphane; Habib, Rafik; Sampalis, Fotini; Boukas, Stella; Sampalis, John S

    2006-01-01

    BACKGROUND For patients who have above-target low-density lipoprotein cholesterol (LDL-C) levels while on statin monotherapy, coadministration of a cholesterol absorption inhibitor with the statin may decrease serum LDL-C levels and improve overall lipid profiles. OBJECTIVES To assess the effectiveness and safety of ezetimibe 10 mg/day coadministered with a statin in patients with primary hypercholesterolemia who have higher than recommended LDL-C levels while on statin monotherapy. METHODS A six-week, prospective, multicentre study of eligible patients who had above-target LDL-C levels while on monotherapy with any statin, regardless of dose, for a minimum of four weeks. All patients were treated for six weeks with 10 mg ezetimibe daily coad-ministered with their current statins. RESULTS A total of 1141 patients were screened, 953 (83.5%) fulfilled the study inclusion criteria and 837 (87.8%) completed the study. Reasons for withdrawal included: lost to follow-up (50 patients [5.2%]); protocol violations (45 patients [4.7%]); adverse events (19 patients [2.0%]); and withdrawal of consent (two patients [0.2%]). After six weeks of treatment, statistically significant (P=0.001) mean reductions were observed in LDL-C (30.05%), total cholesterol (20.84%), triglycerides (10.16%), apolipoprotein B (19.84%) and the total cholesterol to high-density lipoprotein cholesterol ratio (19.88%). At six weeks, 674 patients (80.5%) achieved target LDL-C levels. Fifty predominantly mild, nonserious adverse events related to ezetimibe were reported by 32 patients (3.4%). Frequently reported adverse events included constipation (n=7 [0.7% of patients]), diarrhea (n=4 [0.4%]) and dizziness (n=4 [0.4%]). CONCLUSION Ezetimibe coadministered with statins is effective in reducing LDL-C in patients who do not attain target LDL-C levels while on statin monotherapy. PMID:17036098

  20. SALT and Spelling Achievement.

    ERIC Educational Resources Information Center

    Nelson, Joan

    A study investigated the effects of suggestopedic accelerative learning and teaching (SALT) on the spelling achievement, attitudes toward school, and memory skills of fourth-grade students. Subjects were 20 male and 28 female students from two self-contained classrooms at Kennedy Elementary School in Rexburg, Idaho. The control classroom and the…

  1. Iowa Women of Achievement.

    ERIC Educational Resources Information Center

    Ohrn, Deborah Gore, Ed.

    1993-01-01

    This issue of the Goldfinch highlights some of Iowa's 20th century women of achievement. These women have devoted their lives to working for human rights, education, equality, and individual rights. They come from the worlds of politics, art, music, education, sports, business, entertainment, and social work. They represent Native Americans,…

  2. Schools Achieving Gender Equity.

    ERIC Educational Resources Information Center

    Revis, Emma

    This guide is designed to assist teachers presenting the Schools Achieving Gender Equity (SAGE) curriculum for vocational education students, which was developed to align gender equity concepts with the Kentucky Education Reform Act (KERA). Included in the guide are lesson plans for classes on the following topics: legal issues of gender equity,…

  3. Achieving Peace through Education.

    ERIC Educational Resources Information Center

    Clarken, Rodney H.

    While it is generally agreed that peace is desirable, there are barriers to achieving a peaceful world. These barriers are classified into three major areas: (1) an erroneous view of human nature; (2) injustice; and (3) fear of world unity. In a discussion of these barriers, it is noted that although the consciousness and conscience of the world…

  4. Explorations in achievement motivation

    NASA Technical Reports Server (NTRS)

    Helmreich, Robert L.

    1982-01-01

    Recent research on the nature of achievement motivation is reviewed. A three-factor model of intrinsic motives is presented and related to various criteria of performance, job satisfaction and leisure activities. The relationships between intrinsic and extrinsic motives are discussed. Needed areas for future research are described.

  5. Increasing Male Academic Achievement

    ERIC Educational Resources Information Center

    Jackson, Barbara Talbert

    2008-01-01

    The No Child Left Behind legislation has brought greater attention to the academic performance of American youth. Its emphasis on student achievement requires a closer analysis of assessment data by school districts. To address the findings, educators must seek strategies to remedy failing results. In a mid-Atlantic district of the Unites States,…

  6. Appraising Reading Achievement.

    ERIC Educational Resources Information Center

    Ediger, Marlow

    To determine quality sequence in pupil progress, evaluation approaches need to be used which guide the teacher to assist learners to attain optimally. Teachers must use a variety of procedures to appraise student achievement in reading, because no one approach is adequate. Appraisal approaches might include: (1) observation and subsequent…

  7. Cognitive Processes and Achievement.

    ERIC Educational Resources Information Center

    Hunt, Dennis; Randhawa, Bikkar S.

    For a group of 165 fourth- and fifth-grade students, four achievement test scores were correlated with success on nine tests designed to measure three cognitive functions: sustained attention, successive processing, and simultaneous processing. This experiment was designed in accordance with Luria's model of the three functional units of the…

  8. Graders' Mathematics Achievement

    ERIC Educational Resources Information Center

    Bond, John B.; Ellis, Arthur K.

    2013-01-01

    The purpose of this experimental study was to investigate the effects of metacognitive reflective assessment instruction on student achievement in mathematics. The study compared the performance of 141 students who practiced reflective assessment strategies with students who did not. A posttest-only control group design was employed, and results…

  9. Achieving All Our Ambitions

    ERIC Educational Resources Information Center

    Hartley, Tricia

    2009-01-01

    National learning and skills policy aims both to build economic prosperity and to achieve social justice. Participation in higher education (HE) has the potential to contribute substantially to both aims. That is why the Campaign for Learning has supported the ambition to increase the proportion of the working-age population with a Level 4…

  10. Improving Educational Achievement.

    ERIC Educational Resources Information Center

    New York University Education Quarterly, 1979

    1979-01-01

    This is a slightly abridged version of the report of the National Academy of Education panel, convened at the request of HEW Secretary Joseph Califano and Assistant Secretary for Education Mary F. Berry, to study recent declines in student achievement and methods of educational improvement. (SJL)

  11. The Achievement Club

    ERIC Educational Resources Information Center

    Rogers, Ibram

    2009-01-01

    When Gabrielle Carpenter became a guidance counselor in Northern Virginia nine years ago, she focused on the academic achievement gap and furiously tried to close it. At first, she was compelled by tremendous professional interest. However, after seeing her son lose his zeal for school, Carpenter joined forces with other parents to form an…

  12. Achievement in Problem Solving

    ERIC Educational Resources Information Center

    Friebele, David

    2010-01-01

    This Action Research Project is meant to investigate the effects of incorporating research-based instructional strategies into instruction and their subsequent effect on student achievement in the area of problem-solving. The two specific strategies utilized are the integration of manipulatives and increased social interaction on a regular basis.…

  13. Essays on Educational Achievement

    ERIC Educational Resources Information Center

    Ampaabeng, Samuel Kofi

    2013-01-01

    This dissertation examines the determinants of student outcomes--achievement, attainment, occupational choices and earnings--in three different contexts. The first two chapters focus on Ghana while the final chapter focuses on the US state of Massachusetts. In the first chapter, I exploit the incidence of famine and malnutrition that resulted to…

  14. Advancing Student Achievement

    ERIC Educational Resources Information Center

    Walberg, Herbert J.

    2010-01-01

    For the last half century, higher spending and many modern reforms have failed to raise the achievement of students in the United States to the levels of other economically advanced countries. A possible explanation, says Herbert Walberg, is that much current education theory is ill informed about scientific psychology, often drawing on fads and…

  15. NCLB: Achievement Robin Hood?

    ERIC Educational Resources Information Center

    Bracey, Gerald W.

    2008-01-01

    In his "Wall Street Journal" op-ed on the 25th of anniversary of "A Nation At Risk", former assistant secretary of education Chester E. Finn Jr. applauded the report for turning U.S. education away from equality and toward achievement. It was not surprising, then, that in mid-2008, Finn arranged a conference to examine the…

  16. The energy blocker inside the power house: Mitochondria targeted delivery of 3-bromopyruvate.

    PubMed

    Marrache, Sean; Dhar, Shanta

    2015-03-01

    A key hallmark of many aggressive cancers is accelerated glucose metabolism. The enzymes that catalyze the first step of glucose metabolism are hexokinases. High levels of hexokinase 2 (HK2) are found in cancer cells, but only in a limited number of normal tissues. Metabolic reprogramming of cancer cells using the energy blocker, 3-bromopyruvate (3-BP) that inhibits HK2 has the potential to provide tumor-specific anticancer agents. However, the unique structural and functional characteristics of mitochondria prohibit selective subcellular targeting of 3-BP to modulate the function of this organelle for therapeutic gain. A mitochondria targeted gold nanoparticle (T-3-BP-AuNP) decorated with 3-BP and delocalized lipophilic triphenylphosphonium cations to target the mitochondrial membrane potential (Δψm) was developed for delivery of 3-BP to cancer cell mitochondria by taking advantage of higher Δψm in cancer cells compared to normal cells. In vitro studies demonstrated enhanced anticancer activity of T-3-BP-AuNPs compared to the non-targeted construct NT-3-BP-AuNP or free 3-BP. The anticancer activity of T-3-BP-AuNP was further enhanced upon laser irradiation by exciting the surface plasmon resonance band of AuNP and thereby utilizing a combination of 3-BP chemotherapeutic and AuNP photothermal effects. The less toxic behavior of T-3-BPNPs in normal mesenchymal stem cells indicated that these NPs preferentially kill cancer cells. T-3-BP-AuNPs showed enhanced ability to modulate cancer cell metabolism by inhibiting glycolysis as well as demolishing mitochondrial oxidative phosphorylation. Our findings demonstrated that concerted chemo-photothermal treatment of glycolytic cancer cells with a single NP capable of targeting mitochondria mediating simultaneous release of a glycolytic inhibitor and photothermal ablation may have promise as a new anticancer therapy.

  17. BpTRU(tm) blood pressure monitor for use in a physician's office.

    PubMed

    Allison, C

    2006-08-01

    The BpTRU(tm) is an automated device that takes serial blood pressure (BP) measurements in a physician's office. (1) Preliminary data from non-randomized, uncontrolled trials suggest that the average of five BpTRU measurements, taken while the patient is alone, more reliably reflects "resting" BP compared to manual measurements taken with a stethoscope and sphygmomanometer. (2) BpTRU helps reduce the overestimation of BP due to improper measurement technique, or due to a patient's anxiety in a physician's presence ("white coat" effect). (3) The BpTRU device can improve hypertension management by replacing conventional manual BP measurements, which are often poorly performed and inaccurate. (4) BpTRU is more expensive than the manual manometers used in a physician's office. The serial measurement, taken in a private examining room, requires an average of six to 12 minutes, which could increase the duration of a patient's visit.

  18. Increasing Math Achievement through Use of Music.

    ERIC Educational Resources Information Center

    Bryant-Jones, Marian; Shimmins, Kymberley J.; Vega, Jill D.

    This report describes a program for increasing math achievement through the use of musical interventions including repeated exposure to Mozart classical music and School House Rock, and introduction to teacher-made songs that introduce mathematical concepts in the music classroom. The students of the targeted second and fourth grade classes…

  19. Activity on the classical T Tauri star BP Tauri.

    NASA Astrophysics Data System (ADS)

    Gullbring, E.; Barwig, H.; Chen, P. S.; Gahm, G. F.; Bao, M. X.

    1996-03-01

    We have made a detailed investigation of the short-term variability in optical light (UBVRI) of the classical T Tauri star BP Tauri. Photometric data (in UBVRI) were collected from Wendelstein Observatory, Germany in 1991, 1992 and 1993 with time-resolutions down to 1sec and, from binning, fluctuations with total amplitudes down to a few milli-magnitudes could be resolved. Additional observations (in UBV) were collected in China. The total time of monitoring amounts to 135 hours. The normal state of BP Tau is that it stays completely constant in brightness in all bands, or shows only very slow and smooth changes during a night, to the limit of detection. Brightenings, events, occurred on time-scales from 0.6hours to a few hours but none of these reached a total amplitude >0.3mag in U. As a rule these events do not have the characteristic flare profile as in the lightcurves of stellar surface flares. The total optical energies of the events are a few times 10^35^erg, with a relatively small spread. The energy distributions at peak flux can be represented by black-body radiation. However, the inferred temperature is very low, 7000-8000K, and not significantly different from that derived for the background veiling. Hence, the events on BP Tau are very different from normal stellar flares. From power analysis of the time series, we conclude that there is no power indicating frequent and short lasting phenomena, like surface flares. In particular there is no signal in the U band. Such flares would have been expected to be numerous in this high-sensitivity survey, however, if BP Tau had a magnetic surface activity comparable to that of ordinary flare stars. Also, there is no tail in the distribution of events towards smaller amplitudes and shorter durations. We show that the events of BP Tau are consistent with inhomogeneous mass infall from magnetically controlled accretion between a circumstellar disk and a hot spot at the star. To account for the constancy in

  20. Functional interaction between type III-secreted protein IncA of Chlamydophila psittaci and human G3BP1.

    PubMed

    Borth, Nicole; Litsche, Katrin; Franke, Claudia; Sachse, Konrad; Saluz, Hans Peter; Hänel, Frank

    2011-01-31

    Chlamydophila (Cp.) psittaci, the causative agent of psittacosis in birds and humans, is the most important zoonotic pathogen of the family Chlamydiaceae. These obligate intracellular bacteria are distinguished by a unique biphasic developmental cycle, which includes proliferation in a membrane-bound compartment termed inclusion. All Chlamydiaceae spp. possess a coding capacity for core components of a Type III secretion apparatus, which mediates specific delivery of anti-host effector proteins either into the chlamydial inclusion membrane or into the cytoplasm of target eukaryotic cells. Here we describe the interaction between Type III-secreted protein IncA of Cp. psittaci and host protein G3BP1 in a yeast two-hybrid system. In GST-pull down and co-immunoprecipitation experiments both in vitro and in vivo interaction between full-length IncA and G3BP1 were shown. Using fluorescence microscopy, the localization of G3BP1 near the inclusion membrane of Cp. psittaci-infected Hep-2 cells was demonstrated. Notably, infection of Hep-2 cells with Cp. psittaci and overexpression of IncA in HEK293 cells led to a decrease in c-Myc protein concentration. This effect could be ascribed to the interaction between IncA and G3BP1 since overexpression of an IncA mutant construct disabled to interact with G3BP1 failed to reduce c-Myc concentration. We hypothesize that lowering the host cell c-Myc protein concentration may be part of a strategy employed by Cp. psittaci to avoid apoptosis and scale down host cell proliferation.

  1. Functional Interaction between Type III-Secreted Protein IncA of Chlamydophila psittaci and Human G3BP1

    PubMed Central

    Borth, Nicole; Litsche, Katrin; Franke, Claudia; Sachse, Konrad; Saluz, Hans Peter; Hänel, Frank

    2011-01-01

    Chlamydophila (Cp.) psittaci, the causative agent of psittacosis in birds and humans, is the most important zoonotic pathogen of the family Chlamydiaceae. These obligate intracellular bacteria are distinguished by a unique biphasic developmental cycle, which includes proliferation in a membrane-bound compartment termed inclusion. All Chlamydiaceae spp. possess a coding capacity for core components of a Type III secretion apparatus, which mediates specific delivery of anti-host effector proteins either into the chlamydial inclusion membrane or into the cytoplasm of target eukaryotic cells. Here we describe the interaction between Type III-secreted protein IncA of Cp. psittaci and host protein G3BP1 in a yeast two-hybrid system. In GST-pull down and co-immunoprecipitation experiments both in vitro and in vivo interaction between full-length IncA and G3BP1 were shown. Using fluorescence microscopy, the localization of G3BP1 near the inclusion membrane of Cp. psittaci-infected Hep-2 cells was demonstrated. Notably, infection of Hep-2 cells with Cp. psittaci and overexpression of IncA in HEK293 cells led to a decrease in c-Myc protein concentration. This effect could be ascribed to the interaction between IncA and G3BP1 since overexpression of an IncA mutant construct disabled to interact with G3BP1 failed to reduce c-Myc concentration. We hypothesize that lowering the host cell c-Myc protein concentration may be part of a strategy employed by Cp. psittaci to avoid apoptosis and scale down host cell proliferation. PMID:21304914

  2. BP-Dock: A Flexible Docking Scheme for Exploring Protein–Ligand Interactions Based on Unbound Structures

    PubMed Central

    Bolia, Ashini; Gerek, Z. Nevin; Ozkan, S. Banu

    2016-01-01

    Molecular docking serves as an important tool in modeling protein–ligand interactions. However, it is still challenging to incorporate overall receptor flexibility, especially backbone flexibility, in docking due to the large conformational space that needs to be sampled. To overcome this problem, we developed a novel flexible docking approach, BP-Dock (Backbone Perturbation-Dock) that can integrate both backbone and side chain conformational changes induced by ligand binding through a multi-scale approach. In the BP-Dock method, we mimic the nature of binding-induced events as a first-order approximation by perturbing the residues along the protein chain with a small Brownian kick one at a time. The response fluctuation profile of the chain upon these perturbations is computed using the perturbation response scanning method. These response fluctuation profiles are then used to generate binding-induced multiple receptor conformations for ensemble docking. To evaluate the performance of BP-Dock, we applied our approach on a large and diverse data set using unbound structures as receptors. We also compared the BP-Dock results with bound and unbound docking, where overall receptor flexibility was not taken into account. Our results highlight the importance of modeling backbone flexibility in docking for recapitulating the experimental binding affinities, especially when an unbound structure is used. With BP-Dock, we can generate a wide range of binding site conformations realized in nature even in the absence of a ligand that can help us to improve the accuracy of unbound docking. We expect that our fast and efficient flexible docking approach may further aid in our understanding of protein–ligand interactions as well as virtual screening of novel targets for rational drug design. PMID:24380381

  3. Cell type-specific control of protein synthesis and proliferation by FGF-dependent signaling to the translation repressor 4E-BP.

    PubMed

    Ruoff, Rachel; Katsara, Olga; Kolupaeva, Victoria

    2016-07-05

    Regulation of protein synthesis plays a vital role in posttranscriptional modulation of gene expression. Translational control most commonly targets the initiation of protein synthesis: loading 40S ribosome complexes onto mRNA and AUG start codon recognition. This step is initiated by eukaryotic initiation factor 4E (eIF4E) (the m7GTP cap-binding protein), whose binding to eIF4G (a scaffolding subunit) and eIF4A (an ATP-dependent RNA helicase) leads to assembly of active eIF4F complex. The ability of eIF4E to recognize the cap is prevented by its binding to eIF4E binding protein (4E-BP), which thereby inhibits cap-dependent translation by sequestering eIF4E. The 4E-BP activity is, in turn, inhibited by mTORC1 [mTOR (the mechanistic target of rapamycin) complex 1] mediated phosphorylation. Here, we define a previously unidentified mechanism of mTOR-independent 4E-BP1 regulation that is used by chondrocytes upon FGF signaling. Chondrocytes are responsible for the formation of the skeleton long bones. Unlike the majority of cell types where FGF signaling triggers proliferation, chondrocytes respond to FGF with inhibition. We establish that FGF specifically suppresses protein synthesis in chondrocytes, but not in any other cells of mesenchymal origin. Furthermore, 4E-BP1 repressor activity is necessary not only for suppression of protein synthesis, but also for FGF-induced cell-cycle arrest. Importantly, FGF-induced changes in the 4E-BP1 activity observed in cell culture are likewise detected in vivo and reflect the action of FGF signaling on downstream targets during bone development. Thus, our findings demonstrate that FGF signaling differentially impacts protein synthesis through either stimulation or repression, in a cell-type-dependent manner, with 4E-BP1 being a key player.

  4. Spontaneous 8bp Deletion in Nbeal2 Recapitulates the Gray Platelet Syndrome in Mice

    PubMed Central

    Tomberg, Kärt; Khoriaty, Rami; Westrick, Randal J.; Fairfield, Heather E.; Reinholdt, Laura G.; Brodsky, Gary L.; Davizon-Castillo, Pavel; Ginsburg, David; Di Paola, Jorge

    2016-01-01

    During the analysis of a whole genome ENU mutagenesis screen for thrombosis modifiers, a spontaneous 8 base pair (bp) deletion causing a frameshift in exon 27 of the Nbeal2 gene was identified. Though initially considered as a plausible thrombosis modifier, this Nbeal2 mutation failed to suppress the synthetic lethal thrombosis on which the original ENU screen was based. Mutations in NBEAL2 cause Gray Platelet Syndrome (GPS), an autosomal recessive bleeding disorder characterized by macrothrombocytopenia and gray-appearing platelets due to lack of platelet alpha granules. Mice homozygous for the Nbeal2 8 bp deletion (Nbeal2gps/gps) exhibit a phenotype similar to human GPS, with significantly reduced platelet counts compared to littermate controls (p = 1.63 x 10−7). Nbeal2gps/gps mice also have markedly reduced numbers of platelet alpha granules and an increased level of emperipolesis, consistent with previously characterized mice carrying targeted Nbeal2 null alleles. These findings confirm previous reports, provide an additional mouse model for GPS, and highlight the potentially confounding effect of background spontaneous mutation events in well-characterized mouse strains. PMID:26950939

  5. X-rays from magnetic intermediate mass Ap/Bp stars

    NASA Astrophysics Data System (ADS)

    Robrade, Jan

    2016-09-01

    The X-ray emission of magnetic intermediate mass Ap/Bp stars is reviewed and put into context of intrinsic as well as extrinsic hypotheses for its origin. New X-ray observations of Ap/Bp stars are presented and combined with an updated analysis of the available datasets, providing the largest sample of its type that is currently available. In the studied stars the X-ray detections are found predominantly among the more massive, hotter and more luminous targets. Their X-ray properties are quite diverse and beside strong soft X-ray emission significant magnetic activity is frequently present. While a connection between more powerful winds and brighter X-ray emission is expected in intrinsic models, the scatter in X-ray luminosity at given bolometric luminosity is so far unexplained and several observational features like X-ray light curves and flaring, luminosity distributions and spectral properties are often similar to those of low-mass stars. It remains to be seen if these features can be fully reproduced by magnetospheres of intermediate mass stars. The article discusses implications for magnetically confined wind-shock models (MCWS) and stellar magnetospheres under the assumption that the intrinsic model is applicable, but also examines the role of possible companions. Further, related magnetospheric phenomena are presented and an outlook on future perspectives is given.

  6. Faculty achievement tracking tool.

    PubMed

    Pettus, Sarah; Reifschneider, Ellen; Burruss, Nancy

    2009-03-01

    Faculty development and scholarship is an expectation of nurse educators. Accrediting institutions, such as the Commission on Collegiate Nursing Education, the National League for Nursing Accrediting Commission, and the Higher Learning Commission, all have criteria regarding faculty achievement. A faculty achievement tracking tool (FATT) was developed to facilitate documentation of accreditation criteria attainment. Based on criteria from accrediting organizations, the roles that are addressed include scholarship, service, and practice. Definitions and benchmarks for the faculty as an aggregate are included. Undergoing reviews from different accrediting organizations, the FATT has been used once for accreditation of the undergraduate program and once for accreditation of the graduate program. The FATT is easy to use and has become an excellent adjunct for the preparation for accreditation reports. In addition, the FATT may be used for yearly evaluations, advancement, and merit.

  7. Project ACHIEVE final report

    SciTech Connect

    1997-06-13

    Project ACHIEVE was a math/science academic enhancement program aimed at first year high school Hispanic American students. Four high schools -- two in El Paso, Texas and two in Bakersfield, California -- participated in this Department of Energy-funded program during the spring and summer of 1996. Over 50 students, many of whom felt they were facing a nightmare future, were given the opportunity to work closely with personal computers and software, sophisticated calculators, and computer-based laboratories -- an experience which their regular academic curriculum did not provide. Math and science projects, exercises, and experiments were completed that emphasized independent and creative applications of scientific and mathematical theories to real world problems. The most important outcome was the exposure Project ACHIEVE provided to students concerning the college and technical-field career possibilities available to them.

  8. Calibration of the radiocarbon time scale at 37ka BP

    SciTech Connect

    Southon, J.R.; Deino, A.L.; Orsi, G.

    1995-12-01

    Results from radiocarbon and U-Th measurements on corals have provided a radiocarbon calibration beyond the range covered by tree ring series, but the uncertainties in the measurements beyond 20ka BP are very large. We have obtained new calibration data from radiocarbon dates on material associated with the catastrophic Campanian Ignimbrite eruption from the Phlegrean Fields near Naples. The eruption has been well dated by {sup 40}Ar/{sup 39}Ar to 37ka BP. Radiocarbon measurements were carried out on charcoal from a carbonized branch exposed within the ignimbrite tuff on the wall of an active quarry. The sample was split and analyzed at both the Naples and Lawrence Livermore AMS facilities. The offset between the Ar-Ar data and the radiocarbon results (recalculated using the true 5730-year half life for {sup 14}C) is consistent with predictions from paleomagnetic data and carbon cycle modeling.

  9. USGS aerial resolution targets.

    USGS Publications Warehouse

    Salamonowicz, P.H.

    1982-01-01

    It is necessary to measure the achievable resolution of any airborne sensor that is to be used for metric purposes. Laboratory calibration facilities may be inadequate or inappropriate for determining the resolution of non-photographic sensors such as optical-mechanical scanners, television imaging tubes, and linear arrays. However, large target arrays imaged in the field can be used in testing such systems. The USGS has constructed an array of resolution targets in order to permit field testing of a variety of airborne sensing systems. The target array permits any interested organization with an airborne sensing system to accurately determine the operational resolution of its system. -from Author

  10. Diffusion and Settling in Ap/Bp Stars

    SciTech Connect

    Turcotte, S

    2003-04-09

    Ap/Bp stars are magnetic chemically peculiar early A and late B type stars of the main sequence. They exhibit peculiar surface abundance anomalies that are thought to be the result of gravitational settling and radiative levitation. The physics of diffusion in these stars are reviewed briefly and some model predictions are discussed. While models reproduce some observations reasonably well, more work is needed before the behavior of diffusing elements in a complex magnetic field is fully understood.

  11. Sputter target

    DOEpatents

    Gates, Willard G.; Hale, Gerald J.

    1980-01-01

    The disclosure relates to an improved sputter target for use in the deposition of hard coatings. An exemplary target is given wherein titanium diboride is brazed to a tantalum backing plate using a gold-palladium-nickel braze alloy.

  12. Features extraction of flotation froth images and BP neural network soft-sensor model of concentrate grade optimized by shuffled cuckoo searching algorithm.

    PubMed

    Wang, Jie-sheng; Han, Shuang; Shen, Na-na; Li, Shu-xia

    2014-01-01

    For meeting the forecasting target of key technology indicators in the flotation process, a BP neural network soft-sensor model based on features extraction of flotation froth images and optimized by shuffled cuckoo search algorithm is proposed. Based on the digital image processing technique, the color features in HSI color space, the visual features based on the gray level cooccurrence matrix, and the shape characteristics based on the geometric theory of flotation froth images are extracted, respectively, as the input variables of the proposed soft-sensor model. Then the isometric mapping method is used to reduce the input dimension, the network size, and learning time of BP neural network. Finally, a shuffled cuckoo search algorithm is adopted to optimize the BP neural network soft-sensor model. Simulation results show that the model has better generalization results and prediction accuracy.

  13. Features Extraction of Flotation Froth Images and BP Neural Network Soft-Sensor Model of Concentrate Grade Optimized by Shuffled Cuckoo Searching Algorithm

    PubMed Central

    Wang, Jie-sheng; Han, Shuang; Shen, Na-na; Li, Shu-xia

    2014-01-01

    For meeting the forecasting target of key technology indicators in the flotation process, a BP neural network soft-sensor model based on features extraction of flotation froth images and optimized by shuffled cuckoo search algorithm is proposed. Based on the digital image processing technique, the color features in HSI color space, the visual features based on the gray level cooccurrence matrix, and the shape characteristics based on the geometric theory of flotation froth images are extracted, respectively, as the input variables of the proposed soft-sensor model. Then the isometric mapping method is used to reduce the input dimension, the network size, and learning time of BP neural network. Finally, a shuffled cuckoo search algorithm is adopted to optimize the BP neural network soft-sensor model. Simulation results show that the model has better generalization results and prediction accuracy. PMID:25133210

  14. An Interaction between Human Papillomavirus 16 E2 and TopBP1 Is Required for Optimum Viral DNA Replication and Episomal Genome Establishment

    PubMed Central

    Donaldson, Mary M.; Mackintosh, Lorna J.; Bodily, Jason M.; Dornan, Edward S.; Laimins, Laimonis A.

    2012-01-01

    In human papillomavirus DNA replication, the viral protein E2 forms homodimers and binds to 12-bp palindromic DNA sequences surrounding the origin of DNA replication. Via a protein-protein interaction, it then recruits the viral helicase E1 to an A/T-rich origin of replication, whereupon a dihexamer forms, resulting in DNA replication initiation. In order to carry out DNA replication, the viral proteins must interact with host factors that are currently not all known. An attractive cellular candidate for regulating viral replication is TopBP1, a known interactor of the E2 protein. In mammalian DNA replication, TopBP1 loads DNA polymerases onto the replicative helicase after the G1-to-S transition, and this process is tightly cell cycle controlled. The direct interaction between E2 and TopBP1 would allow E2 to bypass this cell cycle control, resulting in DNA replication more than once per cell cycle, which is a requirement for the viral life cycle. We report here the generation of an HPV16 E2 mutant compromised in TopBP1 interaction in vivo and demonstrate that this mutant retains transcriptional activation and repression functions but has suboptimal DNA replication potential. Introduction of this mutant into a viral life cycle model results in the failure to establish viral episomes. The results present a potential new antiviral target, the E2-TopBP1 interaction, and increase our understanding of the viral life cycle, suggesting that the E2-TopBP1 interaction is essential. PMID:22973044

  15. Achieving closure at Fernald

    SciTech Connect

    Bradburne, John; Patton, Tisha C.

    2001-02-25

    When Fluor Fernald took over the management of the Fernald Environmental Management Project in 1992, the estimated closure date of the site was more than 25 years into the future. Fluor Fernald, in conjunction with DOE-Fernald, introduced the Accelerated Cleanup Plan, which was designed to substantially shorten that schedule and save taxpayers more than $3 billion. The management of Fluor Fernald believes there are three fundamental concerns that must be addressed by any contractor hoping to achieve closure of a site within the DOE complex. They are relationship management, resource management and contract management. Relationship management refers to the interaction between the site and local residents, regulators, union leadership, the workforce at large, the media, and any other interested stakeholder groups. Resource management is of course related to the effective administration of the site knowledge base and the skills of the workforce, the attraction and retention of qualified a nd competent technical personnel, and the best recognition and use of appropriate new technologies. Perhaps most importantly, resource management must also include a plan for survival in a flat-funding environment. Lastly, creative and disciplined contract management will be essential to effecting the closure of any DOE site. Fluor Fernald, together with DOE-Fernald, is breaking new ground in the closure arena, and ''business as usual'' has become a thing of the past. How Fluor Fernald has managed its work at the site over the last eight years, and how it will manage the new site closure contract in the future, will be an integral part of achieving successful closure at Fernald.

  16. Levels of the E2 interacting protein TopBP1 modulate papillomavirus maintenance stage replication

    SciTech Connect

    Kanginakudru, Sriramana; DeSmet, Marsha; Thomas, Yanique; Morgan, Iain M.; Androphy, Elliot J.

    2015-04-15

    The evolutionarily conserved DNA topoisomerase II beta-binding protein 1 (TopBP1) functions in DNA replication, DNA damage response, and cell survival. We analyzed the role of TopBP1 in human and bovine papillomavirus genome replication. Consistent with prior reports, TopBP1 co-localized in discrete nuclear foci and was in complex with papillomavirus E2 protein. Similar to E2, TopBP1 is recruited to the region of the viral origin of replication during G1/S and early S phase. TopBP1 knockdown increased, while over-expression decreased transient virus replication, without affecting cell cycle. Similarly, using cell lines harboring HPV-16 or HPV-31 genome, TopBP1 knockdown increased while over-expression reduced viral copy number relative to genomic DNA. We propose a model in which TopBP1 serves dual roles in viral replication: it is essential for initiation of replication yet it restricts viral copy number. - Highlights: • Protein interaction study confirmed In-situ interaction between TopBP1 and E2. • TopBP1 present at papillomavirus ori in G1/S and early S phase of cell cycle. • TopBP1 knockdown increased, over-expression reduced virus replication. • TopBP1 protein level change did not influence cell survival or cell cycle. • TopBP1 displaced from papillomavirus ori after initiation of replication.

  17. Heritability of HR and BP Response To Exercise Training in the HERITAGE Family Study.

    ERIC Educational Resources Information Center

    Rice, Treva; Gagnon, Jacques; Leon, Arthur S.; Skinner, James S.; Wilmore, Jack H.; Bouchard, Claude; Rao, D. C.

    2002-01-01

    Assessed the heritability of response to exercise training in resting blood pressure (BP) and heart rate (HR) among sedentary Caucasians comprising 98 families who completed an exercise training program. Results indicated that the trainability of systolic BP and HR in families with elevated BP was partially determined by genetic factors. Diastolic…

  18. Modification over time of pulse wave velocity parallel to changes in aortic BP, as well as in 24-h ambulatory brachial BP.

    PubMed

    Oliveras, A; Segura, J; Suarez, C; García-Ortiz, L; Abad-Cardiel, M; Vigil, L; Gómez-Marcos, M A; Sans Atxer, L; Martell-Claros, N; Ruilope, L M; de la Sierra, A

    2016-03-01

    Arterial stiffness as assessed by carotid-femoral pulse wave velocity (cfPWV) is a marker of preclinical organ damage and a predictor of cardiovascular outcomes, independently of blood pressure (BP). However, limited evidence exists on the association between long-term variation (Δ) on aortic BP (aoBP) and ΔcfPWV. We aimed to evaluate the relationship of ΔBP with ΔcfPWV over time, as assessed by office and 24-h ambulatory peripheral BP, and aoBP. AoBP and cfPWV were evaluated in 209 hypertensive patients with either diabetes or metabolic syndrome by applanation tonometry (Sphygmocor) at baseline(b) and at 12 months of follow-up(fu). Peripheral BP was also determined by using validated oscillometric devices (office(o)-BP) and on an outpatient basis by using a validated (Spacelabs-90207) device (24-h ambulatory BP). ΔcfPWV over time was calculated as follows: ΔcfPWV=[(cfPWVfu-cfPWVb)/cfPWVb] × 100. ΔBP over time resulted from the same formula applied to BP values obtained with the three different measurement techniques. Correlations (Spearman 'Rho') between ΔBP and ΔcfPWV were calculated. Mean age was 62 years, 39% were female and 80% had type 2 diabetes. Baseline office brachial BP (mm Hg) was 143±20/82±12. Follow-up (12 months later) office brachial BP (mm Hg) was 136±20/79±12. ΔcfPWV correlated with ΔoSBP (Rho=0.212; P=0.002), Δ24-h SBP (Rho=0.254; P<0.001), Δdaytime SBP (Rho=0.232; P=0.001), Δnighttime SBP (Rho=0.320; P<0.001) and ΔaoSBP (Rho=0.320; P<0.001). A multiple linear regression analysis included the following independent variables: ΔoSBP, Δ24-h SBP, Δdaytime SBP, Δnighttime SBP and ΔaoSBP. ΔcfPWV was independently associated with Δ24-h SBP (β-coefficient=0.195; P=0.012) and ΔaoSBP (β-coefficient= 0.185; P=0.018). We conclude that changes in both 24-h SBP and aoSBP more accurately reflect changes in arterial stiffness than do office BP measurements.

  19. Achievement Goals and Achievement Emotions: A Meta-Analysis

    ERIC Educational Resources Information Center

    Huang, Chiungjung

    2011-01-01

    This meta-analysis synthesized 93 independent samples (N = 30,003) in 77 studies that reported in 78 articles examining correlations between achievement goals and achievement emotions. Achievement goals were meaningfully associated with different achievement emotions. The correlations of mastery and mastery approach goals with positive achievement…

  20. Protease-sensitive prions with 144-bp insertion mutations

    PubMed Central

    Puoti, Gianfranco; Yuan, Jue; Qing, Liuting; Wang, Heming; Kong, Qingzhong; Gambetti, Pierluigi; Zou, Wen-Quan

    2013-01-01

    Insertion of 144-base pair (bp) containing six extra octapeptide repeats between residues 51 and 91 of prion protein (PrP) gene is associated with inherited prion diseases. Most cases linked to this insertion examined by Western blotting showed detectable proteinase K-resistant PrPSc (rPrPSc) resembling PrPSc type 1 and type 2 in sporadic Creutzfeldt-Jakob disease (sCJD), or PrP7-8 in Gerstmann-Sträussler-Scheinker disease. However, cases lacking detectable rPrPSc also have been reported. Which PrP conformer is associated with neuropathological changes in the cases without detectable rPrPSc remains to be determined. Here we report that while all six but one subjects with the 144-bp insertion mutations examined display the pathognomonic PrP patches in the cerebellum, one of them exhibits no detectable typical rPrPSc even in PrPSc-enriched preparations. Instead, a large amount of abnormal PrP is captured from this case by gene 5 protein and sodium phosphotungstate, reagents that have been proved to specifically capture abnormal PrP. All captured abnormal PrP from the cerebellum and other brain regions is virtually sensitive to PK-digestion (termed sPrPSc). The presence of the predominant sPrPSc but absence of rPrPSc in this 144-bp insertion-linked inherited CJD case suggests that mutant sPrPSc is the main component of the PrP deposit patches and sPrPSc is sufficient to cause neurotoxicity and prion disease. PMID:23515139

  1. Feasibility study report for the 200-BP-1 operable unit

    SciTech Connect

    Not Available

    1993-06-01

    This feasibility study examines a range of alternatives and provides recommendations for selecting a preferred alternative for remediating contamination at the 200-BP-1 operable unit. The 200-BP-1 operable unit is located in the center of the Hanford Site along the northern boundary of the 200 East Area. The 241-BY Tank Farm is located immediately to the south of the operable unit. 200-BP-1 is a source operable unit with contaminated soils associated primarily with nine inactive cribs (known as the 216-B cribs). These cribs were used for disposal of low-level radioactive liquid waste from U Plant uranium recovery operations, and waste storage tank condensate from the adjacent 241-BY Tank Farm. The cribs used for disposal of U Plant waste were in operation from 1955--1965, and the cribs used for disposal of tank condensate were in operation from 1965--1975. In addition to the cribs, four unplanned releases of radioactive materials have occurred within the operable unit. Contaminated surface soils associated with the unplanned releases have been consolidated over the cribs and covered with clean soil to reduce contaminant migration and exposure. Discharge of wastes to the cribs has resulted in soil and groundwater contamination. The groundwater is being addressed as part of the 200 East Aggregate Area, groundwater operable unit. Contaminated soils at the site can be categorized by the types of contaminants, their distribution in the soil column, and the risk posed by the various potential exposure pathways. Below the clean soil cover, the near surface soils contain low-levels of contamination with cesium-137, radium-226, strontium-90, thorium-228, and uranium. The lifetime incremental cancer risk associated with these soils if they were exposed at the surface is 9{times}10{sup {minus}5}.

  2. Risk assessment of logistics outsourcing based on BP neural network

    NASA Astrophysics Data System (ADS)

    Liu, Xiaofeng; Tian, Zi-you

    The purpose of this article is to evaluate the risk of the enterprises logistics outsourcing. To get this goal, the paper first analysed he main risks existing in the logistics outsourcing, and then set up a risk evaluation index system of the logistics outsourcing; second applied BP neural network into the logistics outsourcing risk evaluation and used MATLAB to the simulation. It proved that the network error is small and has strong practicability. And this method can be used by enterprises to evaluate the risks of logistics outsourcing.

  3. Liver Protein Targets of Hepatotoxic 4-Bromophenol Metabolites

    PubMed Central

    Koen, Yakov M.; Hajovsky, Heather; Liu, Ke; Williams, Todd D.; Galeva, Nadezhda A.; Staudinger, Jeffrey L.; Hanzlik, Robert P.

    2012-01-01

    The hepatotoxicity of bromobenzene (BB) is directly related to the covalent binding of both initially formed epoxide and secondary quinone metabolites to at least 45 different liver proteins. 4-Bromophenol (4BP) is a significant BB metabolite and a precursor to reactive quinone metabolites, yet when administered exogenously it has negligible hepatotoxicity compared to BB. The protein adducts of 4BP were thus labeled as non-toxic (Monks, T. J.; Hinson, J. A.; Gillette, J. R. (1982) Life Sci. 30, 841–848). To help identify which BB-derived adducts might be related to its cytotoxicity, we sought to identify the supposedly non-toxic adducts of 4BP and eliminate them from the BB target protein list. Administration of [14C]-4BP to phenobarbital-induced rats resulted in covalent binding of 0.25, 0.33 and 0.42 nmol-eq 4BP/mg protein in the mitochondrial, microsomal and cytosolic fractions, respectively. These values may be compared to published values of 3–6 nmol/mg protein from a comparable dose of [14C]-BB. After subcellular fractionation and 2D electrophoresis, 47 radioactive spots on 2D gels of the mitochondrial, microsomal and cytosolic fractions were excised, digested and analyzed by LC-MS/MS. Twenty nine of these spots contained apparently single proteins, of which 14 were non-redundant. Nine of the 14 are known BB targets. Incubating freshly-isolated rat hepatocytes with 4BP (0.1–0.5 mM) produced time- and concentration-dependent increases in lactate dehydrogenase release and changes in cellular morphology. LC-MS/MS analysis of the cell culture medium revealed rapid and extensive sulfation and glucuronidation of 4BP as well as formation of a quinone-derived glutathione conjugate. Studies with 7-hydroxycoumarin (7HC), (−)-borneol or D-(+)-galactosamine (DGN) showed that inhibiting the glucuronidation/sulfation of 4BP increased the formation of a GSH-bromoquinone adduct, increased covalent binding of 4BP to hepatocyte proteins and potentiated its cytotoxicity

  4. Targeting drugs to mitochondria.

    PubMed

    Heller, Anne; Brockhoff, Gero; Goepferich, Achim

    2012-09-01

    Mitochondria are of an increasing interest in pharmaceutical and medical research since it has been reported that dysfunction of these organelles contributes to several diseases with a great diversity of clinical appearance. By the fact that mitochondria are located inside the cell and, in turn, origins of mitochondrial diseases or targets of drugs are located inside mitochondria, a drug molecule has to cross several barriers. This is a severe drawback for the selective accumulation of drug molecules in mitochondria. Therefore, targeting strategies such as direct drug modification or encapsulation into nanocarriers have to be applied to achieve an accumulation of drug molecules in these organelles. In this review, it will be demonstrated how properties and dysfunctions of mitochondria are generating a need for the development of mitochondria specific therapies. Furthermore, intracellular targets of mitochondrial diseases, strategies to utilize mitochondrial specificities and targeting approaches will be discussed. Finally, techniques to investigate mitochondrial characteristics and functionality are reviewed.

  5. 4E-BP2/SH2B1/IRS2 Are Part of a Novel Feedback Loop That Controls β-Cell Mass.

    PubMed

    Blandino-Rosano, Manuel; Scheys, Joshua O; Jimenez-Palomares, Margarita; Barbaresso, Rebecca; Bender, Aaron S; Yanagiya, Akiko; Liu, Ming; Rui, Liangyou; Sonenberg, Nahum; Bernal-Mizrachi, Ernesto

    2016-08-01

    The mammalian target of rapamycin complex 1 (mTORC1) regulates several biological processes, although the key downstream mechanisms responsible for these effects are poorly defined. Using mice with deletion of eukaryotic translation initiation factor 4E-binding protein 2 (4E-BP2), we determine that this downstream target is a major regulator of glucose homeostasis and β-cell mass, proliferation, and survival by increasing insulin receptor substrate 2 (IRS2) levels and identify a novel feedback mechanism by which mTORC1 signaling increases IRS2 levels. In this feedback loop, we show that 4E-BP2 deletion induces translation of the adaptor protein SH2B1 and promotes the formation of a complex with IRS2 and Janus kinase 2, preventing IRS2 ubiquitination. The changes in IRS2 levels result in increases in cell cycle progression, cell survival, and β-cell mass by increasing Akt signaling and reducing p27 levels. Importantly, 4E-BP2 deletion confers resistance to cytokine treatment in vitro. Our data identify SH2B1 as a major regulator of IRS2 stability, demonstrate a novel feedback mechanism linking mTORC1 signaling with IRS2, and identify 4E-BP2 as a major regulator of proliferation and survival of β-cells.

  6. 53BP1 mediates productive and mutagenic DNA repair through distinct phosphoprotein interactions.

    PubMed

    Callen, Elsa; Di Virgilio, Michela; Kruhlak, Michael J; Nieto-Soler, Maria; Wong, Nancy; Chen, Hua-Tang; Faryabi, Robert B; Polato, Federica; Santos, Margarida; Starnes, Linda M; Wesemann, Duane R; Lee, Ji-Eun; Tubbs, Anthony; Sleckman, Barry P; Daniel, Jeremy A; Ge, Kai; Alt, Frederick W; Fernandez-Capetillo, Oscar; Nussenzweig, Michel C; Nussenzweig, André

    2013-06-06

    The DNA damage response (DDR) protein 53BP1 protects DNA ends from excessive resection in G1, and thereby favors repair by nonhomologous end-joining (NHEJ) as opposed to homologous recombination (HR). During S phase, BRCA1 antagonizes 53BP1 to promote HR. The pro-NHEJ and antirecombinase functions of 53BP1 are mediated in part by RIF1, the only known factor that requires 53BP1 phosphorylation for its recruitment to double-strand breaks (DSBs). Here, we show that a 53BP1 phosphomutant, 53BP18A, comprising alanine substitutions of the eight most N-terminal S/TQ phosphorylation sites, mimics 53BP1 deficiency by restoring genome stability in BRCA1-deficient cells yet behaves like wild-type 53BP1 with respect to immunoglobulin class switch recombination (CSR). 53BP18A recruits RIF1 but fails to recruit the DDR protein PTIP to DSBs, and disruption of PTIP phenocopies 53BP18A. We conclude that 53BP1 promotes productive CSR and suppresses mutagenic DNA repair through distinct phosphodependent interactions with RIF1 and PTIP.

  7. Development of and assay methodology for antibodies to benzo(a) pyrene (BP)

    SciTech Connect

    Griffin, G.D.; Thomason, R.; Murchison, C.; St. Wecker, P.; Kurka, K.; Ambrose, K.R.

    1986-05-01

    Rabbits, rats and mice have been immunized with BP-bovine serum albumin (BSA) conjugates, administered subcutaneously in Freund's adjuvant. Activity and specificity of antisera preparations from immunized animals was determined by: Double immunodiffusion, passive hemagglutination, enzyme-linked immunosorbent assay (ELISA) and radioimmunoassay (RIA). All techniques could be successfully used to demonstrate the presence of BP antibodies in immune sera. The fist three assays were used only with BP antigen coupled to a protein. If BSA was used, cross-reactivity against BSA was observed, but differences in extent of reactivity toward BP-BSA and BSA were readily apparent. Antisera from highly immune animals showed anti-BP reactivity at 1-10 x 10/sup 6/ dilutions in the ELISA assay, but did not produce positive reactions in the passive hemagglutination assay at >1:256 dilutions. The RIA assay was used with either /sup 14/C-or /sup 3/H-BP, and relied upon an activated charcoal separation step to effectively remove (>98% efficiency) free BP from antibody-bound BP. Using this RIA assay, estimates of amounts of BP antibodies in antisera (0.1-1% of the immunoglobulin fraction) and antibody specificity for BP structural determinants could be made. These antibodies may form the basis for a novel detection system for BP and/or other polycyclic compounds.

  8. A Structure-Adaptive Hybrid RBF-BP Classifier with an Optimized Learning Strategy.

    PubMed

    Wen, Hui; Xie, Weixin; Pei, Jihong

    2016-01-01

    This paper presents a structure-adaptive hybrid RBF-BP (SAHRBF-BP) classifier with an optimized learning strategy. SAHRBF-BP is composed of a structure-adaptive RBF network and a BP network of cascade, where the number of RBF hidden nodes is adjusted adaptively according to the distribution of sample space, the adaptive RBF network is used for nonlinear kernel mapping and the BP network is used for nonlinear classification. The optimized learning strategy is as follows: firstly, a potential function is introduced into training sample space to adaptively determine the number of initial RBF hidden nodes and node parameters, and a form of heterogeneous samples repulsive force is designed to further optimize each generated RBF hidden node parameters, the optimized structure-adaptive RBF network is used for adaptively nonlinear mapping the sample space; then, according to the number of adaptively generated RBF hidden nodes, the number of subsequent BP input nodes can be determined, and the overall SAHRBF-BP classifier is built up; finally, different training sample sets are used to train the BP network parameters in SAHRBF-BP. Compared with other algorithms applied to different data sets, experiments show the superiority of SAHRBF-BP. Especially on most low dimensional and large number of data sets, the classification performance of SAHRBF-BP outperforms other training SLFNs algorithms.

  9. AMP-activated protein kinase phosphorylates CtBP1 and down-regulates its activity

    SciTech Connect

    Kim, Jae-Hwan; Choi, Soo-Youn; Kang, Byung-Hee; Lee, Soon-Min; Cho, Eun-Jung; Youn, Hong-Duk

    2013-02-01

    Highlights: ► AMPK phosphorylates CtBP1 on serine 158. ► AMPK-mediated phosphorylation of CtBP1 causes the ubiquitination and nuclear export of CtBP1. ► AMPK downregulates the CtBP1-mediated repression of Bax transcription. -- Abstract: CtBP is a transcriptional repressor which plays a significant role in the regulation of cell proliferation and tumor progression. It was reported that glucose withdrawal causes induction of Bax due to the dissociation of CtBP from the Bax promoter. However, the precise mechanism involved in the regulation of CtBP still remains unclear. In this study, we found that an activated AMP-activated protein kinase (AMPK) phosphorylates CtBP1 on Ser-158 upon metabolic stresses. Moreover, AMPK-mediated phosphorylation of CtBP1 (S158) attenuates the repressive function of CtBP1. We also confirmed that triggering activation of AMPK by various factors resulted in an increase of Bax gene expression. These findings provide connections of AMPK with CtBP1-mediated regulation of Bax expression for cell death under metabolic stresses.

  10. A Structure-Adaptive Hybrid RBF-BP Classifier with an Optimized Learning Strategy

    PubMed Central

    Wen, Hui; Xie, Weixin; Pei, Jihong

    2016-01-01

    This paper presents a structure-adaptive hybrid RBF-BP (SAHRBF-BP) classifier with an optimized learning strategy. SAHRBF-BP is composed of a structure-adaptive RBF network and a BP network of cascade, where the number of RBF hidden nodes is adjusted adaptively according to the distribution of sample space, the adaptive RBF network is used for nonlinear kernel mapping and the BP network is used for nonlinear classification. The optimized learning strategy is as follows: firstly, a potential function is introduced into training sample space to adaptively determine the number of initial RBF hidden nodes and node parameters, and a form of heterogeneous samples repulsive force is designed to further optimize each generated RBF hidden node parameters, the optimized structure-adaptive RBF network is used for adaptively nonlinear mapping the sample space; then, according to the number of adaptively generated RBF hidden nodes, the number of subsequent BP input nodes can be determined, and the overall SAHRBF-BP classifier is built up; finally, different training sample sets are used to train the BP network parameters in SAHRBF-BP. Compared with other algorithms applied to different data sets, experiments show the superiority of SAHRBF-BP. Especially on most low dimensional and large number of data sets, the classification performance of SAHRBF-BP outperforms other training SLFNs algorithms. PMID:27792737

  11. Hypertensive Target Organ Damage in Ghanaian Civil Servants with Hypertension

    PubMed Central

    Addo, Juliet; Smeeth, Liam; Leon, David A.

    2009-01-01

    Background Low levels of detection, treatment and control of hypertension have repeatedly been reported from sub Saharan Africa, potentially increasing the likelihood of target organ damage. Methods A cross-sectional study was conducted on 1015 urban civil servants aged≥25 years from seven central government ministries in Accra, Ghana. Participants diagnosed to have hypertension were examined for target organ involvement. Hypertensive target organ damage was defined as the detection of any of the following: left ventricular hypertrophy diagnosed by electrocardiogram, reduction in glomerular filtration rate, the presence of hypertensive retinopathy or a history of a stroke. Results Of the 219 hypertensive participants examined, 104 (47.5%) had evidence of target organ damage. The presence of target organ damage was associated with higher systolic and diastolic blood pressure levels. The odds of developing hypertensive target organ damage was five to six times higher in participants with blood pressure (BP)≥180/110 mmHg compared to those with BP<140/90 mmHg, and there was a trend to higher odds of target organ damage with increasing BP (p = 0.001). Women had about lower odds of developing target organ damage compared to men. Conclusions The high prevalence of target organ damage in this working population associated with increasing blood pressure, emphasises the need for hypertension control programs aimed at improving the detection of hypertension, and importantly addressing the issues inhibiting the effective treatment and control of people with hypertension in the population. PMID:19701488

  12. SPECTROPOLARIMETRY OF THE CLASSICAL T TAURI STAR BP TAU

    SciTech Connect

    Chen, Wei; Johns-Krull, Christopher M. E-mail: cmj@rice.edu

    2013-10-20

    We implement a least-squares deconvolution (LSD) code to study magnetic fields on cool stars. We first apply our code to high-resolution optical echelle spectra of 53 Cam (a magnetic Ap star) and three well-studied cool stars (Arcturus, 61 Cyg A, and ξ Boo A) as well as the Sun (by observing the asteroid Vesta) as tests of the code and the instrumentation. Our analysis is based on several hundred photospheric lines spanning the wavelength range 5000 Å to 9000 Å. We then apply our LSD code to six nights of data on the Classical T Tauri Star BP Tau. A maximum longitudinal field of 370 ± 80 G is detected from the photospheric lines on BP Tau. A 1.8 kG dipole tilted at 129° with respect to the rotation axis and a 1.4 kG octupole tilted at 104° with respect to the rotation axis, both with a filling factor of 0.25, best fit our LSD Stokes V profiles. Measurements of several emission lines (He I 5876 Å, Ca II 8498 Å, and 8542 Å) show the presence of strong magnetic fields in the line formation regions of these lines, which are believed to be the base of the accretion footpoints. The field strength measured from these lines shows night-to-night variability consistent with rotation of the star.

  13. Spectropolarimetry of the Classical T Tauri Star BP Tau

    NASA Astrophysics Data System (ADS)

    Chen, Wei; Johns-Krull, Christopher M.

    2013-10-01

    We implement a least-squares deconvolution (LSD) code to study magnetic fields on cool stars. We first apply our code to high-resolution optical echelle spectra of 53 Cam (a magnetic Ap star) and three well-studied cool stars (Arcturus, 61 Cyg A, and ξ Boo A) as well as the Sun (by observing the asteroid Vesta) as tests of the code and the instrumentation. Our analysis is based on several hundred photospheric lines spanning the wavelength range 5000 Å to 9000 Å. We then apply our LSD code to six nights of data on the Classical T Tauri Star BP Tau. A maximum longitudinal field of 370 ± 80 G is detected from the photospheric lines on BP Tau. A 1.8 kG dipole tilted at 129° with respect to the rotation axis and a 1.4 kG octupole tilted at 104° with respect to the rotation axis, both with a filling factor of 0.25, best fit our LSD Stokes V profiles. Measurements of several emission lines (He I 5876 Å, Ca II 8498 Å, and 8542 Å) show the presence of strong magnetic fields in the line formation regions of these lines, which are believed to be the base of the accretion footpoints. The field strength measured from these lines shows night-to-night variability consistent with rotation of the star.

  14. Research on PGNAA adaptive analysis method with BP neural network

    NASA Astrophysics Data System (ADS)

    Peng, Ke-Xin; Yang, Jian-Bo; Tuo, Xian-Guo; Du, Hua; Zhang, Rui-Xue

    2016-11-01

    A new approach method to dealing with the puzzle of spectral analysis in prompt gamma neutron activation analysis (PGNAA) is developed and demonstrated. It consists of utilizing BP neural network to PGNAA energy spectrum analysis which is based on Monte Carlo (MC) simulation, the main tasks which we will accomplish as follows: (1) Completing the MC simulation of PGNAA spectrum library, we respectively set mass fractions of element Si, Ca, Fe from 0.00 to 0.45 with a step of 0.05 and each sample is simulated using MCNP. (2) Establishing the BP model of adaptive quantitative analysis of PGNAA energy spectrum, we calculate peak areas of eight characteristic gamma rays that respectively correspond to eight elements in each individual of 1000 samples and that of the standard sample. (3) Verifying the viability of quantitative analysis of the adaptive algorithm where 68 samples were used successively. Results show that the precision when using neural network to calculate the content of each element is significantly higher than the MCLLS.

  15. Target Homework to Maximize Learning

    ERIC Educational Resources Information Center

    Heitzmann, Ray

    2007-01-01

    Targeted homework is based upon the belief that homework can make a significant contribution to student achievement in the areas of knowledge, skills, and values. It centers on the notion that homework achieves maximum effectiveness when teachers share the school's homework policy as well as their policy with students and parents or guardians. The…

  16. LIQUID TARGET

    DOEpatents

    Martin, M.D.; Salsig, W.W. Jr.

    1959-01-13

    A liquid handling apparatus is presented for a liquid material which is to be irradiated. The apparatus consists essentially of a reservoir for the liquid, a target element, a drain tank and a drain lock chamber. The target is in the form of a looped tube, the upper end of which is adapted to be disposed in a beam of atomic particles. The lower end of the target tube is in communication with the liquid in the reservoir and a means is provided to continuously circulate the liquid material to be irradiated through the target tube. Means to heat the reservoir tank is provided in the event that a metal is to be used as the target material. The apparatus is provided with suitable valves and shielding to provide maximum safety in operation.

  17. Regulation of the DNA Damage Response and Gene Expression by the Dot1L Histone Methyltransferase and the 53Bp1 Tumour Suppressor

    PubMed Central

    FitzGerald, Jennifer; Moureau, Sylvie; Drogaris, Paul; O'Connell, Enda; Abshiru, Nebiyu; Verreault, Alain; Thibault, Pierre; Grenon, Muriel; Lowndes, Noel F.

    2011-01-01

    Background Dot1L, a histone methyltransferase that targets histone H3 lysine 79 (H3K79), has been implicated in gene regulation and the DNA damage response although its functions in these processes remain poorly defined. Methodology/Principal Findings Using the chicken DT40 model system, we generated cells in which the Dot1L gene is disrupted to examine the function and focal recruitment of the 53Bp1 DNA damage response protein. Detailed kinetic and dose response assays demonstrate that, despite the absence of H3K79 methylation demonstrated by mass spectrometry, 53Bp1 focal recruitment is not compromised in these cells. We also describe, for the first time, the phenotypes of a cell line lacking both Dot1L and 53Bp1. Dot1L−/− and wild type cells are equally resistant to ionising radiation, whereas 53Bp1−/−/Dot1L−/− cells display a striking DNA damage resistance phenotype. Dot1L and 53Bp1 also affect the expression of many genes. Loss of Dot1L activity dramatically alters the mRNA levels of over 1200 genes involved in diverse biological functions. These results, combined with the previously reported list of differentially expressed genes in mouse ES cells knocked down for Dot1L, demonstrates surprising cell type and species conservation of Dot1L-dependent gene expression. In 53Bp1−/− cells, over 300 genes, many with functions in immune responses and apoptosis, were differentially expressed. To date, this is the first global analysis of gene expression in a 53Bp1-deficient cell line. Conclusions/Significance Taken together, our results uncover a negative role for Dot1L and H3K79 methylation in the DNA damage response in the absence of 53Bp1. They also enlighten the roles of Dot1L and 53Bp1 in gene expression and the control of DNA double-strand repair pathways in the context of chromatin. PMID:21383990

  18. Targeted Support

    ERIC Educational Resources Information Center

    Simon, Gabe

    2011-01-01

    Heritage Oak Elementary School (Placer County, CA) has continuously achieved a high level of academic success as measured by the California Standards Test. However, after examining student testing data in depth, staff discovered a large achievement gap between the overall school population, socio-economically disadvantaged students, and students…

  19. Central Tropical Pacific Corals Reveal Reduced ENSO Variability 3-5kyBP

    NASA Astrophysics Data System (ADS)

    Grothe, P. R.; Cobb, K. M.; Liguori, G.; Edwards, R. L.; Cheng, H.; Deocampo, D.; Southon, J. R.; Santos, G.; Lu, Y.; Capotondi, A.; Di Lorenzo, E.

    2015-12-01

    Future projections of the strength of the El Niño-Southern Oscillation (ENSO), the largest source of year-to-year global climate extremes, are highly uncertain. Potential shifts towards stronger and more frequent ENSO extremes (Cai et al., 2014; Kim et al., 2015) would have a profound effect on climate globally. However, the instrumental record of ENSO activity is too short in time to resolve potential anthropogenic trends in ENSO properties, and limits our understanding of the ENSO phenomenon. Thus, we must rely on high-resolution paleoclimate reconstructions of ENSO that extend through the last centuries to millennia to provide a comprehensive view of ENSO variability. Coral δ18O records from the heart of the ENSO region, in the central tropical Pacific, provide monthly-resolved reconstructions of ENSO activity over the last 7000 years. Here, we quantify ENSO variability in 10 new monthly-resolved fossil coral δ18O records from Kiritimati Island (2°N, 157°W) that are U/Th-dated to the 2-6kyBP interval. When combined with previously published coral δ18O records from Cobb et al., 2013, the new coral δ18O records support a prolonged reduction of ~60% in ENSO variability during the 3-5kyBP interval, as compared to the late 20th century. In comparison, ENSO variability during the last millennium was ~30% reduced compared to the late 20th century. These results are consistent with foraminifera and mollusk records from the eastern tropical Pacific (Koutavas and Joanides, 2012; Carre et al., 2014), implying that the observed 3-5kyBP reduction in ENSO variability was not confined to the central Pacific. Taken together, these new records represent a new target - both in terms of amplitude and timing - for modeling efforts designed to uncover the mechanisms governing past ENSO variability. Such data-model comparisons are critical to refining the simulation of ENSO in simulations of future climate change.

  20. Polycomb silencing of the Drosophila 4E-BP gene regulates imaginal disc cell growth

    PubMed Central

    Mason-Suares, Heather; Tie, Feng; Yan, Christopher; Harte, Peter J.

    2015-01-01

    Polycomb group (PcG) proteins are best known for their role in maintaining stable, mitotically heritable silencing of the homeotic (HOX) genes during development. In addition to loss of homeotic gene silencing, some PcG mutants also have small imaginal discs. These include mutations in E(z), Su(z)12, esc and escl, which encode Polycomb Repressive Complex 2 (PRC2) subunits. The cause of this phenotype is not known, but the human homologs of PRC2 subunits have been shown to play a role in cell proliferation, are over-expressed in many tumors, and appear to be required for tumor proliferation. Here we show that the small imaginal disc phenotype arises, at least in part, from a cell growth defect. In homozygous E(z) mutants, imaginal disc cells are smaller than cells in normally proliferating discs. We show that the Thor gene, which encodes eIF4E-Binding Protein (4E-BP), the evolutionarily conserved inhibitor of cap-dependent translation and potent inhibitor of cell growth, is involved in the development of this phenotype. The Thor promoter region contains DNA binding motifs for transcription factors found in well-characterized Polycomb Response Elements (PREs), including PHO/PHOL, GAGA Factor, and others, suggesting that Thor may be a direct target of Polycomb silencing. We present chromatin immunoprecipitation evidence that PcG proteins are bound to the Thor 5’ region in vivo. The Thor gene is normally repressed in imaginal discs, but Thor mRNA and 4E-BP protein levels are elevated in imaginal discs of PRC2 subunit mutant larvae. Deletion of the Thor gene in E(z) mutants partially restores imaginal disc size toward wild-type and results in an increase in the fraction of larvae that pupariate. These results thus suggest that PcG proteins can directly modulate cell growth in Drosophila, in part by regulating Thor expression. PMID:23523430

  1. Sab (SH3BP5), a novel mitochondria-localized JNK-interacting protein.

    PubMed

    Wiltshire, C; Gillespie, D A F; May, G H W

    2004-12-01

    The JNK (c-Jun N-terminal kinase) pathway is activated by diverse stresses and can have an effect on a number of different cellular processes. Protein-protein interactions are critical for efficient signalling from JNK to multiple targets; through a screen for interacting proteins, we identified a novel JNK-interacting protein, Sab (SH3BP5). Sab has previously been found to interact with the Src homology 3 domain of Bruton's tyrosine kinase; however, the interaction with JNK occurs through a mitogen-activated protein KIM (kinase interaction motif) in a region distinct from the Bruton's tyrosine kinase-binding domain. As with c-Jun, the presence of this KIM is essential for Sab to act as a JNK substrate. Interestingly, Sab is associated with the mitochondria and co-localizes with a portion of active JNK after stress treatment. The present study and previously reported work may suggest a possible role for Sab in targeting JNK to this subcellular compartment and/or mediating crosstalk between different signal-transduction pathways.

  2. Recurrent 15q11.2 BP1-BP2 microdeletions and microduplications in the etiology of neurodevelopmental disorders.

    PubMed

    Picinelli, Chiara; Lintas, Carla; Piras, Ignazio Stefano; Gabriele, Stefano; Sacco, Roberto; Brogna, Claudia; Persico, Antonio Maria

    2016-12-01

    Rare and common CNVs can contribute to the etiology of neurodevelopmental disorders. One of the recurrent genomic aberrations associated with these phenotypes and proposed as a susceptibility locus is the 15q11.2 BP1-BP2 CNV encompassing TUBGCP5, CYFIP1, NIPA2, and NIPA1. Characterizing by array-CGH a cohort of 243 families with various neurodevelopmental disorders, we identified five patients carrying the 15q11.2 duplication and one carrying the deletion. All CNVs were confirmed by qPCR and were inherited, except for one duplication where parents were not available. The phenotypic spectrum of CNV carriers was broad but mainly neurodevelopmental, in line with all four genes being implicated in axonal growth and neural connectivity. Phenotypically normal and mildly affected carriers complicate the interpretation of this aberration. This variability may be due to reduced penetrance or altered gene dosage on a particular genetic background. We evaluated the expression levels of the four genes in peripheral blood RNA and found the expected reduction in the deleted case, while duplicated carriers displayed high interindividual variability. These data suggest that differential expression of these genes could partially account for differences in clinical phenotypes, especially among duplication carriers. Furthermore, urinary Mg(2+) levels appear negatively correlated with NIPA2 gene copy number, suggesting they could potentially represent a useful biomarker, whose reliability will need replication in larger samples. © 2016 Wiley Periodicals, Inc.

  3. An Analysis of the Rapidly Rotating Bp star HD 133880

    NASA Technical Reports Server (NTRS)

    Bailey, J. D.; Grunhut, J.; Shultz, M.; Wade, G.; Landstreet, J. D.; Bohlender, D.; Lim, J.; Wong, K.; Drake, S.; Linsky, J.

    2012-01-01

    HD 133880 is a rapidly rotating chemically peculiar B-type (Bp) star (nu sin i approx = 103km/s) and is host to one of the strongest magnetic fields of any Ap/Bp star. A member of the Upper Centaurus Lupus association, it is a star with a well-determined age of 16 Myr. 12 new spectra, four of which are polarimetric, obtained from the FEROS, ESPaDOnS and HARPS instruments, provide sufficient material from which to re-evaluate the magnetic field and obtain a first approximation to the atmospheric abundance distributions of He, O, Mg, Si, Ti. Cr, Fe, Ni, Pr and Nd. An abundance analysis was carried out using ZEEMAN, a program which synthesizes spectral line profiles for stars with permeating magnetic fields. The magnetic field structure was characterized by a colinear multipole expansion from the observed variations of the longitudinal and surface fields with rotational phase. Both magnetic hemispheres are clearly visible during the stellar rotation, and thus a three-ring abundance distribution model encompassing both magnetic poles and magnetic equator with equal spans in colatitude was adopted. Using the new magnetic field measurements and optical photometry together with previously published data, we refine the period of HD 133880 to P = 0.877 476 +/- 0.000009 d. Our simple axisymmetric magnetic field model is based on a predominantly quadrupolar component that roughly describes the field variations. Using spectrum synthesis, we derived mean abundances for O, Mg, Si, Ti, Cr, Fe and Pr. All elements; except Mg, are overabundant compared to the Son. Mg appears to be approximately uniform over the stellar surface, while all other elements are more abundant in the negative magnetic hemisphere than in the positive magnetic hemisphere. In contrast to most Ap/Bp stars which show an underabundance in 0, in HD 133880 this element is clearly overabundant compared to the solar abundance ratio. In studying the Ha and Paschen lines in the optical spectra, we could not

  4. Lifting Minority Achievement: Complex Answers. The Achievement Gap.

    ERIC Educational Resources Information Center

    Viadero, Debra; Johnston, Robert C.

    2000-01-01

    This fourth in a four-part series on why academic achievement gaps exist describes the Minority Achievement Committee scholars program at Shaker Heights High School in Cleveland, Ohio, a powerful antidote to the achievement gap between minority and white and Asian American students. It explains the need to break down stereotypes about academic…

  5. Achievement Motivation of Women: Effects of Achievement and Affiliation Arousal.

    ERIC Educational Resources Information Center

    Gama, Elizabeth Maria Pinheiro

    1985-01-01

    Assigned 139 Brazilian women to neutral, affiliation arousal, and achievement arousal conditions based on their levels of achievement (Ach) and affiliative (Aff) needs. Results of story analyses revealed that achievement arousal increased scores of high Ach subjects and that high Aff subjects obtained higher scores than low Aff subjects. (BL)

  6. Attitude Towards Physics and Additional Mathematics Achievement Towards Physics Achievement

    ERIC Educational Resources Information Center

    Veloo, Arsaythamby; Nor, Rahimah; Khalid, Rozalina

    2015-01-01

    The purpose of this research is to identify the difference in students' attitude towards Physics and Additional Mathematics achievement based on gender and relationship between attitudinal variables towards Physics and Additional Mathematics achievement with achievement in Physics. This research focused on six variables, which is attitude towards…

  7. The Impact of Reading Achievement on Overall Academic Achievement

    ERIC Educational Resources Information Center

    Churchwell, Dawn Earheart

    2009-01-01

    This study examined the relationship between reading achievement and achievement in other subject areas. The purpose of this study was to determine if there was a correlation between reading scores as measured by the Standardized Test for the Assessment of Reading (STAR) and academic achievement in language arts, math, science, and social studies…

  8. BRCA1 Directs the Repair Pathway to Homologous Recombination by Promoting 53BP1 Dephosphorylation.

    PubMed

    Isono, Mayu; Niimi, Atsuko; Oike, Takahiro; Hagiwara, Yoshihiko; Sato, Hiro; Sekine, Ryota; Yoshida, Yukari; Isobe, Shin-Ya; Obuse, Chikashi; Nishi, Ryotaro; Petricci, Elena; Nakada, Shinichiro; Nakano, Takashi; Shibata, Atsushi

    2017-01-10

    BRCA1 promotes homologous recombination (HR) by activating DNA-end resection. By contrast, 53BP1 forms a barrier that inhibits DNA-end resection. Here, we show that BRCA1 promotes DNA-end resection by relieving the 53BP1-dependent barrier. We show that 53BP1 is phosphorylated by ATM in S/G2 phase, promoting RIF1 recruitment, which inhibits resection. 53BP1 is promptly dephosphorylated and RIF1 released, despite remaining unrepaired DNA double-strand breaks (DSBs). When resection is impaired by CtIP/MRE11 endonuclease inhibition, 53BP1 phosphorylation and RIF1 are sustained due to ongoing ATM signaling. BRCA1 depletion also sustains 53BP1 phosphorylation and RIF1 recruitment. We identify the phosphatase PP4C as having a major role in 53BP1 dephosphorylation and RIF1 release. BRCA1 or PP4C depletion impairs 53BP1 repositioning, EXO1 recruitment, and HR progression. 53BP1 or RIF1 depletion restores resection, RAD51 loading, and HR in PP4C-depleted cells. Our findings suggest that BRCA1 promotes PP4C-dependent 53BP1 dephosphorylation and RIF1 release, directing repair toward HR.

  9. Role of the Bp35 cell surface polypeptide in human B-cell activation.

    PubMed Central

    Clark, E A; Shu, G; Ledbetter, J A

    1985-01-01

    A 35-kDa polypeptide, Bp35, expressed on the surface of all B cells, plays a role in B-cell activation. Monoclonal antibodies to Bp35 stimulate human tonsillar B cells to proliferate. The activation induced by anti-Bp35 is similar to anti-Ig-mediated in several ways: the activation does not require T cells but is augmented by T-cell-derived allogeneic factors; monovalent Fab fragments to Bp35 do not trigger proliferation but instead block activation by whole antibody, indicating that cross-linking is required; and induction by anti-Bp35, like the induction by anti-Ig, is inhibited by monoclonal anti-IgM via an Fc domain-dependent mechanism. However, several features of anti-Bp35-mediated proliferation are clearly different from activation by anti-Ig: anti-Bp35 monoclonal antibodies do not require attachment to beads to function, the proliferation induced by anti-Bp35 and anti-Ig is additive, and Fab fragments of anti-Bp35 augment proliferation induced by anti-Ig. Models for the possible function of the Bp35 polypeptide as either a "bridge" or a "second signal" with surface Ig in B-cell activation are discussed. PMID:3872456

  10. Mitochondria: 3-bromopyruvate vs. mitochondria? A small molecule that attacks tumors by targeting their bioenergetic diversity.

    PubMed

    Galina, Antonio

    2014-09-01

    Enhanced glycolysis, the classic bioenergetic phenotype of cancer cells was described by Otto Warburg approximately 90 years ago. However, the Warburg hypothesis does not necessarily imply mitochondrial dysfunction. The alkyl-halogen, 3-bromopyruvate (3BP), would not be expected to have selective targets for cancer therapy due to its high potential reactivity toward many SH side groups. Contrary to predictions, 3BP interferes with glycolysis and oxidative phosphorylation in cancer cells without side effects in normal tissues. The mitochondrial hexokinase II has been claimed as the main target. This "Organelle in focus" article presents a historical view of the use of 3BP in biochemistry and its effects on ATP-producing pathways of cancer cells. I will discuss how the alkylated enzymes contribute to the cooperative collapse of mitochondria and apoptosis. Perspectives for targeting 3BP to bioenergetics enzymes for cancer treatment will be considered.

  11. Identify Melatonin as a Novel Therapeutic Reagent in the Treatment of 1-Bromopropane(1-BP) Intoxication

    PubMed Central

    Xu, Yongpeng; Wang, Shuo; Jiang, Lulu; Wang, Hui; Yang, Yilin; Li, Ming; Wang, Xujing; Zhao, Xiulan; Xie, Keqin

    2016-01-01

    Abstract 1-Bromopropane (1-BP) has been used as an alternative for fluoride compounds and 1-BP intoxication may involve lung, liver, and central neural system (CNS). Our previous studies showed that 1-BP impaired memory ability by compromising antioxidant cellular defenses. Melatonin is a powerful endogenous antioxidant, and the objective of this study was to explore the therapeutic role of melatonin in the treatment of 1-BP intoxication. Rats were intragastrically treated with 1-BP with or without melatonin, and then sacrificed on 27th day after 1-BP administration. The Morris water maze (MWM) test was used to evaluate the spatial learning and memory ability of the experimental animals, and NeuN staining was performed to assess neuron loss in hippocampus. We found that rats treated with 1-BP spent more time and swam longer distance before landing on the hidden platform with a comparable swimming speed, which was markedly mitigated by the pretreatment with melatonin in a concentration-dependent manner. In addition, 1-BP-induced notable decrease in neuron population in hippocampus by promoting apoptosis, and melatonin pretreatment attenuated those changes in brain. The GSH/GSSG ratio was proportionately decreased and heme oxygenase 1 was increased in the rats exposed to 1-BP (Figure 6), and administration of melatonin restored them. Meanwhile, MDA, the level of lipid peroxidation product, was significantly increased upon exposed to 1-BP, which was significantly attenuated by melatonin pretreatment, indicating that administration of 1-BP could interfere with redox homeostasis of brain in rat, and such 1-BP-induced biomedical changes were reversed by treatment with melatonin. We conclude that treatment with melatonin attenuates 1-BP-induced CNS toxicity through its ROS scavenging effect. PMID:26817862

  12. Identify Melatonin as a Novel Therapeutic Reagent in the Treatment of 1-Bromopropane(1-BP) Intoxication.

    PubMed

    Xu, Yongpeng; Wang, Shuo; Jiang, Lulu; Wang, Hui; Yang, Yilin; Li, Ming; Wang, Xujing; Zhao, Xiulan; Xie, Keqin

    2016-01-01

    1-Bromopropane (1-BP) has been used as an alternative for fluoride compounds and 1-BP intoxication may involve lung, liver, and central neural system (CNS). Our previous studies showed that 1-BP impaired memory ability by compromising antioxidant cellular defenses. Melatonin is a powerful endogenousantioxidant, and the objective of this study was to explore the therapeutic role of melatonin in the treatment of 1-BP intoxication. Rats were intragastrically treated with 1-BP with or without melatonin, and then sacrificed on 27th day after 1-BP administration. The Morris water maze (MWM) test was used to evaluate the spatial learning and memory ability of the experimental animals, and NeuN staining was performed to assess neuron loss in hippocampus. We found that rats treated with 1-BP spent more time and swam longer distance before landing on the hidden platform with a comparable swimming speed, which was markedly mitigated by the pretreatment with melatonin in a concentration-dependent manner. In addition, 1-BP-induced notable decrease in neuron population in hippocampus by promoting apoptosis, and melatonin pretreatment attenuated those changes in brain. The GSH/GSSG ratio was proportionately decreased and heme oxygenase 1 was increased in the rats exposed to 1-BP (Figure 6), and administration of melatonin restored them. Meanwhile, MDA, the level of lipid peroxidation product, was significantly increased upon exposed to 1-BP, which was significantly attenuated by melatonin pretreatment, indicating that administration of 1-BP could interfere with redox homeostasis of brain in rat, and such 1-BP-induced biomedical changes were reversed by treatment with melatonin.We conclude that treatment with melatonin attenuates 1-BP-induced CNS toxicity through its ROS scavenging effect.

  13. The Translational Repressor 4E-BP1 Contributes to Diabetes-Induced Visual Dysfunction

    PubMed Central

    Miller, William P.; Mihailescu, Maria L.; Yang, Chen; Barber, Alistair J.; Kimball, Scot R.; Jefferson, Leonard S.; Dennis, Michael D.

    2016-01-01

    Purpose The translational repressor 4E-BP1 interacts with the mRNA cap-binding protein eIF4E and thereby promotes cap-independent translation of mRNAs encoding proteins that contribute to diabetic retinopathy. Interaction of 4E-BP1 with eIF4E is enhanced in the retina of diabetic rodents, at least in part, as a result of elevated 4E-BP1 protein expression. In the present study, we examined the role of 4E-BP1 in diabetes-induced visual dysfunction, as well as the mechanism whereby hyperglycemia promotes 4E-BP1 expression. Methods Nondiabetic and diabetic wild-type and 4E-BP1/2 knockout mice were evaluated for visual function using a virtual optomotor test (Optomotry). Retinas were harvested from nondiabetic and type 1 diabetic mice and analyzed for protein abundance and posttranslational modifications. Similar analyses were performed on cells in culture exposed to hyperglycemic conditions or an O-GlcNAcase inhibitor (Thiamet G [TMG]). Results Diabetes-induced visual dysfunction was delayed in mice deficient of 4E-BP1/2 as compared to controls. 4E-BP1 protein expression was enhanced by hyperglycemia in the retina of diabetic rodents and by hyperglycemic conditions in retinal cells in culture. A similar elevation in 4E-BP1 expression was observed with TMG. The rate of 4E-BP1 degradation was significantly prolonged by either hyperglycemic conditions or TMG. A PEST motif in the C-terminus of 4E-BP1 regulated polyubiquitination, turnover, and binding of an E3 ubiquitin ligase complex containing CUL3. Conclusions The findings support a model whereby elevated 4E-BP1 expression observed in the retina of diabetic rodents is the result of O-GlcNAcylation of 4E-BP1 within its PEST motif. PMID:26998719

  14. Blood pressure goal achievement with olmesartan medoxomil-based treatment: additional analysis of the OLMEBEST study

    PubMed Central

    Barrios, Vivencio; Escobar, Carlos; Calderon, Alberto; Böhm, Michael

    2009-01-01

    Aims Guidelines recommend blood pressure (BP) in hypertensive patients should be <140 systolic BP (SBP) and <90 diastolic BP (DBP) mmHg. This analysis assessed goal rate achievement in hypertensive patients receiving olmesartan-based treatment in the OLMEBEST study. Methods Patients with essential hypertension (DBP ≥ 90 mmHg and <110 mmHg) received open-label olmesartan medoxomil 20 mg/day (n = 2306). After 8 weeks, patients with DBP ≥ 90 mmHg (n = 627) were randomized to 4 weeks’ double-blind treatment with olmesartan 40 mg/day monotherapy or olmesartan 20 mg/day plus hydrochlorothiazide (HCTZ) 12.5 mg/day. For this analysis, the numbers and proportions of patients who achieved SBP < 140 mmHg and/or DBP < 90 mmHg at the end of the 4 weeks were calculated. Results In patients who achieved DBP normalization (<90 mmHg) at week 8 (n = 1546) and continued open-label olmesartan 20 mg/day, 66.7% achieved SBP/DBP < 140/90 mmHg at Week 12. In patients who did not achieve DBP normalization at Week 8, 26.8% of those randomized to olmesartan 40 mg/day and 42.5% of those randomized to olmesartan 20 mg/day plus HCTZ 12.5 mg/day achieved a SBP/DBP < 140/90 mmHg at Week 12. Conclusion Olmesartan 40 mg/day and olmesartan 20 mg/day plus HCTZ 12.5 mg/day allow substantial proportions of patients to achieve BP goals. PMID:19756164

  15. Improving Secondary School Students' Achievement using Intrinsic Motivation

    ERIC Educational Resources Information Center

    Albrecht, Erik; Haapanen, Rebecca; Hall, Erin; Mantonya, Michelle

    2009-01-01

    This report describes a program for increasing students' intrinsic motivation in an effort to increase academic achievement. The targeted population consisted of secondary level students in a middle to upper-middle class suburban area. The students of the targeted secondary level classes appeared to be disengaged from learning due to a lack of…

  16. An Action Plan for Improving Mediocre or Stagnant Student Achievement

    ERIC Educational Resources Information Center

    Redmond, Kimberley B.

    2013-01-01

    Although all of the schools in the target school system adhere to a school improvement process, achievement scores remain mediocre or stagnant within the overseas school in Italy that serves children of United States armed service members. To address this problem, this study explored the target school's improvement process to discover how…

  17. Characterization of the Particulate Emissions from the BP ...

    EPA Pesticide Factsheets

    Opportunistic particle samples were gathered from the sail of a tethered aerostat during at-sea plume sampling of the purposely-burned surface oil during the BP Deepwater Horizon disaster in the Gulf of Mexico. Particles were analyzed for polycyclic aromatic hydrocarbons (PAHs), organic carbon (OC), elemental carbon (EC), metals, and polychlorinated dibenzodioxins/dibenzofurans (PCDDs/PCDFs). Emission factors were calculated using previous sampling values of background-adjusted CO2 and particulate matter (PM)-bound C. The mean of five thermal-optical analyses indicated that the burned crude oil particulate matter was 93% carbon (w/w) with the predominance being refractory elemental carbon (82% w/w) on average. PAHs accounted for roughly 60 ug/g of the PM mass or 4.5 mg/kg oil burned, at least an order of magnitude less than earlier laboratory based studies. Microscopy indicates that the soot from the in situ oil burns is distinct from more common soot by its aggregate size, primary particle size, and nanostructure within the primary particles. The PCDD/PCDF concentration of the PM was 1.5 to 3.3 ng toxic equivalency (TEQ)/kg PM sampled, about 10-fold lower than from a previous dedicated gas/solid sample, indicating loss of small particle-bound and more volatile PCDD/PCDF congeners through the aerostat sail. This work presents an analysis of smoke particles opportunistically caught during the in situ surface oil burns during the 2010 BP Deepwater Horizon di

  18. Achievements in Stratospheric Ozone Protection

    EPA Pesticide Factsheets

    This report describes achievements in protecting the ozone layer, the benefits of these achievements, and strategies involved (e.g., using alternatives to ozone-depleting substances, phasing out harmful substances, and creating partnerships).

  19. Icariside II, a natural mTOR inhibitor, disrupts aberrant energy homeostasis via suppressing mTORC1-4E-BP1 axis in sarcoma cells

    PubMed Central

    Zhang, Chao; Yang, Lei; Geng, Ya-di; An, Fa-liang; Xia, Yuan-zheng; Guo, Chao; Luo, Jian-guang; Zhang, Lu-yong; Guo, Qing-long; Kong, Ling-yi

    2016-01-01

    The aberrant energy homeostasis that characterized by high rate of energy production (glycolysis) and energy consumption (mRNA translation) is associated with the development of cancer. As mammalian target of rapamycin (mTOR) is a critical regulator of aberrant energy homeostasis, it is an attractive target for anti-tumor intervention. The flavonoid compound Icariside II (IS) is a natural mTOR inhibitor derived from Epimedium. Koreanum. Herein, we evaluate the effect of IS on aberrant energy homeostasis. The reduction of glycolysis and mRNA translation in U2OS (osteosarcoma), S180 (fibrosarcoma) and SW1535 (chondrosarcoma) cells observed in our study, indicate that, IS inhibits aberrant energy homeostasis. This inhibition is found to be due to suppression of mammalian target of rapamycin complex 1 (mTORC1)-eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) axis through blocking the assembly of mTORC1. Furthermore, IS inhibits the cap-dependent translation of c-myc through mTORC1-4E-BP1 axis which links the relationship between mRNA translation and glycolysis. Inhibition of aberrant energy homeostasis by IS, contributes to its in vitro and in vivo anti-proliferation activity. These data indicate that IS disrupts aberrant energy homeostasis of sarcoma cells through suppression of mTORC1-4E-BP1 axis, providing a novel mechanism of IS to inhibit cell proliferation in sarcoma cells. PMID:27056897

  20. Lamin A/C-dependent interaction with 53BP1 promotes cellular responses to DNA damage

    PubMed Central

    Gibbs-Seymour, Ian; Markiewicz, Ewa; Bekker-Jensen, Simon; Mailand, Niels; Hutchison, Christopher J

    2015-01-01

    Lamins A/C have been implicated in DNA damage response pathways. We show that the DNA repair protein 53BP1 is a lamin A/C binding protein. In undamaged human dermal fibroblasts (HDF), 53BP1 is a nucleoskeleton protein. 53BP1 binds to lamins A/C via its Tudor domain, and this is abrogated by DNA damage. Lamins A/C regulate 53BP1 levels and consequently lamin A/C-null HDF display a 53BP1 null-like phenotype. Our data favour a model in which lamins A/C maintain a nucleoplasmic pool of 53BP1 in order to facilitate its rapid recruitment to sites of DNA damage and could explain why an absence of lamin A/C accelerates aging. PMID:25645366

  1. Students’ Achievement Goals, Learning-Related Emotions and Academic Achievement

    PubMed Central

    Lüftenegger, Marko; Klug, Julia; Harrer, Katharina; Langer, Marie; Spiel, Christiane; Schober, Barbara

    2016-01-01

    In the present research, the recently proposed 3 × 2 model of achievement goals is tested and associations with achievement emotions and their joint influence on academic achievement are investigated. The study was conducted with 388 students using the 3 × 2 Achievement Goal Questionnaire including the six proposed goal constructs (task-approach, task-avoidance, self-approach, self-avoidance, other-approach, other-avoidance) and the enjoyment and boredom scales from the Achievement Emotion Questionnaire. Exam grades were used as an indicator of academic achievement. Findings from CFAs provided strong support for the proposed structure of the 3 × 2 achievement goal model. Self-based goals, other-based goals and task-approach goals predicted enjoyment. Task-approach goals negatively predicted boredom. Task-approach and other-approach predicted achievement. The indirect effects of achievement goals through emotion variables on achievement were assessed using bias-corrected bootstrapping. No mediation effects were found. Implications for educational practice are discussed. PMID:27199836

  2. Weathered Oil and Tar Sampling Data for BP Spill/Deepwater Horizon

    EPA Pesticide Factsheets

    The Deepwater Horizon oil spill (also referred to as the BP oil spill) began on 20 April 2010 in the Gulf of Mexico on the BP-operated Macondo Prospect. Following the explosion and sinking of the Deepwater Horizon oil rig, a sea-floor oil gusher flowed for 87 days, until it was capped on 15 July 2010.In response to the BP oil spill, EPA sampled air, water, sediment, and waste generated by the cleanup operations.

  3. Relationship between CacyBP/SIP expression and prognosis in astrocytoma.

    PubMed

    Zhao, Wei; Wang, Chunlin; Wang, Junyu; Ge, Aiqing; Li, Yiming; Li, Weiqing; Lu, Yicheng

    2011-09-01

    The aim of this study was to investigate the expression of calcyclin-binding protein (also known as Siah-1-interacting protein [CacyBP/SIP]) in astrocytoma and to determine its prognostic value in overall survival of patients with glioblastoma multiforme (GBM). Tissue specimens were obtained from 77 Chinese patients who had undergone surgery for astrocytoma. The expression of CacyBP/SIP was examined by immunohistochemistry. The relationship between CacyBP/SIP and proliferating cell nuclear antigen index (PCNA) expression was investigated, and the prognostic value of CacyBP/SIP expression in patients with astrocytomas was analyzed. Of 77 tumors, 49 (63.6%) were negative for CacyBP/SIP expression. Loss of CacyBP/SIP expression was significantly associated with a high histological grade and with poor survival in univariate and multivariate analyses. Cox multivariable analysis showed that loss of CacyBP/SIP expression correlated with poor prognosis in patients with astrocytomas and was an independent prognostic factor (p<0.05). The mean survival time of patients with tumors that had lost expression of CacyBP/SIP was 25.58months (95% confidence interval [CI], 15.36-25.81months), compared to a mean survival time of 36.37months (95% CI, 27.90-44.84months) for patients with CacyBP/SIP-expressing tumors. CacyBP/SIP expression was also negatively correlated with PCNA expression in astrocytoma tissue (p<0.05). Our findings suggest that CacyBP/SIP may have an important role as a negative regulator of astrocytoma development and progression, and that CacyBP/SIP might be a useful molecular marker for predicting the prognosis of astrocytoma.

  4. Interactions of the human MCM-BP protein with MCM complex components and Dbf4.

    PubMed

    Nguyen, Tin; Jagannathan, Madhav; Shire, Kathy; Frappier, Lori

    2012-01-01

    MCM-BP was discovered as a protein that co-purified from human cells with MCM proteins 3 through 7; results which were recapitulated in frogs, yeast and plants. Evidence in all of these organisms supports an important role for MCM-BP in DNA replication, including contributions to MCM complex unloading. However the mechanisms by which MCM-BP functions and associates with MCM complexes are not well understood. Here we show that human MCM-BP is capable of interacting with individual MCM proteins 2 through 7 when co-expressed in insect cells and can greatly increase the recovery of some recombinant MCM proteins. Glycerol gradient sedimentation analysis indicated that MCM-BP interacts most strongly with MCM4 and MCM7. Similar gradient analyses of human cell lysates showed that only a small amount of MCM-BP overlapped with the migration of MCM complexes and that MCM complexes were disrupted by exogenous MCM-BP. In addition, large complexes containing MCM-BP and MCM proteins were detected at mid to late S phase, suggesting that the formation of specific MCM-BP complexes is cell cycle regulated. We also identified an interaction between MCM-BP and the Dbf4 regulatory component of the DDK kinase in both yeast 2-hybrid and insect cell co-expression assays, and this interaction was verified by co-immunoprecipitation of endogenous proteins from human cells. In vitro kinase assays showed that MCM-BP was not a substrate for DDK but could inhibit DDK phosphorylation of MCM4,6,7 within MCM4,6,7 or MCM2-7 complexes, with little effect on DDK phosphorylation of MCM2. Since DDK is known to activate DNA replication through phosphorylation of these MCM proteins, our results suggest that MCM-BP may affect DNA replication in part by regulating MCM phosphorylation by DDK.

  5. TopBP1 associates with NBS1 and is involved in homologous recombination repair

    SciTech Connect

    Morishima, Ken-ichi; Sakamoto, Shuichi; Kobayashi, Junya; Izumi, Hideki; Suda, Tetsuji; Matsumoto, Yoshiyuki; Tauchi, Hiroshi; Ide, Hiroshi; Komatsu, Kenshi; Matsuura, Shinya

    2007-11-03

    TopBP1 is involved in DNA replication and DNA damage checkpoint. Recent studies have demonstrated that TopBP1 is a direct positive effecter of ATR. However, it is not known how TopBP1 recognizes damaged DNA. Here, we show that TopBP1 formed nuclear foci after exposure to ionizing radiation, but such TopBP1 foci were abolished in Nijmegen breakage syndrome cells. We also show that TopBP1 physically associated with NBS1 in vivo. These results suggested that NBS1 might regulate TopBP1 recruitment to the sites of DNA damage. TopBP1-depleted cells showed hypersensitivity to Mitomycin C and ionizing radiation, an increased frequency of sister-chromatid exchange level, and a reduced frequency of DNA double-strand break induced homologous recombination repair. Together, these results suggested that TopBP1 might be a mediator of DNA damage signaling from NBS1 to ATR and promote homologous recombination repair.

  6. 3BP2-deficient mice are osteoporotic with impaired osteoblast and osteoclast functions

    PubMed Central

    Levaot, Noam; Simoncic, Paul D.; Dimitriou, Ioannis D.; Scotter, Andrew; La Rose, Jose; Ng, Adeline H.M.; Willett, Thomas L.; Wang, Chiachien J.; Janmohamed, Salima; Grynpas, Marc; Reichenberger, Ernst; Rottapel, Robert

    2011-01-01

    A fine balance between bone resorption by osteoclasts and bone formation by osteoblasts maintains bone homeostasis. In patients with cherubism, gain-of-function mutations in 3BP2, which is encoded by SH3-domain binding protein 2 (SH3BP2), cause cystic lesions with activated osteoclasts that lead to craniofacial abnormalities. However, little is known about the function of wild-type 3BP2 in regulating bone homeostasis. Here we have shown that 3BP2 is required for the normal function of both osteoblasts and osteoclasts. Initial analysis showed that Sh3bp2–/–mice developed osteoporosis as a result of reduced bone formation despite the fact that bone resorption was impaired. We demonstrated using reciprocal bone marrow chimeras, a cell-intrinsic defect of the osteoblast and osteoclast compartments in vivo. Further, Sh3bp2–/– osteoblasts failed to mature and form mineralized nodules in vitro, while Sh3bp2–/– osteoclasts spread poorly and were unable to effectively degrade dentine matrix in vitro. Finally, we showed that 3BP2 was required for Abl activation in osteoblasts and Src activation in osteoclasts, and demonstrated that the in vitro defect of each cell type was restored by the respective expression of activated forms of these kinases. These findings reveal an unanticipated role for the 3BP2 adapter protein in osteoblast function and in coordinating bone homeostatic signals in both osteoclast and osteoblast lineages. PMID:21765218

  7. G3BP1 contributes to tumor metastasis via upregulation of Slug expression in hepatocellular carcinoma

    PubMed Central

    Dou, Ning; Chen, Jingde; Yu, Shijun; Gao, Yong; Li, Yandong

    2016-01-01

    RasGAP SH3-domain-Binding Protein 1 (G3BP1) has been implicated in cell growth, migration, and metastasis of some cancers, yet its function in hepatocellular carcinoma (HCC) remains to be explored. In the present study, we reported that G3BP1 was upregulated in HCC tissues compared with adjacent non-cancerous liver tissues both in mRNA and protein levels, and its high expression was significantly correlated with poor prognosis of HCC patients. Functional analyses demonstrated that forced expression of G3BP1 in HCC cells promoted cell migration, and silenced expression of G3BP1 by RNA interference caused opposite effects. Moreover, G3BP1 knockdown attenuated the distant metastasis capacity of HCC cells through tail vein injection approach in nude mice model. At molecular mechanism, we found G3BP1 knockdown decreased Slug expression, and increased the expression of the epithelial cell marker E-cadherin. Overexpression of Slug could restore the phenotype of G3BP1 silencing induced cell migration inhibition. Together, our data establish G3BP1 as an oncogenic factor involved in the metastasis of HCC and suggest that G3BP1 might serve as a novel predictor for patients’ outcome. PMID:27904777

  8. Distribution of HLA-G 14-bp insertion/deletion polymorphism in six Chinese ethnic groups.

    PubMed

    Tao, Y; Chen, J; Yao, Y; Shi, L; Lin, K; Huang, X; Dong, Z; Chu, J; Shi, L

    2013-04-01

    Recently, a 14-bp insertion/deletion polymorphism (+14 bp/-14 bp) in exon 8 of the Human leucocyte antigen-G (HLA-G) gene has been studied extensively because this polymorphism has been associated with HLA-G mRNA stability and could influence HLA-G mRNA expression. We investigated the distribution of the 14-bp insertion/deletion polymorphism in six different Chinese ethnic groups (Bulang, Wa, Hani, Jinuo, Maonan and Zhuang), which originated from three major ancient tribes (Di-Qiang, Baipu and Baiyue) in China. Comparison of the 14-bp insertion frequency in the six groups with other Chinese groups showed marked variation among the three ancient tribes, Di-Qing (0.490-0.534), Baipu (0.470-0.609) and Baiyue (0.280-0.344). Furthermore, the frequencies of the 14-bp insertion were similar in groups that came from the same ancient tribe, which indicated that the individuals who share the 14-bp insertion have the most probably inherited the 14-bp element from a common ancestor. In addition, an intra-tribal comparison of the 14-bp insertion/deletion frequencies between the descendants of the ancient ancestral tribes suggests that population histories or some environmental effects, such as founder effect or isolation, might also influence the distribution.

  9. The relationship between prenatal exposure to BP-3 and Hirschsprung's disease.

    PubMed

    Huo, Weiwei; Cai, Peng; Chen, Minjian; Li, Hongxing; Tang, Junwei; Xu, Chao; Zhu, Dongmei; Tang, Weibing; Xia, Yankai

    2016-02-01

    Hirschsprung's disease (HSCR) is neonatal intestinal abnormality which derived from the faliure of enteric neural crest cells migration to hindgut during embryogenesis from 5 to 12 weeks. Currenly, the knowledge of environmental factors contributing to HSCR is still scarce. Benzophenone-3 (BP-3) is one of the most widely used UV filters, and has weak estrogen and strong anti-androgenic effects. In order to examine the effect of maternal BP-3 exposure on development of offspring and explore the potential mechanism, we conducted case and control study and in vitro study. In this work, BP-3 concertrations in maternal urine was detected by ultra-high performance liquid chromatography. Besides, we investigated the cytotoxicity and receptor tyrosine kinase (RET) expression in cells exposed to BP-3. The results showed that maternal BP-3 exposure was associated with offspring's HSCR in the population as well as inhibited migration of 293T and SH-SY5Y cells. What's more, we discovered dose-response relationship between RET expression and BP-3 exposure dose, and miR-218 and some other genes involved in SLIT2/ROBO1-miR-218-RET/PLAG1 pathway were also related to BP-3 exposure. Therefore, we deduced that BP-3 influenced cell migration via SLIT2/ROBO1-miR-218-RET/PLAG1 pathway. Our study firstly revealed the relationship between maternal BP-3 exposure and HSCR as well as its potential mechanism.

  10. Transduced PEP-1-FK506BP ameliorates atopic dermatitis in NC/Nga mice.

    PubMed

    Kim, So Young; Sohn, Eun Jeong; Kim, Dae Won; Jeong, Hoon Jae; Kim, Mi Jin; Kang, Hye Won; Shin, Min Jea; Ahn, Eun Hee; Kwon, Soon Won; Kim, Young Nam; Kwon, Hyung Joo; Kim, Tae-Yoon; Lee, Kil Soo; Park, Jinseu; Eum, Won Sik; Choi, Soo Young

    2011-07-01

    Immunophilin, FK506-binding protein 12 (FK506BP), is a receptor protein for the immunosuppressive drug FK506 by the FK506BP/FK506 complex. However, the precise function of FK506BP in inflammatory diseases remains unclear. Therefore, we examined the protective effects of FK506BP on atopic dermatitis (AD) in tumor necrosis factor-α (TNF-α)/interferon-γ (IFN-γ)-induced HaCaT cells and 2,4-dinitrofluorobenzene-induced AD-like dermatitis in Nishiki-nezumi Cinnamon/Nagoya (NC/Nga) mice using a cell-permeable PEP-1-FK506BP. Transduced PEP-1-FK506BP significantly inhibited the expression of cytokines, as well as the activation of NF-κB and mitogen-activated protein kinase (MAPK) in TNF-α/IFN-γ-induced HaCaT cells. Furthermore, topical application of PEP-1-FK506BP to NC/Nga mice markedly inhibited AD-like dermatitis as determined by a histological examination and assessment of serum IgE levels, as well as cytokines and chemokines. These results indicate that PEP-1-FK506BP inhibits NF-κB and MAPK activation in cells and AD-like skin lesions by reducing the expression levels of cytokines and chemokines, thus suggesting that PEP-1-FK506BP may be a potential therapeutic agent for AD.

  11. An analysis of the rapidly rotating Bp star HD 133880

    NASA Astrophysics Data System (ADS)

    Bailey, J. D.; Grunhut, J.; Shultz, M.; Wade, G.; Landstreet, J. D.; Bohlender, D.; Lim, J.; Wong, K.; Drake, S.; Linsky, J.

    2012-06-01

    HD 133880 is a rapidly rotating chemically peculiar B-type (Bp) star (v sin i≃ 103 km s-1) and is host to one of the strongest magnetic fields of any Ap/Bp star. A member of the Upper Centaurus Lupus association, it is a star with a well-determined age of 16 Myr. 12 new spectra, four of which are polarimetric, obtained from the FEROS, ESPaDOnS and HARPS instruments, provide sufficient material from which to re-evaluate the magnetic field and obtain a first approximation to the atmospheric abundance distributions of He, O, Mg, Si, Ti, Cr, Fe, Ni, Pr and Nd. An abundance analysis was carried out using ZEEMAN, a program which synthesizes spectral line profiles for stars with permeating magnetic fields. The magnetic field structure was characterized by a colinear multipole expansion from the observed variations of the longitudinal and surface fields with rotational phase. Both magnetic hemispheres are clearly visible during the stellar rotation, and thus a three-ring abundance distribution model encompassing both magnetic poles and magnetic equator with equal spans in colatitude was adopted. Using the new magnetic field measurements and optical photometry together with previously published data, we refine the period of HD 133880 to P= 0.877 476 ± 0.000 009 d. Our simple axisymmetric magnetic field model is based on a predominantly quadrupolar component that roughly describes the field variations. Using spectrum synthesis, we derived mean abundances for O, Mg, Si, Ti, Cr, Fe and Pr. All elements, except Mg, are overabundant compared to the Sun. Mg appears to be approximately uniform over the stellar surface, while all other elements are more abundant in the negative magnetic hemisphere than in the positive magnetic hemisphere. In contrast to most Ap/Bp stars which show an underabundance in O, in HD 133880 this element is clearly overabundant compared to the solar abundance ratio. In studying the Hα and Paschen lines in the optical spectra, we could not unambiguously

  12. S1219 residue of 53BP1 is phosphorylated by ATM kinase upon DNA damage and required for proper execution of DNA damage response

    SciTech Connect

    Lee, Haemi; Kwak, Hee-Jin; Cho, Il-taeg; Park, Seok Hee; Lee, Chang-Hun

    2009-01-02

    53BP1 is phosphorylated by the protein kinase ATM upon DNA damage. Even though several ATM phosphorylation sites in 53BP1 have been reported, those sites have little functional implications in the DNA damage response. Here, we show that ATM phosphorylates the S1219 residue of 53BP1 in vitro and that the residue is phosphorylated in cells exposed to ionizing radiation (IR). Transfection with siRNA targeting ATM abolished IR-induced phosphorylation at this residue, supporting the theory that this process is mediated by the kinase. To determine the functional relevance of this phosphorylation event, a U2OS cell line expressing S1219A mutant 53BP1 was established. IR-induced foci formation of MDC1 and {gamma}H2AX, DNA damage signaling molecules, was reduced in this cell line, implying that S1219 phosphorylation is required for recruitment of these molecules to DNA damage sites. Furthermore, overexpression of the mutant protein impeded IR-induced G2 arrest. In conclusion, we have shown that S1219 phosphorylation by ATM is required for proper execution of DNA damage response.

  13. S1219 residue of 53BP1 is phosphorylated by ATM kinase upon DNA damage and required for proper execution of DNA damage response.

    PubMed

    Lee, Haemi; Kwak, Hee-Jin; Cho, Il-taeg; Park, Seok Hee; Lee, Chang-Hun

    2009-01-02

    53BP1 is phosphorylated by the protein kinase ATM upon DNA damage. Even though several ATM phosphorylation sites in 53BP1 have been reported, those sites have little functional implications in the DNA damage response. Here, we show that ATM phosphorylates the S1219 residue of 53BP1 in vitro and that the residue is phosphorylated in cells exposed to ionizing radiation (IR). Transfection with siRNA targeting ATM abolished IR-induced phosphorylation at this residue, supporting the theory that this process is mediated by the kinase. To determine the functional relevance of this phosphorylation event, a U2OS cell line expressing S1219A mutant 53BP1 was established. IR-induced foci formation of MDC1 and gammaH2AX, DNA damage signaling molecules, was reduced in this cell line, implying that S1219 phosphorylation is required for recruitment of these molecules to DNA damage sites. Furthermore, overexpression of the mutant protein impeded IR-induced G2 arrest. In conclusion, we have shown that S1219 phosphorylation by ATM is required for proper execution of DNA damage response.

  14. Translational control of entrainment and synchrony of the suprachiasmatic circadian clock by mTOR/4E-BP1 signaling.

    PubMed

    Cao, Ruifeng; Robinson, Barry; Xu, Haiyan; Gkogkas, Christos; Khoutorsky, Arkady; Alain, Tommy; Yanagiya, Akiko; Nevarko, Tatiana; Liu, Andrew C; Amir, Shimon; Sonenberg, Nahum

    2013-08-21

    Protein synthesis is critical for circadian clock function, but little is known of how translational regulation controls the master pacemaker in mammals, the suprachiasmatic nucleus (SCN). Here we demonstrate that the pivotal translational repressor, the eukaryotic translational initiation factor 4E binding protein 1 (4E-BP1), is rhythmically regulated via the mechanistic target of rapamycin (mTOR) signaling in the SCN and preferentially represses vasoactive intestinal peptide (Vip) mRNA translation. Knockout (KO) of Eif4ebp1 (gene encoding 4E-BP1) leads to upregulation of VIP and higher amplitude of molecular rhythms in the SCN. Consequently, the 4E-BP1 null mice exhibit accelerated re-entrainment to a shifted light/dark cycle and are more resistant to the rhythm-disruptive effects of constant light. Conversely, in Mtor(+/-) mice VIP expression is decreased and susceptibility to the effects of constant light is increased. These results reveal a key role for mTOR/4E-BP1-mediated translational control in regulating entrainment and synchrony of the master clock.

  15. Targeting nocturnal hypertension in type 2 diabetes mellitus.

    PubMed

    Rossen, Niklas Blach; Knudsen, Søren Tang; Fleischer, Jesper; Hvas, Anne-Mette; Ebbehøj, Eva; Poulsen, Per Løgstrup; Hansen, Klavs Würgler

    2014-11-01

    Several studies in different populations have suggested that nighttime blood pressure (BP) is a stronger predictor of cardiovascular events than daytime BP. Consequently, treatment strategies to target nighttime BP have come into focus. The aim of the present study was to investigate the effect of change of administration time of antihypertensive drugs. We included 41 patients with type 2 diabetes mellitus and nocturnal hypertension (nighttime systolic BP >120 mm Hg) in an open-label, crossover study. Patients were randomized to 8 weeks of either morning or bedtime administration of all of the individual's once-daily antihypertensive drugs, followed by 8 weeks of switched dosing regimen. Bedtime administration of antihypertensive drugs resulted in a significant reduction in nighttime (7.5 mm Hg; P<0.001) and 24-hour (3.1 mm Hg; P=0.014) systolic BP, with a nonsignificant reduction in daytime (1.3 mm Hg; P=0.336) systolic BP. We did not find morning BP surge to be different between dosing regimens. Levels of C-reactive protein were significantly lower with bedtime administration, which may indicate an effect on low-grade inflammation. We found no difference in urinary albumin excretion, regardless of albuminuria status. Urinary sodium/creatinine was significantly increased and urinary osmolality significantly reduced with bedtime administration, which can be interpreted as increased nocturnal natriuresis. In patients with type 2 diabetes mellitus and nocturnal hypertension, administration of once-daily antihypertensive drugs at bedtime may be favorable. The increased nocturnal natriuresis may reflect increased effect of bedtime-administered thiazides and renin-angiotensin system inhibitors, suggesting a potential mechanism of the observed effects on BP with chronotherapeutic intervention.

  16. On Target.

    ERIC Educational Resources Information Center

    Barbalich, Andrea

    1991-01-01

    Campus public relations professionals offer advice for improving the effectiveness of public relations efforts by (1) setting behavioral goals; (2) targeting audiences carefully; (3) focusing appeals by making messages explicit; (4) connecting the public relations message with larger societal issues; and (5) reaching internal as well as external…

  17. The Mechanics of Human Achievement.

    PubMed

    Duckworth, Angela L; Eichstaedt, Johannes C; Ungar, Lyle H

    2015-07-01

    Countless studies have addressed why some individuals achieve more than others. Nevertheless, the psychology of achievement lacks a unifying conceptual framework for synthesizing these empirical insights. We propose organizing achievement-related traits by two possible mechanisms of action: Traits that determine the rate at which an individual learns a skill are talent variables and can be distinguished conceptually from traits that determine the effort an individual puts forth. This approach takes inspiration from Newtonian mechanics: achievement is akin to distance traveled, effort to time, skill to speed, and talent to acceleration. A novel prediction from this model is that individual differences in effort (but not talent) influence achievement (but not skill) more substantially over longer (rather than shorter) time intervals. Conceptualizing skill as the multiplicative product of talent and effort, and achievement as the multiplicative product of skill and effort, advances similar, but less formal, propositions by several important earlier thinkers.

  18. The Mechanics of Human Achievement

    PubMed Central

    Duckworth, Angela L.; Eichstaedt, Johannes C.; Ungar, Lyle H.

    2015-01-01

    Countless studies have addressed why some individuals achieve more than others. Nevertheless, the psychology of achievement lacks a unifying conceptual framework for synthesizing these empirical insights. We propose organizing achievement-related traits by two possible mechanisms of action: Traits that determine the rate at which an individual learns a skill are talent variables and can be distinguished conceptually from traits that determine the effort an individual puts forth. This approach takes inspiration from Newtonian mechanics: achievement is akin to distance traveled, effort to time, skill to speed, and talent to acceleration. A novel prediction from this model is that individual differences in effort (but not talent) influence achievement (but not skill) more substantially over longer (rather than shorter) time intervals. Conceptualizing skill as the multiplicative product of talent and effort, and achievement as the multiplicative product of skill and effort, advances similar, but less formal, propositions by several important earlier thinkers. PMID:26236393

  19. The Sinuous Target

    SciTech Connect

    Zwaska, R.

    2015-06-01

    We report on the concept for a target material comprised of a multitude of interlaced wires of small dimension. This target material concept is primarily directed at high-power neutrino targets where the thermal shock is large due to small beam sizes and short durations; it also has applications to other high-power targets, particularly where the energy deposition is great or a high surface area is preferred. This approach ameliorates the problem of thermal shock by engineering a material with high strength on the micro-scale, but a very low modulus of elasticity on the meso-scale. The low modulus of elasticity is achieved by constructing the material of spring-like wire segments much smaller than the beam dimension. The intrinsic bends of the wires will allow them to absorb the strain of thermal shock with minimal stress. Furthermore, the interlaced nature of the wires provides containment of any segment that might become loose. We will discuss the progress on studies of analogue materials and fabrication techniques for sinuous target materials.

  20. Design and characterization of novel antimicrobial peptides, R-BP100 and RW-BP100, with activity against Gram-negative and Gram-positive bacteria.

    PubMed

    Torcato, Inês M; Huang, Yen-Hua; Franquelim, Henri G; Gaspar, Diana; Craik, David J; Castanho, Miguel A R B; Troeira Henriques, Sónia

    2013-03-01

    BP100 is a short cationic antimicrobial peptide with a mechanism of action dependent on peptide-lipid interactions and microbial surface charge neutralization. Although active against Gram-negative bacteria, BP100 is inactive against Gram-positive bacteria. In this study we report two newly designed BP100 analogues, RW-BP100 and R-BP100 that have the Tyr residue replaced with a Trp and/or the Lys residues replaced with an Arg. The new analogues in addition to being active against Gram-negative bacteria, possess activity against all tested Gram-positive bacteria. Mechanistic studies using atomic force microscopy, surface plasmon resonance and fluorescence methodologies reveal that the antibacterial efficiency follows the affinity for bacterial membrane. The studies suggest that the activity of BP100 and its analogues against Gram-negative bacteria is mainly driven by electrostatic interactions with the lipopolysaccharide layer and is followed by binding to and disruption of the inner membrane, whereas activity against Gram-positive bacteria, in addition to electrostatic attraction to the exposed lipoteichoic acids, requires an ability to more deeply insert in the membrane environment, which is favoured with Arg residues and is facilitated in the presence of a Trp residue. Knowledge on the mechanism of action of these antimicrobial peptides provides information that assists in the design of antimicrobials with higher efficacy and broader spectra of action, but also on the design of peptides with higher specificity if required.

  1. Cell type-specific control of protein synthesis and proliferation by FGF-dependent signaling to the translation repressor 4E-BP

    PubMed Central

    Ruoff, Rachel; Katsara, Olga; Kolupaeva, Victoria

    2016-01-01

    Regulation of protein synthesis plays a vital role in posttranscriptional modulation of gene expression. Translational control most commonly targets the initiation of protein synthesis: loading 40S ribosome complexes onto mRNA and AUG start codon recognition. This step is initiated by eukaryotic initiation factor 4E (eIF4E) (the m7GTP cap-binding protein), whose binding to eIF4G (a scaffolding subunit) and eIF4A (an ATP-dependent RNA helicase) leads to assembly of active eIF4F complex. The ability of eIF4E to recognize the cap is prevented by its binding to eIF4E binding protein (4E-BP), which thereby inhibits cap-dependent translation by sequestering eIF4E. The 4E-BP activity is, in turn, inhibited by mTORC1 [mTOR (the mechanistic target of rapamycin) complex 1] mediated phosphorylation. Here, we define a previously unidentified mechanism of mTOR-independent 4E-BP1 regulation that is used by chondrocytes upon FGF signaling. Chondrocytes are responsible for the formation of the skeleton long bones. Unlike the majority of cell types where FGF signaling triggers proliferation, chondrocytes respond to FGF with inhibition. We establish that FGF specifically suppresses protein synthesis in chondrocytes, but not in any other cells of mesenchymal origin. Furthermore, 4E-BP1 repressor activity is necessary not only for suppression of protein synthesis, but also for FGF-induced cell-cycle arrest. Importantly, FGF-induced changes in the 4E-BP1 activity observed in cell culture are likewise detected in vivo and reflect the action of FGF signaling on downstream targets during bone development. Thus, our findings demonstrate that FGF signaling differentially impacts protein synthesis through either stimulation or repression, in a cell-type–dependent manner, with 4E-BP1 being a key player. PMID:27313212

  2. BP, cardiovascular disease, and death in the Folic Acid for Vascular Outcome Reduction in Transplantation trial.

    PubMed

    Carpenter, Myra A; John, Alin; Weir, Matthew R; Smith, Stephen R; Hunsicker, Lawrence; Kasiske, Bertram L; Kusek, John W; Bostom, Andrew; Ivanova, Anastasia; Levey, Andrew S; Solomon, Scott; Pesavento, Todd; Weiner, Daniel E

    2014-07-01

    The optimal BP level in kidney transplant recipients remains uncertain. This post hoc analysis of the Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) trial cohort assessed associations of BP with a pooled cardiovascular disease (CVD) outcome and with all-cause mortality. In 3474 prevalent kidney transplant patients, mean age was 52±9 years, 63% were men, 76% were white, 20% had a history of CVD, 40% had a history of diabetes mellitus, and the median time since transplant was 4.1 years (25th to 75th percentiles, 1.7-7.4); mean systolic BP was 136±20 mmHg and mean diastolic BP was 79±12 mmHg. There were 497 CVD events and 406 deaths. After adjustment for demographic and transplant characteristics and CVD risk factors, each 20-mmHg increase in baseline systolic BP associated with a 32% increase in subsequent CVD risk (hazard ratio [HR], 1.32; 95% confidence interval [95% CI], 1.19 to 1.46) and a 13% increase in mortality risk (HR, 1.13; 95% CI, 1.01 to 1.27). Similarly, after adjustment, at diastolic BP levels<70 mmHg, each 10-mmHg decrease in diastolic BP level associated with a 31% increase in CVD risk (HR, 1.31; 95% CI, 1.06 to 1.62) and a 31% increase in mortality risk (HR, 1.31; 95% CI, 1.03 to 1.66). However, at diastolic BP levels>70 mmHg, there was no significant relationship between diastolic BP and outcomes. Higher systolic BP strongly and independently associated with increased risk of CVD and all-cause mortality, without evidence of a J shape, whereas only lower levels of diastolic BP associated with increased risk of CVD and death in this trial.

  3. The BP oil spill and the bounty of Plaquemines Parish.

    PubMed

    Fertel, Randy

    2011-01-01

    The source of 25 to 30 percent of America's seafood, the Mississippi River Delta's cornucopian world is now uncertain. And yet, even if shrimp, oysters, and finfish are unaffected by the BP Oil Spill - a big if - one can already reflect on the passing of the culture once built upon gathering them. For almost three centuries, levees made life possible along the riverbanks and in the wetlands beyond. Those same levees also ensured the wetlands would eventually melt away into the Gulf. Cutting off the silt left behind during annual river inundations subjected the fragile land to erosion. Sulfur, natural gas, and oil production companies dug twenty thousand miles of canals to gain more direct routes to their fields and to pump out their mineral wealth. This caused salt-water intrusion that killed off plant life and caused more erosion. The world that sustained my Plaquemines ancestors was less subject to collapse following disasters not only because the ecosystem before the wetlands' ongoing loss was then more vibrant, complex, and robust; but also because their lives, especially their culinary lives, were more vibrant, complex, and robust. Life was hard, but when it came to putting food on the table, life followed the seasons.

  4. Achieving real-time performance in FIESTA

    NASA Technical Reports Server (NTRS)

    Wilkinson, William; Happell, Nadine; Miksell, Steve; Quillin, Robert; Carlisle, Candace

    1988-01-01

    The Fault Isolation Expert System for TDRSS Applications (FIESTA) is targeted for operation in a real-time online environment. Initial stages of the prototype development concentrated on acquisition and representation of the knowledge necessary to isolate faults in the TDRSS Network. Recent efforts focused on achieving real-time performance including: a discussion of the meaning of FIESTA real-time requirements, determination of performance levels (benchmarking) and techniques for optimization. Optimization techniques presented include redesign of critical relations, filtering of redundant data and optimization of patterns used in rules. Results are summarized.

  5. Camouflage target reconnaissance based on hyperspectral imaging technology

    NASA Astrophysics Data System (ADS)

    Hua, Wenshen; Guo, Tong; Liu, Xun

    2015-08-01

    Efficient camouflaged target reconnaissance technology makes great influence on modern warfare. Hyperspectral images can provide large spectral range and high spectral resolution, which are invaluable in discriminating between camouflaged targets and backgrounds. Hyperspectral target detection and classification technology are utilized to achieve single class and multi-class camouflaged targets reconnaissance respectively. Constrained energy minimization (CEM), a widely used algorithm in hyperspectral target detection, is employed to achieve one class camouflage target reconnaissance. Then, support vector machine (SVM), a classification method, is proposed to achieve multi-class camouflage target reconnaissance. Experiments have been conducted to demonstrate the efficiency of the proposed method.

  6. Insulin signaling controls neurotransmission via the 4eBP-dependent modification of the exocytotic machinery

    PubMed Central

    Mahoney, Rebekah Elizabeth; Azpurua, Jorge; Eaton, Benjamin A

    2016-01-01

    Altered insulin signaling has been linked to widespread nervous system dysfunction including cognitive dysfunction, neuropathy and susceptibility to neurodegenerative disease. However, knowledge of the cellular mechanisms underlying the effects of insulin on neuronal function is incomplete. Here, we show that cell autonomous insulin signaling within the Drosophila CM9 motor neuron regulates the release of neurotransmitter via alteration of the synaptic vesicle fusion machinery. This effect of insulin utilizes the FOXO-dependent regulation of the thor gene, which encodes the Drosophila homologue of the eif-4e binding protein (4eBP). A critical target of this regulatory mechanism is Complexin, a synaptic protein known to regulate synaptic vesicle exocytosis. We find that the amounts of Complexin protein observed at the synapse is regulated by insulin and genetic manipulations of Complexin levels support the model that increased synaptic Complexin reduces neurotransmission in response to insulin signaling. DOI: http://dx.doi.org/10.7554/eLife.16807.001 PMID:27525480

  7. Direct measurement of 11B(p ,γ )12C astrophysical S factors at low energies

    NASA Astrophysics Data System (ADS)

    He, J. J.; Jia, B. L.; Xu, S. W.; Chen, S. Z.; Ma, S. B.; Hou, S. Q.; Hu, J.; Zhang, L. Y.; Yu, X. Q.

    2016-05-01

    We directly measure the absolute cross section of 11B(p ,γ )12C in the energy region of Ec .m .=130 -257 keV by using a thin target for the first time. This work is performed on a 320-kV platform at the Institute of Modern Physics in Lanzhou. The astrophysical S factors of this reaction are obtained for capture to the ground and first excited states of 12C. The properties of the known resonance at ˜150 keV are derived and agree with the previous results. However, in the energy region of 170-240 keV, our S factors are about 15%-50% larger than the adopted values in NACRE II and are also larger than the upper limits of NACRE II by up to ˜20 % . This indicates that our new reaction rate is enhanced by about 15%-50% compared to the NACRE II adopted rate in the temperature region 0.32-0.62 GK.

  8. Comprehensive Cloning of Patient-derived 9022-bp Amplicons of Hepatitis C Virus

    PubMed Central

    Lu, Yang; Xu, Yanjuan; Di Bisceglie, Adrian M.; Fan, Xiaofeng

    2013-01-01

    The instability of recombinant clones accommodating large or full-length viral genomes is frequently a technical challenge in RNA virus research. In an attempt to establish a rapid plasmid-based reverse genetics system that utilizes long RT-PCR technique (LRP), similar difficulty was encountered in the cloning of 9022-bp LRP amplicon. All HCV genotype 1a strains used for LRP cloning showed a remarkable difference in terms of cloning stability. Subsequent analysis revealed the predictive value of phylogenetic positions in determining the cloning stability. Putative E. coli promoters on the HCV genome might be responsible for such cloning difference. An exhaustive exploration, testing nearly one hundred cloning protocols, did not reveal a general approach that can achieve stable cloning for all HCV 1a strains. The selection of appropriate strains, guided by phylogenetic analysis, appears to be necessary prior to the construction of infectious HCV 1a clones. These observations are not only valuable for potentially establishing an HCV 1a cell culture model but also have general implications for other RNA viruses due to concern about cloning instability. PMID:23602804

  9. 75 FR 65309 - National Commission on the BP Deepwater Horizon Oil Spill and Offshore Drilling

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-10-22

    ... National Commission on the BP Deepwater Horizon Oil Spill and Offshore Drilling AGENCY: Department of... meeting of the National Commission on the BP Deepwater Horizon Oil Spill and Offshore Drilling (the... Charter of the Commission can be found at: http://www.OilSpillCommission.gov . DATES: November 8, 2010,...

  10. 75 FR 37783 - National Commission on the BP Deepwater Horizon Oil Spill and Offshore Drilling

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-06-30

    ... National Commission on the BP Deepwater Horizon Oil Spill and Offshore Drilling AGENCY: Department of... meeting of the National Commission on the BP Deepwater Horizon Oil Spill and Offshore Drilling (the... spill and develop options to guard against, and mitigate the impact of, any oil spills associated...

  11. 75 FR 39518 - National Commission on the BP Deepwater Horizon Oil Spill and Offshore Drilling; Correction

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-07-09

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF ENERGY National Commission on the BP Deepwater Horizon Oil Spill and Offshore Drilling; Correction AGENCY: Office..., 2010, of the National Commission on the BP Deepwater Horizon Oil Spill and Offshore Drilling, (75...

  12. 75 FR 47584 - National Commission on the BP Deepwater Horizon Oil Spill and Offshore Drilling

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-08-06

    ... National Commission on the BP Deepwater Horizon Oil Spill and Offshore Drilling AGENCY: Department of... meeting for the National Commission on the BP Deepwater Horizon Oil Spill and Offshore Drilling (the... Charter of the Commission can be found at: http://www.OilSpillCommission.gov . DATES: Wednesday, August...

  13. 75 FR 60097 - National Commission on the BP Deepwater Horizon Oil Spill and Offshore Drilling

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-09-29

    ... National Commission on the BP Deepwater Horizon Oil Spill and Offshore Drilling AGENCY: Department of... meeting of the National Commission on the BP Deepwater Horizon Oil Spill and Offshore Drilling (the... Charter of the Commission can be found at: http://www.OilSpillCommission.gov . DATES: Wednesday,...

  14. 75 FR 56526 - National Commission on the BP Deepwater Horizon Oil Spill and Offshore Drilling

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-09-16

    ... National Commission on the BP Deepwater Horizon Oil Spill and Offshore Drilling AGENCY: Department of... meeting of the National Commission on the BP Deepwater Horizon Oil Spill and Offshore Drilling (the... Charter of the Commission can be found at: http://www.OilSpillCommission.gov . DATES: Monday, September...

  15. 75 FR 29397 - National Commission on the BP Deepwater Horizon Oil Spill and Offshore Drilling

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-05-26

    ... Order 13543 of May 21, 2010 National Commission on the BP Deepwater Horizon Oil Spill and Offshore... National Commission on the BP Deepwater Horizon Oil Spill and Offshore Drilling (the ``Commission''). Sec... against, and mitigating the impact of, oil spills associated with offshore drilling, taking...

  16. 53BP1 contributes to regulation of autophagic clearance of mitochondria.

    PubMed

    Youn, Cha Kyung; Kim, Hong Beum; Wu, Ting Ting; Park, Sanggon; Cho, Sung Il; Lee, Jung-Hee

    2017-03-27

    Autophagy, the primary recycling pathway within cells, plays a critical role in mitochondrial quality control under normal growth conditions and in the cellular response to stress. Here we provide evidence that 53BP1, a DNA damage response protein, is involved in regulating mitochondrial clearance from the cell via a type of autophagy termed mitophagy. We found that when either human or mouse cells were 53BP1-deficient, there was an increase in mitochondrial abnormalities, as observed through staining intensity, aggregation, and increased mass. Moreover, a 53BP1-depleted cell population included an increased number of cells with a high mitochondrial membrane potential (ΔΨm) relative to controls, suggesting that the loss of 53BP1 prevents initiation of mitophagy thereby leading to the accumulation of damaged mitochondria. Indeed, both 53BP1 and the mitophagy-associated protein LC3 translocated to mitochondria in response to damage induced by the mitochondrial uncoupler carbonyl cyanide m-chlorophenylhydrazone (CCCP). The recruitment of parkin, an E3-ubiquitin ligase, to mitochondria in response to CCCP treatment was significantly decreased in 53BP1-deficient cells. And lastly, using p53-deficient H1299 cells, we confirmed that the role of 53BP1 in mitophagy is independent of p53. These data support a model in which 53BP1 plays an important role in modulating mitochondrial homeostasis and in the clearance of damaged mitochondria.

  17. 75 FR 68607 - BP Canada Energy Marketing Corp. Apache Corporation; Notice for Temporary Waivers

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-11-08

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF ENERGY Federal Energy Regulatory Commission BP Canada Energy Marketing Corp. Apache Corporation; Notice for Temporary Waivers November 1, 2010. Take notice that on October 29, 2010, BP Canada Energy Marketing Corp....

  18. 76 FR 69712 - Application To Export Electric Energy; BP Energy Company

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-09

    ... Application To Export Electric Energy; BP Energy Company AGENCY: Office of Electricity Delivery and Energy... its authority to transmit electric energy from the United States to Canada pursuant to section 202(e... (DOE) issued Order No. EA-315, which authorized BP Energy to transmit electric energy from the...

  19. 76 FR 69713 - Application To Export Electric Energy; BP Energy Company

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-09

    ... Application To Export Electric Energy; BP Energy Company AGENCY: Office of Electricity Delivery and Energy... its authority to transmit electric energy from the United States to Mexico pursuant to section 202(e... Order No. EA-314, which authorized BP Energy to transmit electric energy from the United States...

  20. Preparation of PLLA/bpV(pic) microspheres and their effect on nerve cells.

    PubMed

    Lin, Qiang; Chen, Hai-yun; Li, Hao-shen; Cai, Yang-ting

    2014-02-01

    In this study, we prepared PLLA/bpV(pic) microspheres, a bpV(pic) controlled release system and examined their ability to protect nerve cells and promote axonal growth. PLLA microspheres were prepared by employing the o/w single emulsification-evaporation technique. Neural stem cells and dorsal root ganglia were divided into 3 groups in terms of the treatment they received: a routine medium group (cultured in DMEM), a PLLA microsphere group (DMEM containing PLLA microspheres alone) and a PLLA/bpV(pic) group [DMEM containing PLLA/bpV(pic) microspheres]. The effects of PLLA/bpV(pic) microspheres were evaluated by the live-dead test and measurement of axonal length. Our results showed that PLLA/bpV(pic) granulation rate was (88.2±5.6)%; particle size was (16.8±3.1)%, drug loading was (4.05±0.3)%; encapsulation efficiency was (48.5±1.8)%. The release time lasted for 30 days. In PLLA/bpV(pic) microsphere group, the cell survival rate was (95.2 ±4.77)%, and the length of dorsal root ganglion (DRG) was 718±95 μm, which were all significantly greater than those in ordinary routine medium group and PLLA microsphere group. This preliminary test results showed the PLLA/bpV(pic) microspheres were successfully prepared and they could promote the survival and growth of neural cells in DRG.

  1. CacyBP/SIP promotes the proliferation of colon cancer cells.

    PubMed

    Zhai, Huihong; Shi, Yongquan; Chen, Xiong; Wang, Jun; Lu, Yuanyuan; Zhang, Faming; Liu, Zhengxiong; Lei, Ting; Fan, Daiming

    2017-01-01

    CacyBP/SIP is a component of the ubiquitin pathway and is overexpressed in several transformed tumor tissues, including colon cancer, which is one of the most common cancers worldwide. It is unknown whether CacyBP/SIP promotes the proliferation of colon cancer cells. This study examined the expression level, subcellular localization, and binding activity of CacyBP/SIP in human colon cancer cells in the presence and absence of the hormone gastrin. We found that CacyBP/SIP was expressed in a high percentage of colon cancer cells, but not in normal colonic surface epithelium. CacyBP/SIP promoted the cell proliferation of colon cancer cells under both basal and gastrin stimulated conditions as shown by knockdown studies. Gastrin stimulation triggered the translocation of CacyBP/SIP to the nucleus, and enhanced interaction between CacyBP/SIP and SKP1, a key component of ubiquitination pathway which further mediated the proteasome-dependent degradation of p27kip1 protein. The gastrin induced reduction in p27kip1 was prevented when cells were treated with the proteasome inhibitor MG132. These results suggest that CacyBP/SIP may be promoting growth of colon cancer cells by enhancing ubiquitin-mediated degradation of p27kip1.

  2. SN 2015bp: adding to the growing population of transitional Type Ia supernovae

    NASA Astrophysics Data System (ADS)

    Srivastav, Shubham; Anupama, G. C.; Sahu, D. K.; Ravikumar, C. D.

    2017-04-01

    Photometric and spectroscopic observations of Type Ia supernova 2015bp are presented, spanning ∼-6 to ∼+141 d since B-band maximum. Also presented are unpublished HCT spectra of type Ia iPTF13ebh between -11 and +34 d since B-band maximum. SN 2015bp shows rapidly declining light curves with Δm15(B) = 1.72 ± 0.04. The I-band light curve shows a clear secondary maximum and peaks before the B-band maximum, placing SN 2015bp in the transitional category of SNe Ia. The spectral evolution of SN 2015bp resembles other transitional SNe Ia rather than 1991bg-like events. The C II λ6580 feature is detected in both SN 2015bp and iPTF13ebh, though it is present till the epoch of B-band maximum in the case of SN 2015bp. The velocity gradients of Si II λ6355 place SN 2015bp and iPTF13ebh in the FAINT subclass, whereas pseudo-equivalent widths of Si II features place them in the Cool (CL) subclass of SNe Ia. The bolometric light curve of SN 2015bp indicates that ∼0.2 M⊙ of 56Ni was synthesized in the explosion, with a total ejected mass of ∼0.9 M⊙, suggesting a sub-Chandrasekhar mass white dwarf progenitor.

  3. APP-BP1 inhibits Aβ42 levels by interacting with Presenilin-1

    PubMed Central

    Chen, Yuzhi; Bodles, Angela M; McPhie, Donna L; Neve, Rachael L; Mrak, Robert E; Griffin, W Sue T

    2007-01-01

    Background The β-amyloid precursor protein (APP) is sequentially cleaved by the β- and then γ-secretase to generate the amyloid β-peptides Aβ40 and Aβ42. Increased Aβ42/Aβ40 ratios trigger amyloid plaque formations in Alzheimer's disease (AD). APP binds to APP-BP1, but the biological consequence is not well understood. Results We report that when the endogenous APP-BP1 was suppressed by small interfering RNAs (siRNAs), cell-associated Aβ42 was dramatically increased in APP695 expressing primary neurons. The accumulation of Aβ42 was accompanied by significant increases in APP and APP-CTF in APP-BP1 siRNA expressing neurons. In contrast, APP-BP1 overexpression in primary neurons significantly decreased the levels of Aβ and endogenous APP but not APLPs. We also investigated the potential mechanism of APP-BP1-mediated APP processing. APP-BP1 co-precipitated with Presenilin-1 (PS1) in native rat brain extracts, co-migrated with the γ-secretase components in brain membrane extracts in glycerol gradient centrifugation, and colocalized in primary neurons. Further, the endogenous PS1-CTF was significantly downregulated by APP-BP1 expression. Conclusion Our data suggest that APP-BP1 may inhibit Aβ42 production by interacting with PS1 under physiological conditions. PMID:17286867

  4. 53BP1 contributes to regulation of autophagic clearance of mitochondria

    PubMed Central

    Youn, Cha Kyung; Kim, Hong Beum; Wu, Ting Ting; Park, Sanggon; Cho, Sung Il; Lee, Jung-Hee

    2017-01-01

    Autophagy, the primary recycling pathway within cells, plays a critical role in mitochondrial quality control under normal growth conditions and in the cellular response to stress. Here we provide evidence that 53BP1, a DNA damage response protein, is involved in regulating mitochondrial clearance from the cell via a type of autophagy termed mitophagy. We found that when either human or mouse cells were 53BP1-deficient, there was an increase in mitochondrial abnormalities, as observed through staining intensity, aggregation, and increased mass. Moreover, a 53BP1-depleted cell population included an increased number of cells with a high mitochondrial membrane potential (ΔΨm) relative to controls, suggesting that the loss of 53BP1 prevents initiation of mitophagy thereby leading to the accumulation of damaged mitochondria. Indeed, both 53BP1 and the mitophagy-associated protein LC3 translocated to mitochondria in response to damage induced by the mitochondrial uncoupler carbonyl cyanide m-chlorophenylhydrazone (CCCP). The recruitment of parkin, an E3-ubiquitin ligase, to mitochondria in response to CCCP treatment was significantly decreased in 53BP1-deficient cells. And lastly, using p53-deficient H1299 cells, we confirmed that the role of 53BP1 in mitophagy is independent of p53. These data support a model in which 53BP1 plays an important role in modulating mitochondrial homeostasis and in the clearance of damaged mitochondria. PMID:28345606

  5. CacyBP/SIP promotes the proliferation of colon cancer cells

    PubMed Central

    Chen, Xiong; Wang, Jun; Lu, Yuanyuan; Zhang, Faming; Liu, Zhengxiong; Lei, Ting; Fan, Daiming

    2017-01-01

    CacyBP/SIP is a component of the ubiquitin pathway and is overexpressed in several transformed tumor tissues, including colon cancer, which is one of the most common cancers worldwide. It is unknown whether CacyBP/SIP promotes the proliferation of colon cancer cells. This study examined the expression level, subcellular localization, and binding activity of CacyBP/SIP in human colon cancer cells in the presence and absence of the hormone gastrin. We found that CacyBP/SIP was expressed in a high percentage of colon cancer cells, but not in normal colonic surface epithelium. CacyBP/SIP promoted the cell proliferation of colon cancer cells under both basal and gastrin stimulated conditions as shown by knockdown studies. Gastrin stimulation triggered the translocation of CacyBP/SIP to the nucleus, and enhanced interaction between CacyBP/SIP and SKP1, a key component of ubiquitination pathway which further mediated the proteasome-dependent degradation of p27kip1 protein. The gastrin induced reduction in p27kip1 was prevented when cells were treated with the proteasome inhibitor MG132. These results suggest that CacyBP/SIP may be promoting growth of colon cancer cells by enhancing ubiquitin-mediated degradation of p27kip1. PMID:28196083

  6. Target assembly

    DOEpatents

    Lewis, Richard A.

    1980-01-01

    A target for a proton beam which is capable of generating neutrons for absorption in a breeding blanket includes a plurality of solid pins formed of a neutron emissive target material disposed parallel to the path of the beam and which are arranged axially in a plurality of layers so that pins in each layer are offset with respect to pins in all other layers, enough layers being used so that each proton in the beam will strike at least one pin with means being provided to cool the pins. For a 300 mA, 1 GeV beam (300 MW), stainless steel pins, 12 inches long and 0.23 inches in diameter are arranged in triangular array in six layers with one sixth of the pins in each layer, the number of pins being such that the entire cross sectional area of the beam is covered by the pins with minimum overlap of pins.

  7. EDUCATIONAL ACHIEVEMENT AND THE NAVAJO.

    ERIC Educational Resources Information Center

    HAAS, JOHN; MELVILLE, ROBERT

    A STUDY WAS DEVISED TO APPRAISE THE ACADEMIC ACHIEVEMENT OF NAVAJO STUDENTS LIVING IN DORMITORIES AWAY FROM THE INDIAN RESERVATION. THE FOLLOWING SEVEN FACTORS WERE CHOSEN TO BE INVESTIGATED AS BEING DIRECTLY RELATED TO ACHIEVEMENT--(1) INTELLIGENCE, (2) READING ABILITY, (3) ANXIETY, (4) SELF-CONCEPT, (5) MOTIVATION, (6) VERBAL DEVELOPMENT, (7)…

  8. Sociocultural Origins of Achievement Motivation

    ERIC Educational Resources Information Center

    Maehr, Martin L.

    1977-01-01

    Presents a theoretical review of work on sociocultural influences on achievement, focusing on a critical evaluation of the work of David McClellan. Offers an alternative conception of achievement motivation which stresses the role of contextual and situational factors in addition to personality factors. Available from: Transaction Periodicals…

  9. Raising Boys' Achievement in Schools.

    ERIC Educational Resources Information Center

    Bleach, Kevan, Ed.

    This book offers insights into the range of strategies and good practice being used to raise the achievement of boys. Case studies by school-based practitioners suggest ideas and measures to address the issue of achievement by boys. The contributions are: (1) "Why the Likely Lads Lag Behind" (Kevan Bleach); (2) "Helping Boys Do…

  10. Teaching the Low Level Achiever.

    ERIC Educational Resources Information Center

    Salomone, Ronald E., Ed.

    1986-01-01

    Intended for teachers of the English language arts, the articles in this issue offer suggestions and techniques for teaching the low level achiever. Titles and authors of the articles are as follows: (1) "A Point to Ponder" (Rachel Martin); (2) "Tracking: A Self-Fulfilling Prophecy of Failure for the Low Level Achiever" (James Christopher Davis);…

  11. Early Intervention and Student Achievement

    ERIC Educational Resources Information Center

    Hormes, Mridula T.

    2009-01-01

    The United States Department of Education has been rigorous in holding all states accountable with regard to student achievement. The No Child Left Behind Act of 2001 clearly laid out federal mandates for all schools to follow. K-12 leaders of public schools are very aware of the fact that results in terms of student achievement need to improve…

  12. Parental Involvement and Academic Achievement

    ERIC Educational Resources Information Center

    Goodwin, Sarah Christine

    2015-01-01

    This research study examined the correlation between student achievement and parent's perceptions of their involvement in their child's schooling. Parent participants completed the Parent Involvement Project Parent Questionnaire. Results slightly indicated parents of students with higher level of achievement perceived less demand or invitations…

  13. Asperger Syndrome and Academic Achievement.

    ERIC Educational Resources Information Center

    Griswold, Deborah E.; Barnhill, Gena P.; Myles, Brenda Smith; Hagiwara, Taku; Simpson, Richard L.

    2002-01-01

    A study focused on identifying the academic characteristics of 21 children and youth who have Asperger syndrome. Students had an extraordinary range of academic achievement scores, extending from significantly above average to far below grade level. Lowest achievement scores were shown for numerical operations, listening comprehension, and written…

  14. Perils of Standardized Achievement Testing

    ERIC Educational Resources Information Center

    Haladyna, Thomas M.

    2006-01-01

    This article argues that the validity of standardized achievement test-score interpretation and use is problematic; consequently, confidence and trust in such test scores may often be unwarranted. The problem is particularly severe in high-stakes situations. This essay provides a context for understanding standardized achievement testing, then…

  15. Stress Correlates and Academic Achievement.

    ERIC Educational Resources Information Center

    Bentley, Donna Anderson; And Others

    An ongoing concern for educators is the identification of factors that contribute to or are associated with academic achievement; one such group of variables that has received little attention are those involving stress. The relationship between perceived sources of stress and academic achievement was examined to determine if reactions to stress…

  16. School Size and Student Achievement

    ERIC Educational Resources Information Center

    Riggen, Vicki

    2013-01-01

    This study examined whether a relationship between high school size and student achievement exists in Illinois public high schools in reading and math, as measured by the Prairie State Achievement Exam (PSAE), which is administered to all Illinois 11th-grade students. This study also examined whether the factors of socioeconomic status, English…

  17. A targeted enrichment strategy for massively parallel sequencing of angiosperm plastid genomes1

    PubMed Central

    Stull, Gregory W.; Moore, Michael J.; Mandala, Venkata S.; Douglas, Norman A.; Kates, Heather-Rose; Qi, Xinshuai; Brockington, Samuel F.; Soltis, Pamela S.; Soltis, Douglas E.; Gitzendanner, Matthew A.

    2013-01-01

    • Premise of the study: We explored a targeted enrichment strategy to facilitate rapid and low-cost next-generation sequencing (NGS) of numerous complete plastid genomes from across the phylogenetic breadth of angiosperms. • Methods and Results: A custom RNA probe set including the complete sequences of 22 previously sequenced eudicot plastomes was designed to facilitate hybridization-based targeted enrichment of eudicot plastid genomes. Using this probe set and an Agilent SureSelect targeted enrichment kit, we conducted an enrichment experiment including 24 angiosperms (22 eudicots, two monocots), which were subsequently sequenced on a single lane of the Illumina GAIIx with single-end, 100-bp reads. This approach yielded nearly complete to complete plastid genomes with exceptionally high coverage (mean coverage: 717×), even for the two monocots. • Conclusions: Our enrichment experiment was highly successful even though many aspects of the capture process employed were suboptimal. Hence, significant improvements to this methodology are feasible. With this general approach and probe set, it should be possible to sequence more than 300 essentially complete plastid genomes in a single Illumina GAIIx lane (achieving ∼50× mean coverage). However, given the complications of pooling numerous samples for multiplex sequencing and the limited number of barcodes (e.g., 96) available in commercial kits, we recommend 96 samples as a current practical maximum for multiplex plastome sequencing. This high-throughput approach should facilitate large-scale plastid genome sequencing at any level of phylogenetic diversity in angiosperms. PMID:25202518

  18. Purification and functional properties of the membrane fissioning protein CtBP3/BARS.

    PubMed

    Valente, Carmen; Spanò, Stefania; Luini, Alberto; Corda, Daniela

    2005-01-01

    The fissioning protein CtBP3/BARS is a member of the CtBP transcription corepressor family of proteins. The characterization of this fissioning activity of CtBP3/BARS in both isolated Golgi membranes and in intact cells has indicated that the CtBP family includes multifunctional proteins that can act both in the nucleus and in the cytoplasm. The fissiogenic activity of CtBP3/BARS has a role in the fragmentation of the Golgi complex during mitosis and during intracellular membrane transport. This was demonstrated using a number of approaches and reagents, which are discussed in the following text, and which include recombinant proteins and mutants, antibodies, protein overexpression, RNA interference, antisense oligonucleotides, cell permeabilization, and electron miscroscopy, together with biochemical assays such as that for ADP-ribosylation.

  19. Centennial and millennial-scale hydroclimate changes in northwestern Patagonia since 16,000 yr BP

    NASA Astrophysics Data System (ADS)

    Moreno, Patricio I.; Videla, Javiera

    2016-10-01

    We examine hydroclimate changes at centennial/millennial timescales since 16,000 yr BP in northwestern Patagonia based on the pollen and charcoal record from Lago El Salto, a small closed-basin lake located in the Chilean Lake District (41°38‧48.02″S, 73° 5‧48.42″W). We observe cold/wet conditions between 14,500-16,000 yr BP, followed by further cooling with increased precipitation until 13,000 yr BP, enhanced precipitation seasonality and/or variability between 11,600-13,000 yr BP, and an extended warm-and-dry interval between 7600 and 11,300 yr BP with peak paleofire activity. Colder-and-wetter than present conditions and muted paleofire activity prevail between 5300 and 7600 yr BP, followed by alternating cold/wet and centennial-scale warm/dry phases starting at 5300 yr BP with three conspicuous megadroughts since 2500 yr BP. The most recent megadrought occurred during the Medieval Climate Anomaly. We identify a cold reversal that spans the Antarctic Cold Reversal (ACR) and the Younger Dryas (YD) chrons with stronger-than-present westerly influence during the former and enhanced variability during the latter. These results extend the northern limit of strong cooling and increase in precipitation during the ACR and the southern limit of influence of strong hydrologic variations during the YD in terrestrial environments, suggesting an overlap in the spheres of influence of processes originating from southern and northern polar latitudes. An extended warm southern westerly wind (SWW)-minimum interval is evident between 7600 and 11,300 yr BP, followed by a rapid shift to cool-moist conditions between 5300 and 7600 yr BP brought by a mid-Holocene SWW maximum. Since then we observe centennial-scale hydroclimate variability, which has driven biodiversity and fire-regime shifts of evergreen temperate rainforests.

  20. Chemical proteomics reveals a γH2AX-53BP1 interaction in the DNA damage response

    PubMed Central

    Kleiner, Ralph E.; Verma, Priyanka; Molloy, Kelly R.; Chait, Brian T.; Kapoor, Tarun M.

    2015-01-01

    DNA double-strand break repair involves phosphorylation of histone variant H2AX (‘γH2AX’), which accumulates in foci at sites of damage. In current models, the recruitment of multiple DNA repair proteins to γH2AX foci depends mainly on recognition of this ‘mark’ by a single protein, MDC1. However, DNA repair proteins accumulate at γH2AX sites without MDC1, suggesting that other ‘readers’ exist. Here, we use a quantitative chemical proteomics approach to profile direct, phospho-selective γH2AX binders in native proteomes. We identify γH2AX binders, including the DNA repair mediator, 53BP1, which we show recognizes γH2AX through its BRCT domains. Furthermore, we investigate targeting of wild-type 53BP1 or a mutant form deficient in γH2AX binding, to chromosomal breaks resulting from endogenous and exogenous DNA damage. Our results show how direct recognition of γH2AX modulates protein localization at DNA damage sites, and suggest how specific chromatin ‘mark’-‘reader’ interactions contribute to essential mechanisms ensuring genome stability. PMID:26344695

  1. The mTORC1/4E-BP pathway coordinates hemoglobin production with L-leucine availability

    PubMed Central

    Chung, Jacky; Bauer, Daniel E.; Ghamari, Alireza; Nizzi, Christopher P.; Deck, Kathryn M.; Kingsley, Paul D.; Yien, Yvette Y.; Huston, Nicholas C.; Chen, Caiyong; Schultz, Iman J.; Dalton, Arthur J.; Wittig, Johannes G.; Palis, James; Orkin, Stuart H.; Lodish, Harvey F.; Eisenstein, Richard S.; Cantor, Alan B.; Paw, Barry H.

    2015-01-01

    In multicellular organisms, the mechanisms by which diverse cell types acquire distinct amino acids and how cellular function adapts to their availability are fundamental questions in biology. Here, we found that increased neutral essential amino acid (NEAA) uptake was a critical component of erythropoiesis. As red blood cells matured, expression of the amino acid transporter gene Lat3 increased, which increased NEAA import. Inadequate NEAA uptake by pharmacologic inhibition or RNAi-mediated knockdown of LAT3 triggered a specific reduction in hemoglobin production in zebrafish embryos and murine erythroid cells through the mTORC1 (mechanistic target of rapamycin complex 1)/4E-BP (eukaryotic translation initiation factor 4E-binding protein) pathway. CRISPR-mediated deletion of members of the 4E-BP family in murine erythroid cells rendered them resistant to mTORC1 and LAT3 inhibition and restored hemoglobin production. These results identify a developmental role for LAT3 in red blood cells and demonstrate that mTORC1 serves as a homeostatic sensor that couples hemoglobin production at the translational level to sufficient uptake of NEAAs, particularly L-leucine. PMID:25872869

  2. Incorporation of silver nanoparticles on the surface of orthodontic microimplants to achieve antimicrobial properties

    PubMed Central

    Venugopal, Adith; Muthuchamy, Nallal; Tejani, Harsh; Gopalan, Anantha-Iyengar; Lee, Kwang-Pill; Lee, Heon-Jin

    2017-01-01

    Objective Microbial aggregation around dental implants can lead to loss/loosening of the implants. This study was aimed at surface treating titanium microimplants with silver nanoparticles (AgNPs) to achieve antibacterial properties. Methods AgNP-modified titanium microimplants (Ti-nAg) were prepared using two methods. The first method involved coating the microimplants with regular AgNPs (Ti-AgNP) and the second involved coating them with a AgNP-coated biopolymer (Ti-BP-AgNP). The topologies, microstructures, and chemical compositions of the surfaces of the Ti-nAg were characterized by scanning electron microscopy (SEM) equipped with energy-dispersive spectrometer (EDS) and X-ray photoelectron spectroscopy (XPS). Disk diffusion tests using Streptococcus mutans, Streptococcus sanguinis, and Aggregatibacter actinomycetemcomitans were performed to test the antibacterial activity of the Ti-nAg microimplants. Results SEM revealed that only a meager amount of AgNPs was sparsely deposited on the Ti-AgNP surface with the first method, while a layer of AgNP-coated biopolymer extended along the Ti-BP-AgNP surface in the second method. The diameters of the coated nanoparticles were in the range of 10 to 30 nm. EDS revealed 1.05 atomic % of Ag on the surface of the Ti-AgNP and an astounding 21.2 atomic % on the surface of the Ti-BP-AgNP. XPS confirmed the metallic state of silver on the Ti-BP-AgNP surface. After 24 hours of incubation, clear zones of inhibition were seen around the Ti-BP-AgNP microimplants in all three test bacterial culture plates, whereas no antibacterial effect was observed with the Ti-AgNP microimplants. Conclusions Titanium microimplants modified with Ti-BP-AgNP exhibit excellent antibacterial properties, making them a promising implantable biomaterial. PMID:28127534

  3. Accelerator target

    DOEpatents

    Schlyer, D.J.; Ferrieri, R.A.; Koehler, C.

    1999-06-29

    A target includes a body having a depression in a front side for holding a sample for irradiation by a particle beam to produce a radioisotope. Cooling fins are disposed on a backside of the body opposite the depression. A foil is joined to the body front side to cover the depression and sample therein. A perforate grid is joined to the body atop the foil for supporting the foil and for transmitting the particle beam therethrough. A coolant is circulated over the fins to cool the body during the particle beam irradiation of the sample in the depression. 5 figs.

  4. Accelerator target

    DOEpatents

    Schlyer, David J.; Ferrieri, Richard A.; Koehler, Conrad

    1999-01-01

    A target includes a body having a depression in a front side for holding a sample for irradiation by a particle beam to produce a radioisotope. Cooling fins are disposed on a backside of the body opposite the depression. A foil is joined to the body front side to cover the depression and sample therein. A perforate grid is joined to the body atop the foil for supporting the foil and for transmitting the particle beam therethrough. A coolant is circulated over the fins to cool the body during the particle beam irradiation of the sample in the depression.

  5. Targeting Breast Cancer Metastasis

    PubMed Central

    Jin, Xin; Mu, Ping

    2015-01-01

    Metastasis is the leading cause of breast cancer-associated deaths. Despite the significant improvement in current therapies in extending patient life, 30–40% of patients may eventually suffer from distant relapse and succumb to the disease. Consequently, a deeper understanding of the metastasis biology is key to developing better treatment strategies and achieving long-lasting therapeutic efficacies against breast cancer. This review covers recent breakthroughs in the discovery of various metastatic traits that contribute to the metastasis cascade of breast cancer, which may provide novel avenues for therapeutic targeting. PMID:26380552

  6. Childhood Obesity and Cognitive Achievement.

    PubMed

    Black, Nicole; Johnston, David W; Peeters, Anna

    2015-09-01

    Obese children tend to perform worse academically than normal-weight children. If poor cognitive achievement is truly a consequence of childhood obesity, this relationship has significant policy implications. Therefore, an important question is to what extent can this correlation be explained by other factors that jointly determine obesity and cognitive achievement in childhood? To answer this question, we exploit a rich longitudinal dataset of Australian children, which is linked to national assessments in math and literacy. Using a range of estimators, we find that obesity and body mass index are negatively related to cognitive achievement for boys but not girls. This effect cannot be explained by sociodemographic factors, past cognitive achievement or unobserved time-invariant characteristics and is robust to different measures of adiposity. Given the enormous importance of early human capital development for future well-being and prosperity, this negative effect for boys is concerning and warrants further investigation.

  7. Using Design To Achieve Sustainability

    EPA Science Inventory

    Sustainability is defined as meeting the needs of this generation without compromising the ability of future generations to meet their needs. This is a conditional statement that places the responsibility for achieving sustainability squarely in hands of designers and planners....

  8. Achieving Efficiencies in Army Installations.

    DTIC Science & Technology

    2007-11-02

    34" ’■■"■" 1 USAWC STRATEGY RESEARCH PROJECT Achieving Efficiencies in Army Installations by Richard Fliss Col. Richard M. Meinhart Project...government agency. STRATEGY RESEARCH PROJECT ACHIEVING EFFICIENCIES IN ARMY INSTALLATIONS BY RICHARD FLISS DISTRIBUTION STATEMENT A: Approved...for public release. Distribution is unlimited. DTIC QUALITY INSPECTED & USAWC CLASS OF 1998 U.S. ARMY WAR COLLEGE, CARLISLE BARRACKS, PA 17013-5050

  9. Targeting circuits

    PubMed Central

    Rajasethupathy, Priyamvada; Ferenczi, Emily; Deisseroth, Karl

    2017-01-01

    Current optogenetic methodology enables precise inhibition or excitation of neural circuits, spanning timescales as needed from the acute (milliseconds) to the chronic (many days or more), for experimental modulation of network activity and animal behavior. Such broad temporal versatility, unique to optogenetic control, is particularly powerful when combined with brain activity measurements that span both acute and chronic timescales as well. This enables, for instance, the study of adaptive circuit dynamics across the intact brain, and tuning interventions to match activity patterns naturally observed during behavior in the same individual. Although the impact of this approach has been greater on basic research than on clinical translation, it is natural to ask if specific neural circuit activity patterns discovered to be involved in controlling adaptive or maladaptive behaviors could become targets for treatment of neuropsychiatric diseases. Here we consider the landscape of such ideas related to therapeutic targeting of circuit dynamics, taking note of developments not only in optical but also in ultrasonic, magnetic, and thermal methods. We note the recent emergence of first-in-kind optogenetically-guided clinical outcomes, as well as opportunities related to the integration of interventions and readouts spanning diverse circuit-physiology, molecular, and behavioral modalities. PMID:27104976

  10. Radiocarbon dating from 40 to 60 ka BP at Border Cave, South Africa

    NASA Astrophysics Data System (ADS)

    Bird, M. I.; Fifield, L. K.; Santos, G. M.; Beaumont, P. B.; Zhou, Y.; di Tada, M. L.; Hausladen, P. A.

    2003-04-01

    We present 21 radiocarbon dates on 19 charcoal samples from the sedimentary sequence preserved in Border Cave, South Africa. The background radiocarbon activity for charcoal from the cave was determined to be 0.050±0.018 percent modern carbon, from the analysis of a radiocarbon-dead sample from unit 5WA. Radiocarbon ages for individual samples ranged from 25.2 to >58.2 ka BP. The error-weighted mean ages for successively older strata are 38.5+0.85/-0.95 ka BP for unit 1WA, 50.2+1.1/-1.0 ka BP for units 2BS.LR.A and 2BS.LR.B, 56.5+2.7/-2.0 ka BP for unit 2BS.LR.C and 59.2+3.4/-2.4 ka BP for unit 2WA. This radiocarbon chronology is consistent with independent chronologies derived from electron spin resonance and amino acid racemization dating. The results therefore provide further evidence that radiocarbon dating of charcoal by the ABOX-SC technique can yield reliable radiocarbon ages beyond 40 ka BP. They also imply that Border Cave 5, a modern human mandible, predates >58.2 ka BP and that the Middle Stone Age (Mode 3)—Later Stone Age (Mode 5) transition of Border Cave was largely effected between ˜56.5 and ˜41.6 ka ago.

  11. Cell cycle-dependent inhibition of 53BP1 signaling by BRCA1

    PubMed Central

    Feng, Lin; Li, Nan; Li, Yujing; Wang, Jiadong; Gao, Min; Wang, Wenqi; Chen, Junjie

    2015-01-01

    DNA damage response mediator protein 53BP1 is a key regulator of non-homologous end-joining (NHEJ) repair. 53BP1 protects DNA broken ends from resection by recruiting two downstream factors, RIF1 (RAP1-interacting factor 1) and PTIP (Pax transactivation domain-interacting protein), to double-stranded breaks (DSBs) via ATM (ataxia telangiectasia mutated)-mediated 53BP1 phosphorylation, and competes with BRCA1-mediated homologous recombination (HR) repair in G1 phase. In contrast, BRCA1 antagonizes 53BP1-direct NHEJ repair in S/G2 phases. We and others have found that BRCA1 prevents the translocation of RIF1 to DSBs in S/G2 phases; however, the underlying mechanism remains unclear. Here we show that efficient ATM-dependent 53BP1 phosphorylation is restricted to the G1 phase of the cell cycle, as a consequence RIF1 and PTIP accumulation at DSB sites only occur in G1 phase. Mechanistically, both BRCT and RING domains of BRCA1 are required for the inhibition of 53BP1 phosphorylation in S and G2 phases. Thus, our findings reveal how BRCA1 antagonizes 53BP1 signaling to ensure that HR repair is the dominant repair pathway in S/G2 phases. PMID:27462418

  12. nArgBP2 as a hub molecule in the etiology of various neuropsychiatric disorders

    PubMed Central

    Lee, Sang-Eun; Chang, Sunghoe

    2016-01-01

    Recent studies have strongly implicated postsynaptic scaffolding proteins such as SAPAP3 or Shank3 in the pathogenesis of various mood disorders, including autism spectrum disorder, bipolar disorder (BD), and obsessive-compulsive disorders. Neural Abelson-related gene-binding protein 2 (nArgBP2) was originally identified as a protein that interacts with SAPAP3 and Shank3. Recent study shows that the genetic deletion of nArgBP2 in mice leads to manic/bipolar-like behavior resembling symptoms of BD. However, the function of nArgBP2 at synapse, or its connection with the synaptic dysfunctions, is completely unknown. This study provides compelling evidence that nArgBP2 regulates the spine morphogenesis through the activation of Rac1/WAVE/PAK/cofilin pathway, and that its ablation causes a robust and selective inhibition of excitatory synapse formation, by controlling actin dynamics. Our results revealed the underlying mechanism for the synaptic dysfunction caused by nArgBP2 downregulation that associates with analogous human BD. Moreover, since nArgBP2 interacts with key proteins involved in various neuropsychiatric disorders, our finding implies that nArgBP2 could function as a hub linking various etiological factors of different mood disorders. [BMB Reports 2016; 49(9): 457-458] PMID:27530683

  13. M2BP inhibits HIV-1 virion production in a vimentin filaments-dependent manner

    PubMed Central

    Wang, Qin; Zhang, Xiaolin; Han, Yuling; Wang, Xinlu; Gao, Guangxia

    2016-01-01

    M2BP (also called 90K) is an interferon-stimulated gene product that is upregulated in HIV-1 infection. A recent study revealed that M2BP reduces the infectivity of HIV-1 by inhibiting the processing of the viral envelope protein. Here we report that in addition to reducing viral infectivity, M2BP inhibits HIV-1 virion production. We provide evidence showing that M2BP inhibits HIV-1 Gag trafficking to the plasma membrane in a vimentin-dependent manner. When vimentin filaments were collapsed by treating cells with acrylamide or by overexpression of a dominant-negative mutant of vimentin, M2BP inhibition of HIV-1 virion production was significantly relieved. We further show that M2BP interacts with both HIV-1 Gag and vimentin and thereby mediates their interactions. We propose that M2BP traps HIV-1 Gag to vimentin filaments to inhibit the transportation of HIV-1 Gag to the plasma membrane. These findings uncover a novel mechanism by which a host antiviral factor inhibits HIV-1 virion production. PMID:27604950

  14. Tankyrase-binding protein TNKS1BP1 regulates actin cytoskeleton rearrangement and cancer cell invasion.

    PubMed

    Ohishi, Tomokazu; Yoshida, Haruka; Katori, Masamichi; Migita, Toshiro; Muramatsu, Yukiko; Miyake, Mao; Ishikawa, Yuichi; Saiura, Akio; Iemura, Shun-Ichiro; Natsume, Tohru; Seimiya, Hiroyuki

    2017-02-15

    Tankyrase, a poly(ADP-ribose) polymerase (PARP) that promotes telomere elongation and Wnt/β-catenin signaling, has various binding partners, suggesting that it has as-yet unidentified functions. Here we report that the tankyrase-binding protein TNKS1BP1 regulates actin cytoskeleton and cancer cell invasion, which is closely associated with cancer progression. TNKS1BP1 colocalized with actin filaments and negatively regulated cell invasion. In TNKS1BP1-depleted cells, actin filament dynamics, focal adhesion, and lamellipodia ruffling were increased with activation of the ROCK-LIMK-cofilin pathway. TNKS1BP1 bound the actin capping protein CapZA2. TNKS1BP1 depletion dissociated CapZA2 from the cytoskeleton, leading to cofilin phosphorylation and enhanced cell invasion. Tankyrase overexpression increased cofilin phosphorylation, dissociated CapZA2 from cytoskeleton, and enhanced cell invasion in a PARP activity-dependent manner. In clinical samples of pancreatic cancer, TNKS1BP1 expression was reduced in invasive regions. We propose that the tankyrase-TNKS1BP1 axis constitutes a post-translational modulator of cell invasion whose aberration promotes cancer malignancy.

  15. A new SBP-box gene BpSPL1 in silver birch (Betula pendula).

    PubMed

    Lännenpää, Mika; Jänönen, Isto; Hölttä-Vuori, Maarit; Gardemeister, Marika; Porali, Ilkka; Sopanen, Tuomas

    2004-03-01

    The SBP-box gene family represents a group of plant-specific genes encoding putative transcription factors. Thus far, SBP-domain protein binding sites have been found in the promoters of Arabidopsis APETALA1 and Antirrhinum SQUAMOSA. A putative SBP-domain binding element has been observed in the promoter of BpMADS5, a close homologue of Arabidopsis FRUITFULL in silver birch (Betula pendula). A novel SBP-box gene from birch named BpSPL1 has been cloned and characterized. The nucleotide sequence of BpSPL1 is similar to Antirrhinum SBP2 and Arabidopsis SPL3, apart from the unique finding that BpSPL1 does not contain an intron typical to all other known SBP-box genes studied thus far. According to Northern blot analysis, BpSPL1 is expressed in birch inflorescences as well as in shoots and leaves. Studies using electrophoretic mobility shift assay demonstrate that there are nuclear proteins in birch inflorescences which specifically bind to the SBP binding element of the promoter of BpMADS5. BpSPL1 expressed in Escherichia coli also specifically binds to this element. According to Southern blot analysis, there are at least two SBP-box genes in birch. The results suggest that SBP-box genes are involved in the regulation of flower development in birch.

  16. Establishing a Dynamic Self-Adaptation Learning Algorithm of the BP Neural Network and Its Applications

    NASA Astrophysics Data System (ADS)

    Li, Xiaofeng; Xiang, Suying; Zhu, Pengfei; Wu, Min

    2015-12-01

    In order to avoid the inherent deficiencies of the traditional BP neural network, such as slow convergence speed, that easily leading to local minima, poor generalization ability and difficulty in determining the network structure, the dynamic self-adaptive learning algorithm of the BP neural network is put forward to improve the function of the BP neural network. The new algorithm combines the merit of principal component analysis, particle swarm optimization, correlation analysis and self-adaptive model, hence can effectively solve the problems of selecting structural parameters, initial connection weights and thresholds and learning rates of the BP neural network. This new algorithm not only reduces the human intervention, optimizes the topological structures of BP neural networks and improves the network generalization ability, but also accelerates the convergence speed of a network, avoids trapping into local minima, and enhances network adaptation ability and prediction ability. The dynamic self-adaptive learning algorithm of the BP neural network is used to forecast the total retail sale of consumer goods of Sichuan Province, China. Empirical results indicate that the new algorithm is superior to the traditional BP network algorithm in predicting accuracy and time consumption, which shows the feasibility and effectiveness of the new algorithm.

  17. Nuclear Astrophysics at LNL: The 10B(p, α )7Be Reaction Studied at the AN2000 Accelerator

    NASA Astrophysics Data System (ADS)

    Caciolli, Antonio

    The National Laboratory of Legnaro (LNL) has a wealth of experience in Nuclear Physics measurements. Recently a new effort to perform Nuclear Astrophysics studies has been initiated. This effort started with the collaboration of LNL with the LUNA (Laboratory for Underground Nuclear Astrophysics) collaboration for the study of targets. In 2014 the study of 10B(p, α )7Be was performed in order to give a precise normalisation to the indirect measurements. As a matter of fact, a normalization problem was raised in previous works due to discrepancies in the results of different experimental datasets. At LNL the cross section was determined by measuring the activated samples at the low counting facility of the LNL laboratory. The analysis of that experiment is now complete and a detailed report of the obtained results will be presented in this contribution.

  18. A 470 bp WAP-promoter fragment confers lactation independent, progesterone regulated mammary-specific gene expression in transgenic mice.

    PubMed

    Lipnik, Karoline; Petznek, Helga; Renner-Müller, Ingrid; Egerbacher, Monika; Url, Angelika; Salmons, Brian; Günzburg, Walter H; Hohenadl, Christine

    2005-04-01

    The ability of a 470 bp sub-fragment of the murine whey acidic protein (WAP) promoter in the context of a retroviral expression plasmid to direct gene expression to mammary epithelial cells was analysed in a number of independent transgenic mouse lines. In contrast to previous findings with the genuine 2.5 kb promoter fragment, our studies revealed a highly mammary gland-specific expression detectable only in non-lactating animals. This suggested a mainly progesterone-regulated activity of the short fragment. Therefore, transgene expression was examined in the progesterone-determined estrous cycle and during pregnancy. In accordance with in vitro data from stably transfected cell lines, in both situations expression was upregulated at stages associated with high progesterone levels. Taken together these data provide deeper insight into WAP-promoter regulation and stress the usefulness of the shortened fragment for a lactation independent mammary-targeted expression.

  19. Mutation particle swarm optimization of the BP-PID controller for piezoelectric ceramics

    NASA Astrophysics Data System (ADS)

    Zheng, Huaqing; Jiang, Minlan

    2016-01-01

    PID control is the most common used method in industrial control because its structure is simple and it is easy to implement. PID controller has good control effect, now it has been widely used. However, PID method has a few limitations. The overshoot of the PID controller is very big. The adjustment time is long. When the parameters of controlled plant are changing over time, the parameters of controller could hardly change automatically to adjust to changing environment. Thus, it can't meet the demand of control quality in the process of controlling piezoelectric ceramic. In order to effectively control the piezoelectric ceramic and improve the control accuracy, this paper replaced the learning algorithm of the BP with the mutation particle swarm optimization algorithm(MPSO) on the process of the parameters setting of BP-PID. That designed a better self-adaptive controller which is combing the BP neural network based on mutation particle swarm optimization with the conventional PID control theory. This combination is called the MPSO-BP-PID. In the mechanism of the MPSO, the mutation operation is carried out with the fitness variance and the global best fitness value as the standard. That can overcome the precocious of the PSO and strengthen its global search ability. As a result, the MPSO-BP-PID can complete controlling the controlled plant with higher speed and accuracy. Therefore, the MPSO-BP-PID is applied to the piezoelectric ceramic. It can effectively overcome the hysteresis, nonlinearity of the piezoelectric ceramic. In the experiment, compared with BP-PID and PSO-BP-PID, it proved that MPSO is effective and the MPSO-BP-PID has stronger adaptability and robustness.

  20. Stress Granule Components G3BP1 and G3BP2 Play a Proviral Role Early in Chikungunya Virus Replication

    PubMed Central

    Scholte, Florine E. M.; Tas, Ali; Albulescu, Irina C.; Žusinaite, Eva; Merits, Andres; Snijder, Eric J.

    2015-01-01

    ABSTRACT Stress granules (SGs) are protein-mRNA aggregates that are formed in response to environmental stresses, resulting in translational inhibition. SGs are generally believed to play an antiviral role and are manipulated by many viruses, including various alphaviruses. GTPase-activating protein (SH3 domain)-binding protein 1 (G3BP1) is a key component and commonly used marker of SGs. Its homolog G3BP2 is a less extensively studied SG component. Here, we demonstrate that Chikungunya virus (CHIKV) infection induces cytoplasmic G3BP1- and G3BP2-containing granules that differ from bona fide SGs in terms of morphology, composition, and behavior. For several Old World alphaviruses it has been shown that nonstructural protein 3 (nsP3) interacts with G3BPs, presumably to inhibit SG formation, and we have confirmed this interaction in CHIKV-infected cells. Surprisingly, CHIKV also relied on G3BPs for efficient replication, as simultaneous depletion of G3BP1 and G3BP2 reduced viral RNA levels, CHIKV protein expression, and viral progeny titers. The G3BPs colocalized with CHIKV nsP2 and nsP3 in cytoplasmic foci, but no colocalization with nsP1, nsP4, or dsRNA was observed. Furthermore, G3BPs could not be detected in a cellular fraction enriched for CHIKV replication/transcription complexes, suggesting that they are not directly involved in CHIKV RNA synthesis. Depletion of G3BPs did not affect viral entry, translation of incoming genomes, or nonstructural polyprotein processing but resulted in severely reduced levels of negative-stranded (and consequently also positive-stranded) RNA. This suggests a role for the G3BPs in the switch from translation to genome amplification, although the exact mechanism by which they act remains to be explored. IMPORTANCE Chikungunya virus (CHIKV) causes a severe polyarthritis that has affected millions of people since its reemergence in 2004. The lack of approved vaccines or therapeutic options and the ongoing explosive outbreak in the

  1. Sex, Prescribing Practices and Guideline Recommended, Blood Pressure, and LDL Cholesterol Targets at Baseline in the BARI 2D Trial

    PubMed Central

    Magee, Michelle F.; Tamis-Holland, Jacqueline E.; Lu, Jiang; Bittner, Vera A.; Brooks, Maria Mori; Lopes, Neuza; Jacobs, Alice K.; Study Group, BARI 2D

    2015-01-01

    Background. Research has shown less aggressive treatment and poorer control of cardiovascular disease (CVD) risk factors in women than men. Methods. We analyzed sex differences in pharmacotherapy strategies and attainment of goals for hemoglobin A1c (HbA1c), blood pressure (BP), and low density lipoprotein cholesterol (LDL-C) in patients with type 2 diabetes and established coronary artery disease enrolled into the BARI 2D trial. Results. Similar numbers of drugs were prescribed in both women and men. Women were less frequent on metformin or sulfonylurea and more likely to take insulin and to be on higher doses of hydroxymethylglutaryl-CoA reductase inhibitors (statins) than men. After adjusting for baseline differences and treatment prescribed, women were less likely to achieve goals for HbA1c (OR = 0.71, 95% CI 0.57, 0.88) and LDL-C (OR = 0.64, 95% CI 0.53, 0.78). More antihypertensives were prescribed to women, and yet BP ≤ 130/80 mmHg did not differ by sex. Conclusions. Women entering the BARI 2D trial were as aggressively treated with drugs as men. Despite equivalent treatment, women less frequently met targets for HbA1c and LDL-C. Our findings suggest that there may be sex differences in response to drug therapies used to treat diabetes, hypertension, and hyperlipidemia. PMID:25873955

  2. Genetic and Morphological Features of Human iPSC-Derived Neurons with Chromosome 15q11.2 (BP1-BP2) Deletions

    PubMed Central

    Das, Dhanjit K.; Tapias, Victor; D'Aiuto, Leonardo; Chowdari, Kodavali V.; Francis, Lily; Zhi, Yun; Ghosh, Ayantika; Surti, Urvashi; Tischfield, Jay; Sheldon, Michael; Moore, Jennifer C.; Fish, Ken; Nimgaonkar, Vishwajit L.

    2015-01-01

    Background Copy number variation on chromosome 15q11.2 (BP1-BP2) causes a deletion of CYFIP1, NIPA1, NIPA2 and TUBGCP5. Furthermore, it also affects brain structure and elevates the risk for several neurodevelopmental disorders that are associated with dendritic spine abnormalities. In rodents, altered cyfip1 expression changes dendritic spine morphology, motivating analyses of human neuronal cells derived from induced pluripotent stem cells (iPSCs; iPSC-neurons). Methods iPSCs were generated from a mother and her offspring, both carrying the 15q11.2 (BP1-BP2) deletion, and a non-deletion control. Gene expression in the deletion region was estimated using quantitative real-time PCR assays. Neural progenitor cells (NPCs) and iPSC-neurons were characterized using immunocytochemistry. Results CYFIP1, NIPA1, NIPA2 and TUBGCP5 gene expression was lower in iPSCs, NPCs and iPSC-neurons from the mother and her offspring in relation to control cells. CYFIP1 and PSD-95 protein levels were lower in iPSC-neurons derived from the copy number variant-bearing individuals using Western blot analysis. Ten weeks after differentiation, iPSC-neurons appeared to show dendritic spines, and qualitative analysis suggested that dendritic morphology was altered in 15q11.2-deletion subjects compared with control cells. Conclusions The 15q11.2 (BP1-BP2) deletion is associated with a reduced expression of four genes in iPSC-derived neuronal cells; it may also be associated with altered iPSC-neuron dendritic morphology. PMID:26528485

  3. Geoarchaeological evidence from Peru for a 5000 years B.P. onset of El Nino

    SciTech Connect

    Sandweiss, D.H.; Richardson, J.B. III; Rollins, H.B.

    1996-09-13

    For the tropical west coast of South America, where El Nino/Southern Oscillation (ENSO) is most pronounced, archaeological and associated paleontological deposits in northern Peru revealed a major climate change at about 5000 years before the present (yr B.P.). The data implied the presence of stable, warm tropical water as far south as 10{degrees}S during the early mid-Holocene (about 8000 to 5000 yr B.P.). These data suggest that ENSO did not occur for some millennia preceding 5000 yr B.P., when global and regional climate was warmer than today. 36 refs., 1 fig., 3 tabs.

  4. Two Isoforms of the RNA Binding Protein, Coding Region Determinant-binding Protein (CRD-BP/IGF2BP1), Are Expressed in Breast Epithelium and Support Clonogenic Growth of Breast Tumor Cells.

    PubMed

    Fakhraldeen, Saja A; Clark, Rod J; Roopra, Avtar; Chin, Emily N; Huang, Wei; Castorino, John; Wisinski, Kari B; Kim, TaeWon; Spiegelman, Vladimir S; Alexander, Caroline M

    2015-05-22

    CRD-BP/IGF2BP1 has been characterized as an "oncofetal" RNA binding protein typically highly expressed in embryonic tissues, suppressed in normal adult tissues, but induced in many tumor types. In this study, we show that adult breast tissues express ubiquitous but low levels of CRD-BP protein and mRNA. Although CRD-BP mRNA expression is induced in breast tumor cells, levels remain ∼1000-fold lower than in embryonic tissues. Despite low expression levels, CRD-BP is required for clonogenic growth of breast cancer cells. We reveal that because the most common protein isoform in normal adult breast and breast tumors has an N-terminal deletion (lacking two RNA recognition motif (RRM) domains) and is therefore missing antibody epitopes, CRD-BP expression has been under-reported by previous studies. We show that a CRD-BP mutant mouse strain retains expression of the shorter transcript (ΔN-CRD-BP), which originates in intron 2, suggesting that the impact of complete ablation of this gene in mice is not yet known. Either the full-length CRD-BP or the N-terminally truncated version can rescue the clonogenicity of CRD-BP knockdown breast cancer cells, suggesting that clonogenic function is served by either CRD-BP isoform. In summary, although CRD-BP expression levels are low in breast cancer cells, this protein is necessary for clonogenic activity.

  5. Clinical and Immunological Studies of 332 Japanese Patients Tentatively Diagnosed as Anti-BP180-type Mucous Membrane Pemphigoid: A Novel BP180 C-terminal Domain Enzyme-linked Immunosorbent Assay.

    PubMed

    Yasukochi, Atsushi; Teye, Kwesi; Ishii, Norito; Hashimoto, Takashi

    2016-08-23

    Diagnosis of anti-BP180-type mucous membrane pemphigoid (BP180-MMP) is frustrated by the difficulty of detecting BP180 reactivity. A total of 721 patients with suspected MMP, selected from a cohort of 4,698 patients with autoimmune bullous disease (AIBD), were included in this study. Of these, 332 patients were tentatively diagnosed as BP180-MMP if they showed IgG/IgA reactivity with the epidermal side of 1M NaCl-split-skin and/or positive reactivity with BP180 in at least one of our antigen detection methods. Clinically, a predominance of female patients was found. Oral mucosal and cutaneous lesions were found in 85.5% and 41.0% of patients, respectively, and frequent treatments were systemic steroids, tetracycline/minocycline and diaminodiphenyl sulfone. Various immunological methods, including a newly developed BP180 C-terminal domain enzyme-linked immunosorbent assay (ELISA), revealed frequent reactivity with BP180 C-terminal and NC16a domains. Some patients reacted with BP180 and other antigens, indicating that BP180-MMP tends to concur with other AIBDs. This large study of patients with suspected BP180-MMP indicates the difficulty of diagnosis of BP180-MMP and the diagnostic usefulness of BP180 C-terminal domain ELISA.

  6. Molecular mechanism of the dual activity of 4EGI-1: Dissociating eIF4G from eIF4E but stabilizing the binding of unphosphorylated 4E-BP1

    SciTech Connect

    Sekiyama, Naotaka; Arthanari, Haribabu; Papadopoulos, Evangelos; Rodriguez-Mias, Ricard A.; Wagner, Gerhard; Léger-Abraham, Mélissa

    2015-07-13

    The eIF4E-binding protein (4E-BP) is a phosphorylation-dependent regulator of protein synthesis. The nonphosphorylated or minimally phosphorylated form binds translation initiation factor 4E (eIF4E), preventing binding of eIF4G and the recruitment of the small ribosomal subunit. Signaling events stimulate serial phosphorylation of 4E-BP, primarily by mammalian target of rapamycin complex 1 (mTORC1) at residues T37/T46, followed by T70 and S65. Hyperphosphorylated 4E-BP dissociates from eIF4E, allowing eIF4E to interact with eIF4G and translation initiation to resume. Because overexpression of eIF4E is linked to cellular transformation, 4E-BP is a tumor suppressor, and up-regulation of its activity is a goal of interest for cancer therapy. A recently discovered small molecule, eIF4E/eIF4G interaction inhibitor 1 (4EGI-1), disrupts the eIF4E/eIF4G interaction and promotes binding of 4E-BP1 to eIF4E. Structures of 14- to 16-residue 4E-BP fragments bound to eIF4E contain the eIF4E consensus binding motif, 54YXXXXLΦ60 (motif 1) but lack known phosphorylation sites. We report in this paper a 2.1-Å crystal structure of mouse eIF4E in complex with m7GTP and with a fragment of human 4E-BP1, extended C-terminally from the consensus-binding motif (4E-BP150–84). The extension, which includes a proline-turn-helix segment (motif 2) followed by a loop of irregular structure, reveals the location of two phosphorylation sites (S65 and T70). Our major finding is that the C-terminal extension (motif 3) is critical to 4E-BP1–mediated cell cycle arrest and that it partially overlaps with the binding site of 4EGI-1. Finally, the binding of 4E-BP1 and 4EGI-1 to eIF4E is therefore not mutually exclusive, and both ligands contribute to shift the equilibrium toward the inhibition of translation initiation.

  7. Molecular mechanism of the dual activity of 4EGI-1: Dissociating eIF4G from eIF4E but stabilizing the binding of unphosphorylated 4E-BP1

    DOE PAGES

    Sekiyama, Naotaka; Arthanari, Haribabu; Papadopoulos, Evangelos; ...

    2015-07-13

    The eIF4E-binding protein (4E-BP) is a phosphorylation-dependent regulator of protein synthesis. The nonphosphorylated or minimally phosphorylated form binds translation initiation factor 4E (eIF4E), preventing binding of eIF4G and the recruitment of the small ribosomal subunit. Signaling events stimulate serial phosphorylation of 4E-BP, primarily by mammalian target of rapamycin complex 1 (mTORC1) at residues T37/T46, followed by T70 and S65. Hyperphosphorylated 4E-BP dissociates from eIF4E, allowing eIF4E to interact with eIF4G and translation initiation to resume. Because overexpression of eIF4E is linked to cellular transformation, 4E-BP is a tumor suppressor, and up-regulation of its activity is a goal of interest formore » cancer therapy. A recently discovered small molecule, eIF4E/eIF4G interaction inhibitor 1 (4EGI-1), disrupts the eIF4E/eIF4G interaction and promotes binding of 4E-BP1 to eIF4E. Structures of 14- to 16-residue 4E-BP fragments bound to eIF4E contain the eIF4E consensus binding motif, 54YXXXXLΦ60 (motif 1) but lack known phosphorylation sites. We report in this paper a 2.1-Å crystal structure of mouse eIF4E in complex with m7GTP and with a fragment of human 4E-BP1, extended C-terminally from the consensus-binding motif (4E-BP150–84). The extension, which includes a proline-turn-helix segment (motif 2) followed by a loop of irregular structure, reveals the location of two phosphorylation sites (S65 and T70). Our major finding is that the C-terminal extension (motif 3) is critical to 4E-BP1–mediated cell cycle arrest and that it partially overlaps with the binding site of 4EGI-1. Finally, the binding of 4E-BP1 and 4EGI-1 to eIF4E is therefore not mutually exclusive, and both ligands contribute to shift the equilibrium toward the inhibition of translation initiation.« less

  8. Childhood vaccination: achievements and challenges.

    PubMed

    Ndumbe, P

    1996-09-01

    As the goal of eradicating smallpox was being met, the World Health Organization created its Expanded Programme on Immunisation (EPI) in 1974 and reached its initial goal of achieving full vaccination of 80% of the world's children by 1990. This effort was aided by the creation of "cold chain" delivery systems and resulted in the annual saving of 3.5 million children in less-developed countries. Current EPI vaccination goals include 1) eradication of poliomyelitis by the year 2000, 2) elimination of neonatal tetanus by the year 1995, 3) control of measles and hepatitis B, and 4) immunization of 90% of the world's children 1 year or younger by the year 2000. Goals of the Children's Vaccine Initiative (formed in 1991) include 1) provision of an adequate supply of affordable, safe, and effective vaccines; 2) production of improved and new vaccines; and 3) simplification of the logistics of vaccine delivery. Future challenges are to sustain high vaccination coverage, reach the unreached, achieve proper storage of vaccines and reduce waste, integrate new vaccines into national programs, and achieve vaccine self-sufficiency. The fact that these challenges will be difficult to achieve is illustrated by the situation in Africa where the high immunization levels achieved in 1990 have dropped dramatically. Those who must act to implement immunization programs are health personnel, families, governments, and development partners. In order to achieve equity in health, every child must be reached, governments must be made accountable for programs, health workers must convince families of the importance of vaccination, delivery systems must be in place to take advantage of the new vaccines being delivered, and a multisectoral approach must be taken to assure sustainability.

  9. Conduit Magma Storage during the 800 BP Quilotoa Eruption, Ecuador

    NASA Astrophysics Data System (ADS)

    Ort, M. H.; Cashman, K. V.; Di Muro, A.; Best, J. A.; Rosi, M.; Mothes, P. A.; Bustillos, J.

    2013-12-01

    The 800 BP eruption of Quilotoa produced two large ignimbrites, U1 (~5.8 km3 DRE) and U3 (~1.8 km3 DRE). These eruptions were separated by a series of much smaller eruptions over one to several weeks, as inferred from 1) the intercalation of secondary pyroclastic and debris flow deposits between U1 and U3, 2) deposits from phreatic explosions from the U1 ignimbrite surface, 3) oxidation of the upper 2 m of U1, and 4) a lack of erosion of the U1 surface. Why did the main phase of the eruption (U1) stall when eruptable magma was available? How did explosive activity stop and restart? We address these questions by examining deposits (U2) emplaced during the 'hiatus' that provide information on the conditions in the conduit and vent area between explosive episodes. The lowest sub-unit, U2a, forms a series of pumiceous surge deposits found only within 5 km of the crater rim. U2b is a vitric-poor, crystal- and lithic-rich fall deposit distributed to about 15 km from the crater. U2c is a thin gray fine ash containing 2-5-mm-diameter rhyolite lapilli that is present within 6 km of the vent. Similar lapilli also occur in the lowermost few centimeters of U3 and appear to be from a dome that exploded as the new magma arrived at the surface; their presence as small ballistic fragments ties U2c to lowermost U3 in time. U2a appears to have been emplaced by episodic surges and weak fallout plumes, whereas U2b and U2c were deposited from a series of sustained eruption columns. Moreover, the lack of U2b grain-size variation with distance suggests that the grain size was determined at the vent, not by transport. FTIR analysis of CO2 and H2O in melt inclusions (MIs) indicates that a deep magma chamber (>400 MPa; ~12 km) fed U1. U2a and U2b MIs plot along vapor isopleths, suggesting equilibration at pressures to about 300 MPa as CO2 outgassed. U2b MIs have lower CO2 than U2a, perhaps indicating continued degassing during the 'hiatus'. MIs from the lower few centimeters of U3 lie along

  10. Environmental Conditions in northern Gulf of Mexico Estuaries: before and after the BP Oil Spill

    EPA Science Inventory

    This presentation provides a summary of ecological condition and sediment chemistry data for northern Gulf of Mexico estuaries that were exposed to oil and oil-related contaminants from the BP Oil Spill.

  11. 1. ENVIRONMENT, FROM NORTHWEST, SHOWING B&P INTERLOCKING TOWER AND POWER ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    1. ENVIRONMENT, FROM NORTHWEST, SHOWING B&P INTERLOCKING TOWER AND POWER SUBSTATIONS - Baltimore & Potomac Interlocking Tower, Adjacent to AMTRAK railroad tracks in block bounded by Howard Street, Jones Falls Expressway, Maryland Avenue & Falls Road, Baltimore, Independent City, MD

  12. 53BP1 regulates DSB repair using Rif1 to control 5' end resection.

    PubMed

    Zimmermann, Michal; Lottersberger, Francisca; Buonomo, Sara B; Sfeir, Agnel; de Lange, Titia

    2013-02-08

    The choice between double-strand break (DSB) repair by either homology-directed repair (HDR) or nonhomologous end joining (NHEJ) is tightly regulated. Defects in this regulation can induce genome instability and cancer. 53BP1 is critical for the control of DSB repair, promoting NHEJ, and inhibiting the 5' end resection needed for HDR. Using dysfunctional telomeres and genome-wide DSBs, we identify Rif1 as the main factor used by 53BP1 to impair 5' end resection. Rif1 inhibits resection involving CtIP, BLM, and Exo1; limits accumulation of BRCA1/BARD1 complexes at sites of DNA damage; and defines one of the mechanisms by which 53BP1 causes chromosomal abnormalities in Brca1-deficient cells. These data establish Rif1 as an important contributor to the control of DSB repair by 53BP1.

  13. Synthetic Minor NSR Permit: BP America Production Company - Salvador I/II Central Delivery Point

    EPA Pesticide Factsheets

    This page contains the final synthetic minor NSR permit for the BP America Production Company, Salvador I/II Central Delivery Point, located on the Southern Ute Indian Reservation in La Plata County, CO.

  14. ERK1/2 is dephosphorylated by a novel phosphatase--CacyBP/SIP.

    PubMed

    Kilanczyk, Ewa; Filipek, Slawomir; Filipek, Anna

    2011-01-07

    Recently, we have reported that the CacyBP/SIP protein binds ERK1/2 (Kilanczyk et al., BBRC, 2009). In this work we show that CacyBP/SIP exhibits a phosphatase activity toward ERK1/2 kinases while its E217K mutant does not. The K(m) and V(max) values established for a standard phosphatase substrate, p-NPP, are 16.9±3.6 mM and 4.3±0.4 μmol/min, respectively. The CacyBP/SIP phosphatase activity is decreased by okadaic acid (IC(50)=45 nM). Our experimental results are supported by a theoretical analysis which revealed important sequence similarities between CacyBP/SIP and the phosphatase-like proteins as well as certain MAP kinase phosphatases.

  15. Synthetic Minor NSR Permit: BP America Production Company - Wolf Point Central Delivery Point

    EPA Pesticide Factsheets

    This page contains the response to public comments and the final synthetic minor NSR permit for the BP America Production Company, Wolf Point Central Delivery Point, located on the Southern Ute Indian Reservation in La Plata County, CO.

  16. Synthetic Minor NSR Permit: BP America Production Company - Treating Site #8 Central Delivery Point

    EPA Pesticide Factsheets

    This page contains the response to public comments and the final synthetic minor NSR permit for the BP America Production Company, Treating Site #8 Central Delivery Point, located on the Southern Ute Indian Reservation in La Plata County, CO.

  17. Characterization of a birch (Betula pendula Roth.) embryogenic gene, BP8.

    PubMed

    Puupponen-Pimiä, R; Saloheimo, M; Vasara, T; Ra, R; Gaugecz, J; Kurtén, U; Knowles, J K; Keränen, S; Kauppinen, V

    1993-10-01

    We have isolated the birch homologue (BP8) for the carrot embryogenic gene DC8 by heterologous hybridization. The birch BP8 gene encodes a putative protein of 53 kDa, showing 52% sequence identity with the DC8 gene at the amino acid level. The putative BP8 protein contains 20 repeats of 11 amino acids and thus belongs to the group of LEA proteins isolated from such plants as carrot, cotton and wheat. Northern hybridization of mRNA isolated from birch cells representing different stages of somatic embryogenesis and non-embryogenetic material with a PB8 probe gave no signals, suggesting a low expression level of the BP8 gene.

  18. AAV-Mediated Transduction and Targeting of Retinal Bipolar Cells with Improved mGluR6 Promoters in Rodents and Primates

    PubMed Central

    Lu, Q; Ganjawala, TH; Ivanova, E; Cheng, JG; Troilo, D; Pan, Z-H

    2016-01-01

    Adeno-associated virus (AAV) vectors have been a powerful gene delivery vehicle to the retina for basic research and gene therapy. For many of these applications, achieving cell-type specific targeting and high transduction efficiency is desired. Recently, there has been increasing interest in AAV-mediated gene targeting to specific retinal bipolar cell types. A 200-bp enhancer in combination with a basal SV40 promoter has been commonly used to target transgenes into ON-type bipolar cells. In the current study, we searched for additional cis-regulatory elements in the mGluR6 gene for improving AAV-mediated transduction efficiency into retinal bipolar cells. Our results showed that the combination of the endogenous mGluR6 promoter with additional enhancers in the introns of the mGluR6 gene markedly enhanced AAV transduction efficiency as well as made the targeting more selective for rod bipolar cells in mice. Furthermore, the AAV vectors with the improved promoter could target to ON bipolar cells with robust transduction efficiency in the para-fovea and the far peripheral retina of marmoset monkeys. The improved mGluR6 promoter constructs could provide a valuable tool for genetic manipulation in rod bipolar cells in mice and facilitate clinical applications for ON bipolar cell-based gene therapies. PMID:27115727

  19. AAV-mediated transduction and targeting of retinal bipolar cells with improved mGluR6 promoters in rodents and primates.

    PubMed

    Lu, Q; Ganjawala, T H; Ivanova, E; Cheng, J G; Troilo, D; Pan, Z-H

    2016-08-01

    Adeno-associated virus (AAV) vectors have been a powerful gene delivery vehicle to the retina for basic research and gene therapy. For many of these applications, achieving cell type-specific targeting and high transduction efficiency is desired. Recently, there has been increasing interest in AAV-mediated gene targeting to specific retinal bipolar cell types. A 200-bp enhancer in combination with a basal SV40 promoter has been commonly used to target transgenes into ON-type bipolar cells. In the current study, we searched for additional cis-regulatory elements in the mGluR6 gene for improving AAV-mediated transduction efficiency into retinal bipolar cells. Our results showed that the combination of the endogenous mGluR6 promoter with additional enhancers in the introns of the mGluR6 gene markedly enhanced AAV transduction efficiency as well as made the targeting more selective for rod bipolar cells in mice. Furthermore, the AAV vectors with the improved promoter could target to ON bipolar cells with robust transduction efficiency in the parafovea and the far peripheral retina of marmoset monkeys. The improved mGluR6 promoter constructs could provide a valuable tool for genetic manipulation in rod bipolar cells in mice and facilitate clinical applications for ON bipolar cell-based gene therapies.

  20. Role of the CacyBP/SIP protein in gastric cancer.

    PubMed

    Zhai, Huihong; Meng, Juan; Jin, Haifeng; Li, Yuanfei; Wang, Jinbo

    2015-05-01

    Various reports indicate that calcyclin binding protein/Siah-1-interacting protein (CacyBP/SIP) is an important protein in tumorigenesis, but whether CacyBP/SIP promotes or suppresses cancer may depend on the cell type. In order to investigate whether CacyBP/SIP is significant in gastric cancerous tumorigenesis, the present study used immunohistochemistry to analyze 181 gastric cancer tissue samples, as well as 181 healthy tissue samples from the same gastric cancer patients. The immunohistochemical results were compared against patient data and pathological analysis of the tissue slices, including gender, age, degree of tumor differentiation and tumor, node, metastasis (TNM) stage. In addition, the level of CacyBP/SIP expression was detected in three frozen tissue samples of gastric adenocarcinoma using western blot analysis. Of the 181 cases analyzed in the present study, 80 cases were identified as non-metastatic gastric cancer and 101 cases were identified as gastric cancer that had metastasized to the lymph nodes. Tissue biopsies from the two sets of patients were examined using immunohistochemistry to identify the level of CacyBP/SIP expression in metastatic and primary gastric cancer tissues. Statistical analyses were performed on all data. The immunohistochemical analysis revealed that CacyBP/SIP was expressed in 31% (56/181) of gastric adenocarcinoma tissue samples and 7% (12/181) of adjacent non-cancerous gastric tissues (P<0.05). Furthermore, the expression levels of CacyBP/SIP were higher in cancerous tissue compared with the adjacent non-cancerous gastric tissue using western blotting. No association was identified between CacyBP/SIP expression and patient age (P=0.975), gender (P=0.185), degree of tumor differentiation (P=0.076) or TNM stage (P=0.979). Among the 101 patients with metastatic gastric cancer, CacyBP/SIP was expressed at primary sites in 31% (31/101) of cases and at metastatic sites in 26% (26/101) of cases (P=0.434). However, among the

  1. Implementing Target Value Design.

    PubMed

    Alves, Thais da C L; Lichtig, Will; Rybkowski, Zofia K

    2017-04-01

    An alternative to the traditional way of designing projects is the process of target value design (TVD), which takes different departure points to start the design process. The TVD process starts with the client defining an allowable cost that needs to be met by the design and construction teams. An expected cost in the TVD process is defined through multiple interactions between multiple stakeholders who define wishes and others who define ways of achieving these wishes. Finally, a target cost is defined based on the expected profit the design and construction teams are expecting to make. TVD follows a series of continuous improvement efforts aimed at reaching the desired goals for the project and its associated target value cost. The process takes advantage of rapid cycles of suggestions, analyses, and implementation that starts with the definition of value for the client. In the traditional design process, the goal is to identify user preferences and find solutions that meet the needs of the client's expressed preferences. In the lean design process, the goal is to educate users about their values and advocate for a better facility over the long run; this way owners can help contractors and designers to identify better solutions. This article aims to inform the healthcare community about tools and techniques commonly used during the TVD process and how they can be used to educate and support project participants in developing better solutions to meet their needs now as well as in the future.

  2. Washington State's Student Achievement Initiative

    ERIC Educational Resources Information Center

    Pettitt, Maureen; Prince, David

    2010-01-01

    This article describes Washington State's Student Achievement Initiative, an accountability system implemented in 2005-06 that measures students' gains in college readiness, college credits earned, and degree or certificate completion. The goal of the initiative is to increase educational attainment by focusing on the critical momentum points…

  3. Meeting a Math Achievement Crisis

    ERIC Educational Resources Information Center

    Jennings, Lenora; Likis, Lori

    2005-01-01

    An urban community spotlighted declining mathematics achievement and took some measures, in which the students' performance increased substantially. The Benjamin Banneker Charter Public School in Cambridge, Massachusetts, engaged the entire community and launched the campaign called "Math Everywhere", which changed Benjamin Banneker's…

  4. Socioeconomic Determinants of Academic Achievement

    ERIC Educational Resources Information Center

    Tomul, Ekber; Savasci, Havva Sebile

    2012-01-01

    This study aims to investigate the relationship between academic achievement and the socioeconomic characteristics of elementary school 7th grade students in Burdur. The population of the study are 7th grade students who had education at elementary schools in Burdur in the 2007-2008 academic year. Two staged sampling was chosen as suitable for the…

  5. Goal Setting to Achieve Results

    ERIC Educational Resources Information Center

    Newman, Rich

    2012-01-01

    Both districts and individual schools have a very clear set of goals and skills for their students to achieve and master. In fact, except in rare cases, districts and schools develop very detailed goals they wish to pursue. In most cases, unfortunately, only the teachers and staff at a particular school or district-level office are aware of the…

  6. School Districts and Student Achievement

    ERIC Educational Resources Information Center

    Chingos, Matthew M.; Whitehurst, Grover J.; Gallaher, Michael R.

    2015-01-01

    School districts are a focus of education reform efforts in the United States, but there is very little existing research about how important they are to student achievement. We fill this gap in the literature using 10 years of student-level, statewide data on fourth- and fifth-grade students in Florida and North Carolina. A variance decomposition…

  7. Student Achievement, 1986-87.

    ERIC Educational Resources Information Center

    Mangino, Evangelina

    This report summarizes results of student achievement in the Austin (Texas) Independent School District (AISD) on the Texas Educational Assessment of Minimum Skills (TEAMS) tests in 1986-87. Major findings indicate the following: (1) 99.4% of AISD seniors to graduate in May 1987 passed the Exit-Level TEAMS tests, with only 17 denied diplomas in…

  8. Sociocultural Variation in Literacy Achievement

    ERIC Educational Resources Information Center

    Verhoeven, Ludo

    2006-01-01

    The purpose of this study was to describe the variations in literacy achievement among native and non-native upper primary school children (grades three to six) in the Netherlands. Various measures of word decoding, reading literacy and writing skill were collected from 1091 native Dutch children, 753 children with a former Dutch colonial…

  9. Game Addiction and Academic Achievement

    ERIC Educational Resources Information Center

    Sahin, Mehmet; Gumus, Yusuf Yasin; Dincel, Sezen

    2016-01-01

    The primary aim of this study was to investigate the correlation between game addiction and academic achievement. The secondary aim was to adapt a self-report instrument to measure game addiction. Three hundred and seventy high school students participated in this study. Data were collected via an online questionnaire that included a brief…

  10. The Widening Income Achievement Gap

    ERIC Educational Resources Information Center

    Reardon, Sean F.

    2013-01-01

    Has the academic achievement gap between high-income and low-income students changed over the last few decades? If so, why? And what can schools do about it? Researcher Sean F. Reardon conducted a comprehensive analysis of research to answer these questions and came up with some striking findings. In this article, he shows that income-related…

  11. Attribution Theory in Science Achievement

    ERIC Educational Resources Information Center

    Craig, Martin

    2013-01-01

    Recent research reveals consistent lags in American students' science achievement scores. Not only are the scores lower in the United States compared to other developed nations, but even within the United States, too many students are well below science proficiency scores for their grade levels. The current research addresses this problem by…

  12. Grouping Students for Increased Achievements.

    ERIC Educational Resources Information Center

    Holloway, John H.

    2001-01-01

    Reviews results of four recent studies exploring the effects of various student-grouping schemes on academic achievement. Grouping plans included multiage classrooms, full-time ability grouping, and within-classroom grouping. Two studies investigated administrator attitudes toward student grouping. Several studies found that grouping plans…

  13. Achievement, Hedonism and the Teacher.

    ERIC Educational Resources Information Center

    Ryan, Kevin

    1991-01-01

    The problem of poor school achievement is in part because students lack work and discipline values. The article suggests moral and ethical teachings inspire students to be better scholars and people; and teacher education must prepare teachers to be moral educators by reintroducing moral education into the curriculum. (SM)

  14. School Desegregation and Black Achievement.

    ERIC Educational Resources Information Center

    Cook, Thomas; And Others

    Seven papers commissioned by the National Institute of Education in order to clarify the state of recent knowledge about the effects of school desegregation on the academic achievement of black students are contained in this report. The papers, which analyze 19 "core" empirical studies on this topic, include: (1) "What Have Black Children Gained…

  15. Institutional Climate and Minority Achievement.

    ERIC Educational Resources Information Center

    Richardson, Richard C.

    This paper discusses ways that institutions can change the higher education system and environment to accommodate more minority students. The first section, "Institutional Climate and Minority Achievement," presents an overview of the problems facing colleges and universities with respect to recruiting and retaining minority students. In the…

  16. Faculty Development: Assessing Learner Achievement.

    ERIC Educational Resources Information Center

    Frey, Barbara A.; Overfield, Karen

    This study addressed the challenges of developing a faculty professional development workshop on assessment, measurement, and evaluation of achievement in adult learners. The setting for the workshop was a system of postsecondary career colleges throughout the United States. The curriculum development model of D. Kirkpatrick (1994) was used as a…

  17. Can Judges Improve Academic Achievement?

    ERIC Educational Resources Information Center

    Greene, Jay P.; Trivitt, Julie R.

    2008-01-01

    Over the last 3 decades student achievement has remained essentially unchanged in the United States, but not for a lack of spending. Over the same period a myriad of education reforms have been suggested and per-pupil spending has more than doubled. Since the 1990s the education reform attempts have frequently included judicial decisions to revise…

  18. Achieving a sustainable service advantage.

    PubMed

    Coyne, K P

    1993-01-01

    Many managers believe that superior service should play little or no role in competitive strategy; they maintain that service innovations are inherently copiable. However, the author states that this view is too narrow. For a company to achieve a lasting service advantage, it must base a new service on a capability gap that competitors cannot or will not copy.

  19. Teacher Dispositions and Student Achievement

    ERIC Educational Resources Information Center

    Vaughn, Kathleen Adams

    2012-01-01

    In an effort to close the achievement gap between students of minority and majority populations and between students in higher and lower economic circumstances, the National Council for the Accreditation of Teacher Education (NCATE) added instruction and evaluation of teacher dispositions to its requirements for credentialing prospective teachers.…

  20. Epistemological Beliefs and Academic Achievement

    ERIC Educational Resources Information Center

    Arslantas, Halis Adnan

    2016-01-01

    This study aimed to identify the relationship between teacher candidates' epistemological beliefs and academic achievement. The participants of the study were 353 teacher candidates studying their fourth year at the Education Faculty. The Epistemological Belief Scale was used which adapted to Turkish through reliability and validity work by…

  1. Cherubism Gene Sh3bp2 is Important for Optimal Bone Formation, Osteoblast Differentiation and Function

    PubMed Central

    Mukherjee, Padma M.; Wang, Chiachien J.; Chen, I-Ping; Jafarov, Toghrul; Olsen, Bjorn R.; Ueki, Yasuyoshi; Reichenberger, Ernst J.

    2012-01-01

    Introduction Cherubism is a human genetic disorder that causes bilateral symmetrical enlargement of the maxilla and mandible in children. It is caused by mutations in SH3BP2. The exact pathogenesis of the disorder is an area of active research. Sh3bp2 knock-in mice were developed by introducing a Pro416Arg mutation (Pro418Arg in humans) in the mouse genome. The osteoclast phenotype of this mouse model was recently described. Methods We examined the bone phenotype of the cherubism mouse model, the role of Sh3bp2 during bone formation, osteoblast differentiation and osteoblast function. Results We observed delays in early postnatal development of homozygous Sh3bp2KI/KI mice. Sh3bp2KI/KI mice exhibit increased growth plate thickness and significantly decreased trabecular bone thickness and reduced bone mineral density. Histomorphometric and μ-CT analyses reveal bone loss in cranial and appendicular skeleton. Sh3bp2KI/KI mice also exhibit a significant decrease in osteoid formation that indicates a defect in osteoblast function. Calvarial osteoblast cell cultures exhibit a decrease in alkaline phosphatase expression and mineralization suggesting reduced differentiation potential. Gene expression of osteoblast differentiation markers like collagen type-I, alkaline phosphatase and osteocalcin are decreased in osteoblast cultures from Sh3bp2KI/KI mice. Conclusions These data suggest that Sh3bp2 function regulates bone homeostasis not only through osteoclast-specific effects but also through effects on osteoblast differentiation and function. PMID:20691350

  2. Heterostructured hBN-BP-hBN Nanodetectors at Terahertz Frequencies.

    PubMed

    Viti, Leonardo; Hu, Jin; Coquillat, Dominique; Politano, Antonio; Consejo, Christophe; Knap, Wojciech; Vitiello, Miriam S

    2016-09-01

    By reassembling thin isolated atomic planes of hexagonal borum nitride (hBN) with a few layer phosphorene black phosphorus (BP), hBN/BP/hBN heterostructures are mechanically stacked to devise high-efficiency THz photodetectors operating in the 0.3-0.65 THz range, from 4 K to 300 K, with a record signal-to-noise ratio of 20 000.

  3. BP control and left ventricular hypertrophy regression in children with CKD.

    PubMed

    Kupferman, Juan C; Aronson Friedman, Lisa; Cox, Christopher; Flynn, Joseph; Furth, Susan; Warady, Bradley; Mitsnefes, Mark

    2014-01-01

    In adult patients with CKD, hypertension is linked to the development of left ventricular hypertrophy, but whether this association exists in children with CKD has not been determined conclusively. To assess the relationship between BP and left ventricular hypertrophy, we prospectively analyzed data from the Chronic Kidney Disease in Children cohort. In total, 478 subjects were enrolled, and 435, 321, and 142 subjects remained enrolled at years 1, 3, and 5, respectively. Echocardiograms were obtained 1 year after study entry and then every 2 years; BP was measured annually. A linear mixed model was used to assess the effect of BP on left ventricular mass index, which was measured at three different visits, and a mixed logistic model was used to assess left ventricular hypertrophy. These models were part of a joint longitudinal and survival model to adjust for informative dropout. Predictors of left ventricular mass index included systolic BP, anemia, and use of antihypertensive medications other than angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Predictors of left ventricular hypertrophy included systolic BP, female sex, anemia, and use of other antihypertensive medications. Over 4 years, the adjusted prevalence of left ventricular hypertrophy decreased from 15.3% to 12.6% in a systolic BP model and from 15.1% to 12.6% in a diastolic BP model. These results indicate that a decline in BP may predict a decline in left ventricular hypertrophy in children with CKD and suggest additional factors that warrant additional investigation as predictors of left ventricular hypertrophy in these patients.

  4. Discrete Sampling Test Plan for the 200-BP-5 Operable Unit

    SciTech Connect

    Sweeney, Mark D.

    2010-02-04

    The Discrete Groundwater Sampling Project is conducted by the Pacific Northwest National Laboratory (PNNL) on behalf of CH2M HILL Plateau Remediation Company. The project is focused on delivering groundwater samples from proscribed horizons within select groundwater wells residing in the 200-BP-5 Operable Unit (200-BP-5 OU) on the Hanford Site. This document provides the scope, schedule, methodology, and other details of the PNNL discrete sampling effort.

  5. Strict Blood Pressure Control Achieved Using an ICT-Based Home Blood Pressure Monitoring System in a Catastrophically Damaged Area After a Disaster.

    PubMed

    Nishizawa, Masafumi; Hoshide, Satoshi; Okawara, Yukie; Matsuo, Takefumi; Kario, Kazuomi

    2017-01-01

    At the time of the Great East Japan earthquake and tsunami (March 2011), the authors developed a web-based information and communications technology (ICT)-based blood pressure (BP) monitoring system (the Disaster CArdiovascular Prevention [DCAP] Network) and introduced it in an area that was catastrophically damaged (Minamisanriku town) to help control the survivors' BP. Using this system, home BP (HBP) was monitored and the data were automatically transmitted to a central computer database and to the survivors' attending physicians. The study participants, 341 hypertensive patients, continued to use this system for 4 years after the disaster and all of the obtained HBP readings were analyzed. This DCAP HBP-guided approach helped achieve a decrease in the participants' HBPs (initial average: 151.3±20.0/86.9±10.2 mm Hg to 120.2±12.1/70.8±10.2 mm Hg) over the 4 years. In addition, the amplitude of seasonal BP variation was suppressed and the duration from the summer lowest HBP values to the winter peak HBP values was gradually prolonged. This ICT-based approach was useful to achieve strict HBP control and minimize the seasonal BP variation even in a catastrophically damaged area during a 4-year period after the disaster, suggesting that this approach could be a routine way to monitor BP in the community.

  6. 53BP1 fosters fidelity of homology-directed DNA repair.

    PubMed

    Ochs, Fena; Somyajit, Kumar; Altmeyer, Matthias; Rask, Maj-Britt; Lukas, Jiri; Lukas, Claudia

    2016-08-01

    Repair of DNA double-strand breaks (DSBs) in mammals is coordinated by the ubiquitin-dependent accumulation of 53BP1 at DSB-flanking chromatin. Owing to its ability to limit DNA-end processing, 53BP1 is thought to promote nonhomologous end-joining (NHEJ) and to suppress homology-directed repair (HDR). Here, we show that silencing 53BP1 or exhausting its capacity to bind damaged chromatin changes limited DSB resection to hyper-resection and results in a switch from error-free gene conversion by RAD51 to mutagenic single-strand annealing by RAD52. Thus, rather than suppressing HDR, 53BP1 fosters its fidelity. These findings illuminate causes and consequences of synthetic viability acquired through 53BP1 silencing in cells lacking the BRCA1 tumor suppressor. We show that such cells survive DSB assaults at the cost of increasing reliance on RAD52-mediated HDR, which may fuel genome instability. However, our findings suggest that when challenged by DSBs, BRCA1- and 53BP1-deficient cells may become hypersensitive to, and be eliminated by, RAD52 inhibition.

  7. Mind Bomb-Binding Partner RanBP9 Plays a Contributory Role in Retinal Development.

    PubMed

    Yoo, Kyeong-Won; Thiruvarangan, Maivannan; Jeong, Yun-Mi; Lee, Mi-Sun; Maddirevula, Sateesh; Rhee, Myungchull; Bae, Young-Ki; Kim, Hyung-Goo; Kim, Cheol-Hee

    2017-03-28

    Ran-binding protein family member, RanBP9 has been reported in various basic cellular mechanisms and neuropathological conditions including schizophrenia. Previous studies have reported that RanBP9 is highly expressed in the mammalian brain and retina; however, the role of RanBP9 in retinal development is largely unknown. Here, we present the novel and regulatory roles of RanBP9 in retinal development of a vertebrate animal model, zebrafish. Zebrafish embryos exhibited abundant expression of ranbp9 in developing brain tissues as well as in the developing retina. Yeast two-hybrid screening demonstrated the interaction of RanBP9 with Mind bomb, a component of Notch signaling involved in both neurogenesis and neural disease autism. The interaction is further substantiated by co-localization studies in cultured cells. Knockdown of ranbp9 resulted in retinal dysplasia with defective proliferation of retinal cells, downregulation of neuronal differentiation marker huC, elevation of neural proliferation marker her4, and alteration of cell cycle marker p57kip2. Expression of the Müller glial cell marker glutamine synthase was also affected in knockdown morphants. Our results suggest that Mind bombbinding partner RanBP9 plays a role during retinal cell development of zebrafish embryogenesis.

  8. The preparation of BP single crystals by high pressure flux method

    NASA Technical Reports Server (NTRS)

    Kumashiro, Y.; Misawa, S.; Gonda, S.

    1984-01-01

    Single crystals of BP, a III-V compound semiconductor, were obtained by the high pressure flux method. Cu3P and Ni12P5 powders were used as the flux, and mixed with BP powder. Two kinds of mixtures were prepared: (1) 1.8g (BP) + 35 G (Cu3P) and (2) 1.7 g (BP) + 25 g (Ni12P5). They were compressed into pellets, heated at 1300 C for 24 h in an induction furnace under a pressure of 1 MPa using Ar-P2 gas, and slowly cooled to room temperature. In case (1), BP single crystals grew along the (III) plane, and in case (2) they grew as an aggregate of crystallites. The cathodoluminescence spectra of the synthetic BP crystals showed peaks near 680 nm (1.82 eV) for case (1), and 500 nm (2.47 eV) for case (2). By using the high pressure flux method conventional sized crystals were obtained in a relatively short time.

  9. Effects of BP-14, a novel cyclin-dependent kinase inhibitor, on anaplastic thyroid cancer cells.

    PubMed

    Allegri, Lorenzo; Baldan, Federica; Mio, Catia; Puppin, Cinzia; Russo, Diego; Kryštof, Vladimir; Damante, Giuseppe

    2016-04-01

    Anaplastic thyroid carcinoma (ATC) is an extremely aggressive human malignancy characterized by a marked degree of invasiveness, absense of features of thyroid differentiation and resistance to current medical treatment. It is well known that ATCs are characterized by deregulation of genes related to cell cycle regulation, i.e., cyclin-dependent kinases (CDKs) and endogenous cyclin-dependent kinase inhibitors (CDKIs). Therefore, in the present study, the effect of a novel exogenous cyclin-dependent kinase inhibitor, BP-14, was investigated in three human ATC cell lines. The ATC-derived cell lines FRO, SW1736 and 8505C were treated with BP-14 alone or in combination with the mTOR inhibitor everolimus. In all ATC cell lines, treatment with BP-14 decreased cell viability and, in two of them, BP-14 modified expression of genes involved in epithelial-mesenchymal transition. Thus, our data indicate that BP-14 is a potential new compound effective against ATC. Combined treatment with BP-14 and the mTOR inhibitor everolimus had a strong synergistic effect on cell viability in all three cell lines, suggesting that the combined used of CDK and mTOR inhibitors may be a useful strategy for ATC treatment.

  10. Asian-specific mitochondrial genome polymorphism (9-bp deletion) in Hungarian patients with mitochondrial disease.

    PubMed

    Pentelenyi, Klara; Remenyi, Viktoria; Gal, Aniko; Milley, Gyorgy Mate; Csosz, Aranka; Mende, Balazs Gusztav; Molnar, Maria Judit

    2016-05-01

    A 9-bp deletion of the mtDNA is known as an anthropological marker of people with East-Asian origin. This 9-bp mtDNA deletion was analyzed in 1073 Hungarians with suspected mitochondrial disease and in 468 healthy control individuals. Fourteen cases with the 9-bp deletion were found in the cohort of mitochondrial patients, and one individual from 468 controls. In six cases the 9-bp deletion was present together with pathogenic major deletions in the mitochondrial genome. In one patient we found a frame shift mutation in the D-loop region, and in another family a pathogenic m.8322 A > G mutation in the tRNA(Lys) gene. Although the 9-bp deletion is common in the populations of the Pacific region and Asia, it is present in the Hungarian population as well. This 9-bp deletion may induce instability of the mtDNA and may provoke the introduction of other pathogenic mutations.

  11. CacyBP/SIP binds ERK1/2 and affects transcriptional activity of Elk-1.

    PubMed

    Kilanczyk, Ewa; Filipek, Slawomir; Jastrzebska, Beata; Filipek, Anna

    2009-02-27

    In this work we showed for the first time that mouse CacyBP/SIP interacts with extracellular signal regulated kinases 1 and 2 (ERK1/2). We also established that a calcium binding protein, S100A6, competes for this interaction. Moreover, the E217K mutant of CacyBP/SIP does not bind significantly to ERK1/2 although it retains the ability to interact with S100A6. Molecular modeling shows that the E217K mutation in the 189-219 CacyBP/SIP fragment markedly changes its electrostatic potential, suggesting that the binding with ERK1/2 might have an electrostatic character. We also demonstrate that CacyBP/SIP-ERK1/2 interaction inhibits phosphorylation of the Elk-1 transcription factor in vitro and in the nuclear fraction of NB2a cells. Altogether, our data suggest that the binding of CacyBP/SIP with ERK1/2 might regulate Elk-1 phosphorylation/transcriptional activity and that S100A6 might further modulate this effect via Ca(2+)-dependent interaction with CacyBP/SIP and competition with ERK1/2.

  12. CacyBP/SIP protein is important for the proliferation of human glioma cells.

    PubMed

    Shi, Hengliang; Gao, Yong; Tang, Yuan; Wu, Yuxuan; Gong, Hui; Du, Jin; Zheng, Bao; Hu, Jinxia; Shi, Qiong; Yu, Rutong

    2014-04-01

    Recently, calcyclin-binding protein or Siah-1-interacting protein (CacyBP/SIP), a component of a novel ubiquitinylation pathway, could regulate the β-catenin degradation (Fukushima et al., Immunity 2006, 24, 29-39). However, the potential role of CacyBP/SIP itself in human glioma cells has not been clarified. Here, we found that CacyBP/SIP was expressed highly in human glioma tissues. Silencing of CacyBP/SIP by short-hairpin RNA severely suppressed the proliferation of human glioma cell U251, which was at least partly mediated by downregulation of phospho-Akt (p-Akt) and phospho-β-catenin (p-β-catenin) as well as upregulation of p53 and p21. Furthermore, overexpression of CacyBP/SIP obviously promoted the proliferation of human glioma U251, which exhibited the exactly contrary trend in the expression of p-Akt, p-β-catenin, p53, and p21. Taken together, these findings suggest that CacyBP/SIP plays important roles in the proliferation of human glioma cell which might be involved in the development of human glioma.

  13. CacyBP/SIP binds ERK1/2 and affects transcriptional activity of Elk-1

    SciTech Connect

    Kilanczyk, Ewa; Filipek, Slawomir; Jastrzebska, Beata; Filipek, Anna

    2009-02-27

    In this work we showed for the first time that mouse CacyBP/SIP interacts with extracellular signal regulated kinases 1 and 2 (ERK1/2). We also established that a calcium binding protein, S100A6, competes for this interaction. Moreover, the E217K mutant of CacyBP/SIP does not bind significantly to ERK1/2 although it retains the ability to interact with S100A6. Molecular modeling shows that the E217K mutation in the 189-219 CacyBP/SIP fragment markedly changes its electrostatic potential, suggesting that the binding with ERK1/2 might have an electrostatic character. We also demonstrate that CacyBP/SIP-ERK1/2 interaction inhibits phosphorylation of the Elk-1 transcription factor in vitro and in the nuclear fraction of NB2a cells. Altogether, our data suggest that the binding of CacyBP/SIP with ERK1/2 might regulate Elk-1 phosphorylation/transcriptional activity and that S100A6 might further modulate this effect via Ca{sup 2+}-dependent interaction with CacyBP/SIP and competition with ERK1/2.

  14. The closure of Pak1-dependent macropinosomes requires the phosphorylation of CtBP1/BARS.

    PubMed

    Liberali, Prisca; Kakkonen, Elina; Turacchio, Gabriele; Valente, Carmen; Spaar, Alexander; Perinetti, Giuseppe; Böckmann, Rainer A; Corda, Daniela; Colanzi, Antonino; Marjomaki, Varpu; Luini, Alberto

    2008-04-09

    Membrane fission is an essential process in membrane trafficking and other cellular functions. While many fissioning and trafficking steps are mediated by the large GTPase dynamin, some fission events are dynamin independent and involve C-terminal-binding protein-1/brefeldinA-ADP ribosylated substrate (CtBP1/BARS). To gain an insight into the molecular mechanisms of CtBP1/BARS in fission, we have studied the role of this protein in macropinocytosis, a dynamin-independent endocytic pathway that can be synchronously activated by growth factors. Here, we show that upon activation of the epidermal growth factor receptor, CtBP1/BARS is (a) translocated to the macropinocytic cup and its surrounding membrane, (b) required for the fission of the macropinocytic cup and (c) phosphorylated on a specific serine that is a substrate for p21-activated kinase, with this phosphorylation being essential for the fission of the macropinocytic cup. Importantly, we also show that CtBP1/BARS is required for macropinocytic internalization and infection of echovirus 1. These results provide an insight into the molecular mechanisms of CtBP1/BARS activation in membrane fissioning, and extend the relevance of CtBP1/BARS-induced fission to human viral infection.

  15. Students' Target

    NASA Technical Reports Server (NTRS)

    2005-01-01

    [figure removed for brevity, see original site] Context image for PIA03648 Ascraeus Mons

    After examining numerous THEMIS images and using the JMars targeting software, eighth grade students from Charleston Middle School in Charleston, IL, selected the location of -8.37N and 276.66E for capture by the THEMIS visible camera during Mars Odyssey's sixth orbit of Mars on Nov. 22, 2005. The students are investigating relationships between channels, craters, and basins on Mars. The Charleston Middle School students participated in the Mars Student Imaging Project (MSIP) and submitted a proposal to use the THEMIS visible camera.

    Image information: VIS instrument. Latitude 8.8S, Longitude 279.6E. 17 meter/pixel resolution.

    Note: this THEMIS visual image has not been radiometrically nor geometrically calibrated for this preliminary release. An empirical correction has been performed to remove instrumental effects. A linear shift has been applied in the cross-track and down-track direction to approximate spacecraft and planetary motion. Fully calibrated and geometrically projected images will be released through the Planetary Data System in accordance with Project policies at a later time.

    NASA's Jet Propulsion Laboratory manages the 2001 Mars Odyssey mission for NASA's Office of Space Science, Washington, D.C. The Thermal Emission Imaging System (THEMIS) was developed by Arizona State University, Tempe, in collaboration with Raytheon Santa Barbara Remote Sensing. The THEMIS investigation is led by Dr. Philip Christensen at Arizona State University. Lockheed Martin Astronautics, Denver, is the prime contractor for the Odyssey project, and developed and built the orbiter. Mission operations are conducted jointly from Lockheed Martin and from JPL, a division of the California Institute of Technology in Pasadena.

  16. Occurrence of 4-tert-butylphenol (4-t-BP) biodegradation in an aquatic sample caused by the presence of Spirodela polyrrhiza and isolation of a 4-t-BP-utilizing bacterium.

    PubMed

    Ogata, Yuka; Toyama, Tadashi; Yu, Ning; Wang, Xuan; Sei, Kazunari; Ike, Michihiko

    2013-04-01

    Although 4-tert-butylphenol (4-t-BP) is a serious aquatic pollutant, its biodegradation in aquatic environments has not been well documented. In this study, 4-t-BP was obviously and repeatedly removed from water from four different environments in the presence of Spirodela polyrrhiza, giant duckweed, but 4-t-BP persisted in the environmental waters in the absence of S. polyrrhiza. Also, 4-t-BP was not removed from autoclaved pond water with sterilized S. polyrrhiza. These results suggest that the 4-t-BP removal from the environmental waters was caused by biodegradation stimulated by the presence of S. polyrrhiza rather than by uptake by the plant. Moreover, Sphingobium fuliginis OMI capable of utilizing 4-t-BP as a sole carbon and energy source was isolated from the S. polyrrhiza rhizosphere. Strain OMI degraded 4-t-BP via a meta-cleavage pathway, and also degraded a broad range of alkylphenols with linear or branched alkyl side chains containing two to nine carbon atoms. Root exudates of S. polyrrhiza stimulated 4-t-BP degradation and cell growth of strain OMI. Thus, the stimulating effects of S. polyrrhiza root exudates on 4-t-BP-degrading bacteria might have contributed to 4-t-BP removal in the environmental waters with S. polyrrhiza. These results demonstrate that the S. polyrrhiza-bacteria association may be applicable to the removal of highly persistent 4-t-BP from wastewaters or polluted aquatic environments.

  17. Prevalence of Obesity and Its Influence on Achievement of Cardiometabolic Therapeutic Goals in Chinese Type 2 Diabetes Patients: An Analysis of the Nationwide, Cross-Sectional 3B Study

    PubMed Central

    Zhou, Xianghai; Ji, Linong; Ran, Xingwu; Su, Benli; Ji, Qiuhe; Pan, Changyu; Weng, Jianping; Ma, Changsheng; Hao, Chuanming; Zhang, Danyi; Hu, Dayi

    2016-01-01

    Background There are few data on the prevalence of obesity and its influence on achieving blood glucose, blood pressure, and blood lipid (3B) goals in Chinese type 2 diabetes outpatients. Methods Patient demographic data, anthropometric measurements, medications, and blood glucose and lipid profiles of 24,512 type 2 diabetes patients from a large, geographically diverse study (CCMR-3B) were analyzed. Using cut-points for body mass index (BMI) and waist circumference (WC) recommended by the Working Group on Obesity in China, overweight and obesity were defined as BMIs of 24–27.9kg/m2 and ≥28.0kg/m2. Central obesity was defined as a waist circumference ≥80cm in women and ≥85cm in men. The 3B therapeutic goals were HbA1c<7.0%, BP<140/90mmHg and LDL-C<2.6mmol/L. Results Overall, 43.0% of type 2 diabetes patients were overweight and 16.7% were obese; 13.3% of overweight and and10.1% of obese patients achieved all the 3B target goals. Overweight or obese patients were less likely to achieve 3B goals than those with normal BMIs. More than a half the overweight or obese patients (69.6%) were centrally obese. Patients with abdominal obesity were less likely to achieve cardiometabolic targets than those without abdominal obesity. In multivariate logistic regression analysis, female, higher BMI and waist circumference, smoking, drinking, sedentary lifestyle, and longer diabetes duration were significantly correlated with failure to achieve 3B control goals. Conclusions Obesity is highly prevalent and associated with poor 3B control in Chinese type 2 diabetes patients. In clinical practice, more attention and resources should focus on weight loss for such patients. PMID:26726883

  18. Do Pretests Increase Student Achievement as Measured by Posttests?

    ERIC Educational Resources Information Center

    Bancroft, Roger J.

    This report describes a study of the effects of using pretests in science classes on chapter test achievement results. The targeted population consisted of eighth grade science students at a junior high school from 1992 to 2001. Whether giving a pretest followed by a posttest at the end of the chapter, or giving only the test at chapter end…

  19. Increasing Student Music Achievement through the Use of Motivational Strategies.

    ERIC Educational Resources Information Center

    Vega, Louis A.

    This action research project developed and implemented a program to improve student motivation through use of multiple intelligences, authentic assessment, technology and positive teacher feedback to increase levels of student music achievement. The students of the targeted seventh grade music class exhibited low levels of motivation that hindered…

  20. Enhancing Academic Achievement through Direct Instruction of Social Skills.

    ERIC Educational Resources Information Center

    Bendt, Lori; Nunan, Jan

    This paper examines the impact of the explicit teaching of social skills to enhance academic achievement. The targeted population comprised kindergarten and second grade students in a middle-class community located in central Illinois. The problem of inappropriate behaviors and difficulties interacting with peers and how this may affect academic…

  1. Project Achieve Transition Services (PATS), 1993-94. OER Report.

    ERIC Educational Resources Information Center

    Goldberg, Phyllis

    Project Achieve Transition Services (PATS) is a four-year high school attendance improvement, dropout prevention project which targets late-entry students consisting primarily of immigrants, transfers, and long-term absentees. The program uses a case management approach to provide support services, instructional enhancements, and family outreach…

  2. Continuous lake-sediment records of glaciation in the Sierra Nevada between 52,600 and 12,500 14C yr B.P.

    USGS Publications Warehouse

    Benson, L.V.; May, Howard M.; Antweiler, R.C.; Brinton, T.I.; Kashgarian, Michaele; Smoot, J.P.; Lund, S.P.

    1998-01-01

    The chemistry of the carbonate-free clay-size fraction of Owens Lake sediments supports the use of total organic carbon and magnetic susceptibility as indicators of stadial-interstadial oscillations. Owens Lake records of total organic carbon, magnetic susceptibility, and chemical composition of the carbonate-free, clay-size fraction indicate that Tioga glaciation began ~24,500 and ended by ~13,600 14C yr B.P. Many of the components of glacial rock flour (e.g., TiO2, MnO, BaO) found in Owens Lake sediments achieved maximum values during the Tioga glaciation when valley glaciers reached their greatest extent. Total organic carbon and SiO2 (amorphous) concentrations reached minimum values during Tioga glaciation, resulting from decreases in productivity that accompanied the introduction of rock flour into the surface waters of Owens Lake. At least 20 stadial-interstadial oscillations occurred in the Sierra Nevada between 52,600 and 14,000 14C yr B.P. Total organic carbon data from a Pyramid Lake sediment core also indicate oscillations in glacier activity between >39,500 and ~13,600 14C yr B.P. Alpine glacier oscillations occurred on a frequency of ???1900 yr in both basins, suggesting that millennial-scale oscillations occurred in California and Nevada during most of the past 52,600 yr.

  3. 15q11.2 microdeletion (BP1-BP2) and developmental delay, behaviour issues, epilepsy and congenital heart disease: a series of 52 patients.

    PubMed

    Vanlerberghe, Clémence; Petit, Florence; Malan, Valérie; Vincent-Delorme, Catherine; Bouquillon, Sonia; Boute, Odile; Holder-Espinasse, Muriel; Delobel, Bruno; Duban, Bénédicte; Vallee, Louis; Cuisset, Jean-Marie; Lemaitre, Marie-Pierre; Vantyghem, Marie-Christine; Pigeyre, Marie; Lanco-Dosen, Sandrine; Plessis, Ghislaine; Gerard, Marion; Decamp, Matthieu; Mathieu, Michèle; Morin, Gilles; Jedraszak, Guillaume; Bilan, Frédéric; Gilbert-Dussardier, Brigitte; Fauvert, Delphine; Roume, Joëlle; Cormier-Daire, Valérie; Caumes, Roseline; Puechberty, Jacques; Genevieve, David; Sarda, Pierre; Pinson, Lucie; Blanchet, Patricia; Lemeur, Nathalie; Sheth, Frenny; Manouvrier-Hanu, Sylvie; Andrieux, Joris

    2015-03-01

    Proximal region of chromosome 15 long arm is rich in duplicons that, define five breakpoints (BP) for 15q rearrangements. 15q11.2 microdeletion between BP1 and BP2 has been previously associated with developmental delay and atypical psychological patterns. This region contains four highly-conserved and non-imprinted genes: NIPA1, NIPA2, CYFIP1, TUBGCP5. Our goal was to investigate the phenotypes associated with this microdeletion in a cohort of 52 patients. This copy number variation (CNV) was prevalent in 0.8% patients presenting with developmental delay, psychological pattern issues and/or multiple congenital malformations. This was studied by array-CGH at six different French Genetic laboratories. We collected data from 52 unrelated patients (including 3 foetuses) after excluding patients with an associated genetic alteration (known CNV, aneuploidy or known monogenic disease). Out of 52 patients, mild or moderate developmental delay was observed in 68.3%, 85.4% had speech impairment and 63.4% had psychological issues such as Attention Deficit and Hyperactivity Disorder, Autistic Spectrum Disorder or Obsessive-Compulsive Disorder. Seizures were noted in 18.7% patients and associated congenital heart disease in 17.3%. Parents were analysed for abnormalities in the region in 65.4% families. Amongst these families, 'de novo' microdeletions were observed in 18.8% and 81.2% were inherited from one of the parents. Incomplete penetrance and variable expressivity were observed amongst the patients. Our results support the hypothesis that 15q11.2 (BP1-BP2) microdeletion is associated with developmental delay, abnormal behaviour, generalized epilepsy and congenital heart disease. The later feature has been rarely described. Incomplete penetrance and variability of expression demands further assessment and studies.

  4. Inertial-confinement-fusion targets

    SciTech Connect

    Hendricks, C.D.

    1982-08-10

    Much of the research in laser fusion has been done using simple ball on-stalk targets filled with a deuterium-tritium mixture. The targets operated in the exploding pusher mode in which the laser energy was delivered in a very short time (approx. 100 ps or less) and was absorbed by the glass wall of the target. The high energy density in the glass literally exploded the shell with the inward moving glass compressing the DT fuel to high temperatures and moderate densities. Temperatures achieved were high enough to produce DT reactions and accompanying thermonuclear neutrons and alpha particles. The primary criteria imposed on the target builders were: (1) wall thickness, (2) sphere diameter, and (3) fuel in the sphere.

  5. SCF ubiquitin ligase targeted therapies

    PubMed Central

    Skaar, Jeffrey R.; Pagan, Julia K.; Pagano, Michele

    2015-01-01

    Summary The recent clinical successes of inhibitors of the proteasome for the treatment of cancer have highlighted the therapeutic potential of this protein degradation system. Proteasome inhibitors prevent the degradation of numerous proteins, so increased specificity could be achieved by inhibiting the components of the ubiquitin-proteasome system that target specific subsets of proteins for degradation. F-box proteins are the substrate-targeting subunits of SKP1-CUL1-F-box protein (SCF) ubiquitin ligase complexes. Through the degradation of a plethora of diverse substrates, SCF ubiquitin ligases control a large number of processes at the cellular and organismal levels, and their misregulation is implicated in many pathologies. SCF ligases are characterized by a high specificity for their substrates, so they represent promising drug targets. However, the potential for therapeutic manipulation of SCF complexes remains an underdeveloped area. This review will explore and discuss potential strategies to target SCF-mediated biology to treat human diseases. PMID:25394868

  6. Establishing seismic design criteria to achieve an acceptable seismic margin

    SciTech Connect

    Kennedy, R.P.

    1997-01-01

    In order to develop a risk based seismic design criteria the following four issues must be addressed: (1) What target annual probability of seismic induced unacceptable performance is acceptable? (2). What minimum seismic margin is acceptable? (3) Given the decisions made under Issues 1 and 2, at what annual frequency of exceedance should the Safe Shutdown Earthquake ground motion be defined? (4) What seismic design criteria should be established to reasonably achieve the seismic margin defined under Issue 2? The first issue is purely a policy decision and is not addressed in this paper. Each of the other three issues are addressed. Issues 2 and 3 are integrally tied together so that a very large number of possible combinations of responses to these two issues can be used to achieve the target goal defined under Issue 1. Section 2 lays out a combined approach to these two issues and presents three potentially attractive combined resolutions of these two issues which reasonably achieves the target goal. The remainder of the paper discusses an approach which can be used to develop seismic design criteria aimed at achieving the desired seismic margin defined in resolution of Issue 2. Suggestions for revising existing seismic design criteria to more consistently achieve the desired seismic margin are presented.

  7. Metacognition, Achievement Goals, Study Strategies and Academic Achievement: Pathways to Achievement

    ERIC Educational Resources Information Center

    Vrugt, Anneke; Oort, Frans J.

    2008-01-01

    The purpose of this research was to develop and test a model of effective self-regulated learning. Based on effort expenditure we discerned effective self-regulators and less effective self-regulators. The model comprised achievement goals (mastery, performance-approach and -avoidance goals), metacognition (metacognitive knowledge, regulation and…

  8. Targeted Magnetic Liposomes Loaded with Doxorubicin.

    PubMed

    Pradhan, Pallab; Banerjee, Rinti; Bahadur, Dhirendra; Koch, Christian; Mykhaylyk, Olga; Plank, Christian

    2017-01-01

    Targeted delivery systems for anticancer drugs are urgently needed to achieve maximum therapeutic efficacy by site-specific accumulation and thereby minimizing adverse effects resulting from systemic distribution of many potent anticancer drugs. We have prepared folate receptor-targeted magnetic liposomes loaded with doxorubicin, which are designed for tumor targeting through a combination of magnetic and biological targeting. Furthermore, these liposomes are designed for hyperthermia-induced drug release to be mediated by an alternating magnetic field and to be traceable by magnetic resonance imaging (MRI). Here, detailed preparation and relevant characterization techniques of targeted magnetic liposomes encapsulating doxorubicin are described.

  9. Engineering targeted viral vectors for gene therapy.

    PubMed

    Waehler, Reinhard; Russell, Stephen J; Curiel, David T

    2007-08-01

    To achieve therapeutic success, transfer vehicles for gene therapy must be capable of transducing target cells while avoiding impact on non-target cells. Despite the high transduction efficiency of viral vectors, their tropism frequently does not match the therapeutic need. In the past, this lack of appropriate targeting allowed only partial exploitation of the great potential of gene therapy. Substantial progress in modifying viral vectors using diverse techniques now allows targeting to many cell types in vitro. Although important challenges remain for in vivo applications, the first clinical trials with targeted vectors have already begun to take place.

  10. The incongruous achiever in adolescence.

    PubMed

    Kline, S A; Golombek, H

    1974-06-01

    The authors wished to study some of the internal psychological dynamics of achievement in a nonpatient identified high school population. Questionnaires were administered to the Grade 13 students and their parents in a large high school. A number of students whose achievement and educational plans were not congruous with their general background were selected for interview. The findings suggest that a wide variety of ages and developmental stages can be discerned as critical points in the development of a student's attitude toward higher education. These students have many values in common, and their values appear related to a positive or negative identification with parental values. The students themselves show a wide range of personality integration. They relate in a special way to a wide variety of teachers' personalities.

  11. Beam cooling: Principles and achievements

    SciTech Connect

    Mohl, Dieter; Sessler, Andrew M.

    2003-05-18

    After a discussion of Liouville's theorem, and its implications for beam cooling, a brief description is given of each of the various methods of beam cooling: stochastic, electron, radiation, laser, ionization, etc. For each, we present the type of particle for which it is appropriate, its range of applicability, and the currently achieved degree of cooling. For each method we also discuss the present applications and, also, possible future developments and further applications.

  12. Transcriptional down-regulation of Brca1 and E-cadherin by CtBP1 in breast cancer.

    PubMed

    Deng, Yu; Deng, Hui; Liu, Jing; Han, Gangwen; Malkoski, Stephen; Liu, Bolin; Zhao, Rui; Wang, Xiao-Jing; Zhang, Qinghong

    2012-06-01

    Carboxyl-terminal binding protein 1 (CtBP1) is a transcriptional co-repressor with oncogenic potential. Immunohistochemistry staining using human breast cancer tissue arrays revealed that 92% of invasive ductal breast cancer cases have CtBP1-positive staining compared to 4% CtBP1-positive in normal breast tissue. To explore the functional impact of CtBP1 in breast cancer, we examined CtBP1's transcriptional regulation of known tumor suppressors, breast cancer susceptibility gene 1 (Brca1), and E-cadherin. We found CtBP1 was recruited to the promoter regions of Brca1 and E-cadherin genes in breast cancer cells. Concomitantly, Brca1 loss was detected in 57% and E-cadherin loss was detected in 76% of human invasive ductal breast cancers, and correlated with CtBP1 nuclear staining in these lesions. Importantly, siRNA knock down of CtBP1 restored Brca1 and E-cadherin expression in breast cancer cell lines, implying CtBP1 down-regulates Brca1 and E-cadherin genes in human breast cancer. This study provides evidence that although genetic loss of Brca1 and E-cadherin are infrequent in breast cancer, they are down-regulated at the transcriptional level by CtBP1 expression. Thus, CtBP1 activation could be a potential biomarker for breast cancer development.

  13. cMyBP-C was decreased via KLHL3-mediated proteasomal degradation in congenital heart diseases.

    PubMed

    Wang, Leitong; Lai, Guangrui; Chu, Guoming; Liang, Xiaoyan; Zhao, Yanyan

    2017-03-15

    Cardiac myosin binding protein C (cMyBP-C) is a cardiac structural and regulatory protein; mutations of cMyBP-C are frequently associated with hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). Cardiac special transcription factors may regulate the expression of cMyBP-C. However, the role of cMyBP-C in congenital heart diseases (CHD) remains poorly understood. In the current study, western blotting and the MRM approach showed that cMyBP-C expression was significantly reduced in fetuses with CHD compared to those without. Furthermore, we found that cMyBP-C interacted with KLHL3 by immunoprecipitation and immunofluorescence, and the degradation of cMyBP-C was caused by KLHL3-mediated ubiquitination. In addition, homocysteine (Hcy, a risk factor of CHD) treatment caused a decrease in cMyBP-C and an increase in KLHL3 expression, and the proteasome inhibitor MG132 reversed the Hcy-induced reduction of cMyBP-C expression. Finally, we verified that reduced cMyBP-C by Hcy promoted apoptosis in cardiomyocytes. These results demonstrate that Hcy decreases the expression of cMyBP-C through a KLHL3-mediated ubiquitin-proteasome pathway, and thereby influences heart development.

  14. Predicting educational achievement from DNA

    PubMed Central

    Selzam, S; Krapohl, E; von Stumm, S; O'Reilly, P F; Rimfeld, K; Kovas, Y; Dale, P S; Lee, J J; Plomin, R

    2017-01-01

    A genome-wide polygenic score (GPS), derived from a 2013 genome-wide association study (N=127,000), explained 2% of the variance in total years of education (EduYears). In a follow-up study (N=329,000), a new EduYears GPS explains up to 4%. Here, we tested the association between this latest EduYears GPS and educational achievement scores at ages 7, 12 and 16 in an independent sample of 5825 UK individuals. We found that EduYears GPS explained greater amounts of variance in educational achievement over time, up to 9% at age 16, accounting for 15% of the heritable variance. This is the strongest GPS prediction to date for quantitative behavioral traits. Individuals in the highest and lowest GPS septiles differed by a whole school grade at age 16. Furthermore, EduYears GPS was associated with general cognitive ability (~3.5%) and family socioeconomic status (~7%). There was no evidence of an interaction between EduYears GPS and family socioeconomic status on educational achievement or on general cognitive ability. These results are a harbinger of future widespread use of GPS to predict genetic risk and resilience in the social and behavioral sciences. PMID:27431296

  15. Media and attention, cognition, and school achievement.

    PubMed

    Schmidt, Marie Evans; Vandewater, Elizabeth A

    2008-01-01

    Marie Evans Schmidt and Elizabeth Vandewater review research on links between various types of electronic media and the cognitive skills of school-aged children and adolescents. One central finding of studies to date, they say, is that the content delivered by electronic media is far more influential than the media themselves. Most studies, they point out, find a small negative link between the total hours a child spends viewing TV and that child's academic achievement. But when researchers take into account characteristics of the child, such as IQ or socioeconomic status, this link typically disappears. Content appears to be crucial. Viewing educational TV is linked positively with academic achievement; viewing entertainment TV is linked negatively with achievement. When it comes to particular cognitive skills, say the authors, researchers have found that electronic media, particularly video games, can enhance visual spatial skills, such as visual tracking, mental rotation, and target localization. Gaming may also improve problem-solving skills. Researchers have yet to understand fully the issue of transfer of learning from electronic media. Studies suggest that, under some circumstances, young people are able to transfer what they learn from electronic media to other applications, but analysts are uncertain how such transfer occurs. In response to growing public concern about possible links between electronic media use and attention problems in children and adolescents, say the authors, researchers have found evidence for small positive links between heavy electronic media use and mild attention problems among young people but have found only inconsistent evidence so far for a link between attention deficit hyperactivity disorder and media use. The authors point out that although video games, interactive websites, and multimedia software programs appear to offer a variety of possible benefits for learning, there is as yet little empirical evidence to suggest that

  16. Black Phosphorus Based Field Effect Transistors with Simultaneously Achieved Near Ideal Subthreshold Swing and High Hole Mobility at Room Temperature.

    PubMed

    Liu, Xinke; Ang, Kah-Wee; Yu, Wenjie; He, Jiazhu; Feng, Xuewei; Liu, Qiang; Jiang, He; Dan Tang; Wen, Jiao; Lu, Youming; Liu, Wenjun; Cao, Peijiang; Han, Shun; Wu, Jing; Liu, Wenjun; Wang, Xi; Zhu, Deliang; He, Zhubing

    2016-04-22

    Black phosphorus (BP) has emerged as a promising two-dimensional (2D) material for next generation transistor applications due to its superior carrier transport properties. Among other issues, achieving reduced subthreshold swing and enhanced hole mobility simultaneously remains a challenge which requires careful optimization of the BP/gate oxide interface. Here, we report the realization of high performance BP transistors integrated with HfO2 high-k gate dielectric using a low temperature CMOS process. The fabricated devices were shown to demonstrate a near ideal subthreshold swing (SS) of ~69 mV/dec and a room temperature hole mobility of exceeding >400 cm(2)/Vs. These figure-of-merits are benchmarked to be the best-of-its-kind, which outperform previously reported BP transistors realized on traditional SiO2 gate dielectric. X-ray photoelectron spectroscopy (XPS) analysis further reveals the evidence of a more chemically stable BP when formed on HfO2 high-k as opposed to SiO2, which gives rise to a better interface quality that accounts for the SS and hole mobility improvement. These results unveil the potential of black phosphorus as an emerging channel material for future nanoelectronic device applications.

  17. Black Phosphorus Based Field Effect Transistors with Simultaneously Achieved Near Ideal Subthreshold Swing and High Hole Mobility at Room Temperature

    PubMed Central

    Liu, Xinke; Ang, Kah-Wee; Yu, Wenjie; He, Jiazhu; Feng, Xuewei; Liu, Qiang; Jiang, He; Dan Tang; Wen, Jiao; Lu, Youming; Liu, Wenjun; Cao, Peijiang; Han, Shun; Wu, Jing; Liu, Wenjun; Wang, Xi; Zhu, Deliang; He, Zhubing

    2016-01-01

    Black phosphorus (BP) has emerged as a promising two-dimensional (2D) material for next generation transistor applications due to its superior carrier transport properties. Among other issues, achieving reduced subthreshold swing and enhanced hole mobility simultaneously remains a challenge which requires careful optimization of the BP/gate oxide interface. Here, we report the realization of high performance BP transistors integrated with HfO2 high-k gate dielectric using a low temperature CMOS process. The fabricated devices were shown to demonstrate a near ideal subthreshold swing (SS) of ~69 mV/dec and a room temperature hole mobility of exceeding >400 cm2/Vs. These figure-of-merits are benchmarked to be the best-of-its-kind, which outperform previously reported BP transistors realized on traditional SiO2 gate dielectric. X-ray photoelectron spectroscopy (XPS) analysis further reveals the evidence of a more chemically stable BP when formed on HfO2 high-k as opposed to SiO2, which gives rise to a better interface quality that accounts for the SS and hole mobility improvement. These results unveil the potential of black phosphorus as an emerging channel material for future nanoelectronic device applications. PMID:27102711

  18. Black Phosphorus Based Field Effect Transistors with Simultaneously Achieved Near Ideal Subthreshold Swing and High Hole Mobility at Room Temperature

    NASA Astrophysics Data System (ADS)

    Liu, Xinke; Ang, Kah-Wee; Yu, Wenjie; He, Jiazhu; Feng, Xuewei; Liu, Qiang; Jiang, He; Dan Tang; Wen, Jiao; Lu, Youming; Liu, Wenjun; Cao, Peijiang; Han, Shun; Wu, Jing; Liu, Wenjun; Wang, Xi; Zhu, Deliang; He, Zhubing

    2016-04-01

    Black phosphorus (BP) has emerged as a promising two-dimensional (2D) material for next generation transistor applications due to its superior carrier transport properties. Among other issues, achieving reduced subthreshold swing and enhanced hole mobility simultaneously remains a challenge which requires careful optimization of the BP/gate oxide interface. Here, we report the realization of high performance BP transistors integrated with HfO2 high-k gate dielectric using a low temperature CMOS process. The fabricated devices were shown to demonstrate a near ideal subthreshold swing (SS) of ~69 mV/dec and a room temperature hole mobility of exceeding >400 cm2/Vs. These figure-of-merits are benchmarked to be the best-of-its-kind, which outperform previously reported BP transistors realized on traditional SiO2 gate dielectric. X-ray photoelectron spectroscopy (XPS) analysis further reveals the evidence of a more chemically stable BP when formed on HfO2 high-k as opposed to SiO2, which gives rise to a better interface quality that accounts for the SS and hole mobility improvement. These results unveil the potential of black phosphorus as an emerging channel material for future nanoelectronic device applications.

  19. Waiting-time targets. Early learners.

    PubMed

    Moore, Alison

    2007-04-05

    Thirteen 'early achiever' sites have volunteered to deliver the new 18-week target ahead of schedule. The sites have highlighted recurring issues for trusts aiming for 18 weeks: orthopaedics, audiology, endoscopy and some smaller specialties have all proved challenging. The target should be seen as a vital step towards a 'no unnecessary delay' system of working and thinking.

  20. Practically Perfect in Every Way: Can Reframing Perfectionism for High-Achieving Undergraduates Impact Academic Resilience?

    ERIC Educational Resources Information Center

    Dickinson, Mary J.; Dickinson, David A. G.

    2015-01-01

    This study focuses on a pan-disciplinary scheme that targeted high-achieving undergraduate students. Earlier research from the scheme argued that high achievers have discernibly different learning and personal development support needs. One of the most frequent self-reported challenges within this high-achieving group is perfectionism. This…