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Sample records for hits gdp growth

  1. Is Decoupling GDP Growth from Environmental Impact Possible?

    PubMed Central

    Sutton, Paul C.; Werner, Adrian D.; Costanza, Robert; Mohr, Steve H.; Simmons, Craig T.

    2016-01-01

    The argument that human society can decouple economic growth—defined as growth in Gross Domestic Product (GDP)—from growth in environmental impacts is appealing. If such decoupling is possible, it means that GDP growth is a sustainable societal goal. Here we show that the decoupling concept can be interpreted using an easily understood model of economic growth and environmental impact. The simple model is compared to historical data and modelled projections to demonstrate that growth in GDP ultimately cannot be decoupled from growth in material and energy use. It is therefore misleading to develop growth-oriented policy around the expectation that decoupling is possible. We also note that GDP is increasingly seen as a poor proxy for societal wellbeing. GDP growth is therefore a questionable societal goal. Society can sustainably improve wellbeing, including the wellbeing of its natural assets, but only by discarding GDP growth as the goal in favor of more comprehensive measures of societal wellbeing. PMID:27741300

  2. A rho GDP dissociation inhibitor produced by apoptotic T-cells inhibits growth of Mycobacterium tuberculosis.

    PubMed

    Venkatasubramanian, Sambasivan; Dhiman, Rohan; Paidipally, Padmaja; Cheekatla, Satyanarayana S; Tripathi, Deepak; Welch, Elwyn; Tvinnereim, Amy R; Jones, Brenda; Theodorescu, Dan; Barnes, Peter F; Vankayalapati, Ramakrishna

    2015-02-01

    In this study, we found that a subpopulation of CD4(+)CD25(+) (85% Foxp3(+)) cells from persons with latent tuberculosis infection (LTBI) inhibits growth of M. tuberculosis (M. tb) in human monocyte-derived macrophages (MDMs). A soluble factor, Rho GDP dissociation inhibitor (D4GDI), produced by apoptotic CD4(+)CD25(+) (85% Foxp3(+)) cells is responsible for this inhibition of M. tb growth in human macrophages and in mice. M. tb-expanded CD4(+C)D25(+)Foxp3(+)D4GDI(+) cells do not produce IL-10, TGF-β and IFN-γ. D4GDI inhibited growth of M. tb in MDMs by enhancing production of IL-1β, TNF-α and ROS, and by increasing apoptosis of M. tb-infected MDMs. D4GDI was concentrated at the site of disease in tuberculosis patients, with higher levels detected in pleural fluid than in serum. However, in response to M. tb, PBMC from tuberculosis patients produced less D4GDI than PBMC from persons with LTBI. M. tb-expanded CD4+CD25+ (85% Foxp3(+)) cells and D4GDI induced intracellular M. tb to express the dormancy survival regulator DosR and DosR-dependent genes, suggesting that D4GDI induces a non-replicating state in the pathogen. Our study provides the first evidence that a subpopulation of CD4(+)CD25(+) (85% Foxp3+) cells enhances immunity to M. tb, and that production of D4GDI by this subpopulation inhibits M. tb growth.

  3. Carbon dioxide emissions, GDP, energy use, and population growth: a multivariate and causality analysis for Ghana, 1971-2013.

    PubMed

    Asumadu-Sarkodie, Samuel; Owusu, Phebe Asantewaa

    2016-07-01

    In this study, the relationship between carbon dioxide emissions, GDP, energy use, and population growth in Ghana was investigated from 1971 to 2013 by comparing the vector error correction model (VECM) and the autoregressive distributed lag (ARDL). Prior to testing for Granger causality based on VECM, the study tested for unit roots, Johansen's multivariate co-integration and performed a variance decomposition analysis using Cholesky's technique. Evidence from the variance decomposition shows that 21 % of future shocks in carbon dioxide emissions are due to fluctuations in energy use, 8 % of future shocks are due to fluctuations in GDP, and 6 % of future shocks are due to fluctuations in population. There was evidence of bidirectional causality running from energy use to GDP and a unidirectional causality running from carbon dioxide emissions to energy use, carbon dioxide emissions to GDP, carbon dioxide emissions to population, and population to energy use. Evidence from the long-run elasticities shows that a 1 % increase in population in Ghana will increase carbon dioxide emissions by 1.72 %. There was evidence of short-run equilibrium relationship running from energy use to carbon dioxide emissions and GDP to carbon dioxide emissions. As a policy implication, the addition of renewable energy and clean energy technologies into Ghana's energy mix can help mitigate climate change and its impact in the future.

  4. Carbon dioxide emissions, GDP, energy use, and population growth: a multivariate and causality analysis for Ghana, 1971-2013.

    PubMed

    Asumadu-Sarkodie, Samuel; Owusu, Phebe Asantewaa

    2016-07-01

    In this study, the relationship between carbon dioxide emissions, GDP, energy use, and population growth in Ghana was investigated from 1971 to 2013 by comparing the vector error correction model (VECM) and the autoregressive distributed lag (ARDL). Prior to testing for Granger causality based on VECM, the study tested for unit roots, Johansen's multivariate co-integration and performed a variance decomposition analysis using Cholesky's technique. Evidence from the variance decomposition shows that 21 % of future shocks in carbon dioxide emissions are due to fluctuations in energy use, 8 % of future shocks are due to fluctuations in GDP, and 6 % of future shocks are due to fluctuations in population. There was evidence of bidirectional causality running from energy use to GDP and a unidirectional causality running from carbon dioxide emissions to energy use, carbon dioxide emissions to GDP, carbon dioxide emissions to population, and population to energy use. Evidence from the long-run elasticities shows that a 1 % increase in population in Ghana will increase carbon dioxide emissions by 1.72 %. There was evidence of short-run equilibrium relationship running from energy use to carbon dioxide emissions and GDP to carbon dioxide emissions. As a policy implication, the addition of renewable energy and clean energy technologies into Ghana's energy mix can help mitigate climate change and its impact in the future. PMID:27030236

  5. Transforming growth factor β signaling upregulates the expression of human GDP-fucose transporter by activating transcription factor Sp1.

    PubMed

    Xu, Yu-Xin; Ma, Anna; Liu, Li

    2013-01-01

    GDP-fucose transporter plays a crucial role in fucosylation of glycoproteins by providing activated fucose donor, GDP-fucose, for fucosyltransferases in the lumen of the Golgi apparatus. Fucose-containing glycans are involved in many biological processes, which are essential for growth and development. Mutations in the GDP-fucose transporter gene cause leukocyte adhesion deficiency syndrome II, a disease characterized by slow growth, mental retardation and immunodeficiency. However, no information is available regarding its transcriptional regulation. Here, by using human cells, we show that TGF-β1 specifically induces the GDP-fucose transporter expression, but not other transporters tested such as CMP-sialic acid transporter, suggesting a diversity of regulatory pathways for the expression of these transporters. The regulatory elements that are responsive to the TGF-β1 stimulation are present in the region between bp -330 and -268 in the GDP-fucose transporter promoter. We found that this region contains two identical octamer GC-rich motifs (GGGGCGTG) that were demonstrated to be essential for the transporter expression. We also show that the transcription factor Sp1 specifically binds to the GC-rich motifs in vitro and Sp1 coupled with phospho-Smad2 is associated with the promoter region covering the Sp1-binding motifs in vivo using chromatin immunoprecipitation (ChIP) assays. In addition, we further confirmed that Sp1 is essential for the GDP-fucose transporter expression stimulated by TGF-β1 using a luciferase reporter system. These results highlight the role of TGF-β signaling in regulation of the GDP-fucose transporter expression via activating Sp1. This is the first transcriptional study for any nucleotide sugar transporters that have been identified so far. Notably, TGF-β1 receptor itself is known to be modified by fucosylation. Given the essential role of GDP-fucose transporter in fucosylation, the finding that TGF-β1 stimulates the expression of

  6. Applications of the Time-Varying Multi-Hazard Index to Armed Conflicts and GDP Growth Rate

    NASA Astrophysics Data System (ADS)

    Isanuk, M.; Skorik, A.; Lerner-Lam, A.

    2004-12-01

    The time-varying Multi-Hazard Index has many potential applications for comparisons against quantitative measures of sustainable development. We have compared the time-varying severity of multiple natural hazards against time-varying socio-economic data for selected countries. Our analysis compares Gross Domestic Product (GDP) growth and armed conflict occurrence against multiple hazard severity as measured by an empirical time-varying multiple hazard index. The purpose of these analyses is to establish and characterize correlations between the Multi-Hazard Index and trends in GDP and conflicts over the past 25 years. To analyze the relationship between natural hazards and armed conflicts, the Multi-Hazard Index was correlated against the number of conflicts at each intensity level for individual countries. A preliminary analysis was performed studying the apparent relationship as well as the possible existence of time lags. In a similar although more quantitative analysis, the GDP data was correlated against the Multi-Hazard Index for a particular country at different time lags. Analysis involving the conflict datasets yielded varying results from country to country. Colombia shows the strongest correlation, with all positive values of the Multi-Hazard Index followed by an escalation in conflict intensity. The results for other countries are more difficult to interpret as certain years show increases in the number of conflicts at one intensity level and a decrease for other intensity levels. Some issues that need to be addressed include the coding of the intensity for the conflict data, the dating for both conflicts and hazards, and the use of national boundaries as geographic extents. The degree of correlation between GDP growth and the Multi-Hazard Index varies from country to country as well. Our calculations for Honduras show an extremely high correlation, for example, implying a strong economic sensitivity to natural hazards, whereas for China no significant

  7. Identification and characterization of Arabidopsis AtNUDX9 as a GDP-d-mannose pyrophosphohydrolase: its involvement in root growth inhibition in response to ammonium

    PubMed Central

    Tanaka, Hiroyuki; Maruta, Takanori; Ogawa, Takahisa; Tanabe, Noriaki; Tamoi, Masahiro; Yoshimura, Kazuya; Shigeoka, Shigeru

    2015-01-01

    GDP-d-mannose (GDP-d-Man) is an important intermediate in ascorbic acid (AsA) synthesis, cell wall synthesis, protein N-glycosylation, and glycosylphosphatidylinositol-anchoring in plants. Thus, the modulation of intracellular levels of GDP-d-Man could be important for maintaining various cellular processes. Here an Arabidopsis GDP-d-Man pyrophosphohydrolase, AtNUDX9 (AtNUDT9; At3g46200), which hydrolysed GDP-d-Man to GMP and mannose 1-phosphate, was identified. The K m and V max values for GDP-d-Man of AtNUDX9 were 376±24 μM and 1.61±0.15 μmol min–1 mg–1 protein, respectively. Among various tissues, the expression levels of AtNUDX9 and the total activity of GDP-d-Man pyrophosphohydrolase were the highest in the roots. The GDP-d-Man pyrophosphohydrolase activity was increased in the root of plants grown in the presence of ammonium. No difference was observed in the levels of AsA in the leaf and root tissues of the wild-type and knockout-nudx9 (KO-nudx9) plants, whereas a marked increase in N-glycoprotein levels and enhanced growth were detected in the roots of KO-nudx9 plants in the presence of ammonium. These results suggest that AtNUDX9 is involved in the regulation of GDP-d-Man levels affecting ammonium sensitivity via modulation of protein N-glycosylation in the roots. PMID:26049160

  8. Identification and characterization of Arabidopsis AtNUDX9 as a GDP-d-mannose pyrophosphohydrolase: its involvement in root growth inhibition in response to ammonium.

    PubMed

    Tanaka, Hiroyuki; Maruta, Takanori; Ogawa, Takahisa; Tanabe, Noriaki; Tamoi, Masahiro; Yoshimura, Kazuya; Shigeoka, Shigeru

    2015-09-01

    GDP-d-mannose (GDP-d-Man) is an important intermediate in ascorbic acid (AsA) synthesis, cell wall synthesis, protein N-glycosylation, and glycosylphosphatidylinositol-anchoring in plants. Thus, the modulation of intracellular levels of GDP-d-Man could be important for maintaining various cellular processes. Here an Arabidopsis GDP-d-Man pyrophosphohydrolase, AtNUDX9 (AtNUDT9; At3g46200), which hydrolysed GDP-d-Man to GMP and mannose 1-phosphate, was identified. The K m and V max values for GDP-d-Man of AtNUDX9 were 376±24 μM and 1.61±0.15 μmol min(-1) mg(-1) protein, respectively. Among various tissues, the expression levels of AtNUDX9 and the total activity of GDP-d-Man pyrophosphohydrolase were the highest in the roots. The GDP-d-Man pyrophosphohydrolase activity was increased in the root of plants grown in the presence of ammonium. No difference was observed in the levels of AsA in the leaf and root tissues of the wild-type and knockout-nudx9 (KO-nudx9) plants, whereas a marked increase in N-glycoprotein levels and enhanced growth were detected in the roots of KO-nudx9 plants in the presence of ammonium. These results suggest that AtNUDX9 is involved in the regulation of GDP-d-Man levels affecting ammonium sensitivity via modulation of protein N-glycosylation in the roots.

  9. Roughness distribution of multiple hit and long surface diffusion length noise reduced discrete growth models

    NASA Astrophysics Data System (ADS)

    Disrattakit, P.; Chanphana, R.; Chatraphorn, P.

    2016-11-01

    Conventionally, the universality class of a discrete growth model is identified via the scaling of interface width. This method requires large-scale simulations to minimize finite-size effects on the results. The multiple hit noise reduction techniques (m > 1 NRT) and the long surface diffusion length noise reduction techniques (ℓ > 1 NRT) have been used to promote the asymptotic behaviors of the growth models. Lately, an alternative method involving comparison of roughness distribution in the steady state has been proposed. In this work, the roughness distribution of the (2 +1)-dimensional Das Sarma-Tamborenea (DT), Wolf-Villain (WV), and Larger Curvature (LC) models, with and without NRTs, are calculated in order to investigate effects of the NRTs on the roughness distribution. Additionally, effective growth exponents of the noise reduced (2 +1)-dimensional DT, WV and LC models are also calculated. Our results indicate that the NRTs affect the interface width both in the growth and the saturation regimes. In the steady state, the NRTs do not seem to have any impact on the roughness distribution of the DT model, but it significantly changes the roughness distribution of the WV and LC models to the normal distribution curves.

  10. Recruitment of Arf1-GDP to Golgi by Glo3p-Type ArfGAPs Is Crucial for Golgi Maintenance and Plant Growth1[W][OA

    PubMed Central

    Min, Myung Ki; Jang, Mihue; Lee, Myounghui; Lee, Junho; Song, Kyungyoung; Lee, Yongjik; Choi, Kwan Yong; Robinson, David G.; Hwang, Inhwan

    2013-01-01

    ADP-ribosylation factor1 (Arf1), a member of the small GTP-binding proteins, plays a pivotal role in protein trafficking to multiple organelles. In its GDP-bound form, Arf1 is recruited from the cytosol to organelle membranes, where it functions in vesicle-mediated protein trafficking. However, the mechanism of Arf1-GDP recruitment remains unknown. Here, we provide evidence that two Glo3p-type Arf GTPase-activating proteins (ArfGAPs), ArfGAP domain8 (AGD8) and AGD9, are involved in the recruitment of Arf1-GDP to the Golgi apparatus in Arabidopsis (Arabidopsis thaliana). RNA interference plants expressing low levels of AGD8 and AGD9 exhibited abnormal Golgi morphology, inhibition of protein trafficking, and arrest of plant growth and development. In RNA interference plants, Arf1 was poorly recruited to the Golgi apparatus. Conversely, high levels of AGD8 and AGD9 induced Arf1 accumulation at the Golgi and suppressed Golgi disruption and inhibition of vacuolar trafficking that was caused by overexpression of AGD7. Based on these results, we propose that the Glo3p-type ArfGAPs AGD8 and AGD9 recruit Arf1-GDP from the cytosol to the Golgi for Arf1-mediated protein trafficking, which is essential for plant development and growth. PMID:23266962

  11. National Income Inequality and Declining GDP Growth Rates Are Associated with Increases in HIV Diagnoses among People Who Inject Drugs in Europe: A Panel Data Analysis

    PubMed Central

    Nikolopoulos, Georgios K.; Fotiou, Anastasios; Kanavou, Eleftheria; Richardson, Clive; Detsis, Marios; Pharris, Anastasia; Suk, Jonathan E.; Semenza, Jan C.; Costa-Storti, Claudia; Paraskevis, Dimitrios; Sypsa, Vana; Malliori, Melpomeni-Minerva; Friedman, Samuel R.; Hatzakis, Angelos

    2015-01-01

    Background There is sparse evidence that demonstrates the association between macro-environmental processes and drug-related HIV epidemics. The present study explores the relationship between economic, socio-economic, policy and structural indicators, and increases in reported HIV infections among people who inject drugs (PWID) in the European Economic Area (EEA). Methods We used panel data (2003–2012) for 30 EEA countries. Statistical analyses included logistic regression models. The dependent variable was taking value 1 if there was an outbreak (significant increase in the national rate of HIV diagnoses in PWID) and 0 otherwise. Explanatory variables included the growth rate of Gross Domestic Product (GDP), the share of the population that is at risk for poverty, the unemployment rate, the Eurostat S80/S20 ratio, the Gini coefficient, the per capita government expenditure on health and social protection, and variables on drug control policy and drug-using population sizes. Lags of one to three years were investigated. Findings In multivariable analyses, using two-year lagged values, we found that a 1% increase of GDP was associated with approximately 30% reduction in the odds of an HIV outbreak. In GDP-adjusted analyses with three-year lagged values, the effect of the national income inequality on the likelihood of an HIV outbreak was significant [S80/S20 Odds Ratio (OR) = 3.89; 95% Confidence Interval (CI): 1.15 to 13.13]. Generally, the multivariable analyses produced similar results across three time lags tested. Interpretation Given the limitations of ecological research, we found that declining economic growth and increasing national income inequality were associated with an elevated probability of a large increase in the number of HIV diagnoses among PWID in EEA countries during the last decade. HIV prevention may be more effective if developed within national and European-level policy contexts that promote income equality, especially among vulnerable

  12. Heat resistance and salt hypersensitivity in Lactococcus lactis due to spontaneous mutation of llmg_1816 (gdpP) induced by high-temperature growth.

    PubMed

    Smith, William M; Pham, Thi Huong; Lei, Lin; Dou, Junchao; Soomro, Aijaz H; Beatson, Scott A; Dykes, Gary A; Turner, Mark S

    2012-11-01

    During construction of several gene deletion mutants in Lactococcus lactis MG1363 which involved a high-temperature (37.5°C) incubation step, additional spontaneous mutations were observed which resulted in stable heat resistance and in some cases salt-hypersensitive phenotypes. Whole-genome sequencing of one strain which was both heat resistant and salt hypersensitive, followed by PCR and sequencing of four other mutants which shared these phenotypes, revealed independent mutations in llmg_1816 in all cases. This gene encodes a membrane-bound stress signaling protein of the GdpP family, members of which exhibit cyclic dimeric AMP (c-di-AMP)-specific phosphodiesterase activity. Mutations were predicted to lead to single amino acid substitutions or protein truncations. An independent llmg_1816 mutant (Δ1816), created using a suicide vector, also displayed heat resistance and salt hypersensitivity phenotypes which could be restored to wild-type levels following plasmid excision. L. lactis Δ1816 also displayed improved growth in response to sublethal concentrations of penicillin G. High-temperature incubation of a wild-type industrial L. lactis strain also resulted in spontaneous mutation of llmg_1816 and heat-resistant and salt-hypersensitive phenotypes, suggesting that this is not a strain-specific phenomenon and that it is independent of a plasmid integration event. Acidification of milk by the llmg_1816-altered strain was inhibited by lower salt concentrations than the parent strain. This study demonstrates that spontaneous mutations can occur during high-temperature growth of L. lactis and that inactivation of llmg_1816 leads to temperature resistance and salt hypersensitivity.

  13. Beyond GDP: Classifying Alternative Measures for Progress

    ERIC Educational Resources Information Center

    Bleys, Brent

    2012-01-01

    Both the potential pitfalls of macro-economic policies focused on stimulating economic growth and the problems involved in using GDP as a measure of well-being or economic welfare have long been recognized by economists and researchers from other social sciences. Therefore, it is no surprise that alternative measures for policy-making have been…

  14. Prediction of Malaysian monthly GDP

    NASA Astrophysics Data System (ADS)

    Hin, Pooi Ah; Ching, Soo Huei; Yeing, Pan Wei

    2015-12-01

    The paper attempts to use a method based on multivariate power-normal distribution to predict the Malaysian Gross Domestic Product next month. Letting r(t) be the vector consisting of the month-t values on m selected macroeconomic variables, and GDP, we model the month-(t+1) GDP to be dependent on the present and l-1 past values r(t), r(t-1),…,r(t-l+1) via a conditional distribution which is derived from a [(m+1)l+1]-dimensional power-normal distribution. The 100(α/2)% and 100(1-α/2)% points of the conditional distribution may be used to form an out-of sample prediction interval. This interval together with the mean of the conditional distribution may be used to predict the month-(t+1) GDP. The mean absolute percentage error (MAPE), estimated coverage probability and average length of the prediction interval are used as the criterions for selecting the suitable lag value l-1 and the subset from a pool of 17 macroeconomic variables. It is found that the relatively better models would be those of which 2 ≤ l ≤ 3, and involving one or two of the macroeconomic variables given by Market Indicative Yield, Oil Prices, Exchange Rate and Import Trade.

  15. But Can You Hit?

    ERIC Educational Resources Information Center

    Johnson, R. E.

    2009-01-01

    The author shares a story told to him by a colleague more than thirty years ago. The dean of a midsized American university was explaining the path to tenure to a roomful of newly appointed assistant professors. "We know you boys can all "field"," he declared. "Now we want to see if you can hit." A lot has changed over the intervening decades. If…

  16. Characterization of GDP-Fucose

    PubMed Central

    James, Douglas W.; Jones, Russell L.

    1979-01-01

    The peripheral root cap cells of corn (cv. SX-17A) secrete a fucose-rich, high molecular weight, polysaccharide slime via the dictyosome pathway. To study the synthesis of this polysaccharide, a technique for isolating and assaying GDP-fucose:polysaccharide fucosyl transferase activity was developed. Corn roots were excised from germinated seeds, incubated 12 hours at 10 C in water, and ground in 100 millimolar Tris or Pipes buffer (pH 7.0) with or without 0.5 molar sucrose. The membrane-bound enzyme was solubilized by sonication in the presence of 2 molar urea and 1.5% (v/v) Triton X-100 and assayed by monitoring the incorporation of GDP-[14C]fucose into endogenous acceptors. Optimum enzyme activity is expressed at pH 7.0 and 30 C in the presence of 0.8% (v/v) Triton X-100. The enzyme does not require divalent cations for activation and is inhibited by concentrations of MnCl2 or MgCl2 greater than 1 millimolar. Corn root cap slime will serve as an exogenous acceptor for the enzyme if it is first hydrolyzed in 5 millimolar trifluoroacetic acid for 60 minutes at 18 pounds per square inch, 121 C. This procedure prepares the acceptor by removing terminal fucose residues from the slime molecule. Kinetics of fucose release during hydrolysis of native slime and in vitro synthesized product suggests that the two polymers possess similar linkages to fucose. PMID:16661104

  17. Computational Physics' Greatest Hits

    NASA Astrophysics Data System (ADS)

    Bug, Amy

    2011-03-01

    The digital computer, has worked its way so effectively into our profession that now, roughly 65 years after its invention, it is virtually impossible to find a field of experimental or theoretical physics unaided by computational innovation. It is tough to think of another device about which one can make that claim. In the session ``What is computational physics?'' speakers will distinguish computation within the field of computational physics from this ubiquitous importance across all subfields of physics. This talk will recap the invited session ``Great Advances...Past, Present and Future'' in which five dramatic areas of discovery (five of our ``greatest hits'') are chronicled: The physics of many-boson systems via Path Integral Monte Carlo, the thermodynamic behavior of a huge number of diverse systems via Monte Carlo Methods, the discovery of new pharmaceutical agents via molecular dynamics, predictive simulations of global climate change via detailed, cross-disciplinary earth system models, and an understanding of the formation of the first structures in our universe via galaxy formation simulations. The talk will also identify ``greatest hits'' in our field from the teaching and research perspectives of other members of DCOMP, including its Executive Committee.

  18. The Arabidopsis Golgi-localized GDP-L-fucose transporter is required for plant development

    PubMed Central

    Rautengarten, Carsten; Ebert, Berit; Liu, Lifeng; Stonebloom, Solomon; Smith-Moritz, Andreia M.; Pauly, Markus; Orellana, Ariel; Scheller, Henrik Vibe; Heazlewood, Joshua L.

    2016-01-01

    Nucleotide sugar transport across Golgi membranes is essential for the luminal biosynthesis of glycan structures. Here we identify GDP-fucose transporter 1 (GFT1), an Arabidopsis nucleotide sugar transporter that translocates GDP-L-fucose into the Golgi lumen. Using proteo-liposome-based transport assays, we show that GFT preferentially transports GDP-L-fucose over other nucleotide sugars in vitro, while GFT1-silenced plants are almost devoid of L-fucose in cell wall-derived xyloglucan and rhamnogalacturonan II. Furthermore, these lines display reduced L-fucose content in N-glycan structures accompanied by severe developmental growth defects. We conclude that GFT1 is the major nucleotide sugar transporter for import of GDP-L-fucose into the Golgi and is required for proper plant growth and development. PMID:27381418

  19. The Arabidopsis Golgi-localized GDP-L-fucose transporter is required for plant development.

    PubMed

    Rautengarten, Carsten; Ebert, Berit; Liu, Lifeng; Stonebloom, Solomon; Smith-Moritz, Andreia M; Pauly, Markus; Orellana, Ariel; Scheller, Henrik Vibe; Heazlewood, Joshua L

    2016-01-01

    Nucleotide sugar transport across Golgi membranes is essential for the luminal biosynthesis of glycan structures. Here we identify GDP-fucose transporter 1 (GFT1), an Arabidopsis nucleotide sugar transporter that translocates GDP-L-fucose into the Golgi lumen. Using proteo-liposome-based transport assays, we show that GFT preferentially transports GDP-L-fucose over other nucleotide sugars in vitro, while GFT1-silenced plants are almost devoid of L-fucose in cell wall-derived xyloglucan and rhamnogalacturonan II. Furthermore, these lines display reduced L-fucose content in N-glycan structures accompanied by severe developmental growth defects. We conclude that GFT1 is the major nucleotide sugar transporter for import of GDP-L-fucose into the Golgi and is required for proper plant growth and development. PMID:27381418

  20. The Arabidopsis Golgi-localized GDP-L-fucose transporter is required for plant development.

    PubMed

    Rautengarten, Carsten; Ebert, Berit; Liu, Lifeng; Stonebloom, Solomon; Smith-Moritz, Andreia M; Pauly, Markus; Orellana, Ariel; Scheller, Henrik Vibe; Heazlewood, Joshua L

    2016-07-06

    Nucleotide sugar transport across Golgi membranes is essential for the luminal biosynthesis of glycan structures. Here we identify GDP-fucose transporter 1 (GFT1), an Arabidopsis nucleotide sugar transporter that translocates GDP-L-fucose into the Golgi lumen. Using proteo-liposome-based transport assays, we show that GFT preferentially transports GDP-L-fucose over other nucleotide sugars in vitro, while GFT1-silenced plants are almost devoid of L-fucose in cell wall-derived xyloglucan and rhamnogalacturonan II. Furthermore, these lines display reduced L-fucose content in N-glycan structures accompanied by severe developmental growth defects. We conclude that GFT1 is the major nucleotide sugar transporter for import of GDP-L-fucose into the Golgi and is required for proper plant growth and development.

  1. Accommodation of GDP-Linked Sugars in the Active Site of GDP-Perosamine Synthase

    SciTech Connect

    Cook, Paul D.; Carney, Amanda E.; Holden, Hazel M.

    2009-01-12

    Perosamine (4-amino-4,6-dideoxy-d-mannose), or its N-acetylated form, is one of several dideoxy sugars found in the O-antigens of such infamous Gram-negative bacteria as Vibrio cholerae O1 and Escherichia coli O157:H7. It is added to the bacterial O-antigen via a nucleotide-linked version, namely GDP-perosamine. Three enzymes are required for the biosynthesis of GDP-perosamine starting from mannose 1-phosphate. The focus of this investigation is GDP-perosamine synthase from Caulobacter crescentus, which catalyzes the final step in GDP-perosamine synthesis, the conversion of GDP-4-keto-6-deoxymannose to GDP-perosamine. The enzyme is PLP-dependent and belongs to the aspartate aminotransferase superfamily. It contains the typically conserved active site lysine residue, which forms a Schiff base with the PLP cofactor. Two crystal structures were determined for this investigation: a site-directed mutant protein (K186A) complexed with GDP-perosamine and the wild-type enzyme complexed with an unnatural ligand, GDP-3-deoxyperosamine. These structures, determined to 1.6 and 1.7 {angstrom} resolution, respectively, revealed the manner in which products, and presumably substrates, are accommodated within the active site pocket of GDP-perosamine synthase. Additional kinetic analyses using both the natural and unnatural substrates revealed that the K{sub m} for the unnatural substrate was unperturbed relative to that of the natural substrate, but the k{sub cat} was lowered by a factor of approximately 200. Taken together, these studies shed light on why GDP-perosamine synthase functions as an aminotransferase whereas another very similar PLP-dependent enzyme, GDP-4-keto-6-deoxy-d-mannose 3-dehydratase or ColD, catalyzes a dehydration reaction using the same substrate.

  2. Hit finding: towards 'smarter' approaches.

    PubMed

    Langer, Thierry; Hoffmann, Rémy; Bryant, Sharon; Lesur, Brigitte

    2009-10-01

    Drug discovery is complex and risky, and the chances of success are low. One starting point to discover a new drug is the selective screening of a collection of high value and good quality compounds. Selection of compounds for screening is one of the challenging initial steps in the drug discovery process and is crucial for the success of the project. Optimal selection will enhance the chances of successful hit finding with regard to both number and quality of hits. Several scenarios for compound selection can be envisaged, and are primarily driven by knowledge of the target. Deciding the most appropriate scenario is important and appropriate software packages and chemoinformatics tools are available for these purposes. After screening, researchers may face challenges in selecting the best hits for further optimization. Numerous chemoinformatics tools have emerged recently to address challenges in hit analysis, prioritization and optimization. PMID:19576852

  3. Metabolic engineering of Corynebacterium glutamicum to produce GDP-L-fucose from glucose and mannose.

    PubMed

    Chin, Young-Wook; Park, Jin-Byung; Park, Yong-Cheol; Kim, Kyoung Heon; Seo, Jin-Ho

    2013-06-01

    Wild-type Corynebacterium glutamicum was metabolically engineered to convert glucose and mannose into guanosine 5'-diphosphate (GDP)-L-fucose, a precursor of fucosyl-oligosaccharides, which are involved in various biological and pathological functions. This was done by introducing the gmd and wcaG genes of Escherichia coli encoding GDP-D-mannose-4,6-dehydratase and GDP-4-keto-6-deoxy-D-mannose-3,5-epimerase-4-reductase, respectively, which are known as key enzymes in the production of GDP-L-fucose from GDP-D-mannose. Coexpression of the genes allowed the recombinant C. glutamicum cells to produce GDP-L-fucose in a minimal medium containing glucose and mannose as carbon sources. The specific product formation rate was much higher during growth on mannose than on glucose. In addition, the specific product formation rate was further increased by coexpressing the endogenous phosphomanno-mutase gene (manB) and GTP-mannose-1-phosphate guanylyl-transferase gene (manC), which are involved in the conversion of mannose-6-phosphate into GDP-D-mannose. However, the overexpression of manA encoding mannose-6-phosphate isomerase, catalyzing interconversion of mannose-6-phosphate and fructose-6-phosphate showed a negative effect on formation of the target product. Overall, coexpression of gmd, wcaG, manB and manC in C. glutamicum enabled production of GDP-L-fucose at the specific rate of 0.11 mg g cell(-1) h(-1). The specific GDP-L-fucose content reached 5.5 mg g cell(-1), which is a 2.4-fold higher than that of the recombinant E. coli overexpressing gmd, wcaG, manB and manC under comparable conditions. Well-established metabolic engineering tools may permit optimization of the carbon and cofactor metabolisms of C. glutamicum to further improve their production capacity.

  4. Consortia Hit Critical Mass.

    ERIC Educational Resources Information Center

    Oder, Norman

    2000-01-01

    Discusses the growth of library consortia that has been largely driven by the rise in cost and quantity of electronic journals and products. Highlights include activities in addition to purchasing agreements, including staff development, distance learning, and minority recruitment; national consortia; database pricing; vendor opinions;…

  5. Micronutrient deficiencies in early childhood can lower a country's GDP: The Myanmar example.

    PubMed

    Win, Aung Zaw

    2016-01-01

    Myanmar (Burma) is a developing country in South East Asia. While Myanmar is among the 20 countries where 80% of the world's malnourished children live, its military consumes the majority of the national budget. Children who are malnourished between conception and age two are at high risk for impaired physical and mental development, which adversely affects the country's productivity and growth. Myanmar is facing three major micronutrient deficiencies which are iodine, iron and vitamin A deficiencies. The three micronutrient deficiencies can cost about 2.4% of the country's GDP. Children are the future of Myanmar and persistent micronutrient deficiencies will hamper its economic growth and lower its GDP. PMID:26421387

  6. Micronutrient deficiencies in early childhood can lower a country's GDP: The Myanmar example.

    PubMed

    Win, Aung Zaw

    2016-01-01

    Myanmar (Burma) is a developing country in South East Asia. While Myanmar is among the 20 countries where 80% of the world's malnourished children live, its military consumes the majority of the national budget. Children who are malnourished between conception and age two are at high risk for impaired physical and mental development, which adversely affects the country's productivity and growth. Myanmar is facing three major micronutrient deficiencies which are iodine, iron and vitamin A deficiencies. The three micronutrient deficiencies can cost about 2.4% of the country's GDP. Children are the future of Myanmar and persistent micronutrient deficiencies will hamper its economic growth and lower its GDP.

  7. Car Hits Boy on Bicycle

    ERIC Educational Resources Information Center

    Ruiz, Michael J.

    2005-01-01

    In this article we present the fascinating reconstruction of an accident where a car hit a boy riding his bicycle. The boy dramatically flew several metres through the air after the collision and was injured, but made a swift and complete recovery from the accident with no long-term after-effects. Students are challenged to determine the speed of…

  8. An Empirical Analysis of Differences in GDP per Capita and the Role of Human Capital

    ERIC Educational Resources Information Center

    Sfakianakis, George; Magoutas, Anastasios I.; Georgopoulos, Demosthenes

    2010-01-01

    Using a generalized production function approach and insights from empirical research on the determinants of growth, this paper assesses the relative importance of specific factors in explaining differences in the levels of per capita GDP. Emphasis is placed on education, physical capital accumulation, the share of the public sector in economic…

  9. Hitting is contagious in baseball: evidence from long hitting streaks.

    PubMed

    Bock, Joel R; Maewal, Akhilesh; Gough, David A

    2012-01-01

    Data analysis is used to test the hypothesis that "hitting is contagious". A statistical model is described to study the effect of a hot hitter upon his teammates' batting during a consecutive game hitting streak. Box score data for entire seasons comprising [Formula: see text] streaks of length [Formula: see text] games, including a total [Formula: see text] observations were compiled. Treatment and control sample groups ([Formula: see text]) were constructed from core lineups of players on the streaking batter's team. The percentile method bootstrap was used to calculate [Formula: see text] confidence intervals for statistics representing differences in the mean distributions of two batting statistics between groups. Batters in the treatment group (hot streak active) showed statistically significant improvements in hitting performance, as compared against the control. Mean [Formula: see text] for the treatment group was found to be [Formula: see text] to [Formula: see text] percentage points higher during hot streaks (mean difference increased [Formula: see text] points), while the batting heat index [Formula: see text] introduced here was observed to increase by [Formula: see text] points. For each performance statistic, the null hypothesis was rejected at the [Formula: see text] significance level. We conclude that the evidence suggests the potential existence of a "statistical contagion effect". Psychological mechanisms essential to the empirical results are suggested, as several studies from the scientific literature lend credence to contagious phenomena in sports. Causal inference from these results is difficult, but we suggest and discuss several latent variables that may contribute to the observed results, and offer possible directions for future research. PMID:23251507

  10. Hitting is contagious in baseball: evidence from long hitting streaks.

    PubMed

    Bock, Joel R; Maewal, Akhilesh; Gough, David A

    2012-01-01

    Data analysis is used to test the hypothesis that "hitting is contagious". A statistical model is described to study the effect of a hot hitter upon his teammates' batting during a consecutive game hitting streak. Box score data for entire seasons comprising [Formula: see text] streaks of length [Formula: see text] games, including a total [Formula: see text] observations were compiled. Treatment and control sample groups ([Formula: see text]) were constructed from core lineups of players on the streaking batter's team. The percentile method bootstrap was used to calculate [Formula: see text] confidence intervals for statistics representing differences in the mean distributions of two batting statistics between groups. Batters in the treatment group (hot streak active) showed statistically significant improvements in hitting performance, as compared against the control. Mean [Formula: see text] for the treatment group was found to be [Formula: see text] to [Formula: see text] percentage points higher during hot streaks (mean difference increased [Formula: see text] points), while the batting heat index [Formula: see text] introduced here was observed to increase by [Formula: see text] points. For each performance statistic, the null hypothesis was rejected at the [Formula: see text] significance level. We conclude that the evidence suggests the potential existence of a "statistical contagion effect". Psychological mechanisms essential to the empirical results are suggested, as several studies from the scientific literature lend credence to contagious phenomena in sports. Causal inference from these results is difficult, but we suggest and discuss several latent variables that may contribute to the observed results, and offer possible directions for future research.

  11. Quantum walks with infinite hitting times

    SciTech Connect

    Krovi, Hari; Brun, Todd A.

    2006-10-15

    Hitting times are the average time it takes a walk to reach a given final vertex from a given starting vertex. The hitting time for a classical random walk on a connected graph will always be finite. We show that, by contrast, quantum walks can have infinite hitting times for some initial states. We seek criteria to determine if a given walk on a graph will have infinite hitting times, and find a sufficient condition, which for discrete time quantum walks is that the degeneracy of the evolution operator be greater than the degree of the graph. The set of initial states which give an infinite hitting time form a subspace. The phenomenon of infinite hitting times is in general a consequence of the symmetry of the graph and its automorphism group. Using the irreducible representations of the automorphism group, we derive conditions such that quantum walks defined on this graph must have infinite hitting times for some initial states. In the case of the discrete walk, if this condition is satisfied the walk will have infinite hitting times for any choice of a coin operator, and we give a class of graphs with infinite hitting times for any choice of coin. Hitting times are not very well defined for continuous time quantum walks, but we show that the idea of infinite hitting-time walks naturally extends to the continuous time case as well.

  12. Biological effects in hit and non-hit cells

    NASA Astrophysics Data System (ADS)

    Hall, E. J.; Hei, T. K.; Geard, C. R.; Brenner, D. J.; Mitchell, S. A.

    It had long been considered axiomatic that heritable biological effects of radiation required direct damage to DNA. This is no longer the case. The bystander effect refers to the induction of biological effects in cells that are not directly traversed by a charged particle, but are close to cells that are. Experiments suggest that the effect is due to a molecule secreted by irradiated cells which is capable of transferring damage to distant cells. The magnitude of the effect is much larger if cells are in gap junction communication. In cell cultures, a bystander effect has been shown for cell lethality, chromosomal aberrations, mutation, oncogenic transformation and upregulation of gene expression. A similar effect has been observed in artificial 3-dimensional skin cultures. Bystander studies imply that the target for the biological effects of radiation is larger than the cell, and this has implications for biologically based models of carcinogenesis at low doses where not all cells receive a direct hit.

  13. HITS - The Navy's new DATPG system

    NASA Astrophysics Data System (ADS)

    Hosley, L.; Modi, M.

    A new digital automatic test program generation standard called HITS (Hierarchical Integrated Test Simulator), developed by the U.S. Navy as the answer to digital LSI/VLSI circuit technology is discussed. Three major areas of the HITS program which include system flow/unique capabilities, modeling language structures, and management of HITS are preseented. HITS contains the following major software modules: the primary model processor, the secondary model processor, the test language processor, the simulator, and the tester output generator. The functions performed by the individual system modules are described. A circuit description language, which provides user flexibility when describing complex circuit models, and its components are considered. The major areas of HITS management include: (1) HITS accessibility, distribution, and availability; (2) user support; (3) advanced development; and (4) Navy/DOD coordination and standardization.

  14. Studying the HIT-Complexity Interchange.

    PubMed

    Kuziemsky, Craig E; Borycki, Elizabeth M; Kushniruk, Andre W

    2016-01-01

    The design and implementation of health information technology (HIT) is challenging, particularly when it is being introduced into complex settings. While complex adaptive system (CASs) can be a valuable means of understanding relationships between users, HIT and tasks, much of the existing work using CASs is descriptive in nature. This paper addresses that issue by integrating a model for analyzing task complexity with approaches for HIT evaluation and systems analysis. The resulting framework classifies HIT-user tasks and issues as simple, complicated or complex, and provides insight on how to study them. PMID:27332158

  15. Direct incorporation of GDP into microtubules without GTP hydrolysis

    SciTech Connect

    Lin, C.M.; Hamel, E.

    1987-05-01

    Tubulin bearing (8-/sup 14/C)GDP in the exchangeable nucleotide binding site was prepared, and its polymerization was examined with microtubule-associated proteins containing minimal nucleoside diphosphate kinase and nonspecific phosphatase contamination. Although microtubule assembly required GTP, significant incorporation of tubulin-bound GDP into microtubules without exchange of the radiolabeled GDP for GTP was observed under reaction conditions which favored an increased proportion of tubulin x GDP relative to tubulin x GTP. These were low GTP concentrations, low Mg/sup 2 +/ concentrations, high tubulin concentrations, and exogenous GDP in the reaction mixture. The minimum tubulin x GTP:tubulin x GDP ratio required for microtubule assembly was determined to establish the relative importance of the two tubulin species in the initiation of assembly and was found to be about 2:1. In addition, the relative efficiency with which tubulin x GTP and tubulin x GDP were incorporated into microtubules was determined. They found that tubulin x GDP was incorporated into polymer about half as efficiently as tubulin x GTP.

  16. Developing Health Information Technology (HIT) Programs and HIT Curriculum: The Southern Polytechnic State University Experience

    ERIC Educational Resources Information Center

    Zhang, Chi; Reichgelt, Han; Rutherfoord, Rebecca H.; Wang, Andy Ju An

    2014-01-01

    Health Information Technology (HIT) professionals are in increasing demand as healthcare providers need help in the adoption and meaningful use of Electronic Health Record (EHR) systems while the HIT industry needs workforce skilled in HIT and EHR development. To respond to this increasing demand, the School of Computing and Software Engineering…

  17. Hitting Is Contagious: Experience and Action Induction

    ERIC Educational Resources Information Center

    Gray, Rob; Beilock, Sian L.

    2011-01-01

    In baseball, it is believed that "hitting is contagious," that is, probability of success increases if the previous few batters get a hit. Could this effect be partially explained by action induction--that is, the tendency to perform an action related to one that has just been observed? A simulation was used to investigate the effect of inducing…

  18. Recognition of Hits in a Target

    NASA Astrophysics Data System (ADS)

    Semerak, Vojtech; Drahansky, Martin

    This paper describes two possible ways of hit recognition in a target. First method is based on frame differencing with use of a stabilization algorithm to eliminate movements of a target. Second method uses flood fill with random seed point definition to find hits in the target scene.

  19. How I diagnose and manage HIT.

    PubMed

    Warkentin, Theodore E

    2011-01-01

    Heparin-induced thrombocytopenia (HIT) is a prothrombotic drug reaction caused by platelet-activating IgG antibodies that recognize platelet factor 4 (PF4)/polyanion complexes. Platelet activation assays, such as the serotonin-release assay, are superior to PF4-dependent immunoassays in discerning which heparin-induced antibodies are clinically relevant. When HIT is strongly suspected, standard practice includes substituting heparin with an alternative anticoagulant; the 2 US-approved agents are the direct thrombin inhibitors (DTIs) lepirudin and argatroban, which are "niche" agents used only to manage HIT. However, only ~ 10% of patients who undergo serological investigation for HIT actually have this diagnosis. Indeed, depending on the clinical setting, only 10%-50% of patients with positive PF4-dependent immunoassays have platelet-activating antibodies. Therefore, overdiagnosis of HIT can be minimized by insisting that a positive platelet activation assay be required for definitive diagnosis of HIT. For these reasons, a management strategy that considers the real possibility of non-HIT thrombocytopenia is warranted. One approach that I suggest is to administer an indirect, antithrombin (AT)-dependent factor Xa inhibitor (danaparoid or fondaparinux) based upon the following rationale: (1) effectiveness in treating and preventing HIT-associated thrombosis; (2) effectiveness in treating and preventing thrombosis in diverse non-HIT situations; (3) both prophylactic- and therapeutic-dose protocols exist, permitting dosing appropriate for the clinical situation; (4) body weight-adjusted dosing protocols and availability of specific anti-factor Xa monitoring reduce risk of under- or overdosing (as can occur with partial thromboplastin time [PTT]-adjusted DTI therapy); (5) their long half-lives reduce risk of rebound hypercoagulability; (6) easy coumarin overlap; and (7) relatively low cost. PMID:22160026

  20. Computing Principal Eigenvectors of Large Web Graphs: Algorithms and Accelerations Related to PageRank and HITS

    ERIC Educational Resources Information Center

    Nagasinghe, Iranga

    2010-01-01

    This thesis investigates and develops a few acceleration techniques for the search engine algorithms used in PageRank and HITS computations. PageRank and HITS methods are two highly successful applications of modern Linear Algebra in computer science and engineering. They constitute the essential technologies accounted for the immense growth and…

  1. Hitting the Highway? Keep Safety in Mind

    MedlinePlus

    ... medlineplus.gov/news/fullstory_160238.html Hitting the Highway? Keep Safety in Mind Planning ahead is essential ... U.S. Department of Health and Human Services, or federal policy. More Health News on: Traveler's Health Recent ...

  2. Optical spectrosopy of HiTS supernovae

    NASA Astrophysics Data System (ADS)

    Anderson, J.; Forster, F.; Smith, C.; Vivas, K.; Pignata, G.; Olivares, F.; Hamuy, M.; Martin, J. San; Maureira, J. C.; Cabrera, G.; Gonzalez-Gaitan, S.; Galbany, L.; Bufano, F.; de Jaeger, T.; Hsiao, E.; Munoz, R.; Vera, E.

    2015-04-01

    We report optical wavelength spectroscopy obtained using the Goodman instrument mounted on the SOAR at CTIO on UT 2015-03-30, for two supernovae discovered by HiTS, the High Cadence Transient Survey (see ATELs #7289, #7290).

  3. Rising Blood Sugar Hitting More Obese Adults

    MedlinePlus

    ... medlineplus.gov/news/fullstory_159853.html Rising Blood Sugar Hitting More Obese Adults To curb diabetes, researchers ... News) -- Among obese American adults, control of blood sugar is worsening, leading to more diabetes and heart ...

  4. Credit Recovery Hits the Mainstream

    ERIC Educational Resources Information Center

    Carr, Sarah

    2014-01-01

    In communities including New Orleans, Los Angeles, and Chicago, educators are creating alternative schools for struggling students that employ online credit-recovery programs as a core portion, or all, of their curriculum. The growth in online learning generally, including blended learning, has fueled the proliferation of computer-based credit…

  5. A High-Throughput Assay for Rho Guanine Nucleotide Exchange Factors Based on the Transcreener GDP Assay.

    PubMed

    Reichman, Melvin; Schabdach, Amanda; Kumar, Meera; Zielinski, Tom; Donover, Preston S; Laury-Kleintop, Lisa D; Lowery, Robert G

    2015-12-01

    Ras homologous (Rho) family GTPases act as molecular switches controlling cell growth, movement, and gene expression by cycling between inactive guanosine diphosphate (GDP)- and active guanosine triphosphate (GTP)-bound conformations. Guanine nucleotide exchange factors (GEFs) positively regulate Rho GTPases by accelerating GDP dissociation to allow formation of the active, GTP-bound complex. Rho proteins are directly involved in cancer pathways, especially cell migration and invasion, and inhibiting GEFs holds potential as a therapeutic strategy to diminish Rho-dependent oncogenesis. Methods for measuring GEF activity suitable for high-throughput screening (HTS) are limited. We developed a simple, generic biochemical assay method for measuring GEF activity based on the fact that GDP dissociation is generally the rate-limiting step in the Rho GTPase catalytic cycle, and thus addition of a GEF causes an increase in steady-state GTPase activity. We used the Transcreener GDP Assay, which relies on selective immunodetection of GDP, to measure the GEF-dependent stimulation of steady-state GTP hydrolysis by small GTPases using Dbs (Dbl's big sister) as a GEF for Cdc42, RhoA, and RhoB. The assay is well suited for HTS, with a homogenous format and far red fluorescence polarization (FP) readout, and it should be broadly applicable to diverse Rho GEF/GTPase pairs.

  6. Health Care Expenditure and GDP in Oil Exporting Countries: Evidence from OPEC Data, 1995-2012

    PubMed Central

    Fazaeli, Ali Akbar; Ghaderi, Hossein; Salehi, Masoud; Fazaeli, Ali Reza

    2016-01-01

    Background: There is a large body of literature examining income in relation to health expenditures. The share of expenditures in health sector from GDP in developed countries is often larger than in non-developed countries, suggesting that as the level of economic growth increases, health spending increase, too. Objectives: This paper estimates long-run relationships between health expenditures and GDP based on panel data of a sample of 12 countries of the Organization of the Petroleum Exporting Countries (OPEC), using data for the period 1995-2012. Patients & Methods: We use panel data unit root tests, cointegration analysis and ECM model to find long-run and short-run relation. This study examines whether health is a luxury or a necessity for OPEC countries within a unit root and cointegration framework. Results: Panel data analysis indicates that health expenditures and GDP are co-integrated and have Engle and Granger causality. In addition, in oil countries that have oil export income, the share of government expenditures in the health sector is often greater than in private health expenditures similar developed countries. Conclusions: The findings verify that health care is not a luxury good and income has a robust relationship to health expenditures in OPEC countries. PMID:26383195

  7. Differential dynamics of RAS isoforms in GDP- and GTP-bound states.

    PubMed

    Kapoor, Abhijeet; Travesset, Alex

    2015-06-01

    RAS subfamily proteins regulates cell growth promoting signaling processes by cycling between active (GTP-bound) and inactive (GDP-bound) states. Different RAS isoforms, though structurally similar, exhibit functional specificity and are associated with different types of cancers and developmental disorders. Understanding the dynamical differences between the isoforms is crucial for the design of inhibitors that can selectively target a particular malfunctioning isoform. In this study, we provide a comprehensive comparison of the dynamics of all the three RAS isoforms (HRAS, KRAS, and NRAS) using extensive molecular dynamics simulations in both the GDP- (total of 3.06 μs) and GTP-bound (total of 2.4 μs) states. We observed significant differences in the dynamics of the isoforms, which rather interestingly, varied depending on the type of the nucleotide bound and the simulation temperature. Both SwitchI (Residues 25-40) and SwitchII (Residues 59-75) differ significantly in their flexibility in the three isoforms. Furthermore, Principal Component Analysis showed that there are differences in the conformational space sampled by the GTP-bound RAS isoforms. We also identified a previously unreported pocket, which opens transiently during MD simulations, and can be targeted to regulate nucleotide exchange reaction or possibly interfere with membrane localization. Further, we present the first simulation study showing GDP destabilization in the wild-type RAS protein. The destabilization of GDP/GTP occurred only in 1/50 simulations, emphasizing the need of guanine nucleotide exchange factors (GEFs) to accelerate such an extremely unfavorable process. This observation along with the other results presented in this article further support our previously hypothesized mechanism of GEF-assisted nucleotide exchange.

  8. China's post-coal growth

    NASA Astrophysics Data System (ADS)

    Qi, Ye; Stern, Nicholas; Wu, Tong; Lu, Jiaqi; Green, Fergus

    2016-08-01

    Slowing GDP growth, a structural shift away from heavy industry, and more proactive policies on air pollution and clean energy have caused China's coal use to peak. It seems that economic growth has decoupled from growth in coal consumption.

  9. Hitting is contagious: experience and action induction.

    PubMed

    Gray, Rob; Beilock, Sian L

    2011-03-01

    In baseball, it is believed that "hitting is contagious," that is, probability of success increases if the previous few batters get a hit. Could this effect be partially explained by action induction--that is, the tendency to perform an action related to one that has just been observed? A simulation was used to investigate the effect of inducing stimuli on batting performance for more-experienced (ME) and less-experienced (LE) baseball players. Three types of inducing stimuli were compared with a no-induction condition: action (a simulated ball traveling from home plate into left, right, or center field), outcome (a ball resting in either left, right, or center field), and verbal (the word "left", "center", or "right"). For both ME and LE players, fewer pitchers were required for a successful hit in the action condition. For ME players, there was a significant relationship between the inducing stimulus direction and hit direction for both the action and outcome prompts. For LE players, the prompt only had a significant effect on batting performance in the action condition, and the magnitude of the effect was significantly smaller than for ME. The effect of the inducing stimulus decreased as the delay (i.e., no. of pitches between prompt and hit) increased, with the effect being eliminated after roughly 4 pitches for ME and 2 pitches for LE. It is proposed that the differences in the magnitude and time course of action induction as a function of experience occurred because ME have more well-developed perceptual-motor representations for directional hitting. PMID:21443380

  10. Hitting is contagious: experience and action induction.

    PubMed

    Gray, Rob; Beilock, Sian L

    2011-03-01

    In baseball, it is believed that "hitting is contagious," that is, probability of success increases if the previous few batters get a hit. Could this effect be partially explained by action induction--that is, the tendency to perform an action related to one that has just been observed? A simulation was used to investigate the effect of inducing stimuli on batting performance for more-experienced (ME) and less-experienced (LE) baseball players. Three types of inducing stimuli were compared with a no-induction condition: action (a simulated ball traveling from home plate into left, right, or center field), outcome (a ball resting in either left, right, or center field), and verbal (the word "left", "center", or "right"). For both ME and LE players, fewer pitchers were required for a successful hit in the action condition. For ME players, there was a significant relationship between the inducing stimulus direction and hit direction for both the action and outcome prompts. For LE players, the prompt only had a significant effect on batting performance in the action condition, and the magnitude of the effect was significantly smaller than for ME. The effect of the inducing stimulus decreased as the delay (i.e., no. of pitches between prompt and hit) increased, with the effect being eliminated after roughly 4 pitches for ME and 2 pitches for LE. It is proposed that the differences in the magnitude and time course of action induction as a function of experience occurred because ME have more well-developed perceptual-motor representations for directional hitting.

  11. A Reassessment of the Relationship between GDP and Life Satisfaction

    PubMed Central

    Proto, Eugenio; Rustichini, Aldo

    2013-01-01

    The scientific debate on the relation between Gross Domestic Product (GDP) and self reported indices of life satisfaction is still open. In a well-known finding, Easterlin reported no significant relationship between happiness and aggregate income in time-series analysis. However, life satisfaction appears to be strictly monotonically increasing with income when one studies this relation at a point in time across nations. Here, we analyze the relation between per capita GDP and life satisfaction without imposing a functional form and eliminating potentially confounding country-specific factors. We show that this relation clearly increases in country with a per capita GDP below 15,000 USD (2005 in Purchasing Power Parity), then it flattens for richer countries. The probability of reporting the highest level of life satisfaction is more than 12% lower in the poor countries with a per capita GDP below 5,600 USD than in the counties with a per capita GDP of about 15,000 USD. In countries with an income above 17,000 USD the probability of reporting the highest level of life satisfaction changes within a range of 2% maximum. Interestingly enough, life satisfaction seems to peak at around 30,000 USD and then slightly but significantly decline among the richest countries. These results suggest an explanation of the Easterlin paradox: life satisfaction increases with GDP in poor country, but this relation is approximately flat in richer countries. We explain this relation with aspiration levels. We assume that a gap between aspiration and realized income is negatively perceived; and aspirations to higher income increase with income. These facts together have a negative effect on life satisfaction, opposite to the positive direct effect of the income. The net effect is ambiguous. We predict a higher negative effect in individuals with higher sensitivity to losses (measured by their neuroticism score) and provide econometric support of this explanation. PMID:24312179

  12. A reassessment of the relationship between GDP and life satisfaction.

    PubMed

    Proto, Eugenio; Rustichini, Aldo

    2013-01-01

    The scientific debate on the relation between Gross Domestic Product (GDP) and self reported indices of life satisfaction is still open. In a well-known finding, Easterlin reported no significant relationship between happiness and aggregate income in time-series analysis. However, life satisfaction appears to be strictly monotonically increasing with income when one studies this relation at a point in time across nations. Here, we analyze the relation between per capita GDP and life satisfaction without imposing a functional form and eliminating potentially confounding country-specific factors. We show that this relation clearly increases in country with a per capita GDP below 15,000 USD (2005 in Purchasing Power Parity), then it flattens for richer countries. The probability of reporting the highest level of life satisfaction is more than 12% lower in the poor countries with a per capita GDP below 5,600 USD than in the counties with a per capita GDP of about 15,000 USD. In countries with an income above 17,000 USD the probability of reporting the highest level of life satisfaction changes within a range of 2% maximum. Interestingly enough, life satisfaction seems to peak at around 30,000 USD and then slightly but significantly decline among the richest countries. These results suggest an explanation of the Easterlin paradox: life satisfaction increases with GDP in poor country, but this relation is approximately flat in richer countries. We explain this relation with aspiration levels. We assume that a gap between aspiration and realized income is negatively perceived; and aspirations to higher income increase with income. These facts together have a negative effect on life satisfaction, opposite to the positive direct effect of the income. The net effect is ambiguous. We predict a higher negative effect in individuals with higher sensitivity to losses (measured by their neuroticism score) and provide econometric support of this explanation.

  13. Two pathways for importing GDP-fucose into the endoplasmic reticulum lumen function redundantly in the O-fucosylation of Notch in Drosophila.

    PubMed

    Ishikawa, Hiroyuki O; Ayukawa, Tomonori; Nakayama, Minoru; Higashi, Shunsuke; Kamiyama, Shin; Nishihara, Shoko; Aoki, Kazuhisa; Ishida, Nobuhiro; Sanai, Yutaka; Matsuno, Kenji

    2010-02-01

    Notch is a transmembrane receptor that shares homology with proteins containing epidermal growth factor-like repeats and mediates the cell-cell interactions necessary for many cell fate decisions. In Drosophila, O-fucosyltransferase 1 catalyzes the O-fucosylation of these epidermal growth factor-like repeats. This O-fucose elongates, resulting in an O-linked tetrasaccharide that regulates the signaling activities of Notch. Fucosyltransferases utilize GDP-fucose, which is synthesized in the cytosol, but fucosylation occurs in the lumen of the endoplasmic reticulum (ER) and Golgi. Therefore, GDP-fucose uptake into the ER and Golgi is essential for fucosylation. However, although GDP-fucose biosynthesis is well understood, the mechanisms and intracellular routes of GDP-fucose transportation remain unclear. Our previous study on the Drosophila Golgi GDP-fucose transporter (Gfr), which specifically localizes to the Golgi, suggested that another GDP-fucose transporter(s) exists in Drosophila. Here, we identified Efr (ER GDP-fucose transporter), a GDP-fucose transporter that localizes specifically to the ER. Efr is a multifunctional nucleotide sugar transporter involved in the biosynthesis of heparan sulfate-glycosaminoglycan chains and the O-fucosylation of Notch. Comparison of the fucosylation defects in the N-glycans in Gfr and Efr mutants revealed that Gfr and Efr made distinct contributions to this modification; Gfr but not Efr was crucial for the fucosylation of N-glycans. We also found that Gfr and Efr function redundantly in the O-fucosylation of Notch, although they had different localizations and nucleotide sugar transportation specificities. These results indicate that two pathways for the nucleotide sugar supply, involving two nucleotide sugar transporters with distinct characteristics and distributions, contribute to the O-fucosylation of Notch. PMID:19948734

  14. Statistical properties and pre-hit dynamics of price limit hits in the Chinese stock markets.

    PubMed

    Wan, Yu-Lei; Xie, Wen-Jie; Gu, Gao-Feng; Jiang, Zhi-Qiang; Chen, Wei; Xiong, Xiong; Zhang, Wei; Zhou, Wei-Xing

    2015-01-01

    Price limit trading rules are adopted in some stock markets (especially emerging markets) trying to cool off traders' short-term trading mania on individual stocks and increase market efficiency. Under such a microstructure, stocks may hit their up-limits and down-limits from time to time. However, the behaviors of price limit hits are not well studied partially due to the fact that main stock markets such as the US markets and most European markets do not set price limits. Here, we perform detailed analyses of the high-frequency data of all A-share common stocks traded on the Shanghai Stock Exchange and the Shenzhen Stock Exchange from 2000 to 2011 to investigate the statistical properties of price limit hits and the dynamical evolution of several important financial variables before stock price hits its limits. We compare the properties of up-limit hits and down-limit hits. We also divide the whole period into three bullish periods and three bearish periods to unveil possible differences during bullish and bearish market states. To uncover the impacts of stock capitalization on price limit hits, we partition all stocks into six portfolios according to their capitalizations on different trading days. We find that the price limit trading rule has a cooling-off effect (object to the magnet effect), indicating that the rule takes effect in the Chinese stock markets. We find that price continuation is much more likely to occur than price reversal on the next trading day after a limit-hitting day, especially for down-limit hits, which has potential practical values for market practitioners.

  15. Statistical Properties and Pre-Hit Dynamics of Price Limit Hits in the Chinese Stock Markets

    PubMed Central

    Wan, Yu-Lei; Xie, Wen-Jie; Gu, Gao-Feng; Jiang, Zhi-Qiang; Chen, Wei; Xiong, Xiong; Zhang, Wei; Zhou, Wei-Xing

    2015-01-01

    Price limit trading rules are adopted in some stock markets (especially emerging markets) trying to cool off traders’ short-term trading mania on individual stocks and increase market efficiency. Under such a microstructure, stocks may hit their up-limits and down-limits from time to time. However, the behaviors of price limit hits are not well studied partially due to the fact that main stock markets such as the US markets and most European markets do not set price limits. Here, we perform detailed analyses of the high-frequency data of all A-share common stocks traded on the Shanghai Stock Exchange and the Shenzhen Stock Exchange from 2000 to 2011 to investigate the statistical properties of price limit hits and the dynamical evolution of several important financial variables before stock price hits its limits. We compare the properties of up-limit hits and down-limit hits. We also divide the whole period into three bullish periods and three bearish periods to unveil possible differences during bullish and bearish market states. To uncover the impacts of stock capitalization on price limit hits, we partition all stocks into six portfolios according to their capitalizations on different trading days. We find that the price limit trading rule has a cooling-off effect (object to the magnet effect), indicating that the rule takes effect in the Chinese stock markets. We find that price continuation is much more likely to occur than price reversal on the next trading day after a limit-hitting day, especially for down-limit hits, which has potential practical values for market practitioners. PMID:25874716

  16. Structures of NodZ α1,6-fucosyltransferase in complex with GDP and GDP-fucose

    SciTech Connect

    Brzezinski, Krzysztof; Dauter, Zbigniew; Jaskolski, Mariusz

    2012-02-01

    Crystal structures of the bacterial α1,6-fucosyltransferase NodZ in complex with GDP and GDP-fucose are presented. Rhizobial NodZ α1,6-fucosyltransferase (α1,6-FucT) catalyzes the transfer of the fucose (Fuc) moiety from guanosine 5′-diphosphate-β-l-fucose to the reducing end of the chitin oligosaccharide core during Nod-factor (NF) biosynthesis. NF is a key signalling molecule required for successful symbiosis with a legume host for atmospheric nitrogen fixation. To date, only two α1,6-FucT structures have been determined, both without any donor or acceptor molecule that could highlight the structural background of the catalytic mechanism. Here, the first crystal structures of α1,6-FucT in complex with its substrate GDP-Fuc and with GDP, which is a byproduct of the enzymatic reaction, are presented. The crystal of the complex with GDP-Fuc was obtained through soaking of native NodZ crystals with the ligand and its structure has been determined at 2.35 Å resolution. The fucose residue is exposed to solvent and is disordered. The enzyme–product complex crystal was obtained by cocrystallization with GDP and an acceptor molecule, penta-N-acetyl-l-glucosamine (penta-NAG). The structure has been determined at 1.98 Å resolution, showing that only the GDP molecule is present in the complex. In both structures the ligands are located in a cleft formed between the two domains of NodZ and extend towards the C-terminal domain, but their conformations differ significantly. The structures revealed that residues in three regions of the C-terminal domain, which are conserved among α1,2-, α1,6- and protein O-fucosyltransferases, are involved in interactions with the sugar-donor molecule. There is also an interaction with the side chain of Tyr45 in the N-terminal domain, which is very unusual for a GT-B-type glycosyltransferase. Only minor conformational changes of the protein backbone are observed upon ligand binding. The only exception is a movement of the loop

  17. Precise timing when hitting falling balls.

    PubMed

    Brenner, Eli; Driesen, Ben; Smeets, Jeroen B J

    2014-01-01

    People are extremely good at hitting falling balls with a baseball bat. Despite the ball's constant acceleration, they have been reported to time hits with a standard deviation of only about 7 ms. To examine how people achieve such precision, we compared performance when there were no added restrictions, with performance when looking with one eye, when vision was blurred, and when various parts of the ball's trajectory were hidden from view. We also examined how the size of the ball and varying the height from which it was dropped influenced temporal precision. Temporal precision did not become worse when vision was blurred, when the ball was smaller, or when balls falling from different heights were randomly interleaved. The disadvantage of closing one eye did not exceed expectations from removing one of two independent estimates. Precision was higher for slower balls, but only if the ball being slower meant that one saw it longer before the hit. It was particularly important to see the ball while swinging the bat. Together, these findings suggest that people time their hits so precisely by using the changing elevation throughout the swing to adjust the bat's movement to that of the ball. PMID:24904380

  18. Improvements of HITS Algorithms for Spam Links

    NASA Astrophysics Data System (ADS)

    Asano, Yasuhito; Tezuka, Yu; Nishizeki, Takao

    The HITS algorithm proposed by Kleinberg is one of the representative methods of scoring Web pages by using hyperlinks. In the days when the algorithm was proposed, most of the pages given high score by the algorithm were really related to a given topic, and hence the algorithm could be used to find related pages. However, the algorithm and the variants including Bharat's improved HITS, abbreviated to BHITS, proposed by Bharat and Henzinger cannot be used to find related pages any more on today's Web, due to an increase of spam links. In this paper, we first propose three methods to find “linkfarms,” that is, sets of spam links forming a densely connected subgraph of a Web graph. We then present an algorithm, called a trust-score algorithm, to give high scores to pages which are not spam pages with a high probability. Combining the three methods and the trust-score algorithm with BHITS, we obtain several variants of the HITS algorithm. We ascertain by experiments that one of them, named TaN+BHITS using the trust-score algorithm and the method of finding linkfarms by employing name servers, is most suitable for finding related pages on today's Web. Our algorithms take time and memory no more than those required by the original HITS algorithm, and can be executed on a PC with a small amount of main memory.

  19. HiTS additional supernova candidates

    NASA Astrophysics Data System (ADS)

    Forster, F.; Maureira, J. C.; Points, S.; Medina, G.; Munoz, R.; Martin, J. San; Hamuy, M.; Estevez, P.; Smith, R. C.; Vivas, K.; Flores, S.; Huijse, P.; Cabrera, G.; Anderson, J.; Bufano, F.; Gonzalez-Gaitan, S.; Galbany, L.; Pignata, G.; de Jaeger, Th.; Martinez, J.; Munoz, R.; Vera, E.; Perez, C.

    2015-03-01

    HiTS, the High Cadence Transient Survey (see ATELs #5949, #7099), reports the discovery of additional supernova candidates detected using an image subtraction / classification pipeline developed at the Center for Mathematical Modelling (CMM) in collaboration with the Millennium Institute for Astrophysics (MAS).

  20. CEOs: Gulf crisis hits hospitals' bottom line.

    PubMed

    Johnsson, J

    1990-12-01

    Hospital CEOs say the Persian Gulf crisis could hit them hard where it counts. In fact, hospitals are already seeing some adverse impact from events in the Middle East. From fundraising to plant management to strategic planning, the confrontations in the Gulf are having an impact on the hospital's bottom line.

  1. Precise timing when hitting falling balls

    PubMed Central

    Brenner, Eli; Driesen, Ben; Smeets, Jeroen B. J.

    2014-01-01

    People are extremely good at hitting falling balls with a baseball bat. Despite the ball's constant acceleration, they have been reported to time hits with a standard deviation of only about 7 ms. To examine how people achieve such precision, we compared performance when there were no added restrictions, with performance when looking with one eye, when vision was blurred, and when various parts of the ball's trajectory were hidden from view. We also examined how the size of the ball and varying the height from which it was dropped influenced temporal precision. Temporal precision did not become worse when vision was blurred, when the ball was smaller, or when balls falling from different heights were randomly interleaved. The disadvantage of closing one eye did not exceed expectations from removing one of two independent estimates. Precision was higher for slower balls, but only if the ball being slower meant that one saw it longer before the hit. It was particularly important to see the ball while swinging the bat. Together, these findings suggest that people time their hits so precisely by using the changing elevation throughout the swing to adjust the bat's movement to that of the ball. PMID:24904380

  2. Precise timing when hitting falling balls.

    PubMed

    Brenner, Eli; Driesen, Ben; Smeets, Jeroen B J

    2014-01-01

    People are extremely good at hitting falling balls with a baseball bat. Despite the ball's constant acceleration, they have been reported to time hits with a standard deviation of only about 7 ms. To examine how people achieve such precision, we compared performance when there were no added restrictions, with performance when looking with one eye, when vision was blurred, and when various parts of the ball's trajectory were hidden from view. We also examined how the size of the ball and varying the height from which it was dropped influenced temporal precision. Temporal precision did not become worse when vision was blurred, when the ball was smaller, or when balls falling from different heights were randomly interleaved. The disadvantage of closing one eye did not exceed expectations from removing one of two independent estimates. Precision was higher for slower balls, but only if the ball being slower meant that one saw it longer before the hit. It was particularly important to see the ball while swinging the bat. Together, these findings suggest that people time their hits so precisely by using the changing elevation throughout the swing to adjust the bat's movement to that of the ball.

  3. The crystal structure of human GDP-L-fucose synthase.

    PubMed

    Zhou, Huan; Sun, Lihua; Li, Jian; Xu, Chunyan; Yu, Feng; Liu, Yahui; Ji, Chaoneng; He, Jianhua

    2013-09-01

    Human GDP-l-fucose synthase, also known as FX protein, synthesizes GDP-l-fucose from its substrate GDP-4-keto-6-deoxy-d-mannose. The reaction involves epimerization at both C-3 and C-5 followed by an NADPH-dependent reduction of the carbonyl at C-4. In this paper, the first crystal structure of human FX protein was determined at 2.37 Å resolution. The asymmetric unit of the crystal structure contains four molecules which form two homodimers. Each molecule consists of two domains, a Rossmann-fold NADPH-binding motif and a carboxyl terminal domain. Compared with the Escherichia coli GDP-l-fucose synthase, the overall structures of these two enzymes have four major differences. There are four loops in the structure of human FX protein corresponding to two α-helices and two β-sheets in that of the E. coli enzyme. Besides, there are seven different amino acid residues binding with NAPDH comparing human FX protein with that from E. coli. The structure of human FX reveals the key catalytic residues and could be useful for the design of drugs for the treatment of inflammation, auto-immune diseases, and possibly certain types of cancer.

  4. 76 FR 25355 - HIT Standards Committee; Schedule for the Assessment of HIT Policy Committee Recommendations

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-05-04

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF HEALTH AND... Recommendations AGENCY: Office of the National Coordinator for Health Information Technology, HHS. ACTION: Notice..., clinical operations, implementation, and privacy and security. HIT Standards Committee's Schedule for...

  5. Projections of health care expenditures as a share of the GDP: actuarial and macroeconomic approaches.

    PubMed Central

    Warshawsky, M J

    1994-01-01

    STUDY QUESTION. Can the steady increases in health care expenditures as a share of GDP projected by widely cited actuarial models be rationalized by a macroeconomic model with sensible parameters and specification? DATA SOURCES. National Income and Product Accounts, and Social Security and Health Care Financing Administration are the data sources used in parameters estimates. STUDY DESIGN. Health care expenditures as a share of gross domestic product (GDP) are projected using two methodological approaches--actuarial and macroeconomic--and under various assumptions. The general equilibrium macroeconomic approach has the advantage of allowing an investigation of the causes of growth in the health care sector and its consequences for the overall economy. DATA COLLECTION METHODS. Simulations are used. PRINCIPAL FINDINGS. Both models unanimously project a continued increase in the ratio of health care expenditures to GDP. Under the most conservative assumptions, that is, robust economic growth, improved demographic trends, or a significant moderation in the rate of health care price inflation, the health care sector will consume more than a quarter of national output by 2065. Under other (perhaps more realistic) assumptions, including a continuation of current trends, both approaches predict that health care expenditures will comprise between a third and a half of national output. In the macroeconomic model, the increasing use of capital goods in the health care sector explains the observed rise in relative prices. Moreover, this "capital deepening" implies that a relatively modest fraction of the labor force is employed in health care and that the rest of the economy is increasingly starved for capital, resulting in a declining standard of living. PMID:8063567

  6. Probability of Brownian motion hitting an obstacle

    SciTech Connect

    Knessl, C.; Keller, J.B.

    2000-02-01

    The probability p(x) that Brownian motion with drift, starting at x, hits an obstacle is analyzed. The obstacle {Omega} is a compact subset of R{sup n}. It is shown that p(x) is expressible in terms of the field U(x) scattered by {Omega} when it is hit by plane wave. Therefore results for U(x), and methods for finding U(x) can be used to determine p(x). The authors illustrate this by obtaining exact and asymptotic results for p(x) when {Omega} is a slit in R{sup 2}, and asymptotic results when {Omega} is a disc in R{sup 3}.

  7. Hitting and trapping times on branched structures.

    PubMed

    Agliari, Elena; Sartori, Fabio; Cattivelli, Luca; Cassi, Davide

    2015-05-01

    In this work we consider a simple random walk embedded in a generic branched structure and we find a close-form formula to calculate the hitting time H(i,f) between two arbitrary nodes i and j. We then use this formula to obtain the set of hitting times {H(i,f)} for combs and their expectation values, namely, the mean first-passage time, where the average is performed over the initial node while the final node f is given, and the global mean first-passage time, where the average is performed over both the initial and the final node. Finally, we discuss applications in the context of reaction-diffusion problems. PMID:26066144

  8. Visual factors in hitting and catching.

    PubMed

    Regan, D

    1997-12-01

    To hit or catch an approaching ball, it is necessary to move a bat or hand to the right place at the right time. The performance of top sports players is remarkable: positional errors of less than 5 cm and temporal errors of less than 2 or 3 ms are reliably maintained. There are three schools of thought about how this is achieved. One holds that predictive visual information about where the ball will be at some future instance (when) is used to achieve the hit or catch. The second holds that the bat or hand is moved to the correct position by exploiting some relation between visual information and the required movement. The third focuses on the use of prior knowledge to supplement inadequate visual information. For a rigid spherical ball travelling at constant speed along or close to the line of sight, the retinal images contain both binocular and monocular correlates of the ball's instantaneous direction of motion in depth. Also, the retinal images contain both binocular and monocular information about time of arrival. Humans can unconfound and use this visual information, but they are unable to estimate the absolute distance of the ball or its approach speed other than crudely. In cricket, this visual inadequacy allows a slow bowler to cause the batsman to misjudge where the ball will hit the ground. Such a bowler uses a three-pronged strategy: first, to deliver the ball in such a way as to prevent the batsman from obtaining the necessary visual information until it is too late to react; secondly, to force the batsman to rely entirely on inadequate retinal image information; thirdly, to allow the batsman to learn a particular relationship between the early part of the ball's flight and the point where the ball hits the ground, and then to change the relationship with such skill that the batsman does not detect the change. PMID:9486432

  9. Visual factors in hitting and catching.

    PubMed

    Regan, D

    1997-12-01

    To hit or catch an approaching ball, it is necessary to move a bat or hand to the right place at the right time. The performance of top sports players is remarkable: positional errors of less than 5 cm and temporal errors of less than 2 or 3 ms are reliably maintained. There are three schools of thought about how this is achieved. One holds that predictive visual information about where the ball will be at some future instance (when) is used to achieve the hit or catch. The second holds that the bat or hand is moved to the correct position by exploiting some relation between visual information and the required movement. The third focuses on the use of prior knowledge to supplement inadequate visual information. For a rigid spherical ball travelling at constant speed along or close to the line of sight, the retinal images contain both binocular and monocular correlates of the ball's instantaneous direction of motion in depth. Also, the retinal images contain both binocular and monocular information about time of arrival. Humans can unconfound and use this visual information, but they are unable to estimate the absolute distance of the ball or its approach speed other than crudely. In cricket, this visual inadequacy allows a slow bowler to cause the batsman to misjudge where the ball will hit the ground. Such a bowler uses a three-pronged strategy: first, to deliver the ball in such a way as to prevent the batsman from obtaining the necessary visual information until it is too late to react; secondly, to force the batsman to rely entirely on inadequate retinal image information; thirdly, to allow the batsman to learn a particular relationship between the early part of the ball's flight and the point where the ball hits the ground, and then to change the relationship with such skill that the batsman does not detect the change.

  10. Hitting a baseball: a biomechanical description.

    PubMed

    Welch, C M; Banks, S A; Cook, F F; Draovitch, P

    1995-11-01

    A tremendous amount of time and energy has been dedicated to the development of conditioning programs, mechanics drills, and rehabilitation protocols for the throwing athlete. In comparison, a significantly smaller amount has been spent on the needs of the hitting athlete. Before these needs can be addressed, an understanding of mechanics and the demands placed on the body during the swing must be developed. This study uses three-dimensional kinematic and kinetic data to define and quantify biomechanics during the baseball swing. The results show that a hitter starts the swing with a weight shift toward the rear foot and the generation of trunk coil. As the hitter strides forward, force applied by the front foot equal to 123% of body weight promotes segment acceleration around the axis of the trunk. The hip segment rotates to a maximum speed of 714 degrees/sec followed by a maximum shoulder segment velocity of 937 degrees/sec. The product of this kinetic link is a maximum linear bat velocity of 31 m/sec. By quantifying the hitting motion, a more educated approach can be made in developing rehabilitation, strength, and conditioning programs for the hitting athlete. PMID:8580946

  11. Universal Hitting Time Statistics for Integrable Flows

    NASA Astrophysics Data System (ADS)

    Dettmann, Carl P.; Marklof, Jens; Strömbergsson, Andreas

    2016-08-01

    The perceived randomness in the time evolution of "chaotic" dynamical systems can be characterized by universal probabilistic limit laws, which do not depend on the fine features of the individual system. One important example is the Poisson law for the times at which a particle with random initial data hits a small set. This was proved in various settings for dynamical systems with strong mixing properties. The key result of the present study is that, despite the absence of mixing, the hitting times of integrable flows also satisfy universal limit laws which are, however, not Poisson. We describe the limit distributions for "generic" integrable flows and a natural class of target sets, and illustrate our findings with two examples: the dynamics in central force fields and ellipse billiards. The convergence of the hitting time process follows from a new equidistribution theorem in the space of lattices, which is of independent interest. Its proof exploits Ratner's measure classification theorem for unipotent flows, and extends earlier work of Elkies and McMullen.

  12. Hitting a baseball: a biomechanical description.

    PubMed

    Welch, C M; Banks, S A; Cook, F F; Draovitch, P

    1995-11-01

    A tremendous amount of time and energy has been dedicated to the development of conditioning programs, mechanics drills, and rehabilitation protocols for the throwing athlete. In comparison, a significantly smaller amount has been spent on the needs of the hitting athlete. Before these needs can be addressed, an understanding of mechanics and the demands placed on the body during the swing must be developed. This study uses three-dimensional kinematic and kinetic data to define and quantify biomechanics during the baseball swing. The results show that a hitter starts the swing with a weight shift toward the rear foot and the generation of trunk coil. As the hitter strides forward, force applied by the front foot equal to 123% of body weight promotes segment acceleration around the axis of the trunk. The hip segment rotates to a maximum speed of 714 degrees/sec followed by a maximum shoulder segment velocity of 937 degrees/sec. The product of this kinetic link is a maximum linear bat velocity of 31 m/sec. By quantifying the hitting motion, a more educated approach can be made in developing rehabilitation, strength, and conditioning programs for the hitting athlete.

  13. Fragment-Based Whole Cell Screen Delivers Hits against M. tuberculosis and Non-tuberculous Mycobacteria

    PubMed Central

    Moreira, Wilfried; Lim, Jia Jie; Yeo, Si Ying; Ramanujulu, Pondy M.; Dymock, Brian W.; Dick, Thomas

    2016-01-01

    Reactive multi-target ‘fragment drugs’ represent critical components of current tuberculosis regimens. These compounds, such as pyrazinamide, are old synthetic antimycobacterials that are activated inside Mycobacterium tuberculosis bacilli and are smaller than the usual drug-like, single-target molecules. Based on the success of small ‘dirty’ drugs in the chemotherapy of tuberculosis, we suggested previously that fragment-based whole cell screens should be introduced in our current antimycobacterial drug discovery efforts. Here, we carried out such a screen and characterized bactericidal activity, selectivity and spectrum of hits we obtained. A library of 1725 fragments was tested at a single concentration for growth inhibitory activity against M. bovis BCG as screening strain and 38 of 116 primary hits were confirmed in dose response analyses to be active against virulent M. tuberculosis. Bacterial kill experiments showed that most hits displayed bactericidal activity at their minimal inhibitory concentration. Cytotoxicity assays established that a large proportion of hits displayed a favorable selectivity index for mammalian cells. Importantly, one third of M. tuberculosis active fragments were also active against M. abscessus and M. avium, two emerging non-tuberculous mycobacterial (NTM) pathogens, opening the opportunity to develop broad spectrum antimycobacterials. Activity determination against Gram positive (Staphylococcus aureus) and Gram negative (Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa) bacteria, as well as fungi (Candida albicans, Cryptococcus neoformans) showed only a small overlap indicating a generally narrow spectrum of these novel antimicrobial hits for mycobacteria. In conclusion, we carried out the first fragment-based whole cell screen against bacteria and identified a substantial number of hits with excellent physicochemical properties and dual activity against M. tuberculosis and NTM

  14. Fragment-Based Whole Cell Screen Delivers Hits against M. tuberculosis and Non-tuberculous Mycobacteria.

    PubMed

    Moreira, Wilfried; Lim, Jia Jie; Yeo, Si Ying; Ramanujulu, Pondy M; Dymock, Brian W; Dick, Thomas

    2016-01-01

    Reactive multi-target 'fragment drugs' represent critical components of current tuberculosis regimens. These compounds, such as pyrazinamide, are old synthetic antimycobacterials that are activated inside Mycobacterium tuberculosis bacilli and are smaller than the usual drug-like, single-target molecules. Based on the success of small 'dirty' drugs in the chemotherapy of tuberculosis, we suggested previously that fragment-based whole cell screens should be introduced in our current antimycobacterial drug discovery efforts. Here, we carried out such a screen and characterized bactericidal activity, selectivity and spectrum of hits we obtained. A library of 1725 fragments was tested at a single concentration for growth inhibitory activity against M. bovis BCG as screening strain and 38 of 116 primary hits were confirmed in dose response analyses to be active against virulent M. tuberculosis. Bacterial kill experiments showed that most hits displayed bactericidal activity at their minimal inhibitory concentration. Cytotoxicity assays established that a large proportion of hits displayed a favorable selectivity index for mammalian cells. Importantly, one third of M. tuberculosis active fragments were also active against M. abscessus and M. avium, two emerging non-tuberculous mycobacterial (NTM) pathogens, opening the opportunity to develop broad spectrum antimycobacterials. Activity determination against Gram positive (Staphylococcus aureus) and Gram negative (Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa) bacteria, as well as fungi (Candida albicans, Cryptococcus neoformans) showed only a small overlap indicating a generally narrow spectrum of these novel antimicrobial hits for mycobacteria. In conclusion, we carried out the first fragment-based whole cell screen against bacteria and identified a substantial number of hits with excellent physicochemical properties and dual activity against M. tuberculosis and NTM pathogens

  15. Fragment-Based Whole Cell Screen Delivers Hits against M. tuberculosis and Non-tuberculous Mycobacteria

    PubMed Central

    Moreira, Wilfried; Lim, Jia Jie; Yeo, Si Ying; Ramanujulu, Pondy M.; Dymock, Brian W.; Dick, Thomas

    2016-01-01

    Reactive multi-target ‘fragment drugs’ represent critical components of current tuberculosis regimens. These compounds, such as pyrazinamide, are old synthetic antimycobacterials that are activated inside Mycobacterium tuberculosis bacilli and are smaller than the usual drug-like, single-target molecules. Based on the success of small ‘dirty’ drugs in the chemotherapy of tuberculosis, we suggested previously that fragment-based whole cell screens should be introduced in our current antimycobacterial drug discovery efforts. Here, we carried out such a screen and characterized bactericidal activity, selectivity and spectrum of hits we obtained. A library of 1725 fragments was tested at a single concentration for growth inhibitory activity against M. bovis BCG as screening strain and 38 of 116 primary hits were confirmed in dose response analyses to be active against virulent M. tuberculosis. Bacterial kill experiments showed that most hits displayed bactericidal activity at their minimal inhibitory concentration. Cytotoxicity assays established that a large proportion of hits displayed a favorable selectivity index for mammalian cells. Importantly, one third of M. tuberculosis active fragments were also active against M. abscessus and M. avium, two emerging non-tuberculous mycobacterial (NTM) pathogens, opening the opportunity to develop broad spectrum antimycobacterials. Activity determination against Gram positive (Staphylococcus aureus) and Gram negative (Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa) bacteria, as well as fungi (Candida albicans, Cryptococcus neoformans) showed only a small overlap indicating a generally narrow spectrum of these novel antimicrobial hits for mycobacteria. In conclusion, we carried out the first fragment-based whole cell screen against bacteria and identified a substantial number of hits with excellent physicochemical properties and dual activity against M. tuberculosis and NTM

  16. Structures of NodZ α1,6-fucosyltransferase in complex with GDP and GDP-fucose

    PubMed Central

    Brzezinski, Krzysztof; Dauter, Zbigniew; Jaskolski, Mariusz

    2012-01-01

    Rhizobial NodZ α1,6-fucosyltransferase (α1,6-FucT) catalyzes the transfer of the fucose (Fuc) moiety from guanosine 5′-­diphosphate-β-l-fucose to the reducing end of the chitin oligosaccharide core during Nod-factor (NF) biosynthesis. NF is a key signalling molecule required for successful symbiosis with a legume host for atmospheric nitrogen fixation. To date, only two α1,6-FucT structures have been determined, both without any donor or acceptor molecule that could highlight the structural background of the catalytic mechanism. Here, the first crystal structures of α1,6-FucT in complex with its substrate GDP-Fuc and with GDP, which is a byproduct of the enzymatic reaction, are presented. The crystal of the complex with GDP-Fuc was obtained through soaking of native NodZ crystals with the ligand and its structure has been determined at 2.35 Å resolution. The fucose residue is exposed to solvent and is disordered. The enzyme–product complex crystal was obtained by cocrystallization with GDP and an acceptor molecule, penta-N-acetyl-l-­glucosamine (penta-NAG). The structure has been determined at 1.98 Å resolution, showing that only the GDP molecule is present in the complex. In both structures the ligands are located in a cleft formed between the two domains of NodZ and extend towards the C-terminal domain, but their conformations differ significantly. The structures revealed that residues in three regions of the C-­terminal domain, which are conserved among α1,2-, α1,6- and protein O-fucosyltransferases, are involved in interactions with the sugar-donor molecule. There is also an interaction with the side chain of Tyr45 in the N-terminal domain, which is very unusual for a GT-B-type glycosyltransferase. Only minor conformational changes of the protein backbone are observed upon ligand binding. The only exception is a movement of the loop located between strand βC2 and helix αC3. In addition, there is a shift of the αC3 helix itself upon GDP

  17. Structures of NodZ [alpha]1,6-fucosyltransferase in complex with GDP and GDP-fucose

    SciTech Connect

    Brzezinski, Krzysztof; Dauter, Zbigniew; Jaskolski, Mariusz

    2012-03-26

    Rhizobial NodZ {alpha}1,6-fucosyltransferase ({alpha}1,6-FucT) catalyzes the transfer of the fucose (Fuc) moiety from guanosine 5'-diphosphate-{beta}-L-fucose to the reducing end of the chitin oligosaccharide core during Nod-factor (NF) biosynthesis. NF is a key signaling molecule required for successful symbiosis with a legume host for atmospheric nitrogen fixation. To date, only two {alpha}1,6-FucT structures have been determined, both without any donor or acceptor molecule that could highlight the structural background of the catalytic mechanism. Here, the first crystal structures of {alpha}1,6-FucT in complex with its substrate GDP-Fuc and with GDP, which is a byproduct of the enzymatic reaction, are presented. The crystal of the complex with GDP-Fuc was obtained through soaking of native NodZ crystals with the ligand and its structure has been determined at 2.35 {angstrom} resolution. The fucose residue is exposed to solvent and is disordered. The enzyme-product complex crystal was obtained by cocrystallization with GDP and an acceptor molecule, penta-N-acetyl-L-glucosamine (penta-NAG). The structure has been determined at 1.98 {angstrom} resolution, showing that only the GDP molecule is present in the complex. In both structures the ligands are located in a cleft formed between the two domains of NodZ and extend towards the C-terminal domain, but their conformations differ significantly. The structures revealed that residues in three regions of the C-terminal domain, which are conserved among {alpha}1,2-, {alpha}1,6- and protein O-fucosyltransferases, are involved in interactions with the sugar-donor molecule. There is also an interaction with the side chain of Tyr45 in the N-terminal domain, which is very unusual for a GT-B-type glycosyltransferase. Only minor conformational changes of the protein backbone are observed upon ligand binding. The only exception is a movement of the loop located between strand {beta}C2 and helix {alpha}C3. In addition, there is

  18. Human septin isoforms and the GDP-GTP cycle.

    PubMed

    Zent, Eldar; Wittinghofer, Alfred

    2014-02-01

    Septins form oligomeric complexes consisting of septins from different subgroups, which form filaments that are involved in a number of biological processes. They are GTP-binding proteins that contain all the necessary elements to perform the general GDP-to-GTP conformational switch. It is however unclear whether or not such a switch is important for the dynamics of septin filaments. Here we investigate the complex GTPase reaction of members of each of the four human septin groups, which is dominated by the stability of dimer formation via the nucleotide binding or so-called G-interface. The results also show that the actual hydrolysis reaction is very similar for three septin groups in the monomeric state while the Sept6 has no GTPase activity. Sept7, the only member of the Sept7 subgroup, forms a very tight G-interface dimer in the GDP-bound state. Here we show that the stability of the interface is dramatically decreased by exchanging GDP with a nucleoside triphosphate, which is believed to influence filament formation and dynamics via Sept7.

  19. Rescue of Notch signaling in cells incapable of GDP-L-fucose synthesis by gap junction transfer of GDP-L-fucose in Drosophila.

    PubMed

    Ayukawa, Tomonori; Matsumoto, Kenjiroo; Ishikawa, Hiroyuki O; Ishio, Akira; Yamakawa, Tomoko; Aoyama, Naoki; Suzuki, Takuya; Matsuno, Kenji

    2012-09-18

    Notch (N) is a transmembrane receptor that mediates cell-cell interactions to determine many cell-fate decisions. N contains EGF-like repeats, many of which have an O-fucose glycan modification that regulates N-ligand binding. This modification requires GDP-L-fucose as a donor of fucose. The GDP-L-fucose biosynthetic pathways are well understood, including the de novo pathway, which depends on GDP-mannose 4,6 dehydratase (Gmd) and GDP-4-keto-6-deoxy-D-mannose 3,5-epimerase/4-reductase (Gmer). However, the potential for intercellularly supplied GDP-L-fucose and the molecular basis of such transportation have not been explored in depth. To address these points, we studied the genetic effects of mutating Gmd and Gmer on fucose modifications in Drosophila. We found that these mutants functioned cell-nonautonomously, and that GDP-L-fucose was supplied intercellularly through gap junctions composed of Innexin-2. GDP-L-fucose was not supplied through body fluids from different isolated organs, indicating that the intercellular distribution of GDP-L-fucose is restricted within a given organ. Moreover, the gap junction-mediated supply of GDP-L-fucose was sufficient to support the fucosylation of N-glycans and the O-fucosylation of the N EGF-like repeats. Our results indicate that intercellular delivery is a metabolic pathway for nucleotide sugars in live animals under certain circumstances.

  20. Health Information Technology Knowledge and Skills Needed by HIT Employers

    PubMed Central

    Fenton, S.H.; Gongora-Ferraez, M.J.; Joost, E.

    2012-01-01

    Objective To evaluate the health information technology (HIT) workforce knowledge and skills needed by HIT employers. Methods Statewide face-to-face and online focus groups of identified HIT employer groups in Austin, Brownsville, College Station, Dallas, El Paso, Houston, Lubbock, San Antonio, and webinars for rural health and nursing informatics. Results HIT employers reported needing an HIT workforce with diverse knowledge and skills ranging from basic to advanced, while covering information technology, privacy and security, clinical practice, needs assessment, contract negotiation, and many other areas. Consistent themes were that employees needed to be able to learn on the job and must possess the ability to think critically and problem solve. Many employers wanted persons with technical skills, yet also the knowledge and understanding of healthcare operations. Conclusion The HIT employer focus groups provided valuable insight into employee skills needed in this fast-growing field. Additionally, this information will be utilized to develop a statewide HIT workforce needs assessment survey. PMID:23646090

  1. Cryptococcus neoformans dual GDP-mannose transporters and their role in biology and virulence.

    PubMed

    Wang, Zhuo A; Griffith, Cara L; Skowyra, Michael L; Salinas, Nichole; Williams, Matthew; Maier, Ezekiel J; Gish, Stacey R; Liu, Hong; Brent, Michael R; Doering, Tamara L

    2014-06-01

    Cryptococcus neoformans is an opportunistic yeast responsible for lethal meningoencephalitis in humans. This pathogen elaborates a polysaccharide capsule, which is its major virulence factor. Mannose constitutes over one-half of the capsule mass and is also extensively utilized in cell wall synthesis and in glycosylation of proteins and lipids. The activated mannose donor for most biosynthetic reactions, GDP-mannose, is made in the cytosol, although it is primarily consumed in secretory organelles. This compartmentalization necessitates specific transmembrane transporters to make the donor available for glycan synthesis. We previously identified two cryptococcal GDP-mannose transporters, Gmt1 and Gmt2. Biochemical studies of each protein expressed in Saccharomyces cerevisiae showed that both are functional, with similar kinetics and substrate specificities in vitro. We have now examined these proteins in vivo and demonstrate that cells lacking Gmt1 show significant phenotypic differences from those lacking Gmt2 in terms of growth, colony morphology, protein glycosylation, and capsule phenotypes. Some of these observations may be explained by differential expression of the two genes, but others suggest that the two proteins play overlapping but nonidentical roles in cryptococcal biology. Furthermore, gmt1 gmt2 double mutant cells, which are unexpectedly viable, exhibit severe defects in capsule synthesis and protein glycosylation and are avirulent in mouse models of cryptococcosis.

  2. Cryptococcus neoformans Dual GDP-Mannose Transporters and Their Role in Biology and Virulence

    PubMed Central

    Wang, Zhuo A.; Griffith, Cara L.; Skowyra, Michael L.; Salinas, Nichole; Williams, Matthew; Maier, Ezekiel J.; Gish, Stacey R.; Liu, Hong; Brent, Michael R.

    2014-01-01

    Cryptococcus neoformans is an opportunistic yeast responsible for lethal meningoencephalitis in humans. This pathogen elaborates a polysaccharide capsule, which is its major virulence factor. Mannose constitutes over one-half of the capsule mass and is also extensively utilized in cell wall synthesis and in glycosylation of proteins and lipids. The activated mannose donor for most biosynthetic reactions, GDP-mannose, is made in the cytosol, although it is primarily consumed in secretory organelles. This compartmentalization necessitates specific transmembrane transporters to make the donor available for glycan synthesis. We previously identified two cryptococcal GDP-mannose transporters, Gmt1 and Gmt2. Biochemical studies of each protein expressed in Saccharomyces cerevisiae showed that both are functional, with similar kinetics and substrate specificities in vitro. We have now examined these proteins in vivo and demonstrate that cells lacking Gmt1 show significant phenotypic differences from those lacking Gmt2 in terms of growth, colony morphology, protein glycosylation, and capsule phenotypes. Some of these observations may be explained by differential expression of the two genes, but others suggest that the two proteins play overlapping but nonidentical roles in cryptococcal biology. Furthermore, gmt1 gmt2 double mutant cells, which are unexpectedly viable, exhibit severe defects in capsule synthesis and protein glycosylation and are avirulent in mouse models of cryptococcosis. PMID:24747214

  3. GDP-mannose pyrophosphorylase is essential for cell wall integrity, morphogenesis and viability of Aspergillus fumigatus.

    PubMed

    Jiang, Hechun; Ouyang, Haomiao; Zhou, Hui; Jin, Cheng

    2008-09-01

    GDP-mannose pyrophosphorylase (GMPP) catalyses the synthesis of GDP-mannose, which is the precursor for the mannose residues in glycoconjugates, using mannose 1-phosphate and GTP as substrates. Repression of GMPP in yeast leads to phenotypes including cell lysis, defective cell wall, and failure of polarized growth and cell separation. Although several GMPPs have been isolated and characterized in filamentous fungi, the physiological consequences of their actions are not clear. In this study, Afsrb1, which is a homologue of yeast SRB1/PSA1/VIG9, was identified in the Aspergillus fumigatus genome. The Afsrb1 gene was expressed in Escherichia coli, and recombinant AfSrb1 was functionally confirmed as a GMPP. By the replacement of the native Afsrb1 promoter with an inducible Aspergillus nidulans alcA promoter, the conditional inactivation mutant strain YJ-gmpp was constructed. The presence of 3 % glucose completely blocked transcription of P(alcA)-Afsrb1, and was lethal to strain YJ-gmpp. Repression of Afsrb1 expression in strain YJ-gmpp led to phenotypes including hyphal lysis, defective cell wall, impaired polarity maintenance, and branching site selection. Also, rapid germination and reduced conidiation were documented. However, in contrast to yeast, strain YJ-gmpp retained the ability to direct polarity establishment and septation. Our results showed that the Afsrb1 gene is essential for cell wall integrity, morphogenesis and viability of Aspergillus fumigatus.

  4. Statistical mechanics of the hitting set problem.

    PubMed

    Mézard, Marc; Tarzia, Marco

    2007-10-01

    In this paper we present a detailed study of the hitting set (HS) problem. This problem is a generalization of the standard vertex cover to hypergraphs: one seeks a configuration of particles with minimal density such that every hyperedge of the hypergraph contains at least one particle. It can also be used in important practical tasks, such as the group testing procedures where one wants to detect defective items in a large group by pool testing. Using a statistical mechanics approach based on the cavity method, we study the phase diagram of the HS problem, in the case of random regular hypergraphs. Depending on the values of the variables and tests degrees different situations can occur: The HS problem can be either in a replica symmetric phase, or in a one-step replica symmetry breaking one. In these two cases, we give explicit results on the minimal density of particles, and the structure of the phase space. These problems are thus in some sense simpler than the original vertex cover problem, where the need for a full replica symmetry breaking has prevented the derivation of exact results so far. Finally, we show that decimation procedures based on the belief propagation and the survey propagation algorithms provide very efficient strategies to solve large individual instances of the hitting set problem.

  5. Cutaneous presentation of Double Hit Lymphoma

    PubMed Central

    Khelfa, Yousef; Lebowicz, Yehuda

    2016-01-01

    Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma (NHL), representing approximately 25% of diagnosed NHL. DLBCL is heterogeneous disease both clinically and genetically. The 3 most common chromosomal translocations in DLBCL involve the oncogenes BCL2, BCL6, and MYC. Double hit (DH) DLBCL is an aggressive form in which MYC rearrangement is associated with either BCL2 or BCL6 rearrangement. Patients typically present with a rapidly growing mass, often with B symptoms. Extranodal disease is often present. Though there is a paucity of prospective trials in this subtype, double hit lymphoma (DHL) has been linked to very poor outcomes when patients are treated with standard R-CHOP. There is, therefore, a lack of consensus regarding the standard treatment for DHL. Several retrospective analyses have been conducted to help guide treatment of this disease. These suggest that DA EPOCH-R may be the most promising regimen and that achievement of complete resolution predicts better long-term outcomes. PMID:27115017

  6. HitKeeper, a generic software package for hit list management

    PubMed Central

    Hau, Jörg; Muller, Michael; Pagni, Marco

    2007-01-01

    Background The automated annotation of biological sequences (protein, DNA) relies on the computation of hits (predicted features) on the sequences using various algorithms. Public databases of biological sequences provide a wealth of biological "knowledge", for example manually validated annotations (features) that are located on the sequences, but mining the sequence annotations and especially the predicted and curated features requires dedicated tools. Due to the heterogeneity and diversity of the biological information, it is difficult to handle redundancy, frequent updates, taxonomic information and "private" data together with computational algorithms in a common workflow. Results We present HitKeeper, a software package that controls the fully automatic handling of multiple biological databases and of hit list calculations on a large scale. The software implements an asynchronous update system that introduces updates and computes hits as soon as new data become available. A query interface enables the user to search sequences by specifying constraints, such as retrieving sequences that contain specific motifs, or a defined arrangement of motifs ("metamotifs"), or filtering based on the taxonomic classification of a sequence. Conclusion The software provides a generic and modular framework to handle the redundancy and incremental updates of biological databases, and an original query language. It is published under the terms and conditions of version 2 of the GNU Public License and available at . PMID:17391514

  7. Formulation of the Multi-Hit Model With a Non-Poisson Distribution of Hits

    SciTech Connect

    Vassiliev, Oleg N.

    2012-07-15

    Purpose: We proposed a formulation of the multi-hit single-target model in which the Poisson distribution of hits was replaced by a combination of two distributions: one for the number of particles entering the target and one for the number of hits a particle entering the target produces. Such an approach reflects the fact that radiation damage is a result of two different random processes: particle emission by a radiation source and interaction of particles with matter inside the target. Methods and Materials: Poisson distribution is well justified for the first of the two processes. The second distribution depends on how a hit is defined. To test our approach, we assumed that the second distribution was also a Poisson distribution. The two distributions combined resulted in a non-Poisson distribution. We tested the proposed model by comparing it with previously reported data for DNA single- and double-strand breaks induced by protons and electrons, for survival of a range of cell lines, and variation of the initial slopes of survival curves with radiation quality for heavy-ion beams. Results: Analysis of cell survival equations for this new model showed that they had realistic properties overall, such as the initial and high-dose slopes of survival curves, the shoulder, and relative biological effectiveness (RBE) In most cases tested, a better fit of survival curves was achieved with the new model than with the linear-quadratic model. The results also suggested that the proposed approach may extend the multi-hit model beyond its traditional role in analysis of survival curves to predicting effects of radiation quality and analysis of DNA strand breaks. Conclusions: Our model, although conceptually simple, performed well in all tests. The model was able to consistently fit data for both cell survival and DNA single- and double-strand breaks. It correctly predicted the dependence of radiation effects on parameters of radiation quality.

  8. Exploring Patterns of Soil Organic Matter Decomposition with Students through the Global Decomposition Project (GDP) and the Interactive Model of Leaf Decomposition (IMOLD)

    NASA Astrophysics Data System (ADS)

    Steiner, S. M.; Wood, J. H.

    2015-12-01

    As decomposition rates are affected by climate change, understanding crucial soil interactions that affect plant growth and decomposition becomes a vital part of contributing to the students' knowledge base. The Global Decomposition Project (GDP) is designed to introduce and educate students about soil organic matter and decomposition through a standardized protocol for collecting, reporting, and sharing data. The Interactive Model of Leaf Decomposition (IMOLD) utilizes animations and modeling to learn about the carbon cycle, leaf anatomy, and the role of microbes in decomposition. Paired together, IMOLD teaches the background information and allows simulation of numerous scenarios, and the GDP is a data collection protocol that allows students to gather usable measurements of decomposition in the field. Our presentation will detail how the GDP protocol works, how to obtain or make the materials needed, and how results will be shared. We will also highlight learning objectives from the three animations of IMOLD, and demonstrate how students can experiment with different climates and litter types using the interactive model to explore a variety of decomposition scenarios. The GDP demonstrates how scientific methods can be extended to educate broader audiences, and data collected by students can provide new insight into global patterns of soil decomposition. Using IMOLD, students will gain a better understanding of carbon cycling in the context of litter decomposition, as well as learn to pose questions they can answer with an authentic computer model. Using the GDP protocols and IMOLD provide a pathway for scientists and educators to interact and reach meaningful education and research goals.

  9. Hit-and-run planetary collisions.

    PubMed

    Asphaug, Erik; Agnor, Craig B; Williams, Quentin

    2006-01-12

    Terrestrial planet formation is believed to have concluded in our Solar System with about 10 million to 100 million years of giant impacts, where hundreds of Moon- to Mars-sized planetary embryos acquired random velocities through gravitational encounters and resonances with one another and with Jupiter. This led to planet-crossing orbits and collisions that produced the four terrestrial planets, the Moon and asteroids. But here we show that colliding planets do not simply merge, as is commonly assumed. In many cases, the smaller planet escapes from the collision highly deformed, spun up, depressurized from equilibrium, stripped of its outer layers, and sometimes pulled apart into a chain of diverse objects. Remnants of these 'hit-and-run' collisions are predicted to be common among remnant planet-forming populations, and thus to be relevant to asteroid formation and meteorite petrogenesis.

  10. Macro determinants of cause-specific injury mortality in the OECD countries: an exploration of the importance of GDP and unemployment.

    PubMed

    Muazzam, Sana; Nasrullah, Muazzam

    2011-08-01

    Gross Domestic Product (GDP) and unemployment has a strong documented impact on injury mortality. The aim of our study is to investigate the relationship of GDP per capita and unemployment with gender- and cause-specific injury mortalities in the member nations of Organization for Economic Cooperation and Development (OECD). Country-based data on injury mortality per 100,000 population, including males and females aged 1-74, for the 4 year period 1996-1999, were gathered from the World Health Organization's Statistical Information System. We selected fourteen cause-specific injury mortalities. Data on GDP, unemployment rate and population growth were taken from World Development Indicators. GDP and unemployment rate per 100 separately were regressed on total and cause-specific injury mortality rate per 100,000 for males and females. Overall in the OECD countries, GDP per capita increased 12.5% during 1996-1999 (P = 0.03) where as unemployment rate decreased by 12.3% (P = 0.05). Among males, most cause-specific injury mortality rates decreased with increasing GDP except motor vehicle traffic crashes (MTC) that increased with increasing GDP (coefficient = 0.75; P < 0.001). Similar trend was found in females, except suicidal injury mortalities that also increased with increasing GDP (coefficient = 0.31; P = 0.04). When we modeled cause-specific injury mortality rates with unemployment, injuries due to firearm missiles (coefficient = 0.53; P < 0.001), homicide (coefficient = 0.36; P < 0.001), and other violence (coefficient = 0.41; P < 0.001) increased with increase in unemployment rate among males. However, among females only accidental falls (coefficient = 0.36; P = 0.01) were found significantly associated with increasing unemployment rate. GDP is more related to cause-specific injury mortality than unemployment. Injury mortality does not relate similarly to each diagnosis-specific cause among males and females. Further research on

  11. A Two-Hit Model of Autism: Adolescence as the Second Hit

    PubMed Central

    Picci, Giorgia; Scherf, K. Suzanne

    2015-01-01

    Adolescence brings dramatic changes in behavior and neural organization. Unfortunately, for some 30% of individuals with autism, there is marked decline in adaptive functioning during adolescence. We propose a two-hit model of autism. First, early perturbations in neural development function as a “first hit” that sets up a neural system that is “built to fail” in the face of a second hit. Second, the confluence of pubertal hormones, neural reorganization, and increasing social demands during adolescence provides the “second hit” that interferes with the ability to transition into adult social roles and levels of adaptive functioning. In support of this model, we review evidence about adolescent-specific neural and behavioral development in autism. We conclude with predictions and recommendations for empirical investigation about several domains in which developmental trajectories for individuals with autism may be uniquely deterred in adolescence. PMID:26609500

  12. Roughness Optimization at High Modes for GDP CHx Microshells

    SciTech Connect

    Theobald, M.; Dumay, B.; Chicanne, C.; Barnouin, J.; Legaie, O.; Baclet, P.

    2004-03-15

    For the ''Megajoule'' Laser (LMJ) facility of the CEA, amorphous hydrogenated carbon (a-C:H) is the nominal ablator to be used for inertial confinement fusion (ICF) experiments. These capsules contain the fusible deuterium-tritium mixture to achieve ignition. Coatings are prepared by glow discharge polymerization (GDP) with trans-2-butene and hydrogen. The films properties have been investigated. Laser fusion targets must have optimized characteristics: a diameter of about 2.4 mm for LMJ targets, a thickness up to 175 {mu}m, a sphericity and a thickness concentricity better than 99% and an outer and an inner roughness lower than 20 nm at high modes. The surface finish of these laser fusion targets must be extremely smooth to minimize hydrodynamic instabilities.Movchan and Demchishin, and later Thornton introduced a structure zone model (SZM) based on both evaporated and sputtered metals. They investigated the influence of base temperature and the sputtering gas pressure on structure and properties of thick polycrystalline coatings of nickel, titanium, tungsten, aluminum oxide. An original cross-sectional analysis by atomic force microscopy (AFM) allows amorphous materials characterization and permits to make an analogy between the amorphous GDP material and the existing model (SZM). The purpose of this work is to understand the relationship between the deposition parameters, the growing structures and the surface roughness.The coating structure as a function of deposition parameters was first studied on plane silicon substrates and then optimized on PAMS shells. By adjusting the coating parameters, the structures are modified, and in some case, the high modes roughness decreases dramatically.

  13. Improved Curveball Hitting through the Enhancement of Visual Cues.

    ERIC Educational Resources Information Center

    Osborne, Kurt; And Others

    1990-01-01

    The study investigated the effectiveness of using visual cues to highlight the seams of baseballs, to improve the hitting of curveballs by five undergraduate varsity baseball team candidates. Results indicated that subjects hit a greater percentage of marked than unmarked balls. (Author/DB)

  14. Optoelectronic hit/miss transform for screening cervical smear slides

    NASA Astrophysics Data System (ADS)

    Narayanswamy, R.; Turner, R. M.; McKnight, D. J.; Johnson, K. M.; Sharpe, J. P.

    1995-06-01

    An optoelectronic morphological processor for detecting regions of interest (abnormal cells) on a cervical smear slide using the hit/miss transform is presented. Computer simulation of the algorithm tested on 184 Pap-smear images provided 95% detection and 5% false alarm. An optoelectronic implementation of the hit/miss transform is presented, along with preliminary experimental results.

  15. Object Rotation Effects on the Timing of a Hitting Action

    ERIC Educational Resources Information Center

    Scott, Mark A.; van der Kamp, John; Savelsbergh, Geert J. P.; Oudejans, Raoul R. D.; Davids, Keith

    2004-01-01

    In this article, the authors investigated how perturbing optical information affects the guidance of an unfolding hitting action. Using monocular and binocular vision, six participants were required to hit a rectangular foam object, released from two different heights, under four different approach conditions, two with object rotation (to perturb…

  16. Concurrent inhibition of MYC and BCL2 is a potentially effective treatment strategy for double hit and triple hit B-cell lymphomas.

    PubMed

    Cinar, Munevver; Rosenfelt, Fred; Rokhsar, Sepehr; Lopategui, Jean; Pillai, Raju; Cervania, Melissa; Pao, Andy; Cinar, Bekir; Alkan, Serhan

    2015-07-01

    Double hit lymphoma or triple hit lymphoma (DHL/THL) is a rare form of aggressive B-Cell Lymphoma. Overexpression of MYC, BCL2 or/and BCL6 due to genomic rearrangements are the key molecular features of DHL/THL. Patients with DHL/THL show very aggressive disease course and poor survival due to the lack of effective treatment modalities. Here, we established new THL cell model and assessed its in vitro growth characteristics along with the DHL cell line in response to potent MYC inhibitors, 10058-F4 and JQ-1, and a BCL2 inhibitor, ABT-199, with or without chemotherapeutic agent vincristine or doxorubicin. We found that 10058-F4, JQ-1 or ABT-199 exposure as a single agent inhibited the growth of DHL/THL cells in a dose-dependent manner. Combined exposure of 10058-F4 or JQ-1 and ABT-199 as well as vincristine or doxorubicin markedly suppressed the growth of DHL/THL cells compared with the single treatment. As assessed by multiple approaches, apoptosis induced by ABT-199, 10058-F4 or JQ-1 was underlying cause of the observed growth suppression. These findings suggest that co-inhibition of MYC and BCL2 signaling is a promising therapeutic strategy for patients with DHL/THL lymphomas.

  17. Antarctic ozone hole hits record depth

    SciTech Connect

    Not Available

    1991-10-18

    A bad year for the ozone over Antarctica looked like a good bet this year. For the past 2 years, stratospheric ozone destruction has equaled the record set in 1987. Now things look even worse, with a record-setting ozone hole. In 1987, 1989, and 1990, the minimum amount of ozone over Antarctica early each October was 120 to 125 Dobson units compared to the typical level of 220 that prevailed before manmade Chlorofluorocarbons (CFCs) began eating into the ozone layer. The depletion allowed as much as twice the usual amount of biologically damaging ultraviolet light to reach the earth's surface. But researchers took some comfort in the fact that the hole seemed to have hit a barrier to further losses. Now that barrier may have been breached. On 6 October, the satellite-borne Total Ozone Mapping Spectrometer detected an ozone minimum of 110 Dobson units. The region of the lower stratosphere where icy cloud particles and the chlorine of CFCs combine to destroy ozone - between 14 and 24 kilometers - looks much the same as it did in 1987.

  18. Nimodipine in traumatic subarachnoid haemorrhage: a re-analysis of the HIT I and HIT II trials.

    PubMed

    Murray, G D; Teasdale, G M; Schmitz, H

    1996-01-01

    Two large randomised controlled trials have been performed to study the effect of the calcium antagonist nimodipine on the outcome of severe head injury, HIT I [1] amd HIT II [4]. Both trials showed a modest and statistically non-significant increase in the proportion of favourable outcomes in patients treated with nimodipine. A subgroup analysis of the HIT II trial [4, 5] suggested, however, that there could be a substantial protective effect of nimodipine in patients with traumatic subarachnoid haemorrhage (SAH). This report provides a re-analysis of the HIT I data to see whether it provides a re-analysis of the HIT I data to see whether in HIT II. This involved performing a central review of the CT scans for the HIT I patients, to identify those individuals with evidence of traumatic SAH. The sample size was small, but the HIT I data gave no support to the hypothesis that nimodipine is protective in the traumatic SAH subgroup, where 69% of patients had a poor outcome on placebo and 74% of patients had a poor outcome on nimodipine. The data do not exclude the possibility of a clinically relevant beneficial effect of nimodipine in the traumatic SAH subgroup, but further data are required to provide a definitive answer. In addition, we present a pooled analysis of the data from the two trials, which suggests that the overall benefit of treating unselected head injured patients with nimodipine is unlikely to be clinically relevant. PMID:8955434

  19. Cloning and characterization of GDP-perosamine synthetase (Per) from Escherichia coli O157:H7 and synthesis of GDP-perosamine in vitro

    SciTech Connect

    Zhao Guohui; Liu Jun; Liu Xiang; Chen Min; Zhang Houcheng Wang, Peng George

    2007-11-23

    GDP-perosamine synthetase (Per, E.C. not yet classified) is important to the synthesis of Escherichia coli O157:H7 O-antigen. The mutant in per gene can disrupt the synthesis of O157 O-antigen. In this study, GDP-perosamine synthetase was cloned from E. coli O157:H7 and over-expressed in E. coli BL21 (DE3). The recombinant His-tagged Per fusion protein was a decamer with molecular weight of 431 kDa. The optimal pH value of this recombinant protein was 7.5. The divalent ions had no significant effect on Per-catalyzed reaction. The K{sub m} and K{sub cat}/K{sub m} for GDP-4-keto-6-deoxy-D-mannose were 0.09 mM and 2.1 x 10{sup 5} M{sup -1} S{sup -1}, and those for L-glutamate were 2 mM and 0.52 x 10{sup 5} M{sup -1}S{sup -1}, respectively. Per was used to synthesize GDP-perosamine from GDP-mannose together with recombinant GDP-mannose dehydratase (GMD, E.C. 4.2.1.47). The purified GDP-perosamine was identified by MS and NMR. In summary, this work provided a feasible approach for the synthesis of GDP-perosamine which can lead to the study of LPS biosynthesis of pathogenic E. coli O157:H7.

  20. Ozone loss hits us where we live

    SciTech Connect

    Appenzeller, T.

    1991-11-01

    The news about Earth's ozone layer just keeps getting worse. Three weeks ago, NASA researchers reported that the ozone hole over the Antarctic hit a record depth this year. Now comes the United Nations Environment Program, together with the World Meteorological Organization, with an even more distressing assessment of the state of the ozone layer. For the first time, the 80-member UN panel said, measurements show the ozone shield is eroding over temperate latitudes in summer, exposing crops and people to a larger dose of ultraviolet light just when they are most vulnerable. For a small group of atmospheric modelers, though, the bad news is bittersweet. Four months ago researchers predicted summertime ozone losses of just the magnitude the UN panel has now reported: about 3% over the past decade for northern temperate latitudes. Ozone modelers are encouraged by the agreement, particularly because other models are now yielding the same result. The modeling effort was spurred by earlier measurements showing a serious erosion of ozone at midlatitudes, mainly in winter. In 1988, an analysis of data collected from the ground showed that ozone levels at the latitude of the US were dropping by about 1% to 3% per decade; last April, an analysis of measurements from the satellite-borne Total Ozone Mapping Spectrometer boosted that figure to between 4% and 5%. Those findings raised the question: What mechanisms could be driving the midlatitude losses The fact that the losses seemed to be concentrated in winter suggested one possibility. The winter ozone losses at the poles are driven by chemical reactions taking place on the surface of ice crystals in polar stratospheric clouds. Such clouds don't form at temperate latitudes. But some researchers suggested that masses of air already depleted in ozone or enriched in reactive chlorine by the chemistry in the polar clouds might be escaping to temperate latitudes during the winter.

  1. MECHANICAL PROPERTIES OF THIN GDP SHELLS USED AS CRYOGENIC DIRECT DRIVE TARGETS AT OMEGA

    SciTech Connect

    NIKROO,A; CZECHOWICZ,D; CHEN,K.C; DICKEN,M; MORRIS,C; ANDREWS,R; GREENWOOD,A.L; CASTILLO,E

    2003-06-01

    OAK-B135 Thin glow discharge polymer (GDP) shells are currently used as the targets for cryogenic direct drive laser fusion experiments. These shells need to be filled with nearly 1000 atm of D{sub 2} and cooled to cryogenic temperatures without failing due to buckling and bursting pressures they experience in this process. Therefore, the mechanical and permeation properties of these shells are of utmost importance in successful and rapid filling with D{sub 2}. In this paper, they present an overview of buckle and burst pressures of several different types of GDP shells. These include those made using traditional GDP deposition parameters (standard GDP) using a high deposition pressure and using modified parameters (strong GDP) of low deposition pressure that leads to more robust shells.

  2. Biochemical characterization of GDP-L-fucose de novo synthesis pathway in fungus Mortierella alpina

    SciTech Connect

    Ren, Yan; Perepelov, Andrei V.; Wang, Haiyan; Zhang, Hao; Knirel, Yuriy A.; Wang, Lei; Chen, Wei

    2010-01-22

    Mortierella alpina is a filamentous fungus commonly found in soil, which is able to produce large amount of polyunsaturated fatty acids. L-Fucose is an important sugar found in a diverse range of organisms, playing a variety of biological roles. In this study, we characterized the de novo biosynthetic pathway of GDP-L-fucose (the nucleotide-activated form of L-fucose) in M. alpina. Genes encoding GDP-D-mannose 4,6-dehydratase (GMD) and GDP-keto-6-deoxymannose 3,5-epimerase/4-reductase (GMER) were expressed heterologously in Escherichia coli. The recombinant enzymes were produced as His-tagged fusion proteins. Conversion of GDP-mannose to GDP-4-keto-6-deoxy mannose by GMD and GDP-4-keto-6-deoxy mannose to GDP-L-fucose by GMER were analyzed by capillary electrophoresis, electro-spray ionization-mass spectrometry, and nuclear magnetic resonance spectroscopy. The k{sub m} values of GMD for GDP-mannose and GMER for GDP-4-keto-6-deoxy mannose were determined to be 0.77 mM and 1.047 mM, respectively. Both NADH and NADPH may be used by GMER as the coenzyme. The optimum temperature and pH were determined to be 37 {sup o}C and pH 9.0 (GMD) or pH 7.0 (GMER). Divalent cations are not required for GMD and GMER activity, and the activities of both enzymes may be enhanced by DTT. To our knowledge this is the first report on the characterization of GDP-L-fucose biosynthetic pathway in fungi.

  3. Biosynthesis of GDP-fucose and other sugar nucleotides in the blood stages of Plasmodium falciparum.

    PubMed

    Sanz, Sílvia; Bandini, Giulia; Ospina, Diego; Bernabeu, Maria; Mariño, Karina; Fernández-Becerra, Carmen; Izquierdo, Luis

    2013-06-01

    Carbohydrate structures play important roles in many biological processes, including cell adhesion, cell-cell communication, and host-pathogen interactions. Sugar nucleotides are activated forms of sugars used by the cell as donors for most glycosylation reactions. Using a liquid chromatography-tandem mass spectrometry-based method, we identified and quantified the pools of UDP-glucose, UDP-galactose, UDP-N-acetylglucosamine, GDP-mannose, and GDP-fucose in Plasmodium falciparum intraerythrocytic life stages. We assembled these data with the in silico functional reconstruction of the parasite metabolic pathways obtained from the P. falciparum annotated genome, exposing new active biosynthetic routes crucial for further glycosylation reactions. Fucose is a sugar present in glycoconjugates often associated with recognition and adhesion events. Thus, the GDP-fucose precursor is essential in a wide variety of organisms. P. falciparum presents homologues of GDP-mannose 4,6-dehydratase and GDP-L-fucose synthase enzymes that are active in vitro, indicating that most GDP-fucose is formed by a de novo pathway that involves the bioconversion of GDP-mannose. Homologues for enzymes involved in a fucose salvage pathway are apparently absent in the P. falciparum genome. This is in agreement with in vivo metabolic labeling experiments showing that fucose is not significantly incorporated by the parasite. Fluorescence microscopy of epitope-tagged versions of P. falciparum GDP-mannose 4,6-dehydratase and GDP-L-fucose synthase expressed in transgenic 3D7 parasites shows that these enzymes localize in the cytoplasm of P. falciparum during the intraerythrocytic developmental cycle. Although the function of fucose in the parasite is not known, the presence of GDP-fucose suggests that the metabolite may be used for further fucosylation reactions.

  4. KONJAC1 and 2 Are Key Factors for GDP-Mannose Generation and Affect l-Ascorbic Acid and Glucomannan Biosynthesis in Arabidopsis.

    PubMed

    Sawake, Shota; Tajima, Noriaki; Mortimer, Jenny C; Lao, Jeemeng; Ishikawa, Toshiki; Yu, Xiaolan; Yamanashi, Yukiko; Yoshimi, Yoshihisa; Kawai-Yamada, Maki; Dupree, Paul; Tsumuraya, Yoichi; Kotake, Toshihisa

    2015-12-01

    Humans are unable to synthesize l-ascorbic acid (AsA), yet it is required as a cofactor in many critical biochemical reactions. The majority of human dietary AsA is obtained from plants. In Arabidopsis thaliana, a GDP-mannose pyrophosphorylase (GMPP), VITAMIN C DEFECTIVE1 (VTC1), catalyzes a rate-limiting step in AsA synthesis: the formation of GDP-Man. In this study, we identified two nucleotide sugar pyrophosphorylase-like proteins, KONJAC1 (KJC1) and KJC2, which stimulate the activity of VTC1. The kjc1kjc2 double mutant exhibited severe dwarfism, indicating that KJC proteins are important for growth and development. The kjc1 mutation reduced GMPP activity to 10% of wild-type levels, leading to a 60% reduction in AsA levels. On the contrary, overexpression of KJC1 significantly increased GMPP activity. The kjc1 and kjc1kjc2 mutants also exhibited significantly reduced levels of glucomannan, which is also synthesized from GDP-Man. Recombinant KJC1 and KJC2 enhanced the GMPP activity of recombinant VTC1 in vitro, while KJCs did not show GMPP activity. Yeast two-hybrid assays suggested that the stimulation of GMPP activity occurs via interaction of KJCs with VTC1. These results suggest that KJCs are key factors for the generation of GDP-Man and affect AsA level and glucomannan accumulation through the stimulation of VTC1 GMPP activity.

  5. The Chelyabinsk Meteorite Hits an Anomalous Zone in the Urals

    NASA Astrophysics Data System (ADS)

    Kochemasov, G. G.

    2013-09-01

    The Chelyabinsk meteorite is "strange" because it hits an area in the Urals where anomalous events are observed: shining skies, light balls, UFOs, electrphonic bolids. The area tectonically occurs at the intersection of two fold belts: Urals and Timan.

  6. Concussion Study Shows Player-To-Player Hits Most Damaging

    MedlinePlus

    ... page: https://medlineplus.gov/news/fullstory_159936.html Concussion Study Shows Player-to-Player Hits Most Damaging ... American football continue to debate how to prevent concussions, a new study using data from devices inside ...

  7. Does Human Capital Contribute to Economic Growth in Mauritius?

    ERIC Educational Resources Information Center

    Neeliah, Harris; Seetanah, Boopen

    2016-01-01

    Purpose: Real gross domestic product (GDP) growth for Mauritius has averaged more than 5 per cent since 1970 and GDP per capita has increased more than tenfold between 1970 and 2012, from less than $500 to more than $9,000. It has often been reported that human capital, along with other growth enablers, has played an important role in this…

  8. Do pigeons prefer alternatives that include near-hit outcomes?

    PubMed

    Stagner, Jessica P; Case, Jacob P; Sticklen, Mary F; Duncan, Amanda K; Zentall, Thomas R

    2015-07-01

    Pigeons show suboptimal choice on a gambling-like task similar to that shown by humans. Humans also show a preference for gambles in which there are near hits (losses that come close to winning). In the present research, we asked if pigeons would show a preference for alternatives with near-hit-like trials. In Experiment 1, we included an alternative that presented a near hit, in which a stimulus associated with reinforcement (a presumed conditioned reinforcer) changed to a stimulus associated with the absence of reinforcement (a presumed conditioned inhibitor). The pigeons tended to avoid this alternative. In Experiment 2, we varied the duration of the presumed conditioned reinforcer (2 vs. 8 s) that changed to a presumed conditioned inhibitor (8 vs. 2 s) and found that the longer the conditioned reinforcer was presented, the more the pigeons avoided it. In Experiment 3, the near-hit alternative involved an ambiguous stimulus for 8 s that changed to a presumed conditioned reinforcer (or a presumed conditioned inhibitor) for 2 s, but the pigeons still avoided it. In Experiment 4, we controlled for the duration of the conditioned reinforcer by presenting it first for 2 s followed by the ambiguous stimulus for 8 s. Once again, the pigeons avoided the alternative with the near-hit trials. In all 4 experiments, the pigeons tended to avoid alternatives that provided near-hit-like trials. We concluded that humans may be attracted to near-hit trials because near-hit trials give them the illusion of control, whereas this does not appear to be a factor for pigeons.

  9. Thomson Scattering Measurements on HIT-SI3

    NASA Astrophysics Data System (ADS)

    Everson, C. J.; Morgan, K. D.; Jarboe, T. R.

    2015-11-01

    A multi-point Thomson Scattering diagnostic has been implemented on HIT-SI3 (Helicity Injected Torus - Steady Inductive 3) to measure electron temperature. The HIT-SI3 experiment is a modification of the original HIT-SI apparatus that uses three injectors instead of two. This modification alters the configuration of magnetic fields and thus the plasma behavior in the device. The scientific aim of HIT-SI3 is to develop a deeper understanding of how injector behavior and interactions influence current drive and plasma performance in the spheromak. The Thomson Scattering system includes a 20 J (1 GW pulse) Ruby laser that provides the incident beam, and collection optics that are installed such that measurements can be taken at four spatial locations in HIT-SI3 plasmas. For each measurement point, a 3-channel polychromator is used to detect the relative level of scattering. These measurements allow for the presence of temperature gradients in the spheromak to be investigated. Preliminary HIT-SI3 temperature data are presented and can be compared to predictions from computational models. Work supported by the D.O.E.

  10. Verbs in the lexicon: Why is hitting easier than breaking?

    PubMed Central

    Mckoon, Gail; Love, Jessica

    2012-01-01

    Adult speakers use verbs in syntactically appropriate ways. For example, they know implicitly that the boy hit at the fence is acceptable but the boy broke at the fence is not. We suggest that this knowledge is lexically encoded in semantic decompositions. The decomposition for break verbs (e.g. crack, smash) is hypothesized to be more complex than that for hit verbs (e.g. kick, kiss). Specifically, the decomposition of a break verb denotes that “an entity changes state as the result of some external force” whereas the decomposition for a hit verb denotes only that “an entity potentially comes in contact with another entity.” In this article, verbs of the two types were compared in a lexical decision experiment — Experiment 1 — and they were compared in sentence comprehension experiments with transitive sentences (e.g. the car hit the bicycle and the car broke the bicycle) — Experiments 2 and 3. In Experiment 1, processing times were shorter for the hit than the break verbs and in Experiments 2 and 3, processing times were shorter for the hit sentences than the break sentences, results that are in accord with the complexities of the postulated semantic decompositions. PMID:22649484

  11. Superfast Cosmic Jet "Hits the Wall"

    NASA Astrophysics Data System (ADS)

    1999-01-01

    -288. The jet travelled quickly until its advance suddenly was stopped and the endpoint of the jet became brighter than the core. "This fast-moving material obviously hit something," Hjellming said. What did it it hit? "Probably a mixture of external material plus material from a previous jet ejection." Further studies of the collision could yield new information about the physics of cosmic jets. Such jets are believed to be powered by black holes into which material is being drawn. The exact mechanism by which the black hole's gravitational energy accelerates particles to nearly the speed of light is not well understood. There is even dispute about the types of particles ejected. Competing models call for either a mixture of electrons and protons or a mixture of electrons and positrons. Because protons are more than 1,800 times more massive than electrons or positrons (the positively-charged antiparticle of the electron), the electron-proton mixture would be much more massive than the electron-positron pair. Thus, an electron-proton jet is called a heavy jet and an electron-positron jet is called a light jet. A light jet would be much more easily slowed or stopped by tenuous interstellar material than a heavy jet, so the collision of XTE J1748-288's jet may indicate that it is a light jet. "There's still a lot more work to do before anyone can conclude that, but the collision offers the possibility of answering the light-heavy jet question," Hjellming said. A 1998 VLA study by John Wardle of Brandeis University and his colleagues indicated that the jet of a distant quasar is a light, electron-positron jet. Though the black holes in quasars are supermassive, usually millions of times more massive than the Sun, the physics of jet production in them is thought to be similar to the physics of jet production by smaller black holes, only a few times more massive than the sun, such as the one possibly in XTE J1748-288. The VLA is an instrument of the National Radio Astronomy

  12. GDP dissociation inhibitor domain II required for Rab GTPase recycling.

    PubMed

    Gilbert, P M; Burd, C G

    2001-03-16

    Rab GTPases are localized to distinct subsets of organelles within the cell, where they regulate SNARE-mediated membrane trafficking between organelles. One factor required for Rab localization and function is Rab GDP dissociation inhibitor (GDI), which is proposed to recycle Rab after vesicle fusion by extracting Rab from the membrane and loading Rab onto newly formed transport intermediates. GDI is composed of two domains; Rab binding is mediated by Domain I, and the function of Domain II is not known. In this study, Domain II of yeast GDI, encoded by the essential GDI1/SEC19 gene, was targeted in a genetic screen to obtain mutants that might lend insight into the function of this domain. In one gdi1 mutant, the cytosolic pools of all Rabs tested were depleted, and Rab accumulated on membranes, suggesting that this mutant Gdi1 protein has a general defect in extraction of Rab from membranes. In a second gdi1 mutant, the endosomal/vacuolar Rabs Vps21/Ypt51p and Ypt7p accumulated in the cytosol bound to Gdi1p, but localization of Ypt1p and Sec4p were not significantly affected. Using an in vitro assay which reconstitutes Gdi1p-mediated membrane loading of Rab, this mutant Gdi1p was found to be defective in loading of Vps21p but not Ypt1p. Loading of Vps21p by loading-defective Gdi1p was restored when acceptor membranes prepared from a deletion strain lacking Vps21p were used. These results suggest that membrane-associated Rab may regulate recruitment of GDI-Rab from the cytosol, possibly by regulating a GDI-Rab receptor. We conclude that Domain II of Gdi1p is essential for Rab loading and Rab extraction, and confirm that each of these activities is required for Gdi1p function in vivo.

  13. Enhancing GDP-fucose production in recombinant Escherichia coli by metabolic pathway engineering.

    PubMed

    Zhai, Yafei; Han, Donglei; Pan, Ying; Wang, Shuaishuai; Fang, Junqiang; Wang, Peng; Liu, Xian-wei

    2015-02-01

    Guanosine 5'-diphosphate (GDP)-fucose is the indispensible donor substrate for fucosyltransferase-catalyzed synthesis of fucose-containing biomolecules, which have been found involving in various biological functions. In this work, the salvage pathway for GDP-fucose biosynthesis from Bacterioides fragilis was introduced into Escherichia coli. Besides, the biosynthesis of guanosine 5'-triphosphate (GTP), an essential substrate for GDP-fucose biosynthesis, was enhanced via overexpression of enzymes involved in the salvage pathway of GTP biosynthesis. The production capacities of metabolically engineered strains bearing different combinations of recombinant enzymes were compared. The shake flask fermentation of the strain expressing Fkp, Gpt, Gmk and Ndk obtained the maximum GDP-fucose content of 4.6 ± 0.22 μmol/g (dry cell mass), which is 4.2 fold that of the strain only expressing Fkp. Through fed-batch fermentation, the GDP-fucose content further rose to 6.6 ± 0.14 μmol/g (dry cell mass). In addition to a better productivity than previous fermentation processes based on the de novo pathway for GDP-fucose biosynthesis, the established schemes in this work also have the advantage to be a potential avenue to GDP-fucose analogs encompassing chemical modification on the fucose residue.

  14. Interrelationships of tubulin-GDP and tubulin-GTP in microtubule assembly

    SciTech Connect

    Lin, C.M.; Hamel, E.

    1987-11-03

    The author previously reported that direct incorporation of GDP (i.e., without an initial hydrolysis of GTP) into microtubules occurs throughout an assembly cycle in a constant proportion. The exact proportion varied with reaction conditions, becoming greater under all conditions in which tubulin-GDP increased relative to tubulin-GTP (low Mg/sup 2 +/ and GTP concentrations, high tubulin concentrations, and in the presence of exogeneous GDP). These findings led the authors to explore further interrelationships of tubulin-GDP and tubulin-GTP in microtubule assembly. They have now determined the minimum amount of tubulin-GTP required for the initiation of microtubule assembly and the relative efficiency with which tubulin-GDP participates in microtubule elongation. When (8-/sup 14/C)GTP, (8-/sup 14/C)GDP, and tubulin concentrations were varied at a constant Mg/sup 2 +/ concentration (0.2 mM), initiation of assembly required that 35% of the nucleotide-bearing tubulin be in the form of tubulin-GTP, and incorporation of tubulin-GDP into microtubules during elongation was only 60% as efficient as would be predicted on the basis of its proportional concentration in the reaction mixtures. Very different results were obtained when the Mg/sup 2 +/ concentration was varied. In the absence of exogenous Mg/sup 2 +/, only 20% tubulin-GTP was required for initiation, and tubulin-GDP was directly incorporated into microtubules half as efficiently as would be predicted on the basis of its concentration in the reaction mixture. At the highest Mg/sup 2 +/ concentration examined (4 mM), 80% tubulin-GTP was required for initiation of assembly, and tubulin-GDP was incorporated into microtubules as efficiently as tubulin-GTP.

  15. Antimicrobial combinations: Bliss independence and Loewe additivity derived from mechanistic multi-hit models.

    PubMed

    Baeder, Desiree Y; Yu, Guozhi; Hozé, Nathanaël; Rolff, Jens; Regoes, Roland R

    2016-05-26

    Antimicrobial peptides (AMPs) and antibiotics reduce the net growth rate of bacterial populations they target. It is relevant to understand if effects of multiple antimicrobials are synergistic or antagonistic, in particular for AMP responses, because naturally occurring responses involve multiple AMPs. There are several competing proposals describing how multiple types of antimicrobials add up when applied in combination, such as Loewe additivity or Bliss independence. These additivity terms are defined ad hoc from abstract principles explaining the supposed interaction between the antimicrobials. Here, we link these ad hoc combination terms to a mathematical model that represents the dynamics of antimicrobial molecules hitting targets on bacterial cells. In this multi-hit model, bacteria are killed when a certain number of targets are hit by antimicrobials. Using this bottom-up approach reveals that Bliss independence should be the model of choice if no interaction between antimicrobial molecules is expected. Loewe additivity, on the other hand, describes scenarios in which antimicrobials affect the same components of the cell, i.e. are not acting independently. While our approach idealizes the dynamics of antimicrobials, it provides a conceptual underpinning of the additivity terms. The choice of the additivity term is essential to determine synergy or antagonism of antimicrobials.This article is part of the themed issue 'Evolutionary ecology of arthropod antimicrobial peptides'. PMID:27160596

  16. GDP-D-mannose pyrophosphorylase from Pogonatherum paniceum enhances salinity and drought tolerance of transgenic tobacco.

    PubMed

    Ai, Taobo; Liao, Xuehong; Li, Rui; Fan, Linhong; Luo, Fengxue; Xu, Ying; Wang, Shenghua

    2016-01-01

    Pogonatherum paniceum is a highly drought- and salt-tolerant plant species that is typically used for ecological restoration and the conservation of soil and water in many countries. Understanding the molecular mechanisms underlying plant abiotic stress responses, especially to salinity and drought stresses, in species such as P. paniceum could be important to broader crop improvement efforts. GDP-D-mannose pyrophosphorylase (GMPase) is the limiting enzyme in the synthesis of L-ascorbic acid (AsA), which plays a crucial role in the detoxification of reactive oxygen species (ROS). We have cloned and characterized the cDNA of the PpGMP gene of P. paniceum encoding a GMPase. The full-length cDNA sequence contains 1411 nucleotides encoding a putative protein with 361 amino acid residues and an approximate molecular mass of 39.68 kDa. The GMPase transcript was up-regulated in P. paniceum plants subjected to salinity and drought stress, respectively. Transgenic tobacco expressing PpGMPase exhibited enhanced salinity and drought resistance, a higher seed germination rate, better growth performance, a higher AsA content, a more stable redox state, higher superoxide dismutase (SOD) activity, and lower levels of malonaldehyde (MDA) and H2O2 under drought and salinity stress. Taken together, expression of PpGMPase in tobacco conferred salinity and drought stress tolerance by increasing the content of AsA, thereby enhancing ROS-detoxifying functions. Thus, PpGMP is a potential candidate gene for crop improvement.

  17. HIT: a new approach for hiding multimedia information in text

    NASA Astrophysics Data System (ADS)

    El-Kwae, Essam A.; Cheng, Li

    2002-04-01

    A new technique for hiding multimedia data in text, called the Hiding in Text (HIT) technique, is introduced. The HIT technique can transform any type of media represented by a long binary string into innocuous text that follows correct grammatical rules. This technique divides English words into types where each word can appear in any number of types. For each type, there is a dictionary, which maps words to binary codes. Marker types are special types whose words do not repeat in any other type. Each generated sentence must include at least one word from the marker type. In the hiding phase, a binary string is input to the HIT encoding algorithm, which then selects sentence templates at random. The output is a set of English sentences according to the selected templates and the dictionaries of types. In the retrieving phase, the HIT technique uses the position of the marker word to identify the template used to build each sentence. The proposed technique greatly improves the efficiency and the security features of previous solutions. Examples for hiding text and image information in a cover text are given to illustrate the HIT technique.

  18. GTP- and GDP-Dependent Rab27a Effectors in Pancreatic Beta-Cells.

    PubMed

    Yamaoka, Mami; Ishizaki, Toshimasa; Kimura, Toshihide

    2015-01-01

    Small guanosine triphosphatases (GTPases) participate in a wide variety of cellular functions including proliferation, differentiation, adhesion, and intracellular transport. Conventionally, only the guanosine 5'-triphosphate (GTP)-bound small GTPase interacts with effector proteins, and the resulting downstream signals control specific cellular functions. Therefore, the GTP-bound form is regarded as active, and the focus has been on searching for proteins that bind the GTP form to look for their effectors. The Rab family small GTPase Rab27a is highly expressed in some secretory cells and is involved in the control of membrane traffic. The present study reviews recent progress in our understanding of the roles of Rab27a and its effectors in pancreatic beta-cells. In the basal state, GTP-bound Rab27a controls insulin secretion at pre-exocytic stages via its GTP-dependent effectors. We previously identified novel guanosine 5'-diphosphate (GDP)-bound Rab27-interacting proteins. Interestingly, GDP-bound Rab27a controls endocytosis of the secretory membrane via its interaction with these proteins. We also demonstrated that the insulin secretagogue glucose converts Rab27a from its GTP- to GDP-bound forms. Thus, GTP- and GDP-bound Rab27a regulate pre-exocytic and endocytic stages in membrane traffic, respectively. Since the physiological importance of GDP-bound GTPases has been largely overlooked, we consider that the investigation of GDP-dependent effectors for other GTPases is necessary for further understanding of cellular function.

  19. Improved curveball hitting through the enhancement of visual cues.

    PubMed

    Osborne, K; Rudrud, E; Zezoney, F

    1990-01-01

    This study investigated the effectiveness of using visual cues to highlight the seams of baseballs to improve the hitting of curveballs. Five undergraduate varsity baseball team candidates served as subjects. Behavior change was assessed through an alternating treatments design involving unmarked balls and two treatment conditions that included baseballs with 1/4-in. and 1/8-in. orange stripes marking the seams of the baseballs. Results indicated that subjects hit a greater percentage of marked than unmarked balls. These results suggest that the addition of visual cues may be a significant and beneficial technique to enhance hitting performance. Further research is suggested regarding the training procedures, effect of feedback, rate of fading cues, generalization to live pitching, and generalization to other types of pitches.

  20. Improved curveball hitting through the enhancement of visual cues.

    PubMed Central

    Osborne, K; Rudrud, E; Zezoney, F

    1990-01-01

    This study investigated the effectiveness of using visual cues to highlight the seams of baseballs to improve the hitting of curveballs. Five undergraduate varsity baseball team candidates served as subjects. Behavior change was assessed through an alternating treatments design involving unmarked balls and two treatment conditions that included baseballs with 1/4-in. and 1/8-in. orange stripes marking the seams of the baseballs. Results indicated that subjects hit a greater percentage of marked than unmarked balls. These results suggest that the addition of visual cues may be a significant and beneficial technique to enhance hitting performance. Further research is suggested regarding the training procedures, effect of feedback, rate of fading cues, generalization to live pitching, and generalization to other types of pitches. PMID:2249972

  1. Applications of Biophysics in High-Throughput Screening Hit Validation.

    PubMed

    Genick, Christine Clougherty; Barlier, Danielle; Monna, Dominique; Brunner, Reto; Bé, Céline; Scheufler, Clemens; Ottl, Johannes

    2014-06-01

    For approximately a decade, biophysical methods have been used to validate positive hits selected from high-throughput screening (HTS) campaigns with the goal to verify binding interactions using label-free assays. By applying label-free readouts, screen artifacts created by compound interference and fluorescence are discovered, enabling further characterization of the hits for their target specificity and selectivity. The use of several biophysical methods to extract this type of high-content information is required to prevent the promotion of false positives to the next level of hit validation and to select the best candidates for further chemical optimization. The typical technologies applied in this arena include dynamic light scattering, turbidometry, resonance waveguide, surface plasmon resonance, differential scanning fluorimetry, mass spectrometry, and others. Each technology can provide different types of information to enable the characterization of the binding interaction. Thus, these technologies can be incorporated in a hit-validation strategy not only according to the profile of chemical matter that is desired by the medicinal chemists, but also in a manner that is in agreement with the target protein's amenability to the screening format. Here, we present the results of screening strategies using biophysics with the objective to evaluate the approaches, discuss the advantages and challenges, and summarize the benefits in reference to lead discovery. In summary, the biophysics screens presented here demonstrated various hit rates from a list of ~2000 preselected, IC50-validated hits from HTS (an IC50 is the inhibitor concentration at which 50% inhibition of activity is observed). There are several lessons learned from these biophysical screens, which will be discussed in this article.

  2. Crystal structure of a tetrameric GDP-D-mannose 4,6-dehydratase from a bacterial GDP-D-rhamnose biosynthetic pathway

    SciTech Connect

    Webb, N.A.; Mulichak, A.M.; Lam, J.S.; Rocchetta, H.L.; Garavito, R.M.

    2010-03-08

    D-Rhamnose is a rare 6-deoxy monosaccharide primarily found in the lipopolysaccharide of pathogenic bacteria, where it is involved in host-bacterium interactions and the establishment of infection. The biosynthesis of D-rhamnose proceeds through the conversion of GDP-D-mannose by GDP-D-mannose 4,6-dehydratase (GMD) to GDP-4-keto-6-deoxymannose, which is subsequently reduced to GDP-D-rhamnose by a reductase. We have determined the crystal structure of GMD from Pseudomonas aeruginosa in complex with NADPH and GDP. GMD belongs to the NDP-sugar modifying subfamily of the short-chain dehydrogenase/reductase (SDR) enzymes, all of which exhibit bidomain structures and a conserved catalytic triad (Tyr-XXX-Lys and Ser/Thr). Although most members of this enzyme subfamily display homodimeric structures, this bacterial GMD forms a tetramer in the same fashion as the plant MUR1 from Arabidopsis thaliana. The cofactor binding sites are adjoined across the tetramer interface, which brings the adenosyl phosphate moieties of the adjacent NADPH molecules to within 7 {angstrom} of each other. A short peptide segment (Arg35-Arg43) stretches into the neighboring monomer, making not only protein-protein interactions but also hydrogen bonding interactions with the neighboring cofactor. The interface hydrogen bonds made by the Arg35-Arg43 segment are generally conserved in GMD and MUR1, and the interacting residues are highly conserved among the sequences of bacterial and eukaryotic GMDs. Outside of the Arg35-Arg43 segment, residues involved in tetrameric contacts are also quite conserved across different species. These observations suggest that a tetramer is the preferred, and perhaps functionally relevant, oligomeric state for most bacterial and eukaryotic GMDs.

  3. Hit parade: the future of the sports concussion crisis.

    PubMed

    Nowinski, Chris

    2013-01-01

    While concussions have long been linked to brain and central nervous system issues, a new study suggests that repeated hits to the head-mild or otherwise-can lead to memory loss, depression, and dementia. This postmortem brain study, conducted at the Boston University Center for the Study of Traumatic Encephalopathy, provides new and troubling evidence about chronic traumatic encephalopathy (CTE), a long-term degenerative and incurable brain disease. Although military personnel and others are vulnerable to the disease, the highest risk is among athletes involved in contact sports in which hits to the head are considered "part of the game."

  4. Interval Throwing and Hitting Programs in Baseball: Biomechanics and Rehabilitation.

    PubMed

    Chang, Edward S; Bishop, Meghan E; Baker, Dylan; West, Robin V

    2016-01-01

    Baseball injuries from throwing and hitting generally occur as a consequence of the repetitive and high-energy motions inherent to the sport. Biomechanical studies have contributed to understanding the pathomechanics leading to injury and to the development of rehabilitation programs. Interval-based throwing and hitting programs are designed to return an athlete to competition through a gradual progression of sport-specific exercises. Proper warm-up and strict adherence to the program allows the athlete to return as quickly and safely as possible.

  5. Direct determination of the hit locations from experimental HPGe pulses

    NASA Astrophysics Data System (ADS)

    Désesquelles, P.; Boston, A. J.; Boston, H. C.; Cresswell, J. R.; Dimmock, M. R.; Lazarus, I. H.; Ljungvall, J.; Nelson, L.; Nga, D.-T.; Nolan, P. J.; Rigby, S. V.; Simpson, J.; Van-Oanh, N.-T.

    2013-11-01

    The gamma-tracking technique optimises the determination of the energy and emission angle of gamma-rays detected by modern segmented HPGe detectors. This entails the determination, using the delivered pulse shapes, of the interaction points of the gamma-ray within the crystal. The direct method presented here allows the localisation of the hits using only a large sample of pulses detected in the actual operating conditions. No external crystal scanning system or pulse shape simulation code is needed. In order to validate this method, it is applied to sets of pulses obtained using the University of Liverpool scanning system. The hit locations are determined by the method with good precision.

  6. Interval Throwing and Hitting Programs in Baseball: Biomechanics and Rehabilitation.

    PubMed

    Chang, Edward S; Bishop, Meghan E; Baker, Dylan; West, Robin V

    2016-01-01

    Baseball injuries from throwing and hitting generally occur as a consequence of the repetitive and high-energy motions inherent to the sport. Biomechanical studies have contributed to understanding the pathomechanics leading to injury and to the development of rehabilitation programs. Interval-based throwing and hitting programs are designed to return an athlete to competition through a gradual progression of sport-specific exercises. Proper warm-up and strict adherence to the program allows the athlete to return as quickly and safely as possible. PMID:26991569

  7. Different effects of guanine nucleotides (GDP and GTP) on protein-mediated mitochondrial proton leak.

    PubMed

    Woyda-Ploszczyca, Andrzej M; Jarmuszkiewicz, Wieslawa

    2014-01-01

    In this study, we compared the influence of GDP and GTP on isolated mitochondria respiring under conditions favoring oxidative phosphorylation (OXPHOS) and under conditions excluding this process, i.e., in the presence of carboxyatractyloside, an adenine nucleotide translocase inhibitor, and/or oligomycin, an FOF1-ATP synthase inhibitor. Using mitochondria isolated from rat kidney and human endothelial cells, we found that the action of GDP and GTP can differ diametrically depending on the conditions. Namely, under conditions favoring OXPHOS, both in the absence and presence of linoleic acid, an activator of uncoupling proteins (UCPs), the addition of 1 mM GDP resulted in the state 4 (non-phosphorylating respiration)-state 3 (phosphorylating respiration) transition, which is characteristic of ADP oxidative phosphorylation. In contrast, the addition of 1 mM GTP resulted in a decrease in the respiratory rate and an increase in the membrane potential, which is characteristic of UCP inhibition. The stimulatory effect of GDP, but not GTP, was also observed in inside-out submitochondrial particles prepared from rat kidney mitochondria. However, the effects of GDP and GTP were more similar in the presence of OXPHOS inhibitors. The importance of these observations in connection with the action of UCPs, adenine nucleotide translocase (or other carboxyatractyloside-sensitive carriers), carboxyatractyloside- and purine nucleotide-insensitive carriers, as well as nucleoside-diphosphate kinase (NDPK) are considered. Because the measurements favoring oxidative phosphorylation better reflect in vivo conditions, our study strongly supports the idea that GDP cannot be considered a significant physiological inhibitor of UCP. Moreover, it appears that, under native conditions, GTP functions as a more efficient UCP inhibitor than GDP and ATP.

  8. Hit Identification and Optimization in Virtual Screening: Practical Recommendations Based Upon a Critical Literature Analysis

    PubMed Central

    Zhu, Tian; Cao, Shuyi; Su, Pin-Chih; Patel, Ram; Shah, Darshan; Chokshi, Heta B.; Szukala, Richard; Johnson, Michael E.; Hevener, Kirk E.

    2013-01-01

    A critical analysis of virtual screening results published between 2007 and 2011 was performed. The activity of reported hit compounds from over 400 studies was compared to their hit identification criteria. Hit rates and ligand efficiencies were calculated to assist in these analyses and the results were compared with factors such as the size of the virtual library and the number of compounds tested. A series of promiscuity, drug-like, and ADMET filters were applied to the reported hits to assess the quality of compounds reported and a careful analysis of a subset of the studies which presented hit optimization was performed. This data allowed us to make several practical recommendations with respect to selection of compounds for experimental testing, defining hit identification criteria, and general virtual screening hit criteria to allow for realistic hit optimization. A key recommendation is the use of size-targeted ligand efficiency values as hit identification criteria. PMID:23688234

  9. U.S. Teen Births Hit Another Record Low: CDC

    MedlinePlus

    ... https://medlineplus.gov/news/fullstory_161207.html U.S. Teen Births Hit Another Record Low: CDC Less sex, ... Sept. 28, 2016 (HealthDay News) -- Births to U.S. teens reached a record low last year, continuing a ...

  10. Madoff Debacle Hits Colleges and Raises Questions about Trustee Conflicts

    ERIC Educational Resources Information Center

    Fain, Paul

    2009-01-01

    Several colleges and universities lost millions in the alleged $50-billion Ponzi scheme run by the Wall Street trader Bernard L. Madoff. The losses include institutions' endowment holdings in hedge funds that were invested with Madoff as well as hits taken by supporting foundations and donors. Several foundations that have been active in higher…

  11. Appreciating an Old Favorite: Sousa's All-Time Hit

    ERIC Educational Resources Information Center

    Van Outryve, Karen

    2006-01-01

    In this article, the author presents John Philip Sousa's all time hit, "The Stars and Stripes Forever". It is one of the most recognizable pieces of American music. Wherever John Philip Sousa and his band appeared, this march was likely to be played. According to American poet and educator Eli Siegel (1902-78), who first articulated the philosophy…

  12. HiTS real-time supernova detections

    NASA Astrophysics Data System (ADS)

    Forster, F.; Maureira, J. C.; Gonzalez-Gaitan, S.; Medina, G.; Pignata, G.; Galbany, L.; Martin, J. San; Hamuy, M.; Estevez, P.; Smith, R. C.; Vivas, K.; Flores, S.; Huijse, P.; Cabrera, G.; Anderson, J.; Bufano, F.; Jaeger, Th. de; Martinez, J.; Munoz, R.; Vera, E.; Perez, C.

    2015-02-01

    HiTS, the High Cadence Transient Survey (see ATELs #5949, #5956, #7099, #7108, #7115, #7122, #7131, #7132), reports the discovery of 5 additional supernova candidates detected using a novel real-time high-cadence image subtraction / classification pipeline developed at the Center for Mathematical Modelling (CMM) in collaboration with the Millennium Institute for Astrophysics (MAS).

  13. HiTS real-time supernova detections

    NASA Astrophysics Data System (ADS)

    Forster, F.; Maureira, J. C.; Pignata, G.; Martinez, J.; Medina, G.; Galbany, L.; Martin, J. San; Hamuy, M.; Estevez, P.; Smith, R. C.; Vivas, K.; Flores, S.; Huijse, P.; Cabrera, G.; Anderson, J.; Bufano, F.; Munoz, R.; Vera, E.; Perez, C.

    2015-02-01

    Body: HiTS: The High Cadence Transient Survey (see ATELs #5949, #5956, #7099, #7108, #7115) reports the discovery of 9 additional supernova candidates detected using a novel real-time high-cadence image subtraction / classification pipeline developed at the Center for Mathematical Modelling (CMM) in collaboration with the Millennium Institute for Astrophysics (MAS).

  14. HiTS real-time supernova detections

    NASA Astrophysics Data System (ADS)

    Forster, F.; Maureira, J. C.; Galbany, L.; de Jaeger, Th.; Martinez, J.; Cabrera, G.; Martin, J. San; Hamuy, M.; Estevez, P.; Smith, R. C.; Vivas, K.; Flores, S.; Huijse, P.; Anderson, J.; Bufano, F.; Pignata, G.; Medina, G.; Munoz, R.; Vera, E.

    2015-02-01

    HiTS: The High Cadence Transient Survey (ATELs #5949, #5956, #7099) reports the discovery of one additional supernova candidate detected using a novel real-time high-cadence image subtraction / classification pipeline developed at the Center for Mathematical Modelling (CMM) in collaboration with the Millennium Institute for Astrophysics (MAS).

  15. HiTS real-time supernova detections

    NASA Astrophysics Data System (ADS)

    Forster, F.; Maureira, J. C.; Pignata, G.; Gonzalez-Gaitan, S.; Medina, G.; Martinez, J.; Galbany, L.; Martin, J. San; Hamuy, M.; Estevez, P.; Smith, R. C.; Vivas, K.; Flores, S.; Huijse, P.; Cabrera, G.; Anderson, J.; Bufano, F.; Jaeger, Th. de; Munoz, R.; Vera, E.; Perez, C.

    2015-02-01

    HiTS: The High Cadence Transient Survey (see ATELs #5949, #5956, #7099, #7108, #7115, #7122, #7131) reports the discovery of 9 additional supernova candidates detected using a novel real-time high-cadence image subtraction / classification pipeline developed at the Center for Mathematical Modelling (CMM) in collaboration with the Millennium Institute for Astrophysics (MAS).

  16. HiTS real-time supernova detections

    NASA Astrophysics Data System (ADS)

    Forster, F.; Maureira, J. C.; Pignata, G.; Gonzalez-Gaitan, S.; Medina, G.; Martinez, J.; Galbany, Â. L.; Martin, J. San; Hamuy, M.; Estevez, P.; Smith, R. C.; Vivas, K.; Flores, S.; Huijse, P.; Cabrera, G.; Anderson, J.; Bufano, F.; Jaeger, Th. de; Munoz, R.; Vera, E.; Perez, C.

    2015-02-01

    HiTS: The High Cadence Transient Survey (see ATELs #5949, #5956, #7099, #7108, #7115, #7122) reports the discovery of 9 additional supernova candidates detected using a novel real-time high-cadence image subtraction / classification pipeline developed at the Center for Mathematical Modelling (CMM) in collaboration with the Millennium Institute for Astrophysics (MAS).

  17. HiTS real-time supernova detections

    NASA Astrophysics Data System (ADS)

    Forster, F.; Maureira, J. C.; Gonzalez-Gaitan, S.; Medina, G.; Galbany, L.; Martinez, J.; San Martin, J.; Hamuy, M.; Estevez, P.; Smith, R. C.; Vivas, K.; Flores, S.; Huijse, P.; Cabrera, G.; Anderson, J.; Bufano, F.; Pignata, G.; de Jaeger, Th.; Munoz, R.; Vera, E.; Perez, C.; Points, S.

    2015-03-01

    HiTS, the High Cadence Transient Survey (see ATELs #5949, #5956, #7099, #7108, #7115, #7122, #7131, #7146, #7148, #7149), reports the discovery of additional supernova candidates detected using a novel real-time high-cadence image subtraction / classification pipeline developed at the Center for Mathematical Modelling (CMM) in collaboration with the Millennium Institute for Astrophysics (MAS).

  18. HiTS real-time supernova detections

    NASA Astrophysics Data System (ADS)

    Forster, F.; Maureira, J. C.; Galbany, L.; De Jaeger, Th.; Gonzalez-Gaitan, S.; Martinez, J.; Cabrera, G.; San Martin, J.; Hamuy, M.; Estevez, P.; Smith, R. C.,; Vivas, K.; Flores, S.; Huijse, P.; Anderson, J.; Bufano, F.; Pignata, G.; Medina, G.; Munoz, R.; Vera, E.

    2015-02-01

    HiTS: The High Cadence Transient Survey (ATELs #5949, #5956, #7099) reports the discovery of 4 additional supernova candidates detected using a novel real-time high-cadence image subtraction / classification pipeline developed at the Center for Mathematical Modelling (CMM) in collaboration with the Millennium Institute for Astrophysics (MAS).

  19. HiTS real-time supernova detections

    NASA Astrophysics Data System (ADS)

    Forster, F.; Maureira, J. C.; Gonzalez-Gaitan, S.; Medina, G.; Galbany, L.; Martinez, J.; Martin, J. San; Hamuy, M.; Estevez, P.; Smith, R. C.; Vivas, K.; Flores, S.; Huijse, P.; Cabrera, G.; Anderson, J.; Bufano, F.; Pignata, G.; Jaeger, Th. de; Munoz, R.; Vera, E.; Perez, C.

    2015-02-01

    HiTS, the High Cadence Transient Survey (see ATELs #5949, #5956, #7099, #7108, #7115, #7122, #7131, #7146, #7148), reports the discovery of additional supernova candidates detected using a novel real-time high-cadence image subtraction / classification pipeline developed at the Center for Mathematical Modelling (CMM) in collaboration with the Millennium Institute for Astrophysics (MAS).

  20. HiTS real-time supernova detections

    NASA Astrophysics Data System (ADS)

    Forster, F.; Maureira, J. C.; Gonzalez-Gaitan, S.; Medina, G.; Galbany, L.; Martinez, J.; Martin, J. San; Hamuy, M.; Estevez, P.; Smith, R. C.; Vivas, K.; Flores, S.; Huijse, P.; Cabrera, G.; Anderson, J.; Bufano, F.; Pignata, G.; Jaeger, Th. de; Munoz, R.; Vera, E.; Perez, C.

    2015-02-01

    HiTS, the High Cadence Transient Survey (see ATELs #5949, #5956, #7099, #7108, #7115, #7122, #7131, #7146), reports the discovery of additional supernova candidates detected using a novel real-time high-cadence image subtraction / classification pipeline developed at the Center for Mathematical Modelling (CMM) in collaboration with the Millennium Institute for Astrophysics (MAS).

  1. HiTS real-time supernova detections

    NASA Astrophysics Data System (ADS)

    Forster, F.; Maureira, J. C.; Galbany, L.; De Jaeger, Th.; Gonzalez-Gaitan, S.; Martinez, J.; Cabrera, G.; San Martin, J.; Hamuy, M.; Estevez, P.; Smith, R. C.; Vivas, K.; Flores, S.; Huijse, P.; Anderson, J.; Bufano, F.; Pignata, G.; Medina, G.; Munoz, R.; Vera, E.

    2015-02-01

    HiTS: The High Cadence Transient Survey (ATELs #5949, #5956) reports the discovery of 4 possible supernova explosions detected using a novel real-time high-cadence image subtraction / classification pipeline developed at the Center for Mathematical Modelling (CMM) in collaboration with the Millennium Institute for Astrophysics (MAS).

  2. Sexually Transmitted Diseases Hit All-Time High: CDC

    MedlinePlus

    ... news/fullstory_161565.html Sexually Transmitted Diseases Hit All-Time High: CDC More prevention efforts needed, agency ... Oct. 19, 2016 HealthDay Copyright (c) 2016 HealthDay . All rights reserved. News stories are provided by HealthDay ...

  3. Assessing the lipophilicity of fragments and early hits.

    PubMed

    Mortenson, Paul N; Murray, Christopher W

    2011-07-01

    A key challenge in many drug discovery programs is to accurately assess the potential value of screening hits. This is particularly true in fragment-based drug design (FBDD), where the hits often bind relatively weakly, but are correspondingly small. Ligand efficiency (LE) considers both the potency and the size of the molecule, and enables us to estimate whether or not an initial hit is likely to be optimisable to a potent, druglike lead. While size is a key property that needs to be controlled in a small molecule drug, there are a number of additional properties that should also be considered. Lipophilicity is amongst the most important of these additional properties, and here we present a new efficiency index (LLE(AT)) that combines lipophilicity, size and potency. The index is intuitively defined, and has been designed to have the same target value and dynamic range as LE, making it easily interpretable by medicinal chemists. Monitoring both LE and LLE(AT) should help both in the selection of more promising fragment hits, and controlling molecular weight and lipophilicity during optimisation. PMID:21614595

  4. A comparison of age level on baseball hitting kinematics.

    PubMed

    Escamilla, Rafael F; Fleisig, Glenn S; DeRenne, Coop; Taylor, Marcus K; Moorman, Claude T; Imamura, Rodney; Barakatt, Edward; Andrews, James R

    2009-08-01

    We propose that learning proper hitting kinematics should be encouraged at a young age during youth baseball because this may help reinforce proper hitting kinematics as a player progresses to higher levels of baseball in their adult years. To enhance our understanding between youth and adult baseball hitting, kinematic and temporal analyses of baseball hitting were evaluated with a high-speed motion analysis system between 12 skilled youth and 12 skilled adult baseball players. There were only a small number of temporal differences between youth and adult hitters, with adult hitters taking significantly greater time than youth hitters during the stride phase and during the swing. Compared with youth hitters, adult hitters a) had significantly greater (p < .01) lead knee flexion when the hands started to move forward; b) flexed the lead knee over a greater range of motion during the transition phase (31 degrees versus 13 degrees); c) extended the lead knee over a greater range of motion during the bat acceleration phase (59 degrees versus 32 degrees); d) maintained a more open pelvis position at lead foot off ground; and e) maintained a more open upper torso position when the hands started to move forward and a more closed upper torso position at bat-ball contact. Moreover, adult hitters had greater peak upper torso angular velocity (857 degrees/s versus 717 degrees/s), peak left elbow extension angular velocity (752 degrees/s versus 598 degrees/s), peak left knee extension angular velocity (386 degrees/s versus 303 degrees/s), and bat linear velocity at bat-ball contact (30 m/s versus 25 m/s). The numerous differences in kinematic and temporal parameters between youth and adult hitters suggest that hitting mechanics are different between these two groups. PMID:19827470

  5. One-hit models of carcinogenesis: conservative or not

    SciTech Connect

    Bailar, J.C. III; Crouch, E.A.C.; Shaikh, R.; Spiegelman, D.

    1988-12-01

    One-hit formulas are widely believed to be conservative when used to analyze carcinogenesis bioassays, in the sense that they will rarely underestimate risks of cancer at low exposures. Such formulas are generally applied to the lifetime incidence of cancer at a specific site, with risks estimated from animal data at zero dose (control), and two or more additional doses that are appreciable fractions of a maximum tolerated dose. No empirical study has demonstrated that the one-hit formula is conservative in the sense described. The Carcinogenesis Bioassay Database System contains data on 1212 separate bioassays of 308 chemical substances tested at exactly three evaluable doses. These provided sufficient data to examine 8432 specific combination of cancer site with sex, species, and chemical. For each of these they fitted a one-hit formula to the zero and maximum dose data points, then examined the relation of the fitted curve to the incidence rate observed at the mid-dose, with and without adjustment for intercurrent mortality. Both underestimates and overestimates of risk at mid-dose occurred substantially more often than expected by chance. They cannot tell whether such underestimates would occur at lower doses, but offer six biological reasons why underestimates might be expected. In a high percentage of animal bioassays, the one-hit formula is not conservative when applied in the usual way to animal data. It remains possible that the one-hit formula may indeed be conservative at sufficiently low doses (below the observational range), but the usual procedure, applied to the usual dose range, can be nonconservative in estimating the slope of the formula at such low doses. Risk assessments for regulation of carcinogens should incorporate some measure of additional uncertainty.

  6. A comparison of age level on baseball hitting kinematics.

    PubMed

    Escamilla, Rafael F; Fleisig, Glenn S; DeRenne, Coop; Taylor, Marcus K; Moorman, Claude T; Imamura, Rodney; Barakatt, Edward; Andrews, James R

    2009-08-01

    We propose that learning proper hitting kinematics should be encouraged at a young age during youth baseball because this may help reinforce proper hitting kinematics as a player progresses to higher levels of baseball in their adult years. To enhance our understanding between youth and adult baseball hitting, kinematic and temporal analyses of baseball hitting were evaluated with a high-speed motion analysis system between 12 skilled youth and 12 skilled adult baseball players. There were only a small number of temporal differences between youth and adult hitters, with adult hitters taking significantly greater time than youth hitters during the stride phase and during the swing. Compared with youth hitters, adult hitters a) had significantly greater (p < .01) lead knee flexion when the hands started to move forward; b) flexed the lead knee over a greater range of motion during the transition phase (31 degrees versus 13 degrees); c) extended the lead knee over a greater range of motion during the bat acceleration phase (59 degrees versus 32 degrees); d) maintained a more open pelvis position at lead foot off ground; and e) maintained a more open upper torso position when the hands started to move forward and a more closed upper torso position at bat-ball contact. Moreover, adult hitters had greater peak upper torso angular velocity (857 degrees/s versus 717 degrees/s), peak left elbow extension angular velocity (752 degrees/s versus 598 degrees/s), peak left knee extension angular velocity (386 degrees/s versus 303 degrees/s), and bat linear velocity at bat-ball contact (30 m/s versus 25 m/s). The numerous differences in kinematic and temporal parameters between youth and adult hitters suggest that hitting mechanics are different between these two groups.

  7. A cross-section test of Cobb-Douglass production function between market capitalization and GDP

    NASA Astrophysics Data System (ADS)

    Avakian, Adam; Podobnik, Boris; Stanley, H. Eugene

    2012-02-01

    Most classical economic theories imply that both (a) economies with lower output (GDP) per person tend to grow faster in per capita terms and (b) economies with lower capital per person tend to grow faster in per capita terms. It is well-known that the former was found to be wrong. Taking market capitalization as a proxy for physical capital, we analyze a cohort of countries over a 17-year period (1994-2010) and we find the latter statement in agreement with empirical data implying a contradictive result that while capital data worldwide tend to converge, GDP data tend to diverge. However, for the countries analyzed, for which we have both market capitalization and GDP data, we find that even economies with lower output (GDP) per person tend to grow faster in per capita terms. The result that for all countries one obtains divergence while for a group of countries having both market capitalization and GDP data we have convergence is in contrast with the refutation of (a) but our results only apply to countries that have an exchange market, and are thus participating in globalization, indicating the convergent effect of globalization.

  8. GDP-D-mannose pyrophosphorylase from Pogonatherum paniceum enhances salinity and drought tolerance of transgenic tobacco.

    PubMed

    Ai, Taobo; Liao, Xuehong; Li, Rui; Fan, Linhong; Luo, Fengxue; Xu, Ying; Wang, Shenghua

    2016-01-01

    Pogonatherum paniceum is a highly drought- and salt-tolerant plant species that is typically used for ecological restoration and the conservation of soil and water in many countries. Understanding the molecular mechanisms underlying plant abiotic stress responses, especially to salinity and drought stresses, in species such as P. paniceum could be important to broader crop improvement efforts. GDP-D-mannose pyrophosphorylase (GMPase) is the limiting enzyme in the synthesis of L-ascorbic acid (AsA), which plays a crucial role in the detoxification of reactive oxygen species (ROS). We have cloned and characterized the cDNA of the PpGMP gene of P. paniceum encoding a GMPase. The full-length cDNA sequence contains 1411 nucleotides encoding a putative protein with 361 amino acid residues and an approximate molecular mass of 39.68 kDa. The GMPase transcript was up-regulated in P. paniceum plants subjected to salinity and drought stress, respectively. Transgenic tobacco expressing PpGMPase exhibited enhanced salinity and drought resistance, a higher seed germination rate, better growth performance, a higher AsA content, a more stable redox state, higher superoxide dismutase (SOD) activity, and lower levels of malonaldehyde (MDA) and H2O2 under drought and salinity stress. Taken together, expression of PpGMPase in tobacco conferred salinity and drought stress tolerance by increasing the content of AsA, thereby enhancing ROS-detoxifying functions. Thus, PpGMP is a potential candidate gene for crop improvement. PMID:27442366

  9. Crystal structure of Rab6A'(Q72L) mutant reveals unexpected GDP/Mg²⁺ binding with opened GTP-binding domain.

    PubMed

    Shin, Young-Cheul; Yoon, Jong Hwan; Jang, Tae-Ho; Kim, Seo Yun; Heo, Won Do; So, Insuk; Jeon, Ju-Hong; Park, Hyun Ho

    2012-07-27

    The Ras small G protein-superfamily is a family of GTP hydrolases whose activity is regulated by GTP/GDP binding states. Rab6A, a member of the Ras superfamily, is involved in the regulation of vesicle trafficking, which is critical for endocytosis, biosynthesis, secretion, cell differentiation and cell growth. Rab6A exists in two isoforms, termed RabA and Rab6A'. Substitution of Gln72 to Leu72 (Q72L) at Rab6 family blocks GTP hydrolysis activity and this mutation usually causes the Rab6 protein to be constitutively in an active form. Here, we report the crystal structure of the human Rab6A'(Q72L) mutant form at 1.9Å resolution. Unexpectedly, we found that Rab6A'(Q72L) possesses GDP/Mg(2+) in the GTP binding pockets, which is formed by a flexible switch I and switch II. Large conformational changes were also detected in the switch I and switch II regions. Our structure revealed that the non-hydrolysable, constitutively active form of Rab6A' can accommodate GDP/Mg(2+) in the open conformation.

  10. Comparative study of structural models of Leishmania donovani and human GDP-mannose pyrophosphorylases.

    PubMed

    Daligaux, Pierre; Bernadat, Guillaume; Tran, Linh; Cavé, Christian; Loiseau, Philippe M; Pomel, Sébastien; Ha-Duong, Tâp

    2016-01-01

    Leishmania is the parasite responsible for the neglected disease leishmaniasis. Its virulence and survival require biosynthesis of glycoconjugates, whose guanosine diphospho-d-mannose pyrophosphorylase (GDP-MP) is a key player. However, experimentally resolved structures of this enzyme are still lacking. We herein propose structural models of the GDP-MP from human and Leishmania donovani. Based on a multiple sequences alignment, the models were built with MODELLER and then carefully refined with all atom molecular dynamics simulations in explicit solvent. Their quality was evaluated against several standard criteria, including their ability to bind GDP-mannose assessed by redocking calculations. Special attention was given in this study to interactions of the catalytic site residues with the enzyme substrate and competitive inhibitors, opening the perspective of medicinal chemistry developments.

  11. Comparative study of structural models of Leishmania donovani and human GDP-mannose pyrophosphorylases.

    PubMed

    Daligaux, Pierre; Bernadat, Guillaume; Tran, Linh; Cavé, Christian; Loiseau, Philippe M; Pomel, Sébastien; Ha-Duong, Tâp

    2016-01-01

    Leishmania is the parasite responsible for the neglected disease leishmaniasis. Its virulence and survival require biosynthesis of glycoconjugates, whose guanosine diphospho-d-mannose pyrophosphorylase (GDP-MP) is a key player. However, experimentally resolved structures of this enzyme are still lacking. We herein propose structural models of the GDP-MP from human and Leishmania donovani. Based on a multiple sequences alignment, the models were built with MODELLER and then carefully refined with all atom molecular dynamics simulations in explicit solvent. Their quality was evaluated against several standard criteria, including their ability to bind GDP-mannose assessed by redocking calculations. Special attention was given in this study to interactions of the catalytic site residues with the enzyme substrate and competitive inhibitors, opening the perspective of medicinal chemistry developments. PMID:26562546

  12. 77 FR 66617 - HIT Policy and Standards Committees; Workgroup Application Database

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-11-06

    ... HUMAN SERVICES HIT Policy and Standards Committees; Workgroup Application Database AGENCY: Office of the... Application Database. The Office of the National Coordinator (ONC) has launched a new Health Information Technology Federal Advisory Committee Workgroup Application Database. Name of Committees: HIT...

  13. 75 FR 62399 - Office of the National Coordinator for Health Information Technology; HIT Standards Committee...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-10-08

    ... from the HIT Policy Committee regarding health information technology standards, implementation... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF HEALTH AND HUMAN SERVICES Office of the National Coordinator for Health Information Technology; HIT...

  14. 75 FR 32472 - Office of the National Coordinator for Health Information Technology; HIT Standards Committee...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-06-08

    ... HUMAN SERVICES Office of the National Coordinator for Health Information Technology; HIT Standards... Information Technology AGENCY: Office of the National Coordinator for Health Information Technology, HHS... Information Technology (ONC). Name of Committee: HIT Standards Committee. General Function of the...

  15. Manual laterality and hitting performance in major league baseball.

    PubMed

    Grondin, S; Guiard, Y; Ivry, R B; Koren, S

    1999-06-01

    Asymmetrical hand function was examined in the context of expert sports performance: hitting in professional baseball. An archival study was conducted to examine the batting performance of all Major League Baseball players from 1871 to 1992, focusing on those who batted left (n = 1,059) to neutralize the game asymmetry. Among them, left-handers (n = 421) were more likely to hit with power and to strike out than right-handers (n = 638). One possible account, based on the idea of hand dominance and an analogy to tennis, is that batting left involves a double-handed forehand for left-handers and a weaker and more reliable double-handed backhand for right-handers. The results are also interpretable in the light of Y. Guiard's (1987) kinematic chain model of a between-hands asymmetrical division of labor, which provides a detailed account of why left batting is optimal for left-handers. PMID:10385985

  16. A memory model for internet hits after media exposure

    NASA Astrophysics Data System (ADS)

    Chessa, Antonio G.; Murre, Jaap M. J.

    2004-02-01

    We present a cognitive model, based on the mathematical theory of point processes, which extends the results of two studies by Johansen (Physica A 276 (2000) 338; Physica A 296 (2001) 539) on download relaxation dynamics. Responses from subjects are considered as single events, which are received from original listeners or readers and from a network of social contacts, through which a message may propagate further. We collected data on the number of daily visits at our web site after a radio interview with the second author, in which the name of the web site was mentioned. A model based on an exponential hit time distribution and a homogeneous point process for regular visitors fits our data and Johansen's very well and is superior to both the power law and the logarithmic function. The fits suggest that hit data from different sources share the same cognitive mechanism, which are controlled merely by the encoding and retrieval of the target information memorised.

  17. Manual laterality and hitting performance in major league baseball.

    PubMed

    Grondin, S; Guiard, Y; Ivry, R B; Koren, S

    1999-06-01

    Asymmetrical hand function was examined in the context of expert sports performance: hitting in professional baseball. An archival study was conducted to examine the batting performance of all Major League Baseball players from 1871 to 1992, focusing on those who batted left (n = 1,059) to neutralize the game asymmetry. Among them, left-handers (n = 421) were more likely to hit with power and to strike out than right-handers (n = 638). One possible account, based on the idea of hand dominance and an analogy to tennis, is that batting left involves a double-handed forehand for left-handers and a weaker and more reliable double-handed backhand for right-handers. The results are also interpretable in the light of Y. Guiard's (1987) kinematic chain model of a between-hands asymmetrical division of labor, which provides a detailed account of why left batting is optimal for left-handers.

  18. The Effects of Pain Cues on Hitting Behavior.

    ERIC Educational Resources Information Center

    Dubanoski, Richard A.; Kong, Colleen

    This study investigates the effects of pain and non-pain consequences on groups of 22 high- and 22 low-aggression boys, as determined by a peer rating scale. The boys, who had a mean age of 10 years, 8 months, were instructed to hit a punching apparatus. Through earphones, half of each group heard pain cues, i.e., "ouch", while the other half…

  19. Hitting moving targets with a continuously changing temporal window.

    PubMed

    de la Malla, Cristina; López-Moliner, Joan

    2015-09-01

    Hitting a moving target requires that we do not miss the target when it is around the aimed position. The time available for us not to miss the target when it is at the position of interest is usually called the time window and depends on target's speed and size. These variables, among others, have been manipulated in previous studies but kept constant within the same trial or session. Here, we present results of a hitting task in which targets underwent simple harmonic motion, which is defined by a sinusoidal function. Target velocity changes continuously in this motion and so does the time window which is shorter in the centre (peak velocity) and longer at the turning points (lowest velocity) within a single trial. We studied two different conditions in which the target moved with a reliable (across trials) amplitude displacement or reliable peak velocity, respectively, and subjects were free to decide where and when to hit it. Results show that subjects made a compromise between maximum and minimum target's speed, so that they did hit the target at intermediate speed values. Interestingly, the reliability of target peak velocity (or displacement) modulated the point of interception. When target's peak velocity was more reliable, subjects intercepted the target at positions with smaller temporal windows and the reverse was true when displacement was reliable. Subjects adapted the interceptive behaviour to the underlying statistical structure of the targets. Finally, in a control condition in which the temporal window also depended on the instant size and not only on speed, subjects intercepted the target when it moved at similar speeds than when the size was constant. This finding suggests that velocity rather than the temporal window contributed more to controlling the interceptive movements.

  20. Effective progression of nuclear magnetic resonance-detected fragment hits.

    PubMed

    Eaton, Hugh L; Wyss, Daniel F

    2011-01-01

    Fragment-based drug discovery (FBDD) has become increasingly popular over the last decade as an alternate lead generation tool to HTS approaches. Several compounds have now progressed into the clinic which originated from a fragment-based approach, demonstrating the utility of this emerging field. While fragment hit identification has become much more routine and may involve different screening approaches, the efficient progression of fragment hits into quality lead series may still present a major bottleneck for the broadly successful application of FBDD. In our laboratory, we have extensive experience in fragment-based NMR screening (SbN) and the subsequent iterative progression of fragment hits using structure-assisted chemistry. To maximize impact, we have applied this approach strategically to early- and high-priority targets, and those struggling for leads. Its application has yielded a clinical candidate for BACE1 and lead series in about one third of the SbN/FBDD projects. In this chapter, we will give an overview of our strategy and focus our discussion on NMR-based FBDD approaches. PMID:21371601

  1. 42 CFR 495.332 - State Medicaid health information technology (HIT) plan requirements.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 5 2013-10-01 2013-10-01 false State Medicaid health information technology (HIT... HEALTH RECORD TECHNOLOGY INCENTIVE PROGRAM Requirements Specific to the Medicaid Program § 495.332 State Medicaid health information technology (HIT) plan requirements. Each State Medicaid HIT plan must...

  2. Teachers' Perspectives on Hitting Back in School: Between Inexcusable Violence and Self-Defense

    ERIC Educational Resources Information Center

    Fleischmann, Amos

    2015-01-01

    Israeli schools expressly forbid a student to hit back after being attacked. In semistructured interviews, 71 Israeli educators were asked for their views on the hitting-back tactic. The interviews compared their attitude toward hitting back as teachers with their take on the matter as parents. The results, analyzed using grounded theory, show…

  3. Hubs and authorities in the world trade network using a weighted HITS algorithm.

    PubMed

    Deguchi, Tsuyoshi; Takahashi, Katsuhide; Takayasu, Hideki; Takayasu, Misako

    2014-01-01

    We investigate the economic hubs and authorities of the world trade network (WTN) from 1992 to 2012, an era of rapid economic globalization. Using a well-defined weighted hyperlink-induced topic search (HITS) algorithm, we can calculate the values of the weighted HITS hub and authority for each country in a conjugate way. In the context of the WTN, authority values are large for countries with significant imports from large hub countries, and hub values are large for countries with significant exports to high-authority countries. The United States was the largest economic authority in the WTN from 1992 to 2012. The authority value of the United States has declined since 2001, and China has now become the largest hub in the WTN. At the same time, China's authority value has grown as China is transforming itself from the "factory of the world" to the "market of the world." European countries show a tendency to trade mostly within the European Union, which has decreased Europe's hub and authority values. Japan's authority value has increased slowly, while its hub value has declined. These changes are consistent with Japan's transition from being an export-driven economy in its high economic growth era in the latter half of the twentieth century to being a more mature, economically balanced nation.

  4. Hubs and Authorities in the World Trade Network Using a Weighted HITS Algorithm

    PubMed Central

    Deguchi, Tsuyoshi; Takahashi, Katsuhide; Takayasu, Hideki; Takayasu, Misako

    2014-01-01

    We investigate the economic hubs and authorities of the world trade network (WTN) from to , an era of rapid economic globalization. Using a well-defined weighted hyperlink-induced topic search (HITS) algorithm, we can calculate the values of the weighted HITS hub and authority for each country in a conjugate way. In the context of the WTN, authority values are large for countries with significant imports from large hub countries, and hub values are large for countries with significant exports to high-authority countries. The United States was the largest economic authority in the WTN from to . The authority value of the United States has declined since , and China has now become the largest hub in the WTN. At the same time, China's authority value has grown as China is transforming itself from the “factory of the world” to the “market of the world.” European countries show a tendency to trade mostly within the European Union, which has decreased Europe's hub and authority values. Japan's authority value has increased slowly, while its hub value has declined. These changes are consistent with Japan's transition from being an export-driven economy in its high economic growth era in the latter half of the twentieth century to being a more mature, economically balanced nation. PMID:25050940

  5. Hubs and authorities in the world trade network using a weighted HITS algorithm.

    PubMed

    Deguchi, Tsuyoshi; Takahashi, Katsuhide; Takayasu, Hideki; Takayasu, Misako

    2014-01-01

    We investigate the economic hubs and authorities of the world trade network (WTN) from 1992 to 2012, an era of rapid economic globalization. Using a well-defined weighted hyperlink-induced topic search (HITS) algorithm, we can calculate the values of the weighted HITS hub and authority for each country in a conjugate way. In the context of the WTN, authority values are large for countries with significant imports from large hub countries, and hub values are large for countries with significant exports to high-authority countries. The United States was the largest economic authority in the WTN from 1992 to 2012. The authority value of the United States has declined since 2001, and China has now become the largest hub in the WTN. At the same time, China's authority value has grown as China is transforming itself from the "factory of the world" to the "market of the world." European countries show a tendency to trade mostly within the European Union, which has decreased Europe's hub and authority values. Japan's authority value has increased slowly, while its hub value has declined. These changes are consistent with Japan's transition from being an export-driven economy in its high economic growth era in the latter half of the twentieth century to being a more mature, economically balanced nation. PMID:25050940

  6. Identification of different roles for RanGDP and RanGTP in nuclear protein import.

    PubMed Central

    Görlich, D; Panté, N; Kutay, U; Aebi, U; Bischoff, F R

    1996-01-01

    The importin-alpha/beta heterodimer and the GTPase Ran play key roles in nuclear protein import. Importin binds the nuclear localization signal (NLS). Translocation of the resulting import ligand complex through the nuclear pore complex (NPC) requires Ran and is terminated at the nucleoplasmic side by its disassembly. The principal GTP exchange factor for Ran is the nuclear protein RCC1, whereas the major RanGAP is cytoplasmic, predicting that nuclear Ran is mainly in the GTP form and cytoplasmic Ran is in the GDP-bound form. Here, we show that nuclear import depends on cytoplasmic RanGDP and free GTP, and that RanGDP binds to the NPC. Therefore, import might involve nucleotide exchange and GTP hydrolysis on NPC-bound Ran. RanGDP binding to the NPC is not mediated by the Ran binding sites of importin-beta, suggesting that translocation is not driven from these sites. Consistently, a mutant importin-beta deficient in Ran binding can deliver its cargo up to the nucleoplasmic side of the NPC. However, the mutant is unable to release the import substrate into the nucleoplasm. Thus, binding of nucleoplasmic RanGTP to importin-beta probably triggers termination, i.e. the dissociation of importin-alpha from importin-beta and the subsequent release of the import substrate into the nucleoplasm. Images PMID:8896452

  7. Hydrogen bonding in the mechanism of GDP-mannose mannosyl hydrolase

    NASA Astrophysics Data System (ADS)

    Mildvan, A. S.; Xia, Z.; Azurmendi, H. F.; Legler, P. M.; Balfour, M. R.; Lairson, L. L.; Withers, S. G.; Gabelli, S. B.; Bianchet, M. A.; Amzel, L. M.

    2006-06-01

    GDP-mannose mannosyl hydrolase (GDPMH) from E. coli catalyzes the hydrolysis of GDP-α- D-sugars to GDP and β- D-sugars by nucleophilic substitution with inversion at the anomeric C1 of the sugar, with general base catalysis by His-124. The 1.3 Å X-ray structure of the GDPMH-Mg 2+-GDP complex was used to model the complete substrate, GDP-mannose into the active site. The substrate is linked to the enzyme by 12 hydrogen bonds, as well as by the essential Mg 2+. In addition, His-124 was found to participate in a hydrogen bonded triad: His-124-NδH⋯Tyr-127-OH⋯Pro-120(C dbnd6 O). The contributions of these hydrogen bonds to substrate binding and to catalysis were investigated by site-directed mutagenesis. The hydrogen bonded triad detected in the X-ray structure was found to contribute little to catalysis since the Y127F mutation of the central residue shows only 2-fold decreases in both kcat and Km. The GDP leaving group is activated by the essential Mg 2+ which contributes at least 10 5-fold to kcat, and by nine hydrogen bonds, including those from Tyr-103, Arg-37, Arg-52, and Arg-65 (via an intervening water), each of which contribute factors to kcat ranging from 24- to 309-fold. Both Arg-37 and Tyr-103 bind the β-phosphate of the leaving GDP and are only 5.0 Å apart. Accordingly, the R37Q/Y103F double mutant shows partially additive effects of the two single mutants on kcat, indicating cooperativity of Arg-37 and Tyr-103 in promoting catalysis. The extensive activation of the GDP leaving group suggests a mechanism with dissociative character with a cationic oxocarbenium-like transition state and a half-chair conformation of the sugar ring, as found with glycosidase enzymes. Accordingly, Asp-22 which contributes 10 2.1- to 10 2.6-fold to kcat, is positioned to both stabilize a developing cationic center at C1 and to accept a hydrogen bond from the C2-OH of the mannosyl group, and His-88, which contributes 10 2.3-fold to kcat, is positioned to accept

  8. Thermogenesis and mitochondrial GDP binding with age in response to the novel agonist CGP-12177A.

    PubMed

    Scarpace, P J; Matheny, M; Borst, S E

    1992-02-01

    The ability to regulate body temperature diminishes with age in both humans and rodents. To investigate whether attenuation of sympathetically activated thermogenesis in brown adipose tissue (BAT) may account for the loss of thermoregulation with age, we assessed O2 consumption and body temperature in response to norepinephrine and the specific BAT beta-adrenergic agonist CGP-12177A in 6-, 18-, and 24-mo-old rats. In addition, the effects of this agonist on interscapular BAT mitochondrial GDP binding in young and senescent rats were determined. CGP-12177A rapidly induced an elevation in O2 consumption, which peaked at 25 min, followed by a decline over 4 h. The peak increase in O2 consumption over baseline and the cumulative 4-h response were decreased with age [P less than 0.02, analysis of variance (ANOVA)]. CGP-12177A induced an increase in body temperature that paralleled but appropriately lagged behind the increase in O2 consumption and that was decreased with age (P less than 0.02, ANOVA). The norepinephrine-induced increase in O2 consumption was also reduced with age but was not paralleled by a change in body temperature and was associated with a four- to fivefold increase in physical activity. In young rats CGP-12177A increased the number of available BAT mitochondrial GDP binding sites at 20 and 60 min post-injection, but in senescent rats GCP-12177A was unable to increase GDP binding. These data indicate that CGP-12177A is a novel agonist for BAT thermogenesis. With age there is a reduced capacity for thermogenesis that involves a failure to increase GDP binding, either due to a diminished amount of uncoupling protein with age or a failure to unmask reserve GDP binding sites.

  9. The burden of natural and technological disaster-related mortality on gross domestic product (GDP) in the WHO African region.

    PubMed

    Kirigia, Joses M; Sambo, Luis G; Aldis, W; Mwabu, Germano M

    2002-01-01

    The WHO Africa region has the highest disaster mortality rate compared to the other five regions of the organization. Those deaths are hypothesized to have significantly negative effect on per capita gross domestic product (GDP). The objective of this study was to estimate the loss in GDP attributable to natural and technological disaster-related mortality in the WHO African Region. We estimated the impact of disaster-related mortality on GDP using double-log econometric model and cross-sectional data (from the UNDP and the World Bank publications) on 45 out of 46 countries in the WHO African Region. The coefficients for capital (K), educational enrolment (EN), life expectancy (LE) and exports (X) had a positive sign; while imports (M) and disaster mortality (DS) were found to impact negatively on GDP. The abovementioned explanatory variables were found to have statistically significant effect on GDP at 5% level in a t-distribution test. Disaster mortality of a single person was found to reduce GDP by US$0.018. We have demonstrated that disaster mortality has a significant negative effect on GDP. Thus, as policy-makers strive to increase GDP through capital investment, export promotion and increase in educational enrolment, they should always recall that investments in strengthening national capacity to mitigate the effects of national disasters expeditiously and effectively shall yield significant economic returns. PMID:17298162

  10. Dimensions of Well-Being in EU Regions: Do GDP and Unemployment Tell Us All We Need to Know?

    ERIC Educational Resources Information Center

    Stewart, Kitty

    2005-01-01

    Unemployment and GDP are widely used as proxies for a broader concept of well-being in the European Union, especially at regional level. This paper asks whether such an approach is reasonable. Using data from a range of sources, it examines the association between unemployment, GDP and a number of alternative well-being indicators in five…

  11. Estimated Radiation on Mars, Hits per Cell Nucleus

    NASA Technical Reports Server (NTRS)

    2002-01-01

    This global map of Mars shows estimates for amounts of high-energy-particle cosmic radiation reaching the surface, a serious health concern for any future human exploration of the planet.

    The estimates are based on cosmic-radiation measurements made on the way to Mars by the Mars radiation environment experiment, an instrument on NASA's 2001 Mars Odyssey spacecraft, plus information about Mars' surface elevations from the laser altimeter instrument on NASA's Mars Global Surveyor. The areas of Mars expected to have least radiation are where elevation is lowest, because those areas have more atmosphere above them to block out some of the radiation. Earth's thick atmosphere shields us from most cosmic radiation, but Mars has a much thinner atmosphere than Earth does.

    Colors in the map refer to the estimated average number of times per year each cell nucleus in a human there would be hit by a high-energy cosmic ray particle. The range is generally from two hits (color-coded green), a moderate risk level, to eight hits (coded red), a high risk level.

    NASA's Jet Propulsion Laboratory, Pasadena, Calif. manages the 2001 Mars Odyssey and Mars Global Surveyor missions for NASA's Office of Space Science, Washington D.C. The Mars radiation environment experiment was developed by NASA's Johnson Space Center. Lockheed Martin Astronautics, Denver, is the prime contractor for Odyssey, 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.

  12. Test-retest reliability for hitting accuracy tennis test.

    PubMed

    Strecker, Estevam; Foster, Ernest B; Pascoe, David D

    2011-12-01

    Strecker, E, Foster, EB, and Pascoe, DD. Test-retest reliability for hitting accuracy tennis test. J Strength Cond Res 25(12): 3501-3505, 2011-The purpose of this investigation was to assess a test-retest reliability of the hitting accuracy tennis test (HATT). Twelve National Collegiate Athletic Association (NCAA) division I tennis players (4 men and 8 women) volunteered to participate in this investigation. Skill tests consisted of 15 consecutive ground strokes in all 4 directions (forehand [FH] and backhand [BH]; crosscourt and up the line) with not >1 minute between directions. The court was divided into 12 areas, and each area was assigned a value according to a grid system based on offensive, defensive, and neutral shots ranging from 1 point to 6 points. Total score, unforced errors, and shot index (total number of shots that landed on optimal performance areas 5 and 6 minus total number of unforced errors) were used for statistical analysis. The order of shot direction was randomized between participants and trials. The analysis of variance with repeated measures (p value ≤ 0.05) of this investigation showed no statistical difference between trials on any of the measurements. The results also suggest that division I level tennis players have the ability to hit accurately specific targets on a tennis court using either FH or BH with minimal daily variation. Therefore, we conclude that the HATT for trained tennis athletes is a simple, reliable, and accurate assessment tool to measure tennis skill performance based on accuracy. The HATT is also an easy, inexpensive training device that coaches can use to monitor players development.

  13. Dynamic stereoacuity: a test for hitting a baseball?

    PubMed

    Solomon, H; Zinn, W J; Vacroux, A

    1988-07-01

    Vision is a critical ingredient in professional sports such as baseball. It would, therefore, be logical to assume that vision testing should be able to discriminate between good and bad performance. Past attempts to establish this vision/performance relationship have not been successful. We believe the fault is anchored in the fact that all routine vision testing is static and unable to measure motion parameters. Using an instrument of our design to test dynamic stereoacuity, we have been able to detect subtle differences among individuals. The data show a segregation between major league hitters and pitchers. Such information could be used as one clue to predict hitting performance. PMID:3403900

  14. The groin hit: complications of intravenous drug abuse.

    PubMed

    Roszler, M H; McCarroll, K A; Donovan, K R; Rashid, T; Kling, G A

    1989-05-01

    We are seeing an increased number of complications in intravenous drug abusers who resort to injecting the groin for vascular access (the "groin hit"). Vascular complications include venous thrombosis, arteriovenous fistula, mycotic aneurysm, ruptured pseudoaneurysm, and dissecting hematoma. Soft tissue complications include cellulitis and abscess. The latter may dissect into the extraperitoneal space. Skeletal complications include osteomyelitis and septic arthritis. This paper illustrates the radiographic spectrum of these complications. An algorithm will illustrate the radiographic evaluation of a groin mass in a drug addict. PMID:2727357

  15. Hit efficiency study of CMS prototype forward pixel detectors

    SciTech Connect

    Kim, Dongwook; /Johns Hopkins U.

    2006-01-01

    In this paper the author describes the measurement of the hit efficiency of a prototype pixel device for the CMS forward pixel detector. These pixel detectors were FM type sensors with PSI46V1 chip readout. The data were taken with the 120 GeV proton beam at Fermilab during the period of December 2004 to February 2005. The detectors proved to be highly efficient (99.27 {+-} 0.02%). The inefficiency was primarily located near the corners of the individual pixels.

  16. Proteolytic Cleavage of Notch: “HIT and RUN”

    PubMed Central

    van Tetering, G.; Vooijs, M.

    2014-01-01

    The Notch pathway is a highly conserved signaling pathway in multicellular eukaryotes essential in controlling spatial patterning, morphogenesis and homeostasis in embryonic and adult tissues. Notch proteins coordinate cell-cell communication through receptor-ligand interactions between adjacent cells. Notch signaling is frequently deregulated by oncogenic mutation or overexpression in many cancer types. Notch activity is controlled by three sequential cleavage steps leading to ectodomain shedding and transcriptional activation. Here we review the key regulatory steps in the activation of Notch, from receptor maturation to receptor activation (HIT) via a rate-limiting proteolytic cascade (RUN) in the context of species-specific differences. PMID:21506924

  17. Dynamic stereoacuity: a test for hitting a baseball?

    PubMed

    Solomon, H; Zinn, W J; Vacroux, A

    1988-07-01

    Vision is a critical ingredient in professional sports such as baseball. It would, therefore, be logical to assume that vision testing should be able to discriminate between good and bad performance. Past attempts to establish this vision/performance relationship have not been successful. We believe the fault is anchored in the fact that all routine vision testing is static and unable to measure motion parameters. Using an instrument of our design to test dynamic stereoacuity, we have been able to detect subtle differences among individuals. The data show a segregation between major league hitters and pitchers. Such information could be used as one clue to predict hitting performance.

  18. Growth

    NASA Astrophysics Data System (ADS)

    Waag, Andreas

    This chapter is devoted to the growth of ZnO. It starts with various techniques to grow bulk samples and presents in some detail the growth of epitaxial layers by metal organic chemical vapor deposition (MOCVD), molecular beam epitaxy (MBE), and pulsed laser deposition (PLD). The last section is devoted to the growth of nanorods. Some properties of the resulting samples are also presented. If a comparison between GaN and ZnO is made, very often the huge variety of different growth techniques available to fabricate ZnO is said to be an advantage of this material system. Indeed, growth techniques range from low cost wet chemical growth at almost room temperature to high quality MOCVD growth at temperatures above 1, 000∘C. In most cases, there is a very strong tendency of c-axis oriented growth, with a much higher growth rate in c-direction as compared to other crystal directions. This often leads to columnar structures, even at relatively low temperatures. However, it is, in general, not straight forward to fabricate smooth ZnO thin films with flat surfaces. Another advantage of a potential ZnO technology is said to be the possibility to grow thin films homoepitaxially on ZnO substrates. ZnO substrates are mostly fabricated by vapor phase transport (VPT) or hydrothermal growth. These techniques are enabling high volume manufacturing at reasonable cost, at least in principle. The availability of homoepitaxial substrates should be beneficial to the development of ZnO technology and devices and is in contrast to the situation of GaN. However, even though a number of companies are developing ZnO substrates, only recently good quality substrates have been demonstrated. However, these substrates are not yet widely available. Still, the situation concerning ZnO substrates seems to be far from low-cost, high-volume production. The fabrication of dense, single crystal thin films is, in general, surprisingly difficult, even when ZnO is grown on a ZnO substrate. However

  19. [Diagnosis and treatment of heparin-induced thrombocytopenia (HIT) based on its atypical immunological features].

    PubMed

    Miyata, Shigeki; Maeda, Takuma

    2016-03-01

    Heparin-induced thrombocytopenia (HIT) is a prothrombotic side effect of heparin therapy caused by HIT antibodies, i.e., anti-platelet factor 4 (PF4)/heparin IgG with platelet-activating properties. For serological diagnosis, antigen immunoassays are commonly used worldwide. However, such assays do not indicate their platelet-activating properties, leading to low specificity for the HIT diagnosis. Therefore, over-diagnosis is currently the most serious problem associated with HIT. The detection of platelet-activating antibodies using a washed platelet activation assay is crucial for appropriate HIT diagnosis. Recent advances in our understanding of the pathogenesis of HIT include it having several clinical features atypical for an immune-mediated disease. Heparin-naïve patients can develop IgG antibodies as early as day 4, as in a secondary immune response. Evidence for an anamnestic response on heparin re-exposure is lacking. In addition, HIT antibodies are relatively short-lived, unlike those in a secondary immune response. These lines of evidence suggest that the mechanisms underlying HIT antibody formation may be compatible with a non-T cell-dependent immune reaction. These atypical clinical and serological features should be carefully considered while endeavoring to accurately diagnose HIT, which leads to appropriate therapies such as immediate administration of an alternative anticoagulant to prevent thromboembolic events and re-administration of heparin during surgery involving cardiopulmonary bypass when HIT antibodies are no longer detectable.

  20. Health Care Expenditure and GDP in African Countries: Evidence from Semiparametric Estimation with Panel Data

    PubMed Central

    Lv, Zhike; Zhu, Huiming

    2014-01-01

    A large body of literature studies on the relationship between health care expenditure (HCE) and GDP have been analyzed using data intensively from developed countries, but little is known for other regions. This paper considers a semiparametric panel data analysis for the study of the relationship between per capita HCE and per capita GDP for 42 African countries over the period 1995–2009. We found that infant mortality rate per 1,000 live births has a negative effect on per capita HCE, while the proportion of the population aged 65 is statistically insignificant in African countries. Furthermore, we found that the income elasticity is not constant but varies with income level, and health care is a necessity rather than a luxury for African countries. PMID:24741366

  1. A hybrid group method of data handling with discrete wavelet transform for GDP forecasting

    NASA Astrophysics Data System (ADS)

    Isa, Nadira Mohamed; Shabri, Ani

    2013-09-01

    This study is proposed the application of hybridization model using Group Method of Data Handling (GMDH) and Discrete Wavelet Transform (DWT) in time series forecasting. The objective of this paper is to examine the flexibility of the hybridization GMDH in time series forecasting by using Gross Domestic Product (GDP). A time series data set is used in this study to demonstrate the effectiveness of the forecasting model. This data are utilized to forecast through an application aimed to handle real life time series. This experiment compares the performances of a hybrid model and a single model of Wavelet-Linear Regression (WR), Artificial Neural Network (ANN), and conventional GMDH. It is shown that the proposed model can provide a promising alternative technique in GDP forecasting.

  2. The impact of the GDP and population on trade of COMESA using panel data approach

    NASA Astrophysics Data System (ADS)

    Hamzalouh, Lubna; Ismail, Mohd. Tahir; Rahman, Rosmanjawati Abd.

    2016-06-01

    The general consensus from a plethora of literature is that the estimates of variability for analyzing panel data models are precise and achieve accurate inferences. Panel data can also be used to control for heterogeneity through several models, such as the fixed effect model (FEM), the random effects model (REM), and the pooled regression model(PM). This study aims to uncover the increases in trade volume among the member countries of Common Market for Eastern and Southern Africa (COMESA) and identify the important factors that affect COMESA trade using panel data models. In addition, this study intends to investigate the independent variables and their effect on the export and import of COMESA member countries. Results show that in FEM, an increase in GDP leads to a 65% increase in imports, and in REM, an increase in GDP leads to an 86% increase in exports. These findings suggest that FEM and REM are appropriate for explaining the imports and exports of COMESA, respectively.

  3. National GDP, Science Interest and Science Achievement: A Person-by-Nation Interaction

    PubMed Central

    Drob, Elliot M. Tucker; Cheung, Amanda K.; Briley, Daniel A.

    2014-01-01

    Maximizing science achievement is a critical target of educational policy, with important implications for national and international economic and technological competitiveness. Previous research has identified both science interest and socioeconomic status (SES) as robust predictors of science achievement, but little research has examined their joint effects. In a dataset drawn from approximately 400,000 high school students from 57 countries, we document large interest by SES and interest by per capita gross domestic product (GDP) interactions in the prediction of science achievement. Student interest in science is a substantially stronger predictor of science achievement in higher socioeconomic contexts and in higher GDP nations. Our results are consistent with the hypothesis that, in higher opportunity contexts, motivational factors play larger roles in learning and achievement. They add to the growing body of evidence indicating that substantial cross national differences in psychological effect sizes are not simply a logical possibility, but in many cases, an empirical reality. PMID:25304883

  4. A Hit or Miss History of Statistics at Sandia

    SciTech Connect

    Diegert, Kathleen V.

    1999-08-04

    The Statistics and Human Factors Department at SNL has evolved as the Labs' mission has evolved from engineering designs for the non-nuclear parts of nuclear weapons, including the safety and security components, to a multi-program lab focusing on national security. Twenty years ago their client base was the engineers, scientists, and managers of the nuclear weapon stockpile program, at Sandia and other facilities within the DOE complex. Client relationships developed over years of association. Components and systems were assigned to statisticians so that they could develop a knowledge base in that area. Because of the many different component types and system designs in the stockpile, they typically juggled five or six statistical projects at a time. project participation other than statistical consulting was limited. They rarely had the time to lead project teams, and any skills or inclinations in that direction were often undeveloped. This paper describes a (hit-or-miss) selection of some early and recent efforts. This paper also presents their self-assessment metrics and their external assessment metrics. These metrics were selected to track the business aspects of the department; they are systematic (not hit-or-miss). These two types of histories should allow them to judge whether we're doing the right things, and also doing things right.

  5. Multiple cell hits by particle tracks in solid tissues

    NASA Astrophysics Data System (ADS)

    Todd, P.

    1992-08-01

    Relative Biological Effectiveness (RBE) and Quality Factor (Q) at extreme values of Linear Energy Transfer (LET) have been determined on the basis of experiments with single-cell systems and specific tissue responses. In typical single cell systems, each heavy particle (Ar or Fe) passes through a single cell or no cell. In tissue end-point experiments each heavy particle passes through several cells, and the LET can exceed 200 keV/μm in every cell. In most laboratory animal tissue systems, however, only a small portion of the hit cells are capable of expressing the end-point of interest to the investigator, such as cell killing, mutation or carcinogenesis. The following question must therefore be addressed: Do RBE's and Q factors derived from single-cell experiments properly account for the increased probability of multiple-cell damage by HZE tracks? A model is offered in which measured radiation effects and known tissue properties are combined to estimate the value of a multiplier of damage effectiveness on the basis of number of cells at risk, p3n, per track containing a hit cell, where n is the number of cells per track, based on tissue and organ geometry, and p3 is the probability that a cell in the track is capable of expressing the experimental end-point.

  6. Adiabatic condition and the quantum hitting time of Markov chains

    SciTech Connect

    Krovi, Hari; Ozols, Maris; Roland, Jeremie

    2010-08-15

    We present an adiabatic quantum algorithm for the abstract problem of searching marked vertices in a graph, or spatial search. Given a random walk (or Markov chain) P on a graph with a set of unknown marked vertices, one can define a related absorbing walk P{sup '} where outgoing transitions from marked vertices are replaced by self-loops. We build a Hamiltonian H(s) from the interpolated Markov chain P(s)=(1-s)P+sP{sup '} and use it in an adiabatic quantum algorithm to drive an initial superposition over all vertices to a superposition over marked vertices. The adiabatic condition implies that, for any reversible Markov chain and any set of marked vertices, the running time of the adiabatic algorithm is given by the square root of the classical hitting time. This algorithm therefore demonstrates a novel connection between the adiabatic condition and the classical notion of hitting time of a random walk. It also significantly extends the scope of previous quantum algorithms for this problem, which could only obtain a full quadratic speedup for state-transitive reversible Markov chains with a unique marked vertex.

  7. Promiscuous 2-aminothiazoles (PrATs): a frequent hitting scaffold.

    PubMed

    Devine, Shane M; Mulcair, Mark D; Debono, Cael O; Leung, Eleanor W W; Nissink, J Willem M; Lim, San Sui; Chandrashekaran, Indu R; Vazirani, Mansha; Mohanty, Biswaranjan; Simpson, Jamie S; Baell, Jonathan B; Scammells, Peter J; Norton, Raymond S; Scanlon, Martin J

    2015-02-12

    We have identified a class of molecules, known as 2-aminothiazoles (2-ATs), as frequent-hitting fragments in biophysical binding assays. This was exemplified by 4-phenylthiazol-2-amine being identified as a hit in 14/14 screens against a diverse range of protein targets, suggesting that this scaffold is a poor starting point for fragment-based drug discovery. This prompted us to analyze this scaffold in the context of an academic fragment library used for fragment-based drug discovery (FBDD) and two larger compound libraries used for high-throughput screening (HTS). This analysis revealed that such "promiscuous 2-aminothiazoles" (PrATs) behaved as frequent hitters under both FBDD and HTS settings, although the problem was more pronounced in the fragment-based studies. As 2-ATs are present in known drugs, they cannot necessarily be deemed undesirable, but the combination of their promiscuity and difficulties associated with optimizing them into a lead compound makes them, in our opinion, poor scaffolds for fragment libraries. PMID:25559643

  8. Cloning, purification and preliminary crystallographic analysis of the Bacillus subtilis GTPase YphC–GDP complex

    SciTech Connect

    Xu, Ling; Muench, Stephen P.; Roujeinikova, Anna; Sedelnikova, Svetlana E.; Rice, David W.

    2006-05-01

    Crystals of a selenomethionine-incorporated YphC–GDP complex have been grown using the hanging-drop vapour-diffusion method and polyethylene glycol as a precipitating agent. The Bacillus subtilis YphC gene encodes an essential GTPase thought to be involved in ribosome binding and whose protein product may represent a target for the development of a novel antibacterial agent. Sequence analysis reveals that YphC belongs to the EngA family of GTPases, which uniquely contain two adjacent GTP-binding domains. Crystals of a selenomethionine-incorporated YphC–GDP complex have been grown using the hanging-drop vapour-diffusion method and polyethylene glycol as a precipitating agent. The crystals belong to space group P2{sub 1}2{sub 1}2{sub 1}, with unit-cell parameters a = 62.71, b = 65.05, c = 110.61 Å, and have one molecule in the asymmetric unit. Data sets at three different wavelengths were collected on a single crystal to 2.5 Å resolution at the Daresbury SRS in order to solve the structure by MAD. Ultimately, analysis of YphC in complex with GDP may allow a greater understanding of the EngA family of essential GTPases.

  9. The Rabies Virus L Protein Catalyzes mRNA Capping with GDP Polyribonucleotidyltransferase Activity

    PubMed Central

    Ogino, Minako; Ito, Naoto; Sugiyama, Makoto; Ogino, Tomoaki

    2016-01-01

    The large (L) protein of rabies virus (RABV) plays multiple enzymatic roles in viral RNA synthesis and processing. However, none of its putative enzymatic activities have been directly demonstrated in vitro. In this study, we expressed and purified a recombinant form of the RABV L protein and verified its guanosine 5′-triphosphatase and GDP polyribonucleotidyltransferase (PRNTase) activities, which are essential for viral mRNA cap formation by the unconventional mechanism. The RABV L protein capped 5′-triphosphorylated but not 5′-diphosphorylated RABV mRNA-start sequences, 5′-AACA(C/U), with GDP to generate the 5′-terminal cap structure G(5′)ppp(5′)A. The 5′-AAC sequence in the substrate RNAs was found to be strictly essential for RNA capping with the RABV L protein. Furthermore, site-directed mutagenesis showed that some conserved amino acid residues (G1112, T1170, W1201, H1241, R1242, F1285, and Q1286) in the PRNTase motifs A to E of the RABV L protein are required for cap formation. These findings suggest that the putative PRNTase domain in the RABV L protein catalyzes the rhabdovirus-specific capping reaction involving covalent catalysis of the pRNA transfer to GDP, thus offering this domain as a target for developing anti-viral agents. PMID:27213429

  10. The Rabies Virus L Protein Catalyzes mRNA Capping with GDP Polyribonucleotidyltransferase Activity.

    PubMed

    Ogino, Minako; Ito, Naoto; Sugiyama, Makoto; Ogino, Tomoaki

    2016-01-01

    The large (L) protein of rabies virus (RABV) plays multiple enzymatic roles in viral RNA synthesis and processing. However, none of its putative enzymatic activities have been directly demonstrated in vitro. In this study, we expressed and purified a recombinant form of the RABV L protein and verified its guanosine 5'-triphosphatase and GDP polyribonucleotidyltransferase (PRNTase) activities, which are essential for viral mRNA cap formation by the unconventional mechanism. The RABV L protein capped 5'-triphosphorylated but not 5'-diphosphorylated RABV mRNA-start sequences, 5'-AACA(C/U), with GDP to generate the 5'-terminal cap structure G(5')ppp(5')A. The 5'-AAC sequence in the substrate RNAs was found to be strictly essential for RNA capping with the RABV L protein. Furthermore, site-directed mutagenesis showed that some conserved amino acid residues (G1112, T1170, W1201, H1241, R1242, F1285, and Q1286) in the PRNTase motifs A to E of the RABV L protein are required for cap formation. These findings suggest that the putative PRNTase domain in the RABV L protein catalyzes the rhabdovirus-specific capping reaction involving covalent catalysis of the pRNA transfer to GDP, thus offering this domain as a target for developing anti-viral agents.

  11. [Outpatient reinduction therapy with gemcitabine, dexamethasone, Cisplatin (GDP) for patients with relapsed and refractory lymphoma].

    PubMed

    Aota, Yasuo; Tanaka, Masaru; Watanabe, Naoki; Tomomatu, Jyunichi; Gotoh, Akihiko; Komatu, Norio

    2015-01-01

    For younger patients with relapsed or refractory lymphomas who respond to salvage therapy, autologous stem cell trans- plantation(ASCT)is the standard of care. Recently, it was demonstrated that the gemcitabine/dexamethasone/cisplatin (GDP) regimen for patients with relapsed or refractory aggressive non-Hodgkin's lymphoma (NHL) prior to ASCT was not inferior to the standard dexamethasone/cytarabine/cisplatin (DHAP) regimen for patients with relapsed and refractory aggressive lymphoma. In Japan, most patients who receive CDDP-containing regimens are hospitalized because of the substantial transfusions required for preventing renal dysfunction. We initiated GDP therapy combined with a short period of hydration and the administration of a magnesium agent and mannitol for 5 patients with relapsed and refractory aggressive lymphoma. In 4 cases, GDP was safely administered on an outpatient basis. Furthermore, peripheral blood stem cells were successfully collected in 2 patients. After stem cell harvest, ASCT was performed in a patient with diffuse large B-cell lymphoma, with the patient remaining in complete remission (CR) after ASCT.

  12. Two tomato GDP-D-mannose epimerase isoforms involved in ascorbate biosynthesis play specific roles in cell wall biosynthesis and development

    PubMed Central

    Mounet-Gilbert, Louise; Dumont, Marie; Ferrand, Carine; Bournonville, Céline; Monier, Antoine; Jorly, Joana; Lemaire-Chamley, Martine; Mori, Kentaro; Atienza, Isabelle; Hernould, Michel; Stevens, Rebecca; Lehner, Arnaud; Mollet, Jean Claude; Rothan, Christophe; Lerouge, Patrice; Baldet, Pierre

    2016-01-01

    GDP-D-mannose epimerase (GME, EC 5.1.3.18) converts GDP-D-mannose to GDP-L-galactose, and is considered to be a central enzyme connecting the major ascorbate biosynthesis pathway to primary cell wall metabolism in higher plants. Our previous work demonstrated that GME is crucial for both ascorbate and cell wall biosynthesis in tomato. The aim of the present study was to investigate the respective role in ascorbate and cell wall biosynthesis of the two SlGME genes present in tomato by targeting each of them through an RNAi-silencing approach. Taken individually SlGME1 and SlGME2 allowed normal ascorbate accumulation in the leaf and fruits, thus suggesting the same function regarding ascorbate. However, SlGME1 and SlGME2 were shown to play distinct roles in cell wall biosynthesis, depending on the tissue considered. The RNAi-SlGME1 plants harbored small and poorly seeded fruits resulting from alterations of pollen development and of pollination process. In contrast, the RNAi-SlGME2 plants exhibited vegetative growth delay while fruits remained unaffected. Analysis of SlGME1- and SlGME2-silenced seeds and seedlings further showed that the dimerization state of pectin rhamnogalacturonan-II (RG-II) was altered only in the RNAi-SlGME2 lines. Taken together with the preferential expression of each SlGME gene in different tomato tissues, these results suggest sub-functionalization of SlGME1 and SlGME2 and their specialization for cell wall biosynthesis in specific tomato tissues. PMID:27382114

  13. Two tomato GDP-D-mannose epimerase isoforms involved in ascorbate biosynthesis play specific roles in cell wall biosynthesis and development.

    PubMed

    Mounet-Gilbert, Louise; Dumont, Marie; Ferrand, Carine; Bournonville, Céline; Monier, Antoine; Jorly, Joana; Lemaire-Chamley, Martine; Mori, Kentaro; Atienza, Isabelle; Hernould, Michel; Stevens, Rebecca; Lehner, Arnaud; Mollet, Jean Claude; Rothan, Christophe; Lerouge, Patrice; Baldet, Pierre

    2016-08-01

    GDP-D-mannose epimerase (GME, EC 5.1.3.18) converts GDP-D-mannose to GDP-L-galactose, and is considered to be a central enzyme connecting the major ascorbate biosynthesis pathway to primary cell wall metabolism in higher plants. Our previous work demonstrated that GME is crucial for both ascorbate and cell wall biosynthesis in tomato. The aim of the present study was to investigate the respective role in ascorbate and cell wall biosynthesis of the two SlGME genes present in tomato by targeting each of them through an RNAi-silencing approach. Taken individually SlGME1 and SlGME2 allowed normal ascorbate accumulation in the leaf and fruits, thus suggesting the same function regarding ascorbate. However, SlGME1 and SlGME2 were shown to play distinct roles in cell wall biosynthesis, depending on the tissue considered. The RNAi-SlGME1 plants harbored small and poorly seeded fruits resulting from alterations of pollen development and of pollination process. In contrast, the RNAi-SlGME2 plants exhibited vegetative growth delay while fruits remained unaffected. Analysis of SlGME1- and SlGME2-silenced seeds and seedlings further showed that the dimerization state of pectin rhamnogalacturonan-II (RG-II) was altered only in the RNAi-SlGME2 lines. Taken together with the preferential expression of each SlGME gene in different tomato tissues, these results suggest sub-functionalization of SlGME1 and SlGME2 and their specialization for cell wall biosynthesis in specific tomato tissues. PMID:27382114

  14. Two tomato GDP-D-mannose epimerase isoforms involved in ascorbate biosynthesis play specific roles in cell wall biosynthesis and development.

    PubMed

    Mounet-Gilbert, Louise; Dumont, Marie; Ferrand, Carine; Bournonville, Céline; Monier, Antoine; Jorly, Joana; Lemaire-Chamley, Martine; Mori, Kentaro; Atienza, Isabelle; Hernould, Michel; Stevens, Rebecca; Lehner, Arnaud; Mollet, Jean Claude; Rothan, Christophe; Lerouge, Patrice; Baldet, Pierre

    2016-08-01

    GDP-D-mannose epimerase (GME, EC 5.1.3.18) converts GDP-D-mannose to GDP-L-galactose, and is considered to be a central enzyme connecting the major ascorbate biosynthesis pathway to primary cell wall metabolism in higher plants. Our previous work demonstrated that GME is crucial for both ascorbate and cell wall biosynthesis in tomato. The aim of the present study was to investigate the respective role in ascorbate and cell wall biosynthesis of the two SlGME genes present in tomato by targeting each of them through an RNAi-silencing approach. Taken individually SlGME1 and SlGME2 allowed normal ascorbate accumulation in the leaf and fruits, thus suggesting the same function regarding ascorbate. However, SlGME1 and SlGME2 were shown to play distinct roles in cell wall biosynthesis, depending on the tissue considered. The RNAi-SlGME1 plants harbored small and poorly seeded fruits resulting from alterations of pollen development and of pollination process. In contrast, the RNAi-SlGME2 plants exhibited vegetative growth delay while fruits remained unaffected. Analysis of SlGME1- and SlGME2-silenced seeds and seedlings further showed that the dimerization state of pectin rhamnogalacturonan-II (RG-II) was altered only in the RNAi-SlGME2 lines. Taken together with the preferential expression of each SlGME gene in different tomato tissues, these results suggest sub-functionalization of SlGME1 and SlGME2 and their specialization for cell wall biosynthesis in specific tomato tissues.

  15. Influence of corruption on economic growth rate and foreign investment

    NASA Astrophysics Data System (ADS)

    Podobnik, Boris; Shao, Jia; Njavro, Djuro; Ivanov, Plamen Ch.; Stanley, H. E.

    2008-06-01

    We analyze the dependence of the Gross Domestic Product ( GDP) per capita growth rates on changes in the Corruption Perceptions Index ( CPI). For the period 1999 2004 for all countries in the world, we find on average that an increase of CPI by one unit leads to an increase of the annual GDP per capita growth rate by 1.7%. By regressing only the European countries with transition economies, we find that an increase of CPI by one unit generates an increase of the annual GDP per capita growth rate by 2.4%. We also analyze the relation between foreign direct investments received by different countries and CPI, and we find a statistically significant power-law functional dependence between foreign direct investment per capita and the country corruption level measured by the CPI. We introduce a new measure to quantify the relative corruption between countries based on their respective wealth as measured by GDP per capita.

  16. Radial junction solar cells based on heterojunction with intrinsic thin layer (HIT) structure

    NASA Astrophysics Data System (ADS)

    Shen, Haoting

    The radial junction wire array structure was previously proposed as a solar cell geometry to separate the direction of carrier collection from the direction of light absorption, thereby circumventing the need to use high quality but expensive single crystal silicon (c-Si) material that has long minority carrier diffusion lengths. The Si radial junction structure can be realized by forming radial p-n junctions on Si pillar/wire arrays that have a diameter comparable to the minority carrier diffusion length. With proper design, the Si pillar arrays are also able to enhance light trapping and thereby increase the light absorption. However, the larger junction area and surface area on the pillar arrays compared to traditional planar junction Si solar cells makes it challenging to fabricate high performance devices due an in increase in surface defects. Therefore, effective surface passivation strategies are essential for radial junction devices. Hydrogenated amorphous silicon (a-Si:H) deposited by plasma-enhanced chemical vapor deposition (PECVD) using a heterojunction with intrinsic thin layer (HIT) structure has previously been demonstrated as a very effective surface passivation layer for planar c-Si solar cells. It is therefore of interest to use a-Si:H in a HIT layer structure for radial p-n junction c-Si pillar array solar cells. This poses several challenges, however, including the need to fabricate ultra-thin a-Si:H layers conformally on high aspect ratio Si pillars, control the crystallinity at the a-Si:H/c-Si interface to yield a low interface state density and optimize the layer thicknesses, doping and contacts to yield high performance devices. This research in this thesis was aimed at developing the processing technology required to apply the HIT structure to radial junction Si pillar array solar cell devices and to evaluate the device characteristics. Initial studies focused on understanding the effects of process conditions on the growth rate and

  17. 76 FR 46297 - HIT Standards Committee's Workgroup Meetings; Notice of Meetings

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-08-02

    ... access only. Name of Committees: HIT Standards Committee's Workgroups: Clinical Operations, Vocabulary... issues related to their specific subject matter, e.g., clinical operations vocabulary standards,...

  18. 76 FR 14975 - HIT Standards Committee's Workgroup Meetings; Notice of Meetings

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-03-18

    ... access only. Name of Committees: HIT Standards Committee's Workgroups: Clinical Operations, Vocabulary... specific subject matter, e.g., clinical operations vocabulary standards, clinical quality,...

  19. 42 CFR 495.338 - Health information technology implementation advance planning document requirements (HIT IAPD).

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... statement setting forth the security and interface requirements to be employed for all State HIT systems, and related systems, and the system failure and disaster recovery procedures available....

  20. Rational Prediction with Molecular Dynamics for Hit Identification

    PubMed Central

    Nichols, Sara E; Swift, Robert V; Amaro, Rommie E

    2012-01-01

    Although the motions of proteins are fundamental for their function, for pragmatic reasons, the consideration of protein elasticity has traditionally been neglected in drug discovery and design. This review details protein motion, its relevance to biomolecular interactions and how it can be sampled using molecular dynamics simulations. Within this context, two major areas of research in structure-based prediction that can benefit from considering protein flexibility, binding site detection and molecular docking, are discussed. Basic classification metrics and statistical analysis techniques, which can facilitate performance analysis, are also reviewed. With hardware and software advances, molecular dynamics in combination with traditional structure-based prediction methods can potentially reduce the time and costs involved in the hit identification pipeline. PMID:23110535

  1. Hit-to-Lead Studies for the Antimalarial Tetrahydroisoquinolone Carboxanilides.

    PubMed

    Floyd, David M; Stein, Philip; Wang, Zheng; Liu, Jian; Castro, Steve; Clark, Julie A; Connelly, Michele; Zhu, Fangyi; Holbrook, Gloria; Matheny, Amy; Sigal, Martina S; Min, Jaeki; Dhinakaran, Rajkumar; Krishnan, Senthil; Bashyum, Sridevi; Knapp, Spencer; Guy, R Kiplin

    2016-09-01

    Phenotypic whole-cell screening in erythrocytic cocultures of Plasmodium falciparum identified a series of dihydroisoquinolones that possessed potent antimalarial activity against multiple resistant strains of P. falciparum in vitro and show no cytotoxicity to mammalian cells. Systematic structure-activity studies revealed relationships between potency and modifications at N-2, C-3, and C-4. Careful structure-property relationship studies, coupled with studies of metabolism, addressed the poor aqueous solubility and metabolic vulnerability, as well as potential toxicological effects, inherent in the more potent primary screening hits such as 10b. Analogues 13h and 13i, with structural modifications at each site, were shown to possess excellent antimalarial activity in vivo. The (+)-(3S,4S) enantiomer of 13i and similar analogues were identified as the more potent. On the basis of these studies, we have selected (+)-13i for further study as a preclinical candidate. PMID:27505686

  2. Inflammation and the Two-Hit Hypothesis of Schizophrenia

    PubMed Central

    Feigenson, Keith A.; Kusnecov, Alex W.; Silverstein, Steven M.

    2014-01-01

    The high societal and individual cost of schizophrenia necessitates finding better, more effective treatment, diagnosis, and prevention strategies. One of the obstacles in this endeavor is the diverse set of etiologies that comprises schizophrenia. A substantial body of evidence has grown over the last few decades to suggest that schizophrenia is a heterogeneous syndrome with overlapping symptoms and etiologies. At the same time, an increasing number of clinical, epidemiological, and experimental studies have shown links between schizophrenia and inflammatory conditions. In this review, we analyze the literature on inflammation and schizophrenia, with a particular focus on comorbidity, biomarkers, and environmental insults. We then identify several mechanisms by which inflammation could influence the development of schizophrenia via the two-hit hypothesis. Lastly, we note the relevance of these findings to clinical applications in the diagnosis, prevention, and treatment of schizophrenia. PMID:24247023

  3. Pathomechanisms Underlying X-Adrenoleukodystrophy: A Three-Hit Hypothesis

    PubMed Central

    Singh, Inderjit; Pujol, Aurora

    2011-01-01

    X-adrenoleukodystrophy (X-ALD) is a complex disease where inactivation of ABCD1 gene results in clinically diverse phenotypes, the fatal disorder of cerebral ALD (cALD) or a milder disorder of adrenomyeloneuropathy (AMN). Loss of ABCD1 function results in defective beta oxidation of very long chain fatty acids (VLCFA) resulting in excessive accumulation of VLCFA, the biochemical “hall mark” of X-ALD. At present, the ABCD1-mediated mechanisms that determine the different phenotype of X-ALD are not well understood. The studies reviewed here suggest for a “three-hit hypothesis” for neuropathology of cALD. An improved understanding of the molecular mechanisms associated with these three phases of cALD disease should facilitate the development of effective pharmacological therapeutics for X-ALD. PMID:20626745

  4. Ozone hits low levels over Antarctica, U. S

    SciTech Connect

    Zurer, P.

    1993-10-04

    This year's Antarctic ozone hole is as deep as any ever observed and is approaching the record geographical extent of 1992, according to preliminary satellite data. In addition, both groundbased and satellite observations indicate that ozone concentrations over the U.S. hit record lows earlier this year. For more than a decade, almost all the ozone at certain altitudes over Antarctica has been destroyed as the Sun returns to the polar region in September. This dramatic photochemical depletion, catalyzed by chlorine and bromine from man-made compounds, reaches its nadir in early October. Ozone levels return to near normal later in the season, when the circular pattern of winds that isolates air over Antarctica breaks down, and ozone-rich air pours in from the north.

  5. From eye movements to actions: how batsmen hit the ball.

    PubMed

    Land, M F; McLeod, P

    2000-12-01

    In cricket, a batsman watches a fast bowler's ball come toward him at a high and unpredictable speed, bouncing off ground of uncertain hardness. Although he views the trajectory for little more than half a second, he can accurately judge where and when the ball will reach him. Batsmen's eye movements monitor the moment when the ball is released, make a predictive saccade to the place where they expect it to hit the ground, wait for it to bounce, and follow its trajectory for 100-200 ms after the bounce. We show how information provided by these fixations may allow precise prediction of the ball's timing and placement. Comparing players with different skill levels, we found that a short latency for the first saccade distinguished good from poor batsmen, and that a cricket player's eye movement strategy contributes to his skill in the game.

  6. Ecological economics and economic growth.

    PubMed

    Victor, Peter A

    2010-01-01

    Boulding's 1966 paper on the economics of spaceship Earth established the framework for ecological economics and an understanding of economic growth. In ecological economics, economies are conceptualized as open subsystems of the closed biosphere and are subject to biophysical laws and constraints. Economic growth measured as an increase in real gross domestic product (GDP) has generally been associated with increases in the use of energy and materials and the generation of wastes. Scale, composition, and technology are the proximate determinants of environmental impacts. They are often reduced to two: scale (GDP) and intensity (impact per unit GDP). New work described in this paper defines "green" growth as intensity that declines faster than scale increases. Similarly, "brown" growth occurs when intensity declines more slowly than increases in scale, and "black" growth happens when both scale and intensity increase. These concepts are then related to the environmental Kuznets curve, which can be understood as a transition from brown to green growth. Ecological economics provides a macroperspective on economic growth. It offers broad policy principles, and it challenges the primacy of economic growth as a policy objective, but many important questions remain.

  7. In at the deep end--an insight into scuba diving and related dental problems for the GDP.

    PubMed

    Jagger, R G; Jackson, S J; Jagger, D C

    1997-11-22

    Scuba diving is one of the fastest growing sports in the world. It is inevitable that the general dental practitioner (GDP) will have patients who participate in this sport and they should be aware of a number of problems that a diver can experience that are associated with the teeth and related structures. The aim of this article is to introduce the GDP to the dental problems associated with diving and make recommendations on dental care for scuba divers.

  8. Thermodynamics of the GTP-GDP-operated conformational switch of selenocysteine-specific translation factor SelB.

    PubMed

    Paleskava, Alena; Konevega, Andrey L; Rodnina, Marina V

    2012-08-10

    SelB is a specialized translation factor that binds GTP and GDP and delivers selenocysteyl-tRNA (Sec-tRNA(Sec)) to the ribosome. By analogy to elongation factor Tu (EF-Tu), SelB is expected to control the delivery and release of Sec-tRNA(Sec) to the ribosome by the structural switch between GTP- and GDP-bound conformations. However, crystal structures of SelB suggested a similar domain arrangement in the apo form and GDP- and GTP-bound forms of the factor, raising the question of how SelB can fulfill its delivery function. Here, we studied the thermodynamics of guanine nucleotide binding to SelB by isothermal titration calorimetry in the temperature range between 10 and 25 °C using GTP, GDP, and two nonhydrolyzable GTP analogs, guanosine 5'-O-(γ-thio)triphosphate (GTPγS) and guanosine 5'-(β,γ-imido)-triphosphate (GDPNP). The binding of SelB to either guanine nucleotide is characterized by a large heat capacity change (-621, -467, -235, and -275 cal × mol(-1) × K(-1), with GTP, GTPγS, GDPNP, and GDP, respectively), associated with compensatory changes in binding entropy and enthalpy. Changes in heat capacity indicate a large decrease of the solvent-accessible surface area in SelB, amounting to 43 or 32 amino acids buried upon binding of GTP or GTPγS, respectively, and 15-19 amino acids upon binding GDP or GDPNP. The similarity of the GTP and GDP forms in the crystal structures can be attributed to the use of GDPNP, which appears to induce a structure of SelB that is more similar to the GDP than to the GTP-bound form.

  9. Lead generation and examples opinion regarding how to follow up hits.

    PubMed

    Orita, Masaya; Ohno, Kazuki; Warizaya, Masaichi; Amano, Yasushi; Niimi, Tatsuya

    2011-01-01

    In fragment-based drug discovery (FBDD), not only identifying the starting fragment hit to be developed but also generating a drug lead from that starting fragment hit is important. Converting fragment hits to leads is generally similar to a high-throughput screening (HTS) hits-to-leads approach in that properties associated with activity for a target protein, such as selectivity against other targets and absorption, distribution, metabolism, excretion, and toxicity (ADME/Tox), and physicochemical properties should be taken into account. However, enhancing the potency of the fragment hit is a key requirement in FBDD, unlike HTS, because initial fragment hits are generally weak. This enhancement is presently achieved by adding additional chemical groups which bind to additional parts of the target protein or by joining or combining two or more hit fragments; however, strategies for effecting greater improvements in effective activity are needed. X-ray analysis is a key technology attractive for converting fragments to drug leads. This method makes it clear whether a fragment hit can act as an anchor and provides insight regarding introduction of functional groups to improve fragment activity. Data on follow-up chemical synthesis of fragment hits has allowed for the differentiation of four different strategies: fragment optimization, fragment linking, fragment self-assembly, and fragment evolution. Here, we discuss our opinion regarding how to follow up on fragment hits, with a focus on the importance of fragment hits as an anchor moiety to so-called hot spots in the target protein using crystallographic data. PMID:21371599

  10. Hit-and-run, hit-and-stay, and commensal bacteria present different peptide content when viewed from the perspective of the T cell.

    PubMed

    He, Lu; De Groot, Anne S; Bailey-Kellogg, Chris

    2015-11-27

    Different types of bacteria face different pressures from the immune system, with those that persist ("hit-and-stay") potentially having to adapt more in order to escape than those prone to short-lived infection ("hit-and-run"), and with commensal bacteria potentially different from both due to additional physical mechanisms for avoiding immune detection. The Janus Immunogenicity Score (JIS) was recently developed to assess the likelihood of T cell recognition of an antigen, using an analysis that considers both binding of a peptide within the antigen by major histocompatability complex (MHC) and recognition of the peptide:MHC complex by cognate T cell receptor (TCR). This score was shown to be predictive of T effector vs. T regulatory or null responses in experimental data, as well as to distinguish viruses representative of the hit-and-stay vs. hit-and-run phenotypes. Here, JIS-based analyses were conducted in order to characterize the extent to which the pressure to avoid T cell recognition is manifested in genomic differences among representative hit-and-run, hit-and-stay, and commensal bacteria. Overall, extracellular proteins were found to have different JIS profiles from cytoplasmic ones. Contrasting the bacterial groups, extracellular proteins were shown to be quite different across the groups, much more so than intracellular proteins. The differences were evident even at the level of corresponding peptides in homologous protein pairs from hit-and-run and hit-and-stay bacteria. The multi-level analysis of patterns of immunogenicity across different groups of bacteria provides a new way to approach questions of bacterial immune camouflage or escape, as well as to approach the selection and optimization of candidates for vaccine design.

  11. Brown adipose tissue mitochondria: modulation by GDP and fatty acids depends on the respiratory substrates

    PubMed Central

    De Meis, Leopoldo; Ketzer, Luisa A.; Camacho-Pereira, Juliana; Galina, Antonio

    2011-01-01

    The UCP1 [first UCP (uncoupling protein)] that is found in the mitochondria of brown adipocytes [BAT (brown adipose tissue)] regulates the heat production, a process linked to non-shivering thermogenesis. The activity of UCP1 is modulated by GDP and fatty acids. In this report, we demonstrate that respiration and heat released by BAT mitochondria vary depending on the respiratory substrate utilized and the coupling state of the mitochondria. It has already been established that, in the presence of pyruvate/malate, BAT mitochondria are coupled by faf-BSA (fatty-acid-free BSA) and GDP, leading to an increase in ATP synthesis and mitochondrial membrane potential along with simultaneous decreases in both the rates of respiration and heat production. Oleate restores the uncoupled state, inhibiting ATP synthesis and increasing the rates of both respiration and heat production. We now show that in the presence of succinate: (i) the rates of uncoupled mitochondria respiration and heat production are five times slower than in the presence of pyruvate/malate; (ii) faf-BSA and GDP accelerate heat and respiration as a result and, in coupled mitochondria, these two rates are accelerated compared with pyruvate/malate; (iii) in spite of the differences in respiration and heat production noted with the two substrates, the membrane potential and the ATP synthesized were the same; and (iv) oleate promoted a decrease in heat production and respiration in coupled mitochondria, an effect different from that observed using pyruvate/malate. These effects are not related to the production of ROS (reactive oxygen species). We suggest that succinate could stimulate a new route to heat production in BAT mitochondria. PMID:21561434

  12. A GDP-driven model for the binary and weighted structure of the International Trade Network

    NASA Astrophysics Data System (ADS)

    Almog, Assaf; Squartini, Tiziano; Garlaschelli, Diego

    2015-01-01

    Recent events such as the global financial crisis have renewed the interest in the topic of economic networks. One of the main channels of shock propagation among countries is the International Trade Network (ITN). Two important models for the ITN structure, the classical gravity model of trade (more popular among economists) and the fitness model (more popular among networks scientists), are both limited to the characterization of only one representation of the ITN. The gravity model satisfactorily predicts the volume of trade between connected countries, but cannot reproduce the missing links (i.e. the topology). On the other hand, the fitness model can successfully replicate the topology of the ITN, but cannot predict the volumes. This paper tries to make an important step forward in the unification of those two frameworks, by proposing a new gross domestic product (GDP) driven model which can simultaneously reproduce the binary and the weighted properties of the ITN. Specifically, we adopt a maximum-entropy approach where both the degree and the strength of each node are preserved. We then identify strong nonlinear relationships between the GDP and the parameters of the model. This ultimately results in a weighted generalization of the fitness model of trade, where the GDP plays the role of a ‘macroeconomic fitness’ shaping the binary and the weighted structure of the ITN simultaneously. Our model mathematically explains an important asymmetry in the role of binary and weighted network properties, namely the fact that binary properties can be inferred without the knowledge of weighted ones, while the opposite is not true.

  13. Radial junction solar cells based on heterojunction with intrinsic thin layer (HIT) structure

    NASA Astrophysics Data System (ADS)

    Shen, Haoting

    The radial junction wire array structure was previously proposed as a solar cell geometry to separate the direction of carrier collection from the direction of light absorption, thereby circumventing the need to use high quality but expensive single crystal silicon (c-Si) material that has long minority carrier diffusion lengths. The Si radial junction structure can be realized by forming radial p-n junctions on Si pillar/wire arrays that have a diameter comparable to the minority carrier diffusion length. With proper design, the Si pillar arrays are also able to enhance light trapping and thereby increase the light absorption. However, the larger junction area and surface area on the pillar arrays compared to traditional planar junction Si solar cells makes it challenging to fabricate high performance devices due an in increase in surface defects. Therefore, effective surface passivation strategies are essential for radial junction devices. Hydrogenated amorphous silicon (a-Si:H) deposited by plasma-enhanced chemical vapor deposition (PECVD) using a heterojunction with intrinsic thin layer (HIT) structure has previously been demonstrated as a very effective surface passivation layer for planar c-Si solar cells. It is therefore of interest to use a-Si:H in a HIT layer structure for radial p-n junction c-Si pillar array solar cells. This poses several challenges, however, including the need to fabricate ultra-thin a-Si:H layers conformally on high aspect ratio Si pillars, control the crystallinity at the a-Si:H/c-Si interface to yield a low interface state density and optimize the layer thicknesses, doping and contacts to yield high performance devices. This research in this thesis was aimed at developing the processing technology required to apply the HIT structure to radial junction Si pillar array solar cell devices and to evaluate the device characteristics. Initial studies focused on understanding the effects of process conditions on the growth rate and

  14. 75 FR 21629 - HIT Policy Committee Advisory Meeting; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-04-26

    ... Workgroup, the Certification/Adoption Workgroup, the NHIN Workgroup, the Privacy & Security Policy Workgroup... HUMAN SERVICES Office of the National Coordinator for Health Information Technology HIT Policy Committee... will be open to the public. Name of Committee: HIT Policy Committee. General Function of the...

  15. Visual Illusions and the Control of Ball Placement in Goal-Directed Hitting

    ERIC Educational Resources Information Center

    Caljouw, Simone R.; Van der Kamp, John; Savelsbergh, Geert J. P.

    2010-01-01

    When hitting, kicking, or throwing balls at targets, online control in the target area is impossible. We assumed this lack of late corrections in the target area would induce an effect of a single-winged Muller-Lyer illusion on ball placement. After extensive practice in hitting balls to different landing locations, participants (N = 9) had to hit…

  16. 75 FR 17744 - Office of the National Coordinator for Health Information Technology HIT Policy Committee...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-04-07

    ... HUMAN SERVICES Office of the National Coordinator for Health Information Technology HIT Policy Committee... Technology, HHS. ACTION: Notice of change of location for meetings. This notice references forthcoming... Technology (ONC). The meeting will be open to the public. Name of Committee: HIT Policy Committee;...

  17. Hit to lead SAR study on benzoxazole derivatives for an NPY Y5 antagonist.

    PubMed

    Omori, Naoki; Kouyama, Naoki; Yukimasa, Akira; Watanabe, Kana; Yokota, Yasunori; Tanioka, Hideki; Nambu, Hirohide; Yukioka, Hideo; Sato, Norihito; Tanaka, Yukari; Sekiguchi, Kazutaka; Okuno, Takayuki

    2012-03-01

    We report a hit to lead study on a novel benzoxazole NPY Y5 antagonist. Starting from HTS hit 1, structure-activity relationships were developed. Compound 12 showed reduction of food intake and a tendency to suppress body weight gain over the 21-day experimental period.

  18. Construction of the Helicity Injected Torus with Steady Inductive Helicity Injection (HIT-SI)

    NASA Astrophysics Data System (ADS)

    Sieck, P. E.; Gu, P.; Hamp, W. T.; Izzo, V. A.; Jarboe, T. R.; Nelson, B. A.; Rogers, J. A.

    2001-10-01

    HIT-SI is a ``bow tie'' spheromak designed to implement Steady Inductive Helicity Injection (SIHI). The engineering requirements of SIHI lead to several unique design features, including a multiply connected electrically insulating o-ring seal and a close-fitting passive flux conserver that is electrically insulated from the plasma. Prototype tests have been performed to verify the performance of the o-ring seal and the plasma sprayed zirconia insulation. An engineering test of the new HIT-SI front end will be done before it replaces the present HIT-II front end on HIT. Startup and one millisecond of sustainment will be done to test breakdown and verify power supply requirements. The power supplies and external coils are designed to provide 20 MW at 5 kHz to 50 kHz for 1 ms to the helicity injection circuits for this test. Progress in the construction and assembly of HIT-SI will be presented.

  19. PageRank, HITS and a unified framework for link analysis

    SciTech Connect

    Ding, Chris; He, Xiaofeng; Husbands, Parry; Zha, Hongyuan; Simon, Horst

    2001-10-01

    Two popular webpage ranking algorithms are HITS and PageRank. HITS emphasizes mutual reinforcement between authority and hub webpages, while PageRank emphasizes hyperlink weight normalization and web surfing based on random walk models. We systematically generalize/combine these concepts into a unified framework. The ranking framework contains a large algorithm space; HITS and PageRank are two extreme ends in this space. We study several normalized ranking algorithms which are intermediate between HITS and PageRank, and obtain closed-form solutions. We show that, to first order approximation, all ranking algorithms in this framework, including PageRank and HITS, lead to same ranking which is highly correlated with ranking by indegree. These results support the notion that in web resource ranking indegree and outdegree are of fundamental importance. Rankings of webgraphs of different sizes and queries are presented to illustrate our analysis.

  20. SHIELD-HIT12A - a Monte Carlo particle transport program for ion therapy research

    NASA Astrophysics Data System (ADS)

    Bassler, N.; Hansen, D. C.; Lühr, A.; Thomsen, B.; Petersen, J. B.; Sobolevsky, N.

    2014-03-01

    Purpose: The Monte Carlo (MC) code SHIELD-HIT simulates the transport of ions through matter. Since SHIELD-HIT08 we added numerous features that improves speed, usability and underlying physics and thereby the user experience. The "-A" fork of SHIELD-HIT also aims to attach SHIELD-HIT to a heavy ion dose optimization algorithm to provide MC-optimized treatment plans that include radiobiology. Methods: SHIELD-HIT12A is written in FORTRAN and carefully retains platform independence. A powerful scoring engine is implemented scoring relevant quantities such as dose and track-average LET. It supports native formats compatible with the heavy ion treatment planning system TRiP. Stopping power files follow ICRU standard and are generated using the libdEdx library, which allows the user to choose from a multitude of stopping power tables. Results: SHIELD-HIT12A runs on Linux and Windows platforms. We experienced that new users quickly learn to use SHIELD-HIT12A and setup new geometries. Contrary to previous versions of SHIELD-HIT, the 12A distribution comes along with easy-to-use example files and an English manual. A new implementation of Vavilov straggling resulted in a massive reduction of computation time. Scheduled for later release are CT import and photon-electron transport. Conclusions: SHIELD-HIT12A is an interesting alternative ion transport engine. Apart from being a flexible particle therapy research tool, it can also serve as a back end for a MC ion treatment planning system. More information about SHIELD-HIT12A and a demo version can be found on http://www.shieldhit.org.

  1. Characterization of an fungal l-fucokinase involved in Mortierella alpina GDP-l-fucose salvage pathway.

    PubMed

    Wang, Hongchao; Zhang, Chen; Chen, Haiqin; Yang, Qin; Zhou, Xin; Gu, Zhennan; Zhang, Hao; Chen, Wei; Chen, Yong Q

    2016-08-01

    GDP-l-fucose functions as a biological donor for fucosyltransferases, which are required for the catalysis of l-fucose to various acceptor molecules including oligosaccharides, glycoproteins and glycolipids. Mortierella alpina is one of the highest lipid-producing fungi and can biosynthesis GDP-l-fucose in the de novo pathway. Analysis of the M. alpina genome suggests that there is a gene encoding l-fucokinase (FUK) for the conversion of fucose to l-fucose-1-phosphate in the GDP-l-fucose salvage pathway, which has never been found in fungi before. This gene was characterized to explore its role in GDP-l-fucose synthesis. The yield of GDP-l-fucose is relatively higher in lipid accumulation phase (0.096 mg per g cell) than that in cell multiplication phase (0.074 mg per g cell) of M. alpina Additionally, the transcript level of FUK is up regulated by nitrogen exhaustion when M. alpina starts to accumulate lipid, highlights the functional significance of FUK in the GDP-l-fucose biosynthesis in M. alpina Gene encoding FUK was expressed heterologously in Escherichia coli and the resulting protein was purified to homogeneity. The product of FUK reaction was analyzed by liquid chromatography and mass spectrometry. Kinetic parameters and other properties of FUK were investigated. Comparative analyses between the FUK protein and other homologous proteins were performed. To our knowledge, this study is the first to report a comprehensive characterization of FUK in a fungus. Mortierella alpina could be used as an alternative source for the production of GDP-l-fucose.

  2. Backbone resonance assignments for G protein α(i3) subunit in the GDP-bound state.

    PubMed

    Mase, Yoko; Yokogawa, Mariko; Osawa, Masanori; Shimada, Ichio

    2014-10-01

    Guanine-nucleotide binding proteins (G proteins) serve as molecular switches in signaling pathways, by coupling the activation of G protein-coupled receptors (GPCRs) at the cell surface to intracellular responses. In the resting state, G protein forms a heterotrimer, consisting of the G protein α subunit with GDP (Gα·GDP) and the G protein βγ subunit (Gβγ). Ligand binding to GPCRs promotes the GDP-GTP exchange on Gα, leading to the dissociation of the GTP-bound form of Gα (Gα·GTP) and Gβγ. Then, Gα·GTP and Gβγ bind to their downstream effector enzymes or ion channels and regulate their activities, leading to a variety of cellular responses. Finally, Gα hydrolyzes the bound GTP to GDP and returns to the resting state by re-associating with Gβγ. The G proteins are classified with four major families based on the amino acid sequences of Gα: i/o, s, q/11, and 12/13. Here, we established the backbone resonance assignments of human Gαi3, a member of the i/o family with a molecular weight of 41 K, in complex with GDP. The chemical shifts were compared with those of Gα(i3) in complex with a GTP-analogue, GTPγS, which we recently reported, indicating that the residues with significant chemical shift differences are mostly consistent with the regions with the structural differences between the GDP- and GTPγS-bound states, as indicated in the crystal structures. The assignments of Gα(i3)·GDP would be useful for the analyses of the dynamics of Gα(i3) and its interactions with various target molecules.

  3. Per-capita GDP and nonequilibrium wealth-concentration in a model for trade

    NASA Astrophysics Data System (ADS)

    Moukarzel, Cristian F.

    2013-12-01

    Data describing the per-capita Gross Domestic Product of around two hundred countries in years 1960 to 2008 are analyzed and found to decay approximately exponentially with rank. We discuss this experimental fact in the context of a wealth exchange model called Yard-Sale exchange, in which pairs of agents (i.e. nations) 'bet' for a fraction f of the wealth of the poorest of them. If the chances for this poorest agent to win the bet are not large enough, this model presents a 'wealth condensation' phase, in which one lucky agent gets to own the whole wealth in the end. In a recent study of this model [1], it was found that, in the condensed phase, the typical wealth of an agent with rank R decays exponentially with R. By establishing a parallel between wealth of a nation and its per-capita GDP, these observations suggest that international trade rules are such that strong wealth concentration is favored. Possible extensions of this work, that also consider endogenous factors affecting the evolution of GDP, are also discussed.

  4. Improving health and well-being independently of GDP: dividends of greener and prosocial economies.

    PubMed

    Pretty, Jules; Barton, Jo; Bharucha, Zareen Pervez; Bragg, Rachel; Pencheon, David; Wood, Carly; Depledge, Michael H

    2016-01-01

    Increases in gross domestic product (GDP) beyond a threshold of basic needs do not lead to further increases in well-being. An explanation is that material consumption (MC) also results in negative health externalities. We assess how these externalities influence six factors critical for well-being: (i) healthy food; (ii) active body; (iii) healthy mind; (iv) community links; (v) contact with nature; and (vi) attachment to possessions. If environmentally sustainable consumption (ESC) were increasingly substituted for MC, thus improving well-being and stocks of natural and social capital, and sustainable behaviours involving non-material consumption (SBs-NMC) became more prevalent, then well-being would increase regardless of levels of GDP. In the UK, the individualised annual health costs of negative consumption externalities (NCEs) currently amount to £62 billion for the National Health Service, and £184 billion for the economy (for mental ill-health, dementia, obesity, physical inactivity, diabetes, loneliness and cardiovascular disease). A dividend is available if substitution by ESC and SBs-NMC could limit the prevalence of these conditions.

  5. Characterization of GDP-Fucose: Polysaccharide Fucosyl Transferase in Corn Roots (Zea mays L.).

    PubMed

    James, D W; Jones, R L

    1979-12-01

    The peripheral root cap cells of corn (cv. SX-17A) secrete a fucose-rich, high molecular weight, polysaccharide slime via the dictyosome pathway. To study the synthesis of this polysaccharide, a technique for isolating and assaying GDP-fucose:polysaccharide fucosyl transferase activity was developed. Corn roots were excised from germinated seeds, incubated 12 hours at 10 C in water, and ground in 100 millimolar Tris or Pipes buffer (pH 7.0) with or without 0.5 molar sucrose. The membrane-bound enzyme was solubilized by sonication in the presence of 2 molar urea and 1.5% (v/v) Triton X-100 and assayed by monitoring the incorporation of GDP-[(14)C]fucose into endogenous acceptors. Optimum enzyme activity is expressed at pH 7.0 and 30 C in the presence of 0.8% (v/v) Triton X-100. The enzyme does not require divalent cations for activation and is inhibited by concentrations of MnCl(2) or MgCl(2) greater than 1 millimolar. Corn root cap slime will serve as an exogenous acceptor for the enzyme if it is first hydrolyzed in 5 millimolar trifluoroacetic acid for 60 minutes at 18 pounds per square inch, 121 C. This procedure prepares the acceptor by removing terminal fucose residues from the slime molecule. Kinetics of fucose release during hydrolysis of native slime and in vitro synthesized product suggests that the two polymers possess similar linkages to fucose.

  6. The effect of fastball backspin rate on baseball hitting accuracy.

    PubMed

    Higuchi, Takatoshi; Morohoshi, Jun; Nagami, Tomoyuki; Nakata, Hiroki; Kanosue, Kazuyuki

    2013-06-01

    The effectiveness of fastballs of equivalent speed can differ; for example, one element of this difference could be due to the effect of rate and orientation of ball spin on launched ball trajectory. In the present experiment, baseball batters' accuracy in hitting fastballs with different backspin rates at a constant ball velocity of 36 m/s was examined. Thirteen skilled baseball players (professionals, semiprofessionals, and college varsity players) participated in the study. The movements of bat and ball were recorded using two synchronized high-speed video cameras. The Pearson product-moment correlation coefficient (r) was calculated and used to analyze the relationship between ball backspin rate and the vertical distance between ball center and sweet spot at the moment of ball-bat impact. Ball backspin rate was positively correlated with increases in the distance from the optimal contact point of the swung bat (sweet spot) to the actual point of contact (r = .38, P < .001). Batters were most effective at the usual backspin rate for the ball velocity used. The decrease in accuracy of the batter's swing that was observed when the fastball's backspin deviated from the usual rate likely occurred because experienced batters predict ball trajectory from perceived ball speed. PMID:22923374

  7. Scientific impact: the story of your big hit

    NASA Astrophysics Data System (ADS)

    Sinatra, Roberta; Wang, Dashun; Deville, Pierre; Song, Chaoming; Barabasi, Albert-Laszlo

    2014-03-01

    A gradual increase in performance through learning and practice characterize most trades, from sport to music or engineering, and common sense suggests this to be true in science as well. This prompts us to ask: what are the precise patterns that lead to scientific excellence? Does performance indeed improve throughout a scientific career? Are there quantifiable signs of an impending scientific hit? Using citation-based measures as a proxy of impact, we show that (i) major discoveries are not preceded by works of increasing impact, nor are followed by work of higher impact, (ii) the precise time ranking of the highest impact work in a scientist's career is uniformly random, with the higher probability to have a major discovery in the middle of scientific careers being due only to changes in productivity, (iii) there is a strong correlation between the highest impact work and average impact of a scientist's work. These findings suggest that the impact of a paper is drawn randomly from an impact distribution that is unique for each scientist. We present a model which allows to reconstruct the individual impact distribution, making possible to create synthetic careers that exhibit the same properties of the real data and to define a ranking based on the overall impact of a scientist. RS acknowledges support from the James McDonnell Foundation.

  8. Stochastic, weighted hit size theory of cellular radiobiological action

    SciTech Connect

    Bond, V.P.; Varma, M.N.

    1982-01-01

    A stochastic theory that appears to account well for the observed responses of cell populations exposed in radiation fields of different qualities and for different durations of exposure is described. The theory appears to explain well most cellular radiobiological phenomena observed in at least autonomous cell systems, argues for the use of fluence rate (phi) instead of absorbed dose for quantification of the amount of radiation involved in low level radiation exposure. With or without invoking the cell sensitivity function, the conceptual improvement would be substantial. The approach suggested also shows that the absorbed dose-cell response functions currently employed do not reflect the spectrum of cell sensitivities to increasing cell doses of a single agent, nor can RBE represent the potency ratio for different agents that can produce similar quantal responses. Thus, for accurate comparison of cell sensitivities among different cells in the same individual, or between the cells in different kinds of individuals, it is necessary to quantify cell sensitivity in terms of the hit size weighting or cell sensitivity function introduced here. Similarly, this function should be employed to evaluate the relative potency of radiation and other radiomimetic chemical or physical agents.

  9. The "first hit" toward alcohol reinforcement: role of ethanol metabolites.

    PubMed

    Israel, Yedy; Quintanilla, María Elena; Karahanian, Eduardo; Rivera-Meza, Mario; Herrera-Marschitz, Mario

    2015-05-01

    This review analyzes literature that describes the behavioral effects of 2 metabolites of ethanol (EtOH): acetaldehyde and salsolinol (a condensation product of acetaldehyde and dopamine) generated in the brain. These metabolites are self-administered into specific brain areas by animals, showing strong reinforcing effects. A wealth of evidence shows that EtOH, a drug consumed to attain millimolar concentrations, generates brain metabolites that are reinforcing at micromolar and nanomolar concentrations. Salsolinol administration leads to marked increases in voluntary EtOH intake, an effect inhibited by mu-opioid receptor blockers. In animals that have ingested EtOH chronically, the maintenance of alcohol intake is no longer influenced by EtOH metabolites, as intake is taken over by other brain systems. However, after EtOH withdrawal brain acetaldehyde has a major role in promoting binge-like drinking in the condition known as the "alcohol deprivation effect"; a condition seen in animals that have ingested alcohol chronically, are deprived of EtOH for extended periods, and are allowed EtOH re-access. The review also analyzes the behavioral effects of acetate, a metabolite that enters the brain and is responsible for motor incoordination at low doses of EtOH. Also discussed are the paradoxical effects of systemic acetaldehyde. Overall, evidence strongly suggests that brain-generated EtOH metabolites play a major role in the early ("first-hit") development of alcohol reinforcement and in the generation of relapse-like drinking.

  10. The effect of fastball backspin rate on baseball hitting accuracy.

    PubMed

    Higuchi, Takatoshi; Morohoshi, Jun; Nagami, Tomoyuki; Nakata, Hiroki; Kanosue, Kazuyuki

    2013-06-01

    The effectiveness of fastballs of equivalent speed can differ; for example, one element of this difference could be due to the effect of rate and orientation of ball spin on launched ball trajectory. In the present experiment, baseball batters' accuracy in hitting fastballs with different backspin rates at a constant ball velocity of 36 m/s was examined. Thirteen skilled baseball players (professionals, semiprofessionals, and college varsity players) participated in the study. The movements of bat and ball were recorded using two synchronized high-speed video cameras. The Pearson product-moment correlation coefficient (r) was calculated and used to analyze the relationship between ball backspin rate and the vertical distance between ball center and sweet spot at the moment of ball-bat impact. Ball backspin rate was positively correlated with increases in the distance from the optimal contact point of the swung bat (sweet spot) to the actual point of contact (r = .38, P < .001). Batters were most effective at the usual backspin rate for the ball velocity used. The decrease in accuracy of the batter's swing that was observed when the fastball's backspin deviated from the usual rate likely occurred because experienced batters predict ball trajectory from perceived ball speed.

  11. Influence of Bicarbonate/Low-GDP Peritoneal Dialysis Fluid (Bicavera) on In Vitro and Ex Vivo Epithelial-to-Mesenchymal Transition of Mesothelial Cells

    PubMed Central

    Fernández–Perpén, Antonio; Pérez–Lozano, María Luisa; Bajo, María–Auxiliadora; Albar–Vizcaino, Patricia; Correa, Pilar Sandoval; del Peso, Gloria; Castro, María–José; Aguilera, Abelardo; Ossorio, Marta; Peter, Mirjam E.; Passlick–Deetjen, Jutta; Aroeira, Luiz S.; Selgas, Rafael; López–Cabrera, Manuel; Sánchez–Tomero, J. Antonio

    2012-01-01

    ♦ Background: Peritoneal membrane damage induced by peritoneal dialysis (PD) is largely associated with epithelial-to-mesenchymal transition (EMT) of mesothelial cells (MCs), which is believed to be a result mainly of the glucose degradation products (GDPs) present in PD solutions. ♦ Objectives: This study investigated the impact of bicarbonate-buffered, low-GDP PD solution (BicaVera: Fresenius Medical Care, Bad Homburg, Germany) on EMT of MCs in vitro and ex vivo. ♦ Methods: In vitro studies: Omentum-derived MCs were incubated with lactate-buffered standard PD fluid or BicaVera fluid diluted 1:1 with culture medium. Ex vivo studies: From 31 patients randomly distributed to either standard or BicaVera solution and followed for 24 months, effluents were collected every 6 months for determination of EMT markers in effluent MCs. ♦ Results: Culturing of MCs with standard fluid in vitro resulted in morphology change to a non-epithelioid shape, with downregulation of E-cadherin (indicative of EMT) and strong induction of vascular endothelial growth factor (VEGF) expression. By contrast, in vitro exposure of MCs to bicarbonate/low-GDP solution had less impact on both EMT parameters. Ex vivo studies partially confirmed the foregoing results. The BicaVera group, with a higher prevalence of the non-epithelioid MC phenotype at baseline (for unknown reasons), showed a clear and significant trend to gain and maintain an epithelioid phenotype at medium- and longer-term and to show fewer fibrogenic characteristics. By contrast, the standard solution group demonstrated a progressive and significantly higher presence of the non-epithelioid phenotype. Compared with effluent MCs having an epithelioid phenotype, MCs with non-epithelioid morphology showed significantly lower levels of E-cadherin and greater levels of fibronectin and VEGF. In comparing the BicaVera and standard solution groups, MCs from the standard solution group showed significantly higher secretion of

  12. Simulating GTP:Mg and GDP:Mg with a simple force field: a structural and thermodynamic analysis.

    PubMed

    Simonson, Thomas; Satpati, Priyadarshi

    2013-04-01

    Di- and tri-phosphate nucleotides are essential cofactors for many proteins, usually in an Mg(2+) -bound form. Proteins like GTPases often detect the difference between NDP and NTP and respond by changing conformations. To study such complexes, simple, fixed charge force fields have been used, which allow long simulations and precise free energy calculations. The preference for NTP or NDP binding depends on many factors, including ligand structure and Mg(2+) coordination and the changes they undergo upon binding. Here, we use a simple force field to examine two Mg(2+) coordination modes for the unbound GDP and GTP: direct, or "Inner Sphere" (IS) coordination by one or more phosphate oxygens and indirect, "Outer Sphere" (OS) coordination involving one or more bridging waters. We compare GTP: and GDP:Mg binding with OS and IS coordination; combining the results with experimental data then indicates that GTP prefers the latter. We also examine different kinds of IS coordination and their sensitivity to a key force field parameter: the optimal Mg:oxygen van der Waals distance Rmin . Increasing Rmin improves the Mg:oxygen distances, the GTP: and GDP:Mg binding affinities, and the fraction of GTP:Mg with β + γ phosphate coordination, but does not improve or change the GTP/GDP affinity difference, which remains much larger than experiment. It has no effect on the free energy of GDP binding to a GTPase.

  13. Cloning and expression of Helicobacter pylori GDP-l-fucose synthesizing enzymes (GMD and GMER) in Saccharomyces cerevisiae.

    PubMed

    Järvinen, N; Mäki, M; Räbinä, J; Roos, C; Mattila, P; Renkonen, R

    2001-12-01

    Helicobacter pylori is a Gram-negative gastric pathogen causing diseases from mild gastric infections to gastric cancer. The difference in clinical outcome has been suggested to be due to strain differences. H. pylori undergoes phase variation by changing its lipopolysaccharide structure according to the environmental conditions. The O-antigen of H. pylori contains fucosylated glycans, similar to Lewis structures found in human gastric epithelium. These Lewis glycans of H. pylori have been suggested to play a role in pathogenesis in the adhesion of the bacterium to gastric epithelium. In the synthesis of fucosylated structures, GDP-l-fucose is needed as a fucose donor. Here, we cloned the two key enzymes of GDP-l-fucose synthesis, H. pylori gmd coding for GDP-d-mannose dehydratase (GMD), and gmer coding for GDP-4-keto-6-deoxy-d-mannose-3,5-epimerase/4-reductase (GMER) and expressed them in an enzymatically active form in Saccharomyces cerevisiae. The end product of these enzymes, GDP-l-fucose was used as a fucose donor in a fucosyltransferase assay converting sialyl-N-acetyllactosamine to sialyl Lewis X.

  14. Being selective at the plate: processing dependence between perceptual variables relates to hitting goals and performance.

    PubMed

    Gray, Rob

    2013-08-01

    Performance of a skill that involves acting on a goal object (e.g., a ball to be hit) can influence one's judgment of the size and speed of that object. The present study examined how these action-specific effects are affected when the goal of the actor is varied and they are free to choose between alternative actions. In Experiment 1, expert baseball players were asked to perform three different directional hitting tasks in a batting simulation and make interleaved perceptual judgments about three ball parameters (speed, plate crossing location, and size). Perceived ball size was largest (and perceived speed was slowest) when the ball crossing location was optimal for the particular hitting task the batter was performing (e.g., an "outside" pitch for opposite-field hitting). The magnitude of processing dependency between variables (speed vs. location and size vs. location) was positively correlated with batting performance. In Experiment 2, the action-specific effects observed in Experiment 1 were mimicked by systematically changing the ball diameter in the simulation as a function of plate crossing location. The number of swing initiations was greater when ball size was larger, and batters were more successful in the hitting task for which the larger pitches were optimal (e.g., greater number of pull hits than opposite-field hits when "inside" pitches were larger). These findings suggest attentional accentuation of goal-relevant targets underlies action-related changes in perception and are consistent with an action selection role for these effects.

  15. An interactive environmental model for economic growth: evidence from a panel of countries.

    PubMed

    Ramakrishnan, Suresh; Hishan, Sanil S; Nabi, Agha Amad; Arshad, Zeeshan; Kanjanapathy, Malini; Zaman, Khalid; Khan, Faisal

    2016-07-01

    This study aims to determine an interactive environmental model for economic growth that would be supported by the "sustainability principles" across the globe. The study examines the relationship between environmental pollutants (i.e., carbon dioxide emission, sulfur dioxide emission, mono-nitrogen oxide, and nitrous oxide emission); population growth; energy use; trade openness; per capita food production; and it's resulting impact on the real per capita GDP and sectoral growth (i.e., share of agriculture, industry, and services in GDP) in a panel of 34 high-income OECD, high-income non-OECD, and Europe and Central Asian countries, for the period of 1995-2014. The results of the panel fixed effect regression show that per capita GDP are influenced by sulfur dioxide emission, population growth, and per capita food production variability, while energy and trade openness significantly increases per capita income of the region. The results of the panel Seemingly Unrelated Regression (SUR) show that carbon dioxide emission significantly decreases the share of agriculture and industry in GDP, while it further supports the share of services sector to GDP. Both the sulfur dioxide and mono-nitrogen oxide emission decreases the share of services in GDP; nitrous oxide decreases the share of industry in GDP; while mono-nitrogen oxide supports the industrial activities. The following key growth-specific results has been obtained from the panel SUR estimation, i.e., (i) Both the food production per capita and trade openness significantly associated with the increasing share of agriculture, (ii) food production and energy use significantly increases the service sectors' productivity; (iii) food production decreases the industrial activities; (iv) trade openness decreases the share of services to GDP while it supports the industrial share to GDP; and finally, (v) energy demand decreases along with the increase agricultural share in the region. The results emphasize the need for

  16. An interactive environmental model for economic growth: evidence from a panel of countries.

    PubMed

    Ramakrishnan, Suresh; Hishan, Sanil S; Nabi, Agha Amad; Arshad, Zeeshan; Kanjanapathy, Malini; Zaman, Khalid; Khan, Faisal

    2016-07-01

    This study aims to determine an interactive environmental model for economic growth that would be supported by the "sustainability principles" across the globe. The study examines the relationship between environmental pollutants (i.e., carbon dioxide emission, sulfur dioxide emission, mono-nitrogen oxide, and nitrous oxide emission); population growth; energy use; trade openness; per capita food production; and it's resulting impact on the real per capita GDP and sectoral growth (i.e., share of agriculture, industry, and services in GDP) in a panel of 34 high-income OECD, high-income non-OECD, and Europe and Central Asian countries, for the period of 1995-2014. The results of the panel fixed effect regression show that per capita GDP are influenced by sulfur dioxide emission, population growth, and per capita food production variability, while energy and trade openness significantly increases per capita income of the region. The results of the panel Seemingly Unrelated Regression (SUR) show that carbon dioxide emission significantly decreases the share of agriculture and industry in GDP, while it further supports the share of services sector to GDP. Both the sulfur dioxide and mono-nitrogen oxide emission decreases the share of services in GDP; nitrous oxide decreases the share of industry in GDP; while mono-nitrogen oxide supports the industrial activities. The following key growth-specific results has been obtained from the panel SUR estimation, i.e., (i) Both the food production per capita and trade openness significantly associated with the increasing share of agriculture, (ii) food production and energy use significantly increases the service sectors' productivity; (iii) food production decreases the industrial activities; (iv) trade openness decreases the share of services to GDP while it supports the industrial share to GDP; and finally, (v) energy demand decreases along with the increase agricultural share in the region. The results emphasize the need for

  17. Throat hit in users of the electronic cigarette: An exploratory study.

    PubMed

    Etter, Jean-François

    2016-02-01

    A cross-sectional survey on the Internet in 2012-2014 was used to study the "throat hit," the specific sensation in the throat felt by users of e-cigarettes. Participants were 1672 current users of e-cigarettes, visitors of Websites dedicated to e-cigarettes and to smoking cessation. It was assessed whether the strength of the throat hit was associated with the characteristics of e-cigarettes and e-liquids, modifications of the devices, patterns of use, reasons for use, satisfaction with e-cigarettes, dependence on e-cigarettes, smoking behavior, and perceived effects on smoking. The strongest throat hit was obtained by using better-quality models and liquids with high nicotine content. Those who reported a "very strong" throat hit used liquids with 17.3 mg/mL nicotine, versus 7.1 mg/mL for those reporting a "very weak" hit (p < .001). The strength of the throat hit was also associated with ratings of dependence on e-cigarettes, and with the perceived efficacy of e-cigarettes to relieve craving for tobacco and to facilitate smoking cessation. All the variables assessing satisfaction with e-cigarettes were associated with a stronger throat hit. From a public health perspective, there is a trade-off between e-cigarette models that provide high levels of nicotine, a strong throat hit, high satisfaction, and more effects on smoking, but may also be addictive, and models than contain less nicotine and are less addictive, but produce a weaker throat hit, are less satisfactory, and are possibly less efficient at helping people quit smoking. This trade-off must be kept in mind when regulating e-cigarettes. PMID:26653150

  18. Throat hit in users of the electronic cigarette: An exploratory study.

    PubMed

    Etter, Jean-François

    2016-02-01

    A cross-sectional survey on the Internet in 2012-2014 was used to study the "throat hit," the specific sensation in the throat felt by users of e-cigarettes. Participants were 1672 current users of e-cigarettes, visitors of Websites dedicated to e-cigarettes and to smoking cessation. It was assessed whether the strength of the throat hit was associated with the characteristics of e-cigarettes and e-liquids, modifications of the devices, patterns of use, reasons for use, satisfaction with e-cigarettes, dependence on e-cigarettes, smoking behavior, and perceived effects on smoking. The strongest throat hit was obtained by using better-quality models and liquids with high nicotine content. Those who reported a "very strong" throat hit used liquids with 17.3 mg/mL nicotine, versus 7.1 mg/mL for those reporting a "very weak" hit (p < .001). The strength of the throat hit was also associated with ratings of dependence on e-cigarettes, and with the perceived efficacy of e-cigarettes to relieve craving for tobacco and to facilitate smoking cessation. All the variables assessing satisfaction with e-cigarettes were associated with a stronger throat hit. From a public health perspective, there is a trade-off between e-cigarette models that provide high levels of nicotine, a strong throat hit, high satisfaction, and more effects on smoking, but may also be addictive, and models than contain less nicotine and are less addictive, but produce a weaker throat hit, are less satisfactory, and are possibly less efficient at helping people quit smoking. This trade-off must be kept in mind when regulating e-cigarettes.

  19. Current challenges and novel treatment strategies in double hit lymphomas

    PubMed Central

    Anderson, Mary Ann; Tsui, Alpha; Wall, Meaghan; Huang, David C. S.; Roberts, Andrew W.

    2016-01-01

    High-grade B-cell lymphomas with recurrent chromosomal break points have been termed ‘double hit lymphoma’ (DHL). The most commonly seen DHL is diffuse large B-cell lymphoma (DLBCL) with t(14;18) and t(8;14) or t(8;22) resulting in overexpression of BCL2 and MYC, respectively. The increased proliferation due to MYC overexpression, without the ability for an apoptotic brake as a result of BCL2 overexpression, results in ‘the perfect storm of oncogenesis’. Thus this disease presents a number of diagnostic and therapeutic challenges for the hematologist. The first and foremost challenge is to recognize the DHL. As different morphological entities can be affected it is incumbent on pathologists and clinicians to maintain a high index of suspicion especially in disease that appears unusually aggressive or refractory to therapy. Diagnosis by fluorescence in situ hybridization (FISH) is a sensitive and specific method for detection of the disease but is time-consuming and expensive. While detection by immunohistochemistry (IHC) is sensitive and correlates with survival, standardized methods for this are not widely agreed upon. The second and equally important challenge in DHL is optimizing clinical outcome in a group of patients for whom the prognosis is widely regarded as poor. While improvements have been achieved by dose escalating standard chemotherapeutic regimens, many patients continue to do badly. Furthermore as a disease of aging many patients are unsuitable for dose-intensive chemotherapy regimens. There are now multiple novel targeted agents in various stages of clinical development that offer hope for better outcomes without undue toxicity. Among the most exciting of these developments include specific inhibitors of both BCL2 and MYC. PMID:26834954

  20. Double hit lymphoma: the MD Anderson Cancer Center clinical experience.

    PubMed

    Oki, Yasuhiro; Noorani, Mansoor; Lin, Pei; Davis, Richard E; Neelapu, Sattva S; Ma, Long; Ahmed, Mohamed; Rodriguez, Maria Alma; Hagemeister, Fredrick B; Fowler, Nathan; Wang, Michael; Fanale, Michelle A; Nastoupil, Loretta; Samaniego, Felipe; Lee, Hun J; Dabaja, Bouthaina S; Pinnix, Chelsea C; Medeiros, Leonard J; Nieto, Yago; Khouri, Issa; Kwak, Larry W; Turturro, Francesco; Romaguera, Jorge E; Fayad, Luis E; Westin, Jason R

    2014-09-01

    We report our experience with 129 cases of double hit lymphoma (DHL), defined as B-cell lymphoma with translocations and/or extra signals involving MYC plus BCL2 and/or BCL6. All cases were reviewed for histopathological classification. Median age was 62 years (range, 18-85), 84% of patients had advanced-stage disease, and 87% had an International Prognostic Index score ≥2. Fourteen patients (11%) had a history of low-grade follicular lymphoma. MYC translocation was present in 81%, and extra signals of MYC in 25% of patients. IGH-BCL2 translocation was present in 84% and extra signals of BCL2 in 12% of patients. Two-year event-free survival (EFS) rates in all patients and patients who received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), R-EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin), and R-HyperCVAD/MA (rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, alternating with cytarabine plus methotrexate) were 33%, 25%, 67% and 32%, respectively. In patients achieving complete response with initial therapy (n = 71), 2-year EFS rates in patients who did (n = 23) or did not (n = 48) receive frontline stem cell transplantation were 68% and 53%, respectively (P = 0·155). The cumulative incidence of central nervous system involvement was 13% at 3 years. Multivariate analysis identified performance status ≥2 and bone marrow involvement as independent adverse prognostic factors for EFS and OS. Further research is needed to identify predictive and/or targetable biological markers and novel therapeutic approaches for DHL patients.

  1. Statistical Analysis of Probability of Detection Hit/Miss Data for Small Data Sets

    NASA Astrophysics Data System (ADS)

    Harding, C. A.; Hugo, G. R.

    2003-03-01

    This paper examines the validity of statistical methods for determining nondestructive inspection probability of detection (POD) curves from relatively small hit/miss POD data sets. One method published in the literature is shown to be invalid for analysis of POD hit/miss data. Another standard method is shown to be valid only for data sets containing more than 200 observations. An improved method is proposed which allows robust lower 95% confidence limit POD curves to be determined from data sets containing as few as 50 hit/miss observations.

  2. Efficiency of hit generation and structural characterization in fragment-based ligand discovery.

    PubMed

    Larsson, Andreas; Jansson, Anna; Åberg, Anders; Nordlund, Pär

    2011-08-01

    Fragment-based ligand discovery constitutes a useful strategy for the generation of high affinity ligands with suitable physico-chemical properties to serve as drug leads. There is an increasing number of generic biophysical screening strategies established with the potential for accelerating the generation of useful fragment hits. Crystal structures of these hits can subsequently be used as starting points for fragment evolution to high affinity ligands. Emerging understanding of the efficiency and operative aspects of hit generation and structural characterization in FBLD suggests that this method should be well suited for academic ligand development of chemical tools and experimental therapeutics.

  3. Crystal structure of the GTPase domain and the bundle signalling element of dynamin in the GDP state.

    PubMed

    Anand, Roopsee; Eschenburg, Susanne; Reubold, Thomas F

    2016-01-01

    Dynamin is the prototype of a family of large multi-domain GTPases. The 100 kDa protein is a key player in clathrin-mediated endocytosis, where it cleaves off vesicles from membranes using the energy from GTP hydrolysis. We have solved the high resolution crystal structure of a fusion protein of the GTPase domain and the bundle signalling element (BSE) of dynamin 1 liganded with GDP. The structure provides a hitherto missing snapshot of the GDP state of the hydrolytic cycle of dynamin and reveals how the switch I region moves away from the active site after GTP hydrolysis and release of inorganic phosphate. Comparing our structure of the GDP state with the known structures of the GTP state, the transition state and the nucleotide-free state of dynamin 1 we describe the structural changes through the hydrolytic cycle.

  4. Detection of UCP1 protein and measurements of dependent GDP-sensitive proton leak in non-phosphorylating thymus mitochondria.

    PubMed

    Clarke, Kieran J; Carroll, Audrey M; O'Brien, Gemma; Porter, Richard K

    2015-01-01

    Over several years we have provided evidence that uncoupling protein 1 (UCP1) is present in thymus mitochondria. We have demonstrated the conclusive evidence for the presence of UCP1 in thymus mitochondria and we have been able to demonstrate a GDP-sensitive UCP1-dependent proton leak in non-phosphorylating thymus mitochondria. In this chapter, we show how to detect UCP1 in mitochondria isolated from whole thymus using immunoblotting. We show how to measure GDP-sensitive UCP1-dependent oxygen consumption in non-phosphorylating thymus mitochondria and we show that increased reactive oxygen species production occurs on addition of GDP to non-phosphorylating thymus mitochondria. We conclude that reactive oxygen species production rate can be used as a surrogate for detecting UCP1 catalyzed proton leak activity in thymus mitochondria.

  5. Testing the relationships between energy consumption, CO2 emissions, and economic growth in 24 African countries: a panel ARDL approach.

    PubMed

    Asongu, Simplice; El Montasser, Ghassen; Toumi, Hassen

    2016-04-01

    This study complements existing literature by examining the nexus between energy consumption (EC), CO2 emissions (CE), and economic growth (GDP; gross domestic product) in 24 African countries using a panel autoregressive distributed lag (ARDL) approach. The following findings are established. First, there is a long-run relationship between EC, CE, and GDP. Second, a long-term effect from CE to GDP and EC is apparent, with reciprocal paths. Third, the error correction mechanisms are consistently stable. However, in cases of disequilibrium, only EC can be significantly adjusted to its long-run relationship. Fourth, there is a long-run causality running from GDP and CE to EC. Fifth, we find causality running from either CE or both CE and EC to GDP, and inverse causal paths are observable. Causality from EC to GDP is not strong, which supports the conservative hypothesis. Sixth, the causal direction from EC to GDP remains unobservable in the short term. By contrast, the opposite path is observable. There are also no short-run causalities from GDP, or EC, or EC, and GDP to EC. Policy implications are discussed.

  6. Structural basis of GDP release and gating in G protein coupled Fe[superscript 2+] transport

    SciTech Connect

    Guilfoyle, Amy; Maher, Megan J.; Rapp, Mikaela; Clarke, Ronald; Harrop, Stephen; Jormakka, Mika

    2009-09-29

    G proteins are key molecular switches in the regulation of membrane protein function and signal transduction. The prokaryotic membrane protein FeoB is involved in G protein coupled Fe{sup 2+} transport, and is unique in that the G protein is directly tethered to the membrane domain. Here, we report the structure of the soluble domain of FeoB, including the G protein domain, and its assembly into an unexpected trimer. Comparisons between nucleotide free and liganded structures reveal the closed and open state of a central cytoplasmic pore, respectively. In addition, these data provide the first observation of a conformational switch in the nucleotide-binding G5 motif, defining the structural basis for GDP release. From these results, structural parallels are drawn to eukaryotic G protein coupled membrane processes.

  7. Interaction of Anesthetics with the Rho GTPase Regulator Rho GDP Dissociation Inhibitor†

    PubMed Central

    Ho, Cojen; Shanmugasundararaj, Sivananthaperumal; Miller, Keith W.; Malinowski, Steve A.; Cook, Anthony C.; Slater, Simon J.

    2015-01-01

    The physiological effects of anesthetics have been ascribed to their interaction with hydrophobic sites within functionally relevant CNS proteins. Studies have shown that volatile anesthetics compete for luciferin binding to the hydrophobic substrate binding site within firefly luciferase and inhibit its activity (Franks, N. P., and Lieb, W. R. (1984) Nature 310, 599–601). To assess whether anesthetics also compete for ligand binding to a mammalian signal transduction protein, we investigated the interaction of the volatile anesthetic, halothane, with the Rho GDP dissociation inhibitor (RhoGDIα), which binds the geranylgeranyl moiety of GDP-bound Rho GTPases. Consistent with the existence of a discrete halothane binding site, the intrinsic tryptophan fluorescence of RhoGDIα was quenched by halothane (2-bromo-2-chloro-1,1,1-trifluoroethane) in a saturable, concentration-dependent manner. Bromine quenching of tryptophan fluorescence is short range and W192 and W194 of the RhoGDIα are located within the geranylgeranyl binding pocket, suggesting that halothane binds within this region. Supporting this, N-acetyl-geranylgeranyl cysteine reversed tryptophan quenching by halothane. Short chain n-alcohols (n<6) also reversed tryptophan quenching, suggesting that RhoGDIα may also bind n-alkanols. Consistent with this, E193 was photo-labeled by 3-azibutanol. This residue is located in the vicinity of, but outside, the geranylgeranyl chain binding pocket, suggesting that the alcohol binding site is distinct from that occupied by halothane. Supporting this, N-acetyl-geranylgeranyl cysteine enhanced E193 photo-labeling by 3-azibutanol. Overall, the results suggest that halothane binds to a site within the geranylgeranyl chain binding pocket of RhoGDIα, whereas alcohols bind to a distal site that interacts allosterically with this pocket. PMID:18702520

  8. Relating traffic fatalities to GDP in Europe on the long term.

    PubMed

    Antoniou, Constantinos; Yannis, George; Papadimitriou, Eleonora; Lassarre, Sylvain

    2016-07-01

    Modeling road safety development can provide important insight into policies for the reduction of traffic fatalities. In order to achieve this goal, both the quantifiable impact of specific parameters, as well as the underlying trends that cannot always be measured or observed, need to be considered. One of the key relationships in road safety links fatalities with risk and exposure, where exposure reflects the amount of travel, which in turn translates to how much travelers are exposed to risk. In general two economic variables: GDP and unemployment rate are selected to analyse the statistical relationships with some indicators of road accident fatality risk. The objective of this research is to provide an overview of relevant literature on the topic and outline some recent developments in macro-panel data analysis that have resulted in ongoing research that has the potential to improve our ability to forecast traffic fatality trends, especially under turbulent financial situations. For this analysis, time series of the number of fatalities and GDP in 30 European countries for a period of 38 years (1975-2012) are used. This process relies on estimating long-term models (as captured by long term time-series models, which model each country separately). Based on these developments, utilizing state-of-the-art modelling and analysis techniques such as the Common Correlated Effects Mean Group estimator (Pesaran), the long-term elasticity mean value equals 0.63, and is significantly different from zero for 10 countries only. When we take away the countries, where the number of fatalities is stationary, the average elasticity takes a higher value of nearly 1. This shows the strong sensitivity of the estimate of the average elasticity over a panel of European countries and underlines the necessity to be aware of the underlying nature of the time series, to get a suitable regression model. PMID:27042989

  9. Relating traffic fatalities to GDP in Europe on the long term.

    PubMed

    Antoniou, Constantinos; Yannis, George; Papadimitriou, Eleonora; Lassarre, Sylvain

    2016-07-01

    Modeling road safety development can provide important insight into policies for the reduction of traffic fatalities. In order to achieve this goal, both the quantifiable impact of specific parameters, as well as the underlying trends that cannot always be measured or observed, need to be considered. One of the key relationships in road safety links fatalities with risk and exposure, where exposure reflects the amount of travel, which in turn translates to how much travelers are exposed to risk. In general two economic variables: GDP and unemployment rate are selected to analyse the statistical relationships with some indicators of road accident fatality risk. The objective of this research is to provide an overview of relevant literature on the topic and outline some recent developments in macro-panel data analysis that have resulted in ongoing research that has the potential to improve our ability to forecast traffic fatality trends, especially under turbulent financial situations. For this analysis, time series of the number of fatalities and GDP in 30 European countries for a period of 38 years (1975-2012) are used. This process relies on estimating long-term models (as captured by long term time-series models, which model each country separately). Based on these developments, utilizing state-of-the-art modelling and analysis techniques such as the Common Correlated Effects Mean Group estimator (Pesaran), the long-term elasticity mean value equals 0.63, and is significantly different from zero for 10 countries only. When we take away the countries, where the number of fatalities is stationary, the average elasticity takes a higher value of nearly 1. This shows the strong sensitivity of the estimate of the average elasticity over a panel of European countries and underlines the necessity to be aware of the underlying nature of the time series, to get a suitable regression model.

  10. Superoxide activates a GDP-sensitive proton conductance in skeletal muscle mitochondria from king penguin (Aptenodytes patagonicus).

    PubMed

    Talbot, Darren A; Hanuise, Nicolas; Rey, Benjamin; Rouanet, Jean-Louis; Duchamp, Claude; Brand, Martin D

    2003-12-26

    We present the partial nucleotide sequence of the avian uncoupling protein (avUCP) gene from king penguin (Aptenodytes patagonicus), showing that the protein is 88-92% identical to chicken (Gallus gallus), turkey (Meleagris gallopavo), and hummingbird (Eupetomena macroura). We show that superoxide activates the proton conductance of mitochondria isolated from king penguin skeletal muscle. GDP abolishes the superoxide-activated proton conductance, indicating that it is mediated via avUCP. In the absence of superoxide there is no GDP-sensitive component of the proton conductance from penguin muscle mitochondria demonstrating that avUCP plays no role in the basal proton leak. PMID:14651968

  11. Screening a Small Library of Xanthones for Antitumor Activity and Identification of a Hit Compound which Induces Apoptosis.

    PubMed

    Barbosa, João; Lima, Raquel T; Sousa, Diana; Gomes, Ana Sara; Palmeira, Andreia; Seca, Hugo; Choosang, Kantima; Pakkong, Pannee; Bousbaa, Hassan; Pinto, Madalena M; Sousa, Emília; Vasconcelos, M Helena; Pedro, Madalena

    2016-01-13

    Our previous work has described a library of thioxanthones designed to have dual activity as P-glycoprotein modulators and antitumor agents. Some of these compounds had shown a significant cell growth inhibitory activity towards leukemia cell lines, without affecting the growth of non-tumor human fibroblasts. However, their effect in cell lines derived from solid tumors has not been previously studied. The present work aimed at: (i) screening this small series of compounds from an in-house library, for their in vitro cell growth inhibitory activity in human tumor cell lines derived from solid tumors; and (ii) initiate a study of the effect of the most potent compound on apoptosis. The tumor cell growth inhibitory effect of 27 compounds was first analysed in different human tumor cell lines, allowing the identification of a hit compound, TXA1. Its hydrochloride salt TXA1·HCl was then synthesized, to improve solubility and bioavailability. Both TXA1 and TXA1·HCl inhibited the growth of MCF-7, NCI-H460, A375-C5, HeLa, 786-O, Caki-2 and AGS cell lines. The effect of TXA1·HCl in MCF-7 cells was found to be irreversible and was associated, at least in part, with an increase in cellular apoptosis.

  12. Screening a Small Library of Xanthones for Antitumor Activity and Identification of a Hit Compound which Induces Apoptosis.

    PubMed

    Barbosa, João; Lima, Raquel T; Sousa, Diana; Gomes, Ana Sara; Palmeira, Andreia; Seca, Hugo; Choosang, Kantima; Pakkong, Pannee; Bousbaa, Hassan; Pinto, Madalena M; Sousa, Emília; Vasconcelos, M Helena; Pedro, Madalena

    2016-01-01

    Our previous work has described a library of thioxanthones designed to have dual activity as P-glycoprotein modulators and antitumor agents. Some of these compounds had shown a significant cell growth inhibitory activity towards leukemia cell lines, without affecting the growth of non-tumor human fibroblasts. However, their effect in cell lines derived from solid tumors has not been previously studied. The present work aimed at: (i) screening this small series of compounds from an in-house library, for their in vitro cell growth inhibitory activity in human tumor cell lines derived from solid tumors; and (ii) initiate a study of the effect of the most potent compound on apoptosis. The tumor cell growth inhibitory effect of 27 compounds was first analysed in different human tumor cell lines, allowing the identification of a hit compound, TXA1. Its hydrochloride salt TXA1·HCl was then synthesized, to improve solubility and bioavailability. Both TXA1 and TXA1·HCl inhibited the growth of MCF-7, NCI-H460, A375-C5, HeLa, 786-O, Caki-2 and AGS cell lines. The effect of TXA1·HCl in MCF-7 cells was found to be irreversible and was associated, at least in part, with an increase in cellular apoptosis. PMID:26771595

  13. 75 FR 33811 - Office of the National Coordinator for Health Information Technology; HIT Policy Committee's...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-06-15

    ... Policy Committee's Privacy & Security Tiger Team. General Function of the Committee: To provide... HUMAN SERVICES Office of the National Coordinator for Health Information Technology; HIT Policy Committee's Privacy & Security Tiger Team Meeting; Notice of Meeting AGENCY: Office of the...

  14. A functional modulation for timing a movement: a coordinative structure in baseball hitting.

    PubMed

    Katsumata, Hiromu

    2007-02-01

    In baseball hitting, a powerful bat-swing needs to be produced by utilizing ground reaction force (GRF) and it should also be temporally coordinated relative to the flight of the pitch. The temporal organization of hitting movements associated with these task requirements was investigated by analyzing GRF during hitting slow and fast pitches. The timing of stepping with a front foot and shifting weight forward was modulated relative to the pitch's speed. The temporal relation between successive motion phases was compensatory and timing variability progressively reduced up to ball-bat contact. These results demonstrated the coordinative structure of the hitting movement for timing the bat-swing relative to the pitch's flight. PMID:17204344

  15. 76 FR 28784 - HIT Standards Committee's Workgroup Meetings; Notice of Meetings

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-05-18

    ... access only. Name of Committees: HIT Standards Committee's Workgroups: Clinical Operations, Vocabulary... Standards Committee Workgroups will hold the following public meetings during June 2011: June 1st Vocabulary... specific subject matter, e.g., clinical operations vocabulary standards, clinical quality,...

  16. 76 FR 39107 - HIT Standards Committee's Workgroup Meetings; Notice of Meetings

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-07-05

    ... access only. Name of Committees: HIT Standards Committee's Workgroups: Clinical Operations, Vocabulary... Standards Committee Workgroups will hold the following public meetings during July 2011: July 8th Vocabulary... specific subject matter, e.g., clinical operations vocabulary standards, clinical quality,...

  17. 76 FR 22398 - HIT Standards Committee's Workgroup Meetings; Notice of Meetings

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-04-21

    ... access only. Name of Committees: HIT Standards Committee's Workgroups: Clinical Operations, Vocabulary... Standards Committee Workgroups will hold the following public meetings during May 2011: May 5th Vocabulary... specific subject matter, e.g., clinical operations vocabulary standards, clinical quality,...

  18. 76 FR 9784 - Office of the National Coordinator for Health Information Technology; HIT Policy Committee...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-02-22

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF HEALTH AND HUMAN SERVICES Office of the National Coordinator for Health Information Technology; HIT Policy Committee Advisory Meeting; Notice of Meeting AGENCY: Office of the National Coordinator for...

  19. 75 FR 5595 - Office of the National Coordinator for Health Information Technology; HIT Policy Committee...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-02-03

    ... the development and adoption of a nationwide health information technology infrastructure that permits... HUMAN SERVICES Office of the National Coordinator for Health Information Technology; HIT Policy... Information Technology, HHS. ACTION: Notice of meeting. This notice announces a forthcoming meeting of...

  20. 75 FR 16126 - Office of the National Coordinator for Health Information Technology; HIT Policy Committee...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-03-31

    ... the development and adoption of a nationwide health information technology infrastructure that permits... HUMAN SERVICES Office of the National Coordinator for Health Information Technology; HIT Policy... Information Technology, HHS. ACTION: Notice of meeting. This notice announces a forthcoming meeting of...

  1. 75 FR 151 - Office of the National Coordinator for Health Information Technology; HIT Policy Committee...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-01-04

    ... the development and adoption of a nationwide health information technology infrastructure that permits... HUMAN SERVICES Office of the National Coordinator for Health Information Technology; HIT Policy... Information Technology, HHS. ACTION: Notice of meeting. This notice announces a forthcoming meeting of...

  2. 75 FR 6398 - Office of the National Coordinator for Health Information Technology; HIT Policy Committee's...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-02-09

    ... HUMAN SERVICES Office of the National Coordinator for Health Information Technology; HIT Policy Committee's Adoption/Certification Workgroup Meeting; Notice of Meeting AGENCY: Office of the National Coordinator for Health Information Technology, HHS. ACTION: Notice of meeting. This notice announces...

  3. A functional modulation for timing a movement: a coordinative structure in baseball hitting.

    PubMed

    Katsumata, Hiromu

    2007-02-01

    In baseball hitting, a powerful bat-swing needs to be produced by utilizing ground reaction force (GRF) and it should also be temporally coordinated relative to the flight of the pitch. The temporal organization of hitting movements associated with these task requirements was investigated by analyzing GRF during hitting slow and fast pitches. The timing of stepping with a front foot and shifting weight forward was modulated relative to the pitch's speed. The temporal relation between successive motion phases was compensatory and timing variability progressively reduced up to ball-bat contact. These results demonstrated the coordinative structure of the hitting movement for timing the bat-swing relative to the pitch's flight.

  4. 75 FR 369 - Office of the National Coordinator for Health Information Technology; HIT Policy Committee's...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-01-05

    ... HUMAN SERVICES Office of the National Coordinator for Health Information Technology; HIT Policy... Information Technology, HHS. ACTION: Notice of meetings. This notice announces forthcoming subcommittee meetings of a federal advisory committee of the Office of the National Coordinator for Health...

  5. 75 FR 3906 - Office of the National Coordinator for Health Information Technology; HIT Policy Committee's...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-01-25

    ... HUMAN SERVICES Office of the National Coordinator for Health Information Technology; HIT Policy... Information Technology, HHS. ACTION: Notice of meetings. This notice announces forthcoming subcommittee meetings of a federal advisory committee of the Office of the National Coordinator for Health...

  6. 75 FR 12752 - Office of the National Coordinator for Health Information Technology; HIT Policy Committee's...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-03-17

    ... HUMAN SERVICES Office of the National Coordinator for Health Information Technology; HIT Policy... Information Technology, HHS. ACTION: Notice of Meetings. This notice announces forthcoming subcommittee meetings of a Federal advisory committee of the Office of the National Coordinator for Health...

  7. 75 FR 8078 - Office of the National Coordinator for Health Information Technology; HIT Policy Committee's...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-02-23

    ... HUMAN SERVICES Office of the National Coordinator for Health Information Technology; HIT Policy... Information Technology, HHS. ACTION: Notice of meetings. This notice announces forthcoming subcommittee meetings of a Federal advisory committee of the Office of the National Coordinator for Health...

  8. 76 FR 1432 - Office of the National Coordinator for Health Information Technology; HIT Policy Committee's...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-10

    ... HUMAN SERVICES Office of the National Coordinator for Health Information Technology; HIT Policy... Information Technology, HHS. ACTION: Notice of meetings. This notice announces forthcoming subcommittee meetings of a Federal advisory committee of the Office of the National Coordinator for Health...

  9. 75 FR 51819 - Office of the National Coordinator for Health Information Technology; HIT Policy Committee's...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-08-23

    ... HUMAN SERVICES Office of the National Coordinator for Health Information Technology; HIT Policy... Information Technology, HHS. ACTION: Notice of meetings. This notice announces forthcoming subcommittee meetings of a Federal advisory committee of the Office of the National Coordinator for Health...

  10. 75 FR 21630 - Office of the National Coordinator for Health Information Technology; HIT Policy Committee's...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-04-26

    ... HUMAN SERVICES Office of the National Coordinator for Health Information Technology; HIT Policy... Information Technology, HHS. ACTION: Notice of meetings. This notice announces forthcoming subcommittee meetings of a Federal advisory committee of the Office of the National Coordinator for Health...

  11. Economic growth and obesity: an interesting relationship with world-wide implications.

    PubMed

    Egger, Garry; Swinburn, Boyd; Islam, F M Amirul

    2012-03-01

    The prosperity of a country, commonly measured in terms of its annual per capita Gross Domestic Product (GDP), has different relationships with population levels of body weight and happiness, as well as environmental impacts such as carbon emissions. The aim of this study was to examine these relationships and to try to find a level of GDP, which provides for sustainable economic activity, optimal happiness and healthy levels of mean body mass index (BMI). Spline regression analyses were conducted using national indices from 175 countries: GDP, adult BMI, mean happiness scores, and carbon footprint per capita for the year 2007. Results showed that GDP was positively related to BMI and happiness up to ∼$US3000 and ∼$5000 per capita respectively, with no significant relationships beyond these levels. GDP was also positively related to CO(2) emissions with a recognised sustainable carbon footprint of less than 5 tonnes per capita occurring at a GDP of <$US15,000. These findings show that a GDP between $US5 and $15,000 is associated with greater population happiness and environmental stability. A mean BMI of 21-23 kg/m(2), which minimises the prevalence of underweight and overweight in the population then helps to define an ideal position in relation to growth, which few countries appear to have obtained. Within a group of wealthy countries (GDP>$US30,000), those with lower income inequalities and more regulated (less liberal) market systems had lower mean BMIs.

  12. [Heparin-induced thrombocytopenia (HIT). Importance for anesthesia and intensive care].

    PubMed

    Kleinschmidt, S; Seyfert, U T

    1999-11-01

    For many decades, heparins have been used successfully for prophylaxis and treatment of thromboembolic complications world-wide. Although heparin-induced thrombocytopenia (HIT Type II) is a well-known adverse effect of heparin therapy, thromboembolic complications during heparin therapy are rarely diagnosed exactly to be related to HIT. At present an immunologic etiology of HIT by generation of multimodal immune complexes against a neo antigen of heparin and platelet factor 4 is equivocally accepted. The incidence of HIT seems to be related to the type of heparin (unfractioned/low molecular weight) or other underlying risks such as peripheral occlusive vessel disease. Mortality and complications resulting from HIT is reported to be about 20-30% each. For diagnosis of HIT Type II, clinical observation and simultaneous laboratory testing are essential. Discontinuation of heparin is a simple and essential manoeuvre, and anticoagulation has to be continued by alternative drugs. The heparinoid danaparoid-sodium and the thrombin inhibitor recombinant hirudin have been used successfully world-wide for treatment in many patients with HIT Type II including cardiopulmonary bypass surgery or renal replacement procedures. Furthermore, other therapeutical alternatives (e.g. immunoglobulins, prostaglandines) exist. Randomised controlled studies have to evaluate which drug has to be preferred in the future including risk/benefit ratio. The need of supplementary surgical procedures (e.g. embolectomy) depends on the individual clinical status. The patients have to be informed in detail about their underlying disease and further deleterious consequences of re-exposition with heparin. HIT should be recorded in an emergency certificate and the national Committee on Drugs should be informed about this severe side effect of heparin therapy.

  13. USER FRUSTRATION IN HIT INTERFACES: EXPLORING PAST HCI RESEARCH FOR A BETTER UNDERSTANDING OF CLINICIANS’ EXPERIENCES

    PubMed Central

    Opoku-Boateng, Gloria A.

    2015-01-01

    User frustration research has been one way of looking into clinicians’ experience with health information technology use and interaction. In order to understand how clinician frustration with Health Information Technology (HIT) use occurs, there is the need to explore Human-Computer Interaction (HCI) literature that addresses both frustration and HIT use. In the past three decades, HCI frustration research has increased and expanded. Researchers have done a lot of work to understand emotions, end-user frustration and affect. This paper uses a historical literature review approach to review the origins of emotion and frustration research and explore the research question; Does HCI research on frustration provide insights on clinicians’ frustration with HIT interfaces? From the literature review HCI research on emotion and frustration provides additional insights that can indeed help explain user frustration in HIT. Different approaches and HCI perspectives also help frame HIT user frustration research as well as inform HIT system design. The paper concludes with a suggested directions on how future design and research may take. PMID:26958238

  14. USER FRUSTRATION IN HIT INTERFACES: EXPLORING PAST HCI RESEARCH FOR A BETTER UNDERSTANDING OF CLINICIANS' EXPERIENCES.

    PubMed

    Opoku-Boateng, Gloria A

    2015-01-01

    User frustration research has been one way of looking into clinicians' experience with health information technology use and interaction. In order to understand how clinician frustration with Health Information Technology (HIT) use occurs, there is the need to explore Human-Computer Interaction (HCI) literature that addresses both frustration and HIT use. In the past three decades, HCI frustration research has increased and expanded. Researchers have done a lot of work to understand emotions, end-user frustration and affect. This paper uses a historical literature review approach to review the origins of emotion and frustration research and explore the research question; Does HCI research on frustration provide insights on clinicians' frustration with HIT interfaces? From the literature review HCI research on emotion and frustration provides additional insights that can indeed help explain user frustration in HIT. Different approaches and HCI perspectives also help frame HIT user frustration research as well as inform HIT system design. The paper concludes with a suggested directions on how future design and research may take.

  15. On the accuracy of the Head Impact Telemetry (HIT) System used in football helmets.

    PubMed

    Jadischke, Ron; Viano, David C; Dau, Nathan; King, Albert I; McCarthy, Joe

    2013-09-01

    On-field measurement of head impacts has relied on the Head Impact Telemetry (HIT) System, which uses helmet mounted accelerometers to determine linear and angular head accelerations. HIT is used in youth and collegiate football to assess the frequency and severity of helmet impacts. This paper evaluates the accuracy of HIT for individual head impacts. Most HIT validations used a medium helmet on a Hybrid III head. However, the appropriate helmet is large based on the Hybrid III head circumference (58 cm) and manufacturer's fitting instructions. An instrumented skull cap was used to measure the pressure between the head of football players (n=63) and their helmet. The average pressure with a large helmet on the Hybrid III was comparable to the average pressure from helmets used by players. A medium helmet on the Hybrid III produced average pressures greater than the 99th percentile volunteer pressure level. Linear impactor tests were conducted using a large and medium helmet on the Hybrid III. Testing was conducted by two independent laboratories. HIT data were compared to data from the Hybrid III equipped with a 3-2-2-2 accelerometer array. The absolute and root mean square error (RMSE) for HIT were computed for each impact (n=90). Fifty-five percent (n=49) had an absolute error greater than 15% while the RMSE was 59.1% for peak linear acceleration.

  16. Are stripes beneficial? Dazzle camouflage influences perceived speed and hit rates.

    PubMed

    von Helversen, Bettina; Schooler, Lael J; Czienskowski, Uwe

    2013-01-01

    In the animal kingdom, camouflage refers to patterns that help potential prey avoid detection. Mostly camouflage is thought of as helping prey blend in with their background. In contrast, disruptive or dazzle patterns protect moving targets and have been suggested as an evolutionary force in shaping the dorsal patterns of animals. Dazzle patterns, such as stripes and zigzags, are thought to reduce the probability with which moving prey will be captured by impairing predators' perception of speed. We investigated how different patterns of stripes (longitudinal-i.e., parallel to movement direction-and vertical-i.e., perpendicular to movement direction) affect the probability with which humans can hit moving objects and if differences in hitting probability are caused by a misperception of speed. A first experiment showed that longitudinally striped objects were hit more often than unicolored objects. However, vertically striped objects did not differ from unicolored objects. A second study examining the link between perceived speed and hitting probability showed that longitudinally and vertically striped objects were both perceived as moving faster and were hit more often than unicolored objects. In sum, our results provide evidence that striped patterns disrupt the perception of speed, which in turn influences how often objects are hit. However, the magnitude and the direction of the effects depend on additional factors such as speed and the task setup. PMID:23637795

  17. A novel GDP-D-glucose phosphorylase involved in quality control of the nucleoside diphosphate sugar pool in Caenorhabditis elegans and mammals.

    PubMed

    Adler, Lital N; Gomez, Tara A; Clarke, Steven G; Linster, Carole L

    2011-06-17

    The plant VTC2 gene encodes GDP-L-galactose phosphorylase, a rate-limiting enzyme in plant vitamin C biosynthesis. Genes encoding apparent orthologs of VTC2 exist in both mammals, which produce vitamin C by a distinct metabolic pathway, and in the nematode worm Caenorhabditis elegans where vitamin C biosynthesis has not been demonstrated. We have now expressed cDNAs of the human and worm VTC2 homolog genes (C15orf58 and C10F3.4, respectively) and found that the purified proteins also display GDP-hexose phosphorylase activity. However, as opposed to the plant enzyme, the major reaction catalyzed by these enzymes is the phosphorolysis of GDP-D-glucose to GDP and D-glucose 1-phosphate. We detected activities with similar substrate specificity in worm and mouse tissue extracts. The highest expression of GDP-D-glucose phosphorylase was found in the nervous and male reproductive systems. A C. elegans C10F3.4 deletion strain was found to totally lack GDP-D-glucose phosphorylase activity; this activity was also found to be decreased in human HEK293T cells transfected with siRNAs against the human C15orf58 gene. These observations confirm the identification of the worm C10F3.4 and the human C15orf58 gene expression products as the GDP-D-glucose phosphorylases of these organisms. Significantly, we found an accumulation of GDP-D-glucose in the C10F3.4 mutant worms, suggesting that the GDP-D-glucose phosphorylase may function to remove GDP-D-glucose formed by GDP-D-mannose pyrophosphorylase, an enzyme that has previously been shown to lack specificity for its physiological D-mannose 1-phosphate substrate. We propose that such removal may prevent the misincorporation of glucosyl residues for mannosyl residues into the glycoconjugates of worms and mammals.

  18. Book Review: "The Road to Sustainability, GDP and Future Generations" Pulselli et al, WIT Press, Southhampton, UK 197p 2008

    EPA Science Inventory

    “The Road to Sustainability, GDP and future generations” by Pulselli, F.M., Bastianoni, S., Marchettini, N. Tiezzi, E. was reviewed upon request by the journal’s editor. Briefly, this book presents the authors’ perspective on the complex and important topic of sustainability. Su...

  19. Structure of Gαi1 bound to a GDP-selective peptide provides insight into guanine nucleotide exchange

    PubMed Central

    Johnston, Christopher A.; Willard, Francis S.; Jezyk, Mark R.; Fredericks, Zoey; Bodor, Erik T.; Jones, Miller B.; Blaesius, Rainer; Watts, Val J.; Harden, T. Kendall; Sondek, John; Ramer, J. Kevin; Siderovski, David P.

    2005-01-01

    Heterotrimeric G-proteins are molecular switches that regulate numerous signaling pathways involved in cellular physiology. This characteristic is achieved by the adoption of two principal states: an inactive, GDP-bound and an active, GTP-bound state. Under basal conditions G-proteins exist in the inactive GDP-bound state, thus nucleotide exchange is crucial to the onset of signaling. Despite our understanding of G-protein signaling pathways, the mechanism of nucleotide exchange remains elusive. We employed phage display technology to identify nucleotide-state-dependent Gα binding peptides. Herein, we report a GDP-selective Gα-binding peptide, KB-752, that enhances spontaneous nucleotide exchange of Gαi subunits. Structural determination of the Gαi1/peptide complex reveals unique changes in the Gα switch regions predicted to enhance nucleotide exchange by creating a GDP dissociation route. Our results cast light onto a potential mechanism by which Gα subunits adopt a conformation suitable for nucleotide exchange. PMID:16004878

  20. Interconversion of two GDP-bound conformations and their selection in an Arf-family small G protein.

    PubMed

    Okamura, Hideyasu; Nishikiori, Masaki; Xiang, Hongyu; Ishikawa, Masayuki; Katoh, Etsuko

    2011-07-13

    ADP-ribosylation factor (Arf) and other Arf-family small G proteins participate in many cellular functions via their characteristic GTP/GDP conformational cycles, during which a nucleotide(∗)Mg(2+)-binding site communicates with a remote N-terminal helix. However, the conformational interplay between the nucleotides, the helix, the protein core, and Mg(2+) has not been fully delineated. Herein, we report a study of the dynamics of an Arf-family protein, Arl8, under various conditions by means of NMR relaxation spectroscopy. The data indicated that, when GDP is bound, the protein core, which does not include the N-terminal helix, reversibly transition between an Arf-family GDP form and another conformation that resembles the Arf-family GTP form. Additionally, we found that the N-terminal helix and Mg(2+), respectively, stabilize the aforementioned former and latter conformations in a population-shift manner. Given the dynamics of the conformational changes, we can describe the Arl8 GTP/GDP cycle in terms of an energy diagram.

  1. Being selective at the plate: processing dependence between perceptual variables relates to hitting goals and performance.

    PubMed

    Gray, Rob

    2013-08-01

    Performance of a skill that involves acting on a goal object (e.g., a ball to be hit) can influence one's judgment of the size and speed of that object. The present study examined how these action-specific effects are affected when the goal of the actor is varied and they are free to choose between alternative actions. In Experiment 1, expert baseball players were asked to perform three different directional hitting tasks in a batting simulation and make interleaved perceptual judgments about three ball parameters (speed, plate crossing location, and size). Perceived ball size was largest (and perceived speed was slowest) when the ball crossing location was optimal for the particular hitting task the batter was performing (e.g., an "outside" pitch for opposite-field hitting). The magnitude of processing dependency between variables (speed vs. location and size vs. location) was positively correlated with batting performance. In Experiment 2, the action-specific effects observed in Experiment 1 were mimicked by systematically changing the ball diameter in the simulation as a function of plate crossing location. The number of swing initiations was greater when ball size was larger, and batters were more successful in the hitting task for which the larger pitches were optimal (e.g., greater number of pull hits than opposite-field hits when "inside" pitches were larger). These findings suggest attentional accentuation of goal-relevant targets underlies action-related changes in perception and are consistent with an action selection role for these effects. PMID:23163787

  2. Schizophrenia two-hit hypothesis in velo-cardio facial syndrome.

    PubMed

    Williams, Hywel J; Monks, Stephen; Murphy, Kieran C; Kirov, George; O'Donovan, Michael C; Owen, Michael J

    2013-03-01

    Deletion of chr22q11 gives rise to velo-cardio facial syndrome (VCFS) and increases schizophrenia risk. The source of this elevated risk although unknown could result from stochastic, environmental, or genetic factors, the latter encompassing a range of complexity from polygenic mechanisms to "second-hit" mutations. For this study we tested the two-hit hypothesis where additional risk is conferred through a second CNV. We identified large (>100 kb) CNVs in 48 VCFS cases (23 with psychosis--25 without) and show in the psychotic VCFS group there is a significant (P = 0.02) increase in the average size of CNVs (354-227 kb). To identify second-hit loci we focused on individuals possessing gene-centric CNVs and through literature mining identified 4 (31%) psychotic VCFS individuals (n = 13) that overlapped loci previously implicated in neuropsychiatric disorders compared to 1 (10%) from the non-psychotic VCFS individuals (n = 10). For replication 17 VCFS patients with schizophrenia from the molecular genetics of schizophrenia dataset were used to identify further CNVs. Thirteen individuals possessing gene-centric CNVs were identified including 3 (23%) individuals possessing a potential second-hit, taking the overall total in the psychotic VCFS group (n = 26) to 7 (27%) potential second-hit loci. Notably a deletion in a psychotic VCFS patient at 2q23.1 hit the gene MBD5 which when deleted gives rise to intellectual disability, epilepsy, and autistic features. Through this study we potentially extend this phenotypic spectrum to include schizophrenia. Our results suggest the two-hit hypothesis may be relevant to a proportion of VCFS patients with psychosis but sample sizes are small and further studies warranted.

  3. Characterization of the gene coding for GDP-mannose dehydrogenase (algD) from Azotobacter vinelandii.

    PubMed Central

    Campos, M; Martínez-Salazar, J M; Lloret, L; Moreno, S; Núñez, C; Espín, G; Soberón-Chávez, G

    1996-01-01

    Azotobacter vinelandii presents a differentiation process leading to the formation of desiccation-resistant cysts. Alginate, the exopolysaccharide produced by this bacterium, has been postulated to have a role in cyst formation. Here, we report the cloning and characterization of the A. vinelandii gene coding for the enzyme GDP-mannose dehydrogenase (algD), which is the key enzyme for alginate synthesis in Pseudomonas aeruginosa. This gene has a high degree of similarity with the algD gene from P. aeruginosa, and similar proteins seem to be involved in algD regulation in both bacteria. We show the existence of two mRNA start sites; one of these sites corresponds to a promoter transcribed by RNA polymerase containing a sigma E subunit. An A. vinelandii algD mutant which is completely impaired in alginate production and which is unable to form desiccation-resistant cells was constructed. The effects of NH4, NO3, and NaCl concentrations on algD transcription for three A. vinelandii strains producing different alginate levels were evaluated. We found a strict correlation between alginate production and algD transcription for the three strains studied; however, the effects on algD transcription under the conditions studied were different for each strain. The nitrogen source regulates algD expression in the wild-type strain. PMID:8606150

  4. AtGDI2, a novel Arabidopsis gene encoding a Rab GDP dissociation inhibitor.

    PubMed

    Ueda, T; Yoshizumi, T; Anai, T; Matsui, M; Uchimiya, H; Nakano, A

    1998-01-01

    The GTPase cycle of Rab/Ypt proteins is strictly controlled by several classes of regulators to ensure their proper roles in membrane traffic. GDP dissociation inhibitor (GDI) is known to play essential roles in regulating nucleotide states and subcellular localizations of Rab/Ypt proteins. To obtain further knowledge on this regulator molecule in plants, we isolated and characterized two genes of Arabidopsis thaliana that encode different GDIs. AtGDI1 has been identified by a novel functional cloning in yeast [Ueda et al. (1996) Plant Cell, 8, 2079-2091] and AtGDI2 was isolated by cross-hybridization in this study. AtGDI2, as well as AtGDI1, complements the yeast sec19/gdi1 mutant, indicating that they can replace the function of yeast GDI. Evidence is shown that both AtGDI1 and AtGDI2 can interact with Ara4, an Arabidopsis Rab protein, in the yeast ypt1 mutant cells. AtGDI2 is ubiquitously expressed in Arabidopsis tissues with some difference from AtGDI1 in expression level. Genomic DNA hybridization using specific probes reveals the presence of one more GDI gene in Arabidopsis. This may imply differentiated roles of GDI in higher plants.

  5. Rice GDP dissociation inhibitor 3 inhibits OsMAPK2 activity through physical interaction.

    PubMed

    Heo, Jae Bok; Yi, Young Byung; Bahk, Jeong Dong

    2011-11-01

    GDP dissociation inhibitor (GDI) plays an essential role in regulating the state of bound nucleotides and subcellular localizations of Rab proteins. In our previous study, we showed that OsGDI3 facilitates the recycling of OsRab11 with a help of OsGAP1. In this study, we show that OsGDI3 complement the yeast sec19-1 mutant, a temperature-sensitive allele of the yeast GDI gene, suggesting that OsGDI3 is a functional ortholog of yeast GDI. To obtain further knowledge on the function of OsGDI3, candidate OsGDI3-interacting proteins were identified by yeast two-hybrid screens. OsMAPK2 is one of OsGDI3 interacting proteins from yeast two-hybrid screens and subject to further analysis. A kinase assay showed that the autophosphorylation activity of OsMAPK2 is inhibited by OsGDI3 in vitro. In addition, ectopic expressions of OsGDI3-in Arabidopsis cause reductions at the level of phosphorylated AtMPK in phosphorylation activity. Taken together, OsGDI3 functions as a negative regulator of OsMAPK2 through modulating its kinase activity.

  6. 7-methylguanosine diphosphate (m(7)GDP) is not hydrolyzed but strongly bound by decapping scavenger (DcpS) enzymes and potently inhibits their activity.

    PubMed

    Wypijewska, Anna; Bojarska, Elzbieta; Lukaszewicz, Maciej; Stepinski, Janusz; Jemielity, Jacek; Davis, Richard E; Darzynkiewicz, Edward

    2012-10-01

    Decapping scavenger (DcpS) enzymes catalyze the cleavage of a residual cap structure following 3' → 5' mRNA decay. Some previous studies suggested that both m(7)GpppG and m(7)GDP were substrates for DcpS hydrolysis. Herein, we show that mononucleoside diphosphates, m(7)GDP (7-methylguanosine diphosphate) and m(3)(2,2,7)GDP (2,2,7-trimethylguanosine diphosphate), resulting from mRNA decapping by the Dcp1/2 complex in the 5' → 3' mRNA decay, are not degraded by recombinant DcpS proteins (human, nematode, and yeast). Furthermore, whereas mononucleoside diphosphates (m(7)GDP and m(3)(2,2,7)GDP) are not hydrolyzed by DcpS, mononucleoside triphosphates (m(7)GTP and m(3)(2,2,7)GTP) are, demonstrating the importance of a triphosphate chain for DcpS hydrolytic activity. m(7)GTP and m(3)(2,2,7)GTP are cleaved at a slower rate than their corresponding dinucleotides (m(7)GpppG and m(3)(2,2,7)GpppG, respectively), indicating an involvement of the second nucleoside for efficient DcpS-mediated digestion. Although DcpS enzymes cannot hydrolyze m(7)GDP, they have a high binding affinity for m(7)GDP and m(7)GDP potently inhibits DcpS hydrolysis of m(7)GpppG, suggesting that m(7)GDP may function as an efficient DcpS inhibitor. Our data have important implications for the regulatory role of m(7)GDP in mRNA metabolic pathways due to its possible interactions with different cap-binding proteins, such as DcpS or eIF4E.

  7. Sixteen years of GOME/ERS-2 total ozone data: The new direct-fitting GOME Data Processor (GDP) version 5—Algorithm description

    NASA Astrophysics Data System (ADS)

    Van Roozendael, M.; Spurr, R.; Loyola, D.; Lerot, C.; Balis, D.; Lambert, J.-C.; Zimmer, W.; van Gent, J.; van Geffen, J.; Koukouli, M.; Granville, J.; Doicu, A.; Fayt, C.; Zehner, C.

    2012-02-01

    The Global Ozone Monitoring Instrument (GOME) was launched in April 1995 on ESA's ERS-2 platform, and the GOME Data Processor (GDP) operational retrieval algorithm has produced total ozone columns since July 1995. We report on the new GDP5 spectral fitting algorithm used to reprocess the 16-year GOME data record. Previous GDP total ozone algorithms were based on the DOAS method. In contrast, GDP5 uses a direct-fitting algorithm without high-pass filtering of radiances; there is no air mass factor conversion to vertical column amount. GDP5 includes direct radiative transfer simulation of earthshine radiances and Jacobians with respect to total ozone, albedo closure and other ancillary fitting parameters - a temperature profile shift, and amplitudes for undersampling and Ring-effect interference signals. Simulations are based on climatological ozone profiles extracted from the TOMS Version 8 database, classified by total column. GDP5 uses the high-resolution Brion-Daumont-Malicet ozone absorption cross-sections, replacing older GOME-measured flight model data. The semi-empirical molecular Ring correction developed for GDP4 has been adapted for direct fitting. Cloud preprocessing for GDP5 is done using updated versions of cloud-correction algorithms OCRA and ROCINN. The reprocessed GOME GDP5 record maintains the remarkable long-term stability of time series already achieved with GDP4. Furthermore, validation results show a clear improvement in the accuracy of the ozone product with reduced solar zenith angle and seasonal dependences, particularly in comparison with correlative observations from the ground-based network of Brewer spectrophotometers.

  8. Population growth and development: the case of Bangladesh.

    PubMed

    Nakibullah, A

    1998-04-01

    In a poor, overly populated country such as Bangladesh, some believe that a high rate of population growth is a cause of poverty which impedes economic development. Population growth would therefore be exogenous to economic development. However, others believe that rapid population growth is a consequence rather than a cause of poverty. Population growth is therefore endogenous to economic development. Findings are presented from an investigation of whether population growth has been exogenous or endogenous with respect to Bangladesh's development process during the past 3 decades. The increase in per capita real gross domestic product (GDP) is used as a measure of development. Data on population, real GDP per capita, and real investment share of GDP are drawn from the Penn World Table prepared by Summers and Heston in 1991. The data are annual and cover the period 1959-90. Analysis of the data indicate that population growth is endogenous to Bangladesh's development process. These findings are reflected both in the Granger causality tests and the decompositions of variances of detrended real GDP per capita and population growth.

  9. Gorlin syndrome with an ovarian leiomyoma associated with a PTCH1 second hit.

    PubMed

    Akizawa, Yoshika; Miyashita, Toshiyuki; Sasaki, Ryo; Nagata, Reiko; Aoki, Ryoko; Ishitani, Ken; Nagashima, Yoji; Matsui, Hideo; Saito, Kayoko

    2016-04-01

    We describe a Gorlin syndrome (GS) case with two different second hit mutations of PTCH1, one in a keratocystic odontogenic tumor (KCOT) and the other in an ovarian leiomyoma. GS is a rare genetic condition manifesting as multiple basal cell nevi associated with other features such as medulloblastomas, skeletal abnormalities, and ovarian fibromas. A 21-year-old Japanese woman with a history of two KCOTs was diagnosed with GS according to clinical criteria. A PTCH1 mutation, c.1427del T, was detected in peripheral blood. A novel PTCH1 mutation, c.264_265insAATA, had been found in the maxillary KCOT as a second hit mutation. More recently, the ovarian tumor was detected during a gynecological examination. Laparoscopic adnexectomy was performed, and the pathological diagnosis of the ovarian tumor was leiomyoma. Interestingly, another novel mutation, loss of heterozygosity spanning from 9q22.32 to 9q31.2, including PTCH1 and 89 other genes, was detected in this ovarian tumor, providing evidence of a second hit mutation. This is the first report describing a GS-associated ovarian tumor carrying a second hit in the PTCH1 region. We anticipate that accumulation of more cases will clarify the importance of second hit mutations in ovarian tumor formation in GS. PMID:26782978

  10. Atomic features of an autoantigen in heparin-induced thrombocytopenia (HIT).

    PubMed

    Cai, Zheng; Zhu, Zhiqiang; Greene, Mark I; Cines, Douglas B

    2016-07-01

    Autoantigen development is poorly understood at the atomic level. Heparin-induced thrombocytopenia (HIT) is an autoimmune thrombotic disorder caused by antibodies to an antigen composed of platelet factor 4 (PF4) and heparin or cellular glycosaminoglycans (GAGs). In solution, PF4 exists as an equilibrium among monomers, dimers and tetramers. Structural studies of these interacting components helped delineate a multi-step process involved in the pathogenesis of HIT. First, heparin binds to the 'closed' end of the PF4 tetramer and stabilizes its conformation; exposing the 'open' end. Second, PF4 arrays along heparin/GAG chains, which approximate tetramers, form large antigenic complexes that enhance antibody avidity. Third, pathogenic HIT antibodies bind to the 'open' end of stabilized PF4 tetramers to form an IgG/PF4/heparin ternary immune complex and also to propagate the formation of 'ultralarge immune complexes' (ULCs) that contain multiple IgG antibodies. Fourth, ULCs signal through FcγRIIA receptors, activating platelets and monocytes directly and generating thrombin, which transactivates hematopoietic and endothelial cells. A non-pathogenic anti-PF4 antibody prevents tetramer formation, binding of pathogenic antibody, platelet activation and thrombosis, providing a new approach to manage HIT. An improved understanding of the pathogenesis of HIT may lead to novel diagnostics and therapeutics for this autoimmune disease.

  11. Two Methods for Efficient Solution of the Hitting-Set Problem

    NASA Technical Reports Server (NTRS)

    Vatan, Farrokh; Fijany, Amir

    2005-01-01

    A paper addresses much of the same subject matter as that of Fast Algorithms for Model-Based Diagnosis (NPO-30582), which appears elsewhere in this issue of NASA Tech Briefs. However, in the paper, the emphasis is more on the hitting-set problem (also known as the transversal problem), which is well known among experts in combinatorics. The authors primary interest in the hitting-set problem lies in its connection to the diagnosis problem: it is a theorem of model-based diagnosis that in the set-theory representation of the components of a system, the minimal diagnoses of a system are the minimal hitting sets of the system. In the paper, the hitting-set problem (and, hence, the diagnosis problem) is translated from a combinatorial to a computational problem by mapping it onto the Boolean satisfiability and integer- programming problems. The paper goes on to describe developments nearly identical to those summarized in the cited companion NASA Tech Briefs article, including the utilization of Boolean-satisfiability and integer- programming techniques to reduce the computation time and/or memory needed to solve the hitting-set problem.

  12. Double-hit and double-protein-expression lymphomas: aggressive and refractory lymphomas.

    PubMed

    Sarkozy, Clémentine; Traverse-Glehen, Alexandra; Coiffier, Bertrand

    2015-11-01

    Double-hit lymphoma (DHL) is a subgroup of aggressive lymphomas with both MYC and BCL2 gene rearrangements, characterised by a rapidly progressing clinical course that is refractory to aggressive treatment and short survival. Over time, the definition was modified and now includes diffuse large B-cell lymphoma (DLBCL) with MYC translocation combined with an additional translocation involving BCL2 or BCL6. Some cases that have a similar clinical course with concomitant overexpression of MYC or BCL2 proteins were recently characterised as immunohistochemical double-hit lymphomas (ie, double-protein-expression lymphomas [DPLs]). The clinical course of these DPLs is worse than so-called standard DLBCL but suggested by some studies to be slightly better than DHL, although there is overlap between the two categories. Present treatment does not allow cure or long-term survival in patients with genetic or immunohistochemical double-hit lymphomas, but several new drugs are being developed. PMID:26545844

  13. Hitting the Fast Ball and Shaggin' Flies: a Physicist Considers Batting and Fielding in Baseball

    NASA Astrophysics Data System (ADS)

    Adair, Robert

    2003-03-01

    I describe some of the information processing that batters and fielders use to hit and field in baseball. The decision to hit the fast ball must be made using information from the first 15 feet of the ball's travel and the batter might as well not scan the last half of the flight. The procedures an outfielder uses to field a fly ball, adopted instinctively by 9 year old Little Leaguers, follows from mechanisms designed for the tracking of prey by predator and the avoidance of predators by prey. To this we add the utility of the acoustics of the bat-ball collision for balls hit directly at outfielders, and strategies for the avoidance of errors on ground balls to infielders.

  14. Helix Dipole Movement and Conformational Variability Contribute to Allosteric GDP Release in G[alpha] Subunits

    SciTech Connect

    Preininger, Anita M.; Funk, Michael A.; Oldham, William M.; Meier, Scott M.; Johnston, Christopher A.; Adhikary, Suraj; Kimple, Adam J.; Siderovski, David P.; Hamm, Heidi E.; Iverson, Tina M.

    2009-06-01

    Heterotrimeric G proteins (Galphabetagamma) transmit signals from activated G protein-coupled receptors (GPCRs) to downstream effectors through a guanine nucleotide signaling cycle. Numerous studies indicate that the carboxy-terminal alpha5 helix of Galpha subunits participates in Galpha-receptor binding, and previous EPR studies suggest this receptor-mediated interaction induces a rotation and translation of the alpha5 helix of the Galpha subunit [Oldham, W. M., et al. (2006) Nat. Struct. Mol. Biol. 13, 772-777]. On the basis of this result, an engineered disulfide bond was designed to constrain the alpha5 helix of Galpha(i1) into its EPR-measured receptor-associated conformation through the introduction of cysteines at position 56 in the alpha1 helix and position 333 in the alpha5 helix (I56C/Q333C Galpha(i1)). A functional mimetic of the EPR-measured alpha5 helix dipole movement upon receptor association was additionally created by introduction of a positive charge at the amino terminus of this helix, D328R Galpha(i1). Both proteins exhibit a dramatically elevated level of basal nucleotide exchange. The 2.9 A resolution crystal structure of I56C/Q333C Galpha(i1) in complex with GDP-AlF(4)(-) reveals the shift of the alpha5 helix toward the guanine nucleotide binding site that is anticipated by EPR measurements. The structure of the I56C/Q333C Galpha(i1) subunit further revealed altered positions for the switch regions and throughout the Galpha(i1) subunit, accompanied by significantly elevated crystallographic temperature factors. Combined with previous evidence in the literature, the structural analysis supports the critical role of electrostatics of the alpha5 helix dipole and overall conformational variability during nucleotide release.

  15. Doublecortin Is Excluded from Growing Microtubule Ends and Recognizes the GDP-Microtubule Lattice.

    PubMed

    Ettinger, Andreas; van Haren, Jeffrey; Ribeiro, Susana A; Wittmann, Torsten

    2016-06-20

    Many microtubule (MT) functions are mediated by a diverse class of proteins (+TIPs) at growing MT plus ends that control intracellular MT interactions and dynamics and depend on end-binding proteins (EBs) [1]. Cryoelectron microscopy has recently identified the EB binding site as the interface of four tubulin dimers that undergoes a conformational change in response to β-tubulin GTP hydrolysis [2, 3]. Doublecortin (DCX), a MT-associated protein (MAP) required for neuronal migration during cortical development [4, 5], binds to the same site as EBs [6], and recent in vitro studies proposed DCX localization to growing MT ends independent of EBs [7]. Because this conflicts with observations in neurons [8, 9] and the molecular function of DCX is not well understood, we revisited intracellular DCX dynamics at low expression levels. Here, we report that DCX is not a +TIP in cells but, on the contrary, is excluded from the EB1 domain. In addition, we find that DCX-MT interactions are highly sensitive to MT geometry. In cells, DCX binding was greatly reduced at MT segments with high local curvature. Remarkably, this geometry-dependent binding to MTs was completely reversed in the presence of taxanes, which reconciles incompatible observations in cells [9] and in vitro [10]. We propose a model explaining DCX specificity for different MT geometries based on structural changes induced by GTP hydrolysis that decreases the spacing between adjacent tubulin dimers [11]. Our data are consistent with a unique mode of MT interaction in which DCX specifically recognizes this compacted GDP-like MT lattice.

  16. Causal relationship between CO₂ emissions, real GDP, energy consumption, financial development, trade openness, and urbanization in Tunisia.

    PubMed

    Farhani, Sahbi; Ozturk, Ilhan

    2015-10-01

    The aim of this paper is to examine the causal relationship between CO2 emissions, real GDP, energy consumption, financial development, trade openness, and urbanization in Tunisia over the period of 1971-2012. The long-run relationship is investigated by the auto-regressive distributed lag (ARDL) bounds testing approach to cointegration and error correction method (ECM). The results of the analysis reveal a positive sign for the coefficient of financial development, suggesting that the financial development in Tunisia has taken place at the expense of environmental pollution. The Tunisian case also shows a positive monotonic relationship between real GDP and CO2 emissions. This means that the results do not support the validity of environmental Kuznets curve (EKC) hypothesis. In addition, the paper explores causal relationship between the variables by using Granger causality models and it concludes that financial development plays a vital role in the Tunisian economy.

  17. Implementing the essential medicine concept in the country with the highest GDP per capita in the world.

    PubMed

    Cheraghali, A M

    2013-01-01

    Qatar, an oil-exporting country with a population of about 1.7 million, achieved the highest gross domestic product (GDP) per capita in the world in 2010. Total health expenditure as a percentage of GDP in 2010 in Qatar was 2.0%, with the government's share at 75% of the total health care budget. Hamad Medical Corporation hospitals and the independent public Qatar Primary Health Care PHC) centres are the main public health care service providers. PHC consists of 24 centres providing a wide range of health services. The PHC medicines list is a subset of the Hamad Medical Corporation medicine list. However, the PHC list of medicines could be improved both in its selection procedures and medicines included to correlate more directly to type of medical services provided by the Qatar PHC system in its different types of centres.

  18. Solution structure of the zinc finger HIT domain in protein FON

    PubMed Central

    He, Fahu; Umehara, Takashi; Tsuda, Kengo; Inoue, Makoto; Kigawa, Takanori; Matsuda, Takayoshi; Yabuki, Takashi; Aoki, Masaaki; Seki, Eiko; Terada, Takaho; Shirouzu, Mikako; Tanaka, Akiko; Sugano, Sumio; Muto, Yutaka; Yokoyama, Shigeyuki

    2007-01-01

    The zinc finger HIT domain is a sequence motif found in many proteins, including thyroid hormone receptor interacting protein 3 (TRIP-3), which is possibly involved in maturity-onset diabetes of the young (MODY). Novel zinc finger motifs are suggested to play important roles in gene regulation and chromatin remodeling. Here, we determined the high-resolution solution structure of the zinc finger HIT domain in ZNHIT2 (protein FON) from Homo sapiens, by an NMR method based on 567 upper distance limits derived from NOE intensities measured in three-dimensional NOESY spectra. The structure yielded a backbone RMSD to the mean coordinates of 0.19 Å for the structured residues 12–48. The fold consists of two consecutive antiparallel β-sheets and two short C-terminal helices packed against the second β-sheet, and binds two zinc ions. Both zinc ions are coordinated tetrahedrally via a CCCC-CCHC motif to the ligand residues of the zf-HIT domain in an interleaved manner. The tertiary structure of the zinc finger HIT domain closely resembles the folds of the B-box, RING finger, and PHD domains with a cross-brace zinc coordination mode, but is distinct from them. The unique three-dimensional structure of the zinc finger HIT domain revealed a novel zinc-binding fold, as a new member of the treble clef domain family. On the basis of the structural data, we discuss the possible functional roles of the zinc finger HIT domain. PMID:17656577

  19. Multiple NSAID-induced hits injure the small intestine: underlying mechanisms and novel strategies.

    PubMed

    Boelsterli, Urs A; Redinbo, Matthew R; Saitta, Kyle S

    2013-02-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) can cause serious gastrointestinal (GI) injury including jejunal/ileal mucosal ulceration, bleeding, and even perforation in susceptible patients. The underlying mechanisms are largely unknown, but they are distinct from those related to gastric injury. Based on recent insights from experimental models, including genetics and pharmacology in rodents typically exposed to diclofenac, indomethacin, or naproxen, we propose a multiple-hit pathogenesis of NSAID enteropathy. The multiple hits start with an initial pharmacokinetic determinant caused by vectorial hepatobiliary excretion and delivery of glucuronidated NSAID or oxidative metabolite conjugates to the distal small intestinal lumen, where bacterial β-glucuronidase produces critical aglycones. The released aglycones are then taken up by enterocytes and further metabolized by intestinal cytochrome P450s to potentially reactive intermediates. The "first hit" is caused by the NSAID and/or oxidative metabolites that induce severe endoplasmic reticulum stress or mitochondrial stress and lead to cell death. The "second hit" is created by the significant subsequent inflammatory response that would follow such a first-hit injury. Based on these putative mechanisms, strategies have been developed to protect the enterocytes from being exposed to the parent NSAID and/or oxidative metabolites. Among these, a novel strategy already demonstrated in a murine model is the selective disruption of bacteria-specific β-glucuronidases with a novel small molecule inhibitor that does not harm the bacteria and that alleviates NSAID-induced enteropathy. Such mechanism-based strategies require further investigation but provide potential avenues for the alleviation of the GI toxicity caused by multiple NSAID hits.

  20. VvGONST-A and VvGONST-B are Golgi-localised GDP-sugar transporters in grapevine (Vitis vinifera L.).

    PubMed

    Utz, Daniella; Handford, Michael

    2015-02-01

    Plant nucleotide-sugar transporters (NSTs) are responsible for the import of nucleotide-sugar substrates into the Golgi lumen, for subsequent use in glycosylation reactions. NSTs are specific for either GDP- or UDP-sugars, and almost all transporters studied to date have been isolated from Arabidopsis thaliana L. In order to determine the conservation of the import mechanism in other higher plant species, here we report the identification and characterisation of VvGONST-A and VvGONST-B from grapevine (Vitis vinifera L. cv. Thompson Seedless), which are the orthologues of the GDP-sugar transporters GONST3 and GONST4 in Arabidopsis. Both grapevine NSTs possess the molecular features characteristic of GDP-sugar transporters, including a GDP-binding domain (GXL/VNK) towards the C-terminal. VvGONST-A and VvGONST-B expression is highest at berry setting and decreases throughout berry development and ripening. Moreover, we show using green fluorescent protein (GFP) tagged versions and brefeldin A treatments, that both are localised in the Golgi apparatus. Additionally, in vitro transport assays after expression of both NSTs in tobacco leaves indicate that VvGONST-A and VvGONST-B are capable of transporting GDP-mannose and GDP-glucose, respectively, but not a range of other UDP- and GDP-sugars. The possible functions of these NSTs in glucomannan synthesis and/or glycosylation of sphingolipids are discussed.

  1. On hitting children: a review of corporal punishment in the United States.

    PubMed

    Knox, Michele

    2010-01-01

    Research has clearly demonstrated associations between corporal punishment of children and maladaptive behavior patterns such as aggression and delinquency. Hitting children is an act of violence and a clear violation of children's human rights. In this article, the position of the United States on corporal punishment of children is discussed. Professional and international progress on ending corporal punishment is explained, and the relationship between corporal punishment and child abuse is discussed. An appeal is made for prevention efforts such as parent education and removal of social sanctions for hitting children that may hold significant promise for preventing child maltreatment.

  2. Cosmic ray hit frequencies in critical sites in the central nervous system

    NASA Astrophysics Data System (ADS)

    Curtis, S. B.; Vazquez, M. E.; Wilson, J. W.; Atwell, W.; Kim, M.; Capala, J.

    One outstanding question to be addressed in assessing the risk of exposure to space travelers from galactic cosmic rays (GCR) outside the geomagnetosphere is to ascertain the effects of single heavy-ion hits on cells in critical regions of the central nervous system (CNS). As a first step toward this end, it is important to determine how many ``hits'' might be received by a neural cell in several critical CNS areas during an extended mission outside the confines of the earth's magnetic field. Critical sites in the CNS: the macula, and an interior brain point (typical of the genu, thalamus, hippocampus and nucleus basalis of Meynert) were chosen for the calculation of hit frequencies from galactic cosmic rays for a mission to Mars during solar minimum (i.e., at maximum cosmic-ray intensity). The shielding at a given position inside the body was obtained using the Computerized Anatomical Man (CAM) model, and a radiation transport code which includes nuclear fragmentation was used to calculate yearly fluences at the point of interest. Since the final Mars spacecraft shielding configuration has not yet been determined, we considered the minimum amount of aluminum required for pressure vessel-wall requirements in the living quarters of a spacecraft, and a typical duty area as a pressure vessel plus necessary equipment. The conclusions are: (1) variation of the position of the ``target site'' within the head plays only a small role in varying hit frequencies; (2) the average number of hits depends linearly on the cross section of the critical portion of the cell assumed in the calculation; (3) for a three-year mission to Mars at solar minimum (i.e., assuming the 1977 spectrum of galactic cosmic rays), 2% or 13% of the ``critical sites'' of cells in the CNS would be directly hit at least once by iron ions, depending on whether 60 mum^2 or 471 mum^2 is assumed as the critical cross sectional area; and (4) roughly 6 million out of some 43 million hippocampal cells and 55

  3. Cosmic ray hit frequencies in critical sites in the central nervous system.

    PubMed

    Curtis, S B; Vazquez, M E; Wilson, J W; Atwell, W; Kim, M; Capala, J

    1998-01-01

    One outstanding question to be addressed in assessing the risk of exposure to space travelers from galactic cosmic rays (GCR) outside the geomagnetosphere is to ascertain the effects of single heavy-ion hits on cells in critical regions of the central nervous system (CNS). As a first step toward this end, it is important to determine how many "hits" might be received by a neural cell in several critical CNS areas during an extended mission outside the confines of the earth's magnetic field. Critical sites in the CNS: the macula, and an interior brain point (typical of the genu, thalamus, hippocampus and nucleus basalis of Meynert) were chosen for the calculation of hit frequencies from galactic cosmic rays for a mission to Mars during solar minimum (i.e., at maximum cosmic-ray intensity). The shielding at a given position inside the body was obtained using the Computerized Anatomical Man (CAM) model, and a radiation transport code which includes nuclear fragmentation was used to calculate yearly fluences at the point of interest. Since the final Mars spacecraft shielding configuration has not yet been determined, we considered the minimum amount of aluminum required for pressure vessel-wall requirements in the living quarters of a spacecraft, and a typical duty area as a pressure vessel plus necessary equipment. The conclusions are: (1) variation of the position of the "target site" within the head plays only a small role in varying hit frequencies; (2) the average number of hits depends linearly on the cross section of the critical portion of the cell assumed in the calculation; (3) for a three-year mission to Mars at solar minimum (i.e., assuming the 1977 spectrum of galactic cosmic rays), 2% or 13% of the "critical sites" of cells in the CNS would be directly hit at least once by iron ions, depending on whether 60 micrometers2 or 471 micrometers2 is assumed as the critical cross sectional area; and (4) roughly 6 million out of some 43 million hippocampal cells

  4. Cosmic ray hit frequencies in critical sites in the central nervous system.

    PubMed

    Curtis, S B; Vazquez, M E; Wilson, J W; Atwell, W; Kim, M; Capala, J

    1998-01-01

    One outstanding question to be addressed in assessing the risk of exposure to space travelers from galactic cosmic rays (GCR) outside the geomagnetosphere is to ascertain the effects of single heavy-ion hits on cells in critical regions of the central nervous system (CNS). As a first step toward this end, it is important to determine how many "hits" might be received by a neural cell in several critical CNS areas during an extended mission outside the confines of the earth's magnetic field. Critical sites in the CNS: the macula, and an interior brain point (typical of the genu, thalamus, hippocampus and nucleus basalis of Meynert) were chosen for the calculation of hit frequencies from galactic cosmic rays for a mission to Mars during solar minimum (i.e., at maximum cosmic-ray intensity). The shielding at a given position inside the body was obtained using the Computerized Anatomical Man (CAM) model, and a radiation transport code which includes nuclear fragmentation was used to calculate yearly fluences at the point of interest. Since the final Mars spacecraft shielding configuration has not yet been determined, we considered the minimum amount of aluminum required for pressure vessel-wall requirements in the living quarters of a spacecraft, and a typical duty area as a pressure vessel plus necessary equipment. The conclusions are: (1) variation of the position of the "target site" within the head plays only a small role in varying hit frequencies; (2) the average number of hits depends linearly on the cross section of the critical portion of the cell assumed in the calculation; (3) for a three-year mission to Mars at solar minimum (i.e., assuming the 1977 spectrum of galactic cosmic rays), 2% or 13% of the "critical sites" of cells in the CNS would be directly hit at least once by iron ions, depending on whether 60 micrometers2 or 471 micrometers2 is assumed as the critical cross sectional area; and (4) roughly 6 million out of some 43 million hippocampal cells

  5. Structure of the protein core of translation initiation factor 2 in apo, GTP-bound and GDP-bound forms

    SciTech Connect

    Simonetti, Angelita; Fabbretti, Attilio; Hazemann, Isabelle; Jenner, Lasse; Gualerzi, Claudio O.; Klaholz, Bruno P.

    2013-06-01

    The crystal structures of the eubacterial translation initiation factor 2 in apo form and with bound GDP and GTP reveal conformational changes upon nucleotide binding and hydrolysis, notably of the catalytically important histidine in the switch II region. Translation initiation factor 2 (IF2) is involved in the early steps of bacterial protein synthesis. It promotes the stabilization of the initiator tRNA on the 30S initiation complex (IC) and triggers GTP hydrolysis upon ribosomal subunit joining. While the structure of an archaeal homologue (a/eIF5B) is known, there are significant sequence and functional differences in eubacterial IF2, while the trimeric eukaryotic IF2 is completely unrelated. Here, the crystal structure of the apo IF2 protein core from Thermus thermophilus has been determined by MAD phasing and the structures of GTP and GDP complexes were also obtained. The IF2–GTP complex was trapped by soaking with GTP in the cryoprotectant. The structures revealed conformational changes of the protein upon nucleotide binding, in particular in the P-loop region, which extend to the functionally relevant switch II region. The latter carries a catalytically important and conserved histidine residue which is observed in different conformations in the GTP and GDP complexes. Overall, this work provides the first crystal structure of a eubacterial IF2 and suggests that activation of GTP hydrolysis may occur by a conformational repositioning of the histidine residue.

  6. Shock compression of glow discharge polymer (GDP): density functional theory (DFT) simulations and experiments on Sandia's Z-machine

    NASA Astrophysics Data System (ADS)

    Mattsson, Thomas R.; Cochrane, K. R.; Ao, T.; Lemke, R. W.; Flicker, D. G.; Schoff, M. E.; Blue, B. E.; Hamel, S.; Herrmann, M. C.

    2015-11-01

    Glow discharge polymer (GDP) is used extensively as capsule/ablation material in inertial confinement fusion (ICF) capsules. Accurate knowledge of the equation of state (EOS) under shock and release is particularly important for high-fidelity design, analysis, and optimization of ICF experiments since the capsule material is subject to several converging shocks as well as release towards the cryogenic fuel. We performed Density Functional Theory (DFT) based quantum molecular dynamics (QMD) simulations, to gain knowledge of the behavior of GDP - including the effect of changes in chemical composition. The shock pressures calculated from DFT are compared experimental data taken on magnetically launched flyer plate impact experiments on at Sandia's Z-machine. Large GDP samples were grown in a planar geometry to improve the sample quality and maintained in a nitrogen atmosphere following manufacturing, thus allowing for a direct comparison to the DFT/QMD simulations. Sandia National Laboratories is a multi program laboratory managed and operated by Sandia Corporation, a wholly owned subsidiary of Lockheed Martin Corporation, for the U.S. Department of Energy's NNSA under contract DE-AC04-94AL85000.

  7. Shock compression of glow discharge polymer (GDP): density functional theory (DFT) simulations and experiments on Sandia's Z machine

    NASA Astrophysics Data System (ADS)

    Cochrane, Kyle R.; Ao, T.; Lemke, R. W.; Hamel, S.; Schoff, M. E.; Blue, B. E.; Herrmann, M. C.; Mattsson, T. R.

    2014-03-01

    Glow discharge polymer (GDP) is used extensively as capsule/ablation material in inertial confinement fusion (ICF) capsules. Accurate knowledge of the equation of state (EOS) under shock and release is particularly important for high-fidelity design, analysis, and optimization of ICF experiments since the capsule material is subject to several converging shocks as well as release towards the cryogenic fuel. We performed Density Functional Theory (DFT) based quantum molecular dynamics (QMD) simulations, to gain knowledge of the behavior of GDP - for example regarding the role of chemical dissociation during shock compression, we find that the dissociation regime along the Hugoniot extends from 50 GPa to 250 GPa. The shock pressures calculated from DFT are compared experimental data taken at Sandia's Z-machine. The GDP samples were grown in a planar geometry to improve the sample quality and maintained in a nitrogen atmosphere following manufacturing, thus allowing for a direct comparison to the DFT/QMD simulations. Sandia National Laboratories is a multi program laboratory managed and operated by Sandia Corporation, a wholly owned subsidiary of Lockheed Martin Corporation, for the U.S. Department of Energy's NNSA under contract DE-AC04-94AL85000.

  8. Shock compression of glow discharge polymer (GDP): density functional theory (DFT) simulations and experiments on Sandia's Z-machine

    NASA Astrophysics Data System (ADS)

    Cochrane, K. R.; Ao, T.; Hamel, S.; Lemke, R. W.; Schoff, M. E.; Blue, B. E.; Herrmann, M. C.; Mattsson, T. R.

    2015-06-01

    Glow discharge polymer (GDP) is used extensively in inertial confinement fusion (ICF) capsules. Accurate knowledge of the equation of state (EOS) under shock and release is particularly important for high-fidelity design and analysis of ICF experiments since the capsule material is subject to several converging shocks as well as release towards the cryogenic fuel. We performed Density Functional Theory (DFT) based molecular dynamics simulations, to gain knowledge of the behavior of GDP - for example regarding the role of chemical dissociation during shock compression, we find that the dissociation regime along the Hugoniot extends from 50 GPa to 250 GPa. The shock pressures calculated from DFT are compared to experimental data taken on magnetically launched flyer plate impact experiments at Sandia's Z-machine. Large GDP samples were grown in a planar geometry to improve the sample quality and maintained in a nitrogen atmosphere following manufacturing, thus allowing for a direct comparison to the simulations. Sandia National Laboratories is a multi program laboratory managed and operated by Sandia Corporation, a wholly owned subsidiary of Lockheed Martin Corporation, for the U.S. Department of Energy's NNSA under Contract DE-AC04-94AL85000

  9. The biocompatibility of neutral pH, low-GDP peritoneal dialysis solutions: benefit at bench, bedside, or both?

    PubMed

    Perl, Jeffrey; Nessim, Sharon J; Bargman, Joanne M

    2011-04-01

    For patients on peritoneal dialysis (PD), the development of peritonitis, the decline of residual kidney function, and the loss of peritoneal membrane function are central events that affect both patient and technique survival. The use of glucose as the osmotic agent in conventional PD solutions may increase the susceptibility to each of these events. However, its use may also be associated with systemic metabolic perturbations and, in turn, an increase in cardiovascular morbidity. Both in vitro and in vivo evidence suggest that both the local peritoneal and systemic toxicity induced by the use of glucose may be in part mediated by the presence of glucose degradation products (GDPs) coupled with the hyperosmolarity, reduced pH, and use of lactate as the buffer in conventional PD solutions. Therefore, the use of neutral pH, low-GDP (NpHL(GDP)), bicarbonate-buffered PD solutions may represent a promising strategy to attenuate some of these adverse effects. However, the impact of these novel solutions on clinical outcomes remains largely unknown. In this review, we will highlight evidence regarding the biocompatibility of NpHL(GDP) PD solutions, review the utility of current biomarkers in the evaluation of biocompatibility, and discuss the clinical outcome data with these solutions.

  10. The structural basis for catalytic function of GMD and RMD, two closely related enzymes from the GDP-d-rhamnose biosynthesis pathway

    PubMed Central

    Anderson, Erin M.; McNally, David J.; Brisson, Jean-Robert; Messner, Paul; Garavito, R. M.; Lam, Joseph S.

    2015-01-01

    The rare 6-deoxysugar d-rhamnose is a component of bacterial cell surface glycans, including the d-rhamnose homopolymer produced by Pseudomonas aeruginosa, called A-band O polysaccharide. GDP-d-rhamnose synthesis from GDP-d-mannose is catalyzed by two enzymes. The first is a GDP-d-mannose-4,6-dehydratase (GMD). The second enzyme, RMD, reduces the GMD product (GDP-6-deoxy-d-lyxo-hexos-4-ulose) to GDP-d-rhamnose. Genes encoding GMD and RMD are present in P. aeruginosa, and genetic evidence indicates they act in A-band O-polysaccharide biosynthesis. Details of their enzyme functions have not, however, been previously elucidated. We aimed to characterize these enzymes biochemically, and to determine the structure of RMD to better understand what determines substrate specificity and catalytic activity in these enzymes. We used capillary electrophoresis and NMR analysis of reaction products to precisely define P. aeruginosa GMD and RMD functions. P. aeruginosa GMD is bifunctional, and can catalyze both GDP-d-mannose 4,6-dehydration and the subsequent reduction reaction to produce GDP-d-rhamnose. RMD catalyzes the stereospecific reduction of GDP-6-deoxy-d-lyxo-hexos-4-ulose, as predicted. Reconstitution of GDP-d-rhamnose biosynthesis in vitro revealed that the P. aeruginosa pathway may be regulated by feedback inhibition in the cell. We determined the structure of RMD from Aneurinibacillus thermoaerophilus at 1.8 Å resolution. The structure of A. thermoaerophilus RMD is remarkably similar to that of P. aeruginosa GMD, which explains why P. aeruginosa GMD is also able to catalyze the RMD reaction. Comparison of the active sites and amino acid sequences suggests that a conserved amino acid side chain (Arg185 in P. aeruginosa GMD) may be crucial for orienting substrate and cofactor in GMD enzymes. PMID:19459932

  11. LncRNA-HIT Functions as an Epigenetic Regulator of Chondrogenesis through Its Recruitment of p100/CBP Complexes

    PubMed Central

    Carlson, Hanqian L.; Quinn, Jeffrey J.; Yang, Yul W.; Thornburg, Chelsea K.; Chang, Howard Y.; Stadler, H. Scott

    2015-01-01

    Gene expression profiling in E 11 mouse embryos identified high expression of the long noncoding RNA (lncRNA), LNCRNA-HIT in the undifferentiated limb mesenchyme, gut, and developing genital tubercle. In the limb mesenchyme, LncRNA-HIT was found to be retained in the nucleus, forming a complex with p100 and CBP. Analysis of the genome-wide distribution of LncRNA-HIT-p100/CBP complexes by ChIRP-seq revealed LncRNA-HIT associated peaks at multiple loci in the murine genome. Ontological analysis of the genes contacted by LncRNA-HIT-p100/CBP complexes indicate a primary role for these loci in chondrogenic differentiation. Functional analysis using siRNA-mediated reductions in LncRNA-HIT or p100 transcripts revealed a significant decrease in expression of many of the LncRNA-HIT-associated loci. LncRNA-HIT siRNA treatments also impacted the ability of the limb mesenchyme to form cartilage, reducing mesenchymal cell condensation and the formation of cartilage nodules. Mechanistically the LncRNA-HIT siRNA treatments impacted pro-chondrogenic gene expression by reducing H3K27ac or p100 activity, confirming that LncRNA-HIT is essential for chondrogenic differentiation in the limb mesenchyme. Taken together, these findings reveal a fundamental epigenetic mechanism functioning during early limb development, using LncRNA-HIT and its associated proteins to promote the expression of multiple genes whose products are necessary for the formation of cartilage. PMID:26633036

  12. HITS-CLIP yields genome-wide insights into brain alternative RNA processing

    NASA Astrophysics Data System (ADS)

    Licatalosi, Donny D.; Mele, Aldo; Fak, John J.; Ule, Jernej; Kayikci, Melis; Chi, Sung Wook; Clark, Tyson A.; Schweitzer, Anthony C.; Blume, John E.; Wang, Xuning; Darnell, Jennifer C.; Darnell, Robert B.

    2008-11-01

    Protein-RNA interactions have critical roles in all aspects of gene expression. However, applying biochemical methods to understand such interactions in living tissues has been challenging. Here we develop a genome-wide means of mapping protein-RNA binding sites in vivo, by high-throughput sequencing of RNA isolated by crosslinking immunoprecipitation (HITS-CLIP). HITS-CLIP analysis of the neuron-specific splicing factor Nova revealed extremely reproducible RNA-binding maps in multiple mouse brains. These maps provide genome-wide in vivo biochemical footprints confirming the previous prediction that the position of Nova binding determines the outcome of alternative splicing; moreover, they are sufficiently powerful to predict Nova action de novo. HITS-CLIP revealed a large number of Nova-RNA interactions in 3' untranslated regions, leading to the discovery that Nova regulates alternative polyadenylation in the brain. HITS-CLIP, therefore, provides a robust, unbiased means to identify functional protein-RNA interactions in vivo.

  13. Internet Visibility Measured by Search Engine Hits: A Test on Virginia Colleges and Universities.

    ERIC Educational Resources Information Center

    Ridley, Dennis R.

    This study selected 25 private colleges and universities and 14 public colleges and universities in Virginia. Internet search engines were used to record the number of hits they reported for each of the schools, as a measure of the institution's visibility in the Internet world. Findings indicated that there was a high correlation between…

  14. Optimization of a pyrazole hit from FBDD into a novel series of indazoles as ketohexokinase inhibitors

    SciTech Connect

    Zhang, Xuqing; Song, Fengbing; Kuo, Gee-Hong; Xiang, Amy; Gibbs, Alan C.; Abad, Marta C.; Sun, Weimei; Kuo, Lawrence C.; Sui, Zhihua

    2013-11-20

    A series of indazoles have been discovered as KHK inhibitors from a pyrazole hit identified through fragment-based drug discovery (FBDD). The optimization process guided by both X-ray crystallography and solution activity resulted in lead-like compounds with good pharmaceutical properties.

  15. The accelerator facility of the Heidelberg Ion-Beam Therapy Centre (HIT)

    NASA Astrophysics Data System (ADS)

    Peters, Andreas

    The following sections are included: * Introduction * Beam parameters * General layout of the HIT facility * The accelerator chain in detail * Operational aspects of a particle therapy facility * 24/7 accelerator operation at 335 days per year * Safety and regulatory aspects * Status and perspectives * References

  16. Sun exposure causes somatic second-hit mutations and angiofibroma development in tuberous sclerosis complex.

    PubMed

    Tyburczy, Magdalena E; Wang, Ji-An; Li, Shaowei; Thangapazham, Rajesh; Chekaluk, Yvonne; Moss, Joel; Kwiatkowski, David J; Darling, Thomas N

    2014-04-15

    Tuberous sclerosis complex (TSC) is characterized by the formation of tumors in multiple organs and is caused by germline mutation in one of two tumor suppressor genes, TSC1 and TSC2. As for other tumor suppressor gene syndromes, the mechanism of somatic second-hit events in TSC tumors is unknown. We grew fibroblast-like cells from 29 TSC skin tumors from 22 TSC subjects and identified germline and second-hit mutations in TSC1/TSC2 using next-generation sequencing. Eighteen of 22 (82%) subjects had a mutation identified, and 8 of the 18 (44%) subjects were mosaic with mutant allele frequencies of 0 to 19% in normal tissue DNA. Multiple tumors were available from four patients, and in each case, second-hit mutations in TSC2 were distinct indicating they arose independently. Most remarkably, 7 (50%) of the 14 somatic point mutations were CC>TT ultraviolet 'signature' mutations, never seen as a TSC germline mutation. These occurred exclusively in facial angiofibroma tumors from sun-exposed sites. These results implicate UV-induced DNA damage as a cause of second-hit mutations and development of TSC facial angiofibromas and suggest that measures to limit UV exposure in TSC children and adults should reduce the frequency and severity of these lesions.

  17. 75 FR 29761 - Office of the National Coordinator for Health Information Technology: HIT Standards Committee...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-05-27

    ... HUMAN SERVICES Office of the National Coordinator for Health Information Technology: HIT Standards... Information Technology, HHS. ACTION: Notice of meeting. This notice announces a forthcoming meeting of a public advisory committee of the Office of the National Coordinator for Health Information...

  18. 75 FR 8954 - Office of the National Coordinator for Health Information Technology; HIT Standards Committee...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-02-26

    ... HUMAN SERVICES Office of the National Coordinator for Health Information Technology; HIT Standards... Information Technology, HHS ACTION: Notice of meeting. This notice announces a forthcoming meeting of a public advisory committee of the Office of the National Coordinator for Health Information Technology (ONC)....

  19. 75 FR 57027 - Office of the National Coordinator for Health Information Technology; HIT Standards Committee...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-09-17

    ... HUMAN SERVICES Office of the National Coordinator for Health Information Technology; HIT Standards... Information Technology, HHS. ACTION: Notice of meeting. This notice announces a forthcoming meeting of a public advisory committee of the Office of the National Coordinator for Health Information...

  20. 75 FR 21628 - HIT Standards Committee Advisory Meeting; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-04-26

    ... HUMAN SERVICES Office of the National Coordinator for Health Information Technology HIT Standards... Information Technology, HHS ACTION: Notice of meeting. This notice announces a forthcoming meeting of a public advisory committee of the Office of the National Coordinator for Health Information Technology (ONC)....

  1. 75 FR 70923 - Office of the National Coordinator for Health Information Technology; HIT Standards Committee...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-11-19

    ... HUMAN SERVICES Office of the National Coordinator for Health Information Technology; HIT Standards... Information Technology, HHS. ACTION: Notice of meeting. This notice announces a forthcoming meeting of a public advisory committee of the Office of the National Coordinator for Health Information...

  2. 75 FR 65636 - Office of the National Coordinator for Health Information Technology; HIT Standards Committee...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-10-26

    ... HUMAN SERVICES Office of the National Coordinator for Health Information Technology; HIT Standards... Information Technology, HHS. ACTION: Notice of meeting. This notice announces a forthcoming meeting of a public advisory committee of the Office of the National Coordinator for Health Information...

  3. 75 FR 5595 - HIT Standards Committee Advisory Meeting; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-02-03

    ... HUMAN SERVICES Office of the National Coordinator for Health Information Technology HIT Standards... Information Technology, HHS. ] ACTION: Notice of meeting. This notice announces a forthcoming meeting of a public advisory committee of the Office of the National Coordinator for Health Information...

  4. 76 FR 9782 - Office of the National Coordinator for Health Information Technology; HIT Standards Committee's...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-02-22

    ... exchange and use of health information for purposes of adoption, consistent with the implementation of the... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF HEALTH AND HUMAN SERVICES Office of the National Coordinator for Health Information Technology; HIT...

  5. Visits, Hits, Caching and Counting on the World Wide Web: Old Wine in New Bottles?

    ERIC Educational Resources Information Center

    Berthon, Pierre; Pitt, Leyland; Prendergast, Gerard

    1997-01-01

    Although web browser caching speeds up retrieval, reduces network traffic, and decreases the load on servers and browser's computers, an unintended consequence for marketing research is that Web servers undercount hits. This article explores counting problems, caching, proxy servers, trawler software and presents a series of correction factors…

  6. "Hits" (Not "Discussion Posts") Predict Student Success in Online Courses: A Double Cross-Validation Study

    ERIC Educational Resources Information Center

    Ramos, Cheryl; Yudko, Errol

    2008-01-01

    The efficacy of individual components of an online course on positive course outcome was examined via stepwise multiple regression analysis. Outcome was measured as the student's total score on all exams given during the course. The predictors were page hits, discussion posts, and discussion reads. The vast majority of the variance of outcome was…

  7. 30,000 Hits May Be Better than 300: Precision Anomalies in Internet Searches.

    ERIC Educational Resources Information Center

    Eastman, Caroline M.

    2002-01-01

    Discusses results of searches using a variety of query formulations with several Internet search engines which show that strategies intended to give narrower and more precise results may not give improvements in precision even though they result in fewer hits. Describes searches that were performed by students in graduate information retrieval…

  8. 42 CFR 495.338 - Health information technology implementation advance planning document requirements (HIT IAPD).

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... the Medicaid Program § 495.338 Health information technology implementation advance planning document... 42 Public Health 5 2012-10-01 2012-10-01 false Health information technology implementation advance planning document requirements (HIT IAPD). 495.338 Section 495.338 Public Health CENTERS...

  9. 42 CFR 495.338 - Health information technology implementation advance planning document requirements (HIT IAPD).

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... the Medicaid Program § 495.338 Health information technology implementation advance planning document... 42 Public Health 5 2014-10-01 2014-10-01 false Health information technology implementation advance planning document requirements (HIT IAPD). 495.338 Section 495.338 Public Health CENTERS...

  10. 42 CFR 495.338 - Health information technology implementation advance planning document requirements (HIT IAPD).

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... the Medicaid Program § 495.338 Health information technology implementation advance planning document... 42 Public Health 5 2011-10-01 2011-10-01 false Health information technology implementation advance planning document requirements (HIT IAPD). 495.338 Section 495.338 Public Health CENTERS...

  11. 42 CFR 495.338 - Health information technology implementation advance planning document requirements (HIT IAPD).

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... the Medicaid Program § 495.338 Health information technology implementation advance planning document... 42 Public Health 5 2013-10-01 2013-10-01 false Health information technology implementation advance planning document requirements (HIT IAPD). 495.338 Section 495.338 Public Health CENTERS...

  12. 76 FR 22397 - HIT Policy Committee Advisory Meeting; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-04-21

    ... framework for the development and adoption of a nationwide health information technology infrastructure that... Coordinator for Health Information Technology, HHS. ACTION: Notice of meeting. This notice announces a... Information Technology (ONC). The meeting will be open to the public. Name of Committee: HIT Policy...

  13. 75 FR 8953 - Office of the National Coordinator for Health Information Technology HIT Policy Committee...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-02-26

    ... and adoption of a nationwide health information technology infrastructure that permits the electronic... HUMAN SERVICES Office of the National Coordinator for Health Information Technology HIT Policy Committee... Technology, HHS. ACTION: Notice of meeting. This notice announces a forthcoming meeting of a public...

  14. 76 FR 70455 - HIT Policy Committee Advisory Meeting; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-14

    ... framework for the development and adoption of a nationwide health information technology infrastructure that... Coordinator for Health Information Technology, HHS. ACTION: Notice of meeting. This notice announces a... Information Technology (ONC). The meeting will be open to the public. Name of Committee: HIT Policy...

  15. 77 FR 15760 - HIT Policy Committee Advisory Meeting; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-03-16

    ... framework for the development and adoption of a nationwide health information technology infrastructure that... Coordinator for Health Information Technology, HHS. ACTION: Notice of meeting. This notice announces a... Information Technology (ONC). The meeting will be open to the public. Name of Committee: HIT Policy...

  16. 76 FR 50734 - HIT Policy Committee Advisory Meeting; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-08-16

    ... framework for the development and adoption of a nationwide health information technology infrastructure that... Coordinator for Health Information Technology, HHS. ACTION: Notice of meeting. This notice announces a... Information Technology (ONC). The meeting will be open to the public. Name of Committee: HIT Policy...

  17. 77 FR 65691 - HIT Standards Committee Advisory Meeting; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-10-30

    ... National Coordinator for Health Information Technology, HHS. ACTION: Notice of meeting. This notice... Health Information Technology (ONC). The meeting will be open to the public. Name of Committee: HIT... exchange and use of health information for purposes of adoption, consistent with the implementation of...

  18. 77 FR 65691 - HIT Policy Committee Advisory Meeting; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-10-30

    ... framework for the development and adoption of a nationwide health information technology infrastructure that... Coordinator for Health Information Technology, HHS. ACTION: Notice of meeting. This notice announces a... Information Technology (ONC). The meeting will be open to the public. Name of Committee: HIT Policy...

  19. 75 FR 29762 - HIT Policy Committee's Workgroup Meetings; Notice of Meetings

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-05-27

    ... HUMAN SERVICES Office of the National Coordinator for Health Information Technology HIT Policy Committee... Information Technology, HHS. ACTION: Notice of meetings. This notice announces forthcoming subcommittee... Technology (ONC). The meetings will be open to the public via dial-in access only. Name of Committees:...

  20. 77 FR 65690 - HIT Standards Committee Advisory Meeting; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-10-30

    ... National Coordinator for Health Information Technology, HHS. ACTION: Notice of meeting. This notice... Health Information Technology (ONC). The meeting will be open to the public. Name of Committee: HIT... exchange and use of health information for purposes of adoption, consistent with the implementation of...

  1. 42 CFR 495.332 - State Medicaid health information technology (HIT) plan requirements.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... and strategic plan for the next 5 years. (2) A description of how the State Medicaid HIT plan will be... for verifying such information. (c) Monitoring and validation. For monitoring and validation of... information. (5) A description of the process in place for monitoring the compliance of providers coming...

  2. 75 FR 57276 - Office of the National Coordinator for Health Information Technology; HIT Policy Committee...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-09-20

    ... HUMAN SERVICES Office of the National Coordinator for Health Information Technology; HIT Policy... Information Technology, HHS. ACTION: Notice of meeting. This notice announces a forthcoming meeting of a workgroup of a public advisory committee of the Office of the National Coordinator for Health...

  3. 76 FR 4352 - Office of the National Coordinator for Health Information Technology; HIT Policy Committee...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-25

    ... HUMAN SERVICES Office of the National Coordinator for Health Information Technology; HIT Policy... Information Technology, HHS. ACTION: Notice of meeting. This notice announces a forthcoming meeting of a public advisory committee of the Office of the National Coordinator for Health Information...

  4. 75 FR 29762 - Office of the National Coordinator for Health Information Technology; HIT Policy Committee...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-05-27

    ... HUMAN SERVICES Office of the National Coordinator for Health Information Technology; HIT Policy... Information Technology, HHS. ACTION: Notice of meeting. This notice announces a forthcoming meeting of a public advisory committee of the Office of the National Coordinator for Health Information...

  5. 75 FR 65486 - Office of the National Coordinator for Health Information Technology; HIT Policy Committee...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-10-25

    ... HUMAN SERVICES Office of the National Coordinator for Health Information Technology; HIT Policy... Information Technology, HHS. ACTION: Notice of meeting. This notice announces a forthcoming meeting of a public advisory committee of the Office of the National Coordinator for Health Information...

  6. 75 FR 51820 - Office of the National Coordinator for Health Information Technology; HIT Policy Committee...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-08-23

    ... HUMAN SERVICES Office of the National Coordinator for Health Information Technology; HIT Policy... Information Technology, HHS. ACTION: Notice of meeting. This notice announces a forthcoming meeting of a public advisory committee of the Office of the National Coordinator for Health Information...

  7. 75 FR 57026 - Office of the National Coordinator for Health Information Technology; HIT Policy Committee...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-09-17

    ... HUMAN SERVICES Office of the National Coordinator for Health Information Technology; HIT Policy... Information Technology, HHS. ACTION: Notice of meeting. This notice announces a forthcoming meeting of a public advisory committee of the Office of the National Coordinator for Health Information...

  8. 75 FR 42091 - Office of the National Coordinator for Health Information Technology; HIT Policy Committee...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-07-20

    ... HUMAN SERVICES Office of the National Coordinator for Health Information Technology; HIT Policy... Information Technology, HHS. ACTION: Notice of meeting. This notice announces a forthcoming meeting of a public advisory committee of the Office of the National Coordinator for Health Information...

  9. 75 FR 70923 - Office of the National Coordinator for Health Information Technology; HIT Policy Committee...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-11-19

    ... HUMAN SERVICES Office of the National Coordinator for Health Information Technology; HIT Policy... Information Technology, HHS ACTION: Notice of meeting. This notice announces a forthcoming meeting of a public advisory committee of the Office of the National Coordinator for Health Information Technology (ONC)....

  10. 75 FR 51819 - Office of the National Coordinator for Health Information Technology; HIT Policy Committee...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-08-23

    ... HUMAN SERVICES Office of the National Coordinator for Health Information Technology; HIT Policy... Information Technology, HHS. ACTION: Notice of meeting. This notice announces a forthcoming meeting of a public advisory committee of the Office of the National Coordinator for Health Information...

  11. As the Economic Crisis Hits Home, Colleges Seek Help from Congress

    ERIC Educational Resources Information Center

    Field, Kelly

    2008-01-01

    Congress is crafting a second economic-stimulus bill, and the nation's colleges, hit by the deepening fiscal crisis, want a share of the money. Over the last few weeks, colleges and their lobbyists have bombarded members of Congress with letters and phone calls seeking money for research, student aid, and infrastructure. However, Congress is…

  12. 42 CFR 495.332 - State Medicaid health information technology (HIT) plan requirements.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... across multiple service providers, funding sources, settings, and patient conditions— (iii) Universal...) A description of data-sharing components of HIT solutions. (5) A description of how each State will promote secure data exchange, where permissible under the Health Insurance Portability and...

  13. Sub-concussive hit characteristics predict deviant brain metabolism in football athletes.

    PubMed

    Poole, Victoria N; Breedlove, Evan L; Shenk, Trey E; Abbas, Kausar; Robinson, Meghan E; Leverenz, Larry J; Nauman, Eric A; Dydak, Ulrike; Talavage, Thomas M

    2015-01-01

    Magnetic resonance spectroscopy and helmet telemetry were used to monitor the neural metabolic response to repetitive head collisions in 25 high school American football athletes. Specific hit characteristics were determined highly predictive of metabolic alterations, suggesting that sub-concussive blows can produce biochemical changes and potentially lead to neurological problems.

  14. Optimization of a pyrazole hit from FBDD into a novel series of indazoles as ketohexokinase inhibitors.

    PubMed

    Zhang, Xuqing; Song, Fengbing; Kuo, Gee-Hong; Xiang, Amy; Gibbs, Alan C; Abad, Marta C; Sun, Weimei; Kuo, Lawrence C; Sui, Zhihua

    2011-08-15

    A series of indazoles have been discovered as KHK inhibitors from a pyrazole hit identified through fragment-based drug discovery (FBDD). The optimization process guided by both X-ray crystallography and solution activity resulted in lead-like compounds with good pharmaceutical properties. PMID:21767952

  15. Temperature impacts on economic growth warrant stringent mitigation policy

    NASA Astrophysics Data System (ADS)

    Moore, Frances C.; Diaz, Delavane B.

    2015-02-01

    Integrated assessment models compare the costs of greenhouse gas mitigation with damages from climate change to evaluate the social welfare implications of climate policy proposals and inform optimal emissions reduction trajectories. However, these models have been criticized for lacking a strong empirical basis for their damage functions, which do little to alter assumptions of sustained gross domestic product (GDP) growth, even under extreme temperature scenarios. We implement empirical estimates of temperature effects on GDP growth rates in the DICE model through two pathways, total factor productivity growth and capital depreciation. This damage specification, even under optimistic adaptation assumptions, substantially slows GDP growth in poor regions but has more modest effects in rich countries. Optimal climate policy in this model stabilizes global temperature change below 2 °C by eliminating emissions in the near future and implies a social cost of carbon several times larger than previous estimates. A sensitivity analysis shows that the magnitude of climate change impacts on economic growth, the rate of adaptation, and the dynamic interaction between damages and GDP are three critical uncertainties requiring further research. In particular, optimal mitigation rates are much lower if countries become less sensitive to climate change impacts as they develop, making this a major source of uncertainty and an important subject for future research.

  16. Disturbance in hitting accuracy by professional and collegiate baseball players due to intentional change of target position.

    PubMed

    Higuchi, Takatoshi; Nagami, Tomoyuki; Morohoshi, Jun; Nakata, Hiroki; Kanosue, Kazuyuki

    2013-04-01

    The present study investigated bat control of skilled baseball batters during tee batting, faced with an intentional change in target position. Twelve, skilled, male baseball players (M age = 24 yr., SD = 4) participated in the study. Participants were instructed to hit a baseball off a tee 0.8 m from the ground (Hitting condition), and also to deliberately swing just above the ball (Air Swing condition). The task for the participants was to perform, in alternate order, 15 swings at a real baseball on a stationary tee and 15 swings at an imaginary ball that was said to be on top of the real baseball. The participants were instructed to hit the ball toward center field just as they would hit in a game. While most participants could hit the real ball in the sweet area of the bat, only one participant did so in the Air Swing condition. Average distances from the center of the sweet area to ball center at the moment of ball-bat contact in the Air Swing condition (85 mm) were significantly greater than the distance in the Hitting condition (38 mm). The larger error in hitting an imaginary ball in the sweet area could be due to perceptual changes following the batter's altered focus, expectation of a lack of contact, and/or lack of feedback from the swing. It was suggested that baseball batters should be aware of the possible error in hitting accurately when they intentionally shifted the target. PMID:24032335

  17. Disturbance in hitting accuracy by professional and collegiate baseball players due to intentional change of target position.

    PubMed

    Higuchi, Takatoshi; Nagami, Tomoyuki; Morohoshi, Jun; Nakata, Hiroki; Kanosue, Kazuyuki

    2013-04-01

    The present study investigated bat control of skilled baseball batters during tee batting, faced with an intentional change in target position. Twelve, skilled, male baseball players (M age = 24 yr., SD = 4) participated in the study. Participants were instructed to hit a baseball off a tee 0.8 m from the ground (Hitting condition), and also to deliberately swing just above the ball (Air Swing condition). The task for the participants was to perform, in alternate order, 15 swings at a real baseball on a stationary tee and 15 swings at an imaginary ball that was said to be on top of the real baseball. The participants were instructed to hit the ball toward center field just as they would hit in a game. While most participants could hit the real ball in the sweet area of the bat, only one participant did so in the Air Swing condition. Average distances from the center of the sweet area to ball center at the moment of ball-bat contact in the Air Swing condition (85 mm) were significantly greater than the distance in the Hitting condition (38 mm). The larger error in hitting an imaginary ball in the sweet area could be due to perceptual changes following the batter's altered focus, expectation of a lack of contact, and/or lack of feedback from the swing. It was suggested that baseball batters should be aware of the possible error in hitting accurately when they intentionally shifted the target.

  18. Combining Computational Methods for Hit to Lead Optimization in Mycobacterium tuberculosis Drug Discovery

    PubMed Central

    Ekins, Sean; Freundlich, Joel S.; Hobrath, Judith V.; White, E. Lucile; Reynolds, Robert C

    2013-01-01

    Purpose Tuberculosis treatments need to be shorter and overcome drug resistance. Our previous large scale phenotypic high-throughput screening against Mycobacterium tuberculosis (Mtb) has identified 737 active compounds and thousands that are inactive. We have used this data for building computational models as an approach to minimize the number of compounds tested. Methods A cheminformatics clustering approach followed by Bayesian machine learning models (based on publicly available Mtb screening data) was used to illustrate that application of these models for screening set selections can enrich the hit rate. Results In order to explore chemical diversity around active cluster scaffolds of the dose-response hits obtained from our previous Mtb screens a set of 1924 commercially available molecules have been selected and evaluated for antitubercular activity and cytotoxicity using Vero, THP-1 and HepG2 cell lines with 4.3%, 4.2% and 2.7% hit rates, respectively. We demonstrate that models incorporating antitubercular and cytotoxicity data in Vero cells can significantly enrich the selection of non-toxic actives compared to random selection. Across all cell lines, the Molecular Libraries Small Molecule Repository (MLSMR) and cytotoxicity model identified ~10% of the hits in the top 1% screened (>10 fold enrichment). We also showed that seven out of nine Mtb active compounds from different academic published studies and eight out of eleven Mtb active compounds from a pharmaceutical screen (GSK) would have been identified by these Bayesian models. Conclusion Combining clustering and Bayesian models represents a useful strategy for compound prioritization and hit-to lead optimization of antitubercular agents. PMID:24132686

  19. Hit rates and radiation doses to nuclei of bone lining cells from alpha-particle-emitting radionuclides

    NASA Technical Reports Server (NTRS)

    Polig, E.; Jee, W. S.; Kruglikov, I. L.

    1992-01-01

    Factors relating the local concentration of a bone-seeking alpha-particle emitter to the mean hit rate have been determined for nuclei of bone lining cells using a Monte Carlo procedure. Cell nuclei were approximated by oblate spheroids with dimensions and location taken from a previous histomorphometric study. The Monte Carlo simulation is applicable for planar and diffuse labels at plane or cylindrical bone surfaces. Additionally, the mean nuclear dose per hit, the dose mean per hit, the mean track segment length and its second moment, the percentage of stoppers, and the frequency distribution of the dose have been determined. Some basic features of the hit statistics for bone lining cells have been outlined, and the consequences of existing standards of radiation protection with regard to the hit frequency to cell nuclei are discussed.

  20. Exploring Patterns of Soil Organic Matter Decomposition with Students and the Public Through the Global Decomposition Project (GDP)

    NASA Astrophysics Data System (ADS)

    Wood, J. H.; Natali, S.

    2014-12-01

    The Global Decomposition Project (GDP) is a program designed to introduce and educate students and the general public about soil organic matter and decomposition through a standardized protocol for collecting, reporting, and sharing data. This easy-to-use hands-on activity focuses on questions such as "How do environmental conditions control decomposition of organic matter in soil?" and "Why do some areas accumulate organic matter and others do not?" Soil organic matter is important to local ecosystems because it affects soil structure, regulates soil moisture and temperature, and provides energy and nutrients to soil organisms. It is also important globally because it stores a large amount of carbon, and when microbes "eat", or decompose organic matter they release greenhouse gasses such as carbon dioxide and methane into the atmosphere, which affects the earth's climate. The protocol describes a commonly used method to measure decomposition using a paper made of cellulose, a component of plant cell walls. Participants can receive pre-made cellulose decomposition bags, or make decomposition bags using instructions in the protocol and easily obtained materials (e.g., window screen and lignin-free paper). Individual results will be shared with all participants and the broader public through an online database. We will present decomposition bag results from a research site in Alaskan tundra, as well as from a middle-school-student led experiment in California. The GDP demonstrates how scientific methods can be extended to educate broader audiences, while at the same time, data collected by students and the public can provide new insight into global patterns of soil decomposition. The GDP provides a pathway for scientists and educators to interact and reach meaningful education and research goals.

  1. Structure of an archaeal heterotrimeric initiation factor 2 reveals a nucleotide state between the GTP and the GDP states

    PubMed Central

    Yatime, Laure; Mechulam, Yves; Blanquet, Sylvain; Schmitt, Emmanuelle

    2007-01-01

    Initiation of translation in eukaryotes and in archaea involves eukaryotic/archaeal initiation factor (e/aIF)1 and the heterotrimeric initiation factor e/aIF2. In its GTP-bound form, e/aIF2 provides the initiation complex with Met–tRNAiMet. After recognition of the start codon by initiator tRNA, e/aIF1 leaves the complex. Finally, e/aIF2, now in a GDP-bound form, loses affinity for Met–tRNAiMet and dissociates from the ribosome. Here, we report a 3D structure of an aIF2 heterotrimer from the archeon Sulfolobus solfataricus obtained in the presence of GDP. Our report highlights how the two-switch regions involved in formation of the tRNA-binding site on subunit γ exchange conformational information with α and β. The zinc-binding domain of β lies close to the guanine nucleotide and directly contacts the switch 1 region. As a result, switch 1 adopts a not yet described conformation. Moreover, unexpectedly for a GDP-bound state, switch 2 has the “ON” conformation. The stability of these conformations is accounted for by a ligand, most probably a phosphate ion, bound near the nucleotide binding site. The structure suggests that this GDP–inorganic phosphate (Pi) bound state of aIF2 may be proficient for tRNA binding. Recently, it has been proposed that dissociation of eIF2 from the initiation complex is closely coupled to that of Pi from eIF2γ upon start codon recognition. The nucleotide state of aIF2 shown here is indicative of a similar mechanism in archaea. Finally, we consider the possibility that release of Pi takes place after e/aIF2γ has been informed of e/aIF1 dissociation by e/aIF2β. PMID:18000047

  2. Mutagenesis in the switch IV of the helical domain of the human Gsalpha reduces its GDP/GTP exchange rate.

    PubMed

    Echeverría, V; Hinrichs, M V; Torrejón, M; Ropero, S; Martinez, J; Toro, M J; Olate, J

    2000-01-01

    The Galpha subunits of heterotrimeric G proteins are constituted by a conserved GTPase "Ras-like" domain (RasD) and by a unique alpha-helical domain (HD). Upon GTP binding, four regions, called switch I, II, III, and IV, have been identified as undergoing structural changes. Switch I, II, and III are located in RasD and switch IV in HD. All Galpha known functions, such as GTPase activity and receptor, effector, and Gbetagamma interaction sites have been found to be localized in RasD, but little is known about the role of HD and its switch IV region. Through the construction of chimeras between human and Xenopus Gsalpha we have previously identified a HD region, encompassing helices alphaA, alphaB, and alphaC, that was responsible for the observed functional differences in their capacity to activate adenylyl cyclase (Antonelli et al. [1994]: FEBS Lett 340:249-254). Since switch IV is located within this region and contains most of the nonconservative amino acid differences between both Gsalpha proteins, in the present work we constructed two human Gsalpha mutant proteins in which we have changed four and five switch IV residues for the ones present in the Xenopus protein. Mutants M15 (hGsalphaalphaS133N, M135P, P138K, P143S) and M17 (hGsalphaalphaS133N, M135P, V137Y, P138K, P143S) were expressed in Escherichia coli, purified, and characterized by their ability to bind GTPgammaS, dissociate GDP, hydrolyze GTP, and activate adenylyl cyclase. A decreased rate of GDP release, GTPgammaS binding, and GTP hydrolysis was observed for both mutants, M17 having considerably slower kinetics than M15 for all functions tested. Reconstituted adenylyl cyclase activity with both mutants showed normal activation in the presence of AlF(4)(-), but a decreased activation with GTPgammaS, which is consistent with the lower GDP dissociating rate they displayed. These data provide new evidence on the role that HD is playing in modulating the GDP/GTP exchange of the Gsalpha subunit. PMID

  3. Impact of GDP, Spending on R&D, Number of Universities and Scientific Journals on Research Publications among Asian Countries

    PubMed Central

    Meo, Sultan Ayoub; Al Masri, Abeer A.; Usmani, Adnan Mahmood; Memon, Almas Naeem; Zaidi, Syed Ziauddin

    2013-01-01

    Objectives This study aimed to compare the impact of Gross Domestic Product (GDP) per capita, spending on Research and Development (R&D), number of universities, and Indexed Scientific Journals on total number of research documents (papers), citations per document and Hirsch index (H-index) in various science and social science subjects among Asian countries. Materials and Methods In this study, 40 Asian countries were included. The information regarding Asian countries, their GDP per capita, spending on R&D, total number of universities and indexed scientific journals were collected. We recorded the bibliometric indicators, including total number of research documents, citations per document and H-index in various science and social sciences subjects during the period 1996–2011. The main sources for information were World Bank, SCI-mago/Scopus and Web of Science; Thomson Reuters. Results The mean per capita GDP for all the Asian countries is 14448.31±2854.40 US$, yearly per capita spending on R&D 0.64±0.16 US$, number of universities 72.37±18.32 and mean number of ISI indexed journal per country is 17.97±7.35. The mean of research documents published in various science and social science subjects among all the Asian countries during the period 1996–2011 is 158086.92±69204.09; citations per document 8.67±0.48; and H-index 122.8±19.21. Spending on R&D, number of universities and indexed journals have a positive correlation with number of published documents, citations per document and H-index in various science and social science subjects. However, there was no association between the per capita GDP and research outcomes. Conclusion The Asian countries who spend more on R&D have a large number of universities and scientific indexed journals produced more in research outcomes including total number of research publication, citations per documents and H-index in various science and social science subjects. PMID:23840471

  4. The International Baccalaureate and "Growth Scepticism": A "Social Limits" Framework

    ERIC Educational Resources Information Center

    Bunnell, Tristan

    2011-01-01

    The number of schools offering the programmes of the International Baccalaureate (IB) hit 3000 in July 2010. Since 2004 the IB has aimed for further growth within a "wider access" and "greater impact" paradigm. A "further" 7000 schools are expected to be involved by 2020. However, there is now considerable concern about growth, especially within…

  5. High-Growth Firms and the Future of the American Economy. Kauffman Foundation Research Series: Firm Formation and Economic Growth

    ERIC Educational Resources Information Center

    Stangler, Dane

    2010-01-01

    Into early 2010, more than two years after the recession began, the American economy continues to send out mixed signals with respect to economic recovery: GDP (gross domestic product) growth looks set to recover, while unemployment is projected to remain high for many more years. The most important economic matter facing the country is job…

  6. How do output growth-rate distributions look like? Some cross-country, time-series evidence

    NASA Astrophysics Data System (ADS)

    Fagiolo, G.; Napoletano, M.; Roventini, A.

    2007-05-01

    This paper investigates the statistical properties of within-country gross domestic product (GDP) and industrial production (IP) growth-rate distributions. Many empirical contributions have recently pointed out that cross-section growth rates of firms, industries and countries all follow Laplace distributions. In this work, we test whether also within-country, time-series GDP and IP growth rates can be approximated by tent-shaped distributions. We fit output growth rates with the exponential-power (Subbotin) family of densities, which includes as particular cases both Gaussian and Laplace distributions. We find that, for a large number of OECD (Organization for Economic Cooperation and Development) countries including the US, both GDP and IP growth rates are Laplace distributed. Moreover, we show that fat-tailed distributions robustly emerge even after controlling for outliers, autocorrelation and heteroscedasticity.

  7. What Is the Best Launch Angle To Hit a Home Run?

    NASA Astrophysics Data System (ADS)

    Kagan, David

    2010-04-01

    Your students will proudly raise their hands and answer, "45 degrees!" They are, however, answering a different question. It is true that in the absence of air resistance, for a given initial speed, the launch angle that maximizes the range is 45°. For a real homer, there are many complicating factors that make the question far more challenging to answer. Here is a partial list: 1. The initial speed off the bat is not fixed. Garvey's law, "The harder you hit it, the further it goes" is definitely at play; 2. Air resistance is a substantial influence on the flight of the ball. ; 3. The backspin on a well-hit ball creates lift due to the Magnus effect.2; 4. Atmospheric conditions such as humidity, temperature, air density, and the wind affect the motion as well.3; 5. Baseball parks are unique in size and shape. So, a home run in one park may not be a home run in another.

  8. An Automatic Quality Control Pipeline for High-Throughput Screening Hit Identification.

    PubMed

    Zhai, Yufeng; Chen, Kaisheng; Zhong, Yang; Zhou, Bin; Ainscow, Edward; Wu, Ying-Ta; Zhou, Yingyao

    2016-09-01

    The correction or removal of signal errors in high-throughput screening (HTS) data is critical to the identification of high-quality lead candidates. Although a number of strategies have been previously developed to correct systematic errors and to remove screening artifacts, they are not universally effective and still require fair amount of human intervention. We introduce a fully automated quality control (QC) pipeline that can correct generic interplate systematic errors and remove intraplate random artifacts. The new pipeline was first applied to ~100 large-scale historical HTS assays; in silico analysis showed auto-QC led to a noticeably stronger structure-activity relationship. The method was further tested in several independent HTS runs, where QC results were sampled for experimental validation. Significantly increased hit confirmation rates were obtained after the QC steps, confirming that the proposed method was effective in enriching true-positive hits. An implementation of the algorithm is available to the screening community.

  9. B-HIT - A Tool for Harvesting and Indexing Biodiversity Data

    PubMed Central

    Barker, Katharine; Braak, Kyle; Cawsey, E. Margaret; Coddington, Jonathan; Robertson, Tim; Whitacre, Jamie

    2015-01-01

    With the rapidly growing number of data publishers, the process of harvesting and indexing information to offer advanced search and discovery becomes a critical bottleneck in globally distributed primary biodiversity data infrastructures. The Global Biodiversity Information Facility (GBIF) implemented a Harvesting and Indexing Toolkit (HIT), which largely automates data harvesting activities for hundreds of collection and observational data providers. The team of the Botanic Garden and Botanical Museum Berlin-Dahlem has extended this well-established system with a range of additional functions, including improved processing of multiple taxon identifications, the ability to represent associations between specimen and observation units, new data quality control and new reporting capabilities. The open source software B-HIT can be freely installed and used for setting up thematic networks serving the demands of particular user groups. PMID:26544980

  10. "Hits" emerge through self-organized coordination in collective response of free agents

    NASA Astrophysics Data System (ADS)

    Chakrabarti, Anindya S.; Sinha, Sitabhra

    2016-10-01

    Individuals in free societies frequently exhibit striking coordination when making independent decisions en masse. Examples include the regular appearance of hit products or memes with substantially higher popularity compared to their otherwise equivalent competitors or extreme polarization in public opinion. Such segregation of events manifests as bimodality in the distribution of collective choices. Here we quantify how apparently independent choices made by individuals result in a significantly polarized but stable distribution of success in the context of the box-office performance of movies and show that it is an emergent feature of a system of noninteracting agents who respond to sequentially arriving signals. The aggregate response exhibits extreme variability amplifying much smaller differences in individual cost of adoption. Due to self-organization of the competitive landscape, most events elicit only a muted response but a few stimulate widespread adoption, emerging as "hits".

  11. High-Throughput Crystallography: Reliable and Efficient Identification of Fragment Hits.

    PubMed

    Schiebel, Johannes; Krimmer, Stefan G; Röwer, Karine; Knörlein, Anna; Wang, Xiaojie; Park, Ah Young; Stieler, Martin; Ehrmann, Frederik R; Fu, Kan; Radeva, Nedyalka; Krug, Michael; Huschmann, Franziska U; Glöckner, Steffen; Weiss, Manfred S; Mueller, Uwe; Klebe, Gerhard; Heine, Andreas

    2016-08-01

    Today the identification of lead structures for drug development often starts from small fragment-like molecules raising the chances to find compounds that successfully pass clinical trials. At the heart of the screening for fragments binding to a specific target, crystallography delivers structural information essential for subsequent drug design. While it is common to search for bound ligands in electron densities calculated directly after an initial refinement cycle, we raise the important question whether this strategy is viable for fragments characterized by low affinities. Here, we describe and provide a collection of high-quality diffraction data obtained from 364 protein crystals treated with diverse fragments. Subsequent data analysis showed that ∼25% of all hits would have been missed without further refining the resulting structures. To enable fast and reliable hit identification, we have designed an automated refinement pipeline that will inspire the development of optimized tools facilitating the successful application of fragment-based methods. PMID:27452405

  12. An Automatic Quality Control Pipeline for High-Throughput Screening Hit Identification.

    PubMed

    Zhai, Yufeng; Chen, Kaisheng; Zhong, Yang; Zhou, Bin; Ainscow, Edward; Wu, Ying-Ta; Zhou, Yingyao

    2016-09-01

    The correction or removal of signal errors in high-throughput screening (HTS) data is critical to the identification of high-quality lead candidates. Although a number of strategies have been previously developed to correct systematic errors and to remove screening artifacts, they are not universally effective and still require fair amount of human intervention. We introduce a fully automated quality control (QC) pipeline that can correct generic interplate systematic errors and remove intraplate random artifacts. The new pipeline was first applied to ~100 large-scale historical HTS assays; in silico analysis showed auto-QC led to a noticeably stronger structure-activity relationship. The method was further tested in several independent HTS runs, where QC results were sampled for experimental validation. Significantly increased hit confirmation rates were obtained after the QC steps, confirming that the proposed method was effective in enriching true-positive hits. An implementation of the algorithm is available to the screening community. PMID:27313114

  13. Single-hit resolution measurement with MEG II drift chamber prototypes

    NASA Astrophysics Data System (ADS)

    Baldini, A. M.; Baracchini, E.; Cavoto, G.; Cascella, M.; Cei, F.; Chiappini, M.; Chiarello, G.; Chiri, C.; Dussoni, S.; Galli, L.; Grancagnolo, F.; Grassi, M.; Martinelli, V.; Nicolò, D.; Panareo, M.; Pepino, A.; Piredda, G.; Renga, F.; Ripiccini, E.; Signorelli, G.; Tassielli, G. F.; Tenchini, F.; Venturini, M.; Voena, C.

    2016-07-01

    Drift chambers operated with helium-based gas mixtures represent a common solution for tracking charged particles keeping the material budget in the sensitive volume to a minimum. The drawback of this solution is the worsening of the spatial resolution due to primary ionisation fluctuations, which is a limiting factor for high granularity drift chambers like the MEG II tracker. We report on the measurements performed on three different prototypes of the MEG II drift chamber aimed at determining the achievable single-hit resolution. The prototypes were operated with helium/isobutane gas mixtures and exposed to cosmic rays, electron beams and radioactive sources. Direct measurements of the single hit resolution performed with an external tracker returned a value of 110 μm, consistent with the values obtained with indirect measurements performed with the other prototypes.

  14. Hit and lead criteria in drug discovery for infectious diseases of the developing world.

    PubMed

    Katsuno, Kei; Burrows, Jeremy N; Duncan, Ken; Hooft van Huijsduijnen, Rob; Kaneko, Takushi; Kita, Kiyoshi; Mowbray, Charles E; Schmatz, Dennis; Warner, Peter; Slingsby, B T

    2015-11-01

    Reducing the burden of infectious diseases that affect people in the developing world requires sustained collaborative drug discovery efforts. The quality of the chemical starting points for such projects is a key factor in improving the likelihood of clinical success, and so it is important to set clear go/no-go criteria for the progression of hit and lead compounds. With this in mind, the Japanese Global Health Innovative Technology (GHIT) Fund convened with experts from the Medicines for Malaria Venture, the Drugs for Neglected Diseases initiative and the TB Alliance, together with representatives from the Bill &Melinda Gates Foundation, to set disease-specific criteria for hits and leads for malaria, tuberculosis, visceral leishmaniasis and Chagas disease. Here, we present the agreed criteria and discuss the underlying rationale.

  15. Assessing lung cancer risk in railroad workers using a first hitting time regression model

    PubMed Central

    Lee, Mei-Ling Ting; Whitmore, G. A.; Laden, Francine; Hart, Jaime E.; Garshick, Eric

    2005-01-01

    SUMMARY This article examines the application of a first hitting time (FHT) model, using an operational time scale, to assess mortality risk differentials of the work environment. A major case application is presented that applies the model to three job categories of railroad workers. The data set involves a study of more than 50 000 workers with mortality assessed from 1959 to 1996. Lung cancer mortality was assessed because of a suspected link to diesel exhaust exposure. Based on a model that stipulates that death occurs when the disease state of a subject first hits a threshold value, the FHT model provides insights into factors influencing disease progression. In this application, in particular, the findings suggest that a job category in 1959 alters the risk of death from lung cancer. PMID:16741563

  16. MIDAS and HIT-6 French translation: reliability and correlation between tests.

    PubMed

    Magnoux, E; Freeman, M A; Zlotnik, G

    2008-01-01

    The aim was to evaluate the test-retest reliability of the French translation of the Migraine Disability Assessment (MIDAS) and Headache Impact Test (HIT)-6 questionnaires as applied to episodic and chronic headaches and to assess the correlation between these two questionnaires. The MIDAS and HIT-6 questionnaires, which assess the degree of migraine-related functional disability, are widely used in headache treatment clinics. The French translation has not been checked for test-retest reliability. MIDAS involves recall, over the previous 3 months, of the number of days with functional disability with regard to work and to home and social life. HIT-6 involves a more subjective and general assessment of headache-related disability over the previous 4 weeks. We expect that there may be greater impact recall bias for chronic headaches than for episodic headaches and considered it important to be able to determine if the reliability of these questionnaires is equally good for these two patient populations. Given that both questionnaires have the same objective, that of assessing headache impact, it was thought useful to determine if their results might show a correlation and if they could thus be used interchangeably. The study was approved by an external ethics committee. The subjects were patients who regularly visit the Clinique de la Migraine de Montréal, which specializes in the treatment of headaches. The MIDAS and HIT-6 questionnaires were completed by the patients during their regular visit. Twelve days later, the same questionnaires were mailed with a prepaid return envelope. Sixty-five patients were required in both the episodic and chronic headache groups, assuming an 80% questionnaire return rate. One hundred and eighty-five patients were enrolled, and 143 completed the study, 75 with episodic headaches and 68 with chronic headaches. The questionnaire return rate was 78.9%. On average, questionnaires were completed a second time 21 days after the first

  17. Novel current drive experiments on the CDX-U, HIT, and DIII-D Tokamaks

    SciTech Connect

    Ono, M.; Forest, C.B.; Hwang, Y.S.; Armstrong, R.J.; Choe, W.; Darrow, D.S.; Greene, G.; Jones, T.; Jarboe, T.R.; Martin, A.; Nelson, B.A.; Orvis, D.; Painter, C.; Zhou, L.; Rogers, J.A.; Schaffer, M.J.; Hyatt, A.W.; Pinsker, R.I.; Staebler, G.M.; Stambaugh, R.D.; Strait, E.J.; Greene, K.L.; Leuer, J.A.; Lohr, J.M.

    1992-10-01

    Two types of novel, non-inductive current drive concepts for starting-up and maintaining tokamak discharges have been developed on the CDX-U, HIT, and DIII-D Tokamaks. On CDX-U, a new, non-inductive current drive technique utilizing fully internally generated pressure driven currents has been demonstrated. The measured current density profile shows a non-hollow profile which agrees with a modeling calculation including helicity conserving non-classical current transport providing the ``seed current``. Another current drive concept, dc-helicity injection, has been investigated on, CDX-U, HIT and DIII-D. This method utilizes injection of magnetic helicity via low energy electron currents, maintaining the plasma current through helicity conserving relaxiation. In these experiments, non-ohmic tokamak plasmas were formed and maintained in the tens of kA range.

  18. Novel current drive experiments on the CDX-U, HIT, and DIII-D Tokamaks

    SciTech Connect

    Ono, M.; Forest, C.B.; Hwang, Y.S.; Armstrong, R.J.; Choe, W.; Darrow, D.S.; Greene, G.; Jones, T. . Plasma Physics Lab.); Jarboe, T.R.; Martin, A.; Nelson, B.A.; Orvis, D.; Painter, C.; Zhou, L.; Rogers, J.A. ); Schaffer, M.J.; Hyatt, A.W.; Pinsker, R.I.; Staebler, G.M.; Stambaugh, R.D.; Strait, E.J.; Greene, K.L.; Leuer, J.A.; Lohr, J.

    1992-01-01

    Two types of novel, non-inductive current drive concepts for starting-up and maintaining tokamak discharges have been developed on the CDX-U, HIT, and DIII-D Tokamaks. On CDX-U, a new, non-inductive current drive technique utilizing fully internally generated pressure driven currents has been demonstrated. The measured current density profile shows a non-hollow profile which agrees with a modeling calculation including helicity conserving non-classical current transport providing the seed current''. Another current drive concept, dc-helicity injection, has been investigated on, CDX-U, HIT and DIII-D. This method utilizes injection of magnetic helicity via low energy electron currents, maintaining the plasma current through helicity conserving relaxiation. In these experiments, non-ohmic tokamak plasmas were formed and maintained in the tens of kA range.

  19. Elucidation of transcriptome-wide microRNA binding sites in human cardiac tissues by Ago2 HITS-CLIP

    PubMed Central

    Spengler, Ryan M.; Zhang, Xiaoming; Cheng, Congsheng; McLendon, Jared M.; Skeie, Jessica M.; Johnson, Frances L.; Davidson, Beverly L.; Boudreau, Ryan L.

    2016-01-01

    MicroRNAs (miRs) have emerged as key biological effectors in human health and disease. These small noncoding RNAs are incorporated into Argonaute (Ago) proteins, where they direct post-transcriptional gene silencing via base-pairing with target transcripts. Although miRs have become intriguing biological entities and attractive therapeutic targets, the translational impacts of miR research remain limited by a paucity of empirical miR targeting data, particularly in human primary tissues. Here, to improve our understanding of the diverse roles miRs play in cardiovascular function and disease, we applied high-throughput methods to globally profile miR:target interactions in human heart tissues. We deciphered Ago2:RNA interactions using crosslinking immunoprecipitation coupled with high-throughput sequencing (HITS-CLIP) to generate the first transcriptome-wide map of miR targeting events in human myocardium, detecting 4000 cardiac Ago2 binding sites across >2200 target transcripts. Our initial exploration of this interactome revealed an abundance of miR target sites in gene coding regions, including several sites pointing to new miR-29 functions in regulating cardiomyocyte calcium, growth and metabolism. Also, we uncovered several clinically-relevant interactions involving common genetic variants that alter miR targeting events in cardiomyopathy-associated genes. Overall, these data provide a critical resource for bolstering translational miR research in heart, and likely beyond. PMID:27418678

  20. Rethinking of Economic Growth and Life Satisfaction in Post-WWII Japan--A Fresh Approach

    ERIC Educational Resources Information Center

    Kusago, Takayoshi

    2007-01-01

    Gross Domestic Product (GDP) has been utilized by academics and policy makers to indicate the economic well-being of the people. However, economic growth measures cannot capture fully the overall well-being of the people. This paper has tested quality of economic growth in Japan after World War II as to whether it has brought about positive…

  1. Multiple NSAID-Induced Hits Injure the Small Intestine: Underlying Mechanisms and Novel Strategies

    PubMed Central

    Boelsterli, Urs A.

    2013-01-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) can cause serious gastrointestinal (GI) injury including jejunal/ileal mucosal ulceration, bleeding, and even perforation in susceptible patients. The underlying mechanisms are largely unknown, but they are distinct from those related to gastric injury. Based on recent insights from experimental models, including genetics and pharmacology in rodents typically exposed to diclofenac, indomethacin, or naproxen, we propose a multiple-hit pathogenesis of NSAID enteropathy. The multiple hits start with an initial pharmacokinetic determinant caused by vectorial hepatobiliary excretion and delivery of glucuronidated NSAID or oxidative metabolite conjugates to the distal small intestinal lumen, where bacterial β-glucuronidase produces critical aglycones. The released aglycones are then taken up by enterocytes and further metabolized by intestinal cytochrome P450s to potentially reactive intermediates. The “first hit” is caused by the NSAID and/or oxidative metabolites that induce severe endoplasmic reticulum stress or mitochondrial stress and lead to cell death. The “second hit” is created by the significant subsequent inflammatory response that would follow such a first-hit injury. Based on these putative mechanisms, strategies have been developed to protect the enterocytes from being exposed to the parent NSAID and/or oxidative metabolites. Among these, a novel strategy already demonstrated in a murine model is the selective disruption of bacteria-specific β-glucuronidases with a novel small molecule inhibitor that does not harm the bacteria and that alleviates NSAID-induced enteropathy. Such mechanism-based strategies require further investigation but provide potential avenues for the alleviation of the GI toxicity caused by multiple NSAID hits. PMID:23091168

  2. Validation of concussion risk curves for collegiate football players derived from HITS data.

    PubMed

    Funk, James R; Rowson, Steven; Daniel, Ray W; Duma, Stefan M

    2012-01-01

    For several years, Virginia Tech and other schools have measured the frequency and severity of head impacts sustained by collegiate American football players in real time using the Head Impact Telemetry (HIT) System of helmet-mounted accelerometers. In this study, data from 37,128 head impacts collected at Virginia Tech during games from 2006 to 2010 were analyzed. Peak head acceleration exceeded 100 g in 516 impacts, and the Head Injury Criterion (HIC) exceeded 200 in 468 impacts. Four instrumented players in the dataset sustained a concussion. These data were used to develop risk curves for concussion as a function of peak head acceleration and HIC. The validity of this biomechanical approach was assessed using epidemiological data on concussion incidence from other sources. Two specific aspects of concussion incidence were addressed: the variation by player position, and the frequency of repeat concussions. The HIT System data indicated that linemen sustained the highest overall number of head impacts, while skill positions sustained a higher number of more severe head impacts (peak acceleration > 100 g or HIC > 200). When weighted using injury risk curves, the HIT System data predicted a higher incidence of concussion in skill positions compared to linemen at rates that were in strong agreement with the epidemiological literature (Pearson's r = 0.72-0.87). The predicted rates of repeat concussions (21-39% over one season and 33-50% over five seasons) were somewhat higher than the ranges reported in the epidemiological literature. These analyses demonstrate that simple biomechanical parameters that can be measured by the HIT System possess a high level of power for predicting concussion.

  3. Antiproton annihilation physics in the Monte Carlo particle transport code SHIELD-HIT12A

    NASA Astrophysics Data System (ADS)

    Taasti, Vicki Trier; Knudsen, Helge; Holzscheiter, Michael H.; Sobolevsky, Nikolai; Thomsen, Bjarne; Bassler, Niels

    2015-03-01

    The Monte Carlo particle transport code SHIELD-HIT12A is designed to simulate therapeutic beams for cancer radiotherapy with fast ions. SHIELD-HIT12A allows creation of antiproton beam kernels for the treatment planning system TRiP98, but first it must be benchmarked against experimental data. An experimental depth dose curve obtained by the AD-4/ACE collaboration was compared with an earlier version of SHIELD-HIT, but since then inelastic annihilation cross sections for antiprotons have been updated and a more detailed geometric model of the AD-4/ACE experiment was applied. Furthermore, the Fermi-Teller Z-law, which is implemented by default in SHIELD-HIT12A has been shown not to be a good approximation for the capture probability of negative projectiles by nuclei. We investigate other theories which have been developed, and give a better agreement with experimental findings. The consequence of these updates is tested by comparing simulated data with the antiproton depth dose curve in water. It is found that the implementation of these new capture probabilities results in an overestimation of the depth dose curve in the Bragg peak. This can be mitigated by scaling the antiproton collision cross sections, which restores the agreement, but some small deviations still remain. Best agreement is achieved by using the most recent antiproton collision cross sections and the Fermi-Teller Z-law, even if experimental data conclude that the Z-law is inadequately describing annihilation on compounds. We conclude that more experimental cross section data are needed in the lower energy range in order to resolve this contradiction, ideally combined with more rigorous models for annihilation on compounds.

  4. Second hit in cervical carcinogenesis process: involvement of wnt/beta catenin pathway

    PubMed Central

    Perez-Plasencia, Carlos; Duenas-Gonzalez, Alfonso; Alatorre-Tavera, Brenda

    2008-01-01

    The Human papillomavirus plays an important role in the initiation and progression of cervical cancer. However, it is a necessary but not sufficient cause to develop invasive carcinoma; hence, other factors are required in the pathogenesis of this malignancy. In this review we explore the hypothesis of the deregulation of wnt/β-catenin signaling pathway as a "second hit" required to develop cervical cancer. PMID:18606007

  5. Preventive effects of minocycline in a neurodevelopmental two-hit model with relevance to schizophrenia

    PubMed Central

    Giovanoli, S; Engler, H; Engler, A; Richetto, J; Feldon, J; Riva, M A; Schedlowski, M; Meyer, U

    2016-01-01

    Maternal immune activation can increase the vulnerability of the offspring to develop neuroimmune and behavioral abnormalities in response to stress in puberty. In offspring of immune-challenged mothers, stress-induced inflammatory processes precede the adult onset of multiple behavioral dysfunctions. Here, we explored whether an early anti-inflammatory intervention during peripubertal stress exposure might prevent the subsequent emergence of adult behavioral pathology. We used an environmental two-hit model in mice, in which prenatal maternal administration of the viral mimetic poly(I:C) served as the first hit, and exposure to sub-chronic unpredictable stress during peripubertal maturation as the second hit. Using this model, we examined the effectiveness of the tetracycline antibiotic minocycline (MINO) given during stress exposure to block stress-induced inflammatory responses and to prevent subsequent behavioral abnormalities. We found that combined exposure to prenatal immune activation and peripubertal stress caused significant deficits in prepulse inhibition and increased sensitivity to the psychotomimetic drugs amphetamine and dizocilpine in adulthood. MINO treatment during stress exposure prevented the emergence of these behavioral dysfunctions. In addition, the pharmacological intervention blocked hippocampal and prefrontal microglia activation and interleukin-1β expression in offspring exposed to prenatal infection and peripubertal stress. Together, these findings demonstrate that presymptomatic MINO treatment can prevent the subsequent emergence of multiple behavioral abnormalities relevant to human neuropsychiatric disorders with onset in early adulthood, including schizophrenia. Our epidemiologically informed two-hit model may thus encourage attempts to explore the use of anti-inflammatory agents in the early course of brain disorders that are characterized by signs of central nervous system inflammation during development. PMID:27045842

  6. Analysis of impact noise induced by hitting of titanium head golf driver.

    PubMed

    Kim, Young Ho; Kim, Young Chul; Lee, Jun Hee; An, Yong-Hwi; Park, Kyung Tae; Kang, Kyung Min; Kang, Yeon June

    2014-11-01

    The hitting of titanium head golf driver against golf ball creates a short duration, high frequency impact noise. We analyzed the spectra of these impact noises and evaluated the auditory hazards from exposure to the noises. Noises made by 10 titanium head golf drivers with five maximum hits were collected, and the spectra of the pure impact sounds were studied using a noise analysis program. The noise was measured at 1.7 m (position A) and 3.4 m (position B) from the hitting point in front of the hitter and at 3.4 m (position C) behind the hitting point. Average time duration was measured and auditory risk units (ARUs) at position A were calculated using the Auditory Hazard Assessment Algorithm for Humans. The average peak levels at position A were 119.9 dBA at the sound pressure level (SPL) peak and 100.0 dBA at the overall octave level. The average peak levels (SPL and overall octave level) at position B were 111.6 and 96.5 dBA, respectively, and at position C were 111.5 and 96.7 dBA, respectively. The average time duration and ARUs measured at position A were 120.6 ms and 194.9 units, respectively. Although impact noises made by titanium head golf drivers showed relatively low ARUs, individuals enjoying golf frequently may be susceptible to hearing loss due to the repeated exposure of this intense impact noise with short duration and high frequency. Unprotected exposure to impact noises should be limited to prevent cochleovestibular disorders.

  7. Utility of consecutive repeat HIT ELISA testing for heparin-induced thrombocytopenia.

    PubMed

    Chan, Maren; Malynn, Elizabeth; Shaz, Beth; Uhl, Lynne

    2008-03-01

    Heparin-induced thrombocytopenia (HIT) is a serious complication of heparin therapy. Limited data are available regarding repeat HIT antibody testing after an initial negative test. We conducted a retrospective study to determine the utility of repeat testing. Heparin antibodies were detected using the GTI-PF4 enzyme-linked immunoabsorbent assay, ELISA (GTI Diagnostics, Waukesha, WI). Patients (n = 137) were assigned to one of three groups based upon the initial negative test optical density (OD) range of low = 0-0.132, medium = 0.133-0.267, and high = 0.268-0.399. A pretest clinical score was retrospectively determined using the "4T's" (Thrombocytopenia, Timing of platelet fall, Thrombosis, and the absence of oTher causes of thrombocytopenia). A subsequent positive ELISA was found in 16% (22/137) of patients who underwent repeat testing. Most of these patients had a low pretest clinical score (62%). Four patients had an interval change in the pretest score between the initial negative and subsequent positive tests. Only these four patients developed HIT with thrombosis (HITT). Eighty percent of patients with a high initial negative test OD value had a positive ELISA on repeat testing; however, the initial negative test OD value could not predict whether a patient developed HITT. In contrast, an increase in the pretest clinical probability between initial and repeat testing better predicted HITT. Consecutive repeat ELISA testing for heparin antibodies may be warranted in patients with an increase in their pretest clinical score after an initial negative test as an adjunct to confirm the diagnosis of HIT.

  8. Development and formative evaluation of the e-Health Implementation Toolkit (e-HIT)

    PubMed Central

    2010-01-01

    Background The use of Information and Communication Technology (ICT) or e-Health is seen as essential for a modern, cost-effective health service. However, there are well documented problems with implementation of e-Health initiatives, despite the existence of a great deal of research into how best to implement e-Health (an example of the gap between research and practice). This paper reports on the development and formative evaluation of an e-Health Implementation Toolkit (e-HIT) which aims to summarise and synthesise new and existing research on implementation of e-Health initiatives, and present it to senior managers in a user-friendly format. Results The content of the e-HIT was derived by combining data from a systematic review of reviews of barriers and facilitators to implementation of e-Health initiatives with qualitative data derived from interviews of "implementers", that is people who had been charged with implementing an e-Health initiative. These data were summarised, synthesised and combined with the constructs from the Normalisation Process Model. The software for the toolkit was developed by a commercial company (RocketScience). Formative evaluation was undertaken by obtaining user feedback. There are three components to the toolkit - a section on background and instructions for use aimed at novice users; the toolkit itself; and the report generated by completing the toolkit. It is available to download from http://www.ucl.ac.uk/pcph/research/ehealth/documents/e-HIT.xls Conclusions The e-HIT shows potential as a tool for enhancing future e-Health implementations. Further work is needed to make it fully web-enabled, and to determine its predictive potential for future implementations. PMID:20955594

  9. Hierarchical structure of the European countries based on debts as a percentage of GDP during the 2000-2011 period

    NASA Astrophysics Data System (ADS)

    Kantar, Ersin; Deviren, Bayram; Keskin, Mustafa

    2014-11-01

    We investigate hierarchical structures of the European countries by using debt as a percentage of Gross Domestic Product (GDP) of the countries as they change over a certain period of time. We obtain the topological properties among the countries based on debt as a percentage of GDP of European countries over the period 2000-2011 by using the concept of hierarchical structure methods (minimal spanning tree, (MST) and hierarchical tree, (HT)). This period is also divided into two sub-periods related to 2004 enlargement of the European Union, namely 2000-2004 and 2005-2011, in order to test various time-window and observe the temporal evolution. The bootstrap techniques is applied to see a value of statistical reliability of the links of the MSTs and HTs. The clustering linkage procedure is also used to observe the cluster structure more clearly. From the structural topologies of these trees, we identify different clusters of countries according to their level of debts. Our results show that by the debt crisis, the less and most affected Eurozone’s economies are formed as a cluster with each other in the MSTs and hierarchical trees.

  10. Metabolic engineering of Escherichia coli to produce 2'-fucosyllactose via salvage pathway of guanosine 5'-diphosphate (GDP)-l-fucose.

    PubMed

    Chin, Young-Wook; Seo, Nari; Kim, Jae-Han; Seo, Jin-Ho

    2016-11-01

    2'-Fucosyllactose (2-FL) is one of the key oligosaccharides in human milk. In the present study, the salvage guanosine 5'-diphosphate (GDP)-l-fucose biosynthetic pathway from fucose was employed in engineered Escherichia coli BL21star(DE3) for efficient production of 2-FL. Introduction of the fkp gene coding for fucokinase/GDP-l-fucose pyrophosphorylase (Fkp) from Bacteroides fragilis and the fucT2 gene encoding α-1,2-fucosyltransferase from Helicobacter pylori allows the engineered E. coli to produce 2-FL from fucose, lactose and glycerol. To enhance the lactose flux to 2-FL production, the attenuated, and deleted mutants of β-galactosidase were employed. Moreover, the 2-FL yield and productivity were further improved by deletion of the fucI-fucK gene cluster coding for fucose isomerase (FucI) and fuculose kinase (FucK). Finally, fed-batch fermentation of engineered E. coli BL21star(DE3) deleting lacZ and fucI-fucK, and expressing fkp and fucT2 resulted in 23.1 g/L of extracellular concentration of 2-FL and 0.39 g/L/h productivity. Biotechnol. Bioeng. 2016;113: 2443-2452. © 2016 Wiley Periodicals, Inc. PMID:27217241

  11. Metabolic engineering of Escherichia coli to produce 2'-fucosyllactose via salvage pathway of guanosine 5'-diphosphate (GDP)-l-fucose.

    PubMed

    Chin, Young-Wook; Seo, Nari; Kim, Jae-Han; Seo, Jin-Ho

    2016-11-01

    2'-Fucosyllactose (2-FL) is one of the key oligosaccharides in human milk. In the present study, the salvage guanosine 5'-diphosphate (GDP)-l-fucose biosynthetic pathway from fucose was employed in engineered Escherichia coli BL21star(DE3) for efficient production of 2-FL. Introduction of the fkp gene coding for fucokinase/GDP-l-fucose pyrophosphorylase (Fkp) from Bacteroides fragilis and the fucT2 gene encoding α-1,2-fucosyltransferase from Helicobacter pylori allows the engineered E. coli to produce 2-FL from fucose, lactose and glycerol. To enhance the lactose flux to 2-FL production, the attenuated, and deleted mutants of β-galactosidase were employed. Moreover, the 2-FL yield and productivity were further improved by deletion of the fucI-fucK gene cluster coding for fucose isomerase (FucI) and fuculose kinase (FucK). Finally, fed-batch fermentation of engineered E. coli BL21star(DE3) deleting lacZ and fucI-fucK, and expressing fkp and fucT2 resulted in 23.1 g/L of extracellular concentration of 2-FL and 0.39 g/L/h productivity. Biotechnol. Bioeng. 2016;113: 2443-2452. © 2016 Wiley Periodicals, Inc.

  12. Gadolinium heteropoly complex K 17[Gd(P 2W 17O 61) 2] as a potential MRI contrast agent

    NASA Astrophysics Data System (ADS)

    Sun, Guoying; Feng, Jianghua; Wu, Huifeng; Pei, Fengkui; Fang, Ke; Lei, Hao

    2004-10-01

    Gadolinium heteropoly complex K17[Gd(P2W17O61)2] has been evaluated by in vitro and in vivo experiments as a potential contrast agent for magnetic resonance imaging (MRI). The thermal analysis and conductivity study indicate that this complex has good thermal stability and wide pH stability range. The T1 relaxivity is 7.59 mM-1 s-1 in aqueous solution and 7.97 mM-1 s-1 in 0.725 mmol l-1 bovine serum albumin (BSA) solution at 25 °C and 9.39 T, respectively. MR imaging of three male Sprague-Dawley rats showed remarkable enhancement in rat liver after intravenous injection, which persisted longer than with Gd-DTPA. The signal intensity increased by 57.1±16.9% during the whole imaging period at 0.082 mmol kg-1dose. Our preliminary in vitro and in vivo studies indicate that K17[Gd(P2W17O61)2] is a potential liver-specific MRI contrast agent.

  13. A presynaptic role for the ADP ribosylation factor (ARF)-specific GDP/GTP exchange factor msec7-1.

    PubMed

    Ashery, U; Koch, H; Scheuss, V; Brose, N; Rettig, J

    1999-02-01

    ADP ribosylation factors (ARFs) represent a family of small monomeric G proteins that switch from an inactive, GDP-bound state to an active, GTP-bound state. One member of this family, ARF6, translocates on activation from intracellular compartments to the plasma membrane and has been implicated in regulated exocytosis in neuroendocrine cells. Because GDP release in vivo is rather slow, ARF activation is facilitated by specific guanine nucleotide exchange factors like cytohesin-1 or ARNO. Here we show that msec7-1, a rat homologue of cytohesin-1, translocates ARF6 to the plasma membrane in living cells. Overexpression of msec7-1 leads to an increase in basal synaptic transmission at the Xenopus neuromuscular junction. msec7-1-containing synapses have a 5-fold higher frequency of spontaneous synaptic currents than control synapses. On stimulation, the amplitudes of the resulting evoked postsynaptic currents of msec7-1-overexpressing neurons are increased as well. However, further stimulation leads to a decline in amplitudes approaching the values of control synapses. This transient effect on amplitude is strongly reduced on overexpression of msec7-1E157K, a mutant incapable of translocating ARFs. Our results provide evidence that small G proteins of the ARF family and activating factors like msec7-1 play an important role in synaptic transmission, most likely by making more vesicles available for fusion at the plasma membrane.

  14. Ionoluminescence analysis of glass scintillators and application to single-ion-hit real-time detection

    NASA Astrophysics Data System (ADS)

    Yokoyama, Akihito; Kada, Wataru; Satoh, Takahiro; Koka, Masashi; Shimada, Keisuke; Yokoata, Yuya; Miura, Kenta; Hanaizumi, Osamu

    2016-03-01

    In this paper, we propose and test a real-time detection system for single-ion hits using mega-electronvolt (MeV)-heavy ions. The system was constructed using G2000 and G9 glass scintillators, as well as an electron-multiplying charge-coupled device (EMCCD) camera combined with an inverted microscope with a 10× objective lens. Commercially available G2000 and G9 glass scintillators, which have been reported to exhibit strong photoluminescence at 489, 543, 585, and 622 nm as a result of the Tb3+ f-f transition, were employed for highly accurate ionized particle detection. The EMCCD camera had a resolution of 512 × 512 pixels, each with a size of 16 μm × 16 μm, and a maximum linear gain of 8 × 105 electrons. For 260-MeV Ne, 3 ion hits/s were detected by our system. The intensity of the ionoluminescence (IL) peak induced by the heavy ions was 140 times the noise intensity. In contrast, the luminous diameter at the full width at half maximum (FWHM) in both the horizontal and vertical directions was calculated to be approximately 4.5 μm. These results suggest that our detection system can accurately detect single-ion hits with a diameter of the order of 1 μm.

  15. Bat speed, trajectory, and timing for collegiate baseball batters hitting a stationary ball.

    PubMed

    Tabuchi, Noriyuki; Matsuo, Tomoyuki; Hashizume, Ken

    2007-01-01

    The aims of this study were to examine whether batters hit stationary balls at the time of peak speed of the bat head and whether the impact occurs at the lowest point of the bat trajectory. Eight university baseball players hit three balls, each hung with a string; each ball was made of a different material and was different in weight. Bat movement was captured by four 240-Hz infrared cameras and analysed three-dimensionally. Time for peak speed of the bat head varied according to the conditions. When stationary balls of standard weight were used, the bat head was at maximum speed at impact with the ball; then, it decelerated drastically owing to the impact. In contrast, maximum speed was obtained after impact when lightweight stationary balls were used. The time-speed profile of the bat head before impact in the lightweight ball condition was identical with that in the standard weight ball condition. Regardless of conditions, the timing of the lowest point of the bat head was nearly identical for each batter and most participants hit the stationary balls at about the lowest point of the bat trajectory. PMID:17542175

  16. Real time tracker based upon local hit correlation circuit for silicon strip sensors

    NASA Astrophysics Data System (ADS)

    Lehmann, Niklaus; Pirrami, Lorenzo; Blue, Andrew; Diez, Sergio; Dressnandt, Nandor; Duner, Silvan; Garcia-Sciveres, Maurice; Haber, Carl; Halgeri, Amogh; Keener, Paul; Keller, John; Newcomer, Mitchell; Pasner, Jacob; Peschke, Richard; Risbud, Amar; Ropraz, Eric; Stalder, Jonas; Wang, Haichen

    2016-01-01

    For the planned high luminosity upgrade of the Large Hadron Collider (LHC), a significant performance improvement of the detectors is required, including new tracker and trigger systems that makes use of charged track information early on. In this note we explore the principle of real time track reconstruction integrated in the readout electronics. A prototype was built using the silicon strip sensor for the ATLAS phase-II upgrade. The real time tracker is not the baseline for ATLAS but is nevertheless of interest, as the upgraded trigger design has not yet been finalized. For this, a new readout scheme in parallel with conventional readout, called the Fast Cluster Finder (FCF), was included in the latest prototype of the ATLAS strip detector readout chip (ABC130). The FCF is capable of finding hits within 6 ns and transmitting the found hit information synchronously every 25 ns. Using the FCF together with external correlation logic makes it possible to look for pairs of hits consistent with tracks from the interaction point above a transverse momentum threshold. A correlator logic finds correlations between two closely spaced parallel sensors, a "doublet", and can generate information used as input to a lowest level trigger decision. Such a correlator logic was developed as part of a demonstrator and was successfully tested in an electron beam. The results of this test beam experiment proved the concept of the real time track vector processor with FCF.

  17. A business case for HIT adoption: effects of "meaningful use" EHR financial incentives on clinic revenue.

    PubMed

    Behkami, Nima A; Dorr, David A; Morrice, Stuart

    2010-01-01

    The goal of this study is to describe a framework that allows decision makers to efficiently evaluate factors that affect Electronic Health Record (EHR) adoption and test suitable interventions; specifically financial incentives. The United States healthcare delivery system is experiencing a transformation to improve population health. There is strong agreement that "meaningful use" of Health Information Technology (HIT) is a major enabler in this effort. However it's also understood that the high cost of implementing an EHR is an obstacle for adoption. To help understand these complexities we developed a simulation model designed to capture the dynamic nature of policy interventions that affect the adoption of EHR. We found that "Effective" use of HIT approaches break-even-point and larger clinic revenue many times faster that "average" or "poor" use of HIT. This study uses a systems perspective to the evaluate EHR adoption process through the "meaningful use" redesign as proposed in the American Reinvestment and Recovery Act 2009 in the United States healthcare industry by utilizing the System Dynamics methodology and Scenario Analysis.

  18. Hit-to-lead evaluation of a novel class of sphingosine 1-phosphate lyase inhibitors.

    PubMed

    Dinges, Jurgen; Harris, Christopher M; Wallace, Grier A; Argiriadi, Maria A; Queeney, Kara L; Perron, Denise C; Dominguez, Eric; Kebede, Tegest; Desino, Kelly E; Patel, Hetal; Vasudevan, Anil

    2016-05-01

    Inhibition of sphingosine-1-phosphate lyase has recently been proposed as a potential treatment option for inflammatory disorders such as multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease. In this report we describe our hit-to-lead evaluation of the isoxazolecarboxamide 6, a high-throughput screening hit (in vitro IC50=1.0 μM, cell IC50=1.8 μM), as a novel S1P lyase inhibitor. We were able to establish basic structure-activity relationships around 6 and succeeded in obtaining X-ray structural information which enabled structure-based design. With the discovery of 28, enzyme activity was quickly improved to IC50=120 nM and cell potency to IC50=230 nM. The main liability in the established isoxazolecarboxamide hit series was determined to be metabolic stability. In particular we identified that future lead-optimization efforts to overcome this problem should focus on blocking the N-dealkylation on the secondary amine. PMID:27020302

  19. Cosmic Ray Hits in the Central Nervous System at Solar Maximum

    NASA Technical Reports Server (NTRS)

    Curtis, S. B.; Vazquez, M. E.; Wilson, J. W.; Kim, M.-H. Y.

    1997-01-01

    It has been suggested that a manned mission to Mars be launched at solar maximum rather than at solar minimum to minimize the radiation exposure to galactic cosmic rays. It is true that the number of hits from highly ionizing particles to critical regions in the brain will be less at solar maximum, and it is of some interest to estimate how much less. We present here calculations for several sites within the brain from iron ions (z = 26) and from particles with charge, z, greater than or equal to 15. The same shielding configurations and sites in the brain used in an earlier paper for solar minimum are employed so that direct comparison of results between the two solar activity conditions can be made. A simple pressure-vessel wall and an equipment room onboard a spacecraft are chosen as shielding examples. In the equipment room, typical results for the thalamus (100 mm2 area) are that the probability of any given cell nucleus being hit decreases from 10 percent at solar minimum to 6 percent at solar maximum for particles with z greater than or equal to 15 and from 2.3 percent to 1.3 percent for iron ions. We conclude that this modest decrease in hit frequency (less than a factor of two) is not a compelling reason to avoid solar minimum for a manned mission to Mars.

  20. Cosmic Ray Hits in the Central Nervous System at Solar Maximum

    NASA Technical Reports Server (NTRS)

    Curtis, S. B.; Vazquez, M. E.; Wilson, J. W.; Atwell, W.; Kin, M.-H. Y.

    2000-01-01

    It has been suggested that a manned mission to Mars be launched at solar maximum rather than at solar minimum to minimize the radiation exposure to galactic cosmic rays. It is true that the number of hits from highly ionizing particles to critical regions in the brain will be less at solar maximum, and it is of interest to estimate how much less. We present here calculations for several sites within the brain from iron ions (z = 26) and from particles with charge, z, greater than or equal to 15. The same shielding configurations and sites in the brain used in an earlier paper for solar minimum are employed so that direct comparison of results between the two solar activity conditions can be made. A simple pressure-vessel wall and an equipment room onboard a spacecraft are chosen as shielding examples. In the equipment room, typical results for the thalamus are that the probability of any particles with z greater than or equal to 15 and from 2.3 percent to 1.3 percent for iron ions. The extra shielding provided in the equipment room makes little difference in these numbers. We conclude that this decrease in hit frequency (less than a factor of two) does not provide a compelling reason to avoid solar minimum for a manned mission to Mars. This conclusion could be revised, however, if a very small number of hits is found to cause critical malfunction within the brain.

  1. Prediction of Potential Hit Song and Musical Genre Using Artificial Neural Networks

    NASA Astrophysics Data System (ADS)

    Monterola, Christopher; Abundo, Cheryl; Tugaff, Jeric; Venturina, Lorcel Ericka

    Accurately quantifying the goodness of music based on the seemingly subjective taste of the public is a multi-million industry. Recording companies can make sound decisions on which songs or artists to prioritize if accurate forecasting is achieved. We extract 56 single-valued musical features (e.g. pitch and tempo) from 380 Original Pilipino Music (OPM) songs (190 are hit songs) released from 2004 to 2006. Based on an effect size criterion which measures a variable's discriminating power, the 20 highest ranked features are fed to a classifier tasked to predict hit songs. We show that regardless of musical genre, a trained feed-forward neural network (NN) can predict potential hit songs with an average accuracy of ΦNN = 81%. The accuracy is about +20% higher than those of standard classifiers such as linear discriminant analysis (LDA, ΦLDA = 61%) and classification and regression trees (CART, ΦCART = 57%). Both LDA and CART are above the proportional chance criterion (PCC, ΦPCC = 50%) but are slightly below the suggested acceptable classifier requirement of 1.25*ΦPCC = 63%. Utilizing a similar procedure, we demonstrate that different genres (ballad, alternative rock or rock) of OPM songs can be automatically classified with near perfect accuracy using LDA or NN but only around 77% using CART.

  2. Protein-Protein Interaction Inhibition (2P2I)-Oriented Chemical Library Accelerates Hit Discovery.

    PubMed

    Milhas, Sabine; Raux, Brigitt; Betzi, Stéphane; Derviaux, Carine; Roche, Philippe; Restouin, Audrey; Basse, Marie-Jeanne; Rebuffet, Etienne; Lugari, Adrien; Badol, Marion; Kashyap, Rudra; Lissitzky, Jean-Claude; Eydoux, Cécilia; Hamon, Véronique; Gourdel, Marie-Edith; Combes, Sébastien; Zimmermann, Pascale; Aurrand-Lions, Michel; Roux, Thomas; Rogers, Catherine; Müller, Susanne; Knapp, Stefan; Trinquet, Eric; Collette, Yves; Guillemot, Jean-Claude; Morelli, Xavier

    2016-08-19

    Protein-protein interactions (PPIs) represent an enormous source of opportunity for therapeutic intervention. We and others have recently pinpointed key rules that will help in identifying the next generation of innovative drugs to tackle this challenging class of targets within the next decade. We used these rules to design an oriented chemical library corresponding to a set of diverse "PPI-like" modulators with cores identified as privileged structures in therapeutics. In this work, we purchased the resulting 1664 structurally diverse compounds and evaluated them on a series of representative protein-protein interfaces with distinct "druggability" potential using homogeneous time-resolved fluorescence (HTRF) technology. For certain PPI classes, analysis of the hit rates revealed up to 100 enrichment factors compared with nonoriented chemical libraries. This observation correlates with the predicted "druggability" of the targets. A specific focus on selectivity profiles, the three-dimensional (3D) molecular modes of action resolved by X-ray crystallography, and the biological activities of identified hits targeting the well-defined "druggable" bromodomains of the bromo and extraterminal (BET) family are presented as a proof-of-concept. Overall, our present study illustrates the potency of machine learning-based oriented chemical libraries to accelerate the identification of hits targeting PPIs. A generalization of this method to a larger set of compounds will accelerate the discovery of original and potent probes for this challenging class of targets. PMID:27219844

  3. A review of vulnerability and risks for schizophrenia: Beyond the two hit hypothesis

    PubMed Central

    Davis, Justin; Eyre, Harris; Jacka, Felice N; Dodd, Seetal; Dean, Olivia; McEwen, Sarah; Debnath, Monojit; McGrath, John; Maes, Michael; Amminger, Paul; McGorry, Patrick D; Pantelis, Christos; Berk, Michael

    2016-01-01

    Schizophrenia risk has often been conceptualized using a model which requires two hits in order to generate the clinical phenotype—the first as an early priming in a genetically predisposed individual and the second a likely environmental insult. The aim of this paper was to review the literature and reformulate this binary risk-vulnerability model. We sourced the data for this narrative review from the electronic database PUBMED. Our search terms were not limited by language or date of publication. The development of schizophrenia may be driven by genetic vulnerability interacting with multiple vulnerability factors including lowered prenatal vitamin D exposure, viral infections, smoking intelligence quotient, social cognition cannabis use, social defeat, nutrition and childhood trauma. It is likely that these genetic risks, environmental risks and vulnerability factors are cumulative and interactive with each other and with critical periods of neurodevelopmental vulnerability. The development of schizophrenia is likely to be more complex and nuanced than the binary two hit model originally proposed nearly thirty years ago. Risk appears influenced by a more complex process involving genetic risk interfacing with multiple potentially interacting hits and vulnerability factors occurring at key periods of neurodevelopmental activity, which culminate in the expression of disease state. These risks are common across a number of neuropsychiatric and medical disorders, which might inform common preventive and intervention strategies across non-communicable disorders. PMID:27073049

  4. Engineering and Design of the Steady Inductive Helicity Injected Torus (HIT--SI)

    NASA Astrophysics Data System (ADS)

    Sieck, P. E.; Jarboe, T. R.; Nelson, B. A.; Rogers, J. A.; Shumlak, U.

    1999-11-01

    HIT/SIHI/>Steady Inductive Helicity Injection (SIHI) is an inductive helicity injection method that injects helicity at a nearly constant rate, without open field lines, and without removing any helicity or magnetic energy from the plasma.(T.R. Jarboe, Fusion Technology, 36) (1), p. 85, 1999 SIHI directly produces a rotating magnetic field structure, and in the frame of the rotating field the current profile is nearly time independent. The Steady Inductive Helicity Injected Torus (HIT--SI) is a spheromak designed to implement SIHI so that the current profile in the rotating frame is optimized. The geometry of HIT--SI will be presented, including the manufacturing techniques and metallurgical processes planned for construction of the close-fitting flux conserver. The flux conserver is made of aged chromium copper with 80% the conductivity of pure copper. The detailed electrical insulation requirements in the helicity injector design lead to a complex o-ring seal and a plasma-sprayed alumina insulation coating. This has prompted the construction of an o-ring prototype test fixture having the main features of the o-ring design and the alumina coating. The design and evaluation of this fixture will also be presented with vacuum and voltage test results.

  5. Hit-and-run crashes in urban river-crossing road tunnels.

    PubMed

    Jiang, Chenming; Lu, Linjun; Chen, Shengdi; Lu, Jian John

    2016-10-01

    Hit-and-run crashes are a relatively infrequent but severe offense worldwide because the identification and emergency rescue of victims is delayed, which increases the injury severities and the mortality rate. However, no studies have been conducted on hit-and-run crashes in urban river-crossing road tunnels (URCRTs), which can greatly threaten the safety of motorists driving in the tunnels. This study, which employs a dataset of vehicle crashes that happened in thirteen urban road tunnels traversing the Huangpu River, established a binary logistic regression model to identify thirteen factors that contribute to escaping after crashes in Shanghai related to the offending drivers, the vehicular and environmental conditions, the tunnel characteristics and crash information. Among the thirty-five variables considered, this study found that a perpetrator's tendency to leave the crash scene without reporting an accident was higher at night, in the tunnel exit, near to or in short tunnels, when a two-wheeled vehicle or heavy goods vehicle (HGV) was involved and when alcohol was involved. While a perpetrator was more likely to remain on the scene in the tunnel entrance, on a rainy day, in a rear end collision, when a bus was involved, in a single vehicle or a multi-vehicle accident. Based on these findings, several countermeasures for better supervision and hit-and-run prevention are proposed.

  6. A review of vulnerability and risks for schizophrenia: Beyond the two hit hypothesis.

    PubMed

    Davis, Justin; Eyre, Harris; Jacka, Felice N; Dodd, Seetal; Dean, Olivia; McEwen, Sarah; Debnath, Monojit; McGrath, John; Maes, Michael; Amminger, Paul; McGorry, Patrick D; Pantelis, Christos; Berk, Michael

    2016-06-01

    Schizophrenia risk has often been conceptualized using a model which requires two hits in order to generate the clinical phenotype-the first as an early priming in a genetically predisposed individual and the second a likely environmental insult. The aim of this paper was to review the literature and reformulate this binary risk-vulnerability model. We sourced the data for this narrative review from the electronic database PUBMED. Our search terms were not limited by language or date of publication. The development of schizophrenia may be driven by genetic vulnerability interacting with multiple vulnerability factors including lowered prenatal vitamin D exposure, viral infections, smoking intelligence quotient, social cognition cannabis use, social defeat, nutrition and childhood trauma. It is likely that these genetic risks, environmental risks and vulnerability factors are cumulative and interactive with each other and with critical periods of neurodevelopmental vulnerability. The development of schizophrenia is likely to be more complex and nuanced than the binary two hit model originally proposed nearly thirty years ago. Risk appears influenced by a more complex process involving genetic risk interfacing with multiple potentially interacting hits and vulnerability factors occurring at key periods of neurodevelopmental activity, which culminate in the expression of disease state. These risks are common across a number of neuropsychiatric and medical disorders, which might inform common preventive and intervention strategies across non-communicable disorders. PMID:27073049

  7. ChemVassa: A New Method for Identifying Small Molecule Hits in Drug Discovery.

    PubMed

    Moldover, Brian; Solidar, Ada; Montgomery, Christa; Miziorko, Henry; Murphy, Jeff; Wyckoff, Gerald J

    2012-01-01

    ChemVassa, a new chemical structure search technology, was developed to allow rapid in silico screening of compounds for hit and hit-to-lead identification in drug development. It functions by using a novel type of molecular descriptor that examines, in part, the structure of the small molecule undergoing analysis, yielding its "information signature." This descriptor takes into account the atoms, bonds, and their positions in 3-dimensional space. For the present study, a database of ChemVassa molecular descriptors was generated for nearly 16 million compounds (from the ZINC database and other compound sources), then an algorithm was developed that allows rapid similarity searching of the database using a query molecular descriptor (e.g., the signature of atorvastatin, below). A scoring metric then allowed ranking of the search results. We used these tools to search a subset of drug-like molecules using the signature of a commercially successful statin, atorvastatin (Lipitor™). The search identified ten novel compounds, two of which have been demonstrated to interact with HMG-CoA reductase, the macromolecular target of atorvastatin. In particular, one compound discussed in the results section tested successfully with an IC50 of less than 100uM and a completely novel structure relative to known inhibitors. Interactions were validated using computational molecular docking and an Hmg-CoA reductase activity assay. The rapidity and low cost of the methodology, and the novel structure of the interactors, suggests this is a highly favorable new method for hit generation.

  8. Bat speed, trajectory, and timing for collegiate baseball batters hitting a stationary ball.

    PubMed

    Tabuchi, Noriyuki; Matsuo, Tomoyuki; Hashizume, Ken

    2007-01-01

    The aims of this study were to examine whether batters hit stationary balls at the time of peak speed of the bat head and whether the impact occurs at the lowest point of the bat trajectory. Eight university baseball players hit three balls, each hung with a string; each ball was made of a different material and was different in weight. Bat movement was captured by four 240-Hz infrared cameras and analysed three-dimensionally. Time for peak speed of the bat head varied according to the conditions. When stationary balls of standard weight were used, the bat head was at maximum speed at impact with the ball; then, it decelerated drastically owing to the impact. In contrast, maximum speed was obtained after impact when lightweight stationary balls were used. The time-speed profile of the bat head before impact in the lightweight ball condition was identical with that in the standard weight ball condition. Regardless of conditions, the timing of the lowest point of the bat head was nearly identical for each batter and most participants hit the stationary balls at about the lowest point of the bat trajectory.

  9. Cosmic ray hits in the central nervous system at solar maximum.

    PubMed

    Curtis, S B; Vazquez, M E; Wilson, J W; Atwell, W; Kim, M H

    2000-01-01

    It has been suggested that a manned mission to Mars be launched at solar maximum rather than at solar minimum to minimize the radiation exposure to galactic cosmic rays. It is true that the number of hits from highly ionizing particles to critical regions in the brain will be less at solar maximum, and it is of interest to estimate how much less. We present here calculations for several sites within the brain from iron ions (z = 26) and from particles with charge, z, greater than or equal to 15. The same shielding configurations and sites in the brain used in an earlier paper for solar minimum are employed so that direct comparison of results between the two solar activity conditions can be made. A simple pressure-vessel wall and an equipment room onboard a spacecraft are chosen as shielding examples. In the equipment room, typical results for the thalamus are that the probability of any particles with 7 greater than or equal to 15 and from 2.3 percent to 1.3 percent for iron ions. The extra shielding provided in the equipment room makes little difference in these numbers. We conclude that this decrease in hit frequency (less than a factor of two) does not provide a compelling reason to avoid solar minimum for a manned mission to Mars. This conclusion could be revised, however, if a very small number of hits is found to cause critical malfunction within the brain. PMID:11542854

  10. Guidance for horizontal image translation (HIT) of high definition stereoscopic video production

    NASA Astrophysics Data System (ADS)

    Broberg, David K.

    2011-03-01

    Horizontal image translation (HIT) is an electronic process for shifting the left-eye and right-eye images horizontally as a way to alter the stereoscopic characteristics and alignment of 3D content after signals have been captured by stereoscopic cameras. When used cautiously and with full awareness of the impact on other interrelated aspects of the stereography, HIT is a valuable tool in the post production process as a means to modify stereoscopic content for more comfortable viewing. Most commonly it is used to alter the zero parallax setting (ZPS), to compensate for stereo window violations or to compensate for excessive positive or negative parallax in the source material. As more and more cinematic 3D content migrates to television distribution channels the use of this tool will likely expand. Without proper attention to certain guidelines the use of HIT can actually harm the 3D viewing experience. This paper provides guidance on the most effective use and describes some of the interrelationships and trade-offs. The paper recommends the adoption of the cinematic 2K video format as a 3D source master format for high definition television distribution of stereoscopic 3D video programming.

  11. Cosmic ray hits in the central nervous system at solar maximum.

    PubMed

    Curtis, S B; Vazquez, M E; Wilson, J W; Atwell, W; Kim, M H

    2000-01-01

    It has been suggested that a manned mission to Mars be launched at solar maximum rather than at solar minimum to minimize the radiation exposure to galactic cosmic rays. It is true that the number of hits from highly ionizing particles to critical regions in the brain will be less at solar maximum, and it is of interest to estimate how much less. We present here calculations for several sites within the brain from iron ions (z = 26) and from particles with charge, z, greater than or equal to 15. The same shielding configurations and sites in the brain used in an earlier paper for solar minimum are employed so that direct comparison of results between the two solar activity conditions can be made. A simple pressure-vessel wall and an equipment room onboard a spacecraft are chosen as shielding examples. In the equipment room, typical results for the thalamus are that the probability of any particles with 7 greater than or equal to 15 and from 2.3 percent to 1.3 percent for iron ions. The extra shielding provided in the equipment room makes little difference in these numbers. We conclude that this decrease in hit frequency (less than a factor of two) does not provide a compelling reason to avoid solar minimum for a manned mission to Mars. This conclusion could be revised, however, if a very small number of hits is found to cause critical malfunction within the brain.

  12. Patterns of Hits to the Nearshore from a Major Fairway in the Gulf of Finland

    NASA Astrophysics Data System (ADS)

    Viikmae, B.; Soomere, T.

    2012-04-01

    The Baltic Sea hosts one of the heaviest ship traffic in the world. Although relatively small in size, still up to 15% of the world's cargo is transported along its numerous fairways. The largest threat to the environment is oil transportation that has increased more than by a factor of two in 2000-2008 and a 40% increase is expected by the year 2015. One of the major marine highways in the European waters enters the Baltic Sea through the Danish Straits, crosses the Baltic Proper and stretches through the Gulf of Finland to Saint Petersburg. An area that is highly vulnerable to ship pollution is the nearshore that usually has the largest ecological value. While the probability of coastal pollution for open ocean coasts can be reduced by shifting ship routes farther offshore, the problem for narrow bays, like the Gulf of Finland, is how to minimize the probability of hitting any of the coasts. To a certain extent, light can be shed to this problem by means of quantification of the offshore areas in terms of their ability to serve a danger to coastal environment if pollution would happen in these areas. A convenient way to address this problem is to use statistical analysis of a large number of Lagrangian trajectories of test particles representing the potential pollution and passively carried by surface currents. In this paper, we make and attempt to quantify the link between potential sources of pollution along an existing fairway and the sections of the coast reached by current-driven pollution. The problem is analysed by means of considering hits to the nearshore from a major fairway in the Gulf of Finland and by making sure whether certain parts of the coast are hit by pollution particles most frequently and whether or not these pollution particles stem from certain specific parts of the fairway. Trajectories are simulated in the Gulf of Finland by placing tracers among a line that follows one of the major fairways from the Baltic Proper to Saint Petersburg

  13. Overexpression of an alfalfa GDP-mannose 3, 5-epimerase gene enhances acid, drought and salt tolerance in transgenic Arabidopsis by increasing ascorbate accumulation.

    PubMed

    Ma, Lichao; Wang, Yanrong; Liu, Wenxian; Liu, Zhipeng

    2014-11-01

    GDP-mannose 3', 5'-epimerase (GME) catalyses the conversion of GDP-D-mannose to GDP-L-galactose, an important step in the ascorbic acid (ascorbic acid) biosynthetic pathway in higher plants. In this study, a novel cDNA fragment (MsGME) encoding a GME protein was isolated and characterised from alfalfa (Medicago sativa). An expression analysis confirmed that MsGME expression was induced by salinity, PEG and acidity stresses. MsGME overexpression in Arabidopsis enhanced tolerance of the transgenic plants to salt, drought and acid. Real-time PCR analysis revealed that the transcript levels of GDP-D-mannose pyrophosphorylase (GMP), L-galactose-phosphate 1-P phosphatase (GP) and GDP-L-galactose phosphorylase (GGP) were increased in transgenic Arabidopsis (T3 generation). Moreover, the ascorbate content was increased in transgenic Arabidopsis. Our results suggest that MsGME can effectively enhance tolerance of transgenic Arabidopsis to acid, drought and salt by increasing ascorbate accumulation.

  14. Mammalian translation elongation factor eEF1A2: X-ray structure and new features of GDP/GTP exchange mechanism in higher eukaryotes.

    PubMed

    Crepin, Thibaut; Shalak, Vyacheslav F; Yaremchuk, Anna D; Vlasenko, Dmytro O; McCarthy, Andrew; Negrutskii, Boris S; Tukalo, Michail A; El'skaya, Anna V

    2014-11-10

    Eukaryotic elongation factor eEF1A transits between the GTP- and GDP-bound conformations during the ribosomal polypeptide chain elongation. eEF1A*GTP establishes a complex with the aminoacyl-tRNA in the A site of the 80S ribosome. Correct codon-anticodon recognition triggers GTP hydrolysis, with subsequent dissociation of eEF1A*GDP from the ribosome. The structures of both the 'GTP'- and 'GDP'-bound conformations of eEF1A are unknown. Thus, the eEF1A-related ribosomal mechanisms were anticipated only by analogy with the bacterial homolog EF-Tu. Here, we report the first crystal structure of the mammalian eEF1A2*GDP complex which indicates major differences in the organization of the nucleotide-binding domain and intramolecular movements of eEF1A compared to EF-Tu. Our results explain the nucleotide exchange mechanism in the mammalian eEF1A and suggest that the first step of eEF1A*GDP dissociation from the 80S ribosome is the rotation of the nucleotide-binding domain observed after GTP hydrolysis.

  15. Mutational, kinetic, and NMR studies of the mechanism of E. coli GDP-mannose mannosyl hydrolase, an unusual Nudix enzyme.

    PubMed

    Legler, Patricia M; Massiah, Michael A; Mildvan, Albert S

    2002-09-01

    GDP-mannose mannosyl hydrolase (GDPMH) is an unusual Nudix family member, which catalyzes the hydrolysis of GDP-alpha-D-mannose to GDP and the beta-sugar by nucleophilic substitution at carbon rather than at phosphorus (Legler, P. M., Massiah, M. A., Bessman, M. J., and Mildvan, A. S. (2000) Biochemistry 39, 8603-8608). Using the structure and mechanism of MutT, the prototypical Nudix enzyme as a guide, we detected six catalytic residues of GDPMH, three of which were unique to GDPMH, by the kinetic and structural effects of site-specific mutations. Glu-70 (corresponding to Glu-57 in MutT) provides a ligand to the essential divalent cation on the basis of the effects of the E70Q mutation which decreased kcat 10(2.2)-fold, increased the dissociation constant of Mn2+ from the ternary E-Mn2+-GDP complex 3-fold, increased the K(m)Mg2+ 20-fold, and decreased the paramagnetic effect of Mn2+ on 1/T1 of water protons, indicating a change in the coordination sphere of Mn2+. In the E70Q mutant, Gln-70 was shown to be very near the active site metal ion by large paramagnetic effects of Mn2+ on its side chain -NH2 group. With wild-type GDPMH, the effect of pH on log(kcat/K(m)GDPmann) at 37 degrees C showed an ascending limb of unit slope, followed by a plateau yielding a pK(a) of 6.4, which increased to 6.7 +/- 0.1 in the pH dependence of log(kcat). The general base catalyst was identified as a neutral His residue by the DeltaH(ionization) = 7.0 +/- 0.7 kcal/mol, by the increase in pK(a) with ionic strength, and by mutation of each of the four histidine residues of GDPMH to Gln. Only the H124Q mutant showed the loss of the ascending limb in the pH versus log(kcat) rate profile, which was replaced by a weak dependence of rate on hydroxide concentration, as well as an overall 10(3.4)-fold decrease in kcat, indicating His-124 to be the general base, unlike MutT, which uses Glu-53 in this role. The H88Q mutant showed a 10(2.3)-fold decrease in kcat, a 4.4-fold increase in K

  16. Papilledema due to a permanent catheter for renal dialysis and an arteriovenous fistula: a "two hit" hypothesis.

    PubMed

    Simon, Melissa A; Duffis, Ennis J; Curi, Michael A; Turbin, Roger E; Prestigiacomo, Charles J; Frohman, Larry P

    2014-03-01

    Elevated intracranial pressure in patients with chronic renal failure has several potential causes. Its rare occurrence secondary to the hemodynamic effects of hemodialysis is described and the findings support a multifactorial etiology ("two hits").

  17. MEPHISTO - a 128-channel front end chip with real time data sparsification and multi-hit capability

    NASA Astrophysics Data System (ADS)

    Fischer, P.; Comes, G.; Krüger, H.

    1999-07-01

    The MEPHISTO chip uses a novel binary architecture to achieve a high speed readout for multichannel detectors, like silicon strip detectors or MSGCs. The architecture is an alternative to existing designs with raw data pipelines as are commonly used in particle physics applications. The chip receives 128 digital input signals from an analog front end chip at a rate of up to 80 MHz. The hit pattern is sparsified in real time and only the addresses and interaction times of hits are stored temporarily in FIFOs. Multiple hits per event are possible. A trigger selects interesting events for readout. All other hits are automatically discarded. Untriggered readout at high rates is also possible. The occupied chip area depends on the average data rate which can be very small in many applications. Very compact designs with up to ten times less first level storage can therefore be realized.

  18. "It was a thought pitch": personal, situational, and target influences on hit-by-pitch events across time.

    PubMed

    Timmerman, Thomas A

    2007-05-01

    This study tested the possibility that hit-by-pitch events in Major League Baseball could be explained by theories of aggression. Consistent with the general aggression model, personal and situational characteristics interacted to predict these events. Pitchers were more likely to hit batters in situations that allowed them to restore justice and protect valued social identities. Higher order interactions revealed that the likelihood of being hit by a pitch in these situations depended on the background of the pitcher and the race of the batter. Consistent with the culture of honor theory, pitchers from the southern United States were more likely to hit batters in these situations, but primarily if the batter was White.

  19. Growth Versus Government Management Improvement During Economic Downturn

    PubMed Central

    Podobnik, Boris; Baaquie, Belal E.; Bishop, Steven; Njavro, Djuro; Li, Baowen

    2013-01-01

    In estimating how economic growth depends on various inputs, economists commonly use long periods of data encompassing both main extremes to fluctuations in the economy: recession and expansion. Here we focus on recession years because during expansion even countries with bad economic policies may experience large growth. Specifically, we study how growth depends on the proportion of public-sector workforce, p and competitiveness, quantified by the Global Competitiveness Index, GCI. For the 2008–2011 economic downturn and for 57 countries, we find that the growth rate of GDP per capita, g, decreases with p, and increases with ΔGCI. Further, more competitive countries attract more foreign direct investments per capita, I, than less competitive countries, where I ∝ GCIα. We propose a production function, divided into the private and public sectors, where GDP depends on market capitalization, the public (private)-sector workforce, and competitiveness level, used to quantify the public sector efficiency. PMID:23563321

  20. QMRA for Drinking Water: 1. Revisiting the Mathematical Structure of Single-Hit Dose-Response Models.

    PubMed

    Nilsen, Vegard; Wyller, John

    2016-01-01

    Dose-response models are essential to quantitative microbial risk assessment (QMRA), providing a link between levels of human exposure to pathogens and the probability of negative health outcomes. In drinking water studies, the class of semi-mechanistic models known as single-hit models, such as the exponential and the exact beta-Poisson, has seen widespread use. In this work, an attempt is made to carefully develop the general mathematical single-hit framework while explicitly accounting for variation in (1) host susceptibility and (2) pathogen infectivity. This allows a precise interpretation of the so-called single-hit probability and precise identification of a set of statistical independence assumptions that are sufficient to arrive at single-hit models. Further analysis of the model framework is facilitated by formulating the single-hit models compactly using probability generating and moment generating functions. Among the more practically relevant conclusions drawn are: (1) for any dose distribution, variation in host susceptibility always reduces the single-hit risk compared to a constant host susceptibility (assuming equal mean susceptibilities), (2) the model-consistent representation of complete host immunity is formally demonstrated to be a simple scaling of the response, (3) the model-consistent expression for the total risk from repeated exposures deviates (gives lower risk) from the conventional expression used in applications, and (4) a model-consistent expression for the mean per-exposure dose that produces the correct total risk from repeated exposures is developed.

  1. QMRA for Drinking Water: 1. Revisiting the Mathematical Structure of Single-Hit Dose-Response Models.

    PubMed

    Nilsen, Vegard; Wyller, John

    2016-01-01

    Dose-response models are essential to quantitative microbial risk assessment (QMRA), providing a link between levels of human exposure to pathogens and the probability of negative health outcomes. In drinking water studies, the class of semi-mechanistic models known as single-hit models, such as the exponential and the exact beta-Poisson, has seen widespread use. In this work, an attempt is made to carefully develop the general mathematical single-hit framework while explicitly accounting for variation in (1) host susceptibility and (2) pathogen infectivity. This allows a precise interpretation of the so-called single-hit probability and precise identification of a set of statistical independence assumptions that are sufficient to arrive at single-hit models. Further analysis of the model framework is facilitated by formulating the single-hit models compactly using probability generating and moment generating functions. Among the more practically relevant conclusions drawn are: (1) for any dose distribution, variation in host susceptibility always reduces the single-hit risk compared to a constant host susceptibility (assuming equal mean susceptibilities), (2) the model-consistent representation of complete host immunity is formally demonstrated to be a simple scaling of the response, (3) the model-consistent expression for the total risk from repeated exposures deviates (gives lower risk) from the conventional expression used in applications, and (4) a model-consistent expression for the mean per-exposure dose that produces the correct total risk from repeated exposures is developed. PMID:26812257

  2. Structure of an ADP-ribosylation factor, ARF1, from Entamoeba histolytica bound to Mg(2+)-GDP.

    PubMed

    Serbzhinskiy, Dmitry A; Clifton, Matthew C; Sankaran, Banumathi; Staker, Bart L; Edwards, Thomas E; Myler, Peter J

    2015-05-01

    Entamoeba histolytica is the etiological agent of amebiasis, a diarrheal disease which causes amoebic liver abscesses and amoebic colitis. Approximately 50 million people are infected worldwide with E. histolytica. With only 10% of infected people developing symptomatic amebiasis, there are still an estimated 100,000 deaths each year. Because of the emergence of resistant strains of the parasite, it is necessary to find a treatment which would be a proper response to this challenge. ADP-ribosylation factor (ARF) is a member of the ARF family of GTP-binding proteins. These proteins are ubiquitous in eukaryotic cells; they generally associate with cell membranes and regulate vesicular traffic and intracellular signalling. The crystal structure of ARF1 from E. histolytica has been determined bound to magnesium and GDP at 1.8 Å resolution. Comparison with other structures of eukaryotic ARF proteins shows a highly conserved structure and supports the interswitch toggle mechanism of communicating the conformational state to partner proteins.

  3. The Structure of the MUR1 GDP-mannose 4,67-deydratase from A. thaliana: Implications for Ligand Binding Specificity

    SciTech Connect

    Mulichak, A.M.; Bonin, C.P.; Reiter, W.-D.; Garavito, R.M.

    2010-03-08

    GDP-D-mannose 4,6-dehydratase catalyzes the first step in the de novo synthesis of GDP-L-fucose, the activated form of L-fucose, which is a component of glycoconjugates in plants known to be important to the development and strength of stem tissues. We have determined the three-dimensional structure of the MUR1 dehydratase isoform from Arabidopsis thaliana complexed with its NADPH cofactor as well as with the ligands GDP and GDP-D-rhamnose. MUR1 is a member of the nucleoside-diphosphosugar modifying subclass of the short-chain dehydrogenase/reductase enzyme family, having homologous structures and a conserved catalytic triad of Lys, Tyr, and Ser/Thr residues. MUR1 is the first member of this subfamily to be observed as a tetramer, the interface of which reveals a close and intimate overlap of neighboring NADP{sup +}-binding sites. The GDP moiety of the substrate also binds in an unusual syn conformation. The protein-ligand interactions around the hexose moiety of the substrate support the importance of the conserved triad residues and an additional Glu side chain serving as a general base for catalysis. Phe and Arg side chains close to the hexose ring may serve to confer substrate specificity at the O2 position. In the MUR1/GDP-D-rhamnose complex, a single unique monomer within the protein tetramer that has an unoccupied substrate site highlights the conformational changes that accompany substrate binding and may suggest the existence of negative cooperativity in MUR1 function.

  4. Structural and functional analysis of a FeoB A143S G5 loop mutant explains the accelerated GDP release rate.

    PubMed

    Guilfoyle, Amy P; Deshpande, Chandrika N; Vincent, Kimberley; Pedroso, Marcelo M; Schenk, Gerhard; Maher, Megan J; Jormakka, Mika

    2014-05-01

    GTPases (G proteins) hydrolyze the conversion of GTP to GDP and free phosphate, comprising an integral part of prokaryotic and eukaryotic signaling, protein biosynthesis and cell division, as well as membrane transport processes. The G protein cycle is brought to a halt after GTP hydrolysis, and requires the release of GDP before a new cycle can be initiated. For eukaryotic heterotrimeric Gαβγ proteins, the interaction with a membrane-bound G protein-coupled receptor catalyzes the release of GDP from the Gα subunit. Structural and functional studies have implicated one of the nucleotide binding sequence motifs, the G5 motif, as playing an integral part in this release mechanism. Indeed, a Gαs G5 mutant (A366S) was shown to have an accelerated GDP release rate, mimicking a G protein-coupled receptor catalyzed release state. In the present study, we investigate the role of the equivalent residue in the G5 motif (residue A143) in the prokaryotic membrane protein FeoB from Streptococcus thermophilus, which includes an N-terminal soluble G protein domain. The structure of this domain has previously been determined in the apo and GDP-bound states and in the presence of a transition state analogue, revealing conformational changes in the G5 motif. The A143 residue was mutated to a serine and analyzed with respect to changes in GTPase activity, nucleotide release rate, GDP affinity and structural alterations. We conclude that the identity of the residue at this position in the G5 loop plays a key role in the nucleotide release rate by allowing the correct positioning and hydrogen bonding of the nucleotide base.

  5. Inhibitory effects of cytoskeleton disrupting drugs and GDP-locked Rab mutants on bradykinin B₂ receptor cycling.

    PubMed

    Charest-Morin, Xavier; Fortin, Sébastien; Lodge, Robert; Roy, Caroline; Gera, Lajos; Gaudreault, René C; Marceau, François

    2013-05-01

    The bradykinin (BK) B₂ receptor (B₂R) is G protein coupled and phosphorylated upon agonist stimulation; its endocytosis and recycling are documented. We assessed the effect of drugs that affect the cytoskeleton on B2R cycling. These drugs were targeted to tubulin (paclitaxel, or the novel combretastatin A-4 mimetic 3,4,5-trimethoxyphenyl-4-(2-oxoimidazolidin-1-yl)benzenesulfonate [IMZ-602]) and actin (cytochalasin D). Tubulin ligands did not alter agonist-induced receptor endocytosis, as shown using antibodies reactive with myc-tagged B₂Rs (microscopy, cytofluorometry), but rather reduced the progression of the ligand-receptor-β-arrestin complex from the cell periphery to the interior. The 3 fluorescent probes of this complex (B2R-green fluorescent protein [B2R-GFP], the fluorescent agonist fluorescein-5-thiocarbamoyl-D-Arg-[Hyp³, Igl⁵, Oic⁷, Igl⁸]-BK and β-arrestin2-GFP) were condensed in punctuate structures that remained close to the cell surface in the presence of IMZ-602. Cytochalasin D selectively inhibited the recycling of endocytosed B₂R-GFP (B₂R-GFP imaging, [³H]BK binding). Dominant negative (GDP-locked)-Rab5 and -Rab11 reproduced the effects of inhibitors of tubulin and actin, respectively, on the cycling of B₂R-GFP. GDP-locked-Rab4 also inhibited B₂R-GFP recycling to the cell surface. Consistent with the displacement of cargo along specific cytoskeletal elements, Rab5-associated progression of the endocytosed BK B₂R follows microtubules toward their (-) end, while its recycling progresses along actin fibers to the cell surface. However, tubulin ligands do not suppress the tested desensitization or resensitization mechanisms of the B₂R.

  6. Making an Iron Planet: The Case for Repeated Hit and Run Collisions

    NASA Astrophysics Data System (ADS)

    Asphaug, E. I.; Reufer, A.

    2014-12-01

    Earth, Venus, Mars and some of the largest asteroids have massive silicate mantles surrounding iron cores, and chondritic compositions. Against this backdrop are anomalies like the iron planet Mercury, and the Moon with almost no core, and metallic asteroids like Psyche. The Moon can be explained by giant impact, but for Mercury a giant impact (Benz et al., Icarus 1988) is problematic. Mercury must retain substantial volatiles after its obliteration (e.g. Peplowski et al., Science 2011), and must somehow avoid accreting its ejected silicates (Gladman and Coffey, MAPS 2009). SPH simulations have shown (Asphaug and Reufer, Nature Geosciences 2014; Sarid et al., LPSC 2014) that a differentiated chondritic proto-Mercury about 3 times its present mass can be stripped of its mantle in one energetic hit and run collision with a larger planet (proto-Venus or proto-Earth). To preserve Mercury's volatiles we also consider the scenario of lower energy hit and runs, in succession. We show that if 20 Mars-like planets accreted stochastically to form Venus and the Earth, then the statistics of attrition is likely to lead to one planet (Mercury) expressing repeated mantle stripping, and another planet (Mars) relatively undisturbed. For iron asteroids the "missing mantle paradox" likewise looms prominent. Where does it go, and how do we strip away so much mantle rock (in some cases down to a bare iron core; Yang et al., Nature 2007, Moskovitz et al., EPSL 2011) while leaving asteroids like Vesta presumably intact? According to the hit and run hypothesis, the sink for all this missing silicate is the larger accreted bodies at the top of the feeding chain, as they win the pairwise dynamical competition for stripped materials. This exotic origin of relics is only relevant to those few pairwise encounters that do not accrete both bodies. So the small survivors are lucky, and how they are lucky -- their attrition bias -- is manifested as compositional diversity and a preponderance of

  7. Contribution of Visual Information about Ball Trajectory to Baseball Hitting Accuracy

    PubMed Central

    Higuchi, Takatoshi; Nagami, Tomoyuki; Nakata, Hiroki; Watanabe, Masakazu; Isaka, Tadao; Kanosue, Kazuyuki

    2016-01-01

    The contribution of visual information about a pitched ball to the accuracy of baseball-bat contact may vary depending on the part of trajectory seen. The purpose of the present study was to examine the relationship between hitting accuracy and the segment of the trajectory of the flying ball that can be seen by the batter. Ten college baseball field players participated in the study. The systematic error and standardized variability of ball-bat contact on the bat coordinate system and pitcher-to-catcher direction when hitting a ball launched from a pitching machine were measured with or without visual occlusion and analyzed using analysis of variance. The visual occlusion timing included occlusion from 150 milliseconds (ms) after the ball release (R+150), occlusion from 150 ms before the expected arrival of the launched ball at the home plate (A-150), and a condition with no occlusion (NO). Twelve trials in each condition were performed using two ball speeds (31.9 m·s-1 and 40.3 m·s-1). Visual occlusion did not affect the mean location of ball-bat contact in the bat’s long axis, short axis, and pitcher-to-catcher directions. Although the magnitude of standardized variability was significantly smaller in the bat’s short axis direction than in the bat’s long axis and pitcher-to-catcher directions (p < 0.001), additional visible time from the R+150 condition to the A-150 and NO conditions resulted in a further decrease in standardized variability only in the bat’s short axis direction (p < 0.05). The results suggested that there is directional specificity in the magnitude of standardized variability with different visible time. The present study also confirmed the limitation to visual information is the later part of the ball trajectory for improving hitting accuracy, which is likely due to visuo-motor delay. PMID:26848742

  8. Contribution of Visual Information about Ball Trajectory to Baseball Hitting Accuracy.

    PubMed

    Higuchi, Takatoshi; Nagami, Tomoyuki; Nakata, Hiroki; Watanabe, Masakazu; Isaka, Tadao; Kanosue, Kazuyuki

    2016-01-01

    The contribution of visual information about a pitched ball to the accuracy of baseball-bat contact may vary depending on the part of trajectory seen. The purpose of the present study was to examine the relationship between hitting accuracy and the segment of the trajectory of the flying ball that can be seen by the batter. Ten college baseball field players participated in the study. The systematic error and standardized variability of ball-bat contact on the bat coordinate system and pitcher-to-catcher direction when hitting a ball launched from a pitching machine were measured with or without visual occlusion and analyzed using analysis of variance. The visual occlusion timing included occlusion from 150 milliseconds (ms) after the ball release (R+150), occlusion from 150 ms before the expected arrival of the launched ball at the home plate (A-150), and a condition with no occlusion (NO). Twelve trials in each condition were performed using two ball speeds (31.9 m·s-1 and 40.3 m·s-1). Visual occlusion did not affect the mean location of ball-bat contact in the bat's long axis, short axis, and pitcher-to-catcher directions. Although the magnitude of standardized variability was significantly smaller in the bat's short axis direction than in the bat's long axis and pitcher-to-catcher directions (p < 0.001), additional visible time from the R+150 condition to the A-150 and NO conditions resulted in a further decrease in standardized variability only in the bat's short axis direction (p < 0.05). The results suggested that there is directional specificity in the magnitude of standardized variability with different visible time. The present study also confirmed the limitation to visual information is the later part of the ball trajectory for improving hitting accuracy, which is likely due to visuo-motor delay.

  9. Contribution of Visual Information about Ball Trajectory to Baseball Hitting Accuracy.

    PubMed

    Higuchi, Takatoshi; Nagami, Tomoyuki; Nakata, Hiroki; Watanabe, Masakazu; Isaka, Tadao; Kanosue, Kazuyuki

    2016-01-01

    The contribution of visual information about a pitched ball to the accuracy of baseball-bat contact may vary depending on the part of trajectory seen. The purpose of the present study was to examine the relationship between hitting accuracy and the segment of the trajectory of the flying ball that can be seen by the batter. Ten college baseball field players participated in the study. The systematic error and standardized variability of ball-bat contact on the bat coordinate system and pitcher-to-catcher direction when hitting a ball launched from a pitching machine were measured with or without visual occlusion and analyzed using analysis of variance. The visual occlusion timing included occlusion from 150 milliseconds (ms) after the ball release (R+150), occlusion from 150 ms before the expected arrival of the launched ball at the home plate (A-150), and a condition with no occlusion (NO). Twelve trials in each condition were performed using two ball speeds (31.9 m·s-1 and 40.3 m·s-1). Visual occlusion did not affect the mean location of ball-bat contact in the bat's long axis, short axis, and pitcher-to-catcher directions. Although the magnitude of standardized variability was significantly smaller in the bat's short axis direction than in the bat's long axis and pitcher-to-catcher directions (p < 0.001), additional visible time from the R+150 condition to the A-150 and NO conditions resulted in a further decrease in standardized variability only in the bat's short axis direction (p < 0.05). The results suggested that there is directional specificity in the magnitude of standardized variability with different visible time. The present study also confirmed the limitation to visual information is the later part of the ball trajectory for improving hitting accuracy, which is likely due to visuo-motor delay. PMID:26848742

  10. A "Hit and Run" Approach to Inducible Direct Reprogramming of Astrocytes to Neural Stem Cells.

    PubMed

    Poulou, Maria; Mandalos, Nikolaos P; Karnavas, Theodoros; Saridaki, Marannia; McKay, Ronald D G; Remboutsika, Eumorphia

    2016-01-01

    Temporal and spatial control of gene expression can be achieved using an inducible system as a fundamental tool for regulated transcription in basic, applied and eventually in clinical research. We describe a novel "hit and run" inducible direct reprogramming approach. In a single step, 2 days post-transfection, transiently transfected Sox2(FLAG) under the Leu3p-αIPM inducible control (iSox2) triggers the activation of endogenous Sox2, redirecting primary astrocytes into abundant distinct nestin-positive radial glia cells. This technique introduces a unique novel tool for safe, rapid and efficient reprogramming amendable to regenerative medicine. PMID:27148066

  11. The REH theory of protein and nucleic acid divergence - A retrospective update. [Random Evolutionary Hits

    NASA Technical Reports Server (NTRS)

    Holmquist, R.

    1978-01-01

    The random evolutionary hits (REH) theory of evolutionary divergence, originally proposed in 1972, is restated with attention to certain aspects of the theory that have caused confusion. The theory assumes that natural selection and stochastic processes interact and that natural selection restricts those codon sites which may fix mutations. The predicted total number of fixed nucleotide replacements agrees with data for cytochrome c, a-hemoglobin, beta-hemoglobin, and myoglobin. The restatement analyzes the magnitude of possible sources of errors and simplifies calculational methodology by supplying polynomial expressions to replace tables and graphs.

  12. Hit Expansion from Screening Data Based upon Conditional Probabilities of Activity Derived from SAR Matrices.

    PubMed

    Gupta-Ostermann, Disha; Balfer, Jenny; Bajorath, Jürgen

    2015-02-01

    A new methodology for activity prediction of compounds from SAR matrices is introduced that is based upon conditional probabilities of activity. The approach has low computational complexity, is primarily designed for hit expansion from biological screening data, and accurately predicts both active and inactive compounds. Its performance is comparable to state-of-the-art machine learning methods such as support vector machines or Bayesian classification. Matrix-based activity prediction of virtual compounds further extends the spectrum of computational methods for compound design.

  13. Hit Expansion from Screening Data Based upon Conditional Probabilities of Activity Derived from SAR Matrices.

    PubMed

    Gupta-Ostermann, Disha; Balfer, Jenny; Bajorath, Jürgen

    2015-02-01

    A new methodology for activity prediction of compounds from SAR matrices is introduced that is based upon conditional probabilities of activity. The approach has low computational complexity, is primarily designed for hit expansion from biological screening data, and accurately predicts both active and inactive compounds. Its performance is comparable to state-of-the-art machine learning methods such as support vector machines or Bayesian classification. Matrix-based activity prediction of virtual compounds further extends the spectrum of computational methods for compound design. PMID:27490036

  14. Trends in mortality decrease and economic growth.

    PubMed

    Niu, Geng; Melenberg, Bertrand

    2014-10-01

    The vast literature on extrapolative stochastic mortality models focuses mainly on the extrapolation of past mortality trends and summarizes the trends by one or more latent factors. However, the interpretation of these trends is typically not very clear. On the other hand, explanation methods are trying to link mortality dynamics with observable factors. This serves as an intermediate step between the two methods. We perform a comprehensive analysis on the relationship between the latent trend in mortality dynamics and the trend in economic growth represented by gross domestic product (GDP). Subsequently, the Lee-Carter framework is extended through the introduction of GDP as an additional factor next to the latent factor, which provides a better fit and better interpretable forecasts.

  15. Bis-benzimidazole hits against Naegleria fowleri discovered with new high-throughput screens.

    PubMed

    Rice, Christopher A; Colon, Beatrice L; Alp, Mehmet; Göker, Hakan; Boykin, David W; Kyle, Dennis E

    2015-04-01

    Naegleria fowleri is a pathogenic free-living amoeba (FLA) that causes an acute fatal disease known as primary amoebic meningoencephalitis (PAM). The major problem for infections with any pathogenic FLA is a lack of effective therapeutics, since PAM has a case mortality rate approaching 99%. Clearly, new drugs that are potent and have rapid onset of action are needed to enhance the treatment regimens for PAM. Diamidines have demonstrated potency against multiple pathogens, including FLA, and are known to cross the blood-brain barrier to cure other protozoan diseases of the central nervous system. Therefore, amidino derivatives serve as an important chemotype for discovery of new drugs. In this study, we validated two new in vitro assays suitable for medium- or high-throughput drug discovery and used these for N. fowleri. We next screened over 150 amidino derivatives of multiple structural classes and identified two hit series with nM potency that are suitable for further lead optimization as new drugs for this neglected disease. These include both mono- and diamidino derivatives, with the most potent compound (DB173) having a 50% inhibitory concentration (IC50) of 177 nM. Similarly, we identified 10 additional analogues with IC50s of <1 μM, with many of these having reasonable selectivity indices. The most potent hits were >500 times more potent than pentamidine. In summary, the mono- and diamidino derivatives offer potential for lead optimization to develop new drugs to treat central nervous system infections with N. fowleri. PMID:25605363

  16. Pelvic rotation torque during fast-pitch softball hitting under three ball height conditions.

    PubMed

    Iino, Yoichi; Fukushima, Atsushi; Kojima, Takeji

    2014-08-01

    The purpose of this study was to investigate the relevance of hip joint angles to the production of the pelvic rotation torque in fast-pitch softball hitting and to examine the effect of ball height on this production. Thirteen advanced female softball players hit stationary balls at three different heights: high, middle, and low. The pelvic rotation torque, defined as the torque acting on the pelvis through the hip joints about the pelvic superior-inferior axis, was determined from the kinematic and force plate data using inverse dynamics. Irrespective of the ball heights, the rear hip extension, rear hip external rotation, front hip adduction, and front hip flexion torques contributed to the production of pelvic rotation torque. Although the contributions of the adduction and external rotation torques at each hip joint were significantly different among the ball heights, the contributions of the front and rear hip joint torques were similar among the three ball heights owing to cancelation of the two torque components. The timings of the peaks of the hip joint torque components were significantly different, suggesting that softball hitters may need to adjust the timings of the torque exertions fairly precisely to rotate the upper body effectively. PMID:24979815

  17. The HIT-II Spherical Torus: Physics and Key Experimental Results

    NASA Astrophysics Data System (ADS)

    Redd, A. J.; Hamp, W. T.; Izzo, V. A.; Jarboe, T. R.; Nelson, B. A.; O'Neill, R. G.; Raman, R.; Sieck, P. E.; Smith, R. J.

    2004-11-01

    Discharges in the HIT-II spherical torus device [Redd et al., Phys. Plasmas 9, 2006 (2002)] can be driven by either Ohmic or Coaxial Helicity Injection (CHI) current drive. A new CHI operating regime has been explored, with toroidal plasma currents of up to 350 kA, I_p/I_TF ratios of up to 1.2, and internal probing data which may demonstrate the formation of a closed-flux core. The key to acheiving these results is the magnetic field shear in the CHI injector region, with a minimum shear necessary for current build-up. Ohmic plasma performance has also improved, with peak currents up to 300 kA, with and without transient CHI startup. The CHI startup technique [Raman et al., Phys. Plasmas 11, 2565 (2004)] provides more robust discharges, with a wider operating space and more efficient use of the transformer Volt-seconds, than unassisted Ohmic. Finally, CHI can be used to enhance an Ohmic plasma current without significantly degrading the quality of the discharge. Results will be presented for each HIT--II operating regime, including empirical performance scalings and applicable parametric operating spaces.

  18. An Analytic Model for the Success Rate of a Robotic Actuator System in Hitting Random Targets.

    PubMed

    Bradley, Stuart

    2015-11-20

    Autonomous robotic systems are increasingly being used in a wide range of applications such as precision agriculture, medicine, and the military. These systems have common features which often includes an action by an "actuator" interacting with a target. While simulations and measurements exist for the success rate of hitting targets by some systems, there is a dearth of analytic models which can give insight into, and guidance on optimization, of new robotic systems. The present paper develops a simple model for estimation of the success rate for hitting random targets from a moving platform. The model has two main dimensionless parameters: the ratio of actuator spacing to target diameter; and the ratio of platform distance moved (between actuator "firings") to the target diameter. It is found that regions of parameter space having specified high success are described by simple equations, providing guidance on design. The role of a "cost function" is introduced which, when minimized, provides optimization of design, operating, and risk mitigation costs.

  19. Systematic Identification of Matching Molecular Series and Mapping of Screening Hits.

    PubMed

    de la Vega de León, Antonio; Hu, Ye; Bajorath, Jürgen

    2014-04-01

    Matching molecular series (MMS) have originally been introduced as an extension of the matched molecular pair (MMP) concept to facilitate the design of substructure-based structure-activity relationship (SAR) networks. An MMP is defined as a pair of compounds that only differ by a structural change at a single site. In addition, an MMS is defined as an MMP-based series of compounds that have a conserved structural core and are distinguished by modifications at a single site. Systematic generation of MMS from specifically active compounds generalizes the search for series of structural analogs. Potency-ordered MMS provide series associated with SAR information. We have systematically extracted MMS from publicly available compounds with well-defined activity measurements and generated a large database with approx. 40 000 single- and 13 600 multi-target series, which provide a rich source of SAR information. As an application, we introduce MMP-based mapping of screening hits to MMS to search for initial SAR information and determine all SAR environments available for such hits. The MMS database is made freely available to the scientific community.

  20. Discovery of HIV Type 1 Aspartic Protease Hit Compounds through Combined Computational Approaches.

    PubMed

    Xanthopoulos, Dimitrios; Kritsi, Eftichia; Supuran, Claudiu T; Papadopoulos, Manthos G; Leonis, Georgios; Zoumpoulakis, Panagiotis

    2016-08-01

    A combination of computational techniques and inhibition assay experiments was employed to identify hit compounds from commercial libraries with enhanced inhibitory potency against HIV type 1 aspartic protease (HIV PR). Extensive virtual screening with the aid of reliable pharmacophore models yielded five candidate protease inhibitors. Subsequent molecular dynamics and molecular mechanics Poisson-Boltzmann surface area free-energy calculations for the five ligand-HIV PR complexes suggested a high stability of the systems through hydrogen-bond interactions between the ligands and the protease's flaps (Ile50/50'), as well as interactions with residues of the active site (Asp25/25'/29/29'/30/30'). Binding-energy calculations for the three most promising compounds yielded values between -5 and -10 kcal mol(-1) and suggested that van der Waals interactions contribute most favorably to the total energy. The predicted binding-energy values were verified by in vitro inhibition assays, which showed promising results in the high nanomolar range. These results provide structural considerations that may guide further hit-to-lead optimization toward improved anti-HIV drugs. PMID:27411556

  1. Emergence of Chinese drug discovery research: impact of hit and lead identification.

    PubMed

    Zhou, Caihong; Zhou, Yan; Wang, Jia; Zhu, Yue; Deng, Jiejie; Wang, Ming-Wei

    2015-03-01

    The identification of hits and the generation of viable leads is an early and yet crucial step in drug discovery. In the West, the main players of drug discovery are pharmaceutical and biotechnology companies, while in China, academic institutions remain central in the field of drug discovery. There has been a tremendous amount of investment from the public as well as private sectors to support infrastructure buildup and expertise consolidation relative to drug discovery and development in the past two decades. A large-scale compound library has been established in China, and a series of high-impact discoveries of lead compounds have been made by integrating information obtained from different technology-based strategies. Natural products are a major source in China's drug discovery efforts. Knowledge has been enhanced via disruptive breakthroughs such as the discovery of Boc5 as a nonpeptidic agonist of glucagon-like peptide 1 receptor (GLP-1R), one of the class B G protein-coupled receptors (GPCRs). Most of the original hit identification and lead generation were carried out by academic institutions, including universities and specialized research institutes. The Chinese pharmaceutical industry is gradually transforming itself from manufacturing low-end generics and active pharmaceutical ingredients to inventing new drugs.

  2. An Analytic Model for the Success Rate of a Robotic Actuator System in Hitting Random Targets

    PubMed Central

    Bradley, Stuart

    2015-01-01

    Autonomous robotic systems are increasingly being used in a wide range of applications such as precision agriculture, medicine, and the military. These systems have common features which often includes an action by an “actuator” interacting with a target. While simulations and measurements exist for the success rate of hitting targets by some systems, there is a dearth of analytic models which can give insight into, and guidance on optimization, of new robotic systems. The present paper develops a simple model for estimation of the success rate for hitting random targets from a moving platform. The model has two main dimensionless parameters: the ratio of actuator spacing to target diameter; and the ratio of platform distance moved (between actuator “firings”) to the target diameter. It is found that regions of parameter space having specified high success are described by simple equations, providing guidance on design. The role of a “cost function” is introduced which, when minimized, provides optimization of design, operating, and risk mitigation costs. PMID:26610500

  3. Bis-Benzimidazole Hits against Naegleria fowleri Discovered with New High-Throughput Screens

    PubMed Central

    Rice, Christopher A.; Colon, Beatrice L.; Alp, Mehmet; Göker, Hakan; Boykin, David W.

    2015-01-01

    Naegleria fowleri is a pathogenic free-living amoeba (FLA) that causes an acute fatal disease known as primary amoebic meningoencephalitis (PAM). The major problem for infections with any pathogenic FLA is a lack of effective therapeutics, since PAM has a case mortality rate approaching 99%. Clearly, new drugs that are potent and have rapid onset of action are needed to enhance the treatment regimens for PAM. Diamidines have demonstrated potency against multiple pathogens, including FLA, and are known to cross the blood-brain barrier to cure other protozoan diseases of the central nervous system. Therefore, amidino derivatives serve as an important chemotype for discovery of new drugs. In this study, we validated two new in vitro assays suitable for medium- or high-throughput drug discovery and used these for N. fowleri. We next screened over 150 amidino derivatives of multiple structural classes and identified two hit series with nM potency that are suitable for further lead optimization as new drugs for this neglected disease. These include both mono- and diamidino derivatives, with the most potent compound (DB173) having a 50% inhibitory concentration (IC50) of 177 nM. Similarly, we identified 10 additional analogues with IC50s of <1 μM, with many of these having reasonable selectivity indices. The most potent hits were >500 times more potent than pentamidine. In summary, the mono- and diamidino derivatives offer potential for lead optimization to develop new drugs to treat central nervous system infections with N. fowleri. PMID:25605363

  4. Bis-benzimidazole hits against Naegleria fowleri discovered with new high-throughput screens.

    PubMed

    Rice, Christopher A; Colon, Beatrice L; Alp, Mehmet; Göker, Hakan; Boykin, David W; Kyle, Dennis E

    2015-04-01

    Naegleria fowleri is a pathogenic free-living amoeba (FLA) that causes an acute fatal disease known as primary amoebic meningoencephalitis (PAM). The major problem for infections with any pathogenic FLA is a lack of effective therapeutics, since PAM has a case mortality rate approaching 99%. Clearly, new drugs that are potent and have rapid onset of action are needed to enhance the treatment regimens for PAM. Diamidines have demonstrated potency against multiple pathogens, including FLA, and are known to cross the blood-brain barrier to cure other protozoan diseases of the central nervous system. Therefore, amidino derivatives serve as an important chemotype for discovery of new drugs. In this study, we validated two new in vitro assays suitable for medium- or high-throughput drug discovery and used these for N. fowleri. We next screened over 150 amidino derivatives of multiple structural classes and identified two hit series with nM potency that are suitable for further lead optimization as new drugs for this neglected disease. These include both mono- and diamidino derivatives, with the most potent compound (DB173) having a 50% inhibitory concentration (IC50) of 177 nM. Similarly, we identified 10 additional analogues with IC50s of <1 μM, with many of these having reasonable selectivity indices. The most potent hits were >500 times more potent than pentamidine. In summary, the mono- and diamidino derivatives offer potential for lead optimization to develop new drugs to treat central nervous system infections with N. fowleri.

  5. Analysis of the 5 iron golf swing when hitting for maximum distance.

    PubMed

    Healy, Aoife; Moran, Kieran A; Dickson, Jane; Hurley, Cillian; Smeaton, Alan F; O'Connor, Noel E; Kelly, Philip; Haahr, Mads; Chockalingam, Nachiappan

    2011-07-01

    Most previous research on golf swing mechanics has focused on the driver club. The aim of this study was to identify the kinematic factors that contribute to greater hitting distance when using the 5 iron club. Three-dimensional marker coordinate data were collected (250 Hz) to calculate joint kinematics at eight key swing events, while a swing analyser measured club swing and ball launch characteristics. Thirty male participants were assigned to one of two groups, based on their ball launch speed (high: 52.9 ± 2.1 m · s(-1); low: 39.9 ± 5.2 m · s(-1)). Statistical analyses were used to identify variables that differed significantly between the two groups. Results showed significant differences were evident between the two groups for club face impact point and a number of joint angles and angular velocities, with greater shoulder flexion and less left shoulder internal rotation in the backswing, greater extension angular velocity in both shoulders at early downswing, greater left shoulder adduction angular velocity at ball contact, greater hip joint movement and X Factor angle during the downswing, and greater left elbow extension early in the downswing appearing to contribute to greater hitting distance with the 5 iron club. PMID:21678149

  6. The Head Tracks and Gaze Predicts: How the World’s Best Batters Hit a Ball

    PubMed Central

    Mann, David L.; Spratford, Wayne; Abernethy, Bruce

    2013-01-01

    Hitters in fast ball-sports do not align their gaze with the ball throughout ball-flight; rather, they use predictive eye movement strategies that contribute towards their level of interceptive skill. Existing studies claim that (i) baseball and cricket batters cannot track the ball because it moves too quickly to be tracked by the eyes, and that consequently (ii) batters do not – and possibly cannot – watch the ball at the moment they hit it. However, to date no studies have examined the gaze of truly elite batters. We examined the eye and head movements of two of the world’s best cricket batters and found both claims do not apply to these batters. Remarkably, the batters coupled the rotation of their head to the movement of the ball, ensuring the ball remained in a consistent direction relative to their head. To this end, the ball could be followed if the batters simply moved their head and kept their eyes still. Instead of doing so, we show the elite batters used distinctive eye movement strategies, usually relying on two predictive saccades to anticipate (i) the location of ball-bounce, and (ii) the location of bat-ball contact, ensuring they could direct their gaze towards the ball as they hit it. These specific head and eye movement strategies play important functional roles in contributing towards interceptive expertise. PMID:23516460

  7. Discovery of HIV Type 1 Aspartic Protease Hit Compounds through Combined Computational Approaches.

    PubMed

    Xanthopoulos, Dimitrios; Kritsi, Eftichia; Supuran, Claudiu T; Papadopoulos, Manthos G; Leonis, Georgios; Zoumpoulakis, Panagiotis

    2016-08-01

    A combination of computational techniques and inhibition assay experiments was employed to identify hit compounds from commercial libraries with enhanced inhibitory potency against HIV type 1 aspartic protease (HIV PR). Extensive virtual screening with the aid of reliable pharmacophore models yielded five candidate protease inhibitors. Subsequent molecular dynamics and molecular mechanics Poisson-Boltzmann surface area free-energy calculations for the five ligand-HIV PR complexes suggested a high stability of the systems through hydrogen-bond interactions between the ligands and the protease's flaps (Ile50/50'), as well as interactions with residues of the active site (Asp25/25'/29/29'/30/30'). Binding-energy calculations for the three most promising compounds yielded values between -5 and -10 kcal mol(-1) and suggested that van der Waals interactions contribute most favorably to the total energy. The predicted binding-energy values were verified by in vitro inhibition assays, which showed promising results in the high nanomolar range. These results provide structural considerations that may guide further hit-to-lead optimization toward improved anti-HIV drugs.

  8. How often do jets of geoeffective size hit the dayside magnetopause?

    NASA Astrophysics Data System (ADS)

    Plaschke, Ferdinand; Hietala, Heli

    2016-04-01

    Magnetosheath high-speed jets are characterized by a larger dynamic pressure with respect to the surrounding plasma. In the subsolar sheath, they occur much more frequently under quasi-radial, i. e., low interplanetary magnetic field (IMF) cone angle conditions. Jets transport mass, momentum, and energy from the bow shock to the magnetopause in a concentrated manner. It has been shown that these jets can cause large amplitude boundary indentations, if they impinge on the dayside magnetopause, and trigger magnetopause surface waves and inner-magnetospheric ULF waves. These waves may then be able, e. g., to modify the drift paths of radiation belt electrons and/or to remove electrons from the radiation belts by magnetopause shadowing. Clearly, the severity of the downstream consequences of impacting jets scales with their size. An important question is: How often do jets of geoeffective size hit the dayside magnetopause? We are able to address this question, for the first time, by inferring scale size distributions of magnetosheath high-speed jets from THEMIS multi-spacecraft observations. We find that a reference area of 100 RE2 (Earth radii squared) of the subsolar magnetopause should be hit almost 3 times per hour, in general, by jets with cross-sectional diameters of 2 RE or larger. Under low IMF cone angle conditions (less than 30°) that rate increases to 9 times per hour, which emphasizes the significance of the magnetosheath jet phenomenon within the framework of solar wind-magnetosphere-ionosphere coupling.

  9. Multiple Hits, Including Oxidative Stress, as Pathogenesis and Treatment Target in Non-Alcoholic Steatohepatitis (NASH)

    PubMed Central

    Takaki, Akinobu; Kawai, Daisuke; Yamamoto, Kazuhide

    2013-01-01

    Multiple parallel hits, including genetic differences, insulin resistance and intestinal microbiota, account for the progression of non-alcoholic steatohepatitis (NASH). Multiple hits induce adipokine secretion, endoplasmic reticulum (ER) and oxidative stress at the cellular level that subsequently induce hepatic steatosis, inflammation and fibrosis, among which oxidative stress is considered a key contributor to progression from simple fatty liver to NASH. Although several clinical trials have shown that anti-oxidative therapy can effectively control hepatitis activities in the short term, the long-term effect remains obscure. Several trials of long-term anti-oxidant protocols aimed at treating cerebrovascular diseases or cancer development have failed to produce a benefit. This might be explained by the non-selective anti-oxidative properties of these drugs. Molecular hydrogen is an effective antioxidant that reduces only cytotoxic reactive oxygen species (ROS) and several diseases associated with oxidative stress are sensitive to hydrogen. The progress of NASH to hepatocellular carcinoma can be controlled using hydrogen-rich water. Thus, targeting mitochondrial oxidative stress might be a good candidate for NASH treatment. Long term clinical intervention is needed to control this complex lifestyle-related disease. PMID:24132155

  10. The head tracks and gaze predicts: how the world's best batters hit a ball.

    PubMed

    Mann, David L; Spratford, Wayne; Abernethy, Bruce

    2013-01-01

    Hitters in fast ball-sports do not align their gaze with the ball throughout ball-flight; rather, they use predictive eye movement strategies that contribute towards their level of interceptive skill. Existing studies claim that (i) baseball and cricket batters cannot track the ball because it moves too quickly to be tracked by the eyes, and that consequently (ii) batters do not - and possibly cannot - watch the ball at the moment they hit it. However, to date no studies have examined the gaze of truly elite batters. We examined the eye and head movements of two of the world's best cricket batters and found both claims do not apply to these batters. Remarkably, the batters coupled the rotation of their head to the movement of the ball, ensuring the ball remained in a consistent direction relative to their head. To this end, the ball could be followed if the batters simply moved their head and kept their eyes still. Instead of doing so, we show the elite batters used distinctive eye movement strategies, usually relying on two predictive saccades to anticipate (i) the location of ball-bounce, and (ii) the location of bat-ball contact, ensuring they could direct their gaze towards the ball as they hit it. These specific head and eye movement strategies play important functional roles in contributing towards interceptive expertise.

  11. Pelvic rotation torque during fast-pitch softball hitting under three ball height conditions.

    PubMed

    Iino, Yoichi; Fukushima, Atsushi; Kojima, Takeji

    2014-08-01

    The purpose of this study was to investigate the relevance of hip joint angles to the production of the pelvic rotation torque in fast-pitch softball hitting and to examine the effect of ball height on this production. Thirteen advanced female softball players hit stationary balls at three different heights: high, middle, and low. The pelvic rotation torque, defined as the torque acting on the pelvis through the hip joints about the pelvic superior-inferior axis, was determined from the kinematic and force plate data using inverse dynamics. Irrespective of the ball heights, the rear hip extension, rear hip external rotation, front hip adduction, and front hip flexion torques contributed to the production of pelvic rotation torque. Although the contributions of the adduction and external rotation torques at each hip joint were significantly different among the ball heights, the contributions of the front and rear hip joint torques were similar among the three ball heights owing to cancelation of the two torque components. The timings of the peaks of the hip joint torque components were significantly different, suggesting that softball hitters may need to adjust the timings of the torque exertions fairly precisely to rotate the upper body effectively.

  12. wwLigCSRre: a 3D ligand-based server for hit identification and optimization

    PubMed Central

    Sperandio, O.; Petitjean, M.; Tuffery, P.

    2009-01-01

    The wwLigCSRre web server performs ligand-based screening using a 3D molecular similarity engine. Its aim is to provide an online versatile facility to assist the exploration of the chemical similarity of families of compounds, or to propose some scaffold hopping from a query compound. The service allows the user to screen several chemically diversified focused banks, such as Kinase-, CNS-, GPCR-, Ion-channel-, Antibacterial-, Anticancer- and Analgesic-focused libraries. The server also provides the possibility to screen the DrugBank and DSSTOX/Carcinogenic compounds databases. User banks can also been downloaded. The 3D similarity search combines both geometrical (3D) and physicochemical information. Starting from one 3D ligand molecule as query, the screening of such databases can lead to unraveled compound scaffold as hits or help to optimize previously identified hit molecules in a SAR (Structure activity relationship) project. wwLigCSRre can be accessed at http://bioserv.rpbs.univ-paris-diderot.fr/wwLigCSRre.html. PMID:19429687

  13. [Double-Hit Follicular Lymphoma with BCL2 and MYC Translocations].

    PubMed

    Horiuchi, Mirei; Fuseya, Hoyuri; Tsutsumi, Minako; Hayashi, Yoshiki; Hagihara, Kiyoyuki; Kanashima, Hiroshi; Nakao, Takafumi; Fukushima, Yuko; Inoue, Takeshi; Yamane, Takahisa

    2016-09-01

    Double-hit lymphomas are rare tumors that are defined by a chromosomal breakpoint affecting the MYC/8q24 locus in combination with another recurrent breakpoint, mainly a t(14; 18)(q32;q21)involving BCL2. We report a case of a 38-yearold woman with a 2-month history of abdominaldistention. 18F-FDG PET showed multiple positive systemic lymph nodes, positive peritoneum, and multiple positive intra-abdominal masses. Histopathology results of the cervical lymph node were compatible with double-hit follicular lymphoma(Grade 3A)because fluorescence in situ hybridization(FISH)demonstrated both MYC rearrangement and BCL2 gene fusion. She was initially started on R-CHOP(rituximab and doxorubicin, vincristine, cyclophosphamide, and prednisolone), but after one course the regimen was changed to dose-adjusted EPOCH-R(rituximab and doxorubicin, etoposide, vincristine, cyclophosphamide, and prednisolone). However, she showed no response to this chemotherapy regimen or haploidentical stem cell transplantation. The treatment strategy included salvage chemothera- py. An autologous and/or allogeneic hematopoietic transplantation is important for non-responders to DA-EPOCH-R. PMID:27628560

  14. How to hit home runs: Optimum baseball bat swing parameters for maximum range trajectories

    NASA Astrophysics Data System (ADS)

    Sawicki, Gregory S.; Hubbard, Mont; Stronge, William J.

    2003-11-01

    Improved models for the pitch, batting, and post-impact flight phases of a baseball are used in an optimal control context to find bat swing parameters that produce maximum range. The improved batted flight model incorporates experimental lift and drag profiles (including the drag crisis). An improved model for bat-ball impact includes the dependence of the coefficient of restitution on the approach relative velocity and the dependence of the incoming pitched ball angle on speed. The undercut distance and bat swing angle are chosen to maximize the range of the batted ball. The sensitivity of the maximum range is calculated for all model parameters including bat and ball speed, bat and ball spin, and wind speed. Post-impact conditions are found to be independent of the ball-bat coefficient of friction. The lift is enhanced by backspin produced by undercutting the ball during batting. An optimally hit curve ball will travel farther than an optimally hit fastball or knuckleball due to increased lift during flight.

  15. Agricultural growth, the status of women, and fertility.

    PubMed

    Whittington, L A; Stapleton, D C

    1995-08-01

    This study tests the hypothesis that fertility is affected differently by economic growth depending upon the specific sector (agriculture, manufacturing, heavy industry, and services) where growth occurred. The hypothesis is that fertility responses are not identical across sectors. The sample includes 51 World Bank member countries in varying stages of development. The econometric model pertains to 1965-88 and the percentage change in the total fertility rate (TFR). During the study period the average TFR declined by over 22%, but the extent of change varied by country and included, for instance, countries such as Ethiopia that experienced fertility increases from 5.8 to 6.5. Hong Kong's TFR declined by 66% from 4.7 to 1.6. Analysis included measures of changes in gross domestic product (GDP) for each of the four sectors and change in real per capita exports in agricultural commodities, resources, and manufactured products. Changes in educational status and changes in infant mortality were also included in some models. There were mixed results for the impact of total GDP. Sectoral analysis shows a positive, small significant impact on TFR from changes in the GDP per capita in agriculture (domestic and export products), and a negative, small significant impact from manufacturing growth. Heavy industry and services produced insignificant impact. In the model with only domestic consumption, results show a stronger coefficient and continued significance for agricultural productivity, agricultural exports, and manufacturing changes per capita. Manufacturing exports produced a negative, insignificant impact. The null hypothesis is rejected only in models comparing aggregate GDP in agriculture and manufacturing industries plus control variables (excluding heavy industry and services). Only secondary education was a negative, significant determinant of fertility. Infant mortality was insignificant when sectoral growth and education were included in the model. The evidence

  16. Concurrent IMRT and weekly cisplatin followed by GDP chemotherapy in newly diagnosed, stage IE to IIE, nasal, extranodal NK/T-Cell lymphoma.

    PubMed

    Ke, Q-H; Zhou, S-Q; Du, W; Liang, G; Lei, Y; Luo, F

    2014-01-01

    On the basis of the benefits of frontline radiation in early-stage, extranodal natural killer (NK)/T-cell lymphoma (ENKTL), we conducted the trial of concurrent chemoradiotherapy (CCRT) followed by three cycles of gemcitabine, dexamethasone and cisplatin (GDP). Thirty-two patients with newly diagnosed, stage IE to IIE, nasal ENKTL received CCRT (that is, all patients received intensity-modulated radiotherapy 56 Gy and cisplatin 30 mg/m(2) weekly, 3-5 weeks). Three cycles of GDP (gemcitabine 1000 mg/m(2) intravenously (i.v.) on days 1 and 8, dexamethasone 40 mg orally on days 1-4 and cisplatin 75 mg/m(2) i.v. on day 1 (GDP), every 21 days as an outpatient were scheduled after CCRT. All patients completed CCRT, which resulted in 100% response that included 24 complete responses (CRs) and eight partial responses. The CR rate after CCRT was 75.0% (that is, 24 of 32 responses). Twenty-eight of the 32 patients completed the planned three cycles of GDP, whereas four patients did not because they withdrew (n = 1) or because they had an infection (n = 3). The overall response rate and the CR rate were 90.6% (that is, 29 of 32 responses) and 84.4% (that is, 27 of 32 responses), respectively. Only two patient experienced grade 3 toxicity during CCRT (nausea), whereas 13 of the 30 patients experienced grade 4 neutropenia. The estimated 3-year overall survival and progression-free rates were 87.50% and 84.38%, respectively. In conclusion, CCRT followed by GDP chemotherapy can be a feasible and effective treatment strategy for stage IE to IIE nasal ENKTL.

  17. Influence of GTP/GDP and magnesium ion on the solvated structure of the protein FtsZ: a molecular dynamics study.

    PubMed

    Jamous, Carla; Basdevant, Nathalie; Ha-Duong, Tap

    2014-01-01

    We present here a structural analysis of ten extensive all-atom molecular dynamics simulations of the monomeric protein FtsZ in various binding states. Since the polymerization and GTPase activities of FtsZ depend on the nature of a bound nucleotide as well as on the presence of a magnesium ion, we studied the structural differences between the average conformations of the following five systems: FtsZ-Apo, FtsZ-GTP, FtsZ-GDP, FtsZ-GTP-Mg, and FtsZ-GDP-Mg. The in silico solvated average structure of FtsZ-Apo significantly differs from the crystallographic structure 1W59 of FtsZ which was crystallized in a dimeric form without nucleotide and magnesium. The simulated Apo form of the protein also clearly differs from the FtsZ structures when it is bound to its ligand, the most important discrepancies being located in the loops surrounding the nucleotide binding pocket. The three average structures of FtsZ-GTP, FtsZ-GDP, and FtsZ-GTP-Mg are overall similar, except for the loop T7 located at the opposite side of the binding pocket and whose conformation in FtsZ-GDP notably differs from the one in FtsZ-GTP and FtsZ-GTP-Mg. The presence of a magnesium ion in the binding pocket has no impact on the FtsZ conformation when it is bound to GTP. In contrast, when the protein is bound to GDP, the divalent cation causes a translation of the nucleotide outwards the pocket, inducing a significant conformational change of the loop H6-H7 and the top of helix H7.

  18. Effects of elevated CO{sub 2} on plant-grazer interactions: The importance of urine-hits and simulated grazing on the response of a C{sub 3} grass from Yellowstone National Park

    SciTech Connect

    Wilsey, B.J.; Coleman, J.S.; McNaughton, S.J.

    1995-06-01

    Although grazing mammals are an important component of most grassland ecosystems, previous research on plant responses to elevated CO{sub 2} has rarely considered their effects. In a growth chamber experiment, we tested whether regrowth following simulated grazing was affected by elevated CO{sub 2} and urine hits (40 g/m{sup 2} urea N) in the C{sub 3} grass, Stipa occidentalis, which is common in Yellowstone National Park. Plant response (end of experiment biomass and productivity [biomass + clippings]) to elevated CO{sub 2} depended on whether plants received urine-hits and were clipped: plants only had increased growth in response to CO{sub 2} enrichment if they had received urea and were not clipped. Plants that received the entire grazing treatment (urea and clipping) had biomass and productivity values that were similar to controls. Thus, grazing mammals will tend to dampen the predicted CO{sub 2} effect in grasslands by significantly lowering increases in plant growth response to elevated CO{sub 2} levels.

  19. "I Wish the Hitting Would Stop . . . " An Assessment of a Domestic Violence Education Program for Elementary Students.

    PubMed

    Dahle, Thorvald O; Archbold, Carol A

    2014-01-23

    School officials across the country have recognized that many of their students live in homes where domestic violence occurs. As a result, several elementary schools have implemented education-based programs focused on this issue. The current study evaluates the efficacy of the "I Wish the Hitting Would Stop . . . " program that was presented to elementary school children in two school districts in the Midwest. This study examines the level of knowledge retention by students who participated in the "I Wish the Hitting Would Stop . . . " program during the 2010-2011 and 2011-2012 academic years. Fourth- and fifth-grade students responded to open-ended questions regarding their understanding of domestic violence and their retention of the concepts presented in the "I Wish the Hitting Would Stop . . . " curriculum. While the results suggest that students retain the information presented in the program, there also appears to be a gender difference in knowledge retention.

  20. A GDP-bound of rab1 inhibits protein export from the endoplasmic reticulum and transport between Golgi compartments

    PubMed Central

    1994-01-01

    Rab1 is a small GTPase regulating vesicular traffic between early compartments of the secretory pathway. To explore the role of rab1 we have analyzed the function of a mutant (rab1a[S25N]) containing a substitution which perturbs Mg2+ coordination and reduces the affinity for GTP, resulting in a form which is likely to be restricted to the GDP-bound state. The rab1a(S25N) mutant led to a marked reduction in protein export from the ER in vivo and in vitro, indicating that a guanine nucleotide exchange protein (GEP) is critical for the recruitment of rab1 during vesicle budding. The mutant protein required posttranslational isoprenylation for inhibition and behaved as a competitive inhibitor of wild-type rab1 function. Both rab1a and rab1b (92% identity) were able to antagonize the inhibitory activity of the rab1a(S25N) mutant, suggesting that these two isoforms are functionally interchangeable. The rab1 mutant also inhibited transport between Golgi compartments and resulted in an apparent loss of the Golgi apparatus, suggesting that Golgi integrity is coupled to rab1 function in vesicular traffic. PMID:8163542

  1. Structural Studies of the Nudix GDP-mannose Hydrolase from E. coli Reveals a New Motif for Mannose Recognition

    SciTech Connect

    A Boto; W Xu; J Jakoncic; A Pannuri; T Romeo; M Bessman; S Gabelli; L Amzel

    2011-12-31

    The Nudix hydrolase superfamily, characterized by the presence of the signature sequence GX5EX7REUXEEXGU (where U is I, L, or V), is a well-studied family in which relations have been established between primary sequence and substrate specificity for many members. For example, enzymes that hydrolyze the diphosphate linkage of ADP-ribose are characterized by having a proline 15 amino acids C-terminal of the Nudix signature sequence. GDPMK is a Nudix enzyme that conserves this characteristic proline but uses GDP-mannose as the preferred substrate. By investigating the structure of the GDPMK alone, bound to magnesium, and bound to substrate, the structural basis for this divergent substrate specificity and a new rule was identified by which ADP-ribose pyrophosphatases can be distinguished from purine-DP-mannose pyrophosphatases from primary sequence alone. Kinetic and mutagenesis studies showed that GDPMK hydrolysis does not rely on a single glutamate as the catalytic base. Instead, catalysis is dependent on residues that coordinate the magnesium ions and residues that position the substrate properly for catalysis. GDPMK was thought to play a role in biofilm formation because of its upregulation in response to RcsC signaling; however, GDPMK knockout strains show no defect in their capacity of forming biofilms.

  2. Structural Studies of the Nudix GDP-mannose Hydrolase from E. coli Reveals a New Motif for Mannose Recognition

    PubMed Central

    Boto, Agedi N.; Xu, Wenlian; Jakoncic, Jean; Pannuri, Archana; Romeo, Tony; Bessman, Maurice J.; Gabelli, Sandra B.; Amzel, L. Mario

    2011-01-01

    The Nudix hydrolase superfamily, characterized by the presence of the signature sequence GX5EX7REUXEEXGU (where U is I, L, or V), is a well studied family in which relations have been established between primary sequence and substrate specificity for many members. For example, enzymes that hydrolyze the diphosphate linkage of ADP-ribose are characterized by having a proline 15 amino acids C-terminal of the Nudix signature sequence. GDPMK is a Nudix enzyme that conserves this characteristic proline but uses GDP-mannose as the preferred substrate. By investigating the structure of the GDPMK alone, bound to magnesium, and bound to substrate, the structural basis for this divergent substrate specificity and a new rule was identified by which ADP-ribose pyrophosphatases can be distinguished from Purine-DP-mannose pyrophosphatases from primary sequence alone. Kinetic and mutagenesis studies showed that GDPMK hydrolysis does not rely on a single glutamate as the catalytic base. Instead, catalysis is dependent on residues that coordinate the magnesium ions and residues that position the substrate properly for catalysis. GDPMK was thought to play a role in biofilm formation due to its upregulation in response to RcsC signalling; however, GDPMK knockout strains show no defect in their capacity of forming biofilms. PMID:21638333

  3. Overexpression, purification, biochemical characterization, and molecular modeling of recombinant GDP-mannosyltransferase (GumH) from Xylella fastidiosa.

    PubMed

    Muniz, João Renato C; Alves, Claudia A; de Pieri, Celina; Beltramini, Leila M; Selistre-de-Araújo, Heloisa S; Vettore, André L; da Silva, Felipe R; Arruda, Paulo; Garratt, Richard C; Oliva, Glaucius; Souza, Dulce H F

    2004-03-01

    The GumH enzyme from Xylella fastidiosa catalyzes the transfer reaction of a mannose from GDP-mannose to the carrier lipid cellobiose-pyrophosphate-polyprenol (Glc(2)-PP-Lip), an intermediary in the reaction for the synthesis of the exopolysaccharide (EPS) fastidian gum. The gumH gene was subcloned in the pMal-c2x vector, allowing the expression of the GumH-MBP fusion protein. Various attempts were made to obtain protein with the necessary degree of purity for crystallographic studies but the yield was very low. The gumH gene was then subcloned in the pET28a vector allowing the expression of the GumH enzyme in fusion with a histidine-rich peptide. The protein was purified and characterized. The three-dimensional structure of the X. fastidiosa GumH enzyme was modeled by threading studies. The model consists of N- and C-terminal domains similar in size and topology and separated by a deep cleft, which includes the EX(7)E motif that can be involved in the catalysis of GumH. PMID:14766234

  4. The three-hit concept of vulnerability and resilience: towards understanding adaptation to early-life adversity outcome

    PubMed Central

    Daskalakis, Nikolaos P.; Bagot, Rosemary C.; Parker, Karen J.; Vinkers, Christiaan H.; de Kloet, E. R.

    2013-01-01

    Stressful experiences during early-life can modulate the genetic programming of specific brain circuits underlying emotional and cognitive aspects of behavioral adaptation to stressful experiences later in life. Although this programming effect exerted by experience-related factors is an important determinant of mental health, its outcome depends on cognitive inputs and hence the valence an individual assigns to a given environmental context. From this perspective we will highlight, with studies in rodents, non-human primates and humans, the three-hit concept of vulnerability and resilience to stress-related mental disorders, which is based on gene-environment interactions during critical phases of perinatal and juvenile brain development. The three-hit (i.e., hit-1: genetic predisposition, hit-2: early-life environment, and hit-3: later-life environment) concept accommodates the cumulative stress hypothesis stating that in a given context vulnerability is enhanced when failure to cope with adversity accumulates. Alternatively, the concept also points to the individual’s predictive adaptive capacity, which underlies the stress inoculation and match/mismatch hypotheses. The latter hypotheses propose that the experience of relatively mild early-life adversity prepares for the future and promotes resilience to similar challenges in later-life; when a mismatch occurs between early and later-life experience, coping is compromised and vulnerability is enhanced. The three-hit concept is fundamental for understanding how individuals can either be prepared for coping with life to come and remain resilient or are unable to do so and succumb to a stress-related mental disorder, under seemingly identical circumstances. PMID:23838101

  5. The role of energy in economic growth.

    PubMed

    Stern, David I

    2011-02-01

    This paper reviews the mainstream, resource economics, and ecological economics models of growth. A possible synthesis of energy-based and mainstream models is presented. This shows that when energy is scarce it imposes a strong constraint on the growth of the economy; however, when energy is abundant, its effect on economic growth is much reduced. The industrial revolution released the constraints on economic growth by the development of new methods of using coal and the discovery of new fossil fuel resources. Time-series analysis shows that energy and GDP cointegrate, and energy use Granger causes GDP when capital and other production inputs are included in the vector autoregression model. However, various mechanisms can weaken the links between energy and growth. Energy used per unit of economic output has declined in developed and some developing countries, owing to both technological change and a shift from poorer quality fuels, such as coal, to the use of higher quality fuels, especially electricity. Substitution of other inputs for energy and sectoral shifts in economic activity play smaller roles.

  6. Heparin-induced thrombocytopenia (HIT) causing portosplenic, superior mesenteric, and splenic vein thrombosis resulting in splenic rupture and pulmonary emboli formation.

    PubMed

    Lammering, Jeanne C; Wang, David S; Shin, Lewis K

    2012-01-01

    Heparin-induced thrombocytopenia (HIT) is a life-threatening complication of heparin administration. Of the few reported cases of HIT-associated intra-abdominal thrombosis, none to our knowledge provide multidetector-row computed tomography (MDCT) imaging findings or emphasize its utility in diagnosis. We describe a case of HIT with MDCT images demonstrating extensive intra-abdominal thrombosis and end-organ complications including splenic rupture and pulmonary emboli. This case emphasizes the potential role of MDCT in the rapid detection of HIT-related thromboembolic complications in patients with nonspecific abdominal pain.

  7. Synthetic Medicinal Chemistry in Chagas’ Disease: Compounds at The Final Stage of “Hit-To-Lead” Phase

    PubMed Central

    Cerecetto, Hugo; González, Mercedes

    2010-01-01

    Chagas’ disease, or American trypanosomosiasis, has been the most relevant illness produced by protozoa in Latin America. Synthetic medicinal chemistry efforts have provided an extensive number of chemodiverse hits at the “active-to-hit” stage. However, only a more limited number of these have been studied in vivo in models of Chagas’ disease. Herein, we survey some of the cantidates able to surpass the “hit-to-lead” stage discussing their limitations or merit to enter in clinical trials in the short term.

  8. Sepsis Patients with First and Second-Hit Infections Show Different Outcomes Depending on the Causative Organism

    PubMed Central

    Morgan, Matt P.; Szakmany, Tamas; Power, Sarah G.; Olaniyi, Patrick; Hall, Judith E.; Rowan, Kathy; Eberl, Matthias

    2016-01-01

    Objective: With improving rates of initial survival in severe sepsis, second-hit infections that occur following resolution of the primary insult carry an increasing burden of morbidity. However, despite the clinical relevance of these infections, no data are available on differential outcomes in patients with first and second-hit infections depending on the nature of the causative organism. This study aims to explore any differences in these subgroups. Design: In a retrospective, observational cohort study, the United Kingdom Intensive Care National Audit & Research Centre (ICNARC) database was used to explore the outcomes of patient with first-hit infections leading to sepsis, and sepsis patients with second-hit infections grouped according to the Gram status of the causative organism. Setting: General critical care units in England, Wales, and Northern Ireland participating in the ICNARC programme between 1 January, 2007 and 30 June, 2012. Patients: Patient groups analyzed included 2119 patients with and 1319 patients without sepsis who developed an intensive care unit acquired infection in blood. Subgroups included patients with trauma, emergency neurosurgery, elective surgery, and cardiogenic shock. Measurements and main results: Gram-negative organisms were associated with poorer outcomes in first-hit infections. The 90-day mortality of patients who developed a Gram-negative infection was 43.6% following elective surgery and 27.9% following trauma. This compared with a mortality of 25.6 and 20.6%, respectively, in Gram-positive infections. Unexpectedly, an inverse relationship between Gram status and mortality was observed in second-hit infections. Patients with an initial diagnosis of sepsis who developed secondary infections caused by Gram-negative organisms had a 90-day mortality of 40.4%, compared with 43.6% in Gram-positive infections. Conclusions: Our study identifies a fundamental difference in patient outcomes between first-hit and second-hit

  9. Dual hit lipopolysaccharide & oleic acid combination induced rat model of acute lung injury/acute respiratory distress syndrome

    PubMed Central

    Hagawane, T.N.; Gaikwad, R.V.; Kshirsagar, N.A.

    2016-01-01

    Background & objectives: Despite advances in therapy and overall medical care, acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) management remains a problem. Hence the objective of this study was to develop a rat model that mimics human ALI/ARDS. Methods: Four groups of Wistar rats, 48 per group were treated with (i) intratracheal (IT) lipopolysaccharide (LPS) (5 mg/kg) dissolved in normal saline (NS), (ii) intravenous (iv) oleic acid (OA) (250 μl/kg) suspension in bovine serum albumin (BSA), (iii) dual hit: IT LPS (2 mg/kg) dissolved in NS and iv OA (100 μl/kg) and (iv) control group: IT NS and iv BSA. From each group at set periods of time various investigations like chest X-rays, respiratory rate (RR), tidal volume (TV), total cell count, differential cell count, total protein count and cytokine levels in bronchoalveolar lavage fluid (BALF), lung wet/dry weight ratio and histopathological examination were done. Results: It was noted that the respiratory rate, and tumour necrosis factor-α (TNF-α) levels were significantly higher at 4 h in the dual hit group as compared to LPS, OA and control groups. Interleukin-6 (IL-6) levels were significantly higher in the dual hit group as compared to LPS at 8 and 24 h, OA at 8 h and control (at all time intervals) group. IL-1β levels were significantly higher in LPS and dual hit groups at all time intervals, but not in OA and control groups. The injury induced in dual hit group was earlier and more sustained as compared to LPS and OA alone. Interpretation & conclusions: The lung pathology and changes in respiration functions produced by the dual hit model were closer to the diagnostic criteria of ALI/ARDS in terms of clinical manifestations and pulmonary injury and the injury persisted longer as compared to LPS and OA single hit model. Therefore, the ARDS model produced by the dual hit method was closer to the diagnostic criteria of ARDS in terms of clinical manifestations and pulmonary injury. PMID

  10. Effect of the Exclusion of Behavioral Health from Health Information Technology (HIT) Legislation on the Future of Integrated Health Care.

    PubMed

    Cohen, Deborah

    2015-10-01

    Past research has shown abundant comorbidity between physical chronic health conditions and mental illness. The focal point of the conversation to reduce cost is better care coordination through the implementation of health information technology (HIT). At the policy level, the Health Information Technology for Economic and Clinical Health Act of 2009 (HITECH Act) was implemented as a way to increase the implementation of HIT. However, behavioral health providers have been largely excluded from obtaining access to the funds provided by the HITECH Act. Without further intervention, disjointed care coordination between physical and behavioral health providers will continue.

  11. Synthetic Medicinal Chemistry in Chagas’ Disease: Compounds at The Final Stage of “Hit-To-Lead” Phase

    PubMed Central

    Cerecetto, Hugo; González, Mercedes

    2010-01-01

    Chagas’ disease, or American trypanosomosiasis, has been the most relevant illness produced by protozoa in Latin America. Synthetic medicinal chemistry efforts have provided an extensive number of chemodiverse hits at the “active-to-hit” stage. However, only a more limited number of these have been studied in vivo in models of Chagas’ disease. Herein, we survey some of the cantidates able to surpass the “hit-to-lead” stage discussing their limitations or merit to enter in clinical trials in the short term. PMID:27713281

  12. A double hit model for the distribution of time to AIDS onset

    NASA Astrophysics Data System (ADS)

    Chillale, Nagaraja Rao

    2013-09-01

    Incubation time is a key epidemiologic descriptor of an infectious disease. In the case of HIV infection this is a random variable and is probably the longest one. The probability distribution of incubation time is the major determinant of the relation between the incidences of HIV infection and its manifestation to Aids. This is also one of the key factors used for accurate estimation of AIDS incidence in a region. The present article i) briefly reviews the work done, points out uncertainties in estimation of AIDS onset time and stresses the need for its precise estimation, ii) highlights some of the modelling features of onset distribution including immune failure mechanism, and iii) proposes a 'Double Hit' model for the distribution of time to AIDS onset in the cases of (a) independent and (b) dependent time variables of the two markers and examined the applicability of a few standard probability models.

  13. Revisiting hippocampal sclerosis in mesial temporal lobe epilepsy according to the "two-hit" hypothesis.

    PubMed

    Hamelin, S; Depaulis, A

    2015-03-01

    Hippocampal sclerosis (HS) is the most common neuropathological pattern observed in pharmacoresistant epilepsy and represents a critical feature in mesial temporal lobe epilepsy syndrome. However, its pathophysiological mechanisms and neuropathological consequences on seizures remain mostly unresolved. The new international classification of hippocampal sclerosis aims at standardizing its description to allow comparisons between different clinical studies. However, several aspects are not considered in this classification (granule cell dispersion, sprouting, glial modifications…). In this chapter, we discuss these different features associated with hippocampal sclerosis in perspective with the "two-hit" hypothesis and propose mechanisms that could be involved in the modulation of some specific neuropathological aspects like early life stress, hyperthermic seizures, brain lesions or hormonal modifications.

  14. Hepatitis C and double-hit B cell lymphoma successfully treated by antiviral therapy

    PubMed Central

    Galati, Giovanni; Rampa, Lorenzo; Vespasiani-Gentilucci, Umberto; Marino, Mirella; Pisani, Francesco; Cota, Carlo; Guidi, Alessandro; Picardi, Antonio

    2016-01-01

    B cells lymphoma is one of the most challenging extra-hepatic manifestations of hepatitis C virus (HCV). Recently, a new kind of B-cell lymphoma, named double-hit B (DHL), was characterized with an aggressive clinical course whereas a potential association with HCV was not investigated. The new antiviral direct agents (DAAs) against HCV are effective and curative in the majority of HCV infections. We report the first case, to our knowledge, of DHL and HCV-infection successfully treated by new DAAs. According to our experience, a DHL must be suspected in case of HCV-related lymphoma, and an early diagnosis could direct towards a different hematological management because a worse prognosis might be expected. A possible effect of DAAs on DHL regression should be investigated, but eradicating HCV would avoid life-threatening reactivation of viral hepatitis during pharmacological immunosuppression in onco-haematological diseases. PMID:27803769

  15. Development of a neutron detector with broad dynamic range and multi-hit capability

    NASA Astrophysics Data System (ADS)

    Pawelczak, Iwona; Toke, Jan; Tsai, Yun-Tse; Udo Schröder, W.

    2007-10-01

    A new type of Gd-loaded plastic neutron detector with a broad dynamic range (from thermal to MeV range) and multi-hit capability has been designed and subjected to series of tests. The device consists of a stack of alternating plastic scintillator (Saint Gobain BC-408) slabs and thin radiator films (PDMS -- SYLGARD 184) loaded with 0.5% of Gd per weight, viewed by a photomultiplier tube. The scintillator functions as neutron moderator, provides a prompt integrated neutron energy signal, and detects delayed n capture by Gd nuclei via associated capture γ-rays. The design, Monte Carlo simulations carried out with an extended code DENIS(E), as well as first measurements with the detector will be discussed.

  16. Novel Cancer Chemotherapy Hits by Molecular Topology: Dual Akt and Beta-Catenin Inhibitors

    PubMed Central

    Morell, Cecilia; Rodríguez-Henche, Nieves; Recio-Iglesias, Maria Carmen; Garcia-Domenech, Ramon

    2015-01-01

    Background and Purpose Colorectal and prostate cancers are two of the most common types and cause of a high rate of deaths worldwide. Therefore, any strategy to stop or at least slacken the development and progression of malignant cells is an important therapeutic choice. The aim of the present work is the identification of novel cancer chemotherapy agents. Nowadays, many different drug discovery approaches are available, but this paper focuses on Molecular Topology, which has already demonstrated its extraordinary efficacy in this field, particularly in the identification of new hit and lead compounds against cancer. This methodology uses the graph theoretical formalism to numerically characterize molecular structures through the so called topological indices. Once obtained a specific framework, it allows the construction of complex mathematical models that can be used to predict physical, chemical or biological properties of compounds. In addition, Molecular Topology is highly efficient in selecting and designing new hit and lead drugs. According to the aforementioned, Molecular Topology has been applied here for the construction of specific Akt/mTOR and β-catenin inhibition mathematical models in order to identify and select novel antitumor agents. Experimental Approach Based on the results obtained by the selected mathematical models, six novel potential inhibitors of the Akt/mTOR and β-catenin pathways were identified. These compounds were then tested in vitro to confirm their biological activity. Conclusion and Implications Five of the selected compounds, CAS n° 256378-54-8 (Inhibitor n°1), 663203-38-1 (Inhibitor n°2), 247079-73-8 (Inhibitor n°3), 689769-86-6 (Inhibitor n°4) and 431925-096 (Inhibitor n°6) gave positive responses and resulted to be active for Akt/mTOR and/or β-catenin inhibition. This study confirms once again the Molecular Topology’s reliability and efficacy to find out novel drugs in the field of cancer. PMID:25910265

  17. Galactic cosmic rays and cell-hit frequencies outside the magnetosphere.

    PubMed

    Curtis, S B; Letaw, J R

    1989-01-01

    An evaluation of the exposure of space travelers to galactic cosmic radiation outside the earth's magnetosphere is made by calculating fluences of high-energy primary and secondary particles with various charges traversing a sphere of area 100 microns2. Calculations relating to two shielding configurations are presented: the center of a spherical aluminum shell of thickness 1 g/cm2, and the center of a 4 g/cm2 thick aluminum spherical shell within which there is a 30 g/cm2 diameter spherical water phantom with the point of interest 5 g/cm2 from the surface. The area of 100 microns2 was chosen to simulate the nucleus of a cell in the body. The frequencies as a function of charge component in both shielding configurations reflects the odd-even disparity of the incident particle abundances. For a three-year mission, 33% of the cells in the more heavily shielded configuration would be hit by at least one particle with Z greater than 10. Six percent would be hit by at least two such particles. This emphasizes the importance of studying single high-Z particle effects both on cells which might be "at risk" for cancer induction and on critical neural cells or networks which might be vulnerable to inactivation by heavy charged particle tracks. Synergistic effects with the more numerous high-energy protons and helium ions cannot be ruled out. In terms of more conventional radiation risk assessment, the dose equivalent decreased by a factor of 2.85 from free space to that in the more heavily shielded configuration. Roughly half of this was due to the decrease in energy deposition (absorbed dose) and half to the decrease in biological effectiveness (quality factor).

  18. Female Education as a Determinant of Economic Growth: The Case Study of Pakistan

    ERIC Educational Resources Information Center

    Fatima, Goher

    2011-01-01

    The contribution of female education has been very important in the GDP growth of the country, but this very sector has been ignored by the Government. This paper focuses on the importance of female education and highlights its significance for national development. It also brings out some impediments, obstacles and barriers confronting female…

  19. Stringent Mitigation Policy Implied By Temperature Impacts on Economic Growth

    NASA Astrophysics Data System (ADS)

    Moore, F.; Turner, D.

    2014-12-01

    Integrated assessment models (IAMs) compare the costs of greenhouse gas mitigation with damages from climate change in order to evaluate the social welfare implications of climate policy proposals and inform optimal emissions reduction trajectories. However, these models have been criticized for lacking a strong empirical basis for their damage functions, which do little to alter assumptions of sustained GDP growth, even under extreme temperature scenarios. We implement empirical estimates of temperature effects on GDP growth-rates in the Dynamic Integrated Climate and Economy (DICE) model via two pathways, total factor productivity (TFP) growth and capital depreciation. Even under optimistic adaptation assumptions, this damage specification implies that optimal climate policy involves the elimination of emissions in the near future, the stabilization of global temperature change below 2°C, and a social cost of carbon (SCC) an order of magnitude larger than previous estimates. A sensitivity analysis shows that the magnitude of growth effects, the rate of adaptation, and the dynamic interaction between damages from warming and GDP are three critical uncertainties and an important focus for future research.

  20. Interleukin-9 (IL-9) and NPM-ALK each generate mast cell hyperplasia as single 'hit' and cooperate in producing a mastocytosis-like disease in mice.

    PubMed

    Merz, Hartmut; Kaehler, Christian; Hoefig, Kai P; Branke, Biggi; Uckert, Wolfgang; Nadrowitz, Roger; Cerny-Reiterer, Sabine; Herrmann, Harald; Feller, Alfred C; Valent, Peter

    2010-06-01

    Mast cell neoplasms are characterized by abnormal growth and focal accumulation of mast cells (MC) in one or more organs. Although several cytokines, including stem cell factor (SCF) and interleukin-9 (IL-9) have been implicated in growth of normal MC, little is known about pro-oncogenic molecules and conditions triggering differentiation and growth of MC far enough to lead to the histopathological picture of overt mastocytosis. The anaplastic lymphoma kinase (ALK) has recently been implicated in growth of neoplastic cells in malignant lymphomas. Here, we describe that transplantation of NPM-ALK-transplanted mouse bone marrow progenitors into lethally irradiated IL-9 transgenic mice not only results in lymphoma-formation, but also in the development of a neoplastic disease exhibiting histopathological features of systemic mastocytosis, including multifocal dense MC-infiltrates, occasionally with devastating growth in visceral organs. Transplantation of NPM-ALK-transduced progenitors into normal mice or maintenance of IL-9-transgenic mice without NPM-ALK each resulted in MC hyperplasia, but not in mastocytosis. Neoplastic MC in mice not only displayed IL-9, but also the IL-9 receptor, and the same was found to hold true for human neoplastic MC. Together, our data show that neoplastic MC express IL-9 receptors, that IL-9 and NPM-ALK upregulate MC-production in vivo, and that both'hits' act in concert to induce a mastocytosis-like disease in mice. These data may have pathogenetic and clinical implications and fit well with the observation that neoplastic MC in advanced SM strongly express NPM and multiple "lymphoid" antigens including CD25 and CD30.

  1. Interleukin-9 (IL-9) and NPM-ALK each generate mast cell hyperplasia as single 'hit' and cooperate in producing a mastocytosis-like disease in mice.

    PubMed

    Merz, Hartmut; Kaehler, Christian; Hoefig, Kai P; Branke, Biggi; Uckert, Wolfgang; Nadrowitz, Roger; Cerny-Reiterer, Sabine; Herrmann, Harald; Feller, Alfred C; Valent, Peter

    2010-06-01

    Mast cell neoplasms are characterized by abnormal growth and focal accumulation of mast cells (MC) in one or more organs. Although several cytokines, including stem cell factor (SCF) and interleukin-9 (IL-9) have been implicated in growth of normal MC, little is known about pro-oncogenic molecules and conditions triggering differentiation and growth of MC far enough to lead to the histopathological picture of overt mastocytosis. The anaplastic lymphoma kinase (ALK) has recently been implicated in growth of neoplastic cells in malignant lymphomas. Here, we describe that transplantation of NPM-ALK-transplanted mouse bone marrow progenitors into lethally irradiated IL-9 transgenic mice not only results in lymphoma-formation, but also in the development of a neoplastic disease exhibiting histopathological features of systemic mastocytosis, including multifocal dense MC-infiltrates, occasionally with devastating growth in visceral organs. Transplantation of NPM-ALK-transduced progenitors into normal mice or maintenance of IL-9-transgenic mice without NPM-ALK each resulted in MC hyperplasia, but not in mastocytosis. Neoplastic MC in mice not only displayed IL-9, but also the IL-9 receptor, and the same was found to hold true for human neoplastic MC. Together, our data show that neoplastic MC express IL-9 receptors, that IL-9 and NPM-ALK upregulate MC-production in vivo, and that both'hits' act in concert to induce a mastocytosis-like disease in mice. These data may have pathogenetic and clinical implications and fit well with the observation that neoplastic MC in advanced SM strongly express NPM and multiple "lymphoid" antigens including CD25 and CD30. PMID:21297223

  2. MDP(Lysyl)GDP, a nontoxic muramyl dipeptide derivative, inhibits cytokine production by activated macrophages and protects mice from phorbol ester- and oxazolone-induced inflammation.

    PubMed

    Zunic, M; Bahr, G M; Mudde, G C; Meingassner, J G; Lam, C

    1998-07-01

    High levels of pro-inflammatory cytokines and nitric oxide are proposed to orchestrate pathophysiologic mechanism(s) associated with various inflammatory dermatoses. This study examines whether a water soluble 3-O-[N-acetylmuramyl-L-lysyl-D-iso]-2-di-on-glycine [MDP(Lysyl)GDP], a nontoxic and nonpyrogenic derivative of muramyl dipeptide (MDP), can inhibit the in vitro production of inflammatory mediators by lipopolysaccharide- or interferon-gamma-activated macrophages, and whether such an inhibitory effect can translate into in vivo protection of mice from irritant and allergic contact dermatitis. Thioglycollate-elicited peritoneal macrophages cultured in medium alone or in medium supplemented with MDP(Lysyl)GDP (1-100 microg per ml) expressed neither mRNA transcripts for inducible nitric oxide synthase, interleukin-1beta, and tumor necrosis factor-alpha, nor cytokine proteins and nitric oxide activity. Incubation of the cells with either lipopolysaccharide or interferon-gamma for 6 h resulted in a significant induction of inducible nitric oxide synthase, interleukin-1beta, and tumor necrosis factor-alpha mRNA, and the accumulation of high levels of monokines and nitrites in cultures by 24 h. Co-incubation of the macrophages with lipopolysaccharide or interferon-gamma and MDP(Lysyl)GDP (1-100 microg per ml) resulted in a concentration-dependent suppression of the steady-state mRNA transcripts for inducible nitric oxide synthase, tumor necrosis factor-alpha, and interleukin-1beta, induced by lipopolysaccharide, but not by interferon-gamma. In mouse models of phorbol ester- and oxazolone-induced ear inflammation, topical application of MDP(Lysyl)GDP significantly suppressed ear swelling in a dose-dependent manner. Likewise, oral treatment with MDP(Lysyl)GDP at days -3, -2, and -1 before elicitation with oxazolone also significantly inhibited ear inflammation. Taken together, our findings suggest that MDP(Lysyl)GDP has the potential to be a therapeutic application in

  3. Salvage chemotherapy of gemcitabine, dexamethasone, and cisplatin (GDP) for patients with relapsed or refractory peripheral T-cell lymphomas: a consortium for improving survival of lymphoma (CISL) trial.

    PubMed

    Park, Byeong-Bae; Kim, Won Seog; Suh, Cheolwon; Shin, Dong-Yeop; Kim, Jeong-A; Kim, Hoon-Gu; Lee, Won Sik

    2015-11-01

    There is no standard salvage chemotherapy for relapsed or refractory peripheral T-cell lymphomas (PTCLs). Gemcitabine combined with cisplatin has been known as an effective regimen for lymphoma treatment in the salvage setting. We investigated the efficacy and toxicity of gemcitabine, dexamethasone, and cisplatin (GDP) for relapsed or refractory PTCLs in search of a more effective and less toxic therapy. Patients with relapsed or refractory PTCLs with more than one previous regimen were eligible. Treatment consisted of gemcitabine 1000 mg/m(2) intravenously (i.v.) on days 1 and 8, dexamethasone 40 mg orally on days 1-4, and cisplatin 70 mg/m(2) i.v. on day 1, and then every 21 days. Patients could proceed to autologous stem cell transplantation (ASCT) after four cycles of GDP or receive up to six treatment cycles. Twenty-five eligible patients were evaluated for toxicity and response. The diagnoses of participants included 14 cases of PTCL-not otherwise specified (NOS) (56 %) and four cases of angioimmunoblastic T-cell lymphoma (16 %) among others. The median age of the patients was 59 years (range 20-75 years). After treatments with GDP, which delivered a median of four GDP cycles, there were 12 patients with complete responses (CR; 48 %) and six with partial responses (PR; 24 %). The overall response rate (RR) was 72 %. Four patients preceded to ASCT, and three patients finally achieved CR. The median progression free survival was 9.3 months (95 % confidence interval (CI); 4.1-14.6) with a median follow-up duration of 27.1 months. In a total of 86 cycles of GDP, grade 3 or 4 neutropenia and thrombocytopenia occurred in 16.3 and 12.8 % of cycles, respectively. Three patients (3.3 %) experienced febrile neutropenia. GDP is a highly effective and optimal salvage regimen for relapsed or refractory PTCLs and can be administered with acceptable toxicity.

  4. Helix dipole movement and conformational variability contribute to allosteric GDP release in Gαi subunits†‡

    PubMed Central

    Preininger, Anita M.; Funk, Michael A.; Meier, Scott M.; Oldham, William M.; Johnston, Christopher A.; Adhikary, Suraj; Kimple, Adam J.; Siderovski, David P.; Hamm, Heidi E.; Iverson, Tina M.

    2009-01-01

    Heterotrimeric G proteins (Gαβγ) transmit signals from activated G protein coupled receptors (GPCRs) to downstream effectors through a guanine nucleotide signaling cycle. Numerous studies indicate that the carboxy-terminal α5 helix of Gα subunits participate in Gα-receptor binding, and previous EPR studies suggest this receptor-mediated interaction induces a rotation and translation of the α5 helix of the Gα subunit [Oldham et al., Nat. Struct. Mol. Biol., 13: 772-7 (2006)]. Based on this result, an engineered disulfide bond was designed to constrain the α5 helix of Gαi1 into its EPR-measured receptor-associated conformation through the introduction of cysteines at positions 56 in the α1 helix and 333 in the α5 helix (I56C/Q333C Gαi1). A functional mimetic of the EPR-measured α5 helix dipole movement upon receptor association was additionally created by introduction of a positive charge at the amino-terminus of this helix, D328R Gαi1. Both proteins exhibit dramatically elevated basal nucleotide exchange. The 2.9 Å resolution crystal structure of the I56C/Q333C Gαi1 in complex with GDP-AlF4 − reveals the shift of the α5 helix toward the guanine nucleotide-binding site that is anticipated by EPR measurements. The structure of the I56C/Q333C Gαi1 subunit further revealed altered positions for the switch regions and throughout the Gαi1 subunit, accompanied by significantly elevated crystallographic temperature factors. Combined with previous evidence in the literature, the structural analysis supports the critical role of electrostatics of the α5 helix dipole and overall conformational variability during nucleotide release. PMID:19222191

  5. Relationships between Parents' Use of Corporal Punishment and Their Children's Endorsement of Spanking and Hitting Other Children

    ERIC Educational Resources Information Center

    Simons, Dominique A.; Wurtele, Sandy K.

    2010-01-01

    Objectives: To explore the intergenerational cycle of violence, the present study examined the relationship between parental approval and children's approval of corporal punishment (CP) and the subsequent relationship between children's CP experience and preference for hitting to resolve interpersonal conflict. Method: Participants consisted of…

  6. Student Hits in an Internet-Supported Course: How Can Instructors Use Them and What Do They Mean?

    ERIC Educational Resources Information Center

    Baugher, Dan; Varanelli, Andrew; Weisbord, Ellen

    2003-01-01

    The world of education is changing as Web-based technology and courseware are increasingly used for delivery of course material. In this environment, instructors may need new measures for determining student involvement, and ultimately student performance. This study examines whether hits to a Web site have any value for predicting student…

  7. A Comparison of OCLC and WLN Hit Rates for Monographs and an Analysis of the Types of Records Retrieved.

    ERIC Educational Resources Information Center

    Ross, Rosemary E.

    1993-01-01

    Describes a study that was conducted to determine the types of records found in OCLC and WLN (Washington Library Network) for new monographs being cataloged at the Central Washington University library. Highlights include a summary of pertinent literature; hit rates; classification numbers; duplicate records; and serial and monograph records.…

  8. Comparing among the Experiences of Self-Cutting, Hitting, and Scratching in Chinese Adolescents Attending Secondary Schools: An Interview Study

    ERIC Educational Resources Information Center

    You, Jianing; Ma, Congfen; Lin, Min-Pei; Leung, Freedom

    2015-01-01

    This study examined adolescents' experiences associated with nonsuicidal self-injury (NSSI) and compared among the experiences of self-cutting, hitting, and scratching. Participants included 42 Chinese adolescents attending secondary schools. They had at least three NSSI episodes in the preceding year. Information about their experiences of NSSI…

  9. The influence of aqueous content in small scale salt screening--improving hit rate for weakly basic, low solubility drugs.

    PubMed

    Tarsa, Peter B; Towler, Christopher S; Woollam, Grahame; Berghausen, Jörg

    2010-09-11

    Salt screening and selection is a well established approach for improving the properties of drug candidates, including dissolution rate and bioavailability. Typically during early development only small amounts of compound are available for solid state profiling, including salt screening. In order to probe large areas of experimental space, high-throughput screening is utilized and is often designed in a way to search for suitable crystallization parameters within hundreds or even thousands of conditions. However, the hit rate in these types of screens can be very low. In order to allow for selection of a salt form early within the drug development process whilst using smaller amounts of compounds, a screening procedure taking into account the compounds properties and the driving forces for salt formation is described. Experiments were carried out on the model compounds clotrimazole, cinnarizine itraconazole and atropine. We found an increase in crystalline hit rate for water-insoluble drugs crystallized from solutions that included at least 10% aqueous content. Conversely it was observed that compounds with greater water solubility did not benefit from aqueous content in salt screening, instead organic solvents lead to more crystalline screening hits. Results from four model compounds show that the inclusion of an aqueous component to the salt reaction can enhance the chance of salt formation and significantly improve the crystalline hit rate for low water soluble drugs.

  10. Integration of a rapid automated solubility classification into early validation of hits obtained by high throughput screening.

    PubMed

    Fligge, Thilo A; Schuler, Andrea

    2006-10-11

    Besides the structural verification of hits generated by high throughput screening also the determination of physicochemical properties is essential for an efficient lead identification. Especially solubility is fundamental for the correct planning and interpretation of experiments. We describe the set up of a fast automated solubility test within our existing workflow for hit validation to assure compound identity and purity. 384-Well plates with hit validation compound solution are used for analysis employing liquid chromatography and mass spectrometry (LC/MS). The remaining compound solution was used for a fast automated solubility classification employing a nephelometer integrated into a Tecan robotic workstation. Thereby 9000 compounds were classified as poorly- and well-soluble. This rapid and simple test does not require any additional amount of sample or sample processing than before but provides additional information on the hits at an early stage of lead identification. Validated by a more detailed nephelometric analysis for 500 out of the 9000 compounds in different buffer systems this simple test has shown to produce relevant data.

  11. Formation and sustainment of a very low aspect ratio tokamak using coaxial helicity injection (the Helicity Injected Torus (HIT) experiment)

    SciTech Connect

    Jarboe, T.R.; Nelson, B.A.

    1992-01-01

    In the paper we will detail the progress of the HIT experiment construction, including the following components: preliminary data and interpretation; diagnostic systems; vacuum vessel and pumping system; helicity source and power supplies; toroidal field coil and power supply; data acquisition system; collaboration with general atomics, with a brief summary given on each.

  12. Engithidong Xugixudhoy: Their Stories of Long Ago. Told in Deg Hit'an Athabaskan by Belle Deacon of Anvik.

    ERIC Educational Resources Information Center

    Deacon, Belle; Kari, James, Ed.

    Nine stories, told by a woman of the Lower Yukon Valley (Alaska), are presented here in Deg Hit'an Athabaskan on the left page and in English translation on the right page. The storyteller's English version of five of the stories is also included. Introductory sections contain a biography of Belle Deacon and notes on the gathering, transcription,…

  13. Using ProHits to store, annotate and analyze affinity purification - mass spectrometry (AP-MS) data

    PubMed Central

    Liu, Guomin; Zhang, Jianping; Choi, Hyungwon; Lambert, Jean-Philippe; Srikumar, Tharan; Larsen, Brett; Nesvizhskii, Alexey I.; Raught, Brian; Tyers, Mike; Gingras, Anne-Claude

    2012-01-01

    Affinity purification coupled with mass spectrometry (AP-MS) is a robust technique used to identify protein-protein interactions. With recent improvements in sample preparation, and dramatic advances in MS instrumentation speed and sensitivity, this technique is becoming more widely used throughout the scientific community. To meet the needs of research groups both large and small, we have developed software solutions for tracking, scoring and analyzing AP-MS data. Here, we provide details for the installation and utilization of ProHits, a Laboratory Information Management System designed specifically for AP-MS interaction proteomics. This protocol explains: (i) how to install the complete ProHits system, including modules for the management of mass spectrometry files and the analysis of interaction data, and (ii) alternative options for the use of pre-existing search results in simpler versions of ProHits, including a virtual machine implementation of our ProHits Lite software. We also describe how to use the main features of the software to analyze AP-MS data. PMID:22948730

  14. Probability of cell hits in selected organs and tissues by high-LET particles at the ISS orbit

    NASA Technical Reports Server (NTRS)

    Yasuda, H.; Komiyama, T.; Fujitaka, K.; Badhwar, G. D. (Principal Investigator)

    2002-01-01

    The fluence of high-LET particles (HLP) with LET infinity H2O greater than 15 keV micrometers-1 in selected organs and tissues were measured with plastic nuclear track detectors using a life-size human phantom on the 9th Shuttle-Mir Mission (STS-91). The planar-track fluence of HLP during the 9.8-day mission ranged from 1.9 x 10(3) n cm-2 (bladder) to 5.1 x 10(3) n cm-2 (brain) by a factor of 2.7. Based on these data, a probability of HLP hits to a matured cell of each organ or tissue was roughly estimated for a 90-day ISS mission. In the calculation, all cells were assumed to be spheres with a geometric cross-sectional area of 500 micrometers2 and the cell-hit frequency from isotropic space radiation can be described by the Poisson-distribution function. As results, the probability of one or more than 1 hit to a single cell by HLP for 90 days ranged from 17% to 38%; that of two or more than 2 hits was estimated to be 1.3-8.2%. c2002 COSPAR. Published by Elsevier Science Ltd. All rights reserved.

  15. EF-Tu dynamics during pre-translocation complex formation: EF-Tu·GDP exits the ribosome via two different pathways

    PubMed Central

    Liu, Wei; Chen, Chunlai; Kavaliauskas, Darius; Knudsen, Charlotte R.; Goldman, Yale E.; Cooperman, Barry S.

    2015-01-01

    The G-protein EF-Tu, which undergoes a major conformational change when EF-Tu·GTP is converted to EF-Tu·GDP, forms part of an aminoacyl(aa)-tRNA·EF-Tu·GTP ternary complex (TC) that accelerates the binding of aa-tRNA to the ribosome during peptide elongation. Such binding, placing a portion of EF-Tu in contact with the GTPase Associated Center (GAC), is followed by GTP hydrolysis and Pi release, and results in formation of a pretranslocation (PRE) complex. Although tRNA movement through the ribosome during PRE complex formation has been extensively studied, comparatively little is known about the dynamics of EF-Tu interaction with either the ribosome or aa-tRNA. Here we examine these dynamics, utilizing ensemble and single molecule assays employing fluorescent labeled derivatives of EF-Tu, tRNA, and the ribosome to measure changes in either FRET efficiency or fluorescence intensity during PRE complex formation. Our results indicate that ribosome-bound EF-Tu separates from the GAC prior to its full separation from aa-tRNA, and suggest that EF-Tu·GDP dissociates from the ribosome by two different pathways. These pathways correspond to either reversible EF-Tu·GDP dissociation from the ribosome prior to the major conformational change in EF-Tu that follows GTP hydrolysis, or irreversible dissociation after or concomitant with this conformational change. PMID:26338772

  16. EF-Tu dynamics during pre-translocation complex formation: EF-Tu·GDP exits the ribosome via two different pathways.

    PubMed

    Liu, Wei; Chen, Chunlai; Kavaliauskas, Darius; Knudsen, Charlotte R; Goldman, Yale E; Cooperman, Barry S

    2015-10-30

    The G-protein EF-Tu, which undergoes a major conformational change when EF-Tu·GTP is converted to EF-Tu·GDP, forms part of an aminoacyl(aa)-tRNA·EF-Tu·GTP ternary complex (TC) that accelerates the binding of aa-tRNA to the ribosome during peptide elongation. Such binding, placing a portion of EF-Tu in contact with the GTPase Associated Center (GAC), is followed by GTP hydrolysis and Pi release, and results in formation of a pretranslocation (PRE) complex. Although tRNA movement through the ribosome during PRE complex formation has been extensively studied, comparatively little is known about the dynamics of EF-Tu interaction with either the ribosome or aa-tRNA. Here we examine these dynamics, utilizing ensemble and single molecule assays employing fluorescent labeled derivatives of EF-Tu, tRNA, and the ribosome to measure changes in either FRET efficiency or fluorescence intensity during PRE complex formation. Our results indicate that ribosome-bound EF-Tu separates from the GAC prior to its full separation from aa-tRNA, and suggest that EF-Tu·GDP dissociates from the ribosome by two different pathways. These pathways correspond to either reversible EF-Tu·GDP dissociation from the ribosome prior to the major conformational change in EF-Tu that follows GTP hydrolysis, or irreversible dissociation after or concomitant with this conformational change.

  17. A conserved phenylalanine as a relay between the α5 helix and the GDP binding region of heterotrimeric Gi protein α subunit.

    PubMed

    Kaya, Ali I; Lokits, Alyssa D; Gilbert, James A; Iverson, Tina M; Meiler, Jens; Hamm, Heidi E

    2014-08-29

    G protein activation by G protein-coupled receptors is one of the critical steps for many cellular signal transduction pathways. Previously, we and other groups reported that the α5 helix in the G protein α subunit plays a major role during this activation process. However, the precise signaling pathway between the α5 helix and the guanosine diphosphate (GDP) binding pocket remains elusive. Here, using structural, biochemical, and computational techniques, we probed different residues around the α5 helix for their role in signaling. Our data showed that perturbing the Phe-336 residue disturbs hydrophobic interactions with the β2-β3 strands and α1 helix, leading to high basal nucleotide exchange. However, mutations in β strands β5 and β6 do not perturb G protein activation. We have highlighted critical residues that leverage Phe-336 as a relay. Conformational changes are transmitted starting from Phe-336 via β2-β3/α1 to Switch I and the phosphate binding loop, decreasing the stability of the GDP binding pocket and triggering nucleotide release. When the α1 and α5 helices were cross-linked, inhibiting the receptor-mediated displacement of the C-terminal α5 helix, mutation of Phe-336 still leads to high basal exchange rates. This suggests that unlike receptor-mediated activation, helix 5 rotation and translocation are not necessary for GDP release from the α subunit. Rather, destabilization of the backdoor region of the Gα subunit is sufficient for triggering the activation process.

  18. Impact of Oxidative Stress on Ascorbate Biosynthesis in Chlamydomonas via Regulation of the VTC2 Gene Encoding a GDP-l-galactose Phosphorylase*

    PubMed Central

    Urzica, Eugen I.; Adler, Lital N.; Page, M. Dudley; Linster, Carole L.; Arbing, Mark A.; Casero, David; Pellegrini, Matteo; Merchant, Sabeeha S.; Clarke, Steven G.

    2012-01-01

    The l-galactose (Smirnoff-Wheeler) pathway represents the major route to l-ascorbic acid (vitamin C) biosynthesis in higher plants. Arabidopsis thaliana VTC2 and its paralogue VTC5 function as GDP-l-galactose phosphorylases converting GDP-l-galactose to l-galactose-1-P, thus catalyzing the first committed step in the biosynthesis of l-ascorbate. Here we report that the l-galactose pathway of ascorbate biosynthesis described in higher plants is conserved in green algae. The Chlamydomonas reinhardtii genome encodes all the enzymes required for vitamin C biosynthesis via the l-galactose pathway. We have characterized recombinant C. reinhardtii VTC2 as an active GDP-l-galactose phosphorylase. C. reinhardtii cells exposed to oxidative stress show increased VTC2 mRNA and l-ascorbate levels. Genes encoding enzymatic components of the ascorbate-glutathione system (e.g. ascorbate peroxidase, manganese superoxide dismutase, and dehydroascorbate reductase) are also up-regulated in response to increased oxidative stress. These results indicate that C. reinhardtii VTC2, like its plant homologs, is a highly regulated enzyme in ascorbate biosynthesis in green algae and that, together with the ascorbate recycling system, the l-galactose pathway represents the major route for providing protective levels of ascorbate in oxidatively stressed algal cells. PMID:22393048

  19. UK and Twenty Comparable Countries GDP-Expenditure-on-Health 1980-2013: The Historic and Continued Low Priority of UK Health-Related Expenditure

    PubMed Central

    Harding, Andrew J.E.; Pritchard, Colin

    2016-01-01

    It is well-established that for a considerable period the United Kingdom has spent proportionally less of its gross domestic product (GDP) on health-related services than almost any other comparable country. Average European spending on health (as a % of GDP) in the period 1980 to 2013 has been 19% higher than the United Kingdom, indicating that comparable countries give far greater fiscal priority to its health services, irrespective of its actual fiscal value or configuration. While the UK National Health Service (NHS) is a comparatively lean healthcare system, it is often regarded to be at a ‘crisis’ point on account of low levels of funding. Indeed, many state that currently the NHS has a sizeable funding gap, in part due to its recently reduced GDP devoted to health but mainly the challenges around increases in longevity, expectation and new medical costs. The right level of health funding is a political value judgement. As the data in this paper outline, if the UK ‘afforded’ the same proportional level of funding as the mean average European country, total expenditure would currently increase by one-fifth.

  20. Partial purification and identification of GDP-mannose 3",5"-epimerase of Arabidopsis thaliana, a key enzyme of the plant vitamin C pathway

    PubMed Central

    Wolucka, Beata A.; Persiau, Geert; Van Doorsselaere, Jan; Davey, Mark W.; Demol, Hans; Vandekerckhove, Joël; Van Montagu, Marc; Zabeau, Marc; Boerjan, Wout

    2001-01-01

    The first step in the biosynthetic pathway of vitamin C in plants is the formation, at the level of sugar nucleotide, of l-galactosyl residues, catalyzed by a largely unknown GDP-d-mannose 3",5"-epimerase. By using combined conventional biochemical and mass spectrometry methods, we obtained a highly purified preparation of GDP-d-mannose 3",5"-epimerase from an Arabidopsis thaliana cell suspension. The native enzyme is an 84-kDa dimer, composed of two apparently identical subunits. In-gel tryptic digestion of the enzyme subunit, followed by peptide sequencing and a blast search, led to the identification of the epimerase gene. The closest homolog of the plant epimerase is the BlmG gene product of Streptomyces sp., a putative NDP-d-mannose 5"-epimerase. The plant GDP-d-mannose 3",5"-epimerase is, to our knowledge, a novel member of the extended short-chain dehydrogenase/reductase family. The enzyme was cloned and expressed in Escherichia coli cells. PMID:11752432