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241.
242.
Fobian YM Freskos JN Barta TE Bedell LJ Heintz R Kassab DJ Kiefer JR Mischke BV Molyneaux JM Mullins P Munie GE Becker DP 《Bioorganic & medicinal chemistry letters》2011,21(10):2823-2825
Continuing our interest in designing compounds preferentially potent and selective for MMP-13, we report on a series of hydroxamic acids with a flexible amide P1′ substituents. We identify an amide which spares both MMP-1 and -14, and shows >500 fold selectivity for MMP-13 versus MMP-2 and -8. 相似文献
243.
Barta TE Becker DP Bedell LJ Easton AM Hockerman SL Kiefer J Munie GE Mathis KJ Li MH Rico JG Villamil CI Williams JM 《Bioorganic & medicinal chemistry letters》2011,21(10):2820-2822
Seeking compounds preferentially potent and selective for MMP-13, we reported in the preceding Letter on a series of hydroxamic acids with a flexible benzamide tail groups.1a Here, we replace the amide moiety with non-hydrolyzable heterocycles in an effort to improve half-life. We identify a hydroxamate tetrazole 4e that spares MMP-1 and -14, shows >400-fold selectivity versus MMP-8 and >600-fold selectivity versus MMP-2, and has a 4.8 h half-life in rats. X-ray data (1.9 Å) for tetrazole 4c is presented. 相似文献
244.
The thioredoxin family of oxidoreductases plays an important role in redox signaling and control of protein function. Not only are thioredoxins linked to a variety of disorders, but their stable structure has also seen application in protein engineering. Both sequence-based and structure-based tools exist for thioredoxin identification, but remote homolog detection remains a challenge. We developed a thioredoxin predictor using the approach of integrating sequence with structural information. We combined a sequence-based Hidden Markov Model (HMM) with a molecular dynamics enhanced structure-based recognition method (dynamic FEATURE, DF). This hybrid method (HMMDF) has high precision and recall (0.90 and 0.95, respectively) compared with HMM (0.92 and 0.87, respectively) and DF (0.82 and 0.97, respectively). Dynamic FEATURE is sensitive but struggles to resolve closely related protein families, while HMM identifies these evolutionary differences by compromising sensitivity. Our method applied to structural genomics targets makes?a strong prediction of a novel thioredoxin. 相似文献
245.
Mbeunkui F Grace MH Lategan C Smith PJ Raskin I Lila MA 《Journal of chromatography. B, Analytical technologies in the biomedical and life sciences》2011,879(21):1886-1892
The development of new antiplasmodial drugs is of primary importance due to the growing problem of multi-drug resistance of malaria parasites. Spilanthes acmella, a plant traditionally used for the treatment of toothache, was targeted as a lead for its potential antiplasmodial activity. A systematic approach for investigating a suitable centrifugal partition chromatography (CPC) solvent system for N-alkylamides separation was reported. The partition behavior of three N-alkylamides has been studied using several biphasic solvent mixtures in search of an adequate CPC solvent system for this class of compounds. Major N-alkylamides in S. acmella were isolated from a methanolic crude extract of flowers by CPC with the solvent system heptanes-ethyl acetate-methanol-water (3:2:3:2, v/v/v/v). Four N-alkylamides were purified and the structures were illustrated by electrospray ionization-ion trap-time of flight-mass spectrometry (ESI-IT-TOF-MS), 1H nuclear magnetic resonance (1H NMR) and 13C nuclear magnetic resonance (13C NMR). The CPC fractions, which contained natural mixtures of phytochemicals, demonstrated significantly higher antiplasmodial activity compared to corresponding purified N-alkylamides, thus suggesting that interactions between these N-alkylamides may potentiate antiplasmodial bioactivity. 相似文献
246.
Chung MH Richardson BA Tapia K Benki-Nugent S Kiarie JN Simoni JM Overbaugh J Attwa M John-Stewart GC 《PLoS medicine》2011,8(3):e1000422
Background
Behavioral interventions that promote adherence to antiretroviral medications may decrease HIV treatment failure. Antiretroviral treatment programs in sub-Saharan Africa confront increasing financial constraints to provide comprehensive HIV care, which include adherence interventions. This study compared the impact of counseling and use of an alarm device on adherence and biological outcomes in a resource-limited setting.Methods and Findings
A randomized controlled, factorial designed trial was conducted in Nairobi, Kenya. Antiretroviral-naïve individuals initiating free highly active antiretroviral therapy (HAART) in the form of fixed-dose combination pills (d4T, 3TC, and nevirapine) were randomized to one of four arms: counseling (three counseling sessions around HAART initiation), alarm (pocket electronic pill reminder carried for 6 months), counseling plus alarm, and neither counseling nor alarm. Participants were followed for 18 months after HAART initiation. Primary study endpoints included plasma HIV-1 RNA and CD4 count every 6 months, mortality, and adherence measured by monthly pill count. Between May 2006 and September 2008, 400 individuals were enrolled, 362 initiated HAART, and 310 completed follow-up. Participants who received counseling were 29% less likely to have monthly adherence <80% (hazard ratio [HR] = 0.71; 95% confidence interval [CI] 0.49–1.01; p = 0.055) and 59% less likely to experience viral failure (HIV-1 RNA ≥5,000 copies/ml) (HR 0.41; 95% CI 0.21–0.81; p = 0.01) compared to those who received no counseling. There was no significant impact of using an alarm on poor adherence (HR 0.93; 95% CI 0.65–1.32; p = 0.7) or viral failure (HR 0.99; 95% CI 0.53–1.84; p = 1.0) compared to those who did not use an alarm. Neither counseling nor alarm was significantly associated with mortality or rate of immune reconstitution.Conclusions
Intensive early adherence counseling at HAART initiation resulted in sustained, significant impact on adherence and virologic treatment failure during 18-month follow-up, while use of an alarm device had no effect. As antiretroviral treatment clinics expand to meet an increasing demand for HIV care in sub-Saharan Africa, adherence counseling should be implemented to decrease the development of treatment failure and spread of resistant HIV.Trial registration
ClinicalTrials gov Please see later in the article for the Editors'' Summary NCT00273780相似文献247.
Most emerging diseases of humans originate in animals, and zoonotic emerging infectious diseases (EIDs) threaten human, animal,
and environment health. We report on a scoping study to assess actors, linkages, priorities, and needs related to management
of these diseases from the perspective of key stakeholders in three countries in Southeast Asia. A comprehensive interview
guide was developed and in-depth interviews completed with 21 key stakeholders in Vietnam, Lao People’s Democratic Republic,
and Cambodia. We found numerous relevant actors with a predominance of public sector and medical disciplines. More capacity
weaknesses than strengths were reported, with risk analysis and research skills most lacking. Social network analysis of information
flows showed policy-makers were regarded as mainly information recipients, research institutes as more information providers,
and universities as both. Veterinary and livestock disciplines emerged as an important “boundary-spanning” organization with
linkages to both human health and rural development. Avian influenza was regarded as the most important zoonotic EID, perhaps
reflecting the priority-setting influence of actors outside the region. Stakeholders reported a high awareness of the ecological
and socioeconomic drivers of disease emergence and a demand for disease prioritization, epidemiological skills, and economic
and qualitative studies. Evaluated from an ecohealth perspective, human health is weakly integrated with socioeconomics, linkages
to policy are stronger than to communities, participation occurs mainly at lower levels, and equity considerations are not
fully considered. However, stakeholders have awareness of ecological and social determinants of health, and a basis exists
on which transdisciplinarity, equity, and participation can be strengthened. 相似文献
248.
Highkin MK Yates MP Nemirovskiy OV Lamarr WA Munie GE Rains JW Masferrer JL Nagiec MM 《Journal of biomolecular screening》2011,16(2):272-277
To facilitate discovery of compounds modulating sphingosine-1-phosphate (S1P) signaling, the authors used high-throughput mass spectrometry technology to measure S1P formation in human whole blood. Since blood contains endogenous sphingosine (SPH) and S1P, mass spectrometry was chosen to detect the conversion of an exogenously added 17-carbon-long variant of sphingosine, C17SPH, into C17S1P. The authors developed procedures to achieve homogeneous mixing of whole blood in 384-well plates and for a method requiring minimal manipulations to extract S1P from blood in 96- and 384-well plates prior to analyses using the RapidFire(?) mass spectrometry system. 相似文献
249.
Choksi S Lin Y Pobezinskaya Y Chen L Park C Morgan M Li T Jitkaew S Cao X Kim YS Kim HS Levitt P Shih G Birre M Deng CX Liu ZG 《Molecular cell》2011,42(5):597-609
The regulation of apoptosis is critical for controlling tissue homeostasis and preventing tumor formation and growth. Reactive oxygen species (ROS) generation plays a key role in such regulation. Here, we describe a HIF-1 target, Vasn/ATIA (anti-TNFα-induced apoptosis), which protects cells against TNFα- and hypoxia-induced apoptosis. Through the generation of ATIA knockout mice, we show that ATIA protects cells from apoptosis through regulating the function of the mitochondrial antioxidant, thioredoxin-2, and ROS generation. ATIA is highly expressed in human glioblastoma, and ATIA knockdown in glioblastoma cells renders them sensitive to hypoxia-induced apoptosis. Therefore, ATIA is not only a HIF-1 target that regulates mitochondrial redox pathways but also a potentially diagnostic marker and therapeutic target in human glioblastoma. 相似文献
250.
Sigrid Dengel Peter E. Levy John Grace Stephanie K. Jones Ute M. Skiba 《Global Change Biology》2011,17(12):3524-3533
Methane (CH4) is an important greenhouse gas, contributing 0.4–0.5 W m?2 to global warming. Methane emissions originate from several sources, including wetlands, rice paddies, termites and ruminating animals. Previous measurements of methane flux from farm animals have been carried out on animals in unnatural conditions, in laboratory chambers or fitted with cumbersome masks. This study introduces eddy covariance measurements of CH4, using the newly developed LI‐COR LI‐7700 open‐path methane analyser, to measure field‐scale fluxes from sheep grazing freely on pasture. Under summer conditions, fluxes of methane in the morning averaged 30 nmol m?2 s?1, whereas those in the afternoon were above 100 nmol m?2 s?1, and were roughly two orders of magnitude larger than the small methane emissions from the soil. Methane emissions showed no clear relationship with air temperature or photosynthetically active radiation, but some diurnal pattern was apparent, probably linked to sheep grazing behaviour and metabolism. Over the measurement period (days 60–277, year 2010), cumulative methane fluxes were 0.34 mol CH4 m?2, equating to 134.3 g CO2 equivalents m?2. By comparison, a carbon dioxide (CO2) sink of 819 g CO2 equivalents m?2 was measured over the same period, but it is likely that much of this would be released back to the atmosphere during the winter or as off‐site losses (through microbial and animal respiration). By dividing methane fluxes by the number of sheep in the field each day, we calculated CH4 emissions per head of livestock as 7.4 kg CH4 sheep?1 yr?1, close to the published IPCC emission factor of 8 kg CH4 sheep?1 yr?1. 相似文献