排序方式: 共有29条查询结果,搜索用时 15 毫秒
1.
Ng HP Buckman BO Eagen KA Guilford WJ Kochanny MJ Mohan R Shaw KJ Wu SC Lentz D Liang A Trinh L Ho E Smith D Subramanyam B Vergona R Walters J White KA Sullivan ME Morrissey MM Phillips GB 《Bioorganic & medicinal chemistry》2002,10(3):657-666
A novel series of triaryloxypyridines have been designed to inhibit factor Xa, a serine protease strategically located in the coagulation cascade. Inhibitor 5e has a K(I) against factor Xa of 0.12nM and is greater than 8000- and 2000-fold selective over two related serine proteases, thrombin and trypsin, respectively. The 4-position of the central pyridine has been identified as a site that tolerates various substitutions without deleterious effects on potency and selectivity. This suggests that the 4-position of the pyridine ring is an ideal site for chemical modifications to identify inhibitors with improved pharmacokinetic characteristics. This investigation has resulted in inhibitor 5d, which has an oral availability of 6% in dogs. The synthesis, in vitro activity, and in vivo profile of this class of inhibitors is outlined. 相似文献
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Chelliah MV Chackalamannil S Xia Y Eagen K Greenlee WJ Ahn HS Agans-Fantuzzi J Boykow G Hsieh Y Bryant M Chan TM Chintala M 《Bioorganic & medicinal chemistry letters》2012,22(7):2544-2549
Discovery of a novel nor-seco himbacine analog as potent thrombin receptor (PAR-1) antagonist is described. Despite low plasma level, these new analogs showed excellent ex vivo efficacy in the monkey platelet aggregation assay. A potent hydroxy metabolite generated in vivo was identified as the agent responsible for the ex vivo efficacy. Following this discovery, the metabolite series was optimized to obtain analogs that showed very good ex vivo efficacy along with excellent pharmacokinetic profile in c. monkey. 相似文献
3.
Mallikarjun S Beelagi SR Santosh Kumar Uma Bharathi Indrabalan Sharanagouda S Patil Ashwini Prasad KP Suresh Shiva Prasad Kollur Veeresh Santhebennur Jayappa Siddappa B Kakkalameli Chandrashekar Srinivasa Prabhakarareddy Anapalli Venkataravana Chandan Shivamallu 《Bioinformation》2021,17(4):479
Crimean-Congo hemorrhagic fever (CCHF) virus is one among the major zoonosis viral diseases that use the Hyalomma ticks as their transmission vector to cause viral infection to the human and mammalian community. The fatality of infectious is high across the world especially in Africa, Asia, Middle East, and Europe. This study regarding codon usage bias of S, M, and L segments of the CCHF virus pertaining to the host Homo sapiens, reveals in-depth information about the evolutionary characteristics of CCHFV. Relative Synonymous Codon Usage (RSCU), Effective number of codons (ENC) were calculated, to determine the codon usage pattern in each segment. Correlation analysis between Codon adaptation index (CAI), GRAVY (Hydrophobicity), AROMO (Aromaticity), and nucleotide composition revealed bias in the codon usage pattern. There was no strong codon bias found among any segments of the CCHF virus, indicating both the factors i.e., natural selection and mutational pressure shapes the codon usage bias. 相似文献
4.
Paulo HG Mansur Lacordaire KP Cury José OB Leite Adriano A Pereira Nilson Penha-Silva Adriano O Andrade 《Biomedical engineering online》2010,9(1):29
Background
The main problem of tremor is the damage caused to the quality of the life of patients, especially those at more advanced ages. There is not a consensus yet about the origins of this disorder, but it can be examined in the correlations between the biological signs of aging and the tremor characteristics. 相似文献5.
Grace Y. Lin Richard Breitwieser Feng Cheng John T. Eagen Markus Ettl 《Flexible Services and Manufacturing Journal》2000,12(2-3):145-163
This paper studies the impact of a reduction in hardware complexity on the supply-chain inventory against various customer on-time delivery alternatives and manufacturing environments. Different methods of reducing hardware complexity are proposed, and their impact on total supply-chain inventory and customer serviceability quantified. An analytical inventory optimization scheme taking into account multistage supply networks, product structure, forecast accuracy, lead-time variability, and supplier reliability is used to determine optimal inventory levels in a stochastic modeling environment. The analysis is based on a business case for an IBM midrange computer family consisting of more than 200 models and upgrades with hundreds of features. We investigate different hardware complexity reduction strategies, including low-usage feature reduction, low-volume feature reduction, and feature substitution, as well as quick response and postponement mechanisms. Our computational results show that, in a fabrication-fulfillment center environment, reducing hardware complexity results in significantly higher inventory savings than in an integrated manufacturing environment. The results presented in this paper were used to reduce hardware complexity in IBM's midrange computer division. 相似文献
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In wetlands the effects of fire on vegetation dynamics are somewhat uncertain. A change detection analysis in the herbaceous wetlands of KwaMbonambi, South Africa, which were subject to frequent fires, revealed that in 1937 the study area comprised grassland (69%), herbaceous wetland (25%), indigenous swamp forest (4%) and tree plantations (1%). However, by 1970, tree plantations occupied 78% of the landscape and grasslands and herbaceous wetlands had declined to 9% and 6%, respectively, whereas indigenous swamp forest had increased to 6%. By 2009 tree plantations had been removed from the wetland areas. Despite this opportunity for herbaceous wetlands to recover their historical extent, they decreased to only 2%, mostly changing to indigenous swamp forest or to an herbaceous/fern (Stenochlaena tenuifolia)/woodland mosaic. Fire records showed suppression of fire to be an important contributing factor, particularly in wetlands that had been disturbed by tree plantations, although subsequently removed. A pilot burning experiment revealed that S. tenuifolia did not inhibit fire. It is therefore practicable to increase fire frequency to prevent the mosaic developing into forest. A conceptual model of the influence of fire regime on wetland vegetation type is presented and priorities for further research on wetlands and fire are recommended. 相似文献
8.
Thalidomide attenuates nitric oxide mediated angiogenesis by blocking migration of endothelial cells
KP Tamilarasan Gopi Krishna Kolluru Megha Rajaram M Indhumathy R Saranya Suvro Chatterjee 《BMC cell biology》2006,7(1):17-13
Background
Thalidomide is an immunomodulatory agent, which arrests angiogenesis. The mechanism of anti-angiogenic activity of thalidomide is not fully understood. As nitric oxide is involved in angiogenesis, we speculate a cross-talk between thalidomide and nitric oxide signaling pathway to define angiogenesis. The aim of present study is to understand the mechanistic aspects of thalidomide-mediated attenuation of angiogenesis induced by nitric oxide at the cellular level. 相似文献9.
The fruit fly, Drosophila melanogaster, innately avoids even low levels of CO2. CO2 is part of the so-called Drosophila stress odor produced by stressed flies, but also a byproduct of fermenting fruit, a main food source, making the strong avoidance behavior somewhat surprising. Therefore, we addressed whether feeding states might influence the fly’s behavior and processing of CO2. In a recent report, we showed that this innate behavior is differentially processed and modified according to the feeding state of the fly. Interestingly, we found that hungry flies require the function of the mushroom body, a higher brain center required for olfactory learning and memory, but thought to be dispensable for innate olfactory behaviors. In addition, we anatomically and functionally characterized a novel bilateral projection neuron connecting the CO2 sensory input to the mushroom body. This neuron was essential for processing of CO2 in the starved fly but not in the fed fly. In this Extra View article, we provide evidence for the potential involvement of the neuromodulator dopamine in state-dependent CO2 avoidance behavior. Taken together, our work demonstrates that CO2 avoidance behavior is mediated by alternative neural pathways in a context-dependent manner. Furthermore, it shows that the mushroom body is not only involved in processing of learned olfactory behavior, as previously suggested, but also in context-dependent innate olfaction. 相似文献
10.
We present the medical students' perspective on the hotly contested topic of professionalism in medical education and explore why students are often hostile to education in professionalism. We then suggest ways to improve professionalism education in the medical curriculum. 相似文献