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991.
A novel bis-tetrahydrofuranylurethane-containing nonpeptidic protease inhibitor (PI), GRL-98065, is potent against multiple-PI-resistant human immunodeficiency virus in vitro
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Amano M Koh Y Das D Li J Leschenko S Wang YF Boross PI Weber IT Ghosh AK Mitsuya H 《Antimicrobial agents and chemotherapy》2007,51(6):2143-2155
We designed, synthesized, and identified GRL-98065, a novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) containing the structure-based designed privileged cyclic ether-derived nonpeptide P2 ligand, 3(R),3a(S),6a(R)-bis-tetrahydrofuranylurethane (bis-THF), and a sulfonamide isostere, which is highly potent against laboratory HIV-1 strains and primary clinical isolates (50% effective concentration [EC(50)], 0.0002 to 0.0005 microM) with minimal cytotoxicity (50% cytotoxicity, 35.7 microM in CD4(+) MT-2 cells). GRL-98065 blocked the infectivity and replication of each of the HIV-1(NL4-3) variants exposed to and selected by up to a 5 microM concentration of saquinavir, indinavir, nelfinavir, or ritonavir and a 1 microM concentration of lopinavir or atazanavir (EC(50), 0.0015 to 0.0075 microM), although it was less active against HIV-1(NL4-3) selected by amprenavir (EC(50), 0.032 microM). GRL-98065 was also potent against multiple-PI-resistant clinical HIV-1 variants isolated from patients who had no response to existing antiviral regimens after having received a variety of antiviral agents, HIV-1 isolates of various subtypes, and HIV-2 isolates examined. Structural analyses revealed that the close contact of GRL-98065 with the main chain of the protease active-site amino acids (Asp29 and Asp30) is important for its potency and wide-spectrum activity against multiple-PI-resistant HIV-1 variants. The present data demonstrate that the privileged nonpeptide P2 ligand, bis-THF, is critical for the binding of GRL-98065 to the HIV protease substrate binding site and that this scaffold can confer highly potent antiviral activity against a wide spectrum of HIV isolates. 相似文献
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994.
Concentration of Myo-inositol in Skeletal Muscle of the Rat Occurs without Active Transport 总被引:2,自引:2,他引:2
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![点击此处可从《The Journal of clinical investigation》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Bruce A. Molitoris Irene E. Karl William H. Daughaday 《The Journal of clinical investigation》1980,65(4):783-788
The cellular uptake of nonphosphorylated myo-inositol (MI) and its incorporation into phosphoinositide in the rat epitrochlearis muscle was measured. Cellular uptake of [2-3H]MI was determined by the difference between total uptake and [2-3H]MI present in the extracellular fluid determined with [1-14C]mannitol. Cellular uptake was parabolic and directly proportional to medium MI concentrations between 25 and 3,200 μM. Saturation of a MI carrier was not evident. Moreover, uptake was not inhibited by 2 mM ouabain, 0.3 mM 2,4-dinitrophenol, or 22 mM glucose. Insulin, 100 mU/ml, was without effect on either cellular uptake of [2-3H]MI or its incorporation into phosphoinositides. In muscles that were preloaded with [2-3H]MI and then incubated in media that contained a constant amount of MI but no [2-3H]MI, 44.3% of the [2-3H]MI was released after 10 min increasing to 62.5% by 120 min. Cellular MI concentrations were 0.18 μmol/g wet tissue (four times plasma levels) in rapidly isolated and frozen epitrochlearis muscle. When muscle was incubated without MI, 48% of endogenous MI was lost rapidly. Restoration of cellular MI in 50 μM MI media occurred in two phases, a rapid uptake phase lasting 10 min and a subsequent slow phase of MI uptake. 相似文献
995.
Tuffrey-Wijne I 《International journal of palliative nursing》2002,8(5):222-232
This article describes a case study that aimed to consider the unique needs of a client who has intellectual disabilities and a terminal illness. Data collection included semi-structured interviews with the client and professionals involved in his care. Five broad sets of themes emerged from these interviews. Although these are not unique to the rapidly evolving field of palliative care, they are less familiar within the specialism of intellectual disabilities, i.e. difficulties and delays around diagnosing the illness, consent issues, conflicts between the carers and the family, truth-telling, and the need for professional support. Professionals who work with a person with intellectual disabilities and a terminal illness need to be aware that special issues may arise. The effects of potential problems with comprehension and communication need to be assessed individually. A close collaboration between all professionals, carers, family and the client, and the mutual sharing of expertise, is essential to ensure the best possible care. 相似文献
996.
Stathakos D Pratsinis H Zachos I Vlahaki I Gianakopoulou A Zianni D Kletsas D 《Experimental gerontology》2005,40(6):512-518
Centenarians represent an intriguing model for ageing studies, since they demonstrate extreme longevity by definition, and at the same time a proportion of them have aged successfully. Here, we present data from the first nationwide study on Greek centenarians concerning their functional health status and life-style characteristics. We have identified 489 individuals (77% women) born in 1900 or before who were still alive between the years 2000 and 2002. Socio-demographic characteristics, activities of daily living (ADLs), living conditions, dependence on other people, former and current diseases and health disorders, current medication, nutrition and personal habits were recorded for every subject. Interestingly, only 2% of Greek centenarians lived in nursing homes, while the majority lived with their family or relatives. Furthermore, 6% were free from severe health disorders, autonomous (based on simple criteria for ADLs) and also leading an active social life, and hence may be considered as being in optimal condition. This group of centenarians may serve as a valuable source of information on genetic, environmental, and psychosocial determinants of successful ageing. 相似文献
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998.
Lapin Brittany R. Thompson Nicolas R. Schuster Andrew Katzan Irene L. 《Quality of life research》2019,28(6):1585-1594
Quality of Life Research - Assessment of outcomes from a proxy is often substituted for the patient’s self-report when the patient is unable or unwilling to report their status. Research has... 相似文献
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