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排序方式: 共有154条查询结果,搜索用时 15 毫秒
31.
The widely-used food dye Erythrosin B inhibited ATP-dependent Ca2+ accumulation by rat brain microsomes, half-maximal inhibition requiring 1 microM dye. Addition of 0.5-20 microM dye to microsomes preloaded with Ca2+ did not cause any net Ca2+ release. 10 microM dye produced a constant inhibition of Ca2+ accumulation as the intravesicular free Ca2+ was lowered suggesting that, at low concentrations, it acts on the uptake system only. Ca2+ accumulation was ten-fold more sensitive to the dye than Erythrosin B-induced neurotransmitter release reported by others. Higher dye concentrations (100 microM) caused Ca2+ release. 相似文献
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Sarah M. Bronner Karl A. Merrick Jeremy Murray Laurent Salphati John G. Moffat Jodie Pang Christopher J. Sneeringer Nicholas Dompe Patrick Cyr Hans Purkey Gladys de Leon Boenig Jun Li Aleksandr Kolesnikov Robin Larouche-Gauthier Kwong Wah Lai Xiaoli Shen Samuel Aubert-Nicol Yi-Chen Chen Timothy P. Heffron 《Bioorganic & medicinal chemistry letters》2019,29(16):2294-2301
CDK4 and CDK6 are kinases with similar sequences that regulate cell cycle progression and are validated targets in the treatment of cancer. Glioblastoma is characterized by a high frequency of CDKN2A/CCND2/CDK4/CDK6 pathway dysregulation, making dual inhibition of CDK4 and CDK6 an attractive therapeutic approach for this disease. Abemaciclib, ribociclib, and palbociclib are approved CDK4/6 inhibitors for the treatment of HR+/HER2? breast cancer, but these drugs are not expected to show strong activity in brain tumors due to poor blood brain barrier penetration. Herein, we report the identification of a brain-penetrant CDK4/6 inhibitor derived from a literature molecule with low molecular weight and topological polar surface area (MW = 285 and TPSA = 66 Å2), but lacking the CDK2/1 selectivity profile due to the absence of a basic amine. Removal of a hydrogen bond donor via cyclization of the pyrazole allowed for the introduction of basic and semi-basic amines, while maintaining in many cases efflux ratios reasonable for a CNS program. Ultimately, a basic spiroazetidine (cpKa = 8.8) was identified that afforded acceptable selectivity over anti-target CDK1 while maintaining brain-penetration in vivo (mouse Kp,uu = 0.20–0.59). To probe the potency and selectivity, our lead compound was evaluated in a panel of glioblastoma cell lines. Potency comparable to abemaciclib was observed in Rb-wild type lines U87MG, DBTRG-05MG, A172, and T98G, while Rb-deficient cell lines SF539 and M059J exhibited a lack of sensitivity. 相似文献
34.
Hormonal Contraception and the Risk of HIV Acquisition: An Individual Participant Data Meta-analysis
Charles S. Morrison Pai-Lien Chen Cynthia Kwok Jared M. Baeten Joelle Brown Angela M. Crook Lut Van Damme Sinead Delany-Moretlwe Suzanna C. Francis Barbara A. Friedland Richard J. Hayes Renee Heffron Saidi Kapiga Quarraisha Abdool Karim Stephanie Karpoff Rupert Kaul R. Scott McClelland Sheena McCormack Nuala McGrath Landon Myer Helen Rees Ariane van der Straten Deborah Watson-Jones Janneke H. H. M. van de Wijgert Randy Stalter Nicola Low 《PLoS medicine》2015,12(1)
BackgroundObservational studies of a putative association between hormonal contraception (HC) and HIV acquisition have produced conflicting results. We conducted an individual participant data (IPD) meta-analysis of studies from sub-Saharan Africa to compare the incidence of HIV infection in women using combined oral contraceptives (COCs) or the injectable progestins depot-medroxyprogesterone acetate (DMPA) or norethisterone enanthate (NET-EN) with women not using HC.ConclusionsThis IPD meta-analysis found no evidence that COC or NET-EN use increases women’s risk of HIV but adds to the evidence that DMPA may increase HIV risk, underscoring the need for additional safe and effective contraceptive options for women at high HIV risk. A randomized controlled trial would provide more definitive evidence about the effects of hormonal contraception, particularly DMPA, on HIV risk. 相似文献
35.
The primary purpose of this study was to examine the effect of energy restriction on antioxidant capacity in trained athletes. Secondly, our study determined whether dietary protein source influenced the antioxidant response, performance, and immunity. Twenty male cyclists consumed either whey or casein supplement (40 g/day) in addition to their diet for 17 days. All subjects subsequently underwent 4 days of energy restriction using a formula diet (20 kcal/kg) while continuing protein supplementation. Energy restriction caused 2.7 +/- 0.3 kg weight loss, increased lymphocyte total glutathione (tGSH) 37%, red blood cell glutathione peroxidase 48%, plasma cysteine 12%, and decreased whole blood reduced to oxidized GSH (rGSH/GSSG) ratio by 52%. The only immunity factor altered by energy restriction was an increase in stimulated phagocytosis (65%). Acute submaximal exercise reduced blood tGSH but increased glutathione peroxidase. Performance of a high intensity cycle test following 45 min of moderate exercise tended to be reduced by energy restriction (P = 0.06) but was unaffected by protein source. Energy restriction caused a negative nitrogen balance with no difference from dietary protein source. In conclusion, acute energy restriction increased plasma cysteine and several markers of the glutathione antioxidant system in trained athletes. A high cysteine dietary protein source did not influence these responses. 相似文献
36.
Costa C Silvari V Melchini A Catania S Heffron JJ Trovato A De Pasquale R 《Mutation research》2009,672(1):40-44
Imidacloprid is a neonicotinoid insecticide combining excellent efficiency against parasites with low toxicity for mammals. Commercially, it is co-formulated with dimethyl sulfoxide, methylpyrrolidone, propylene carbonate and mineral oil, which can modify its bioavailability and toxicological profile for humans following occupational exposure. A combined in vitro approach employing the comet assay and the micronucleus test was used to assess the genotoxicity of imidacloprid in relation to formulation, metabolic activation and exposure level. Human peripheral blood lymphocytes from unexposed healthy volunteers were treated with imidacloprid (0.2, 2 and 20 μM) and with equimolar concentrations of a commercial product, with and without addition of S9 fraction. Imidacloprid significantly increased the comet score and the frequency of micronuclei only at the highest concentration tested. DNA damage was slightly more severe with the commercial product, and was increased, though not significantly, by metabolic activation. Formation of reactive oxygen species (ROS) does not seem to be involved as a mechanism of genotoxicity, but this result may be explained by the insufficient sensitivity of the 2',7'-dichlorofluorescein diacetate assay at the test concentrations of imidacloprid. These results suggest that at concentrations<20 μM imidacloprid is not genotoxic to human lymphocytes in vitro. Nonetheless, the presence of co-formulants in the commercial product and occupational exposure, along with poor safety procedures, may present an increased risk for DNA fragmentation and chromosomal aberrations. 相似文献
37.
The mechanism of iron transport in Francisella is still a puzzle since none of the sequenced Francisella strains appears to encode a TonB protein, the energy transducer of the proton motive force necessary to act on the bacterial
outer membrane siderophore receptor to allow the internalization of iron. In this work we demonstrate using kinetic experiments
of radioactive Fe3+ utilization, that iron uptake in Francisella novicida, although with no recognizable TonB protein, is indeed dependent on energy generated by the proton motive force. Moreover,
mutants of a predicted outer membrane receptor still transport iron and are sensitive to the iron dependent antimicrobial
compound streptonigrin. Our studies suggest that alternative pathways to internalize iron might exist in Francisella. 相似文献
38.
Timothy P. Heffron Megan Berry Georgette Castanedo Christine Chang Irina Chuckowree Jennafer Dotson Adrian Folkes Janet Gunzner John D. Lesnick Cristina Lewis Simon Mathieu Jim Nonomiya Alan Olivero Jodie Pang David Peterson Laurent Salphati Deepak Sampath Steve Sideris Daniel P. Sutherlin Vickie Tsui Bing-yan Zhu 《Bioorganic & medicinal chemistry letters》2010,20(8):2408-2411
Efforts to identify potent small molecule inhibitors of PI3 kinase and mTOR led to the discovery of the exceptionally potent 6-aryl morpholino thienopyrimidine 6. In an effort to reduce the melting point in analogs of 6, the thienopyrimidine was modified by the addition of a methyl group to disrupt planarity. This modification resulted in a general improvement in in vivo clearance. This discovery led to the identification of GNE-477 (8), a potent and efficacious dual PI3K/mTOR inhibitor. 相似文献
39.
Adkins JN Mottaz HM Norbeck AD Gustin JK Rue J Clauss TR Purvine SO Rodland KD Heffron F Smith RD 《Molecular & cellular proteomics : MCP》2006,5(8):1450-1461
Salmonella enterica serovar Typhimurium (also known as Salmonella typhimurium) is a facultative intracellular pathogen that causes approximately 8,000 reported cases of acute gastroenteritis and diarrhea each year in the United States. Although many successful physiological, biochemical, and genetic approaches have been taken to determine the key virulence determinants encoded by this organism, the sheer number of uncharacterized reading frames observed within the S. enterica genome suggests that many more virulence factors remain to be discovered. We used a liquid chromatography-mass spectrometry-based "bottom-up" proteomic approach to generate a more complete picture of the gene products that S. typhimurium synthesizes under typical laboratory conditions as well as in culture media that are known to induce expression of virulence genes. When grown to logarithmic phase in rich medium, S. typhimurium is known to express many genes that are required for invasion of epithelial cells. Conversely stationary phase cultures of S. typhimurium express genes that are needed for both systemic infection and growth within infected macrophages. Lastly bacteria grown in an acidic, magnesium-depleted minimal medium (MgM) designed to mimic the phagocytic vacuole have been shown to up-regulate virulence gene expression. Initial comparisons of protein abundances from bacteria grown under each of these conditions indicated that the majority of proteins do not change significantly. However, we observed subsets of proteins whose expression was largely restricted to one of the three culture conditions. For example, cells grown in MgM had a higher abundance of Mg(2+) transport proteins than found in other growth conditions. A second more virulent S. typhimurium strain (14028) was also cultured under these same growth conditions, and the results were directly compared with those obtained for strain LT2. This comparison offered a unique opportunity to contrast protein populations in these closely related bacteria. Among a number of proteins displaying a higher abundance in strain 14028 were the products of the pdu operon, which encodes enzymes required for propanediol utilization. These pdu operon proteins were validated in culture and during macrophage infection. Our work provides further support for earlier observations that suggest pdu gene expression contributes to S. typhimurium pathogenesis. 相似文献
40.