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131.
Sarver RW Peevers J Cody WL Ciske FL Dyer J Emerson SD Hagadorn JC Holsworth DD Jalaie M Kaufman M Mastronardi M McConnell P Powell NA Quin J Van Huis CA Zhang E Mochalkin I 《Analytical biochemistry》2007,360(1):30-40
Renin is an aspartyl protease involved in the production of angiotensin II, a potent vasoconstrictor. Renin inhibitors can prevent blood vessel constriction and therefore could be useful for the treatment of hypertension. High-throughput screening efforts identified a small molecule renin inhibitor with a core substituted diaminopyrimidine ring. Parallel medicinal chemistry efforts based on this lead resulted in compound 1. A complex of 1 bound to renin was crystallized, and structural data were obtained by X-ray diffraction. The structure indicated that there were adjacent unoccupied binding pockets. Synthetic efforts were initiated to extend functionality into these pockets so as to improve affinity and adjust pharmacokinetic parameters. Thermodynamics data for inhibitor binding to renin were also collected using isothermal titration calorimetry. These data were used to help guide inhibitor optimization by suggesting molecular alterations to improve binding affinity from both thermodynamic and structural perspectives. The addition of a methoxypropyl group extending into the S3 subpocket improved inhibitor affinity and resulted in greater binding enthalpy. Initial additions to the pyrimidine ring template that extended into the large hydrophobic S2 pocket did not improve affinity and dramatically altered the thermodynamic driving force for the binding interaction. Binding of the core template was enthalpically driven, whereas binding of initial inhibitors with S2 extensions was both enthalpically and entropically driven but lost significant binding enthalpy. Additional electrostatic interactions were then incorporated into the S2 extension to improve binding enthalpy while taking advantage of the favorable entropy. 相似文献
132.
Man in 't Veld WA 《Mycologia》2007,99(2):222-226
Isozyme analysis and cytochrome oxidase sequences were used to examine whether differentiation of P. fragariae var. fragariae and P. fragariae var. rubi at the variety level is justified. In isozyme studies six strains of both P. fragariae varieties were analyzed with malate dehydrogenase (MDH), glucose phosphate isomerase (GPI), aconitase (ACO), isocitrate dehydrogenase (IDH) and phosphogluconate dehydrogenase (PGD), comprising altogether seven putative loci. Five unique alleles (Mdh-1(A), Mdh-2(B), Gpi(A), Aco(B) and Idh-1(B)) were found in strains of P. fragariae var. fragariae, whereas five unique alleles (Mdh-1(B), Mdh-2(A), Gpi(B), Aco(A) and Idh-1(A)) were present in strains of P. fragariae var. rubi. It was inferred from these data that there is no gene flow between the two P. fragariae varieties. Cytochrome oxidase I (Cox I) sequences showed consistent differences at 15 positions between strains of Fragaria and Rubus respectively. Based on isozyme data, cytochrome oxidase I sequences, and previously published differences in restyriction enzyme patterns of mitochondrial DNA, sequences of nuclear and mitochondrial genes, AFLP patterns and pathogenicity, it was concluded that both specific pathogenic varieties of P. fragariae are reproductively isolated and constitute a distinct species. Consequently strains isolated from Rubus idaeus are assigned to Phytophthora rubi comb. nov. 相似文献
133.
William Tinzaara Clifford. S. Gold Marcel Dicke Arnold Van Huis Caroline M. Nankinga Godfrey H. Kagezi 《Biocontrol Science and Technology》2007,17(2):111-124
Candidate strains of Beauveria bassiana were identified for use in integrated pest management of the banana weevil Cosmopolites sordidus. Horizontal field transmission of B. bassiana between banana weevils using different delivery systems, including aggregation pheromones, was investigated. We observed that infected weevils could transmit the fungal pathogen to healthy individuals. Most dead weevils (52%) due to B. bassiana infection were found at the base of banana plants in the leaf sheath or in the soil near banana plants. Significantly more weevils died from the pathogen in plots where B. bassiana was applied in combination with the pheromone than where it was applied alone. Our data demonstrate that C. sordidus aggregation pheromone can be a valuable tool to enhance the dissemination of B. bassiana for the control of C. sordidus. 相似文献
134.
Treatment with the chimerical monoclonal antibody rituximab results in CD20-directed B cell depletion. Although this depletion
is almost complete in the peripheral blood of nearly all patients with rheumatoid arthritis, a proportion of patients does
not exhibit a clinical response. The paper by Nakou and colleagues suggests that a decrease in CD19+CD27+ memory B cells in
both peripheral blood and bone marrow precedes the clinical response to rituximab. This finding adds to the emerging evidence
that lack of response to rituximab is associated with persistence of B lineage cells in specific body compartments. 相似文献
135.
136.
Chemotherapeutic agents available for use against toxoplasmosis are usually not suitable for prophylactic purposes because of their toxicity. The observed increasing number of activated latent infections with Toxoplasma, especially in immune suppressed patients, requires that safe techniques are available for use during the patient's regression period. Pretreatment of mice with Toxoplasma killed by irradiation appeared to induce resistance to challenge with virulent organisms. Survival times of six months have been observed to date. Increasing effectiveness was seen after more than one administration. Further investigation into the duration of effective resistance is needed; the question of at which intervals subsequent inoculations should be performed in order to acquire a booster effect, if any, has still to be solved before application to man can be recommended. 相似文献
137.
Influence of ethanol and temperature on the cellular fatty acid composition of Zygosaccharomyces bailii spoilage yeasts 总被引:1,自引:1,他引:0
M. Margarida Baleiras Couto J.H.J. Huis in't Veld 《Journal of applied microbiology》1995,78(3):327-334
Changes in the fatty acid profile of Zygosaccharomyces bailii strains, isolated from different sources, after growth at increasing concentrations of ethanol and/or decreasing temperatures were determined. Differences in fatty acid composition between Zygosaccharomyces bailii strains at standard conditions (25°C, 0% initial ethanol) were observed and could be related to ethanol tolerance. Zygosaccharomyces bailii strain isolated from wine showed the highest ethanol tolerance in relation to growth rate. Surprisingly, an increase in ethanol concentration or a decrease in growth temperature caused a decrease in the degree of unsaturation of total cellular fatty acids. On the other hand, the mean chain length increased (high ethanol concentration) or decreased (low temperature) depending on the stress factor. When both stress situations (high ethanol concentration and low temperature) were present at the same time, the degree of unsaturation remained approximately constant. With decreasing temperatures, the C16/C18 ratio increased in studies of initial ethanol content below 5%, and above 5% ethanol, decreased. 相似文献
138.
Sandra Stefanovic‐Barrett Anna S Dickson Stephen P Burr James C Williamson Ian T Lobb Dick JH van den Boomen Paul J Lehner James A Nathan 《EMBO reports》2018,19(5)
Misfolded or damaged proteins are typically targeted for destruction by proteasome‐mediated degradation, but the mammalian ubiquitin machinery involved is incompletely understood. Here, using forward genetic screens in human cells, we find that the proteasome‐mediated degradation of the soluble misfolded reporter, mCherry‐CL1, involves two ER‐resident E3 ligases, MARCH6 and TRC8. mCherry‐CL1 degradation is routed via the ER membrane and dependent on the hydrophobicity of the substrate, with complete stabilisation only observed in double knockout MARCH6/TRC8 cells. To identify a more physiological correlate, we used quantitative mass spectrometry and found that TRC8 and MARCH6 depletion altered the turnover of the tail‐anchored protein heme oxygenase‐1 (HO‐1). These E3 ligases associate with the intramembrane cleaving signal peptide peptidase (SPP) and facilitate the degradation of HO‐1 following intramembrane proteolysis. Our results highlight how ER‐resident ligases may target the same substrates, but work independently of each other, to optimise the protein quality control of selected soluble and tail‐anchored proteins. 相似文献
139.
140.
Catharina J. van Oostveen Dirk T. Ubbink Judith G. Huis in het Veld Piet J. Bakker Hester Vermeulen 《PloS one》2014,9(5)