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951.
Lili Hao Xiaomeng Ge Haolei Wan Songnian Hu Martin J Lercher Jun Yu Wei-Hua Chen 《BMC evolutionary biology》2010,10(1):316
Background
Many functional, structural and evolutionary features of human genes have been observed to correlate with expression breadth and/or gene age. Here, we systematically explore these correlations. 相似文献952.
Williams TM Stump CA Nguyen DN Quigley AG Bell IM Gallicchio SN Zartman CB Wan BL Penna KD Kunapuli P Kane SA Koblan KS Mosser SD Rutledge RZ Salvatore C Fay JF Vacca JP Graham SL 《Bioorganic & medicinal chemistry letters》2006,16(10):2595-2598
High-throughput screening of the Merck sample collection identified benzodiazepinone tetralin-spirohydantoin 1 as a CGRP receptor antagonist with micromolar activity. Comparing the structure of 1 with those of earlier peptide-based antagonists such as BIBN 4096 BS, a key hydrogen bond donor-acceptor pharmacophore was hypothesized. Subsequent structure activity studies supported this hypothesis and led to benzodiazepinone piperidinyldihydroquinazolinone 7, CGRP receptor K(i)=44nM and IC(50)=38nM. Compound 7 was orally bioavailabile in rats and is a lead in the development of orally bioavailable CGRP antagonists for the treatment of migraine. 相似文献
953.
Purandare AV Wan H Gao A Somerville J Burke C Vaccaro W Yang X McIntyre KW Poss MA 《Bioorganic & medicinal chemistry letters》2006,16(1):204-207
The design, synthesis, and activity of novel and selective small molecule antagonists of the CC chemokine receptor-4 (CCR4) are presented. Compound 8c was efficacious in a murine allergic inflammation model (ED(50) 30 mg/kg). 相似文献
954.
Moretto AF Kirincich SJ Xu WX Smith MJ Wan ZK Wilson DP Follows BC Binnun E Joseph-McCarthy D Foreman K Erbe DV Zhang YL Tam SK Tam SY Lee J 《Bioorganic & medicinal chemistry》2006,14(7):2162-2177
A novel pyridothiophene inhibitor of PTP1B was discovered by rational screening of phosphotyrosine mimics at high micromolar concentrations. The potency of this lead compound has been improved significantly by medicinal chemistry guided by X-ray crystallography and molecular modeling. Excellent consistency has been observed between structure-activity relationships and structural information from PTP1B-inhibitor complexes. 相似文献
955.
为了研究胶质细胞源性神经营养因子 (GDNF) 在中枢神经系统疾病中的治疗应用,运用基因突变、蛋白质融合表达和蛋白质纯化技术获得分子质量较小的GDNF(ΔN39)活性片段. 将HIV-1 Tat 蛋白转导区 (protein transduction domain,PTD) 的9个碱性氨基酸49RKKRRQRRR57模拟物9个精氨酸(R9)与GDNF(ΔN39)活性片段融合表达,获得纯度达95%以上的GDNF(ΔN39)-R9融合蛋白. 将GDNF、GDNF(ΔN39)、GDNF(ΔN39)-R9分别加入原代培养的中脑多巴胺能神经元和转染GDNF受体GFRα1和Ret的PC12细胞中,观察它们的神经营养活性和毒性. 运用脑微血管内皮细胞株B-Endo 3,观察GDNF(ΔN39)-R9蛋白穿越血管内皮细胞膜的功能;运用脑血管内皮细胞和Matrigel铺板模拟血脑屏障,Transwell法检测Tat-GDNF(ΔN39)蛋白穿越脑血管内皮细胞和外周胶质膜的能力. 结果显示:GDNF(ΔN39)-R9蛋白具有类似GDNF的神经营养活性,促进原代培养的中脑多巴胺能神经元和稳定表达GFRα1和Ret受体的PC12-GFRα1-Ret细胞株的存活,没有显示毒性,并且能很好地穿过脑微血管内皮细胞层和模拟的血脑屏障. 相似文献
956.
为了研究胶质细胞源性神经营养因子(GDNF)在中枢神经系统疾病中的治疗应用,运用基因突变、蛋白质融合表达和蛋白质纯化技术获得分子质量较小的GDNF(△N39)活性片段.将HIV-1 Tat蛋白转导区(protein transduction domain,PTD)的9个碱性氨基酸49RKKRRQRRR57模拟物9个精氨酸(R9)与GDNF(△N39)活性片段融合表达,获得纯度达95%以上的GDNF(△N39)-R9融合蛋白.将GDNF、GDNF(△N39)、GDNF(△N39)-R9分别加入原代培养的中脑多巴胺能神经元和转染GDNF受体GFRαl和Ret的PC12细胞中,观察它们的神经营养活性和毒性.运用脑微血管内皮细胞株B-Endo 3,观察GDNF(△N39)-R9蛋白穿越血管内皮细胞膜的功能;运用脑血管内皮细胞和Matrigel铺板模拟血脑屏障,Transwell法检测Tat-GDNF(△N39)蛋白穿越脑血管内皮细胞和外周胶质膜的能力.结果显示:GDNF(△N39)-R9蛋白具有类似GDNF的神经营养活性,促进原代培养的中脑多巴胺能神经元和稳定表达GFRα1和Ret受体的PC12-GFRα1-Ret细胞株的存活,没有显示毒性,并且能很好地穿过脑微血管内皮细胞层和模拟的血脑屏障. 相似文献
957.
目的:观察鲍肤索对血管性痴呆大鼠学习与记忆能力的干预及机制。方法:制备生物鲍肤索,分剂量喂饲血管性痴呆大鼠,测试学习与记忆能力、红细胞和血红蛋白。结果:鲍肤素提高大鼠Y型迷宫测试的分值和红细胞、血红蛋白水平。结论:鲍肤素能提高血管性痴呆大鼠的学习与记忆能力和红细胞、血红蛋白水平。 相似文献
958.
Zhang YH Bhunia A Wan KF Lee MC Chan SL Yu VC Mok YK 《Journal of molecular biology》2006,364(3):536-549
The ratio of the levels of pro-survival and pro-apoptotic members of the Bcl-2 protein family is thought to be an important regulatory factor for determining the sensitivity of the mammalian cells to apoptotic stimuli. High levels of expression of pro-survival members such as Bcl(XL) in human cancers were frequently found to be a good prognostic indicator predicting poor response to chemotherapy. The pro-survival members of the Bcl-2 family mediate their effects through heterodimerization with the BH3 region of the pro-apoptotic members. Structural analyses of the binding complex of the BH3 peptide and Bcl(XL) showed that a hydrophobic groove termed the BH3 binding cleft is the docking site for the BH3 region. Chemical mimetics of the BH3 region such as BH3I-1 that target the BH3 binding cleft indeed exhibit pro-apoptotic activities. Chelerythrine (CHE) and sanguinarine (SAN) are natural benzophenanthridine alkaloids that are structurally homologous to each other. CHE was previously identified as an inhibitor of Bcl(XL) function from a high-throughput screen of natural products, but its mode of interaction with Bcl(XL) is not known. By determining the effect of site-directed mutagenesis on ligand binding and using saturation transfer difference (STD) NMR experiments, we have verified locations of these docked ligands. Surprisingly, CHE and SAN bind separately at the BH groove and BH1 region of Bcl(XL) respectively, different from the BH3 binding cleft where other known inhibitors of Bcl(XL) target. Interestingly, certain residues on the flexible loop between helices alpha1 and alpha2 of Bcl(XL) are also perturbed upon CHE, but not SAN or BH3I-1 binding. Although CHE and SAN are similarly effective as BH3I-1 in displacing bound BH3 peptide, they are much more effective in inducing apoptosis, raising the possibility that CHE and SAN might be able to antagonize other pro-survival mechanisms in addition to the one that involves BH3 region binding. 相似文献
959.
Ying-Wooi Wan Ebrahim Sabbagh Rebecca Raese Yong Qian Dajie Luo James Denvir Val Vallyathan Vincent Castranova Nancy Lan Guo 《PloS one》2010,5(8)
Background
Lung cancer remains the leading cause of cancer-related deaths worldwide. The recurrence rate ranges from 35–50% among early stage non-small cell lung cancer patients. To date, there is no fully-validated and clinically applied prognostic gene signature for personalized treatment.Methodology/Principal Findings
From genome-wide mRNA expression profiles generated on 256 lung adenocarcinoma patients, a 12-gene signature was identified using combinatorial gene selection methods, and a risk score algorithm was developed with Naïve Bayes. The 12-gene model generates significant patient stratification in the training cohort HLM & UM (n = 256; log-rank P = 6.96e-7) and two independent validation sets, MSK (n = 104; log-rank P = 9.88e-4) and DFCI (n = 82; log-rank P = 2.57e-4), using Kaplan-Meier analyses. This gene signature also stratifies stage I and IB lung adenocarcinoma patients into two distinct survival groups (log-rank P<0.04). The 12-gene risk score is more significant (hazard ratio = 4.19, 95% CI: [2.08, 8.46]) than other commonly used clinical factors except tumor stage (III vs. I) in multivariate Cox analyses. The 12-gene model is more accurate than previously published lung cancer gene signatures on the same datasets. Furthermore, this signature accurately predicts chemoresistance/chemosensitivity to Cisplatin, Carboplatin, Paclitaxel, Etoposide, Erlotinib, and Gefitinib in NCI-60 cancer cell lines (P<0.017). The identified 12 genes exhibit curated interactions with major lung cancer signaling hallmarks in functional pathway analysis. The expression patterns of the signature genes have been confirmed in RT-PCR analyses of independent tumor samples.Conclusions/Significance
The results demonstrate the clinical utility of the identified gene signature in prognostic categorization. With this 12-gene risk score algorithm, early stage patients at high risk for tumor recurrence could be identified for adjuvant chemotherapy; whereas stage I and II patients at low risk could be spared the toxic side effects of chemotherapeutic drugs. 相似文献960.
Marsano A Maidhof R Wan LQ Wang Y Gao J Tandon N Vunjak-Novakovic G 《Biotechnology progress》2010,26(5):1382-1390
We investigated the effects of the initial stiffness of a three-dimensional elastomer scaffold--highly porous poly(glycerol sebacate)--on functional assembly of cardiomyocytes cultured with perfusion for 8 days. The polymer elasticity varied with the extent of polymer cross-links, resulting in three different stiffness groups, with compressive modulus of 2.35 ± 0.03 (low), 5.28 ± 0.36 (medium), and 5.99 ± 0.40 (high) kPa. Laminin coating improved the efficiency of cell seeding (from 59 ± 15 to 90 ± 21%), resulting in markedly increased final cell density, construct contractility, and matrix deposition, likely because of enhanced cell interaction and spreading on scaffold surfaces. Compact tissue was formed in the low and medium stiffness groups, but not in the high stiffness group. In particular, the low stiffness group exhibited the greatest contraction amplitude in response to electric field pacing, and had the highest compressive modulus at the end of culture. A mathematical model was developed to establish a correlation between the contractile amplitude and the cell distribution within the scaffold. Taken together, our findings suggest that the contractile function of engineered cardiac constructs positively correlates with low compressive stiffness of the scaffold. 相似文献