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61.
GABA_B受体变构剂药学研究进展 总被引:1,自引:0,他引:1
γ-氨基丁酸B受体(GABAB receptor,GABABR)是最具有药理学意义的药物靶点之一,具有复杂而精细的激活机制。传统的GABABR靶点药物开发集中于激动剂和拮抗剂,这类药物受到多种因素的制约,包括较强的副作用、药物代谢困难、机体耐药性明显等。变构剂结合于正构位点之外,能够调节GABABR异源二聚体亚基或结构域间的相互作用。正向变构剂(positiveallosteric modulators,PAMs)和负向变构剂(negative allosteric modulators,NAMs)分别可以提高或降低GABABR的活性,并具有较高的特异性和药物安全性,同时还能够保持GABABR信号在时间和空间上的可控性。变构剂为GABABR靶点药物开发提供了新思路。 相似文献
62.
63.
Gene class, ontology, or pathway testing analysis has become increasingly popular in microarray data analysis. Such approaches allow the integration of gene annotation databases, such as Gene Ontology and KEGG Pathway, to formally test for subtle but coordinated changes at a system level. Higher power in gene class testing is gained by combining weak signals from a number of individual genes in each pathway. We propose an alternative approach for gene-class testing based on mixed models, a class of statistical models that: a) provides the ability to model and borrow strength across genes that are both up and down in a pathway, b) operates within a well-established statistical framework amenable to direct control of false positive or false discovery rates, c) exhibits improved power over widely used methods under normal location-based alternative hypotheses, and d) handles complex experimental designs for which permutation resampling is difficult. We compare the properties of this mixed models approach with nonparametric method GSEA and parametric method PAGE using a simulation study, and illustrate its application with a diabetes data set and a dose-response data set. 相似文献
64.
百合不定芽的快速诱导 总被引:1,自引:0,他引:1
为获得麝香百合组织培养最优外植体及探讨蔗糖、6-BA和NAA的最佳用量,本文以MS固体培养基为基础培养基,通过4因素3水平(L9 (34)) 3次重复正交试验,研究不同花器官及不同浓度的蔗糖、6-BA (6 苄基嘌呤)和NAA (α-萘乙酸)对麝香百合组织培养诱导不定芽的影响.结果表明,花托为诱导不定芽最优外植体,诱导不定芽最佳培养基为MS+6-BA 1.0 mg/L+NAA 0.3 mg/L+蔗糖90 g/L.同时经过分析,可以判断本试验中设计的4个试验因素对百合组培的影响程度依次为外植体>蔗糖>奈乙酸和6-苄氨基嘌呤.本研究结果将为百合优良品种的生产提供重要的技术支撑和资源保证. 相似文献
65.
Shenqiang Rao Shuangmei Liu Lifang Zou Tianyu Jia Shanhong Zhao Bing Wu Zhihua Yi Shouyu Wang Yun Xue Yun Gao Changshui Xu Guilin Li Hong Xu Chunping Zhang Shangdong Liang 《Purinergic signalling》2017,13(2):227-235
Type 2 diabetes mellitus (T2DM) accounts for more than 90% of all cases of diabetes mellitus (DM). Diabetic neuropathic pain (DNP) is a common complication of T2DM. Sinomenine is a natural bioactive component extracted from the Sinomenium acutum and has anti-inflammatory effects. The aim of our study was to investigate the effects of sinomenine on DNP mediated by the P2X3 receptor in dorsal root ganglia (DRG). The mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) in T2DM rats were lower than those of control rats. MWT and TWL in T2DM rats treated with sinomenine were higher compared with those in T2DM rats. The expression levels of the P2X3 protein and mRNA in T2DM rat DRG were higher compared with those of the control, while those in T2DM rats treated with sinomenine were significantly lower compared with those of the T2DM rats. Sinomenine significantly inhibited P2X3 agonist ATP-activated currents in HEK293 cells transfected with the P2X3 receptor. Sinomenine decreased the phosphorylation and activation of P38MAPK in T2DM DRG. Therefore, sinomenine treatment may suppress the up-regulated expression and activation of the P2X3 receptor and relieve the hyperalgesia potentiated by the activation of P38MAPK in T2DM rats. 相似文献
66.
Mitochondrial PKC‐ε deficiency promotes I/R‐mediated myocardial injury via GSK3β‐dependent mitochondrial permeability transition pore opening 下载免费PDF全文
Gang Zhao Yong Cheng Ting Wu Bing Wu You‐en Zhang 《Journal of cellular and molecular medicine》2017,21(9):2009-2021
Mitochondrial fission is critically involved in cardiomyocyte apoptosis, which has been considered as one of the leading causes of ischaemia/reperfusion (I/R)‐induced myocardial injury. In our previous works, we demonstrate that aldehyde dehydrogenase‐2 (ALDH2) deficiency aggravates cardiomyocyte apoptosis and cardiac dysfunction. The aim of this study was to elucidate whether ALDH2 deficiency promotes mitochondrial injury and cardiomyocyte death in response to I/R stress and the underlying mechanism. I/R injury was induced by aortic cross‐clamping for 45 min. followed by unclamping for 24 hrs in ALDH2 knockout (ALDH2?/?) and wild‐type (WT) mice. Then myocardial infarct size, cell apoptosis and cardiac function were examined. The protein kinase C (PKC) isoform expressions and their mitochondrial translocation, the activity of dynamin‐related protein 1 (Drp1), caspase9 and caspase3 were determined by Western blot. The effects of N‐acetylcysteine (NAC) or PKC‐δ shRNA treatment on glycogen synthase kinase‐3β (GSK‐3β) activity and mitochondrial permeability transition pore (mPTP) opening were also detected. The results showed that ALDH2?/? mice exhibited increased myocardial infarct size and cardiomyocyte apoptosis, enhanced levels of cleaved caspase9, caspase3 and phosphorylated Drp1. Mitochondrial PKC‐ε translocation was lower in ALDH2?/? mice than in WT mice, and PKC‐δ was the opposite. Further data showed that mitochondrial PKC isoform ratio was regulated by cellular reactive oxygen species (ROS) level, which could be reversed by NAC pre‐treatment under I/R injury. In addition, PKC‐ε inhibition caused activation of caspase9, caspase3 and Drp1Ser616 in response to I/R stress. Importantly, expression of phosphorylated GSK‐3β (inactive form) was lower in ALDH2?/? mice than in WT mice, and both were increased by NAC pre‐treatment. I/R‐induced mitochondrial translocation of GSK‐3β was inhibited by PKC‐δ shRNA or NAC pre‐treatment. In addition, mitochondrial membrane potential (?Ψm) was reduced in ALDH2?/? mice after I/R, which was partly reversed by the GSK‐3β inhibitor (SB216763) or PKC‐δ shRNA. Collectively, our data provide the evidence that abnormal PKC‐ε/PKC‐δ ratio promotes the activation of Drp1 signalling, caspase cascades and GSK‐3β‐dependent mPTP opening, which results in mitochondrial injury‐triggered cardiomyocyte apoptosis and myocardial dysfuction in ALDH2?/? mice following I/R stress. 相似文献
67.
微生物多样性对土壤氮磷钾转化、酶活性及油菜生长的影响 总被引:8,自引:0,他引:8
采用灭菌土壤分别接种不同稀释倍数(1、10~(-2)、10~(-4)和10~(-6))未灭菌土壤悬浊液的方法,研究了土壤微生物多样性降低对油菜生长和养分吸收、土壤养分有效性和酶活性的影响。结果表明:(1)随着接种土壤悬浊液稀释倍数增加,油菜生物量逐渐降低,10-4的油菜生物量显著低于1和10~(-2),10~(-6)仅为1的26%;(2)油菜氮、磷和钾的吸收量与油菜生物量呈现相同的变化规律;(3)土壤铵态氮浓度随接种土壤悬浊液稀释倍数增加而降低;而土壤硝态氮则以10~(-4)为最高,其它处理间没有显著差异;土壤有效磷未发生显著变化;有效钾反而有上升趋势;(4)土壤多酚氧化酶(PhO X)活性随接种土壤悬浊液稀释倍数增加逐渐升高;β-1,4-葡萄糖苷酶(βG)活性以10~(-6)为最高,而其它处理差异不显著;土壤亮氨酸酶氨肽酶(LAP)活性和酸性磷酸酶(AP)活性变化不显著;(5)相关分析表明,油菜生物量与土壤铵态氮浓度的对数显著正相关;与多酚氧化酶、葡萄糖苷酶和亮氨酸氨肽酶活性显著负相关。研究表明,微生物多样性降低主要通过抑制土壤氮素释放影响植物生长。 相似文献
68.
Brown algae are one of the largest groups of oceanic primary producers for CO2 removal and carbon sinks for coastal regions. However, the mechanism for brown alga assimilation remains largely unknown in thermophilic microorganisms. In this work, a thermophilic alginolytic community was enriched from coastal sediment, from which an obligate anaerobic and thermophilic bacterial strain, designated Alg1, was isolated. Alg1 shared a 16S rRNA gene identity of 94.6% with Defluviitalea saccharophila LIND6LT2T. Phenotypic, chemotaxonomic, and phylogenetic studies suggested strain Alg1 represented a novel species of the genus Defluviitalea, for which the name Defluviitalea phaphyphila sp. nov. is proposed. Alg1 exhibited an intriguing ability to convert carbohydrates of brown algae, including alginate, laminarin, and mannitol, to ethanol and acetic acid. Three gene clusters participating in this process were predicted to be in the genome, and candidate enzymes were successfully expressed, purified, and characterized. Six alginate lyases were demonstrated to synergistically deconstruct alginate into unsaturated monosaccharide, followed by one uronic acid reductase and two 2-keto-3-deoxy-d-gluconate (KDG) kinases to produce pyruvate. A nonclassical mannitol 1-phosphate dehydrogenase, catalyzing d-mannitol 1-phosphate to fructose 1-phosphate in the presence of NAD+, and one laminarase also were disclosed. This work revealed that a thermophilic brown alga-decomposing system containing numerous novel thermophilic alginate lyases and a unique mannitol 1-phosphate dehydrogenase was adopted by the natural ethanologenic strain Alg1 during the process of evolution in hostile habitats. 相似文献
69.
目的克隆人AnnexinⅡ全长cDNA序列,并构建其真核表达载体。方法根据Genbank中AnnexinⅡ基因的碱基序列,利用RT-PCR的方法从人肾脏组织中扩增编码AnnexinⅡ基因,将目的片段与pBS-T载体连接,利用亚克隆的方法将AnnexinⅡ的cDNA片段克隆到pcDNA3.1载体中,并进行序列测定。结果DNA测序证实该片段序列与Genbank完全一致。结论成功克隆人Annexin II全长cDNA序列,并构建出pcDNA3.1—Annexin II真核表达载体,为进一步研究其在肾脏疾病中的作用和机制奠定基础。 相似文献
70.
Wang B Zhang S Cui S Yang B Zhao Y Chen H Hao X Shen Q Zhou J 《Biotechnology letters》2012,34(1):19-28
Two new types of stable ternary complexes were formed by mixing chitosan with DOTAP/pDNA lipoplex and DOTAP with chitosan/pDNA
polyplex via non-covalent conjugation for the efficient delivery of plasmid DNA. They were characterized by atomic force microscopy,
gel retarding, and dynamic light scattering. The DOTAP/CTS/pDNA complexes were in compacted spheroids and irregular lump of
larger aggregates in structure, while the short rod- and toroid-like and donut shapes were found in CTS/DOTAP/pDNA complexes.
The transfection efficiency of the lipopolyplexes showed higher GFP gene expression than DOTAP/pDNA and CTS/pDNA controls
in Hep-2 and Hela cells, and luciferase gene expression 2–3-fold than DOTAP/pDNA control and 70–120-fold than CTS/pDNA control
in Hep-2 cells. The intracellular trafficking was examined by confocal laser scanning microscopy. Rapid pDNA delivery to the
nucleus enchanced by chitosan was achieved after 4 h transfection. 相似文献