全文获取类型
收费全文 | 72505篇 |
免费 | 5035篇 |
国内免费 | 2641篇 |
专业分类
80181篇 |
出版年
2024年 | 138篇 |
2023年 | 1219篇 |
2022年 | 1809篇 |
2021年 | 2414篇 |
2020年 | 2350篇 |
2019年 | 3263篇 |
2018年 | 2837篇 |
2017年 | 2034篇 |
2016年 | 2010篇 |
2015年 | 2513篇 |
2014年 | 4741篇 |
2013年 | 5893篇 |
2012年 | 3653篇 |
2011年 | 4691篇 |
2010年 | 3572篇 |
2009年 | 3868篇 |
2008年 | 3940篇 |
2007年 | 3967篇 |
2006年 | 3518篇 |
2005年 | 3053篇 |
2004年 | 2704篇 |
2003年 | 2146篇 |
2002年 | 1927篇 |
2001年 | 1228篇 |
2000年 | 951篇 |
1999年 | 972篇 |
1998年 | 976篇 |
1997年 | 764篇 |
1996年 | 684篇 |
1995年 | 613篇 |
1994年 | 565篇 |
1993年 | 431篇 |
1992年 | 432篇 |
1991年 | 356篇 |
1990年 | 293篇 |
1989年 | 241篇 |
1988年 | 211篇 |
1987年 | 184篇 |
1986年 | 161篇 |
1985年 | 272篇 |
1984年 | 455篇 |
1983年 | 336篇 |
1982年 | 347篇 |
1981年 | 264篇 |
1980年 | 201篇 |
1979年 | 194篇 |
1978年 | 172篇 |
1977年 | 143篇 |
1976年 | 115篇 |
1975年 | 108篇 |
排序方式: 共有10000条查询结果,搜索用时 0 毫秒
831.
M. Ising K. A. Mather P. Zimmermann T. Brückl N. Höhne A. Heck L. A. Schenk D. Rujescu N. J. Armstrong P. S. Sachdev S. Reppermund 《Genes, Brain & Behavior》2014,13(5):501-507
Information processing is a cognitive trait forming the basis of complex abilities like executive function. The Trail Making Test (TMT) is a well‐established test of information processing with moderate to high heritability. Age of the individual also plays an important role. A number of genetic association studies with the TMT have been performed, which, however, did not consider age as a moderating factor. We report the results of genome‐wide association studies (GWASs) on age‐independent and age‐dependent TMT performance in two population‐representative community samples (Munich Antidepressant Response Signature, MARS: N1 = 540; Ludwig Maximilians University, LMU: N2 = 350). Age‐dependent genome‐wide findings were then evaluated in a third sample of healthy elderly subjects (Sydney Memory and Ageing Study, Sydney MAS: N3 = 448). While a meta‐analysis on the GWAS findings did not reveal age‐independent TMT associations withstanding correction for multiple testing, we found a genome‐wide significant age‐moderated effect between variants in the DSG1 gene region and TMT‐A performance predominantly reflecting visual processing speed (rs2199301, Pmeta‐analysis = 1.3 × 10?7). The direction of the interaction suggests for the minor allele a beneficial effect in younger adults turning into a detrimental effect in older adults. The detrimental effect of the missense single nucleotide polymorphism rs1426310 within the same DSG1 gene region could be replicated in Sydney MAS participants aged 70–79, but not in those aged 80 years and older, presumably a result of survivor bias. Our findings demonstrate opposing effects of DSG1 variants on information processing speed depending on age, which might be related to the complex processes that DSG1 is involved with, including cell adhesion and apoptosis. 相似文献
832.
Sung Wook Park Jin Hyoung Kim Ko‐Eun Kim Moon Hee Jeong Hyunsung Park Bongju Park Young‐Ger Suh Woo Jin Park Jeong Hun Kim 《Journal of cellular and molecular medicine》2014,18(5):875-884
Retinal neovascularization in retinopathy of prematurity (ROP) is the most common cause of blindness for children. Despite evidence that hypoxia inducible factor (HIF)‐1α ‐VEGF axis is associated with the pathogenesis of ROP, the inhibitors of HIF‐1α have not been established as a therapeutic target in the control of ROP pathophysiology. We investigated the hypothesis that degradation of HIF‐1α as a master regulator of angiogenesis in hypoxic condition, using β‐lapachone, would confer protection against hypoxia‐induced retinopathy without affecting physiological vascular development in mice with oxygen‐induced retinopathy (OIR), an animal model of ROP. The effects of β‐lapachone were examined after intraocular injection in mice with OIR. Intraocular administration of β‐lapachone resulted in significant reduction in hypoxia‐induced retinal neovascularization without retinal toxicity or perturbation of developmental retinal angiogenesis. Our results demonstrate that HIF‐1α–mediated VEGF expression in OIR is associated with pathological neovascularization, not physiological angiogenesis. Thus, strategies blocking HIF‐1α in the developing eye in the pathological hypoxia could serve as a novel therapeutic target for ROP. 相似文献
833.
834.
835.
钙调素对细胞周期的调节 总被引:1,自引:0,他引:1
RC3细胞是一种用真核表达载体1~(CaM)转染NIH 3T3细胞建成的可调钙凋素(Calmodulin,CaM)高表达细胞模型。通过分子杂交及蛋白免疫印迹方法证实在地塞米松(Dexamethasome,DXM)作用下,RC3细胞可高表达CaM。CaM的过表达使G_1期细胞减少,S期细胞增加;CaM拮抗剂三氟拉嗪(trifluoperazine,TFP)则使G_1期细胞增加,S期细胞减少。高表达CaM使细胞分裂指数提高,G_2期细胞减少,有丝分裂前期细胞增加,M中期细胞比例下降。而TFP处理则使分裂指数下降,G_2期细胞增加,M前期细胞减少,M中期细胞增加。实验结果表明CaM在G_1/S、G_2/M和M中期/M后期3个位点上对细胞周期进行调控;通过加速G_1至S期,G_2至M期和M中期至M后期的进程,使细胞倍增时间缩短,促进细胞增殖。本工作表明,RC3细胞作为CaM表达可调细胞模型,是研究细胞周期调控的有力工具。 相似文献
836.
Kristian Aspegren Leena Mannonen Anneli Ritala Riitta Puupponen-Pimiä Ulrika Kurtén Marjatta Salmenkallio-Marttila Veli Kauppinen Teemu H. Teeri 《Molecular breeding : new strategies in plant improvement》1995,1(1):91-99
Transgenic plant cell cultures have a potential for production and secretion of important proteins and peptides. To assess the possibilities of using a stable barley suspension culture for secretion of heterologous proteins in active form, we expressed the cDNA of the thermostable-glucanase (EGI) ofTrichoderma reesei in barley suspension cells. The cDNA coding for EGI and its signal sequence was placed under the control of the CaMV 35S promoter and the construction was transferred to the cells by particle bombardment. Stably transformed lines were obtained by selecting for a cotransformed antibiotic resistance marker. The expression of EGI cDNA led to accumulation of EGI in the culture medium, as shown by analysis with EGI-specific antibodies. Enzymatic assays confirmed that the EGI secreted by the suspension cells retained its activity and thermostable character. Furthermore, it was shown that the enzyme produced by the transgenic suspension culture could be used for degradation of soluble-glucans during mashing. 相似文献
837.
838.
The ε-subunit of ATP-synthase is an endogenous inhibitor of the hydrolysis activity of the complex and its α-helical C-terminal domain (εCTD) undergoes drastic changes among at least two different conformations. Even though this domain is not essential for ATP synthesis activity, there is evidence for its involvement in the coupling mechanism of the pump. Recently, it was proposed that coupling of the ATP synthase can vary as a function of ADP and Pi concentration. In the present work, we have explored the possible role of the εCTD in this ADP- and Pi-dependent coupling, by examining an εCTD-lacking mutant of Escherichia coli. We show that the loss of Pi-dependent coupling can be observed also in the εCTD-less mutant, but the effects of Pi on both proton pumping and ATP hydrolysis were much weaker in the mutant than in the wild-type. We also show that the εCTD strongly influences the binding of ADP to a very tight binding site (half-maximal effect ≈ 1 nM); binding at this site induces higher coupling in EFOF1 and increases responses to Pi. It is proposed that one physiological role of the εCTD is to regulate the kinetics and affinity of ADP/Pi binding, promoting ADP/Pi-dependent coupling. 相似文献
839.
Monocyte chemoattractant/chemotactic protein-1 (MCP-1), a member of the CC chemokine family, is one of the key chemokines that regulate migration and tissue infiltration of monocytes/macrophages. Its role in the pathophysiology of several inflammatory diseases has been widely recognized, thus making MCP-1 a possible target for anti-inflammatory treatments. Curcumin (diferuloylmethane) is a natural polyphenol derived from the rhizomes of Curcuma Longa L. (turmeric). Anti-inflammatory action underlies numerous pharmacological effects of curcumin in the control and prevention of several diseases. The purpose of this review is to evaluate the effects of curcumin on the regulation of MCP-1 as a key mediator of chemotaxis and inflammation, and the biological consequences thereof. In vitro studies have shown that curcumin can decrease MCP-1 production in various cell lines. Animal studies have also revealed that curcumin can attenuate MCP-1 expression and improve a range of inflammatory diseases through multiple molecular targets and mechanisms of action. There is limited data from human clinical trials showing the decreasing effect of curcumin on MCP-1 concentrations and improvement of the course of inflammatory diseases. Most of the in vitro and animal studies confirm that curcumin exert its MCP-1-lowering and anti-inflammatory effects by down-regulating the mitogen-activated protein kinase (MAPK) and NF-κB signaling pathway. As yet, there is limited data from human clinical trials showing the effect of curcumin on MCP-1 levels and improvement of the course of inflammatory diseases. More evidence, especially from human studies, is needed to better assess the effects of curcumin on circulating MCP-1 in different human diseases and the role of this modulatory effect in the putative anti-inflammatory properties of curcumin. 相似文献
840.
Pasupuleti Santhosh Kumar Katari Venkatesh Gopal Sowjenya Lokanathan Srikanth Manne Mudhu Sunitha Uppu Venkateswara Prasad 《Journal of biomolecular structure & dynamics》2013,31(10):2094-2103
Distal renal tubular acidosis (dRTA) is an autosomal recessive syndrome results defect in either proximal tubule bicarbonate reabsorption or in distal tubule H+ secretion and is characterized by severe hyperchloraemic metabolic acidosis in childhood. dRTA is associated with functional variations in the ATP6V1B1 gene encoding β1 subunit of H+-ATPase, key membrane transporters for net acid excretion of α-intercalated cells of medullary collecting ducts. In the present study, a 13-year-old male patient suffering with nephropathy and sensorineural deafness was reported in the Department of Nephrology. We predicted improper functioning of ATP6V1B1 gene could be the reason for diseased condition. Therefore, exons 3, 4, and 7 contributing active site of ATP6V1B1 gene was amplified and sequenced (Accession numbers: KF571726, KM222653). The obtained sequences were BLAST searched against the wild type ATP6V1B1 gene which showed novel mutations c.307 A > G, c.308 C > A, c.310 C > G, c.704 T > C, c.705 G > T, c.709 A > G, c.710 A > G, c.714 G > A, c.716 C > A, c.717delC, c.722 C > G, c.728insG, c.741insT, c.753G > C. These mutations resulted in the expression of truncated protein terminating at Lys 209. The mutated ATP6V1B1structure superimposed with wild type showed extensive variations with RMSD 1.336 Å and could not bind to substrate ADP leading to non-functional ATPase. These results conclusively explain these mutations in ATP6V1B1 gene resulted in structural changes causing accumulation of H+ ions contributing to dRTA with sensorineural deafness. 相似文献