全文获取类型
收费全文 | 30932篇 |
免费 | 2753篇 |
国内免费 | 2570篇 |
出版年
2024年 | 78篇 |
2023年 | 385篇 |
2022年 | 985篇 |
2021年 | 1498篇 |
2020年 | 1106篇 |
2019年 | 1305篇 |
2018年 | 1321篇 |
2017年 | 1000篇 |
2016年 | 1431篇 |
2015年 | 2031篇 |
2014年 | 2436篇 |
2013年 | 2497篇 |
2012年 | 2962篇 |
2011年 | 2735篇 |
2010年 | 1599篇 |
2009年 | 1542篇 |
2008年 | 1734篇 |
2007年 | 1572篇 |
2006年 | 1352篇 |
2005年 | 1151篇 |
2004年 | 1098篇 |
2003年 | 835篇 |
2002年 | 716篇 |
2001年 | 440篇 |
2000年 | 372篇 |
1999年 | 320篇 |
1998年 | 243篇 |
1997年 | 198篇 |
1996年 | 181篇 |
1995年 | 156篇 |
1994年 | 146篇 |
1993年 | 86篇 |
1992年 | 117篇 |
1991年 | 101篇 |
1990年 | 109篇 |
1989年 | 93篇 |
1988年 | 57篇 |
1987年 | 63篇 |
1986年 | 38篇 |
1985年 | 35篇 |
1984年 | 35篇 |
1983年 | 23篇 |
1982年 | 18篇 |
1981年 | 11篇 |
1980年 | 4篇 |
1979年 | 4篇 |
1978年 | 4篇 |
1977年 | 5篇 |
1966年 | 3篇 |
1962年 | 3篇 |
排序方式: 共有10000条查询结果,搜索用时 218 毫秒
921.
Jie Dong Yu Chen Xi Xu Rong Jin Fei Teng Fan Yan Hui Tang Pingping Li Xiuyuan Sun Yan Li Hounan Wu Yu Zhang Qing Ge 《PloS one》2013,8(2)
After a tightly regulated developmental program in the thymus, “mature” single positive (SP) thymocytes leave the thymus and enter the periphery. These newly arrived recent thymic emigrants (RTEs) are phenotypically and functionally immature, and will complete a dynamic maturation in the peripheral lymphoid organs before being licensed to be resident naïve T cells. To study the early events occurring in the RTE maturation process, we identified the phenotype of CD4+ pre-RTEs, a population of CD4+ SP thymocytes that have acquired the thymus egress capability. Compared to peripheral naïve T cells, CD4+ pre-RTEs displayed superior survival capability in lymphoreplete mice and faster proliferation under lymphopenic condition. The differences in Bcl2/Bim expression and/or heightened IL-7 signaling pathway may account for the pre-RTEs’ better responsiveness to homeostatic signals. Qa2, the expression of which indicates the phenotypic maturation of SPs and RTEs, was found to be upregulated in CD4+ pre-RTEs in thymic perivascular space. Migratory dendritic cells that surround this region contribute to Qa2 expression in pre-RTEs. The dendritic cell-driven Qa2 induction of CD4+ pre-RTEs is independent of MHC class II and Aire molecules. 相似文献
922.
An unbalanced chromosome number (aneuploidy) is present in most malignant tumours and has been attributed to mitotic mis-segregation of chromosomes. However, recent studies have shown a relatively high rate of chromosomal mis-segregation also in non-neoplastic human cells, while the frequency of aneuploid cells remains low throughout life in most normal tissues. This implies that newly formed aneuploid cells are subject to negative selection in healthy tissues and that attenuation of this selection could contribute to aneuploidy in cancer. To test this, we modelled cellular growth as discrete time branching processes, during which chromosome gains and losses were generated and their host cells subjected to selection pressures of various magnitudes. We then assessed experimentally the frequency of chromosomal mis-segregation as well as the prevalence of aneuploid cells in human non-neoplastic cells and in cancer cells. Integrating these data into our models allowed estimation of the fitness reduction resulting from a single chromosome copy number change to an average of ≈30% in normal cells. In comparison, cancer cells showed an average fitness reduction of only 6% (p = 0.0008), indicative of aneuploidy tolerance. Simulations based on the combined presence of chromosomal mis-segregation and aneuploidy tolerance reproduced distributions of chromosome aberrations in >400 cancer cases with higher fidelity than models based on chromosomal mis-segregation alone. Reverse engineering of aneuploid cancer cell development in silico predicted that aneuploidy intolerance is a stronger limiting factor for clonal expansion of aneuploid cells than chromosomal mis-segregation rate. In conclusion, our findings indicate that not only an elevated chromosomal mis-segregation rate, but also a generalised tolerance to novel chromosomal imbalances contribute to the genomic landscape of human tumours. 相似文献
923.
De-Xiang Zhuo Xiao-Wei Zhang Bo Jin Zheng Zhang Bu-Shan Xie Cheng-Lin Wu Kan Gong Ze-Bin Mao 《PloS one》2013,8(6)
Akt/protein kinase B is a pivotal component downstream of phosphatidylinositol 3-kinase (PI3K) pathway, whose activity regulates the balance between cell survival and apoptosis. Phosphorylation of Akt occurs at two key sites either at Thr308 site in the activation loop or at Ser473 site in the hydrophobic motif. The phosphorylated form of Akt (pAkt) is activated to promote cell survival. The mechanisms of pAkt dephosphorylation and how the signal transduction of Akt pathway is terminated are still largely unknown. In this study, we identified a novel protein phosphatase CSTP1(complete s transactivated protein 1), which interacts and dephosphorylates Akt specifically at Ser473 site in vivo and in vitro, blocks cell cycle progression and promotes cell apoptosis. The effects of CSTP1 on cell survival and cell cycle were abrogated by depletion of phosphatase domain of CSTP1 or by expression of a constitutively active form of Akt (S473D), suggesting Ser473 site of Akt as a primary cellular target of CSTP1. Expression profile analysis showed that CSTP1 expression is selectively down-regulated in non-invasive bladder cancer tissues and over-expression of CSTP1 suppressed the size of tumors in nude mice. Kaplan-Meier curves revealed that decreased expression of CSTP1 implicated significantly reduced recurrence-free survival in patients suffered from non-invasive bladder cancers. 相似文献
924.
Rong Jin Shiyong Yu Zifang Song Xiaolei Zhu Cuiping Wang Jinchuan Yan Fusheng Wu Anil Nanda D. Neil Granger Guohong Li 《PloS one》2013,8(6)
Recent work has revealed an essential involvement of soluble CD40L (sCD40L) in inflammation and vascular disease. Activated platelets are the major source of sCD40L, which has been implicated in platelet and leukocyte activation, although its exact functional impact on leukocyte-platelet interactions and the underlying mechanisms remain undefined. We aimed to determine the impact and the mechanisms of sCD40L on neutrophils. We studied neutrophil interactions with activated, surface-adherent platelets as a model for leukocyte recruitment to the sites of injury. Our data show that CD40L contributes to neutrophil firm adhesion to and transmigration across activated surface-adherent platelets, possibly through two potential mechanisms. One involves the direct interaction of ligand-receptor (CD40L-CD40), i.e., platelet surface CD40L interaction with neutrophil CD40; another involves an indirect mechanism, i.e. soluble CD40L stimulates activation of the leukocyte-specific β2 integrin Mac-1 in neutrophils and thereby further promotes neutrophil adhesion and migration. Activation of the integrin Mac-1 is known to be critical for mediating neutrophil adhesion and migration. sCD40L activated Mac-1 in neutrophils and enhanced neutrophil-platelet interactions in wild-type neutrophils, but failed to elicit such responses in CD40-deficient neutrophils. Furthermore, our data show that the protein kinase C zeta (PKCζ) is critically required for sCD40L-induced Mac-1 activation and neutrophil adhesive function. sCD40L strongly stimulated the focal clustering of Mac-1 (CD11b) and the colocalization of Mac-1 with PKCζ in wild-type neutrophils, but had minimal effect in CD40-deficient neutrophils. Blocking PKCζ completely inhibited sCD40L-induced neutrophil firm adhesion. Moreover, sCD40L strongly stimulates neutrophil oxidative burst via CD40-dependent activation of PI3K/NF-KB, but independent of Mac-1 and PKCζ. These findings may contribute to a better understanding of the underlying mechanisms by which sCD40L/CD40 pathway contributes to inflammation and vascular diseases. 相似文献
925.
926.
Huifang Hao Yutaka Maeda Takuya Fukazawa Tomoki Yamatsuji Munenori Takaoka Xiao-Hong Bao Junji Matsuoka Tatsuo Okui Tsuyoshi Shimo Nagio Takigawa Yasuko Tomono Motowo Nakajima Iris M. Fink-Baldauf Sandra Nelson William Seibel Ruben Papoian Jeffrey A. Whitsett Yoshio Naomoto 《PloS one》2013,8(8)
Midkine (MDK) is a heparin-binding growth factor that is highly expressed in many malignant tumors, including lung cancers. MDK activates the PI3K pathway and induces anti-apoptotic activity, in turn enhancing the survival of tumors. Therefore, the inhibition of MDK is considered a potential strategy for cancer therapy. In the present study, we demonstrate a novel small molecule compound (iMDK) that targets MDK. iMDK inhibited the cell growth of MDK-positive H441 lung adenocarcinoma cells that harbor an oncogenic KRAS mutation and H520 squamous cell lung cancer cells, both of which are types of untreatable lung cancer. However, iMDK did not reduce the cell viability of MDK-negative A549 lung adenocarcinoma cells or normal human lung fibroblast (NHLF) cells indicating its specificity. iMDK suppressed the endogenous expression of MDK but not that of other growth factors such as PTN or VEGF. iMDK suppressed the growth of H441 cells by inhibiting the PI3K pathway and inducing apoptosis. Systemic administration of iMDK significantly inhibited tumor growth in a xenograft mouse model in vivo. Inhibition of MDK with iMDK provides a potential therapeutic approach for the treatment of lung cancers that are driven by MDK. 相似文献
927.
铁还原菌降解石油烃的研究进展 总被引:1,自引:0,他引:1
铁还原菌是指能够利用细胞外Fe(III)作为末端电子受体,通过氧化有机物将Fe(III)还原为Fe(II)微生物的总称。铁还原作用广泛存在于土壤、河流、海洋、地表含水层以及高温高压的地下深部油藏。在厌氧或兼性厌氧条件下,Fe(III)还原耦合有机物的降解,对铁、碳元素的生物地球化学循环具有重要意义。本文介绍了铁还原菌的多样性和铁还原作用机理,综述了铁还原菌在石油烃降解方面的研究进展。此外,还总结了铁还原菌在生物修复中的潜在作用,并对未来的研究方向进行了展望。 相似文献
928.
玉米螟赤眼蜂Trichogramma ostriniae Pang et Chen是玉米螟的重要卵寄生性天敌,控制适宜的温度有利于室内大规模繁育。本试验以麦蛾卵为寄主,研究了不同温度(18℃、20℃、23℃、25℃、28℃、30℃、33℃、36℃)对玉米螟赤眼蜂的寿命、生殖力、子代羽化率和发育历期的影响。结果表明,20℃-25℃条件下雌蜂寿命最长,达7.9-9.0 d。在18℃-30℃亲代生殖力和子代羽化率无显著差异,亲代产卵量为40.9-61.7粒;羽化率为74.31%-84.22%。玉米螟赤眼蜂从卵到羽化的发育历期随温度的升高而显著缩短,由18℃时的22.6 d缩短至33℃的7.0 d。36℃时,雌蜂的寿命仅为0.56 d,且不能进行正常的生殖活动。因此,室内用麦蛾卵大规模繁育玉米螟赤眼蜂,适宜的温度为28℃-30℃;仅保存蜂种时,可选用温度18℃-20℃。 相似文献
929.
Macroautophagy/autophagy is a conserved intracellular degradation system that traffics substrates including protein aggregates, defunct or disused organelles and invading pathogens to lysosomes via double-membrane vesicles called autophagosomes. BECN1/Beclin 1 functions as a key protein in autophagy initiation and progression; however, the role of BECN1 in innate immunity has not been fully investigated. Recently, we have found that USP19 affects the ubiquitination of BECN1, hence promoting the formation of autophagosomes and inhibiting DDX58/RIG-I-mediated type I interferon signaling. 相似文献
930.
FUNDC1 is a novel mitochondrial-associated-membrane (MAM) protein required for hypoxia-induced mitochondrial fission and mitophagy 总被引:1,自引:0,他引:1
Mitochondria need to be fragmented prior to engulfment by phagophores, the precursors to autophagosomes. However, how these 2 processes are finely regulated and integrated is poorly understood. We have shown that the outer mitochondrial membrane protein FUNDC1 is a novel mitochondrial-associated membrane (MAM) protein, enriched at the MAM by interacting with the ER resident protein CANX (calnexin) under hypoxia. As mitophagy proceeds, it dissociates from CANX and preferably recruits DNM1L/DRP1 to drive mitochondrial fission in response to hypoxic stress. In addition, knocking down of FUNDC1, DNM1L or CANX in hypoxic cells increases the number of elongated mitochondria and also reduces the colocalization of autophagosome and mitochondria, thus preventing mitophagy. These findings identify FUNDC1 as a molecular hub integrating mitochondrial fission and mitophagy at the MAM in response to hypoxia. 相似文献