全文获取类型
收费全文 | 2366篇 |
免费 | 219篇 |
国内免费 | 2篇 |
出版年
2023年 | 10篇 |
2022年 | 25篇 |
2021年 | 41篇 |
2020年 | 25篇 |
2019年 | 34篇 |
2018年 | 35篇 |
2017年 | 31篇 |
2016年 | 47篇 |
2015年 | 101篇 |
2014年 | 104篇 |
2013年 | 135篇 |
2012年 | 171篇 |
2011年 | 172篇 |
2010年 | 111篇 |
2009年 | 77篇 |
2008年 | 141篇 |
2007年 | 124篇 |
2006年 | 117篇 |
2005年 | 135篇 |
2004年 | 136篇 |
2003年 | 137篇 |
2002年 | 128篇 |
2001年 | 32篇 |
2000年 | 27篇 |
1999年 | 30篇 |
1998年 | 17篇 |
1997年 | 26篇 |
1996年 | 22篇 |
1995年 | 21篇 |
1994年 | 14篇 |
1993年 | 30篇 |
1992年 | 19篇 |
1991年 | 17篇 |
1990年 | 13篇 |
1989年 | 9篇 |
1988年 | 13篇 |
1987年 | 10篇 |
1986年 | 14篇 |
1985年 | 20篇 |
1984年 | 18篇 |
1983年 | 11篇 |
1982年 | 27篇 |
1981年 | 16篇 |
1980年 | 17篇 |
1979年 | 9篇 |
1978年 | 11篇 |
1976年 | 11篇 |
1975年 | 11篇 |
1974年 | 9篇 |
1973年 | 12篇 |
排序方式: 共有2587条查询结果,搜索用时 15 毫秒
201.
Katarzyna A. Rejniak Shizhen E. Wang Nicole S. Bryce Hang Chang Bahram Parvin Jerome Jourquin Lourdes Estrada Joe W. Gray Carlos L. Arteaga Alissa M. Weaver Vito Quaranta Alexander R. A. Anderson 《PLoS computational biology》2010,6(8)
Most tumors arise from epithelial tissues, such as mammary glands and lobules, and their initiation is associated with the disruption of a finely defined epithelial architecture. Progression from intraductal to invasive tumors is related to genetic mutations that occur at a subcellular level but manifest themselves as functional and morphological changes at the cellular and tissue scales, respectively. Elevated proliferation and loss of epithelial polarization are the two most noticeable changes in cell phenotypes during this process. As a result, many three-dimensional cultures of tumorigenic clones show highly aberrant morphologies when compared to regular epithelial monolayers enclosing the hollow lumen (acini). In order to shed light on phenotypic changes associated with tumor cells, we applied the bio-mechanical IBCell model of normal epithelial morphogenesis quantitatively matched to data acquired from the non-tumorigenic human mammary cell line, MCF10A. We then used a high-throughput simulation study to reveal how modifications in model parameters influence changes in the simulated architecture. Three parameters have been considered in our study, which define cell sensitivity to proliferative, apoptotic and cell-ECM adhesive cues. By mapping experimental morphologies of four MCF10A-derived cell lines carrying different oncogenic mutations onto the model parameter space, we identified changes in cellular processes potentially underlying structural modifications of these mutants. As a case study, we focused on MCF10A cells expressing an oncogenic mutant HER2-YVMA to quantitatively assess changes in cell doubling time, cell apoptotic rate, and cell sensitivity to ECM accumulation when compared to the parental non-tumorigenic cell line. By mapping in vitro mutant morphologies onto in silico ones we have generated a means of linking the morphological and molecular scales via computational modeling. Thus, IBCell in combination with 3D acini cultures can form a computational/experimental platform for suggesting the relationship between the histopathology of neoplastic lesions and their underlying molecular defects. 相似文献
202.
203.
Li Z Xu M Xing S Ho WT Ishii T Li Q Fu X Zhao ZJ 《The Journal of biological chemistry》2007,282(6):3428-3432
JAK2(V617F), a mutant of tyrosine kinase JAK2, is found in most patients with polycythemia vera (PV) and a substantial proportion of patients with idiopathic myelofibrosis or essential thrombocythemia. The JAK2 mutant displays a much increased kinase activity and generates a PV-like phenotype in mouse bone marrow transplant models. This study shows that the anti-cancer drug erlotinib (Tarceva) is a potent inhibitor of JAK2(V617F) activity. In vitro colony culture assays revealed that erlotinib at micro-molar concentrations effectively suppresses the growth and expansion of PV hematopoietic progenitor cells while having little effect on normal cells. Furthermore, JAK2(V617F)-positive cells from PV patients show greater susceptibility to the inhibitor than their negative counterparts. Similar inhibitory effects were found with the JAK2(V617F)-positive human erythroleukemia HEL cell line. These data suggest that erlotinib may be used for treatment of JAK2(V617F)-positive PV and other myeloproliferative disorders. 相似文献
204.
Kolkert JL 't Hart NA van Dijk A Ottens PJ Ploeg RJ Leuvenink HG 《Laboratory animals》2007,41(3):363-371
Organs used for transplantation are usually derived from heart-beating brain dead donors. However, brain death is known to have negative effects on donor organ quality, previously studied using a difficult to control sudden onset experimental model. We have now developed a reproducible gradual onset brain death model in rats without requiring inotropic support. Fisher inbred rats weighing 260-300 g were used. Brain death was induced by a gradual inflation of a subdurally placed balloon catheter. During induction and the period following brain death, the animals were mechanically ventilated and blood pressure was continuously monitored. The blood pressure registration showed a characteristic pattern during brain death induction, in which a decrease in blood pressure, a hypotensive period in which the Cushing response occurred, and a sharp peak were consistent findings. After brain death was induced, blood pressure was maintained at normotensive levels up to 4 h. After the experiments, neuropathological evaluation of the brain located haemorrhagic cerebral parenchyma, and immunocytochemistry of liver tissue revealed a significant influx of polymorph nuclear cells, as was previously observed as well. This improved model allows the study of brain death on donor organ quality without the use of inotropic support. 相似文献
205.
Jiang W Tran JA Tucci FC Fleck BA Hoare SR Markison S Wen J Chen CW Marinkovic D Arellano M Foster AC Chen C 《Bioorganic & medicinal chemistry letters》2007,17(23):6546-6552
A series of trans-4-phenylpyrrolidine-3-carboxamides were synthesized and characterized as potent ligands of the human melanocortin-4 receptor. Interestingly, a pair of diastereoisomers 20f-1 and 20f-2 displayed potent functional agonist and antagonist activity, respectively. Thus, the 3S,4R-compound 20f-1 possessed a K(i) of 11nM and an EC(50) of 24nM, while its 3R,4S-isomer 20f-2 exhibited a K(i) of 8.6 and an IC(50) of 65nM. Both compounds were highly selective over other melanocortin receptor subtypes. The MC4R agonist 20f-1 also demonstrated efficacy in diet-induced obese rats. 相似文献
206.
Biftu T Scapin G Singh S Feng D Becker JW Eiermann G He H Lyons K Patel S Petrov A Sinha-Roy R Zhang B Wu J Zhang X Doss GA Thornberry NA Weber AE 《Bioorganic & medicinal chemistry letters》2007,17(12):3384-3387
Molecular modeling was used to design a rigid analog of sitagliptin 1. The X-ray crystal structure of sitagliptin bound to DPP-4 suggested that the central beta-amino butyl amide moiety could be replaced with a cyclohexylamine group. This was confirmed by structural analysis and the resulting analog 2a was synthesized and found to be a potent DPP-4 inhibitor (IC(50)=21 nM) with excellent in vivo activity and pharmacokinetic profile. 相似文献
207.
Lafontaine JA Day RF Dibrino J Hadcock JR Hargrove DM Linhares M Martin KA Maurer TS Nardone NA Tess DA Dasilva-Jardine P 《Bioorganic & medicinal chemistry letters》2007,17(18):5245-5250
A novel series of heterocycle-based analogs were prepared and evaluated for their in vitro and in vivo biological activity as human beta(3)-adrenergic receptor (AR) agonists. Several analogs demonstrated potent agonist activity at the beta(3)-AR, functional selectivity against beta(1)- and beta(2)-ARs, and favorable pharmacokinetic profiles in vivo. Compound 17 increased oxygen consumption in rats, a measure of energy expenditure, with an ED(20%) of 2mg/kg. 相似文献
208.
Adaptive evolution has targeted the C-terminal domain of the RXLR effectors of plant pathogenic oomycetes 总被引:1,自引:0,他引:1 下载免费PDF全文
Win J Morgan W Bos J Krasileva KV Cano LM Chaparro-Garcia A Ammar R Staskawicz BJ Kamoun S 《The Plant cell》2007,19(8):2349-2369
Oomycete plant pathogens deliver effector proteins inside host cells to modulate plant defense circuitry and to enable parasitic colonization. These effectors are defined by a conserved motif, termed RXLR (for Arg, any amino acid, Leu, Arg), that is located downstream of the signal peptide and that has been implicated in host translocation. Because the phenotypes of RXLR effectors extend to plant cells, their genes are expected to be the direct target of the evolutionary forces that drive the antagonistic interplay between pathogen and host. We used the draft genome sequences of three oomycete plant pathogens, Phytophthora sojae, Phytophthora ramorum, and Hyaloperonospora parasitica, to generate genome-wide catalogs of RXLR effector genes and determine the extent to which these genes are under positive selection. These analyses revealed that the RXLR sequence is overrepresented and positionally constrained in the secretome of Phytophthora relative to other eukaryotes. The three examined plant pathogenic oomycetes carry complex and diverse sets of RXLR effector genes that have undergone relatively rapid birth and death evolution. We obtained robust evidence of positive selection in more than two-thirds of the examined paralog families of RXLR effectors. Positive selection has acted for the most part on the C-terminal region, consistent with the view that RXLR effectors are modular, with the N terminus involved in secretion and host translocation and the C-terminal domain dedicated to modulating host defenses inside plant cells. 相似文献
209.
Ichinohe T Kawaguchi A Tamura S Takahashi H Sawa H Ninomiya A Imai M Itamura S Odagiri T Tashiro M Chiba J Sata T Kurata T Hasegawa H 《Microbes and infection / Institut Pasteur》2007,9(11):1333-1340
The avian H5N1 influenza virus has the potential to cause a new pandemic. Since it is difficult to predict which strain of influenza will cause a pandemic, it is advantageous to produce vaccines that confer cross-protective immunity. Mucosal vaccine administration was reported to induce cross-protective immunity by inducing secretion of IgA at the mucosal surface. Adjuvants can also enhance the development of fully protective mucosal immunity. Here we show that a new mucosal adjuvant, poly I:poly C12U (Ampligen), a Toll-like receptor 3 agonist proven to be safe in a Phase III human trial, is an effective adjuvant for H5N1 influenza vaccination. Intranasal administration of a candidate influenza vaccine with Ampligen resulted in secretion of IgA, and protected mice that were subsequently challenged with homologous A/Vietnam/1194/2004 and heterologous A/HK/483/97 and A/Indonesia/6/2005 virus. 相似文献
210.