全文获取类型
收费全文 | 1549篇 |
免费 | 184篇 |
出版年
2021年 | 28篇 |
2020年 | 13篇 |
2019年 | 14篇 |
2018年 | 13篇 |
2017年 | 8篇 |
2016年 | 19篇 |
2015年 | 62篇 |
2014年 | 50篇 |
2013年 | 83篇 |
2012年 | 85篇 |
2011年 | 91篇 |
2010年 | 42篇 |
2009年 | 45篇 |
2008年 | 86篇 |
2007年 | 75篇 |
2006年 | 82篇 |
2005年 | 67篇 |
2004年 | 54篇 |
2003年 | 74篇 |
2002年 | 59篇 |
2001年 | 58篇 |
2000年 | 61篇 |
1999年 | 51篇 |
1998年 | 19篇 |
1997年 | 20篇 |
1996年 | 19篇 |
1995年 | 20篇 |
1994年 | 25篇 |
1993年 | 21篇 |
1992年 | 27篇 |
1991年 | 22篇 |
1990年 | 33篇 |
1989年 | 27篇 |
1988年 | 28篇 |
1987年 | 18篇 |
1986年 | 15篇 |
1985年 | 18篇 |
1984年 | 17篇 |
1983年 | 15篇 |
1982年 | 9篇 |
1981年 | 12篇 |
1979年 | 20篇 |
1978年 | 15篇 |
1977年 | 13篇 |
1976年 | 10篇 |
1975年 | 8篇 |
1974年 | 8篇 |
1973年 | 12篇 |
1972年 | 8篇 |
1967年 | 7篇 |
排序方式: 共有1733条查询结果,搜索用时 406 毫秒
71.
Christian P?tschke Wolfram Kessler Stefan Maier Claus-Dieter Heidecke Barbara M. Br?ker 《PloS one》2013,8(11)
Patients with sepsis are often immune suppressed, and experimental mouse models of sepsis also display this feature. However, acute sepsis in mice is also characterized by a generalized B cell activation and plasma cell differentiation, resulting in a marked increase in serum antibody concentration. Its effects on humoral memory are not clearly defined. We measured the effects of experimental sepsis on long-term immunological memory for a defined antigen: we induced colon ascendens stent peritonitis (CASP) 8 weeks after 2 rounds of immunization with ovalbumin. Four weeks later, the antigen-specific bone marrow plasma cell count had doubled in immunized non-septic animals, but remained unchanged in immunized septic animals. Sepsis also caused a decrease in antigen-specific serum antibody concentration. We conclude that sepsis weakens humoral memory by impeding the antigen-specific plasma cell pool’s development, which is not complete 8 weeks after secondary immunization. 相似文献
72.
73.
Hilka Rauert-Wunderlich Daniela Siegmund Eduard Maier Tina Giner Ralf C. Bargou Harald Wajant Thorsten Stühmer 《PloS one》2013,8(3)
Multiple myeloma (MM) displays an NFκB activity-related gene expression signature and about 20% of primary MM samples harbor genetic alterations conducive to intrinsic NFκB signaling activation. The relevance of blocking the classical versus the alternative NFκB signaling pathway and the molecular execution mechanisms involved, however, are still poorly understood. Here, we comparatively tested NFκB activity abrogation through TPCA-1 (an IKK2 inhibitor), BAY 11-7082 (an IKK inhibitor poorly selective for IKK1 and IKK2), and MLN4924 (an NEDD8 activating enzyme (NAE)-inhibitor), and analyzed their anti-MM activity. Whereas TPCA-1 interfered selectively with activation of the classical NFκB pathway, the other two compounds inhibited classical and alternative NFκB signaling without significant discrimination. Noteworthy, whereas TPCA-1 and MLN4924 elicited rather mild anti-MM effects with slight to moderate cell death induction after 1 day BAY 11-7082 was uniformly highly toxic to MM cell lines and primary MM cells. Treatment with BAY 11-7082 induced rapid cell swelling and its initial effects were blocked by necrostatin-1 or the ROS scavenger BHA, but a lasting protective effect was not achieved even with additional blockade of caspases. Because MLN4924 inhibits the alternative NFκB pathway downstream of IKK1 at the level of p100 processing, the quite discordant effects between MLN4924 and BAY 11-7082 must thus be due to blockade of IKK1-mediated NFκB-independent necrosis-inhibitory functions or represent an off-target effect of BAY 11-7082. In accordance with the latter, we further observed that concomitant knockdown of IKK1 and IKK2 did not have any major short-term adverse effect on the viability of MM cells. 相似文献
74.
75.
Rakka M. Orejas C. Maier S. R. Van Oevelen D. Godinho A. Bilan M. Carreiro-Silva M. 《Coral reefs (Online)》2020,39(5):1469-1482
Coral Reefs - Benthic suspension feeders have developed a variety of feeding strategies and food availability has often proven to be a key factor explaining their occurrence and distribution. The... 相似文献
76.
Furqan Muqri Alex Helkin Kristopher G. Maier Vivian Gahtan 《Journal of cellular biochemistry》2020,121(10):4154-4165
The thrombospondins (TSPs), multifunctional matricellular proteins, are known mediators of endothelial cell (EC) angiogenesis and apoptosis. TSP-1, an antiangiogenic molecule, is important in the progression of vascular disease, in part by inducing EC apoptosis. TSP-2, although less studied, also induces EC apoptosis and inhibits angiogenesis. The effects of TSP-5 are largely unexplored in ECs, but TSP-5 is believed to be protective against arterial disease. Statin drugs have been shown to have beneficial pleiotropic effects, including decreasing EC apoptosis, increasing angiogenesis, and blocking TSP signaling. We hypothesized TSP-5 will be proangiogenic and antiapoptotic, and statin pretreatment would reverse the proapoptotic and antiangiogenic phenotype of TSP-1 and TSP-2. ECs were exposed to serum-free medium, TSP-1, TSP-2, or TSP-5 with or without fluvastatin pretreatment. Quantitative real-time polymerase chain reaction was performed on 96 apoptosis and 96 angiogenesis-related genes using microfluidic card assays. Angiogenesis was measured using Matrigel assays, while apoptosis was measured by fluorescent caspase assay. TSP-5 suppressed apoptotic genes and had a mixed effect on the angiogenic genes; however, TSP-5 did not alter apoptois but was proangiogenic. Pretreatment with fluvastatin downregulated proapoptotic genes and apoptosis and upregulated proangiogenic genes and angiogenesis. Findings indicate TSP-5 and fluvastatin have a protective effect on ECs, being proangiogenic and reversing the antiangiogenic effects of TSP-1 and TSP-2. In conclusion, TSP-5 and fluvastatin may be beneficial for inducing angiogenesis in the setting of ischemia. 相似文献
77.
Madeleine Scharf Stefan Neef Robert Freund Cornelia Geers-Kn?rr Mirita Franz-Wachtel Almuth Brandis Dorothee Krone Heike Schneider Stephanie Groos Manoj B. Menon Kin-Chow Chang Theresia Kraft Joachim D. Meissner Kenneth R. Boheler Lars S. Maier Matthias Gaestel Renate J. Scheibe 《Molecular and cellular biology》2013,33(13):2586-2602
78.
Engulfment of a red or green alga by another eukaryote and subsequent reduction of the symbiont to an organelle, termed a complex plastid, is a process known as secondary endosymbiosis and is shown in a diverse group of eukaryotic organisms. Important members are heterokontophytes, haptophytes, cryptophytes, and apicomplexan parasites, all of them with complex plastids of red algal origin surrounded by four membranes. Although the evolutionary relationship between these organisms is still debated, they share common mechanisms for plastid protein import. In this review, we describe recent findings and current models on preprotein import into complex plastids with a special focus on the second outermost plastid membrane. Derived from the plasma membrane of the former endosymbiont, the evolution of protein transport across this so-called periplastidal membrane most likely represented the challenge in the transition from an endosymbiont to a host-dependent organelle. Here, remodeling and relocation of the symbiont endoplasmic reticulum-associated degradation (ERAD) machinery gave rise to a translocon complex termed symbiont-specific ERAD-like machinery and provides a fascinating insight into complex cellular evolution. 相似文献
79.
Disulfated and trisulfated steroids have been synthesized from cholesterol and their acetylcholinesterase inhibitory activity has been evaluated. In our studies we have found that the activity was not only dependent on the location of the sulfate groups but on their configurations. 2β,3α,6α-trihydroxy-5α-cholestan-6-one trisulfate (18) was the most active steroid with an IC50 value of 15.48 μM comparable to that of 2β,3α-dihydroxy-5α-cholestan-6-one disulfate (1). Both compounds were found to be less active than the reference compound eserine. The butyrylcholinesterase activity of 1 and 18 was one magnitude lower than that against acetylcholinesterase revealing a selective inhibitor profile. 相似文献
80.
Judith A H Wodke Maria Lluch‐Senar Josep Marcos Eva Yus Miguel Godinho Ricardo Gutiérrez‐Gallego Vitor A P Martins dos Santos Luis Serrano Edda Klipp Tobias Maier 《Molecular systems biology》2013,9(1)
Mycoplasma pneumoniae, a threatening pathogen with a minimal genome, is a model organism for bacterial systems biology for which substantial experimental information is available. With the goal of understanding the complex interactions underlying its metabolism, we analyzed and characterized the metabolic network of M. pneumoniae in great detail, integrating data from different omics analyses under a range of conditions into a constraint‐based model backbone. Iterating model predictions, hypothesis generation, experimental testing, and model refinement, we accurately curated the network and quantitatively explored the energy metabolism. In contrast to other bacteria, M. pneumoniae uses most of its energy for maintenance tasks instead of growth. We show that in highly linear networks the prediction of flux distributions for different growth times allows analysis of time‐dependent changes, albeit using a static model. By performing an in silico knock‐out study as well as analyzing flux distributions in single and double mutant phenotypes, we demonstrated that the model accurately represents the metabolism of M. pneumoniae. The experimentally validated model provides a solid basis for understanding its metabolic regulatory mechanisms. 相似文献