全文获取类型
收费全文 | 17961篇 |
免费 | 1241篇 |
国内免费 | 2篇 |
出版年
2024年 | 6篇 |
2023年 | 136篇 |
2022年 | 275篇 |
2021年 | 559篇 |
2020年 | 375篇 |
2019年 | 435篇 |
2018年 | 575篇 |
2017年 | 500篇 |
2016年 | 785篇 |
2015年 | 1147篇 |
2014年 | 1208篇 |
2013年 | 1533篇 |
2012年 | 1782篇 |
2011年 | 1565篇 |
2010年 | 984篇 |
2009年 | 826篇 |
2008年 | 1029篇 |
2007年 | 1022篇 |
2006年 | 925篇 |
2005年 | 763篇 |
2004年 | 721篇 |
2003年 | 616篇 |
2002年 | 502篇 |
2001年 | 105篇 |
2000年 | 73篇 |
1999年 | 105篇 |
1998年 | 97篇 |
1997年 | 78篇 |
1996年 | 67篇 |
1995年 | 55篇 |
1994年 | 59篇 |
1993年 | 41篇 |
1992年 | 34篇 |
1991年 | 24篇 |
1990年 | 24篇 |
1989年 | 21篇 |
1988年 | 14篇 |
1987年 | 18篇 |
1986年 | 8篇 |
1985年 | 11篇 |
1984年 | 15篇 |
1983年 | 15篇 |
1982年 | 5篇 |
1981年 | 10篇 |
1980年 | 10篇 |
1979年 | 6篇 |
1978年 | 7篇 |
1977年 | 7篇 |
1975年 | 5篇 |
1972年 | 5篇 |
排序方式: 共有10000条查询结果,搜索用时 234 毫秒
131.
Karl Enquist Mawritz Fransson Carolina Boekel Inger Bengtsson Lisa Lang Sofia Johansson IngMarie Nilsson 《Journal of molecular biology》2009,387(5):1153-354
To what extent do corresponding transmembrane helices in related integral membrane proteins have different membrane-insertion characteristics? Here, we compare, side-by-side, the membrane insertion characteristics of the 12 transmembrane helices in the adenosine triphosphate-binding cassette (ABC) transporters, P-glycoprotein (P-gp) and the cystic fibrosis transmembrane conductance regulator (CFTR). Our results show that 10 of the 12 CFTR transmembrane segments can insert independently into the ER membrane. In contrast, only three of the P-gp transmembrane segments are independently stable in the membrane, while the majority depend on the presence of neighboring loops and/or transmembrane segments for efficient insertion. Membrane-insertion characteristics can thus vary widely between related proteins. 相似文献
132.
We studied the effect of high-fat diet on the expression and activation of the three caveolins in rat skeletal muscle and their association with the insulin signalling cascade. Initial response was characterized by increased signalling through Cav-1 and Cav-3 phosphorylation, suggesting that both participate in an initial acute response to the calorie surplus. Afterwards, Cav-1 signalling was slightly reduced, whereas Cav-3 remained active. Late chronic phase signalling through both proteins was impaired inducing a prediabetic state. Summarizing, caveolins seem to mediate a time-dependent regulation of insulin cascade in response to high-fat diet in muscle. 相似文献
133.
Catarina Macedo-Silva Vera Miranda-Gonalves Ana Lameirinhas Joana Lencart Alexandre Pereira Joo Lobo Rita Guimares Ana Teresa Martins Rui Henrique Isabel Bravo Carmen Jernimo 《Cell death & disease》2020,11(12)
Esophageal squamous cell carcinoma (ESCC), the most frequent esophageal cancer (EC) subtype, entails dismal prognosis. Hypoxia, a common feature of advanced ESCC, is involved in resistance to radiotherapy (RT). RT response in hypoxia might be modulated through epigenetic mechanisms, constituting novel targets to improve patient outcome. Post-translational methylation in histone can be partially modulated by histone lysine demethylases (KDMs), which specifically removes methyl groups in certain lysine residues. KDMs deregulation was associated with tumor aggressiveness and therapy failure. Thus, we sought to unveil the role of Jumonji C domain histone lysine demethylases (JmjC-KDMs) in ESCC radioresistance acquisition. The effectiveness of RT upon ESCC cells under hypoxic conditions was assessed by colony formation assay. KDM3A/KDM6B expression, and respective H3K9me2 and H3K27me3 target marks, were evaluated by RT-qPCR, Western blot, and immunofluorescence. Effect of JmjC-KDM inhibitor IOX1, as well as KDM3A knockdown, in in vitro functional cell behavior and RT response was assessed in ESCC under hypoxic conditions. In vivo effect of combined IOX1 and ionizing radiation treatment was evaluated in ESCC cells using CAM assay. KDM3A, KDM6B, HIF-1α, and CAIX immunoexpression was assessed in primary ESCC and normal esophagus. Herein, we found that hypoxia promoted ESCC radioresistance through increased KDM3A/KDM6B expression, enhancing cell survival and migration and decreasing DNA damage and apoptosis, in vitro. Exposure to IOX1 reverted these features, increasing ESCC radiosensitivity and decreasing ESCC microtumors size, in vivo. KDM3A was upregulated in ESCC tissues compared to the normal esophagus, associating and colocalizing with hypoxic markers (HIF-1α and CAIX). Therefore, KDM3A upregulation in ESCC cell lines and primary tumors associated with hypoxia, playing a critical role in EC aggressiveness and radioresistance. KDM3A targeting, concomitant with conventional RT, constitutes a promising strategy to improve ESCC patients’ survival.Subject terms: Predictive markers, Cancer 相似文献
134.
The outer membrane protein (omp40) component from the chemolithoautotrophic acidophilic Thiobacillus ferrooxidans is apparently regulated by the external pH and the concentration of phosphorus. Its amino-terminal sequence showed little identity with the Escherichia coli OmpC, OmpF or PhoE porins, but was 38.5% identical to the outer membrane channel-forming protein NosA from Pseudomonas stutzeri, whose expression is also regulated environmentally. In addition, the partial amino acid sequence of T. ferrooxidans omp40 showed between 34 and 38% identity with the amino-terminal end of the small outer membrane proteins Rck and PagC from Salmonella typhimurium and OmpX from Enterobacter cloacae. 相似文献
135.
Elsa Leitão Ana Catarina Costa Claudia Brito Lionel Costa Rita Pombinho 《Cell cycle (Georgetown, Tex.)》2014,13(6):928-940
Listeria monocytogenes (Lm) is a human intracellular pathogen widely used to uncover the mechanisms evolved by pathogens to establish infection. However, its capacity to perturb the host cell cycle was never reported. We show that Lm infection affects the host cell cycle progression, increasing its overall duration but allowing consecutive rounds of division. A complete Lm infectious cycle induces a S-phase delay accompanied by a slower rate of DNA synthesis and increased levels of host DNA strand breaks. Additionally, DNA damage/replication checkpoint responses are triggered in an Lm dose-dependent manner through the phosphorylation of DNA-PK, H2A.X, and CDC25A and independently from ATM/ATR. While host DNA damage induced exogenously favors Lm dissemination, the override of checkpoint pathways limits infection. We propose that host DNA replication disturbed by Lm infection culminates in DNA strand breaks, triggering DNA damage/replication responses, and ensuring a cell cycle delay that favors Lm propagation. 相似文献
136.
Riccardo Danielli Roberto Patuzzo Anna Maria Di Giacomo Gianfranco Gallino Andrea Maurichi Annabella Di Florio Ornella Cutaia Andrea Lazzeri Carolina Fazio Clelia Miracco Leonardo Giovannoni Giuliano Elia Dario Neri Michele Maio Mario Santinami 《Cancer immunology, immunotherapy : CII》2015,64(8):999-1009
137.
Ana Espinel-Ingroff 《Revista iberoamericana de micología》2009,26(1):15-22
BackgroundThe incidence and prevalence of serious mycoses continues to be a public health problem. Despite aggressive treatment with new or more established licensed antifungal agents, these infections are an important cause of morbidity and mortality, especially in immunocompromised patients.AimsTo critically review the literature regarding important new developments in the field of antifungal therapy both in the English and Spanish versions.MethodsThe search of the literature focused on different antifungal targets or mechanisms of action as well as new agents or strategies that could improve antifungal therapy.ResultsThe review produced a huge amount of information on the use of virulent factors such as growth, filamentation, pathogen tissue clearance, among others, as putative targets of antifungal activity. More recently, the chemical-genetic relationships for licensed agents as well as for other compounds have been provided by the identification of the genes related to the mechanism of action.ConclusionsAlthough the antifungal activity of numerous compounds has been examined, most of them are at the in vitro or animal models of efficacy stages. Therefore, further investigation should be carried out to realize the true clinical utility of these compounds. 相似文献
138.
Diana Marcela Penarete-Vargas Ana?s Boisson Serge Urbach Hervé Chantelauze Suzanne Peyrottes Laurent Fraisse Henri J. Vial 《PloS one》2014,9(12)
Plasmodium falciparum is responsible for severe malaria which is one of the most prevalent and deadly infectious diseases in the world. The antimalarial therapeutic arsenal is hampered by the onset of resistance to all known pharmacological classes of compounds, so new drugs with novel mechanisms of action are critically needed. Albitiazolium is a clinical antimalarial candidate from a series of choline analogs designed to inhibit plasmodial phospholipid metabolism. Here we developed an original chemical proteomic approach to identify parasite proteins targeted by albitiazolium during their native interaction in living parasites. We designed a bifunctional albitiazolium-derived compound (photoactivable and clickable) to covalently crosslink drug–interacting parasite proteins in situ followed by their isolation via click chemistry reactions. Mass spectrometry analysis of drug–interacting proteins and subsequent clustering on gene ontology terms revealed parasite proteins involved in lipid metabolic activities and, interestingly, also in lipid binding, transport, and vesicular transport functions. In accordance with this, the albitiazolium-derivative was localized in the endoplasmic reticulum and trans-Golgi network of P. falciparum. Importantly, during competitive assays with albitiazolium, the binding of choline/ethanolamine phosphotransferase (the enzyme involved in the last step of phosphatidylcholine synthesis) was substantially displaced, thus confirming the efficiency of this strategy for searching albitiazolium targets. 相似文献
139.
Daniel R. Henríquez Felipe J. Bodaleo Carolina Montenegro-Venegas Christian González-Billault 《PloS one》2012,7(12)
Microtubule-associated protein 1B (MAP1B) is a neuronal protein involved in the stabilization of microtubules both in the axon and somatodendritic compartments. Acute, genetic inactivation of MAP1B leads to delayed axonal outgrowth, most likely due to changes in the post-translational modification of tubulin subunits, which enhances microtubule polymerization. Furthermore, MAP1B deficiency is accompanied by abnormal actin microfilament polymerization and dramatic changes in the activity of small GTPases controlling the actin cytoskeleton. In this work, we showed that MAP1B interacts with a guanine exchange factor, termed Tiam1, which specifically activates Rac1. These proteins co-segregated in neurons, and interact in both heterologous expression systems and primary neurons. We dissected the molecular domains involved in the MAP1B-Tiam1 interaction, and demonstrated that pleckstrin homology (PH) domains in Tiam1 are responsible for MAP1B binding. Interestingly, only the light chain 1 (LC1) of MAP1B was able to interact with Tiam1. Moreover, it was able to increase the activity of the small GTPase, Rac1. These results suggest that the interaction between Tiam1 and MAP1B, is produced by the binding of LC1 with PH domains in Tiam1. The formation of such a complex impacts on the activation levels of Rac1 confirming a novel function of MAP1B related with the control of small GTPases. These results also support the idea of cross-talk between cytoskeleton compartments inside neuronal cells. 相似文献
140.