全文获取类型
收费全文 | 4705篇 |
免费 | 453篇 |
国内免费 | 4篇 |
出版年
2023年 | 41篇 |
2022年 | 66篇 |
2021年 | 174篇 |
2020年 | 110篇 |
2019年 | 117篇 |
2018年 | 135篇 |
2017年 | 128篇 |
2016年 | 173篇 |
2015年 | 291篇 |
2014年 | 304篇 |
2013年 | 297篇 |
2012年 | 444篇 |
2011年 | 432篇 |
2010年 | 218篇 |
2009年 | 212篇 |
2008年 | 290篇 |
2007年 | 258篇 |
2006年 | 234篇 |
2005年 | 211篇 |
2004年 | 182篇 |
2003年 | 147篇 |
2002年 | 121篇 |
2001年 | 31篇 |
2000年 | 19篇 |
1999年 | 23篇 |
1998年 | 29篇 |
1997年 | 19篇 |
1996年 | 20篇 |
1995年 | 18篇 |
1994年 | 15篇 |
1993年 | 15篇 |
1992年 | 21篇 |
1991年 | 20篇 |
1990年 | 17篇 |
1989年 | 19篇 |
1988年 | 14篇 |
1987年 | 12篇 |
1986年 | 14篇 |
1985年 | 16篇 |
1984年 | 12篇 |
1983年 | 11篇 |
1982年 | 15篇 |
1981年 | 19篇 |
1980年 | 12篇 |
1979年 | 18篇 |
1978年 | 10篇 |
1977年 | 14篇 |
1976年 | 12篇 |
1975年 | 12篇 |
1974年 | 13篇 |
排序方式: 共有5162条查询结果,搜索用时 15 毫秒
101.
Nathan Ford Zara Shubber Andrew Hill Marco Vitoria Meg Doherty Edward J. Mills Andy Gray 《PloS one》2013,8(11)
Introduction
Lamivudine and emtricitabine are considered equivalent by several guidelines, but evidence of comparable efficacy is conflicting.Methods
We searched two databases up to June 30 2013 to identify randomized and quasi-randomized trials in which lamivudine and emtricitabine were used as part of combination antiretroviral therapy for treatment-naïve or experienced HIV-positive adult patients. We only included trials where partner drugs in the regimen were identical or could be considered to be comparable. We allowed for comparisons between tenofovir and abacavir provided the study population did not begin treatment with a viral load >100,000 copies/ml.Results
12 trials contributed 15 different randomized comparisons providing data on 2251 patients receiving lamivudine and 2662 patients receiving emtricitabine. Treatment success was not significantly different in any of the 12 trials. In the three trials that directly compared lamivudine and emtricitabine, the relative risk for achieving treatment success was non-significant (RR 1.03 95%CI 0.96-1.10). For all trials combined, the pooled relative risk for treatment success was not significantly different (RR 1.00, 95%CI 0.97–1.02). No heterogeneity was observed (I 2 = 0). Similarly, there was no difference in the pooled relative risk for treatment failure (RR 1.08, 95%CI 0.94–1.22, I 2 = 3.4%).Conclusions
The findings of this systematic review suggest that lamivudine and emtricitabine are clinically equivalent. 相似文献102.
Zhiwei Chen Jose H. Pereira Hanbin Liu Huu M. Tran Nathan S. Y. Hsu Dean Dibble Seema Singh Paul D. Adams Rajat Sapra Masood Z. Hadi Blake A. Simmons Kenneth L. Sale 《PloS one》2013,8(11)
Ionic liquid pretreatment of biomass has been shown to greatly reduce the recalcitrance of lignocellulosic biomass, resulting in improved sugar yields after enzymatic saccharification. However, even under these improved saccharification conditions the cost of enzymes still represents a significant proportion of the total cost of producing sugars and ultimately fuels from lignocellulosic biomass. Much of the high cost of enzymes is due to the low catalytic efficiency and stability of lignocellulolytic enzymes, especially cellulases, under conditions that include high temperatures and the presence of residual pretreatment chemicals, such as acids, organic solvents, bases, or ionic liquids. Improving the efficiency of the saccharification process on ionic liquid pretreated biomass will facilitate reduced enzyme loading and cost. Thermophilic cellulases have been shown to be stable and active in ionic liquids but their activity is typically at lower levels. Cel5A_Tma, a thermophilic endoglucanase from Thermotoga maritima, is highly active on cellulosic substrates and is stable in ionic liquid environments. Here, our motivation was to engineer mutants of Cel5A_Tma with higher activity on 1-ethyl-3-methylimidazolium acetate ([C2mim][OAc]) pretreated biomass. We developed a robotic platform to screen a random mutagenesis library of Cel5A_Tma. Twelve mutants with 25–42% improvement in specific activity on carboxymethyl cellulose and up to 30% improvement on ionic-liquid pretreated switchgrass were successfully isolated and characterized from a library of twenty thousand variants. Interestingly, most of the mutations in the improved variants are located distally to the active site on the protein surface and are not directly involved with substrate binding. 相似文献
103.
Aasya Nasar Laurajo Ryan Christopher R. Frei Jason M. Cota Nathan P. Wiederhold 《Current fungal infection reports》2013,7(2):89-95
The echinocandins target fungi by inhibiting the production of (1,3)-β-d-glucan, an essential component of the fungal cell wall. These agents have less toxicity to mammalian cells, as compared to other antifungals; however, they maintain potent activity against many pathogenic fungi, including polyene- and azole-resistant isolates. Members of this class are highly protein-bound, and the addition of serum or albumin to the growth medium has profound effects on their in vitro potency and pharmacodynamics. In addition, studies have demonstrated an association between in vitro activity, in the presence of serum, and outcomes in animal models of invasive fungal infections. Serum and albumin may also be useful to help detect echinocandin-resistant Candida isolates with point mutations in the gene that encodes for glucan synthase. Thus, in vitro studies evaluating echinocandins in the presence of protein can provide valuable insight regarding their potency and pharmacodynamics. 相似文献
104.
William R. Kirkpatrick Nathan P. Wiederhold Laura K. Najvar Thomas F. Patterson 《Current fungal infection reports》2013,7(1):68-78
Animal models have long been used to explore various pathophysiological, immunological and microbiological questions in the field of medical mycology. These models have been adapted and altered over time, yet their use has persisted. They remain valuable as research tools due to similarities to processes in human physiology and disease, and are evolving to include more fungal pathogens and infections that better mimic disease in humans. Animal availability, animal cost, housing requirements, the need for immunosuppression, the potential for tissue, fluid or blood samples, a researcher’s familiarity with the model, as well as governmental or institutional regulations, must all be considered when selecting an appropriate one to use. Although the questions of interest have changed over the past 30 years, one idea persists: animal models are valuable tools in research that span the gap between the bench and the clinic. 相似文献
105.
106.
Background
Recent experimental evidence suggests that stressed males find heavier women more attractive than non-stressed males. The aim of this study is to examine whether these results also appear in actual mating patterns of adults from a national sample.Methods
Regression analysis linking partner weight measures to own measures of childhood stress, as measured by mistreatment. Cross-sectional data from the National Longitudinal Study of Adolescent Health, Romantic Partners Sample is used to measure partner weight, childhood stressful events, and socio-demographic characteristics. Childhood experiences of adult mistreatment are retrospectively collected.Results
Men who experienced childhood mistreatment are more likely to have obese female partners during young adulthood. The results are strongest for interactions with social services, adult neglect and physical abuse. We also present novel evidence of the opposite association in similarly stressed women whose male partners are more likely to be thin.Conclusions
These results suggest that preferences for partner characteristics are sensitive to histories of stress and that previously hypothesized patterns occur outside the experimental setting. 相似文献107.
Matthew J. Cooper Nathan J. Cox Eric I. Zimmerman Brian J. Dewar James S. Duncan Martin C. Whittle Thien A. Nguyen Lauren S. Jones Sreerupa Ghose Roy David M. Smalley Pei Fen Kuan Kristy L. Richards Richard I. Christopherson Jian Jin Stephen V. Frye Gary L. Johnson Albert S. Baldwin Lee M. Graves 《PloS one》2013,8(6)
Protein kinases play key roles in oncogenic signaling and are a major focus in the development of targeted cancer therapies. Imatinib, a BCR-Abl tyrosine kinase inhibitor, is a successful front-line treatment for chronic myelogenous leukemia (CML). However, resistance to imatinib may be acquired by BCR-Abl mutations or hyperactivation of Src family kinases such as Lyn. We have used multiplexed kinase inhibitor beads (MIBs) and quantitative mass spectrometry (MS) to compare kinase expression and activity in an imatinib-resistant (MYL-R) and -sensitive (MYL) cell model of CML. Using MIB/MS, expression and activity changes of over 150 kinases were quantitatively measured from various protein kinase families. Statistical analysis of experimental replicates assigned significance to 35 of these kinases, referred to as the MYL-R kinome profile. MIB/MS and immunoblotting confirmed the over-expression and activation of Lyn in MYL-R cells and identified additional kinases with increased (MEK, ERK, IKKα, PKCβ, NEK9) or decreased (Abl, Kit, JNK, ATM, Yes) abundance or activity. Inhibiting Lyn with dasatinib or by shRNA-mediated knockdown reduced the phosphorylation of MEK and IKKα. Because MYL-R cells showed elevated NF-κB signaling relative to MYL cells, as demonstrated by increased IκBα and IL-6 mRNA expression, we tested the effects of an IKK inhibitor (BAY 65-1942). MIB/MS and immunoblotting revealed that BAY 65-1942 increased MEK/ERK signaling and that this increase was prevented by co-treatment with a MEK inhibitor (AZD6244). Furthermore, the combined inhibition of MEK and IKKα resulted in reduced IL-6 mRNA expression, synergistic loss of cell viability and increased apoptosis. Thus, MIB/MS analysis identified MEK and IKKα as important downstream targets of Lyn, suggesting that co-targeting these kinases may provide a unique strategy to inhibit Lyn-dependent imatinib-resistant CML. These results demonstrate the utility of MIB/MS as a tool to identify dysregulated kinases and to interrogate kinome dynamics as cells respond to targeted kinase inhibition. 相似文献
108.
Samantha F. Friend Lisa K. Peterson Eric Treacy Adrianne L. Stefanski Tomasz Sosinowski Nathan D. Pennock Allison J. Berger Virginia D. Winn Leonard L. Dragone 《PloS one》2013,8(10)
While neddylation is known to activate cullin (CUL)-RING ubiquitin ligases (CRLs), its role in regulating T cell signaling is poorly understood. Using the investigational NEDD8 activating enzyme (NAE) inhibitor, MLN4924, we found that neddylation negatively regulates T cell receptor (TCR) signaling, as its inhibition increases IL-2 production, T cell proliferation and Treg development in vitro. We also discovered that loss of CUL neddylation occurs upon TCR signaling, and CRLs negatively regulate IL-2 production. Additionally, we found that tyrosine kinase signaling leads to CUL deneddylation in multiple cell types. These studies indicate that CUL neddylation is a global regulatory mechanism for tyrosine kinase signaling. 相似文献
109.
110.
Nathan D. Grubaugh Scott S. McMenamy Michael J. Turell John S. Lee 《PLoS neglected tropical diseases》2013,7(8)