全文获取类型
收费全文 | 875篇 |
免费 | 58篇 |
专业分类
933篇 |
出版年
2023年 | 9篇 |
2022年 | 16篇 |
2021年 | 33篇 |
2020年 | 19篇 |
2019年 | 21篇 |
2018年 | 25篇 |
2017年 | 24篇 |
2016年 | 25篇 |
2015年 | 39篇 |
2014年 | 40篇 |
2013年 | 74篇 |
2012年 | 58篇 |
2011年 | 62篇 |
2010年 | 47篇 |
2009年 | 30篇 |
2008年 | 46篇 |
2007年 | 40篇 |
2006年 | 36篇 |
2005年 | 32篇 |
2004年 | 29篇 |
2003年 | 40篇 |
2002年 | 23篇 |
2001年 | 6篇 |
2000年 | 14篇 |
1999年 | 5篇 |
1998年 | 17篇 |
1997年 | 4篇 |
1996年 | 5篇 |
1995年 | 4篇 |
1992年 | 5篇 |
1991年 | 5篇 |
1990年 | 7篇 |
1989年 | 5篇 |
1988年 | 3篇 |
1987年 | 4篇 |
1985年 | 3篇 |
1983年 | 5篇 |
1982年 | 6篇 |
1981年 | 6篇 |
1980年 | 5篇 |
1977年 | 5篇 |
1970年 | 4篇 |
1966年 | 2篇 |
1965年 | 3篇 |
1961年 | 2篇 |
1958年 | 3篇 |
1956年 | 2篇 |
1946年 | 3篇 |
1937年 | 2篇 |
1912年 | 2篇 |
排序方式: 共有933条查询结果,搜索用时 15 毫秒
31.
32.
The effect of pyrethroid resistance on the fitness of a laboratory strain of Anopheles funestus originating from southern Mozambique was evaluated by comparing the developmental and reproductive characteristics of a pyrethroid resistant strain with an insecticide susceptible strain. Fitness was evaluated in terms of fecundity, fertility, egg production, developmental time and life stage progression and survival. Of the eggs laid by females of the resistant strain, 81.5% hatched while only 66.9% were recorded in the susceptible strain. The time from egg hatch to adult emergence was longer for the resistant strain (15.9 days) than the susceptible strain (15.2 days). A significantly higher proportion of eggs from the resistant strain (61.6%) survived to adulthood compared with those of the susceptible strain (49%). Fecundity and larval and pupal survival did not differ significantly between strains. Of spermathecae dissected from females of the resistant strain, 56.8% were fertilized compared to 52.6% from the susceptible strain. The proportion of females that successfully produced eggs was 43.3% and 23.3% for the resistant and susceptible strains respectively. Complete failure of larval hatch was recorded in 28.6% of susceptible strain families compared to 7.7% of resistant families. Our results show that pyrethroid resistance in southern African An. funestus does not incur any loss of fitness under laboratory conditions. These results suggest that the removal of pyrethroid insecticide selection pressure may not lead to a regression of resistance alleles in pyrethroid resistant An. funestus populations in southern Africa. 相似文献
33.
34.
35.
Xiang Liu Bo Zhao Timothy I Shaw Brooke L Fridley Derek R Duckett Aik
Choon Tan Mingxiang Teng 《Nucleic acids research》2022,50(6):3115
Super enhancers (SEs) are broad enhancer domains usually containing multiple constituent enhancers that hold elevated activities in gene regulation. Disruption in one or more constituent enhancers causes aberrant SE activities that lead to gene dysregulation in diseases. To quantify SE aberrations, differential analysis is performed to compare SE activities between cell conditions. The state-of-art strategy in estimating differential SEs relies on overall activities and neglect the changes in length and structure of SEs. Here, we propose a novel computational method to identify differential SEs by weighting the combinatorial effects of constituent-enhancer activities and locations (i.e. internal dynamics). In addition to overall activity changes, our method identified four novel classes of differential SEs with distinct enhancer structural alterations. We demonstrate that these structure alterations hold distinct regulatory impact, such as regulating different number of genes and modulating gene expression with different strengths, highlighting the differentiated regulatory roles of these unexplored SE features. When compared to the existing method, our method showed improved identification of differential SEs that were linked to better discernment of cell-type-specific SE activity and functional interpretation. 相似文献
36.
Nan Bai Kristin M. Riching Aman Makaju Hao Wu Timothy M. Acker Shu-Ching Ou Yaru Zhang Xiaomeng Shen Daryl N. Bulloch Huan Rui Bradford W. Gibson Danette L. Daniels Marjeta Urh Brooke M. Rock Sara C. Humphreys 《The Journal of biological chemistry》2022,298(4)
PROteolysis TArgeting Chimeras (PROTACs) are hetero-bifunctional small molecules that can simultaneously recruit target proteins and E3 ligases to form a ternary complex, promoting target protein ubiquitination and degradation via the Ubiquitin-Proteasome System (UPS). PROTACs have gained increasing attention in recent years due to certain advantages over traditional therapeutic modalities and enabling targeting of previously “undruggable” proteins. To better understand the mechanism of PROTAC-induced Target Protein Degradation (TPD), several computational approaches have recently been developed to study and predict ternary complex formation. However, mounting evidence suggests that ubiquitination can also be a rate-limiting step in PROTAC-induced TPD. Here, we propose a structure-based computational approach to predict target protein ubiquitination induced by cereblon (CRBN)-based PROTACs by leveraging available structural information of the CRL4A ligase complex (CRBN/DDB1/CUL4A/Rbx1/NEDD8/E2/Ub). We generated ternary complex ensembles with Rosetta, modeled multiple CRL4A ligase complex conformations, and predicted ubiquitination efficiency by separating the ternary ensemble into productive and unproductive complexes based on the proximity of the ubiquitin to accessible lysines on the target protein. We validated our CRL4A ligase complex models with published ternary complex structures and additionally employed our modeling workflow to predict ubiquitination efficiencies and sites of a series of cyclin-dependent kinases (CDKs) after treatment with TL12–186, a pan-kinase PROTAC. Our predictions are consistent with CDK ubiquitination and site-directed mutagenesis of specific CDK lysine residues as measured using a NanoBRET ubiquitination assay in HEK293 cells. This work structurally links PROTAC-induced ternary formation and ubiquitination, representing an important step toward prediction of target “degradability.” 相似文献
37.
Brooke M. Helfer Anthony Balducci Aaron D. Nelson Jelena M. Janjic Roberto R. Gil Pawel Kalinski I. Jolanda M. de Vries Eric T. Ahrens Robbie B. Mailliard 《Cytotherapy》2010,12(2):238-250
Background aimsDendritic cells (DC) are increasingly being used as cellular vaccines to treat cancer and infectious diseases. While there have been some promising results in early clinical trials using DC-based vaccines, the inability to visualize non-invasively the location, migration and fate of cells once adoptively transferred into patients is often cited as a limiting factor in the advancement of these therapies. A novel perflouropolyether (PFPE) tracer agent was used to label human DC ex vivo for the purpose of tracking the cells in vivo by 19F magnetic resonance imaging (MRI). We provide an assessment of this technology and examine its impact on the health and function of the DC.MethodsMonocyte-derived DC were labeled with PFPE and then assessed. Cell viability was determined by examining cell membrane integrity and mitochondrial lipid content. Immunostaining and flow cytometry were used to measure surface antigen expression of DC maturation markers. Functional tests included bioassays for interleukin (IL)-12p70 production, T-cell stimulatory function and chemotaxis. MRI efficacy was demonstrated by inoculation of PFPE-labeled human DC into NOD-SCID mice.ResultsDC were effectively labeled with PFPE without significant impact on cell viability, phenotype or function. The PFPE-labeled DC were clearly detected in vivo by 19F MRI, with mature DC being shown to migrate selectively towards draining lymph node regions within 18 h.ConclusionsThis study is the first application of PFPE cell labeling and MRI cell tracking using human immunotherapeutic cells. These techniques may have significant potential for tracking therapeutic cells in future clinical trials. 相似文献
38.
The CRM1 nuclear export receptor controls pathological cardiac gene expression 总被引:1,自引:0,他引:1 下载免费PDF全文
Harrison BC Roberts CR Hood DB Sweeney M Gould JM Bush EW McKinsey TA 《Molecular and cellular biology》2004,24(24):10636-10649
39.
40.
Loss of distinct arterial and venous boundaries in mice lacking endoglin,a vascular-specific TGFbeta coreceptor 总被引:5,自引:0,他引:5
Several characteristic morphological and functional differences distinguish arteries from veins. It was thought that hemodynamic forces shaped these differences; however, increasing evidence suggests that morphogenetic programs play a central role in blood vessel differentiation. Hereditary hemorrhagic telangiectasia (HHT) is a vascular dysplasia characterized by the inappropriate fusion of arterioles with venules. The genes implicated in this disease, ALK1 and endoglin, may be involved in defining the fundamental boundaries between arteries and veins. We previously showed that mice lacking Alk1 lost structural, molecular, and functional distinctions between arteries and veins. Here, we report that mice lacking endoglin develop arterial-venous malformations and fail to confine intraembryonic hematopoiesis to arteries. In contrast to Alk1 mutants, endoglin mutants do not show profound vessel dilation or downregulation of arterial ephrinB2. Finally, our data indicate that a failure in cardiac cushion formation observed in both strains may be secondary to the peripheral vasculature defect. The phenotypic similarities, yet reduced severity, implicates endoglin as an accessory coreceptor that specifically modulates Alk1 signaling. We propose that endoglin and Alk1 are necessary for the maintenance of distinct arterial-venous vascular beds and that attenuation of the Alk1 signaling pathway is the precipitating event in the etiology of HHT. 相似文献