全文获取类型
收费全文 | 287篇 |
免费 | 20篇 |
国内免费 | 18篇 |
出版年
2022年 | 3篇 |
2021年 | 6篇 |
2020年 | 4篇 |
2019年 | 3篇 |
2018年 | 3篇 |
2017年 | 2篇 |
2016年 | 3篇 |
2015年 | 9篇 |
2014年 | 9篇 |
2013年 | 13篇 |
2012年 | 17篇 |
2011年 | 13篇 |
2010年 | 16篇 |
2009年 | 7篇 |
2008年 | 8篇 |
2007年 | 7篇 |
2006年 | 14篇 |
2005年 | 5篇 |
2004年 | 14篇 |
2003年 | 9篇 |
2002年 | 10篇 |
2001年 | 8篇 |
2000年 | 8篇 |
1999年 | 4篇 |
1998年 | 8篇 |
1997年 | 4篇 |
1996年 | 3篇 |
1995年 | 6篇 |
1994年 | 4篇 |
1993年 | 3篇 |
1992年 | 6篇 |
1991年 | 5篇 |
1990年 | 13篇 |
1989年 | 10篇 |
1988年 | 4篇 |
1987年 | 7篇 |
1986年 | 3篇 |
1985年 | 6篇 |
1984年 | 3篇 |
1983年 | 2篇 |
1982年 | 4篇 |
1981年 | 3篇 |
1980年 | 9篇 |
1979年 | 6篇 |
1975年 | 7篇 |
1974年 | 2篇 |
1972年 | 2篇 |
1971年 | 2篇 |
1970年 | 2篇 |
1935年 | 1篇 |
排序方式: 共有325条查询结果,搜索用时 140 毫秒
21.
Letavic MA Axt MZ Barberia JT Carty TJ Danley DE Geoghegan KF Halim NS Hoth LR Kamath AV Laird ER Lopresti-Morrow LL McClure KF Mitchell PG Natarajan V Noe MC Pandit J Reeves L Schulte GK Snow SL Sweeney FJ Tan DH Yu CH 《Bioorganic & medicinal chemistry letters》2002,12(10):1387-1390
A series of novel, selective TNF-alpha converting enzyme inhibitors based on 4-hydroxy and 5-hydroxy pipecolate hydroxamic acid scaffolds is described. The potency and selectivity of TACE inhibition is dramatically influenced by the nature of the sulfonamide group which interacts with the S1' site of the enzyme. Substituted 4-benzyloxybenzenesulfonamides exhibit excellent TACE potency with >100x selectivity over inhibition of matrix metalloprotease-1 (MMP-1). Alkyl substituents on the ortho position of the benzyl ether moiety give the most potent inhibition of TNF-alpha release in LPS-treated human whole blood. 相似文献
22.
Letavic MA Barberia JT Carty TJ Hardink JR Liras J Lopresti-Morrow LL Mitchell PG Noe MC Reeves LM Snow SL Stam EJ Sweeney FJ Vaughn ML Yu CH 《Bioorganic & medicinal chemistry letters》2003,13(19):3243-3246
A series of novel MMP-13 and TNF-alpha converting enzyme inhibitors based on piperazine 2-hydroxamic acid scaffolds are described. The TACE, MMP-1 and MMP-13 activity of these inhibitors as well as the effect of substitution of the piperazine nitrogen and the P-1' benzyloxy tailpiece is discussed. Moderate in vivo activity is observed with several members of this group. 相似文献
23.
Nikisha Carty Nadège Berson Karsten Tillack Christina Thiede Diana Scholz Karsten Kottig Yalda Sedaghat Christina Gabrysiak George Yohrling Heinz von der Kammer Andreas Ebneth Volker Mack Ignacio Munoz-Sanjuan Seung Kwak 《PloS one》2015,10(4)
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the huntingtin gene. Major pathological hallmarks of HD include inclusions of mutant huntingtin (mHTT) protein, loss of neurons predominantly in the caudate nucleus, and atrophy of multiple brain regions. However, the early sequence of histological events that manifest in region- and cell-specific manner has not been well characterized. Here we use a high-content histological approach to precisely monitor changes in HTT expression and characterize deposition dynamics of mHTT protein inclusion bodies in the recently characterized zQ175 knock-in mouse line. We carried out an automated multi-parameter quantitative analysis of individual cortical and striatal cells in tissue slices from mice aged 2–12 months and confirmed biochemical reports of an age-associated increase in mHTT inclusions in this model. We also found distinct regional and subregional dynamics for inclusion number, size and distribution with subcellular resolution. We used viral-mediated suppression of total HTT in the striatum of zQ175 mice as an example of a therapeutically-relevant but heterogeneously transducing strategy to demonstrate successful application of this platform to quantitatively assess target engagement and outcome on a cellular basis. 相似文献
24.
25.
26.
Charlotte E Page Shaun Smale Sara M Carty Nicholas Amos Sarah N Lauder Rhian M Goodfellow Peter J Richards Simon A Jones Nicholas Topley Anwen S Williams 《Arthritis research & therapy》2010,12(2):R49
Introduction
The first few months after symptom onset represents a pathologically distinct phase in rheumatoid arthritis (RA). We used relevant experimental models to define the pathological role of interferon-γ (IFN-γ) during early inflammatory arthritis. 相似文献27.
28.
29.
Experiments designed to assess balance recovery in older adults often involve exposing participants to repeated loss of balance. The purpose of this study was to investigate the adaptive balance recovery response exhibited by older adults following repeated exposure to forward loss of balance induced by releasing participants from a static forward lean angle. Fifty-eight healthy, community-dwelling older adults, aged 65-80 years, participated in the study. Participants were instructed to attempt to recover with a single step and performed four trials at each of three lean angles. Adaptive recovery responses at four events (cable release, toe-off of the stepping foot, foot contact and maximum knee flexion angle following landing in the stepping leg) were quantified for trials performed at the intermediate lean angle using the concept of margin of stability. The antero-posterior and medio-lateral margin of stability were computed as the difference between the velocity-adjusted position of the whole body centre of mass and the corresponding anterior or lateral boundary of the base of support. Across repeated trials adaptations in reactive stepping responses were detected that resulted in improved antero-posterior stability at foot contact and maximum knee flexion angle. Improved antero-posterior stability following repeated trials was explained by more effective control of the whole body centre of mass during the reactive stepping response and not by adjustments in step timing or base of support. The observed adaptations occurred within a single testing session and need to be considered in the design of balance recovery experiments. 相似文献
30.
Joseph HA Vissers Francesco Nicassio Maarten van Lohuizen Pier Paolo Di Fiore Elisabetta Citterio 《Cell division》2008,3(1):1-14
Increasing knowledge on the cell cycle deregulations in cancers has promoted the introduction of phytochemicals, which can either modulate signaling pathways leading to cell cycle regulation or directly alter cell cycle regulatory molecules, in cancer therapy. Most human malignancies are driven by chromosomal translocations or other genetic alterations that directly affect the function of critical cell cycle proteins such as cyclins as well as tumor suppressors, e.g., p53. In this respect, cell cycle regulation and its modulation by curcumin are gaining widespread attention in recent years. Extensive research has addressed the chemotherapeutic potential of curcumin (diferuloylmethane), a relatively non-toxic plant derived polyphenol. The mechanisms implicated are diverse and appear to involve a combination of cell signaling pathways at multiple levels. In the present review we discuss how alterations in the cell cycle control contribute to the malignant transformation and provide an overview of how curcumin targets cell cycle regulatory molecules to assert anti-proliferative and/or apoptotic effects in cancer cells. The purpose of the current article is to present an appraisal of the current level of knowledge regarding the potential of curcumin as an agent for the chemoprevention of cancer via an understanding of its mechanism of action at the level of cell cycle regulation. Taken together, this review seeks to summarize the unique properties of curcumin that may be exploited for successful clinical cancer prevention. 相似文献