全文获取类型
收费全文 | 509篇 |
免费 | 42篇 |
出版年
2021年 | 7篇 |
2019年 | 9篇 |
2018年 | 6篇 |
2017年 | 6篇 |
2016年 | 6篇 |
2015年 | 16篇 |
2014年 | 10篇 |
2013年 | 24篇 |
2012年 | 13篇 |
2011年 | 24篇 |
2010年 | 17篇 |
2009年 | 13篇 |
2008年 | 15篇 |
2007年 | 12篇 |
2006年 | 8篇 |
2005年 | 5篇 |
2004年 | 17篇 |
2003年 | 13篇 |
2002年 | 12篇 |
2001年 | 15篇 |
2000年 | 10篇 |
1999年 | 10篇 |
1998年 | 8篇 |
1997年 | 5篇 |
1996年 | 7篇 |
1995年 | 7篇 |
1993年 | 7篇 |
1992年 | 11篇 |
1991年 | 13篇 |
1990年 | 6篇 |
1989年 | 8篇 |
1988年 | 10篇 |
1987年 | 10篇 |
1986年 | 16篇 |
1985年 | 11篇 |
1984年 | 9篇 |
1983年 | 10篇 |
1982年 | 6篇 |
1979年 | 12篇 |
1978年 | 9篇 |
1977年 | 8篇 |
1976年 | 7篇 |
1975年 | 5篇 |
1974年 | 8篇 |
1970年 | 7篇 |
1969年 | 5篇 |
1967年 | 4篇 |
1966年 | 4篇 |
1965年 | 4篇 |
1961年 | 4篇 |
排序方式: 共有551条查询结果,搜索用时 27 毫秒
51.
Daniel A. Bachovchin Monique R. Wolfe Kim Masuda Steven J. Brown Timothy P. Spicer Virneliz Fernandez-Vega Peter Chase Peter S. Hodder Hugh Rosen Benjamin F. Cravatt 《Bioorganic & medicinal chemistry letters》2010,20(7):2254-2258
We recently described a fluorescence polarization platform for competitive activity-based protein profiling (fluopol-ABPP) that enables high-throughput inhibitor screening for enzymes with poorly characterized biochemical activity. Here, we report the discovery of a class of oxime ester inhibitors for the unannotated serine hydrolase RBBP9 from a full-deck (200,000+ compound) fluopol-ABPP screen conducted in collaboration with the Molecular Libraries Screening Center Network (MLSCN). We show that these compounds covalently inhibit RBBP9 by modifying enzyme’s active site serine nucleophile and, based on competitive ABPP in cell and tissue proteomes, are selective for RBBP9 relative to other mammalian serine hydrolases. 相似文献
52.
Alarm substances elicit behavioural responses in a wide range of animals but effects on early embryonic development are virtually unknown. Here we investigated whether skin injury-induced alarm substances caused physiological responses in embryos produced by two Danio species (Danio rerio and Danio albolineatus). Both species showed more rapid physiological development in the presence of alarm substance, although there were subtle differences between them: D. rerio had advanced muscle contraction and heart function, whereas D. albolineatus had advanced heart function only. Hence, alarm cues from injured or dying fish may be of benefit to their offspring, inducing physiological responses and potentially increasing their inclusive fitness. 相似文献
53.
Jennifer MP Woo Zhuofeng Lin Mohamad Navab Casey Van Dyck Yvette Trejo-Lopez Krystal MT Woo Hongyun Li Lawrence W Castellani Xuping Wang Noriko Iikuni Ornella J Rullo Hui Wu Antonio La Cava Alan M Fogelman Aldons J Lusis Betty P Tsao 《Arthritis research & therapy》2010,12(3):R93
Introduction
The purpose of this study was to evaluate the effects of L-4F, an apolipoprotein A-1 mimetic peptide, alone or with pravastatin, in apoE-/-Fas-/-C57BL/6 mice that spontaneously develop immunoglobulin G (IgG) autoantibodies, glomerulonephritis, osteopenia, and atherosclerotic lesions on a normal chow diet.Methods
Female mice, starting at eight to nine weeks of age, were treated for 27 weeks with 1) pravastatin, 2) L-4F, 3) L-4F plus pravastatin, or 4) vehicle control, followed by disease phenotype assessment.Results
In preliminary studies, dysfunctional, proinflammatory high-density lipoproteins (piHDL) were decreased six hours after a single L-4F, but not scrambled L-4F, injection in eight- to nine-week old mice. After 35 weeks, L-4F-treated mice, in the absence/presence of pravastatin, had significantly smaller lymph nodes and glomerular tufts (PL, LP < 0.05), lower serum levels of IgG antibodies to double stranded DNA (dsDNA) (PL < 0.05) and oxidized phospholipids (oxPLs) (PL, LP < 0.005), and elevated total and vertebral bone mineral density (PL, LP < 0.01) compared to vehicle controls. Although all treatment groups presented larger aortic root lesions compared to vehicle controls, enlarged atheromas in combination treatment mice had significantly less infiltrated CD68+ macrophages (PLP < 0.01), significantly increased mean α-actin stained area (PLP < 0.05), and significantly lower levels of circulating markers for atherosclerosis progression, CCL19 (PL, LP < 0.0005) and VCAM-1 (PL < 0.0002).Conclusions
L-4F treatment, alone or with pravastatin, significantly reduced IgG anti-dsDNA and IgG anti-oxPLs, proteinuria, glomerulonephritis, and osteopenia in a murine lupus model of accelerated atherosclerosis. Despite enlarged aortic lesions, increased smooth muscle content, decreased macrophage infiltration, and decreased pro-atherogenic chemokines in L-4F plus pravastatin treated mice suggest protective mechanisms not only on lupus-like disease, but also on potential plaque remodeling in a murine model of systemic lupus erythematosus (SLE) and accelerated atherosclerosis. 相似文献54.
The phylogenetic relationships in an endemic group of Malagasy 'assassin spiders' (Araneae, Archaeidae: Eriauchenius) called the gracilicollis group, are inferred from mitochondrial 12S, 16S and COI DNA sequence data. Archaeid spiders of Madagascar have evolved varying degrees of elongation in the cephalic area. These molecular data support the monophyly of the gracilicollis group. The evolution of the cephalic area is examined by performing an ancestral character reconstruction on this character, which reveals that the cephalic area is elongating independently. The biogeography of the gracilicollis group reveals an east-west split of the clade on Madagascar. 相似文献
55.
Molecular architecture of the ribosome‐bound Hepatitis C Virus internal ribosomal entry site RNA
下载免费PDF全文
![点击此处可从《The EMBO journal》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Justus Loerke Jochen Ismer Andrea Schmidt Tarek Hilal Thiemo Sprink Kaori Yamamoto Thorsten Mielke Jörg Bürger Tanvir R Shaikh Marylena Dabrowski Peter W Hildebrand Patrick Scheerer Christian MT Spahn 《The EMBO journal》2015,34(24):3042-3058
Internal ribosomal entry sites (IRESs) are structured cis‐acting RNAs that drive an alternative, cap‐independent translation initiation pathway. They are used by many viruses to hijack the translational machinery of the host cell. IRESs facilitate translation initiation by recruiting and actively manipulating the eukaryotic ribosome using only a subset of canonical initiation factor and IRES transacting factors. Here we present cryo‐EM reconstructions of the ribosome 80S‐ and 40S‐bound Hepatitis C Virus (HCV) IRES. The presence of four subpopulations for the 80S•HCV IRES complex reveals dynamic conformational modes of the complex. At a global resolution of 3.9 Å for the most stable complex, a derived atomic model reveals a complex fold of the IRES RNA and molecular details of its interaction with the ribosome. The comparison of obtained structures explains how a modular architecture facilitates mRNA loading and tRNA binding to the P‐site. This information provides the structural foundation for understanding the mechanism of HCV IRES RNA‐driven translation initiation. 相似文献
56.
Jian Yang Robert A. Spicer Teresa E. V. Spicer Nan Crystal Arens Frédéric M. B. Jacques Tao Su Elizabeth M. Kennedy Alexei B. Herman David C. Steart Gaurav Srivastava Rakesh C. Mehrotra Paul J. Valdes Naresh C. Mehrotra Zhe‐Kun Zhou Jiang‐Shan Lai 《Global Ecology and Biogeography》2015,24(10):1113-1125
57.
Shao L Ma J Wang F Malcolm SC Hewitt MC Campbell UC Spicer NA Hardy LW Schreiber R Spear KL Varney MA 《Bioorganic & medicinal chemistry letters》2011,21(1):520-523
The present work describes a series of novel tetrahydroquinoline amines that potently inhibit the in vitro reuptake of serotonin and dopamine (dual reuptake inhibitors). The compounds are structurally related to a series we disclosed previously, but are improved with respect to cytochrome P-450 enzyme (CYP) and potassium ion channel Kv11.1 (hERG) inhibition and synthetic accessibility. The detailed synthesis and in vitro activity and ADME profile of the compounds is described, which represent a previously undisclosed dual reuptake inhibitor chemotype. 相似文献
58.
Lyons DM Huttunen KM Browne KA Ciccone A Trapani JA Denny WA Spicer JA 《Bioorganic & medicinal chemistry》2011,19(13):4091-4100
A high throughput screen showed the ability of a 1-amino-2,4-dicyanopyrido[1,2-a]benzimidazole analogue to directly inhibit the lytic activity of the pore-forming protein perforin. A series of analogues were prepared to study structure-activity relationships (SAR) for the this activity, either directly added to cells or released in situ by KHYG-1 NK cells, at non-toxic concentrations. These studies showed that the pyridobenzimidazole moiety was required for effective activity, with strongly basic centres disfavoured. This class of compounds was relatively unaffected by the addition of serum, which was not the case for a previous class of direct inhibitors. 相似文献
59.
Sicard A Semblat JP Doerig C Hamelin R Moniatte M Dorin-Semblat D Spicer JA Srivastava A Retzlaff S Heussler V Waters AP Doerig C 《Cellular microbiology》2011,13(6):836-845
Merozoites of malaria parasites invade red blood cells (RBCs), where they multiply by schizogony, undergoing development through ring, trophozoite and schizont stages that are responsible for malaria pathogenesis. Here, we report that a protein kinase-mediated signalling pathway involving host RBC PAK1 and MEK1, which do not have orthologues in the Plasmodium kinome, is selectively stimulated in Plasmodium falciparum-infected (versus uninfected) RBCs, as determined by the use of phospho-specific antibodies directed against the activated forms of these enzymes. Pharmacological interference with host MEK and PAK function using highly specific allosteric inhibitors in their known cellular IC50 ranges results in parasite death. Furthermore, MEK inhibitors have parasiticidal effects in vitro on hepatocyte and erythrocyte stages of the rodent malaria parasite Plasmodium berghei, indicating conservation of this subversive strategy in malaria parasites. These findings have profound implications for the development of novel strategies for antimalarial chemotherapy. 相似文献
60.
L Hackett L Theodosiou C Robson F Spicer R Lever 《Mental health in family medicine》2011,8(3):173-179
Background In a time of limited resources and the need for cohesive services, understanding levels of need and prevalence is key. Manchester has a diverse range of cultures and socio-economic groups; national data is valuable but not always representative of local need.Aim To assess the prevalence of mental health needs in secondary school pupils in Manchester.Method Parents and teachers in three secondary schools were invited to complete the Strengths and Difficulties Questionnaire (SDQ) and a tool examining unmet needs.Results Initially, 560 pupils were chosen. Having excluded families that opted out, 503 questionnaires were distributed. Teachers returned 200 questionnaires and parents returned 127. Higher than average levels of need were identified with teachers reporting that 18% of pupils scored abnormally on the SDQ. Parent rates were also higher than the national average at 13.4%.Discussion Parents and teachers wanted children to be seen at home and at school, the need for consultation and outreach from mental health into schools is emphasised. 相似文献