全文获取类型
收费全文 | 1993篇 |
免费 | 189篇 |
国内免费 | 2篇 |
出版年
2023年 | 5篇 |
2022年 | 15篇 |
2021年 | 46篇 |
2020年 | 23篇 |
2019年 | 21篇 |
2018年 | 43篇 |
2017年 | 31篇 |
2016年 | 60篇 |
2015年 | 85篇 |
2014年 | 103篇 |
2013年 | 126篇 |
2012年 | 187篇 |
2011年 | 146篇 |
2010年 | 88篇 |
2009年 | 104篇 |
2008年 | 128篇 |
2007年 | 120篇 |
2006年 | 124篇 |
2005年 | 131篇 |
2004年 | 98篇 |
2003年 | 112篇 |
2002年 | 97篇 |
2001年 | 23篇 |
2000年 | 21篇 |
1999年 | 16篇 |
1998年 | 38篇 |
1997年 | 23篇 |
1996年 | 24篇 |
1995年 | 21篇 |
1994年 | 15篇 |
1993年 | 17篇 |
1992年 | 11篇 |
1991年 | 11篇 |
1990年 | 10篇 |
1989年 | 6篇 |
1988年 | 7篇 |
1987年 | 3篇 |
1986年 | 3篇 |
1985年 | 3篇 |
1984年 | 5篇 |
1983年 | 2篇 |
1981年 | 3篇 |
1979年 | 2篇 |
1978年 | 3篇 |
1977年 | 6篇 |
1976年 | 2篇 |
1972年 | 4篇 |
1968年 | 1篇 |
1966年 | 3篇 |
1959年 | 1篇 |
排序方式: 共有2184条查询结果,搜索用时 734 毫秒
171.
Bommarius B Maxwell D Swimm A Leung S Corbett A Bornmann W Kalman D 《Molecular microbiology》2007,63(6):1748-1768
Enteropathogenic Escherichia coli (EPEC) cause intestinal inflammation, severe diarrhoea and mortality, particularly among children in developing nations. Upon attachment to intestinal epithelial cells, EPEC induces actin-filled membrane protrusions called 'pedestals' and disrupts microvilli to form attaching and effacing (A/E) lesions. EPEC also disrupts epithelial barrier function and causes colitis. Here we have investigated how virulence factors which orchestrate formation of actin pedestals interface with host tyrosine kinases. We show that Tec-family tyrosine kinases localize beneath EPEC and, with Abl-family kinases, comprise a set of redundant host kinases utilized by EPEC to form actin pedestals. We also show that Tir, a virulence factor required for pathogenesis, contains a polyproline region (PPR) that interacts with SH3 domains of redundant kinases, and a phosphorylation site (Y474) that interacts with kinase SH2 domains. These interactions are essential for pedestal formation, and mimic activation of kinases by cellular ligands. Our results suggest that a positive feedback loop exists in which initial phosphorylation of Tir on Y474 by tyrosine kinases causes recruitment of additional redundant kinases via PPR-SH3 interactions and PO(3)-Y474-SH2 interactions, which in turn phosphorylate other Tir molecules as well as proteins that catalyse formation of actin pedestals. 相似文献
172.
An experimental test of the symbiosis specificity between the ciliate Paramecium bursaria and strains of the unicellular green alga Chlorella 总被引:1,自引:0,他引:1
The ciliate Paramecium bursaria living in mutualistic relationship with the unicellular green alga Chlorella is known to be easily infected by various potential symbionts/parasites such as bacteria, yeasts and other algae. Permanent symbiosis, however, seems to be restricted to Chlorella taxa. To test the specificity of this association, we designed infection experiments with two aposymbiotic P. bursaria strains and Chlorella symbionts isolated from four Paramecium strains, seven other ciliate hosts and two Hydra strains, as well as three free-living Chlorella species. Paramecium bursaria established stable symbioses with all tested Chlorella symbionts of ciliates, but never with symbiotic Chlorella of Hydra viridissima or with free-living Chlorella. Furthermore, we tested the infection specificity of P. bursaria with a 1:1:1 mixture of three compatible Chlorella strains, including the native symbiont, and then identified the strain of the newly established symbiosis by sequencing the internal transcribed spacer region 1 of the 18S rRNA gene. The results indicated that P. bursaria established symbiosis with its native symbiont. We conclude that despite clear preferences for their native Chlorella, the host-symbiont relationship in P. bursaria is flexible. 相似文献
173.
Molecular basis for the functional interaction of dynein light chain with the nuclear-pore complex 总被引:1,自引:0,他引:1
Stelter P Kunze R Flemming D Höpfner D Diepholz M Philippsen P Böttcher B Hurt E 《Nature cell biology》2007,9(7):788-796
Nucleocytoplasmic transport occurs through nuclear pore complexes (NPCs) embedded in the nuclear envelope. Here, we discovered an unexpected role for yeast dynein light chain (Dyn2) in the NPC. Dyn2 is a previously undescribed nucleoporin that functions as molecular glue to dimerize and stabilize the Nup82-Nsp1-Nup159 complex, a module of the cytoplasmic pore filaments. Biochemical analyses showed that Dyn2 binds to a linear motif (termed DID(Nup159)) inserted between the Phe-Gly repeat and coiled-coil domain of Nup159. Electron microscopy revealed that the reconstituted Dyn2-DID(Nup159) complex forms a rigid rod-like structure, in which five Dyn2 homodimers align like 'pearls on a string' between two extented DID(Nup159) strands. These findings imply that the rigid 20 nm long Dyn2-DID(Nup159) filament projects the Nup159 Phe-Gly repeats from the Nup82 module. Thus, it is possible that dynein light chain plays a role in organizing natively unfolded Phe-Gly repeats within the NPC scaffold to facilitate nucleocytoplasmic transport. 相似文献
174.
The etiology of osteoarthritis is multifactorial, with inflammatory, metabolic, and mechanical causes. Pain in osteoarthritis
is initiated by mild intra-articular inflammation and degeneration of articular cartilage and subchondral bone. The principle
of treatment with acetaminophen or non-steroidal anti-inflammatory drugs is to reduce pain and improve joint function. Recently,
animal models for osteoarthritic pain behavior have been established. The most frequently used rat model for analyzing properties
of drugs on the pathology of osteoarthritis is the injection of the metabolic inhibitor monosodium iodoacetate into the joint,
which inhibits the activity of glyceraldehyde-3-phosphate dehydrogenase in chondrocytes. Here, we characterize the effect
on pain behavior of lacosamide, a member of a family of functionalized amino acids that are analogues of endogenous amino
acids and D-serine, in the monosodium iodoacetate rat model for osteoarthritis in comparison to diclofenac and morphine. Lacosamide
(3, 10, and 30 mg/kg) was able to reduce secondary mechanical allodynia and hyperalgesia similarly to morphine (3 mg/kg).
In contrast, diclofenac (30 mg/kg) was only effective in reducing secondary mechanical hyperalgesia. During the first week,
pain is induced mainly by inflammation in the iodoacetate model, but afterwards inflammation plays only a minor role in pain.
Lacosamide was able to inhibit pain at days 3, 7 and 14 after induction of arthritis. This shows that lacosamide is able to
reduce pain behavior induced by multiple mechanisms in animals. 相似文献
175.
The protease domain of procollagen C-proteinase (BMP1) lacks substrate selectivity, which is conferred by non-proteolytic domains 总被引:1,自引:0,他引:1
Wermter C Höwel M Hintze V Bombosch B Aufenvenne K Yiallouros I Stöcker W 《Biological chemistry》2007,388(5):513-521
Procollagen C-proteinase (PCP) removes the C-terminal pro-peptides of procollagens and also processes other matrix proteins. The major splice form of the PCP is termed BMP1 (bone morphogenetic protein 1). Active BMP1 is composed of an astacin-like protease domain, three CUB (complement, sea urchin Uegf, BMP1) domains and one EGF-like domain. Here we compare the recombinant human full-length BMP1 with its isolated proteolytic domain to further unravel the functional influence of the CUB and EGF domains. We show that the protease domain alone cleaves truncated procollagen VII within the short telopeptide region into fragments of similar size as the full-length enzyme does. However, unlike full-length BMP1, the protease domain does not stop at this point, but degrades its substrate completely. Moreover, the protease domain cleaves other matrix proteins such as fibronectin, collagen I and collagen IV, which are left intact by the full-length enzyme. In addition, we show for the first time that thrombospondin-1 is differently cleaved by both BMP1 and its catalytic domain. In summary, our data support the concept that the C-terminal domains of BMP1 are important for substrate recognition and for controlling and restricting its proteolytic activity via exosite binding. 相似文献
176.
177.
Baskal Svetlana Beckmann Bibiana Stahmer Laura Peter Corinna Bohnhorst Bettina Das Anibh Martin Tsikas Dimitrios 《Amino acids》2022,54(12):1611-1619
Amino Acids - We measured free and proteinic concentrations of native and modified amino acids from post-translational modifications (PTMs) and correlated them with the activity of SIRT1 and SIRT3... 相似文献
178.
Hanjiang Yang Felix Christof Wahlmüller Bettina Sarg Margareta Furtmüller Margarethe Geiger 《The Journal of biological chemistry》2015,290(5):3081-3091
Protein C inhibitor (PCI) is a serpin with broad protease reactivity. It binds glycosaminoglycans and certain phospholipids that can modulate its inhibitory activity. PCI can penetrate through cellular membranes via binding to phosphatidylethanolamine. The exact mechanism of PCI internalization and the intracellular role of the serpin are not well understood. Here we showed that testisin, a glycosylphosphatidylinositol-anchored serine protease, cleaved human PCI and mouse PCI (mPCI) at their reactive sites as well as at sites close to their N terminus. This cleavage was observed not only with testisin in solution but also with cell membrane-anchored testisin on U937 cells. The cleavage close to the N terminus released peptides rich in basic amino acids. Synthetic peptides corresponding to the released peptides of human PCI (His1–Arg11) and mPCI (Arg1–Ala18) functioned as cell-penetrating peptides. Because intact mPCI but not testisin-cleaved mPCI was internalized by Jurkat T cells, a truncated mPCI mimicking testisin-cleaved mPCI was created. The truncated mPCI lacking 18 amino acids at the N terminus was not taken up by Jurkat T cells. Therefore our model suggests that testisin or other proteases could regulate the internalization of PCI by removing its N terminus. This may represent one of the mechanisms regulating the intracellular functions of PCI. 相似文献
179.
Magdalena Chojnacka Agnieszka Gornicka Silke Oeljeklaus Bettina Warscheid Agnieszka Chacinska 《The Journal of biological chemistry》2015,290(24):15304-15312
The mitochondrial contact site and cristae organizing system (MICOS) is a recently discovered protein complex that is crucial for establishing and maintaining the proper inner membrane architecture and contacts with the outer membrane of mitochondria. The ways in which the MICOS complex is assembled and its integrity is regulated remain elusive. Here, we report a direct link between Cox17, a protein involved in the assembly of cytochrome c oxidase, and the MICOS complex. Cox17 interacts with Mic60, thereby modulating MICOS complex integrity. This interaction does not involve Sco1, a partner of Cox17 in transferring copper ions to cytochrome c oxidase. However, the Cox17-MICOS interaction is regulated by copper ions. We propose that Cox17 is a newly identified factor involved in maintaining the architecture of the MICOS complex. 相似文献