全文获取类型
收费全文 | 169篇 |
免费 | 9篇 |
出版年
2021年 | 2篇 |
2019年 | 2篇 |
2016年 | 3篇 |
2015年 | 7篇 |
2014年 | 8篇 |
2013年 | 8篇 |
2012年 | 7篇 |
2011年 | 10篇 |
2010年 | 14篇 |
2009年 | 9篇 |
2008年 | 4篇 |
2007年 | 7篇 |
2006年 | 1篇 |
2005年 | 4篇 |
2004年 | 5篇 |
2002年 | 3篇 |
2001年 | 13篇 |
2000年 | 2篇 |
1999年 | 3篇 |
1998年 | 3篇 |
1997年 | 2篇 |
1996年 | 2篇 |
1994年 | 3篇 |
1993年 | 4篇 |
1992年 | 4篇 |
1991年 | 3篇 |
1990年 | 2篇 |
1989年 | 4篇 |
1988年 | 2篇 |
1987年 | 2篇 |
1986年 | 1篇 |
1984年 | 3篇 |
1983年 | 4篇 |
1982年 | 3篇 |
1981年 | 5篇 |
1980年 | 1篇 |
1979年 | 4篇 |
1977年 | 1篇 |
1975年 | 2篇 |
1974年 | 1篇 |
1973年 | 1篇 |
1972年 | 1篇 |
1971年 | 2篇 |
1970年 | 2篇 |
1969年 | 3篇 |
1965年 | 1篇 |
排序方式: 共有178条查询结果,搜索用时 15 毫秒
21.
A potent thrombin inhibitor, [D-Phe45, Arg47] hirudin 45-65, that contains an active site-directed sequence D-Phe-Pro-Arg-Pro, an exosite specific fragment hirudin 55-65 (H55-65) and a linker portion hirudin 49-54, was designed based on the hirudin sequence [DiMaio et al. (1990) J. Biol. Chem., 265, 21698-21798]. A three-dimensional model of the complex between the B-chain of human thrombin and the inhibitor [D-Phe45, Arg47] hirudin 45-65 was constructed using molecular modelling starting from the X-ray C alpha coordinates of the thrombin-hirudin complex and the NMR-derived structure of the thrombin-bound hirudin 55-65. The contribution of the H49-54 fragment to the thrombin-inhibitor interaction was deduced by examining a series of analogs containing single glycine substitution and analogs with reduced number of residues within the linker. The results were consistent with the molecular modelling observations i.e. the H49-54 fragment serves the role of a spacer in the binding interaction and could be replaced by four glycine residues. The studies on the interaction of the exosite-directed portion of the inhibitor with thrombin using a series of synthetic H55-65 analogs demonstrated that residues AspH55 to ProH60 play a major role in binding to human thrombin where the side chains of PheH56, IleH59 and GluH57 showed critical contributions. Molecular modelling suggested that these side chains may contribute to inter- and intramolecular hydrophobic and electrostatic interactions, respectively. 相似文献
22.
Z Szewczuk P Buczek P Stefanowicz K Krajewski Z Wieczorek I Z Siemion 《Acta biochimica Polonica》2001,48(1):121-130
Our previous studies showed that the nonapeptide fragment of HLA-DQ of the sequence H-Thr-Pro-Gln-Arg-Gly-Asp-Val-Tyr-Thr-OH, located in the beta164-172 loop, strongly suppresses the humoral and cellular immune responses, while its shorter analogs, H-Arg-Gly-Asp-Val-OH, H-Arg-Gly-Asp-Val-Tyr-OH and H-Gln-Arg-Gly-Asp-Val-Tyr-OH show only a weak stimulatory activity in respect to the humoral immunological response. These fragments contain the Arg-Gly-Asp (RGD) sequence, known for its importance for cellular association phenomena. Based on the crystal structure of HLA-DR1, we also designed and synthesized a cyclic analog H-Cys-Arg-Gly-Asp-Val-Tyr-Cys-OH with restricted conformation, which strongly suppresses the immune response and selectively inhibits the alphavbeta3 integrin, suggesting that the mechanism of the immunosuppressory action of the peptide is associated with inhibition of the integrin. In this paper we present the design and synthesis of the cyclodimeric peptide, Arg-Gly-Asp-Arg-Gly-Asp, which is also known as a selective alphavbeta3 inhibitor. The synthesized peptide strongly suppresses both the humoral and cellular immune response. The results support our hypothesis that the immunomodulatory activity of HLA-DQ fragments may be connected with their interactions with some particular integrins on the cell surface. 相似文献
23.
A total of 65 yeast strains were screened for their ability to grow and ferment lactose in a standard DURHAM tube test at 30 °C. Based on the kinetic parameters for lactose and whey lactose fermentations in shake flask cultures, the strain Candida psedotropicalis 65 was chosen for further studies. Some of the cultural parameters affecting ethanolic fermentations on lactose were standardized. At an initial lactose concentration of 100–120 g/l in the medium containing concentrated whey or lactose, at 40 °C and within 48 h, the selected strain reached an ethanol concentration of 41–59 g/l, an ethanol productivity of 1.3–3.0 g/l/h, a lactose consumption of 99%, an ethanol yield 0.4–0.49 g/g and a biomass yield of 0.027 g/g. 相似文献
24.
The use of penicillocarboxypeptidase-S1 in amino acid sequencing 总被引:2,自引:0,他引:2
A Hui L Rao A Kurosky A Jones S R Jones G Mains J W Dixon A Szewczuk T Hofmann 《Archives of biochemistry and biophysics》1974,160(2):577-587
25.
26.
Recruitment of TBK1 to cytosol‐invading Salmonella induces WIPI2‐dependent antibacterial autophagy 下载免费PDF全文
Teresa LM Thurston Keith B Boyle Mark Allen Benjamin J Ravenhill Maryia Karpiyevich Stuart Bloor Annie Kaul Jessica Noad Agnes Foeglein Sophie A Matthews David Komander Mark Bycroft Felix Randow 《The EMBO journal》2016,35(16):1779-1792
Mammalian cells deploy autophagy to defend their cytosol against bacterial invaders. Anti‐bacterial autophagy relies on the core autophagy machinery, cargo receptors, and “eat‐me” signals such as galectin‐8 and ubiquitin that label bacteria as autophagy cargo. Anti‐bacterial autophagy also requires the kinase TBK1, whose role in autophagy has remained enigmatic. Here we show that recruitment of WIPI2, itself essential for anti‐bacterial autophagy, is dependent on the localization of catalytically active TBK1 to the vicinity of cytosolic bacteria. Experimental manipulation of TBK1 recruitment revealed that engagement of TBK1 with any of a variety of Salmonella‐associated “eat‐me” signals, including host‐derived glycans and K48‐ and K63‐linked ubiquitin chains, suffices to restrict bacterial proliferation. Promiscuity in recruiting TBK1 via independent signals may buffer TBK1 functionality from potential bacterial antagonism and thus be of evolutionary advantage to the host. 相似文献
27.
Łukasz Jaremko Mariusz Jaremko Paweł Pasikowski Marek Cebrat Piotr Stefanowicz Marek Lisowski Jolanta Artym Michał Zimecki Igor Zhukov Zbigniew Szewczuk 《Biopolymers》2009,91(6):423-431
Recently, ubiquitin was suggested as a promising anti‐inflammatory protein therapeutic. We found that a peptide fragment corresponding to the ubiquitin50–59 sequence (LEDGRTLSDY) possessed the immunosuppressive activity comparable with that of ubiquitin. CD and NMR spectroscopies were used to determine the conformational preferences of LEDGRTLSDY in solution. The peptide mixture, obtained by pepsin digestion of ubiquitin, was even more potent than the intact protein. Although the peptide exhibited a well‐defined conformation in methanol, its structure was distinct from the corresponding 50–59 fragment in the native ubiquitin molecule. © 2009 Wiley Periodicals, Inc. Biopolymers 91: 423–431, 2009. This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com 相似文献
28.
Dependence of pathogen molecule-induced Toll-like receptor activation and cell function on Neu1 sialidase 总被引:1,自引:0,他引:1
Schammim Ray Amith Preethi Jayanth Susan Franchuk Sarah Siddiqui Volkan Seyrantepe Katrina Gee Sameh Basta Rudi Beyaert Alexey V. Pshezhetsky Myron R. Szewczuk 《Glycoconjugate journal》2009,26(9):1197-1212
The signaling pathways of mammalian Toll-like receptors (TLR) are well characterized, but the initial molecular mechanisms activated following ligand interactions with the receptors remain poorly defined. Here, we show a membrane controlling mechanism that is initiated by ligand binding to TLR-2, -3 and-4 to induce Neu1 sialidase activity within minutes in live primary bone marrow (BM) macrophage cells and macrophage and dendritic cell lines. Central to this process is that Neu1 and not Neu2,-3 and-4 forms a complex with TLR-2,-3 and-4 on the cell surface of naïve macrophage cells. Neuraminidase inhibitors BCX1827, 2-deoxy-2,3-dehydro-N-acetylneuraminic acid (DANA), zanamivir and oseltamivir carboxylate have a limited significant inhibition of the LPS-induced sialidase activity in live BMC-2 macrophage cells but Tamiflu (oseltamivir phosphate) completely blocks this activity. Tamiflu inhibits LPS-induced sialidase activity in live BMC-2 cells with an IC50 of 1.2?μM compared to an IC50 of 1015?μM for its hydrolytic metabolite oseltamivir carboxylate. Tamiflu blockage of LPS-induced Neu1 sialidase activity is not affected in BMC-2 cells pretreated with anticarboxylesterase agent clopidogrel. Endotoxin LPS binding to TLR4 induces Neu1 with subsequent activation of NFκB and the production of nitric oxide and pro-inflammatory IL-6 and TNFα cytokines in primary and macrophage cell lines. Hypomorphic cathepsin A mice with a secondary Neu1 deficiency respond poorly to LPS-induced pro-inflammatory cytokines compared to the wild-type or hypomorphic cathepsin A with normal Neu1 mice. Our findings establish an unprecedented mechanism for pathogen molecule-induced TLR activation and cell function, which is critically dependent on Neu1 sialidase activity associated with TLR ligand treated live primary macrophage cells and macrophage and dendritic cell lines. 相似文献
29.
Emily HM Wong David K Smith Raul Rabadan Malik Peiris Leo LM Poon 《BMC evolutionary biology》2010,10(1):253
Background
The influenza A virus is an important infectious cause of morbidity and mortality in humans and was responsible for 3 pandemics in the 20th century. As the replication of the influenza virus is based on its host's machinery, codon usage of its viral genes might be subject to host selection pressures, especially after interspecies transmission. A better understanding of viral evolution and host adaptive responses might help control this disease. 相似文献30.
Schammim R. Amith Preethi Jayanth Trisha Finlay Susan Franchuk Alanna Gilmour Samar Abdulkhalek Myron R. Szewczuk 《Journal of visualized experiments : JoVE》2010,(43)
Mammalian Toll-like receptors (TLRs) are a family of receptors that recognize pathogen-associated molecular patterns. Not only are TLRs crucial sensors of microbial (e.g., viruses, bacteria and parasite) infections, they also play an important role in the pathophysiology of infectious diseases, inflammatory diseases, and possibly in autoimmune diseases. Thus, the intensity and duration of TLR responses against infectious diseases must be tightly controlled. It follows that understanding the structural integrity of sensor receptors, their ligand interactions and signaling components is essential for subsequent immunological protection. It would also provide important opportunities for disease modification through sensor manipulation. Although the signaling pathways of TLR sensors are well characterized, the parameters controlling interactions between the sensors and their ligands still remain poorly defined. We have recently identified a novel mechanism of TLR activation by its natural ligand, which has not been previously observed 1,2. It suggests that ligand-induced TLR activation is tightly controlled by Neu1 sialidase activation. We have also reported that Neu1 tightly regulates neurotrophin receptors like TrkA and TrkB 3, which involve Neu1 and matrix metalloproteinase-9 (MMP-9) cross-talk in complex with the receptors 4. The sialidase assay has been initially use to find a novel ligand, thymoquinone, in the activation of Neu4 sialidase on the cell surface of macrophages, dendritic cells and fibroblast cells via GPCR Gαi proteins and MMP-9 5. For TLR receptors, our data indicate that Neu1 sialidase is already in complex with TLR-2, -3 and -4 receptors, and is induced upon ligand binding to either receptor. Activated Neu1 sialidase hydrolyzes sialyl α-2,3-linked β-galactosyl residues distant from ligand binding to remove steric hinderance to TLR-4 dimerization, MyD88/TLR4 complex recruitment, NFkB activation and pro-inflammatory cell responses. In a collaborative report, Neu1 sialidase has been shown to regulate phagocytosis in macrophage cells 6. Taken together, the sialidase assay has provided us with powerful insights to the molecular mechanisms of ligand-induced receptor activation. Although the precise relationship between Neu1 sialidase and the activation of TLR, Trk receptors has yet to be fully elucidated, it would represent a new or pioneering approach to cell regulation pathways.Download video file.(57M, mov) 相似文献