全文获取类型
收费全文 | 1611篇 |
免费 | 73篇 |
国内免费 | 2篇 |
专业分类
1686篇 |
出版年
2023年 | 4篇 |
2022年 | 13篇 |
2021年 | 16篇 |
2020年 | 10篇 |
2019年 | 19篇 |
2018年 | 16篇 |
2017年 | 34篇 |
2016年 | 27篇 |
2015年 | 52篇 |
2014年 | 68篇 |
2013年 | 117篇 |
2012年 | 90篇 |
2011年 | 91篇 |
2010年 | 72篇 |
2009年 | 79篇 |
2008年 | 116篇 |
2007年 | 98篇 |
2006年 | 104篇 |
2005年 | 99篇 |
2004年 | 111篇 |
2003年 | 97篇 |
2002年 | 95篇 |
2001年 | 8篇 |
2000年 | 9篇 |
1999年 | 12篇 |
1998年 | 19篇 |
1997年 | 17篇 |
1996年 | 15篇 |
1995年 | 8篇 |
1994年 | 13篇 |
1993年 | 24篇 |
1992年 | 12篇 |
1991年 | 8篇 |
1990年 | 11篇 |
1989年 | 15篇 |
1988年 | 4篇 |
1987年 | 9篇 |
1986年 | 7篇 |
1985年 | 10篇 |
1984年 | 7篇 |
1983年 | 3篇 |
1982年 | 13篇 |
1981年 | 8篇 |
1980年 | 5篇 |
1978年 | 4篇 |
1977年 | 2篇 |
1974年 | 2篇 |
1971年 | 3篇 |
1970年 | 3篇 |
1965年 | 2篇 |
排序方式: 共有1686条查询结果,搜索用时 15 毫秒
91.
Kubota D Ishikawa M Yamamoto M Murakami S Hachisu M Katano K Ajito K 《Bioorganic & medicinal chemistry》2006,14(7):2089-2108
In order to generate novel compounds with integrin alpha(v)beta3-antagonistic activity together with antiplatelet activity, tricyclic pharmacophore-based molecules were designed and synthesized. Although piperazine-containing compounds initially prepared were selective alpha(IIb)beta3 antagonists, replacement of piperazine with piperidine furnished a potent alpha(v)beta3/alpha(IIb)beta3 dual antagonist. Structure-activity relationship (SAR) studies provided clues for further development of tricyclic pharmacophore-based integrin antagonists. 相似文献
92.
Population Ecology - Here we considered two fundamental questions in community ecology regarding the relationship between seasonal changes in community structure and environmental gradients: (i)... 相似文献
93.
Teruyo Ito Keiichi Hiramatsu Yoshihiro Ohshita Takeshi Yokota 《Microbiology and immunology》1993,37(4):281-288
In cultures of Vibrio cholerae strains of Ogawa serotype, variant strains which had undergone serotype conversion from Ogawa to Inaba were identified. The rfbT genes cloned from the parent strains were found to produce a 31-kDa protein in the maxicell system, and to cause serotype conversion when introduced into E. coli cells expressing Inaba serotype specificity. On the other hand, rfbT genes cloned from the variant strains neither produced the 31-kDa protein nor caused serotype conversion. Nucleotide sequence of these rfbT genes as well as those of two clinical Vibrio cholerae strains of Inaba serotype revealed that mutations causing premature termination of their rfbT genes were invariably present in strains expressing Inaba serotype specificity. The result strongly suggested that genetic alteration of the rfbT gene is responsible for serotype conversion of Vibrio cholerae O1. 相似文献
94.
Hiroshi Takashima Michiru Tanaka Yuko Hasegawa Keiichi Tsukahara 《Journal of biological inorganic chemistry》2003,8(5):499-506
We have designed and synthesized new optically active bisviologens ([BNMV](4+)) containing a binaphthyl moiety to examine the stereoselective photoinduced electron-transfer (ET) reactions with zinc-substituted myoglobin (ZnMb) by flash photolysis. The photoexcited triplet state of ZnMb, (3)(ZnMb)*, was successfully quenched by [BNMV](4+) ions to form the radical pair of a ZnMb cation (ZnMb(.+)) and a reduced viologen ([BNMV](.3+)), followed by a thermal ET reaction to the ground state. The rate constants ( k(q)) for the ET quenching at 25 degrees C were obtained as k(q)( R)=(2.9+/-0.2)x10(7) M(-1) s(-1) and k(q)( S)=(2.2+/-0.2)x10(7) M(-1) s(-1), respectively. The ratio of k(q)( R)/ k(q)( S)=1.3 indicates that the ( R)-isomer of the chiral viologen preferentially quenches (3)(ZnMb)*. On the other hand, the rate constants ( k) for the thermal ET reaction from [BNMV](.3+) to ZnMb(-+) at 25 degrees C were k( R)=(1.2+/-0.1)x10(8) M(-1) s(-1) and k( S)=(0.47+/-0.03)x10(8) M(-1) s(-1), respectively, and the ratio remarkably increased to k( R)/ k( S)=2.6. The activation parameters, Delta H(not equal) and Delta S(not equal), were determined from the kinetic measurements at various temperatures (10-30 degrees C) to understand the ET mechanisms. In the quenching reaction, the energy differences of Delta Delta H*(R- S) and T Delta Delta S*( R- S) at 25 degrees C were calculated to be -3.9+/-1.6 and -3.3+/-0.2 kJ mol(-1), respectively, whereas Delta Delta H*( R-S)=7.7+/-1.9 kJ mol(-1 )and T Delta Delta S*( R-S)=9.9+/-0.5 kJ mol(-1 )were found for the thermal ET reaction. Therefore, the thermal ET reaction to the ground state was proved to be dominated by the entropy term, and the large stereoselectivity may arise from the decrease in charge repulsion between donor and acceptor. 相似文献
95.
Two major glycoproteins of bovine peripheral nerve myelin were isolated from the acid-insoluble residue of the myelin by a procedure involving delipidation with chloroform/methanol (2:1, v/v) and chromatography on Sephadex G-200 column with a buffer containing sodium dodecyl sulfate. The separation patterns of the proteins on the gel were affected considerably by the dodecyl sulfate concentration in the elution buffer. At above 2% dodecyl sulfate concentration in the elution buffer, the glycoproteins could be separated clearly on the gel and were purified. The purified proteins, the BR protein (mol. wt. 28 000) and the PAS-II protein (mol. wt. 13 000), were homogeneous on dodecyl sulfate-polyacrylamide gel electrophoresis. The NH2-terminal amino acids of the BR and the PAS-II proteins were isoleucine and methionine, respectively. The BR protein contained glucosamine, mannose, galactose, fucose and sialic acids and the PAS-II protein contained glucosamine, mannose, galactose, fucose and glucose. Neither the BR protein nor the PAS-II were a glycosylated derivative of a basic protein of bovine peripheral nerve myelin, a deduction based on the results of amino acid analysis. The two major glycoproteins were observed commonly in the peripheral nerve myelin of cows, pigs, rabbits and guinea pigs, using dodecyl sulfate-polyacrylamide gel electrophoresis. 相似文献
96.
Daisuke Suzuki Keiichi Inoue Makoto Sakai Hideki Kandori Yuki Sudo 《Journal of molecular biology》2009,392(1):48-4922
Microbial organisms utilize light not only as energy sources but also as signals by which rhodopsins (containing retinal as a chromophore) work as photoreceptors. Sensory rhodopsin I (SRI) is a dual photoreceptor that regulates both negative and positive phototaxis in microbial organisms, such as the archaeon Halobacterium salinarum and the eubacterium Salinibacter ruber. These organisms live in highly halophilic environments, suggesting the possibility of the effects of salts on the function of SRI. However, such effects remain unclear because SRI proteins from H. salinarum (HsSRI) are unstable in dilute salt solutions. Recently, we characterized a new SRI protein (SrSRI) that is stable even in the absence of salts, thus allowing us to investigate the effects of salts on the photochemical properties of SRI. In this study, we report that the absorption maximum of SrSRI is shifted from 542 to 556 nm in a Cl−-dependent manner with a Km of 307 ± 56 mM, showing that Cl−-binding sites exist in SRI. The bathochromic shift was caused not only by NaCl but also by other salts (NaI, NaBr, and NaNO3), implying that I−, Br−, and NO3− can also bind to SrSRI. In addition, the photochemical properties during the photocycle are also affected by chloride ion binding. Mutagenesis studies strongly suggested that a conserved residue, His131, is involved in the Cl−-binding site. In light of these results, we discuss the effects of the Cl− binding to SRI and the roles of Cl− binding in its function. 相似文献
97.
98.
Kanei-Ishii C Nomura T Takagi T Watanabe N Nakayama KI Ishii S 《The Journal of biological chemistry》2008,283(45):30540-30548
The c-myb proto-oncogene product (c-Myb) is degraded in response to Wnt-1 signaling via a pathway involving TAK1 (transforming growth factor-beta-activated kinase 1), HIPK2 (homeodomain-interacting protein kinase 2), and NLK (Nemo-like kinase). NLK directly binds to c-Myb, which results in the phosphorylation of c-Myb at multiple sites, and induces its ubiquitination and proteasome-dependent degradation. Here, we report that Fbxw7, the F-box protein of an SCF complex, targets c-Myb for degradation in a Wnt-1- and NLK-dependent manner. Fbxw7alpha directly binds to c-Myb via its C-terminal WD40 domain and induces the ubiquitination of c-Myb in the presence of NLK in vivo and in vitro. The c-Myb phosphorylation site mutant failed to interact with Fbxw7alpha, suggesting that the c-Myb/Fbxw7alpha interaction is enhanced by NLK phosphorylation of c-Myb. Treatment of M1 cells with Fbxw7 small interfering RNA (siRNA) rescued the Wnt-induced c-Myb degradation and also the Wnt-induced inhibition of cell proliferation. NLK bound to Cul1, a component of the SCF complex, while HIPK2 interacted with both Fbxw7alpha and Cul1, suggesting that both kinases enhance the c-Myb/SCF interaction. In contrast to c-Myb, the v-myb gene product (v-Myb) encoded by the avian myeloblastosis virus was resistant to NLK/Fbxw7alpha-induced degradation. Thus, Fbxw7 is an E3 ubiquitin ligase of c-Myb, and the increased c-Myb levels may contribute, at least partly, to transformation induced by mutation of Fbxw7. 相似文献
99.
Keiichi Ito Jie Chen Tomohiko Asano E. Darracott Vaughan Dix P. Poppas Masamichi Hayakawa Diane Felsen 《Human cell》2008,17(1):17-28
Gene therapy directed to the kidney has been attempted to improve renal disorders such as inherited kidney diseases and common renal diseases that cause interstitial fibrosis, tubular atrophy, and glomerulosclerosis. Viral and non-viral vectors have been tried and been modulated to obtain sufficient transgene expression. However, gene delivery to the kidney is usually difficult because of characteristics of renal cell biology. Among non-viral vectors, the liposome system is a promising procedure for kidney-targeted gene therapy. Using cationic liposome, tubular cells were effectively transduced by retrograde injection of liposome/cDNA complex. Although transgene expression was reportedly modest using cationic liposomes, this method improved renal disease models such as carbonic anhydrase II deficiency and unilateral ureteral obstruction. In contrast, HVJ-liposome system is an effective transfection method to glomerular cells using intra-renal arterial infusion and improved glomerular disease models such as glomerulonephritis and glomerulosclerosis. In addition, intra-renal pelvic injection of DNA by HVJ-liposome system showed transgene expression in interstitial fibroblasts. In kidney-targeted gene therapy, liposome-mediated gene transfer is an attractive method because of its simplicity and reduced toxicity. In spite of modest transgene expression, several renal disease models were successfully modulated by liposome system. Although one limitation of liposome-mediated gene delivery is the duration of transgene expression, the liposome/cDNA complex can be repeatedly administered due to the absence of an immune response. 相似文献
100.
Takagaki K Iwafune M Kakizaki I Ishido K Kato Y Endo M 《The Journal of biological chemistry》2002,277(21):18397-18403
We previously found that endo-beta-xylosidase from Patinopecten is an endo-type glycosidase that cleaves the xylosyl serine linkage between a glycosaminoglycan chain and its core protein (Takagaki, K., Kon, A., Kawasaki, H., Nakamura, T., Tamura, S., and Endo, M. (1990) J. Biol. Chem. 265, 854-860). Screening for endo-beta-xylosidase activity in several cellulases detected this activity in the enzymes from Aspergillus niger, Penicillium funiculosum, Trichoderma reesei, Trichoderma viride, and Irpex lacteus. The cellulase derived from A. niger was purified, and its molecular weight was determined to be 26,000 by SDS-PAGE. Examination of the specificity of the cellulase revealed that 1) the enzyme acts on the linkage region (xylosyl serine) between a core peptide and a glycosaminoglycan chain; 2) enzymatic activity is greater with shorter glycosaminoglycan chains; 3) the enzyme readily hydrolyzes the linkage in glycosaminoglycan peptides, but intact proteoglycan is cleaved only slowly; and 4) the activity is unaffected by the glycosaminoglycan component (chondroitin sulfate, dermatan sulfate, and heparan sulfate). Judging from these enzymatic characteristics, this cellulase is different from the endo-beta-xylosidase of Patinopecten. We believe that this cellulase will become a useful tool in the further development of glycotechnology, because, like the endo-beta-xylosidase of Patinopecten, it enables the release of intact glycosaminoglycans from glycosaminoglycan peptides. 相似文献