全文获取类型
收费全文 | 971篇 |
免费 | 142篇 |
国内免费 | 1篇 |
出版年
2022年 | 10篇 |
2021年 | 16篇 |
2020年 | 13篇 |
2018年 | 15篇 |
2017年 | 14篇 |
2016年 | 15篇 |
2015年 | 27篇 |
2014年 | 35篇 |
2013年 | 29篇 |
2012年 | 28篇 |
2011年 | 49篇 |
2010年 | 34篇 |
2009年 | 21篇 |
2008年 | 41篇 |
2007年 | 44篇 |
2006年 | 35篇 |
2005年 | 25篇 |
2004年 | 30篇 |
2003年 | 17篇 |
2002年 | 27篇 |
2001年 | 22篇 |
2000年 | 20篇 |
1999年 | 19篇 |
1997年 | 13篇 |
1995年 | 10篇 |
1993年 | 9篇 |
1992年 | 15篇 |
1991年 | 16篇 |
1990年 | 20篇 |
1989年 | 26篇 |
1988年 | 21篇 |
1987年 | 26篇 |
1986年 | 17篇 |
1985年 | 25篇 |
1984年 | 15篇 |
1982年 | 13篇 |
1981年 | 12篇 |
1980年 | 11篇 |
1979年 | 12篇 |
1978年 | 20篇 |
1977年 | 13篇 |
1976年 | 13篇 |
1975年 | 16篇 |
1974年 | 17篇 |
1973年 | 20篇 |
1972年 | 15篇 |
1971年 | 14篇 |
1970年 | 16篇 |
1968年 | 18篇 |
1966年 | 10篇 |
排序方式: 共有1114条查询结果,搜索用时 31 毫秒
81.
Dinsmore CJ Zartman CB Bergman JM Abrams MT Buser CA Culberson JC Davide JP Ellis-Hutchings M Fernandes C Graham SL Hartman GD Huber HE Lobell RB Mosser SD Robinson RG Williams TM 《Bioorganic & medicinal chemistry letters》2004,14(3):639-643
A series of macrocyclic piperazinone compounds with dual farnesyltransferase/geranylgeranyltransferase-I inhibitory activity was prepared. These compounds were found to be potent inhibitors of protein prenylation in cell culture. A hypothesis for the binding mode of compound 3o in FPTase is proposed. 相似文献
82.
Wu Z Fraley ME Bilodeau MT Kaufman ML Tasber ES Balitza AE Hartman GD Coll KE Rickert K Shipman J Shi B Sepp-Lorenzino L Thomas KA 《Bioorganic & medicinal chemistry letters》2004,14(4):909-912
3,7-Diarylsubstituted imidazopyridines were designed and developed as a new class of KDR kinase inhibitors. A variety of imidazopyridines were synthesized and potent inhibitors of KDR kinase activity were identified with good aqueous solubility. 相似文献
83.
Srivastava P Schito M Fattah RJ Hara T Hartman T Buckheit RW Turpin JA Inman JK Appella E 《Bioorganic & medicinal chemistry》2004,12(24):6437-6450
A combinatorial chemistry approach was employed to prepare a restricted library of N-substituted S-acyl-2-mercaptobenzamide thioesters. It was shown that many members of this chemotype display anti-HIV activity via their ability to interact with HIV-1, HIV-2, SIV-infected cells, cell-free virus, and chronically and latently infected cells in a manner consistent with targeting of the highly conserved HIV-1 NCp7 zinc fingers. Compounds were initially screened using two different in vitro antiviral assays and evaluated for stability in neutral buffer containing 10% pooled human serum using a spectrophotometric assay. These data revealed that there was no significant correlation between thioester stability and antiviral activity, however, a slight inverse correlation between serum stability and virucidal activity was noted. Based on the virucidal capability and the ability to select lead compounds to inhibit virus expression from latently infected TNF-induced U1 cells, we next determined if these compounds could prevent HIV cell-to-cell transmission. Several thioesters demonstrated potent inhibition of HIV cell-to-cell transmission with EC50 values in the 80–100 nM range. Thus, we have optimized a series of restricted thioesters and provided evidence that serum stability is not required for antiviral activity. Moreover, selected compounds show potential for development as topical microbicides. 相似文献
84.
Vishwanath P Favaretto P Hartman H Mohr SC Smith TF 《Molecular phylogenetics and evolution》2004,33(3):615-625
Amino acid sequence alignments of orthologous ribosomal proteins found in Bacteria, Archaea, and Eukaryota display, relative to one another, an unusual segment or block structure, with major evolutionary implications. Within each of the prokaryotic phylodomains the sequences exhibit substantial similarity, but cross-domain alignments break up into (a) universal blocks (conserved in both phylodomains), (b) bacterial blocks (unalignable with any archaeal counterparts), and (c) archaeal blocks (unalignable with any bacterial counterparts). Sequences of those eukaryotic cytoplasmic riboproteins that have orthologs in both Bacteria and Archaea, exclusively match the archaeal block structure. The distinct blocks do not correlate consistently with any identifiable functional or structural feature including RNA and protein contacts. This phylodomain-specific block pattern also exists in a number of other proteins associated with protein synthesis, but not among enzymes of intermediary metabolism. While the universal blocks imply that modern Bacteria and Archaea (as defined by their translational machinery) clearly have had a common ancestor, the phylodomain-specific blocks imply that these two groups derive from single, phylodomain-specific types that came into existence at some point long after that common ancestor. The simplest explanation for this pattern would be a major evolutionary bottleneck, or other scenario that drastically limited the progenitors of modern prokaryotic diversity at a time considerably after the evolution of a fully functional translation apparatus. The vast range of habitats and metabolisms that prokaryotes occupy today would thus reflect divergent evolution after such a restricting event. Interestingly, phylogenetic analysis places the origin of eukaryotes at about the same time and shows a closer relationship of the eukaryotic ribosome-associated proteins to crenarchaeal rather than euryarchaeal counterparts. 相似文献
85.
Pds5p regulates the maintenance of sister chromatid cohesion and is sumoylated to promote the dissolution of cohesion 总被引:1,自引:0,他引:1
Stead K Aguilar C Hartman T Drexel M Meluh P Guacci V 《The Journal of cell biology》2003,163(4):729-741
Pds5p and the cohesin complex are required for sister chromatid cohesion and localize to the same chromosomal loci over the same cell cycle window. However, Pds5p and the cohesin complex likely have distinct roles in cohesion. We report that pds5 mutants establish cohesion, but during mitosis exhibit precocious sister dissociation. Thus, unlike the cohesin complex, which is required for cohesion establishment and maintenance, Pds5p is required only for maintenance. We identified SMT4, which encodes a SUMO isopeptidase, as a high copy suppressor of both the temperature sensitivity and precocious sister dissociation of pds5 mutants. In contrast, SMT4 does not suppress temperature sensitivity of cohesin complex mutants. Pds5p is SUMO conjugated, with sumoylation peaking during mitosis. SMT4 overexpression reduces Pds5p sumoylation, whereas smt4 mutants have increased Pds5p sumoylation. smt4 mutants were previously shown to be defective in cohesion maintenance during mitosis. These data provide the first link between a protein required for cohesion, Pds5p, and sumoylation, and suggest that Pds5p sumoylation promotes the dissolution of cohesion. 相似文献
86.
A novel approach to measuring receptor-stimulated phosphoinositide hydrolysis was developed based on the principles of immobilized metal ion affinity chromatography (IMAC) and scintillation proximity assay (SPA). Hard Lewis metal ions, such as Zr(4+), Ga(3+), Al(3+), Fe(3+), Lu(3+), and Sc(3+), were immobilized on SPA beads via metal chelate and utilized as affinity ligands to entrap inositol phosphates. [3H]Inositol phosphates bound to IMAC-SPA beads through the strong interaction of their phosphate group with the immobilized metal ions. The binding brought [3H]inositol phosphates in close proximity to the scintillant embedded in the SPA beads, thereby allowing the radioactivity to be quantified. Quantification of [3H]inositol phosphate production in cells preincubated with [3H]inositol provided a highly sensitive measurement of phosphoinositide hydrolysis. The utility of this approach was demonstrated in measuring the response mediated by the G-protein-coupled neurokinin NK1 receptor and the tyrosine kinase-linked platelet-derived growth factor (PDGF) receptor. Substance P stimulated phosphoinositide hydrolysis concentration-dependently in CHO cells expressing NK1 receptors with a maximal 12-fold increase in inositol phosphate production. Similarly, PDGF-BB stimulated a 5-fold increase in phosphoinositide hydrolysis in quiescent Swiss 3T3 cells. This new approach is highly sensitive, fast, simple, easily performed on 96-well plates, and amenable for high-throughput screening. 相似文献
87.
88.
Ishiguro H Yasuda K Ishii N Ihara K Ohkubo T Hiyoshi M Ono K Senoo-Matsuda N Shinohara O Yosshii F Murakami M Hartman PS Tsuda M 《IUBMB life》2001,51(4):263-268
The mechanisms that lead to mitochondrial damage under oxidative stress conditions were examined in primary and cultured cells as well as in the nematode Caenorhabditis elegans (C. elegans) treated simultaneously with electron transport inhibitors and oxygen gas. Oxygen loading enhanced the damage of PC 12 cells by thenoyltrifluoroacetone (TTFA, a complex II inhibitor), but did not by rotenone (a complex I inhibitor), antimycin (a complex III inhibitor), and sodium azide (a complex IV inhibitor). In primary hepatocytes, the enhancement was observed with the addition of sodium azide and rotenone, but not by TTFA or antimycin. In the nematode, only rotenone and TTFA enhanced the sensitivity under hyperoxia. These results demonstrate that highly specific inhibitors of electron transport can induce oxygen hypersensitivity in cell levels such as PC 12 cells and primary hepatocytes, and animal level of C. elegans. In addition the cell damage is different dependent on cell type and organism. 相似文献
89.
Brashear KM Hunt CA Kucer BT Duggan ME Hartman GD Rodan GA Rodan SB Leu CT Prueksaritanont T Fernandez-Metzler C Barrish A Homnick CF Hutchinson JH Coleman PJ 《Bioorganic & medicinal chemistry letters》2002,12(23):3483-3486
A series of novel, highly potent alpha(v)beta(3) receptor antagonists with favorable pharmacokinetic profiles has been identified. In this series of antagonists, 2-aryl beta-amino acids function as potent aspartic acid replacements. 相似文献
90.
Coleman PJ Askew BC Hutchinson JH Whitman DB Perkins JJ Hartman GD Rodan GA Leu CT Prueksaritanont T Fernandez-Metzler C Merkle KM Lynch R Lynch JJ Rodan SB Duggan ME 《Bioorganic & medicinal chemistry letters》2002,12(17):2463-2465
Potent non-peptidic alpha(v)beta(3) antagonists have been prepared where deletion of an amide bond from an earlier series of linear RGD-mimetics provides a novel series of chain-shortened alpha(v)beta(3) antagonists with significantly improved oral pharmacokinetics. These chain-shortened alpha(v)beta(3) antagonists represent structurally novel integrin inhibitors. 相似文献