全文获取类型
收费全文 | 1265篇 |
免费 | 68篇 |
出版年
2022年 | 8篇 |
2021年 | 20篇 |
2020年 | 17篇 |
2019年 | 18篇 |
2018年 | 28篇 |
2017年 | 19篇 |
2016年 | 31篇 |
2015年 | 40篇 |
2014年 | 62篇 |
2013年 | 83篇 |
2012年 | 101篇 |
2011年 | 92篇 |
2010年 | 55篇 |
2009年 | 48篇 |
2008年 | 85篇 |
2007年 | 72篇 |
2006年 | 59篇 |
2005年 | 63篇 |
2004年 | 51篇 |
2003年 | 58篇 |
2002年 | 49篇 |
2001年 | 13篇 |
2000年 | 21篇 |
1999年 | 13篇 |
1998年 | 12篇 |
1997年 | 8篇 |
1996年 | 10篇 |
1995年 | 13篇 |
1994年 | 13篇 |
1993年 | 7篇 |
1992年 | 15篇 |
1991年 | 8篇 |
1990年 | 15篇 |
1989年 | 19篇 |
1988年 | 8篇 |
1987年 | 11篇 |
1986年 | 6篇 |
1985年 | 6篇 |
1984年 | 5篇 |
1983年 | 8篇 |
1982年 | 6篇 |
1980年 | 9篇 |
1978年 | 3篇 |
1977年 | 3篇 |
1976年 | 3篇 |
1974年 | 3篇 |
1973年 | 4篇 |
1972年 | 3篇 |
1968年 | 4篇 |
1963年 | 3篇 |
排序方式: 共有1333条查询结果,搜索用时 15 毫秒
71.
72.
Ghelli S Rinaldi M Barlocco D Gelain A Pecorari P Tondi D Rastelli G Costi MP 《Bioorganic & medicinal chemistry》2003,11(6):951-963
Thymidylate synthase (TS) (EC 2.1.1.45), an enzyme involved in the DNA synthesis of both prokaryotic and eukaryotic cells, is a potential target for the development of anticancer and antinfective agents. Recently, we described a series of phthalein and naphthalein derivatives as TS inhibitors. These compounds have structures unrelated to the folate (Non-Analogue Antifolate Inhibitors, NAAIs) and were selective for the bacterial versus the human TS (hTS). In particular, halogen-substituted molecules were the most interesting. In the present paper the halogen derivatives of variously substituted 3,3-bis(4-hydroxyphenyl)-1H,3H-naphtho[2,3-c]furan-1-one (1-5) and 3,3-bis(4-hydroxyphenyl)-1H,3H-naphtho[1,8-c,d]pyran-1-one (6-14) were synthesized to investigate the biological effect of halogen substitution on the inhibition and selectivity for the TS enzymes. Conformational properties of the naphthalein series were explored in order to highlight possible differences between molecules that show species-specific biological profile with respect to non species-specific ones. With this aim, the conformational properties of the synthesized compounds were investigated by NMR, in various solvents and at different temperatures, and by computational analysis. The apparent inhibition constants (K(i)) for Lactobacillus casei TS (LcTS) were found to range from 0.7 to 7.0 microM, with the exception of the weakly active iodo-derivatives (4, 10, 13); all] the compounds were poorly active against hTS. The di-halogenated compounds 7, 8, 14 showed the highest specificity towards LcTS, their specificity index (SI) ranging between 40 and >558. The di-halogenated 1,8-naphthalein derivatives (7-10) exhibited different conformational properties with respect to the tetra-haloderivatives. Though a clear explanation for the observed specificity by means of conformational analysis is difficult to find, some interesting conformational effects are discussed in the context of selective recognition of the compounds investigated by the LcTS enzyme. 相似文献
73.
Autoinhibition of c-Abl 总被引:10,自引:0,他引:10
Despite years of investigation, the molecular mechanism responsible for regulation of the c-Abl tyrosine kinase has remained elusive. We now report inhibition of the catalytic activity of purified c-Abl in vitro, demonstrating that regulation is an intrinsic property of the molecule. We show that the interaction of the N-terminal 80 residues with the rest of the protein mediates autoregulation. This N-terminal "cap" is required to achieve and maintain inhibition, and its loss turns c-Abl into an oncogenic protein and contributes to deregulation of BCR-Abl. 相似文献
74.
Scheggi S Leggio B Masi F Grappi S Gambarana C Nanni G Rauggi R De Montis MG 《Journal of neurochemistry》2002,83(4):895-903
Stressful events are accompanied by modifications in dopaminergic transmission in distinct brain regions. As the activity of the neuronal dopamine (DA) transporter (DAT) is considered to be a critical mechanism for determining the extent of DA receptor activation, we investigated whether a 3-week exposure to unavoidable stress, which produces a reduction in DA output in the nucleus accumbens shell (NAcS) and medial prefrontal cortex (mPFC), would affect DAT density and DA D1 receptor complex activity in the NAcS, mPFC and caudate-putamen (CPu). Rats exposed to unavoidable stress showed a decreased DA output in the NAcS accompanied by a decrease in the number of DAT binding sites, and an increase in the number of DA D1 binding sites and Vmax of SKF 38393-stimulated adenylyl cyclase. In the mPFC, stress exposure produced a decrease in DA output with no modification in DAT binding or in DA D1 receptor complex activity. Moreover, in the CPu stress exposure induced no changes in DA output or in the other neurochemical variables examined. This study shows that exposure to a chronic unavoidable stress that produces a decrease in DA output in frontomesolimbic areas induced several adaptive neurochemical modifications selectively in the nucleus accumbens. 相似文献
75.
Donetti E Baetta R Comparato C Altana C Sartore S Paoletti R Castano P Gabbiani G Corsini A 《Experimental cell research》2002,274(2):197-206
The importance of mononuclear leukocyte (MO) adhesion to dysfunctional endothelium and migration to the subendothelial space in the early phases of atherogenesis is well established. Few studies have addressed the relevance of polymorphonuclear leukocytes (PMNs) in the context of evolving lesions, and nothing is known about PMN interaction with vascular smooth muscle cells (SMCs). In this study, we investigated leukocyte/SMC interactions in a model of rabbit carotid injury induced by placement of a silastic collar. This procedure leads to the development of intimal thickening characterized by SMC accumulation preceded by an abundant leukocyte infiltration. By transmission electron microscopy and immunocytochemistry, we demonstrated the occurrence of PMN infiltration starting at 6 h and ceasing within 72 h after collar placement. A previously unknown extensive interaction between medial myocytes and PMNs was detected, referring to emperipolesis, an active phenomenon of cells engulfing other cells in a process other than phagocytosis. PMNs, but not MOs, were internalized by SMCs, which showed ultrastructural features intermediate between the true contractile and the fully synthetic phenotype without exhibiting any sign of injury. Emperipolesis preceded any detectable cell proliferation in the vessel wall and disappeared within 72 h, following the kinetic of PMN infiltration in the vessel wall. In summary, our findings show the occurrence of an active and selective interaction between PMNs and SMCs via emperipolesis during the early phases of intimal thickening after perivascular collaring. However, the overall etiology of the phenomena described in the present study and their pathophysiological significance should be further investigated. 相似文献
76.
Di Giulio M 《Journal of molecular evolution》2002,55(5):616-622
A logical-evolutionary analysis is conducted to clarify whether or not pathways of type Glu-tRNAGln \rightarrow Gln-tRNAGln
are molecular fossils of the mechanism that gave rise to the evolutionary organization of the genetic code. The result of
this analysis is that these pathways are most likely a manifestation of this mechanism. This provides strong evidence in favor
of the coevolution theory of genetic code origin, as this theory is based on the amino acid biosynthetic transformation taking
place on tRNA-like molecules which imprinted the genetic code structuring. Comments on the different interpretations of these
pathways found in the literature are also provided. 相似文献
77.
Bettati S Campanini B Vaccari S Mozzarelli A Schianchi G Hazlett TL Gratton E Benci S 《Biochimica et biophysica acta》2002,1596(1):47-54
Proteins utilizing pyridoxal 5'-phosphate as a coenzyme constitute a large superfamily and are currently classified into three functional groups and five structural fold types. Despite the variability of sequences and catalyzed reactions, they share relevant structural, dynamic and functional properties. Therefore, they constitute an optimal system to investigate the relative influence of primary sequence and coenzyme interactions on folding pathways, structural stability and enzymatic function. O-Acetylserine sulfhydrylase is a dimeric pyridoxal 5'-phosphate dependent enzyme that catalyzes the synthesis of L-cysteine from O-acetylserine and sulfide. The time-resolved fluorescence study of O-acetylserine sulfhydrylase unfolding, here reported, indicates that the coenzyme stabilizes the protein structure. The dependence on denaturant concentration of tryptophan lifetimes in the holo- and apo-enzyme demonstrates that the interactions with the coenzyme stabilize the C-terminal domain to a higher extent with respect to the N-terminal domain. This result is discussed in terms of a linkage between the differential stabilization brought about by the coenzyme and the different degrees of conformational flexibility required by the specialized functional role of distinct protein regions. 相似文献
78.
Bäckesjö CM Vargas L Superti-Furga G Smith CI 《Biochemical and biophysical research communications》2002,299(3):510-515
Bruton's tyrosine kinase (Btk) is necessary for B-lymphocyte development. Mutation in the gene coding for Btk causes X-linked agammaglobulinemia (XLA) in humans. Similar to Btk, c-Abl is a tyrosine kinase shuttling between the cytoplasm and the nucleus where it is involved in different functions depending on the localization. In this report we describe for the first time that c-Abl and Btk physically interact and that c-Abl can phosphorylate tyrosine 223 in the SH3 domain of Btk. Interestingly, the Btk sequence matched a v-Abl substrate [correction] identified from a randomized peptide library and was also highly related to a number of previously found c-Abl substrates. 相似文献
79.
Di Giulio C Huang W Waters V Mokashi A Bianchi G Cacchio M Macrì MA Lahiri S 《Comparative biochemistry and physiology. Part A, Molecular & integrative physiology》2003,134(1):27-31
It is known that atrial natriuretic peptide (ANP) is released from cardiac myocyte and other stores during hypoxia and is involved in pulmonary-cardiovascular reflexes and in natriuresis and diuresis. Since the carotid body initiates hypoxic chemoreflexes, we hypothesized that ANP could potentiate the hypoxic stimulation of the carotid body chemoreceptor in vivo. We studied the effect of close intra-arterial injection of ANP on carotid chemoreceptor activity in anesthetized male cats which were paralyzed and artificially ventilated. Graded doses of ANP (0-10 nmoles) were administered by intra-arterial injections and they produced an excitatory response. Single dose of ANP (6.5 nmoles) at four steady-state levels of arterial PO(2), at constant PCO(2), produced increases of chemoreceptor activity. This increase of chemoreceptor activity with ANP in the presence of CO(2)-HCO(3)(-) in vitro could make a difference from those without CO(2)-HCO(3)(-) in vivo. 相似文献
80.
Tettamanti G Grimaldi A Ferrarese R Palazzi M Perletti G Valvassori R Cooper EL Lanzavecchia G de Eguileor M 《Tissue & cell》2003,35(3):199-212
The aim of the present work is to describe histologically, histochemically and immunocytochemically, the sequence of events that lead to first and second set rejection of allo- or xenograft in leeches. Graft responses of leeches are comparable and are described following specific steps: inflammatory phase, rejection phase and granulation tissue formation (including re-epithelialisation, angiogenesis and fibroplasia).The responses to first and second graft in first set graft rejection as well as to the first transplant in second set graft experiments are identical and in the time span of a week all grafts are destroyed and disappear. In the second set graft rejection experiments the responses against the second transplant are markedly accelerated. The second graft shows massive structural alterations and it is rapidly rejected, within 3-4 days.Our results permit to highlight that in leeches there is a specific responsiveness of immune system similar to those described in highly divergent phyla. 相似文献