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721.
Felipe F.D. Oliveira Diego C.B.D. Santos Alexandre A.M. Lapis José R. Corrêa Alexandre F. Gomes Fabio C. Gozzo Paulo F. Moreira Virgínia C. de Oliveira Frank H. Quina Brenno A.D. Neto 《Bioorganic & medicinal chemistry letters》2010,20(20):6001-6007
Newly designed 2,1,3-benzothiadiazole-containing fluorescent probes with four excited state intramolecular proton transfer (ESIPT) sites were successfully tested in live cell-imaging assays using a confluent monolayer of human stem-cells (tissue). All tested dyes were compared with the commercially available DAPI and gave far better results. 相似文献
722.
Cossu F Malvezzi F Canevari G Mastrangelo E Lecis D Delia D Seneci P Scolastico C Bolognesi M Milani M 《Protein science : a publication of the Protein Society》2010,19(12):2418-2429
Inhibitor of apoptosis proteins (IAPs) are negative regulators of apoptosis. As IAPs are overexpressed in many tumors, where they confer chemoresistance, small molecules inactivating IAPs have been proposed as anticancer agents. Accordingly, a number of IAP-binding pro-apoptotic compounds that mimic the sequence corresponding to the N-terminal tetrapeptide of Smac/DIABLO, the natural endogenous IAPs inhibitor, have been developed. Here, we report the crystal structures of the BIR3 domain of cIAP1 in complex with Smac037, a Smac-mimetic known to bind potently to the XIAP-BIR3 domain and to induce degradation of cIAP1, and in complex with the novel Smac-mimetic compound Smac066. Thermal stability and fluorescence polarization assays show the stabilizing effect and the high affinity of both Smac037 and Smac066 for cIAP1- and cIAP2-BIR3 domains. 相似文献
723.
724.
Ana T. Varela Anabela M. Simões João S. Teodoro Filipe V. Duarte Ana P. Gomes Carlos M. Palmeira Anabela P. Rolo 《Mitochondrion》2010,10(5):456-463
Indirubin-3′-oxime is an indirubin analogue that shows favorable inhibitory activity targeting glycogen synthase kinase 3β (GSK-3β). In this study, we evaluated if acute treatment with indirubin-3′-oxime (Ind) prevents hepatic ischemia/reperfusion (I/R) damage. Wistar rats were subjected to 150 min of 70% warm ischemia and 16 h of reperfusion. In the treated group 1 μM indirubin-3′-oxime was administered in the hepatic artery 30 min before ischemia. Acute treatment with Ind decreased serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) levels, comparatively to I/R livers. Bax translocation to the mitochondria and cytochrome c release were higher in I/R livers. Ind treatment significantly attenuated Bax translocation and preserved mitochondrial cytochrome c content. Ind also protected mitochondria from calcium-induced mitochondrial permeability transition (MPT), as well as the decrease in state 3 mitochondrial respiration, the delay in the repolarization after a phosphorylative cycle and the decrease in ATP content caused by I/R. By addressing GSK-3β activity and phosphorylated GSK-3β at Ser9 content in liver homogenates and isolated mitochondria, data suggests that inhibition of GSK-3β by indirubin-3′-oxime prevents the increase in mitochondrial phosphorylated GSK-3β at Ser9 induced by I/R, thus correlating with MPT inhibition and preservation of cytochrome c content. Pre-treatment with indirubin-3′-oxime in conditions of hepatic I/R, protects the liver by maintaining mitochondrial function and hepatic energetic balance. 相似文献
725.
Cancer is an ever-increasing problem that is yet to be harnessed. Frequent mutations make this pathology very variable and, consequently, a considerable challenge. Intriguingly, mitochondria have recently emerged as novel targets for cancer therapy. A group of agents with anti-cancer activity that induce apoptosis by way of mitochondrial destabilisation, termed mitocans, have been a recent focus of research. Of these compounds, many are hydrophobic agents that associate with various sub-cellular organelles. Clearly, modification of such structures with mitochondria-targeting moieties, for example tagging them with lipophilic cations, would be expected to enhance their activity. This may be accomplished by the addition of triphenylphosphonium groups that direct such compounds to mitochondria, enhancing their activity. In this paper, we will review agents that possess anti-cancer activity by way of destabilising mitochondria and their possible targets. We propose that mitochondrial targeting, in particular where the agent associates directly with the target, results in more specific and efficient anti-cancer drugs of potential high clinical relevance. 相似文献
726.
Ismael Bustos-Jaimes Rodrigo Mora-Lugo Mario L. Calcagno Amelia Farrés 《Biochimica et Biophysica Acta - Proteins and Proteomics》2010,1804(12):2222-2227
Lipases are useful catalysts for a wide variety of industrial purposes. Herein we report the stability and thermal dependence of the activity of wild-type Bacillus pumilus lipase (BplA) and four site-directed mutants designed to improve its thermal stability. The Gly28:Ser mutation produces a dramatic four-fold increase in its kcat and a remarkable increase in its stability. While the increase in kcat is temperature-independent, the increase in stability shows that the resultant interactions of this mutation have a strong enthalpic component. Thermal dependence of stability, kcat, KM and kcat/KM were analysed to gain insight on the structural effects of mutations on BplA. Our results are consistent with a gain in enzyme mobility for those mutants displaying enhanced catalytic properties; the analysis of thermal dependence of kinetic parameters indicates that the mutations did not change either the catalytic mechanism or the rate-limiting step of catalysis. 相似文献
727.
Trincavelli ML Cuboni S Catena Dell'osso M Maggio R Klotz KN Novi F Panighini A Daniele S Martini C 《Purinergic signalling》2010,6(4):373-381
A(2A) adenosine receptors are considered an excellent target for drug development in several neurological and psychiatric disorders. It is noteworthy that the responses evoked by A(2A) adenosine receptors are regulated by D(2) dopamine receptor ligands. These two receptors are co-expressed at the level of the basal ganglia and interact to form functional heterodimers. In this context, possible changes in A(2A) adenosine receptor functional responses caused by the chronic blockade/activation of D(2) dopamine receptors should be considered to optimise the therapeutic effectiveness of dopaminergic agents and to reduce any possible side effects. In the present paper, we investigated the regulation of A(2A) adenosine receptors induced by antipsychotic drugs, commonly acting as D(2) dopamine receptor antagonists, in a cellular model co-expressing both A(2A) and D(2) receptors. Our data suggest that the treatment of cells with the classical antipsychotic haloperidol increased both the affinity and responsiveness of the A(2A) receptor and also affected the degree of A(2A)-D(2) receptor heterodimerisation. In contrast, an atypical antipsychotic, clozapine, had no effect on A(2A) adenosine receptor parameters, suggesting that the two classes of drugs have different effects on adenosine-dopamine receptor interaction. Modifications to A(2A) adenosine receptors may play a significant role in determining cerebral adenosine effects during the chronic administration of antipsychotics in psychiatric diseases and may account for the efficacy of A(2A) adenosine receptor ligands in pathologies associated with dopaminergic system dysfunction. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11302-010-9201-z) contains supplementary material, which is available to authorized users. 相似文献
728.
Teresa Mancilla-Percino José Correa-Basurto José Trujillo-Ferrara Fernando R. Ramos-Morales Mario E. Acosta Hernández Jesús S. Cruz-Sánchez Margarita Saavedra-Vélez 《Journal of molecular modeling》2010,16(8):1377-1382
Two series of isoindolines 1(a–g) and 2(a–g) were found by docking calculations to be possible L-type Ca2+ channel (LCC) blockers. The theoretical 3-D model of the outer vestibule and the selective filter of the LCC was provided
by Professor Lipkind; this model consists of transmembrane segments S5 and S6 and P-loops contributed by each of four repeats
(I, II, III, and IV) of Cav 1.2. Therefore, two well-known LCC blockers, nifedipine 3 and (R)-ethosuccinimide 4 were also evaluated, and their binding sites on the LCC were identified and compared with those obtained for 1(a–g) and 2(a–g). Analysis of the results shows that the target compounds tested probably could be LCC blockers, since they interact with
or near the glutamic acid residues Glu393, Glu736, Glu1145 and Glu1446 (the EEEE locus), which belong to the LCC selectivity
region. The ∆G values for all of the Ca2+ channel ligands are between−10.78 and −3.67 (kcal mol−1), showing that LCC-1b, -1e and -1f complexes are more stable than the other compounds tested. Therefore, theoretically calculated dissociation constants K
d (μM) were obtained for all compounds. Comparing these values reveals that compounds 1b (0.0244 μM), 1e (0.0176 μM) and 1f (0.0125 μM) exhibit more affinity for the LCC than the other compounds. This screening shows that the two series of isoindolines
probably could act as LCC blockers. 相似文献
729.
Valente F Lago BV Castro CA Almeida AJ Gomes SA Soares CC 《Memórias do Instituto Oswaldo Cruz》2010,105(8):970-977
An estimated 360 million people are infected with hepatitis B virus (HBV) worldwide. Among these, 65 million live in Africa. Despite the high levels of hepatitis B in Africa, HBV epidemiology is still poorly documented in most African countries. In this work, the epidemiological and molecular characteristics of HBV infection were evaluated among the staff, visitors and adult patients (n = 508) of a public hospital in Luanda, Angola. The overall prevalence of hepatitis B core antibody (anti-HBc) and hepatitis B surface antigen was 79.7% and 15.1%, respectively. HBV infection was higher in males and was more prevalent in individuals younger than 50 years old. HBV-DNA was detected in 100% of HBV "e" antigen-positive serum samples and in 49% of anti-hepatitis Be antibody-positive samples. Thirty-five out of the 40 HBV genotypes belonged to genotype E. Circulation of genotypes A (4 samples) and D (1 sample) was also observed. The present study demonstrates that HBV infection is endemic in Luanda, which has a predominance of genotype E. This genotype is only sporadically found outside of Africa and is thought to have emerged in Africa at a time when the trans-Atlantic slave trade had stopped. 相似文献
730.
Two new species of Pleonotoma Miers (Bignonieae, Bignoniaceae) from Brazilian Amazonia are described and illustrated: Pleonotoma fissicalyx B. M. Gomes & Proen?a and P. longiflora B. M. Gomes & Proen?a. P. fissicalyx is characterised by foliaceous prophylls of the axillary bud, 3-ternate leaves, a large number of short racemes concentrated
at the apex of the flowering branch with many visible pedicel scars, a laterally fissured, almost spathaceous calyx, and a
small, narrow hypocrateriform corolla with subexserted anthers; the fruits are unknown. P. longiflora is characterised by the combination of weakly tetragonal branchlets with unribbed angles, non-foliaceous, flat, rounded prophylls
of axillary bud with an eccentric tip, 2-ternate leaves, broad axillary racemes, an elongate tubular calyx and a hypocrateriform
corolla up to 12 cm long; its inclusion within Pleonotoma is confirmed by molecular phylogeny. 相似文献