全文获取类型
收费全文 | 1818篇 |
免费 | 147篇 |
出版年
2023年 | 4篇 |
2022年 | 7篇 |
2021年 | 28篇 |
2020年 | 21篇 |
2019年 | 27篇 |
2018年 | 47篇 |
2017年 | 28篇 |
2016年 | 49篇 |
2015年 | 78篇 |
2014年 | 77篇 |
2013年 | 135篇 |
2012年 | 144篇 |
2011年 | 135篇 |
2010年 | 100篇 |
2009年 | 90篇 |
2008年 | 142篇 |
2007年 | 122篇 |
2006年 | 111篇 |
2005年 | 114篇 |
2004年 | 105篇 |
2003年 | 93篇 |
2002年 | 80篇 |
2001年 | 10篇 |
2000年 | 14篇 |
1999年 | 19篇 |
1998年 | 25篇 |
1997年 | 17篇 |
1996年 | 9篇 |
1995年 | 11篇 |
1994年 | 16篇 |
1993年 | 13篇 |
1992年 | 10篇 |
1991年 | 11篇 |
1990年 | 10篇 |
1989年 | 8篇 |
1988年 | 6篇 |
1987年 | 4篇 |
1986年 | 4篇 |
1985年 | 5篇 |
1984年 | 3篇 |
1983年 | 5篇 |
1982年 | 4篇 |
1981年 | 3篇 |
1980年 | 8篇 |
1979年 | 4篇 |
1978年 | 2篇 |
1977年 | 2篇 |
1976年 | 2篇 |
1974年 | 2篇 |
1972年 | 1篇 |
排序方式: 共有1965条查询结果,搜索用时 718 毫秒
991.
Morini G Comini M Rivara M Rivara S Bordi F Plazzi PV Flammini L Saccani F Bertoni S Ballabeni V Barocelli E Mor M 《Bioorganic & medicinal chemistry》2008,16(23):9911-9924
The combination of antagonism at histamine H(3) receptors and inhibition of acetylcholinesterase has been recently proposed as an approach to devise putative new therapeutic agents for cognitive diseases. The 4,4'-biphenyl fragment has been reported by us as a rigid scaffold leading to potent and selective non-imidazole H(3)-antagonists. Starting from these premises, the current work presents an expanded series of histamine H(3) receptor antagonists, characterized by a central 4,4'-biphenyl scaffold, where the structure-activity profile of both mono-basic and di-basic compounds is further explored and their ability to inhibit rat brain cholinesterase activity is determined. The steric properties and basicity of the terminal groups were modulated in symmetrical compounds, carrying identical substituents, and in asymmetrical compounds, having a piperidine ring at one end and different groups at the other. The length of the linker connecting the biphenyl scaffold to the terminal groups was also modulated. Binding studies at rat and human H(3) receptors evidenced the highest binding affinities for di-basic compounds, in the order of nM concentrations, and that the steric requirements for the two terminal groups are different. Many potent compounds showed good selectivity profiles over the other histamine receptors. Interestingly, some derivatives displayed a moderate ability to inhibit rat brain cholinesterase, for example compound 12 (1-[2-(4'-piperidinomethyl-biphenyl-4-yl)ethyl]piperidine) has a pIC(50)=5.96 for cholinesterase inhibition and high H(3) receptor binding affinity and antagonist potency (pK(i)=8.70; pK(B)=9.28). These compounds can be considered as rigid analogs of a recently reported class of dual-acting compounds and as a promising starting point for the design of new H(3)-antagonists with anti-cholinesterase activity. 相似文献
992.
Local application of the agonists of serotonin receptors of third type 5-HTQ, SR57277A and quipazine into the interblastomere cleft of the sea urchin Paracentrotus lividus embryo during first cleavage division, evokes specific membrane currents, whereas application of these drugs out of contact area show currents of lower amplitude and longer latent period. At the same time 5-HT3-receptor agonist quipazine imitates interblastomere signal in half embryos, but corresponding antagonists prevent it. Present data develop the hypothesis of protosynapse, demonstrating that the distribution of membrane serotonin receptors is limited to the period of cleavage division and localized in the interblastomere contact area. A possible role of spatial-temporal restriction of receptors at the interblastomere contact area is discussed in relation to the subsequent embryo development. 相似文献
993.
Rosario Nicoletti Elisabetta Buommino Anna De Filippis Maria Pilar Lopez-Gresa Emiliano Manzo Angela Carella Marcella Petrazzuolo Maria Antonietta Tufano 《World journal of microbiology & biotechnology》2008,24(2):189-195
Microorganisms are increasingly exploited as a source of new pharmaceuticals. Soil fungi are particularly promising to this
regard since their biocenotic competitiveness is often based on the production of antibiotics and other inhibitory substances.
About 15 Penicillium strains possessing some extent of antifungal ability were evaluated as a possible source of antitumor products based on the
antiproliferative and pro-apoptotic effects of their culture extracts on human tumor cell lines. About 12 strains showed some
extent of antitumor properties that in several cases corresponded to the effect of the extrolites purified from the culture
extracts themselves. The study showed that a quick screening of fungal isolates can be operated by assaying their fungal extracts
on tumor cells directly, with the ensuing advantage of restricting the work required for the characterization of the bioactive
compounds to a reduced number of promising strains. 相似文献
994.
Scipione L De Vita D Musella A Flammini L Bertoni S Barocelli E 《Bioorganic & medicinal chemistry letters》2008,18(1):309-312
Several carbamate derivatives of 4-aminopyridine were synthesized and their anticholinesterase activity was evaluated. Compound 4d showed the highest inhibitory effect blocking non-competitively acetylcholinesterase and competitively butyrylcholinesterase. Furthermore, carbamate 4d was able to revert the amnesic effects of scopolamine in the passive avoidance test in rats. 相似文献
995.
Iori E Pagnin E Gallo A Calò L Murphy E Ostuni F Fadini GP Avogaro A 《Life sciences》2008,82(7-8):383-392
Hyperglycaemia is associated with oxidative stress. The inducible isoform of heme oxygenase (HO-1) is an effective system to counteract oxidative stress, yet it is unclear how hyperglycaemia affects HO-1. In this study, we explored: 1) the HO-1 protein content and HO activity in human umbilical vein endothelial cells (HUVECs) exposed to different glucose concentrations, and 2) the mechanisms which account for the high glucose-induced effects on HO-1. We evaluated HO-1 protein expression, HO activity, apoptosis and reactive oxygen species (ROS) in HUVECs treated for 48 h with 5.5, 10 and 20 mM glucose. A dose-dependent production of reactive oxygen species was observed. At 10 mM glucose, an increase of HO-1 protein expression and HO activity was observed, whereas at 20 mM, there was no change in protein content and activity relative to at 5.5 mM glucose. HO-1 protein expression in HUVECs exposed to 20 mM of glucose was increased in the presence of 20 U/ml superoxide dismutase (SOD). HO-1 gene silencing augments ROS production both at 5.5 and 10 mM glucose, leading to an increased apoptosis. We conclude that, in endothelial cells, the regulation of HO-1 by glucose is dependent upon levels of glucose itself. Lack of homeostatic HO-1 upregulation fails to protect from oxidative damage and results in a higher rate of apoptotic cell death. 相似文献
996.
Dynamics of Persistent TT Virus Infection, as Determined in Patients Treated with Alpha Interferon for Concomitant Hepatitis C Virus Infection 下载免费PDF全文
Fabrizio Maggi Mauro Pistello Marialinda Vatteroni Silvano Presciuttini Santino Marchi Patrizia Isola Claudia Fornai Sabina Fagnani Elisabetta Andreoli Guido Antonelli Mauro Bendinelli 《Journal of virology》2001,75(24):11999-12004
TT virus (TTV) is a recently identified widespread DNA virus of humans that produces persistent viremia in the absence of overt clinical manifestations. In an attempt to shed light on the dynamics of chronic infection, we measured the levels of TTV in the plasma of 25 persistently infected patients during the first 3 months of alpha interferon (IFN-alpha) treatment for concomitant hepatitis C virus (HCV) infection. The first significant decline of TTV loads was observed at day 3 versus day 1 for HCV. Subsequently, the loads of TTV became progressively lower in most patients, but some initial responders relapsed before the end of the follow-up, suggesting that at least in some subjects the effects of IFN on TTV can be very short-lived. No correlation between the responses of TTV and HCV to therapy was found. Fitting the viremia data obtained during the first week of treatment into previously developed mathematical models showed that TTV sustains very active chronic infections, with over 90% of the virions in plasma cleared and replenished daily and a minimum of approximately 3.8 x 10(10) virions generated per day. Low levels of TTV were occasionally detected in the peripheral blood mononuclear cells of patients who had cleared plasma viremia, thus corroborating previous results showing that these cells may support TTV replication and/or persistence. 相似文献
997.
Damiana?Chiavolini Sergio?Tripodi Riccardo?Parigi Marco?R?Oggioni Elisabetta?Blasi Marcella?Cintorino Gianni?Pozzi Susanna?RicciEmail author 《BMC microbiology》2004,4(1):36
Background
Streptococcus pneumoniae is the leading cause of bacterial meningitis. Pneumococcal meningitis is associated with the highest mortality among bacterial meningitis and it may also lead to neurological sequelae despite the use of antibiotic therapy. Experimental animal models of pneumococcal meningitis are important to study the pathogenesis of meningitis, the host immune response induced after infection, and the efficacy of novel drugs and vaccines. 相似文献998.
Bobbio-Pallavicini F Alpini C Caporali R Avalle S Bugatti S Montecucco C 《Arthritis research & therapy》2004,6(3):R264-R272
The aim of the present study was to investigate the effect of long-term infliximab treatment on various autoantibodies in
patients with rheumatoid arthritis. Serum samples from 30 consecutive patients, who were prospectively followed during infliximab
and methotrexate therapy for refractory rheumatoid arthritis, were tested at baseline and after 30, 54 and 78 weeks. At these
points, median values of the Disease Activity Score were 6.38 (interquartile range 5.30–6.75), 3.69 (2.67–4.62), 2.9 (2.39–4.65)
and 3.71 (2.62–5.06), respectively. Various autoantibodies were assessed by standard indirect immunofluorescence and/or ELISA.
Initially, 50% of patients were positive for antinuclear antibodies, and this figure increased to 80% after 78 weeks (P = 0.029). A less marked, similar increase was found for IgG and IgM anticardiolipin antibody titre, whereas the frequency
of anti-double-stranded DNA antibodies (by ELISA) exhibited a transient rise (up to 16.7%) at 54 weeks and dropped to 0% at
78 weeks. Antibodies to proteinase-3 and myeloperoxidase were not detected. The proportion of patients who were positive for
rheumatoid factor (RF) was similar at baseline and at 78 weeks (87% and 80%, respectively). However, the median RF titre exhibited
a progressive reduction from 128 IU/ml (interquartile range 47–290 IU/ml) to 53 IU/ml (18–106 IU/ml). Anti-cyclic citrullinated
peptide (CCP) antibodies were found in 83% of patients before therapy; anti-CCP antibody titre significantly decreased at
30 weeks but returned to baseline thereafter. In conclusion, the presence of anti-double-stranded DNA antibodies is a transient
phenomenon, despite a stable increase in antinuclear and anticardiolipin antibodies. Also, the evolution of RF titres and
that of anti-CCP antibody titres differed during long-term infliximab therapy. 相似文献
999.
Evans JP Kelley JL Bisazza A Finazzo E Pilastro A 《Proceedings. Biological sciences / The Royal Society》2004,271(1552):2035-2042
According to the good-genes hypothesis, females choose among males to ensure the inheritance of superior paternal genes by their offspring. Despite increasing support for this prediction, in some cases differential (non-genetic) maternal effects may obscure or amplify the relationship between paternal attractiveness and offspring quality. Artificial insemination controls such effects because it uncouples mate choice from copulation, therefore denying females the opportunity of assessing male attractiveness. We adopted this technique in the live-bearing fish Poecilia reticulata and examined whether paternal coloration was associated with the behavioural performance of newborn offspring. Sexually receptive virgin females were inseminated with sperm taken individually from donor males that exhibited high variation in the area of orange pigmentation, a trait known to influence female choice in the study population. Our analysis of offspring performance focused on the anti-predator behaviour of newborn fish, including schooling by sibling pairs, the response (swimming speed) of these fishes to a simulated avian predator, and the time taken for a naive investigator to capture the offspring. Although we found no significant effect of sire coloration on either schooling or swimming speed, our analysis revealed a significant positive association between sire coloration and the ability of newborn offspring to evade capture. This finding supports the view that at least one aspect of anti-predator behaviour in newborn offspring is influenced by sire genotype, which in turn is revealed by the expression of secondary sexual traits. 相似文献
1000.
Grifantini R Frigimelica E Delany I Bartolini E Giovinazzi S Balloni S Agarwal S Galli G Genco C Grandi G 《Molecular microbiology》2004,54(4):962-979
We have previously shown that in the human pathogen Neisseria meningitidis group B (MenB) more than 200 genes are regulated in response to growth with iron. Among the Fur-dependent, upregulated genes identified by microarray analysis was a putative operon constituted by three genes, annotated as NMB1436, NMB1437 and NMB1438 and encoding proteins with so far unknown function. The operon was remarkably upregulated in the presence of iron and, on the basis of gel retardation analysis, its regulation was Fur dependent. In this study, we have further characterized the role of iron and Fur in the regulation of the NMB1436-38 operon and we have mapped the promoter and the Fur binding site. We also demonstrate by mutant analysis that the NMB1436-38 operon is required for protection of MenB to hydrogen peroxide-mediated killing. By using both microarray analysis and S1 mapping, we demonstrate that the operon is not regulated by oxidative stress signals. We also show that the deletion of the NMB1436-38 operon results in an impaired capacity of MenB to survive in the blood of mice using an adult mouse model of MenB infection. Finally, we show that the NMB1436-38 deletion mutant exhibits increased susceptibility to the killing activity of polymorphonuclears (PMNs), suggesting that the 'attenuated' phenotype is mediated in part by the increased sensitivity to reactive oxygen species-producing cells. This study represents one of the first examples of the use of DNA microarray to assign a biological role to hypothetical genes in bacteria. 相似文献