全文获取类型
收费全文 | 1143篇 |
免费 | 30篇 |
国内免费 | 17篇 |
出版年
2023年 | 5篇 |
2022年 | 7篇 |
2021年 | 12篇 |
2020年 | 17篇 |
2019年 | 41篇 |
2018年 | 30篇 |
2017年 | 14篇 |
2016年 | 11篇 |
2015年 | 7篇 |
2014年 | 80篇 |
2013年 | 87篇 |
2012年 | 50篇 |
2011年 | 69篇 |
2010年 | 52篇 |
2009年 | 47篇 |
2008年 | 53篇 |
2007年 | 49篇 |
2006年 | 53篇 |
2005年 | 42篇 |
2004年 | 21篇 |
2003年 | 28篇 |
2002年 | 16篇 |
2001年 | 8篇 |
2000年 | 10篇 |
1999年 | 5篇 |
1998年 | 10篇 |
1997年 | 10篇 |
1996年 | 5篇 |
1995年 | 9篇 |
1994年 | 6篇 |
1993年 | 5篇 |
1992年 | 6篇 |
1991年 | 4篇 |
1989年 | 3篇 |
1988年 | 4篇 |
1987年 | 3篇 |
1986年 | 5篇 |
1985年 | 39篇 |
1984年 | 58篇 |
1983年 | 54篇 |
1982年 | 45篇 |
1981年 | 21篇 |
1980年 | 12篇 |
1979年 | 14篇 |
1978年 | 12篇 |
1977年 | 13篇 |
1976年 | 6篇 |
1975年 | 9篇 |
1974年 | 8篇 |
1973年 | 8篇 |
排序方式: 共有1190条查询结果,搜索用时 15 毫秒
111.
Paul W Jones Stephen I Rennard Alvar Agusti Pascal Chanez Helgo Magnussen Leonardo Fabbri James F Donohue Eric D Bateman Nicholas J Gross Rosa Lamarca Cynthia Caracta Esther Garcia Gil 《Respiratory research》2011,12(1):55
Background
The long-term efficacy and safety of aclidinium bromide, a novel, long-acting muscarinic antagonist, were investigated in patients with moderate to severe chronic obstructive pulmonary disease (COPD).Methods
In two double-blind, 52-week studies, ACCLAIM/COPD I (n = 843) and II (n = 804), patients were randomised to inhaled aclidinium 200 μg or placebo once-daily. Patients were required to have a post-bronchodilator forced expiratory volume in 1 second (FEV1)/forced vital capacity ratio of ≤70% and FEV1 <80% of the predicted value. The primary endpoint was trough FEV1 at 12 and 28 weeks. Secondary endpoints were health status measured by St George''s Respiratory Questionnaire (SGRQ) and time to first moderate or severe COPD exacerbation.Results
At 12 and 28 weeks, aclidinium improved trough FEV1 versus placebo in ACCLAIM/COPD I (by 61 and 67 mL; both p < 0.001) and ACCLAIM/COPD II (by 63 and 59 mL; both p < 0.001). More patients had a SGRQ improvement ≥4 units at 52 weeks with aclidinium versus placebo in ACCLAIM/COPD I (48.1% versus 39.5%; p = 0.025) and ACCLAIM/COPD II (39.0% versus 32.8%; p = 0.074). The time to first exacerbation was significantly delayed by aclidinium in ACCLAIM/COPD II (hazard ratio [HR] 0.7; 95% confidence interval [CI] 0.55 to 0.92; p = 0.01), but not ACCLAIM/COPD I (HR 1.0; 95% CI 0.72 to 1.33; p = 0.9). Adverse events were minor in both studies.Conclusion
Aclidinium is effective and well tolerated in patients with moderate to severe COPD.Trial registration
ClinicalTrials.gov: (ACCLAIM/COPD I) and NCT00363896 (ACCLAIM/COPD II). NCT00358436相似文献112.
Detection of viable and dead Listeria monocytogenes on gouda-like cheeses by real-time PCR 总被引:4,自引:0,他引:4
AIMS: Surface contamination by Listeria monocytogenes of gouda-like cheeses during processing represents a potential public health problem. The aim of this work was to develop novel real-time PCR diagnostics to detect the presence of viable, dead or viable but not culturable (VBNC) cells on gouda-like cheeses. METHODS AND RESULTS: We used ethidium monoazide bromide (EMA)-PCR for direct quantification of viable and dead cells, while semiquantitative detection of culturable cells below the PCR detection limit (c. 100 CFU g(-1)) was obtained by combining growth and real-time PCR. We were able to quantify the fraction of >0.5% viable cells in a background of dead cells by EMA-PCR, given that the viable cell concentration was above the PCR detection limit. The combined growth and real-time PCR complemented the EMA-PCR, and enabled semiquantitative detection of low levels of culturable cells (10 and 100 CFU g(-1)). SIGNIFICANCE AND IMPACT OF THE STUDY: The significance of this work is that we have developed a novel concept for detection of viable and potentially infectious L. monocytogenes. 相似文献
113.
Mild one-pot protocols for the preparation of glycosyl bromides and alkyl bromides via in situ generation of HBr is reported here. 相似文献
114.
Grifolin is a natural biologically active substance isolated from the fresh fruiting bodies of the mushroom Albatrellus confluens. Here, for the first time, we describe a novel activity of grifolin, namely its ability to inhibit the growth of tumor cells by the induction of apoptosis. Grifolin strongly inhibited the growth of tumor cell lines: CNE1, HeLa, MCF7, SW480, K562, Raji and B95-8. Analysis of acridine orange (AO)/ethidium bromide (EB) staining and flow cytometry showed that grifolin possessed apoptosis induction activity to CNE1, HeLa, MCF7 and SW480. Furthermore, the cytochrome c release from mitochondria was detected by confocal microscopy in CNE1 cells after a 12h treatment with grifolin. The increase of caspase-8, 9, 3 activities revealed that caspase was a key mediator of the apoptotic pathway induced by grifolin, and the underexpression of Bcl-2 and up-regulation of Bax resulted in the increase of Bax: Bcl-2 ratio, suggesting that Bcl-2 family involved in the control of apoptosis. Owing to the combination of the significant antitumor activity by inducing apoptosis and natural abundance of the compound, grifolin holds the promise of being an interesting antitumor agent that deserves further laboratory and in vivo exploration. 相似文献
115.
Understanding the molecular pathway(s) of antioxidant gene regulation is of crucial importance for developing antioxidant-inducing agents for the intervention of oxidative cardiac disorders. Accordingly, this study was undertaken to determine the role of Nrf2 signaling in the basal expression as well as the chemical inducibility of endogenous antioxidants and phase 2 enzymes in cardiac fibroblasts. The basal expression of a scope of key cellular antioxidants and phase 2 enzymes was significantly lower in cardiac fibroblasts derived from Nrf2-/- mice than those from wild type control. These include catalase, reduced glutathione (GSH), glutathione reductase (GR), GSH S-transferase (GST), and NAD(P)H:quinone oxidoreductase-1 (NQO1). Incubation of Nrf2+/+ cardiac fibroblasts with 3H-1,2-dithiole-3-thione (D3T) led to a significant induction of superoxide dismutase (SOD), catalase, GSH, GR, glutathione peroxidase (GPx), GST, and NQO1. The inducibility of SOD, catalase, GSH, GR, GST, and NQO1, but not GPx by D3T was completely abolished in Nrf2-/- cells. The Nrf2-/- cardiac fibroblasts were much more sensitive to reactive oxygen and nitrogen species-mediated cytotoxicity. Upregulation of antioxidants and phase 2 enzymes by D3T in Nrf2+/+ cardiac fibroblasts resulted in a dramatically increased resistance to the above species-induced cytotoxicity. In contrast, D3T-treatment of the Nrf2-/- cells only provided a slight cytoprotection. Taken together, this study demonstrates for the first time that Nrf2 is critically involved in the regulation of the basal expression and chemical induction of a number of antioxidants and phase 2 enzymes in cardiac fibroblasts, and is an important factor in controlling cardiac cellular susceptibility to reactive oxygen and nitrogen species-induced cytotoxicity. 相似文献
116.
Inhibitory effects of anticancer peptide from Mercenaria on the BGC-823 cells and several enzymes 总被引:8,自引:0,他引:8
An anti-cancer peptide was purified from the Mercenaria (Meretrix meretrix Linnaeus) by the method of chromatography on Sephadex G-25 and FPLC, and its molecular weight was determined to be 3147 Da by the way of MALDI-TOF mass spectrum. The effects of this peptide on human gastric gland carcinoma cells (BGC-823) and their cytoskeletal morphology were investigated. The results showed that the peptide could inhibit the proliferation of BGC-823 cells and obviously destroy the skeletal structures of the cells. When the concentration of the peptide reached 4.0 microg/ml, the inhibition percentage of the cell growth was about 60%. The effects of this anticancer peptide on the activities of superoxide dismutase (SOD), alkaline phosphatase (ALP) and tyrosinase were studied. The results showed that the peptide activated ALP and SOD, but inhibit the tyrosinase activity. When the concentration of the peptide reached to 0.5 microg/ml, the relative activities of SOD, ALP and tyrosinase were determined to be 188.5%, 122.0% and 27.5%, respectively. 相似文献
117.
The complexes of horse myoglobin (Mb) with the anionic surfactant sodium dodecyl sulfate (SDS), and with the cationic surfactants cetyltrimethylammonium chloride (CTAC) and decyltrimethylammonium bromide (DeTAB), have been studied by a combination of surface tension measurements and optical spectroscopy, including heme absorption and aromatic amino acid fluorescence. SDS interacts in a monomeric form with Mb, which suggests the existence of a specific binding site for SDS, and induces the formation of a hexacoordinated Mb heme, possibly involving the distal histidine. Fluorescence spectra display an increase of tryptophan emission. Both effects point to an increased protein flexibility. SDS micelles induce both the appearance of two more heme species, one of which has the features of free heme, and protein unfolding. Mb/CTAC complexes display a very different behavior. CTAC monomers have no effect on the absorption spectra, and only a slight effect on the fluorescence spectra, whereas the formation of CTAC aggregates on the protein strongly affects both absorption and fluorescence. Mb/DeTAB complexes behave in a very similar way as Mb/CTAC complexes. The surface activity of the different Mb/surfactant complexes, as well as the interactions between the surfactants and Mb, are discussed on the basis of their structural properties. 相似文献
118.
Amyloid beta peptide (A beta) is believed to play a central role in the pathogenesis of Alzheimer's disease (AD). However, the form of A beta that induces neurodegeneration in AD, defined here as bioactive A beta, is not clear. Preventing the formation of bioactive A beta or inactivating previously formed bioactive A beta should be a promising approach to treat AD. We have previously developed a cell-based assay for the detection of bioactive A beta species. The assay is based upon the correlation between the ability of an A beta sample to induce a unique form of cellular MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] formazan exocytosis, and its ability to activate glia and induce neurotoxicity. Here, we show that this cell-based assay is not only useful for a cellular model of A beta amyloidogenesis but is also able to detect bioactive A beta species in a transgenic mouse model of AD, as well as in post-mortem cortex samples from AD patients. There is a good correlation between the extent of glia activation and the level of bioactive A beta species in the mouse brain. A promising deuteroporphyrin that can inactivate bioactive A beta species was also identified using this assay. These novel insights and findings should have important implications for the treatment of AD. 相似文献
119.
Paolo Paoli Francesca Sbrana Anna Caselli Paolo Cirri Lucia Formigli Giampaolo Manao Giampietro Ramponi 《Journal of molecular biology》2010,400(4):889-907
Previous works reported that a mild increase in homocysteine level is a risk factor for cardiovascular and neurodegenerative diseases in humans. Homocysteine thiolactone is a cyclic thioester, most of which is produced by an error-editing function of methionyl-tRNA synthetase, causing in vivo post-translational protein modifications by reacting with the ?-amino group of lysine residues. In cells, the rate of homocysteine thiolactone synthesis is strictly dependent on the levels of the precursor metabolite, homocysteine. In this work, using bovine serum albumin as a model, we investigated the impact of N-homocysteinylation on protein conformation as well as its cellular actions. Previous works demonstrated that protein N-homocysteinylation causes enzyme inactivation, protein aggregation, and precipitation. In addition, in the last few years, several pieces of evidence have indicated that protein unfolding and aggregation are crucial events leading to the formation of amyloid fibrils associated with a wide range of human pathologies. For the first time, our results reveal how the low level of protein N-homocysteinylation can induce mild conformational changes leading to the formation of native-like aggregates evolving over time, producing amyloid-like structures. Taking into account the fact that in humans about 70% of circulating homocysteine is N-linked to blood proteins such as serum albumin and hemoglobin, the results reported in this article could have pathophysiological relevance and could contribute to clarify the mechanisms underlying some pathological consequences described in patients affected by hyperhomocysteinemia. 相似文献
120.
Shafqat Nadeem Saeed Ahmad Tahira Fazeelat Muhammad Khawar Rauf Sadia Siddiq Abdul Hameed 《Inorganica chimica acta》2010,363(13):3261-3269
Palladium(II) complexes with triphenylphosphine (PPh3) and thioamides of the general formulae, [Pd(L)2(PPh3)2]Cl2 and [Pd(L)2(PPh3)2] have been prepared and characterized by elemental analysis, IR and NMR (1H, 13C and 31P) methods, and two of them (trans-[Pd(PPh3)2(Dmtu)2]Cl2·(H2O)(CH3OH)0.5 (1) and trans-[Pd(PPh3)2(Mpy)2] (2)) by X-ray crystallography; where L = thiourea (Tu), methylthiourea (Metu), N,N′-dimethylthiourea (Dmtu), tetramethylthiourea (Tmtu), 2-mercaptopyridine (Mpy), 2-mercaptopyrimidine (Mpm) and thionicotinamide (Tna). The spectral data of the complexes are consistent with the sulfur coordination of thioamides to palladium(II). The crystal structures of the complexes show that (1) has ionic character consisting of [Pd(PPh3)2(Dmtu)2]+2 cations and uncoordinated Cl− ions, while (2) is a neutral complex with Mpy behaving as anionic thiolate ligand. The coordination environment around palladium in (2) is nearly regular square-planar, while in (1) the trans angles show significant distortions from 180°. The complexes were screened for antibacterial effects, brine shrimps lethality bioassay and antitumor activity. These complexes showed significant activities in most of the cases against the tested bacteria as compared to that of a standard drug. Their antitumor activity against prostate cancer cells (PC3) is comparable with doxorubicin, together with no cytotoxic effects in brine shrimps lethality bioassay study. 相似文献