全文获取类型
收费全文 | 2070篇 |
免费 | 129篇 |
国内免费 | 2篇 |
出版年
2023年 | 10篇 |
2022年 | 9篇 |
2021年 | 41篇 |
2020年 | 22篇 |
2019年 | 41篇 |
2018年 | 44篇 |
2017年 | 38篇 |
2016年 | 63篇 |
2015年 | 99篇 |
2014年 | 107篇 |
2013年 | 140篇 |
2012年 | 169篇 |
2011年 | 166篇 |
2010年 | 97篇 |
2009年 | 93篇 |
2008年 | 132篇 |
2007年 | 121篇 |
2006年 | 115篇 |
2005年 | 100篇 |
2004年 | 108篇 |
2003年 | 92篇 |
2002年 | 95篇 |
2001年 | 19篇 |
2000年 | 12篇 |
1999年 | 18篇 |
1998年 | 10篇 |
1997年 | 18篇 |
1996年 | 10篇 |
1995年 | 8篇 |
1994年 | 13篇 |
1993年 | 14篇 |
1992年 | 16篇 |
1991年 | 5篇 |
1990年 | 15篇 |
1989年 | 6篇 |
1988年 | 9篇 |
1987年 | 7篇 |
1986年 | 6篇 |
1985年 | 5篇 |
1984年 | 10篇 |
1983年 | 10篇 |
1982年 | 8篇 |
1981年 | 7篇 |
1980年 | 7篇 |
1979年 | 6篇 |
1978年 | 9篇 |
1975年 | 6篇 |
1974年 | 5篇 |
1969年 | 4篇 |
1966年 | 4篇 |
排序方式: 共有2201条查询结果,搜索用时 15 毫秒
61.
Julie Cattelotte Nicolas Tournier Nathalie Rizzo-Padoin† Alfred H. Schinkel‡ Jean-Michel Scherrmann Salvatore Cisternino§ 《Journal of neurochemistry》2009,108(3):767-775
Cationic 99m Tc-agents like 99m Tc-hexakis-2-methoxyisobutyl isonitrile (99m Tc-MIBI) cannot be used for brain imaging because they do not enter the brain as readily as some uncharged 99m Tc-compounds. The mechanism by which cationic 99m Tc-agents are transported across the blood–brain barrier (BBB) remains unclear. We explored 99m Tc-MIBI transport by in situ mouse brain perfusion to determine the influence of BBB features like the ATP-binding cassette transporters (Abcb1/P-glycoprotein (P-gp), Abcc1/Mrp1, and Abcg2/Bcrp), organic cation transporters (Slc22a1-3/Oct1-3), the transmembrane potential and the dipole membrane potential. P-gp reduced 99m Tc-MIBI transport across the BBB of P-gp-deficient mice 2.2-fold, as confirmed by PSC833 and GF120918 inhibition. Paradoxically verapamil decreased its transport '0.6-fold'. Reducing the BBB dipole membrane potential with tetraphenylborate or phloretin increased 99m Tc-MIBI transport about 12- and 20-fold, respectively. Guanidine, diphenhydramine, and carnitine significantly decreased 99m Tc-MIBI transport, but tetraethylammonium did not. 99m Tc-MIBI transport at the BBB is restricted by P-gp but not by Mrp1 or Bcrp. Some organic cations reduced the influx of 99m Tc-MIBI into the brain independently of Oct1, 2 and 3, but this could be due to their effect on another cation transporter. The membrane dipole potential of the luminal BBB membrane appeared to be the main factor restricting 99m Tc-MIBI permeability. 相似文献
62.
Federica Taddei Laura Gazza Salvatore Conti Vera Muccilli Salvatore Foti Norberto Edgar Pogna 《TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik》2009,119(7):1205-1212
The starch granule proteins from 113 einkorn wheat (Triticum monococcum ssp monococcum) accessions were analyzed by acidic, polyacrylamide gel electrophoresis (A-PAGE), and two-dimensional A-PAGE x SDS-PAGE.
All accessions were confirmed to contain equal amounts of two polypeptide chains corresponding to puroindoline B (Pin-B),
as well as a prominent component plus a faint band corresponding to puroindoline A (Pin-A). When compared with soft-textured
common wheat, “monococcum” accessions showed an increase of 3.2- and 2.7-fold in Pin-A and Pin-B levels on the starch granules,
respectively. In addition, all accessions contained a novel component of the 2S super-family of seed proteins named Einkorn
Trypsin Inhibitor (ETI), which was found to be encoded as a pre-protein 148 residues long. Wild-type ETI encoded by allele
Eti-A
m
1a and “valine-type” ETI encoded by allele Eti-A
m
1b, which occurred in 107 and six einkorn accessions, respectively, were found to accumulate on starch granules as a mature
protein of 121 amino acids with a hydrophobic central domain. The einkorn accessions exhibited an average SKCS index as low
as −2.05 ± 11.4, which is typical of extra-soft kernels. The total surface area of starch granules in “monococcum” wheat,
as determined by visual assessments in counting chambers, was estimated at 764 mm2/mg of starch, and was about 1.5 times higher than that for common wheat. The results are discussed in relation to the identification
of factors that cause the extra-soft texture of einkorn kernels. 相似文献
63.
Diego La Mendola Serena Caminati Salvatore S. Emmi Giuseppe Maccarrone Adriana Pietropaolo 《Journal of inorganic biochemistry》2009,103(2):195-204
Potentiometric and spectroscopic (UV-Vis, CD and EPR) studies were carried out on copper(II) complexes with chicken prion protein N-terminal fragments, Ac-(PHNPGY)4-NH2, and the mutated residue, Ac-(PHNPGF)4-NH2, to assess the role of tyrosine in the copper coordination. Both thermodynamic and spectroscopic results indicate that chicken prion fragments are not able to bind more than two copper ions and only with the involvement of side chain tyrosine groups. The prevailing complex shows one copper ion bound to four imidazole nitrogen atoms in the 1:1 metal to ligand ratio systems. The superoxide dismutase (SOD)-like activity of copper(II) complexes with the avian peptides and mammal analogue, Ac-(PHGGGWGQ)4-NH2, was also investigated by means of Pulse radiolysis. The copper(II) complexes with avian peptides do not display SOD-like activity, while very low activity has been detected for the copper(II) complexes with mammalian tetraoctarepeat. 相似文献
64.
Simon N. Haydar Chiara Ghiron Laura Bettinetti Hendrick Bothmann Thomas A. Comery John Dunlop Salvatore La Rosa Iolanda Micco Martina Pollastrini Joanna Quinn Renza Roncarati Carla Scali Michela Valacchi Maurizio Varrone Riccardo Zanaletti 《Bioorganic & medicinal chemistry》2009,17(14):5247-5258
Alpha 7 nicotinic acetylcholine receptor (α7 nAChR) agonists are promising therapeutic candidates for the treatment of cognitive impairment associated with a variety of disorders including Alzheimer’s disease and schizophrenia. Alpha 7 nAChRs are expressed in brain regions associated with cognitive function, regulate cholinergic neurotransmission and have been shown to be down regulated in both schizophrenia and Alzheimer’s disease. Herein we report a novel, potent small molecule agonist of the alpha 7 nAChR, SEN12333/WAY-317538. This compound is a selective agonist of the α7 nAChR with excellent in vitro and in vivo profiles, excellent brain penetration and oral bioavailability, and demonstrates in vivo efficacy in multiple behavioural cognition models. The SAR and biological evaluation of this series of compounds are discussed. 相似文献
65.
Ines Batinić-Haberle Salvatore Cuzzocrea Júlio S. Rebouças Gerardo Ferrer-Sueta Emanuela Mazzon Rosanna Di Paola Rafael Radi Ivan Spasojević Ludmil Benov Daniela Salvemini 《Free radical biology & medicine》2009,46(2):192-201
MnTBAP is often referred to as an SOD mimic in numerous models of oxidative stress. We have recently reported that pure MnTBAP does not dismute superoxide, but commercial or poorly purified samples are able to perform O2·?dismutation with low-to-moderate efficacy via non-innocent Mn-containing impurities. Herein, we show that neither commercial nor pure MnTBAP could substitute for SOD enzyme in a SOD-deficient Escherichia coli model, whereas MnTE-2-PyP-treated SOD-deficient E. coli grew as well as a wild-type strain. This SOD-specific system indicates that MnTBAP does not act as an SOD mimic in vivo. In another model, carrageenan-induced pleurisy in mice, inflammation was evidenced by increased pleural fluid exudate and neutrophil infiltration and activation: these events were blocked by 0.3 mg/kg MnTE-2-PyP and, to a slightly lesser extent, by 10 mg/kg of either MnTBAP. Also, 3-nitrotyrosine formation, an indication of peroxynitrite existence in vivo, was blocked by both compounds; again MnTE-2-PyP was 33-fold more effective. Pleurisy model data indicate that MnTBAP exerts some protective actions in common with MnTE-2-PyP, which are not O2·? related and can be fully rationalized if one considers that the common biological role shared by MnTBAP and MnTE-2-PyP is related to their reduction of peroxynitrite and carbonate radical, the latter arising from ONOOCO2 adduct. The log kcat (O2·?) value for MnTBAP is estimated to be about 3.16, which is ~ 5 and ~ 6 orders of magnitude smaller than the SOD activities of the potent SOD mimic MnTE-2-PyP and Cu,Zn-SOD, respectively. This very low value indicates that MnTBAP is too inefficient at dismuting superoxide to be of any biological impact, which was confirmed in the SOD-deficient E. coli model. The peroxynitrite scavenging ability of MnTBAP, however, is only ~ 2.5 orders of magnitude smaller than that of MnTE-2-PyP and is not significantly affected by the presence of the SOD-active impurities in the commercial MnTBAP sample (log kred (ONOO?) = 5.06 for pure and 4.97 for commercial sample). The reduction of carbonate radical is equally fast with MnTBAP and MnTE-2-PyP. The dose of MnTBAP required to yield oxidative stress protection and block nitrotyrosine formation in the pleurisy model is > 1.5 orders of magnitude higher than that of MnTE-2-PyP, which could be related to the lower ability of MnTBAP to scavenge peroxynitrite. The slightly better protection observed with the commercial MnTBAP sample (relative to the pure MnTBAP) could arise from its impurities, which, by scavenging O2·?, reduce consequently the overall peroxynitrite and secondary ROS/RNS levels. These observations have profound biological repercussions as they may suggest that the effect of MnTBAP observed in numerous studies may conceivably relate to peroxynitrite scavenging. Moreover, provided that pure MnTBAP is unable to dismute superoxide at any significant extent, but is able to partially scavenge peroxynitrite and carbonate radical, this compound may prove valuable in distinguishing ONOO?/CO3·? from O2·? pathways. 相似文献
66.
S. Arpaia J.E.U. Schmidt G.M. Di Leo M.C. Fiore 《Biocontrol Science and Technology》2009,19(9):971-984
Generalist predators are relevant natural enemies of the Colorado potato beetle (CPB) in Europe. In fields of insect resistant genetically modified plants (GMPs), predators could be exposed to toxins either directly (e.g., via pollen), or indirectly through feeding on herbivorous prey. Hence, they represent an important functional group to consider when studying environmental impacts of GMPs. CPB females show a ‘bet-hedging’ strategy in spatial and temporal distribution of eggs, through which the species tries to minimize the risks of progeny loss due to adverse conditions. Experimental fields of GM eggplants expressing Cry3Bb toxin and potatoes expressing Cry1Ab toxin were set up. CPB egg masses were counted on naturally infested plants at four time points during the field season of each crop. To assess predation, newly deposited egg masses were marked at the same dates. Daily visual observations were conducted recording the numbers of intact or preyed eggs and neonate larvae. In both cases, oviposition was similar between GM and control plots, as the number of egg masses per plant and the number of eggs per mass did not differ significantly between treatments. A statistical analysis of the spatial distribution of egg masses revealed a similar aggregation in the potato field, whereas in the eggplant field, the variance of the number of egg masses per plant was smaller than expected in GMP plots. The predation rate was similar between treatments. These results suggest that the ecological function of natural predation on CPB eggs in GM plots was not impaired. 相似文献
67.
cAMP‐dependent, PKA‐independent effects on cell proliferation are mediated by cAMP binding to EPAC and activation of Rap signaling. In this report, we employed the analogue 8‐CPT‐2‐O‐Me‐cAMP to study binding to EPAC and subsequent activation of B‐Raf/ERK and mTOR signaling in human cancer cells. This compound significantly stimulated DNA synthesis, protein synthesis, and cellular proliferation of human 1‐LN prostate cancer cells. By study of phosphorylation‐dependent activation, we demonstrate that EPAC‐mediated cellular effects require activation of the B‐Raf/ERK and mTOR signaling cascades. RNAi directed against EPAC gene expression as well as inhibitors of ERK, PI 3‐kinase, and mTOR were employed to further demonstrate the role of these pathways in regulating prostate cancer cell proliferation. These studies were then extended to several other human prostate cancer cell lines and melanoma cells with comparable results. We conclude that B‐Raf/ERK and mTOR signaling play an essential role in cAMP‐dependent, but PKA‐independent, proliferation of cancer cells. J. Cell. Biochem. 108: 998–1011, 2009. © 2009 Wiley‐Liss, Inc. 相似文献
68.
Sandra Lorenzini Silvia Olmastroni Francesco Pezzo Maria Cristina Salvatore Carlo Baroni 《Polar Biology》2009,32(7):1077-1086
Ornithogenic soils (N = 97) dated up to 7000 Before Present (bp) were sampled in 16 relict and modern breeding colonies of Adélie penguin along the Victoria Land coast (Ross Sea, Antarctica).
Taxonomic identification of fish otoliths (N = 677) recovered in these soils allowed to identify the Antarctic silverfish as the most eaten prey (90.1%) throughout the
investigated period. A morphometric analysis of the otoliths revealed that the Adélie penguin primarily selected prey averaging
67.23 ± 23 mm of standard length. Temporal distribution of Pleuragramma antarcticum showed a peak between 2,000 and 4,000 years bp, a period corresponding to the maximum spread of Adélie penguin in the Victoria Land. Possible explanations of the variations
of the abundance of the fish prey in the diet are discussed in the context of the paleoclimatic events and as possible consequences
of dietary shifts due to the temporal variation of prey availability in the Ross Sea ecosystem. 相似文献
69.
Sergio Papa Vittoria Petruzzella Salvatore Scacco Arcangela Iuso Rita Vitale Domenico De Rasmo Claudia Piccoli Michele Scivetti Teresa Rizza 《BBA》2009,1787(5):502-764
This paper covers genetic and biochemical aspects of mitochondrial bioenergetics dysfunction in hereditary neurological disorders associated with complex I defects. Three types of hereditary complex I dysfunction are dealt with: (i) homozygous mutations in the nuclear genes NDUFS1 and NDUFS4 of complex I, associated with mitochondrial encephalopathy; (ii) a recessive hereditary epileptic neurological disorder associated with enhanced proteolytic degradation of complex I; (iii) homoplasmic mutations in the ND5 and ND6 mitochondrial genes of the complex, cohexistent with mutation in the nuclear PINK1 gene in familial Parkinsonism. The genetic and biochemical data examined highlight different mechanisms by which mitochondrial bioenergetics is altered in these hereditary defects of complex I. This knowledge, besides clarifying molecular aspects of the pathogenesis of hereditary diseases, can also provide hints for understanding the involvement of complex I in sporadic neurological disorders and aging, as well as for developing therapeutical strategies. 相似文献
70.
Eddy Karnabi Yongxia Qu Salvatore Mancarella Raj Wadgaonkar Mohamed Boutjdir 《Biochemical and biophysical research communications》2009,384(4):409-414
Cav1.2 (α1C) and Cav1.3 (α1D) L-type Ca channels are co-expressed in the heart. To date, there are no pharmacological or biophysical tools to separate α1D from α1C Ca currents (ICa-L) in cardiomyocytes. Here, we established a physiological model to study α1D ICa-L in native myocytes using RNA interference. Transfection of rat neonatal cardiomyocytes (RNC) with α1C specific siRNA resulted in low silencing efficiency (50-60%) at the mRNA and protein levels. The use of lentivirus shRNA resulted in 100% transfection efficiency and 92% silencing of the α1C gene by real-time PCR and Western blot. Electrophysiological experiments showed that the total ICa-L was similarly reduced by 80% in lentivirus transfected cells. Both biochemical and functional data demonstrated high transfection and silencing efficiency in the cardiomyocytes using lentiviral shRNA. This novel approach allows for the assessments of the roles of α1C and α1D Ca channels in native myocytes and could be used to examine their roles in physiological and pathological settings. 相似文献