全文获取类型
收费全文 | 1016篇 |
免费 | 81篇 |
专业分类
1097篇 |
出版年
2023年 | 2篇 |
2022年 | 11篇 |
2021年 | 18篇 |
2020年 | 11篇 |
2019年 | 16篇 |
2018年 | 29篇 |
2017年 | 25篇 |
2016年 | 32篇 |
2015年 | 55篇 |
2014年 | 52篇 |
2013年 | 84篇 |
2012年 | 69篇 |
2011年 | 90篇 |
2010年 | 48篇 |
2009年 | 36篇 |
2008年 | 68篇 |
2007年 | 60篇 |
2006年 | 51篇 |
2005年 | 52篇 |
2004年 | 49篇 |
2003年 | 44篇 |
2002年 | 39篇 |
2001年 | 7篇 |
2000年 | 7篇 |
1999年 | 9篇 |
1998年 | 6篇 |
1997年 | 13篇 |
1996年 | 8篇 |
1995年 | 15篇 |
1994年 | 10篇 |
1993年 | 4篇 |
1992年 | 2篇 |
1991年 | 8篇 |
1990年 | 7篇 |
1989年 | 6篇 |
1988年 | 8篇 |
1987年 | 2篇 |
1986年 | 3篇 |
1985年 | 7篇 |
1984年 | 6篇 |
1983年 | 3篇 |
1982年 | 9篇 |
1981年 | 3篇 |
1977年 | 2篇 |
1976年 | 2篇 |
1975年 | 2篇 |
1971年 | 1篇 |
1968年 | 1篇 |
1967年 | 1篇 |
1965年 | 1篇 |
排序方式: 共有1097条查询结果,搜索用时 0 毫秒
991.
Thomas A. Munro Xi-Ping Huang Carmela Inglese Maria Grazia Perrone Ashlee Van't Veer F. Ivy Carroll Cécile Béguin William A. Carlezon Jr Nicola A. Colabufo Bruce M. Cohen Bryan L. Roth 《PloS one》2013,8(8)
Background
Nor-BNI, GNTI and JDTic induce selective κ opioid antagonism that is delayed and extremely prolonged, but some other effects are of rapid onset and brief duration. The transient effects of these compounds differ, suggesting that some of them may be mediated by other targets.Results
In binding assays, the three antagonists showed no detectable affinity (K i≥10 µM) for most non-opioid receptors and transporters (26 of 43 tested). There was no non-opioid target for which all three compounds shared detectable affinity, or for which any two shared sub-micromolar affinity. All three compounds showed low nanomolar affinity for κ opioid receptors, with moderate selectivity over μ and δ (3 to 44-fold). Nor-BNI bound weakly to the α2C-adrenoceptor (K i = 630 nM). GNTI enhanced calcium mobilization by noradrenaline at the α1A-adrenoceptor (EC50 = 41 nM), but did not activate the receptor, displace radioligands, or enhance PI hydrolysis. This suggests that it is a functionally-selective allosteric enhancer. GNTI was also a weak M1 receptor antagonist (K B = 3.7 µM). JDTic bound to the noradrenaline transporter (K i = 54 nM), but only weakly inhibited transport (IC50 = 1.1 µM). JDTic also bound to the opioid-like receptor NOP (K i = 12 nM), but gave little antagonism even at 30 µM. All three compounds exhibited rapid permeation and active efflux across Caco-2 cell monolayers.Conclusions
Across 43 non-opioid CNS targets, only GNTI exhibited a potent functional effect (allosteric enhancement of α1A-adrenoceptors). This may contribute to GNTI''s severe transient effects. Plasma concentrations of nor-BNI and GNTI may be high enough to affect some peripheral non-opioid targets. Nonetheless, κ opioid antagonism persists for weeks or months after these transient effects dissipate. With an adequate pre-administration interval, our results therefore strengthen the evidence that nor-BNI, GNTI and JDTic are highly selective κ opioid antagonists. 相似文献992.
Marco Busnelli Stefano Manzini Alberto Froio Alessia Vargiolu Maria Grazia Cerrito Ryszard T. Smolenski Massimo Giunti Alessandro Cinti Augusta Zannoni Biagio Eugenio Leone Monica Forni Maria Laura Bacci Giorgio Maria Biasi Roberto Giovannoni Marialuisa Lavitrano 《PloS one》2013,8(11)
Objective
The aim of the present study was to comprehensively evaluate systemic and local inflammation as well as progression of vascular inflammation in normal and mechanically injured vessels in a large animal model of mild hypercholesterolemia. Our aim was also to test the effect of high-dose statin treatment on these processes.Methods
Pigs were kept for 120 days on a standard diet (SD, n=7), high-cholesterol diet (HCD, n=7) or high-cholesterol diet with Atorvastatin starting after 50 days (STATIN, n=7). Left carotid artery balloon injury was conducted in all groups after 60 days of diet treatment. Biochemical analysis together with evaluation of blood and tissue markers of vascular injury and inflammation were performed in all groups at the end of experiment.Results
HCD compared to SD induced systemic inflammation demonstrated by increased number of circulating monocytes and lymphocytes. HCD compared to SD induced also local inflammation demonstrated by adipocyte hypertrophy and infiltration of T-lymphocytes in abdominal white adipose tissue, activation of hepatic stellate cells with infiltration of T- and B-lymphocytes and macrophages in the liver and increased macrophage content in lung parenchyma. These changes were accompanied by increased Intima/Media thickness, stenosis, matrix deposition and activated T-cell infiltrates in injured but not in uninjured contralateral carotid artery as we previously reported. The treatment with high-dose statin attenuated all aspects of systemic and local inflammation as well as pathological changes in injured carotid artery.Conclusions
Diet related mild hypercholesterolemia induce systemic and local inflammation in the liver, lung and adipose tissue that coincide with enhanced inflammation of injured vessel but is without deleterious effect on uninjured vessels. High dose statin attenuated systemic and local inflammation and protected injured vessels. However, finding exact role of reduced systemic and remote inflammation in vascular protection requires further studies. 相似文献993.
Barbara Andria Adele Bracco Chiara Attanasio Sigismondo Castaldo Maria Grazia Cerrito Santolo Cozzolino Daniele Di Napoli Roberto Giovannoni Antonio Mancini Antonino Musumeci Ernesto Mezza Mario Nasti Vincenzo Scuderi Stefania Staibano Marialuisa Lavitrano Leo E. Otterbein Fulvio Calise 《PloS one》2013,8(7)
Ischemia reperfusion injury (IRI) in organ transplantation remains a serious and unsolved problem. Organs that undergo significant damage during IRI, function less well immediately after reperfusion and tend to have more problems at later times when rejection can occur. Biliverdin has emerged as an agent that potently suppress IRI in rodent models. Since the use of biliverdin is being developed as a potential therapeutic modality for humans, we tested the efficacy for its effects on IRI of the liver in swine, an accepted and relevant pre-clinical animal model. Administration of biliverdin resulted in rapid appearance of bilirubin in the serum and significantly suppressed IRI-induced liver dysfunction as measured by multiple parameters including urea and ammonia clearance, neutrophil infiltration and tissue histopathology including hepatocyte cell death. Taken together, our findings, in a large animal model, provide strong support for the continued evaluation of biliverdin as a potential therapeutic in the clinical setting of transplantation of the liver and perhaps other organs. 相似文献
994.
Romina Camilli Laura Daprai Francesca Cavrini Donatella Lombardo Fabio D’Ambrosio Maria Del Grosso Maria Fenicia Vescio Maria Paola Landini Maria Grazia Pascucci Erminio Torresani Maria Laura Garlaschi Vittorio Sambri Annalisa Pantosti 《PloS one》2013,8(10)
Background
In mid 2010, the 7-valent pneumococcal conjugate vaccine (PCV7) was replaced by the 13-valent conjugate vaccine (PCV13) for childhood immunization in Italy. Our objective in this study was to obtain a snapshot of pneumococcal carriage frequency, colonizing serotypes, and antibiotic resistance in healthy children in two Italian cities one year after PCV13 was introduced.Methods
Nasopharyngeal swabs were obtained from 571 children aged 0-5 years from November 2011-April 2012. Pneumococcal isolates were serotyped and tested for antimicrobial susceptibility. Penicillin and/or erythromycin non-susceptible isolates were analyzed by Multi Locus Sequence Typing (MLST).Results
Among the children examined, 81.2% had received at least one dose of PCV7 or PCV13 and 74.9% had completed the recommended vaccination schedule for their age. Among the latter, 57.3% of children had received PCV7, 27.1% PCV13, and 15.6% a combination of the two vaccines. The overall carriage rate was 32.9%, with children aged 6-35 months the most prone to pneumococcal colonization (6-23 months OR: 3.75; 95% CI: 2.19-6.43 and 24-35 months OR: 3.15, 95%CI: 2.36-4.22). A total of 184 pneumococcal isolates were serotyped and divided into PCV7 (5.4%), PCV13 (18.0%), and non-PCV13 (82.0%) serotypes. Serotypes 6C, 24F, and 19A were the most prevalent (10.3%, 8.6%, and 8.1%, respectively). The proportion of penicillin non-susceptible (MIC >0.6 mg/L) isolates was 30.9%, while 42.3% were erythromycin resistant. Non-PCV13 serotypes accounted for 75.4% and 70.8% of the penicillin and erythromycin non-susceptible isolates, respectively.Conclusions
Our results revealed low rates of PCV7 and PCV13 serotypes in Italian children, potentially due to the effects of vaccination. As the use of PCV13 continues, its potential impact on vaccine serotypes such as 19A and cross-reactive serotypes such as 6C will be assessed, with this study providing a baseline for further analysis of surveillance isolates. 相似文献995.
Benfenati V Nicchia GP Svelto M Rapisarda C Frigeri A Ferroni S 《Journal of neurochemistry》2007,100(1):87-104
In the brain, the astroglial syncytium is crucially involved in the regulation of water homeostasis. Accumulating evidence indicates that a dysregulation of the astrocytic processes controlling water homeostasis has a pathogenetic role in several brain injuries. Here, we have analysed by RNA interference technology the functional interactions occurring between the most abundant water channel in the brain, aquaporin-4 (AQP4), and the swelling-activated Cl(-) current expressed by cultured rat cortical astrocytes. We show that in primary cultured rat cortical astrocytes transfected with control small interfering RNA (siRNA), hypotonic shock promotes an increase in cellular volume accompanied by augmented membrane conductance mediated by volume-regulated anion channels (VRAC). Conversely, astroglia in which AQP4 was knocked down (AQP4 KD) by transfection with AQP4 siRNA changed their morphology from polygonal to process-bearing, and displayed normal cell swelling but reduced VRAC activity. Pharmacological manipulations of actin cytoskeleton in rat astrocytes, and functional analysis in mouse astroglial cells, which retain their morphology upon knockdown of AQP4, suggest that stellation of AQP4 KD rat cortical astrocytes was not causally linked to reduction of VRAC current. Molecular analysis of possible candidates of swelling-activated Cl(-) current provided evidence that in AQP4 KD astrocytes, there was a down-regulation of chloride channel-2 (CIC-2), which, however, was not involved in VRAC conductance. Inclusion of ATP in the intracellular saline restored VRAC activity upon hypotonicity. Collectively, these results support the view that in cultured astroglial cells, plasma membrane proteins involved in cell volume homeostasis are assembled in a functional platform. 相似文献
996.
Battaglia G Farrace MG Mastroberardino PG Viti I Fimia GM Van Beeumen J Devreese B Melino G Molinaro G Busceti CL Biagioni F Nicoletti F Piacentini M 《Journal of neurochemistry》2007,100(1):36-49
Transglutaminase 2 (TG2) represents the most ubiquitous isoform belonging to the TG family, and has been implicated in the pathophysiology of basal ganglia disorders, such as Parkinson's disease and Huntington's disease. We show that ablation of TG2 in knockout mice causes a reduced activity of mitochondrial complex I associated with an increased activity of complex II in the whole forebrain and striatum. Interestingly, TG2-/- mice were protected against nigrostriatal damage induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, which is converted in vivo into the mitochondrial complex I inhibitor, 1-methyl-4-phenyl-pyridinium ion. In contrast, TG2-/- mice were more vulnerable to nigrostriatal damage induced by methamphetamine or by the complex II inhibitor, 3-nitropropionic acid. Proteomic analysis showed that proteins involved in the mitochondrial respiratory chain, such as prohibitin and the beta-chain of ATP synthase, are substrates for TG2. These data suggest that TG2 is involved in the regulation of the respiratory chain both in physiology and pathology, contributing to set the threshold for neuronal damage in extrapyramidal disorders. 相似文献
997.
Quantification of PPAR-gamma protein in monocyte/macrophages from healthy smokers and non-smokers: a possible direct effect of nicotine 总被引:1,自引:0,他引:1
Previous observations demonstrated that Peroxisome Proliferator-Activated Receptor-gamma (PPAR-gamma), a key regulator of adipocyte differentiation, is expressed in a large variety of cells, including cells of the monocyte/macrophage lineage. This study was aimed to quantify both the constitutive and ligand-induced PPAR-gamma expression in monocytes and monocyte-derived macrophages (MDM) isolated from healthy smokers and non-smokers, and to evaluate the possible direct effect of nicotine. PPAR-gamma protein was detected by Western blot and quantification was performed by calculating the ratio between PPAR-gamma and beta-actin protein expression. Cytokine release was measured with enzyme-linked immunoassay kits. Constitutive PPAR-gamma protein was detected in human monocytes and its expression was up-regulated along with differentiation to MDM. The endogenous ligand 15-deoxy-delta(12,14)-prostaglandin J(2) and the synthetic agonist ciglitazone enhanced PPAR-gamma expression, the former being effective also at low micromolar concentrations. Both agonists significantly inhibited the basal secretion of pro-inflammatory cytokines (e.g., TNF-alpha, IL-6), ciglitazone being more potent. Monocytes and MDM from healthy smokers presented a significantly enhanced (4-fold and 2.5-fold, respectively) constitutive PPAR-gamma expression, as compared to those from healthy non-smokers. However, ligand-induced PPAR-gamma expression and inhibition of cytokine secretion were similar in healthy smokers and non-smokers. Nicotine dose-dependently enhanced PPAR-gamma expression with a maximum at 10 muM, and inhibited release of pro-inflammatory cytokines; these effects were reversed by alpha-bungarotoxin. Nicotine and PPAR-gamma agonists did not exert synergistic effects. In conclusion, monocytes and MDM from healthy smokers present a constitutively enhanced PPAR-gamma expression; this effect is reproduced, to some extent, by nicotine in vitro. 相似文献
998.
Transglutaminase activity changes during the hypersensitive reaction, a typical defense response of tobacco NN plants to TMV 总被引:1,自引:0,他引:1
Del Duca S Betti L Trebbi G Serafini-Fracassini D Torrigiani P 《Physiologia plantarum》2007,131(2):241-250
The occurrence of glutamyl polyamines (PAs) and changes in activity and levels of transglutaminase (TGase, EC 2.3.2.13), the enzyme responsible for their synthesis, are reported during the progression of the hypersensitive reaction (HR) of resistant NN tobacco plants ( Nicotiana tabacum L. cv. Samsun) to tobacco mosaic virus (TMV). Mature leaves of tobacco were collected over 0–72 h after inoculation with TMV or phosphate buffer (mock). In vivo synthesis of polyamine glutamyl derivatives (glutamyl PAs), catalyzed by TGase activity, was evaluated after supplying labeled putrescine (Pu, a physiological substrate of TGase) to leaves. Results show that, starting from 24 h, mono-( γ -glutamyl)-Pu and bis-( γ -glutamyl)-Sd were recovered in TMV-inoculated samples but not in mock-inoculated ones; 2 days later, in the former, the amount of glutamyl derivatives further increased. An in vitro radiometric assay showed that, in TMV-inoculated leaves, TGase activity increased from 24 h onwards relative to mock controls. An immunoblot analysis with AtPng1p polyclonal antibody detected a 72-kDa protein whose amount increased at 72 h in TMV-inoculated leaves and in the lesion-enriched areas. A biotin-labeled cadaverine incorporation assay showed that TGase activity occurred in S1 (containing soluble proteins), S2 (proteins released by both cell walls and membranes) and S3 (membrane intrinsic proteins) fractions. In S3 fraction, where changes were the most relevant, TGase activity was enhanced in both mock-inoculated and TMV-inoculated samples, but the stimulation persisted only in the latter case. These data are discussed in the light of a possible role of TGase activity and glutamyl PAs in the defense against a viral plant pathogen. 相似文献
999.
Brisdelli F Coccia C Cinque B Cifone MG Bozzi A 《Molecular and cellular biochemistry》2007,296(1-2):137-149
This work shows that 25 μM quercetin caused a marked inhibition of K562 cells growth together with a mild cytotoxicity, while
HSB-2 cells were practically unaffected. Moreover, quercetin induced caspase-3 and cytochrome c-dependent apoptosis almost exclusively in the former cell line. Exposure of K562 cells to quercetin caused also a significant
increase of cells in G2/M phase that reached the maximum peak at 24 h (4-fold with respect to the basal value). The major sensitivity exhibited by
K562 cells was only in part imputable to their higher glutathione content, as compared to HSB-2 cells, thus confirming previous
reports describing the formation of intracellular quercetin–thiol toxic adducts in cells exposed to the flavonoid. In fact,
after induction of intracellular glutathione increase we detected in both cell lines a significant rise of apoptotic cells,
again more marked in K562 cells. By contrast, glutathione-depleted cells, failed to show a decrease of apoptosis in both cell
lines, thus contradicting our previous findings and literature data. Since the yet unresolved question about the anti-oxidant
or the pro-oxidant capacity of quercetin, we investigated which of these two properties worked in our experimental model.
Interestingly, not only quercetin did not produce reactive oxygen species but also prevented their formation, as observed
in cells exposed to the oxidizing agent ter-butylhydroperoxide, acting as an efficient oxygen radicals scavenger. This result
indicates that quercetin exhibited, in these cell lines, anti-oxidant more than pro-oxidant ability. 相似文献
1000.