全文获取类型
收费全文 | 10416篇 |
免费 | 851篇 |
国内免费 | 9篇 |
专业分类
11276篇 |
出版年
2023年 | 49篇 |
2022年 | 90篇 |
2021年 | 197篇 |
2020年 | 129篇 |
2019年 | 124篇 |
2018年 | 177篇 |
2017年 | 139篇 |
2016年 | 298篇 |
2015年 | 458篇 |
2014年 | 547篇 |
2013年 | 690篇 |
2012年 | 836篇 |
2011年 | 830篇 |
2010年 | 498篇 |
2009年 | 477篇 |
2008年 | 636篇 |
2007年 | 683篇 |
2006年 | 651篇 |
2005年 | 556篇 |
2004年 | 573篇 |
2003年 | 541篇 |
2002年 | 533篇 |
2001年 | 109篇 |
2000年 | 84篇 |
1999年 | 120篇 |
1998年 | 152篇 |
1997年 | 105篇 |
1996年 | 97篇 |
1995年 | 106篇 |
1994年 | 90篇 |
1993年 | 83篇 |
1992年 | 90篇 |
1991年 | 43篇 |
1990年 | 49篇 |
1989年 | 37篇 |
1988年 | 38篇 |
1987年 | 25篇 |
1986年 | 36篇 |
1985年 | 32篇 |
1984年 | 27篇 |
1983年 | 27篇 |
1982年 | 37篇 |
1981年 | 29篇 |
1980年 | 23篇 |
1979年 | 19篇 |
1978年 | 11篇 |
1977年 | 25篇 |
1976年 | 17篇 |
1974年 | 8篇 |
1973年 | 11篇 |
排序方式: 共有10000条查询结果,搜索用时 0 毫秒
961.
Pirnay S Bouchonnet S Hervé F Libong D Milan N D'Athis P Baud F Ricordel I 《Journal of chromatography. B, Analytical technologies in the biomedical and life sciences》2004,807(2):335-342
Buprenorphine (BUP), a synthetic opioid analgesic, is frequently abused alone, and in association with benzodiazepines. Fatalities involving buprenorphine alone seem very unusual while its association with benzodiazepines, such as flunitrazepam (FNZ), has been reported to result in severe respiratory depression and death. The quantitative relationship between these drugs remain, however, uncertain. Our objective was to develop an analytical method that could be used as a means to study and explore, in animals, the toxicity and pharmacological interaction mechanisms between buprenorphine, flunitrazepam and their active metabolites. A procedure based on gas chromatography-mass spectrometry (GC-MS) is described for the simultaneous analysis of buprenorphine, norbuprenorphine (NBUP), flunitrazepam, N-desmethylflunitrazepam (N-DMFNZ) and 7-aminoflunitrazepam (7-AFNZ) in rat plasma. The method was set up and adapted for the analysis of small plasma samples taken from rats. Plasma samples were extracted by liquid-liquid extraction using Toxi-tubes A. Extracted compounds were derivatized with N,O-bis-(trimethylsilyl)trifluoroacetamide (BSTFA), using trimethylchlorosilane (TMCS) as a catalyst. They were then separated by GC on a crosslinked 5% phenyl-methylpolysiloxane analytical column and determined by a quadrupole mass spectrometer detector operated under selected ion monitoring mode. Excellent linearity was found between 0.125 and 25 ng/microl plasma for BUP, 0.125 and 12.5 ng/microl for NBUP and N-DMFNZ, 0.125 and 5 ng/microl for FNZ, and between 0.025 and 50 ng/microl for 7-AFNZ. The limit of quantification was 0.025 ng/microl plasma for 7-AFNZ and 0.125 ng/microl for the four other compounds. A good reproducibility (intra-assay CV=0.32-11.69%; inter-assay CV=0.63-9.55%) and accuracy (intra-assay error=2.58-12.73%; inter-assay error=0.83-11.07%) were attained. Recoveries were 71, 67 and 81%, for BUP, FNZ and N-DMFNZ, respectively, and 51% for NBUP and 7-AFNZ, with CV ranging from 5.4 to 13.9%, and were concentration-independent. The GC-MS method was successfully applied to the pharmacokinetic study of BUP, NBUP, FNZ, DMFNZ and 7-AFNZ in rats, after administration of BUP and FNZ. 相似文献
962.
Sansonetti PJ 《Nature reviews. Immunology》2004,4(12):953-964
That we live with numerous bacteria in our gut without any adverse effects is a remarkable feat by the body's immune system, particularly considering the wealth of sensing and effector systems that are available to trigger inflammatory or innate immune responses to microbial intrusion. So, a fine line seems to exist between the homeostatic balance maintained in the presence of commensal gut flora and the necessarily destructive response to bacterial pathogens that invade the gut mucosa. This review discusses the mechanisms for establishing and controlling the 'dialogue' between unresponsiveness and initiation of active immune defences in the gut. Si vis pacem, para bellum. (If you wish for peace, prepare for war.). 相似文献
963.
Renault J Bernard A Brajeul S Verhaeghe P Butt S Fabis F Dauphin F Uriac P Rault S 《Journal of enzyme inhibition and medicinal chemistry》2004,19(6):577-583
A series of N-omega-aminoalkyl- or N-omega-amidinoalkyl-2,4,6-triisopropyl benzenesulfonamides has been synthesized and their respective affinity indices on 5-HT6 receptor determined. This evaluation clearly showed that the compounds possessing an arylpiperazine moiety or an amidine function exhibited good affinity for the model. 相似文献
964.
Farce A Loge C Gallet S Lebegue N Carato P Chavatte P Berthelot P Lesieur D 《Journal of enzyme inhibition and medicinal chemistry》2004,19(6):541-547
Cancer is a major cause of mortality in developed countries, following only cardiovascular diseases. Death of cancerous cells can be achieved by stopping mitosis and the antimitotic class of drugs formed by the spindle poisons can be used for this purpose. Their role is to disorganize the mitotic spindle by targeting its main constituent, the microtubules, themselves made of heterodimers of alpha and beta-tubulin. They disrupt the dynamics of the microtubules either by stabilizing them, as do paclitaxel or epothilones, or destabilizing them, as do colchicine. The binding site of colchicine seems to lie between the two units of the tubulin dimer. Here, we report on the characterization of this site by the docking of a series of reference compounds, and the subsequent docking of ligands prepared in our laboratory. 相似文献
965.
Yannick?AllanoreEmail author Didier?Borderie Axel?Périanin Hervé?Lemaréchal Ohvanesse?Garabed?Ekindjian André?Kahan 《Arthritis research & therapy》2004,7(1):R93
We have reported previously that dihydropyridine-type calcium-channel antagonists (DTCCA) such as nifedipine decrease plasma
markers of oxidative stress damage in systemic sclerosis (SSc). To clarify the cellular basis of these beneficial effects,
we investigated the effects in vivo and in vitro of nifedipine on superoxide anion (O2
•-) production by peripheral blood monocytes. We compared 10 healthy controls with 12 patients with SSc, first after interruption
of treatment with DTCCA and second after 2 weeks of treatment with nifedipine (60 mg/day). O2
•- production by monocytes stimulated with phorbol myristate acetate (PMA) was quantified by the cytochrome c reduction method. We also investigated the effects in vitro of DTCCA on O2
•- production and protein phosphorylation in healthy monocytes and on protein kinase C (PKC) activity using recombinant PKC.
After DTCCA had been washed out, monocytes from patients with SSc produced more O2
•- than those from controls. Nifedipine treatment considerably decreased O2
•- production by PMA-stimulated monocytes. Treatment of healthy monocytes with nifedipine in vitro inhibited PMA-induced O2
•- production and protein phosphorylation in a dose-dependent manner. Finally, nifedipine strongly inhibited the activity of
recombinant PKC in vitro. Thus, the oxidative stress damage observed in SSc is consistent with O2
•- overproduction by primed monocytes. This was decreased by nifedipine treatment both in vivo and in vitro. This beneficial property of nifedipine seems to be mediated by its cellular action and by the inhibition of PKC activity.
This supports the hypothesis that this drug could be useful for the treatment of diseases associated with oxidative stress. 相似文献
966.
Picard M Duval-Terrié C Dé E Champeil P 《Protein science : a publication of the Protein Society》2004,13(11):3056-3058
Amphipathic polymers derived from polysaccharides, namely hydrophobically modified pullulans, were previously suggested to be useful as polymeric substitutes of ordinary surfactants for efficient and structure-conserving solubilization of membrane proteins, and one such polymer, 18C(10), was optimized for solubilization of proteins derived from bacterial outer membranes (Duval-Terrie et al. 2003). We asked whether a similar ability to solubilize proteins could also be demonstrated in eukaryotic membranes, namely sarcoplasmic reticulum (SR) fragments, the major protein of which is SERCA1a, an integral membrane protein with Ca(2+)-dependent ATPase and Ca(2+)-pumping activity. We found that 18C(10)-mediated solubilization of these SR membranes did not occur. Simultaneously, however, we found that low amounts of this hydrophobically modified pullulan were very efficient at preventing long-term aggregation of these SR membranes. This presumably occurred because the negatively charged polymer coated the membranous vesicles with a hydrophilic corona (a property shared by many other amphipathic polymers), and thus minimized their flocculation. Reminiscent of the old Arabic gum, which stabilizes Indian ink by coating charcoal particles, the newly designed amphipathic polymers might therefore unintentionally prove useful also for stabilization of membrane suspensions. 相似文献
967.
Houle-Leroy P Guderley H Swallow JG Garland T 《American journal of physiology. Regulatory, integrative and comparative physiology》2003,284(2):R433-R443
After 14 generations of selection for voluntary wheel running, mice from the four replicate selected lines ran, on average, twice as many revolutions per day as those from the four unselected control lines. To examine whether the selected lines followed distinct strategies in the correlated responses of the size and metabolic capacities of the hindlimb muscles, we examined mice from selected lines, housed for 8 wk in cages with access to running wheels that were either free to rotate ("wheel access" group) or locked ("sedentary"). Thirteen of twenty individuals in one selected line (line 6) and two of twenty in another (line 3) showed a marked reduction ( approximately 50%) in total hindlimb muscle mass, consistent with the previously described expression of a small-muscle phenotype. Individuals with these "mini-muscles" were not significantly smaller in total body mass compared with line-mates with normal-sized muscles. Access to free wheels did not affect the relative mass of the mini-muscles, but did result in typical mammalian training effects for mitochondrial enzyme activities. Individuals with mini-muscles showed a higher mass-specific muscle aerobic capacity as revealed by the maximal in vitro rates of citrate synthase and cytochrome c oxidase. Moreover, these mice showed the highest activities of hexokinase and carnitine palmitoyl transferase. Females with mini-muscles showed the highest levels of phosphofructokinase, and males with mini-muscles the highest levels of pyruvate dehydrogenase. As shown by total muscle enzyme contents, the increase in mass-specific aerobic capacity almost completely compensated for the reduction caused by the "loss" of muscle mass. Moreover, the mini-muscle mice exhibited the lowest contents of lactate dehydrogenase and glycogen phosphorylase. Interestingly, metabolic capacities of mini-muscled mice resemble those of muscles after endurance training. Overall, our results demonstrate that during selection for voluntary wheel running, distinct adaptive paths that differentially exploit the genetic variation in morphological and physiological traits have been followed. 相似文献
968.
Ruot B Papet I Bechereau F Denis P Buffiere C Gimonet J Glomot F Elyousfi M Breuille D Obled C 《American journal of physiology. Regulatory, integrative and comparative physiology》2003,284(3):R707-R713
The mechanisms leading to hypoalbuminemia in sepsis were explored by measuring plasma volume, albumin distribution, plasma albumin transcapillary escape rate (TER), and efflux (TER x albumin intravascular pool). These parameters were quantified in infected rats, injected intravenously with live Escherichia coli, and pair-fed and well-fed rats using an injection of (35)S-albumin and measuring plasma and whole body albumin concentrations. Animals were studied on days 1, 6, and 10 after infection. In pair-fed rats, neither albumin distribution nor exchange rate between the intra- and extravascular compartments was modified. The increase of plasma volume after infection partly explained hypoalbuminemia. Infection resulted in a reduction of the total albumin pool of the body all along the experimental period, indicating a net loss of the protein. Albumin TER (%/day) was significantly increased 1 and 6 days after infection, but the absolute efflux was increased only on day 1. Normal values were observed on day 10. Therefore, an accelerated plasma efflux contributes to hypoalbuminemia only during the early period of sepsis. During this phase, the protein was retained in the extravascular space where it was probably catabolized. Later on, other factors are probably involved. 相似文献
969.
Génissel A Augustin S Courtin C Pilate G Lorme P Bourguet D 《Proceedings. Biological sciences / The Royal Society》2003,270(1517):791-797
Globally, the estimated total area planted with transgenic plants producing Bacillus thuringiensis (Bt) toxins was 12 million hectares in 2001. The risk of target pests becoming resistant to these toxins has led to the implementation of resistance-management strategies. The efficiency and sustainability of these strategies, including the high-dose plus refuge strategy currently recommended for North American maize, depend on the initial frequency of resistance alleles. In this study, we estimated the initial frequencies of alleles conferring resistance to transgenic Bt poplars producing Cry3A in a natural population of the poplar pest Chrysomela tremulae (Coleoptera: Chrysomelidae). We used the F(2) screen method developed for detecting resistance alleles in natural pest populations. At least three parents of the 270 lines tested were heterozygous for a major Bt resistance allele. We estimated mean resistance-allele frequency for the period 1999-2001 at 0.0037 (95% confidence interval = 0.00045-0.0080) with a detection probability of 90%. These results demonstrate that (i) the F(2) screen method can be used to detect major alleles conferring resistance to Bt-producing plants in insects and (ii) the initial frequency of alleles conferring resistance to Bt toxin can be close to the highest theoretical values that are expected prior to the use of Bt plants if considering fitness costs and typical mutation rates. 相似文献
970.
Vermeiren GL Willems R Claeys MJ Vrints C Slegers H Jorens PG 《Mediators of inflammation》2003,12(5):269-275
BACKGROUND: Many papers have focused on the importance of granulocytes in the process of reperfusion and ischemia. Most of the clinical studies measured several parameters of this process during and after coronary angiography, without taking into account the effect of the radiographic contrast media (RCM) used during this procedure. MATERIALS AND METHODS: We performed a randomized patient study (n = 37) to evaluate the effect of ionic and non-ionic RCM on granulocyte adhesion during coronary angiography. We also evaluated the influence of the ionicity and osmolarity of the different substances on granulocyte adhesion molecules in in vitro experiments. RESULTS: The osmolarity of patient serum samples increased from 302 +/- 1 to 309 +/- 1 mOsm/kg (p < 0.05) after infusion of RCM. The CD11b expression in the samples of the non-ionic RCM treated group increased from 221 +/- 21 MFI to 377 +/- 30 MFI (p < 0.05) measured as the absolute mean fluorescence intensity (MFI), yet did not alter significantly in the ionic RCM group. In contrast, the in vitro experiments showed a reduction of the CD11b expression from 360 +/- 70 MFI to 149 +/- 30 MFI (p < 0.05) in the ionic RCM group. CONCLUSIONS: The upregulation of adhesion molecules was significantly reduced in vivo with ionic RCM, while ionic substances caused opposite effects in vitro. This effect should be taken into account when performing leukocyte functional analysis of samples taken during angiography. 相似文献