全文获取类型
收费全文 | 1571篇 |
免费 | 71篇 |
国内免费 | 10篇 |
专业分类
耳鼻咽喉 | 7篇 |
儿科学 | 58篇 |
妇产科学 | 42篇 |
基础医学 | 109篇 |
口腔科学 | 45篇 |
临床医学 | 101篇 |
内科学 | 342篇 |
皮肤病学 | 47篇 |
神经病学 | 242篇 |
特种医学 | 191篇 |
外科学 | 206篇 |
综合类 | 15篇 |
预防医学 | 70篇 |
眼科学 | 7篇 |
药学 | 85篇 |
中国医学 | 1篇 |
肿瘤学 | 84篇 |
出版年
2023年 | 9篇 |
2022年 | 17篇 |
2021年 | 34篇 |
2020年 | 20篇 |
2019年 | 26篇 |
2018年 | 34篇 |
2017年 | 19篇 |
2016年 | 24篇 |
2015年 | 24篇 |
2014年 | 50篇 |
2013年 | 49篇 |
2012年 | 51篇 |
2011年 | 57篇 |
2010年 | 52篇 |
2009年 | 65篇 |
2008年 | 66篇 |
2007年 | 52篇 |
2006年 | 65篇 |
2005年 | 46篇 |
2004年 | 52篇 |
2003年 | 48篇 |
2002年 | 31篇 |
2001年 | 36篇 |
2000年 | 40篇 |
1999年 | 59篇 |
1998年 | 36篇 |
1997年 | 50篇 |
1996年 | 54篇 |
1995年 | 40篇 |
1994年 | 29篇 |
1993年 | 47篇 |
1992年 | 30篇 |
1991年 | 27篇 |
1990年 | 33篇 |
1989年 | 22篇 |
1988年 | 21篇 |
1987年 | 41篇 |
1986年 | 35篇 |
1985年 | 19篇 |
1984年 | 22篇 |
1983年 | 8篇 |
1982年 | 25篇 |
1981年 | 10篇 |
1980年 | 10篇 |
1979年 | 5篇 |
1977年 | 14篇 |
1976年 | 7篇 |
1975年 | 9篇 |
1969年 | 5篇 |
1967年 | 6篇 |
排序方式: 共有1652条查询结果,搜索用时 31 毫秒
991.
G Sciamanna A Tassone G Mandolesi F Puglisi G Ponterio G Martella G Madeo G Bernardi DG Standaert P Bonsi A Pisani 《The Journal of neuroscience》2012,32(35):11991-12004
Projections from thalamic intralaminar nuclei convey sensory signals to striatal cholinergic interneurons. These neurons respond with a pause in their pacemaking activity, enabling synaptic integration with cortical inputs to medium spiny neurons (MSNs), thus playing a crucial role in motor function. In mice with the DYT1 dystonia mutation, stimulation of thalamostriatal axons, mimicking a response to salient events, evoked a shortened pause and triggered an abnormal spiking activity in interneurons. This altered pattern caused a significant rearrangement of the temporal sequence of synaptic activity mediated by M(1) and M(2) muscarinic receptors in MSNs, consisting of an increase in postsynaptic currents and a decrease of presynaptic inhibition, respectively. Consistent with a major role of acetylcholine, either lowering cholinergic tone or antagonizing postsynaptic M(1) muscarinic receptors normalized synaptic activity. Our data demonstrate an abnormal time window for synaptic integration between thalamostriatal and corticostriatal inputs, which might alter the action selection process, thereby predisposing DYT1 gene mutation carriers to develop dystonic movements. 相似文献
992.
Gorgone G Currò M Ferlazzo N Parisi G Parnetti L Belcastro V Tambasco N Rossi A Pisani F Calabresi P Ientile R Caccamo D 《Neuromolecular medicine》2012,14(1):84-90
There is evidence that increased homocysteine (Hcy) levels might accelerate dopaminergic cell death in Parkinson's disease (PD) through neurotoxic effects. Homocysteine neurotoxicity mainly relies on redox state alterations. The present work was aimed at investigating the relationships between plasma Hcy concentrations and percent content of oxidized versus total Coenzyme Q10 (%CoQ10) in 60 PD patients and 82 healthy subjects. Both groups were screened for plasma levels of Hcy, vitamin B12, folate, %CoQ10 and C677T methylenetetrahydrofolate reductase (MTHFR) gene polymorphism. The MTHFR TT677 mutated genotype was found more frequently in patients than in controls (p = 0.01). In a multivariate analysis, Hcy levels and %CoQ10 were associated with the case/control category (p < 0.0001), MTHFR genotype (p < 0.0001) and their interaction term (p = 0.0015), even after adjusting for age, sex, folate and vitamin B12. Patients carrying the TT677 genotype exhibited the highest values of Hcy and %CoQ10 (p < 0.0001). Structural equation modelling evidenced that the TT677 genotype and levodopa daily dose were independently and directly correlated with Hcy (p < 0.0001, and p = 0.003, respectively), which, in turn, showed a significant correlation (p < 0.0001) with the %CoQ10 in PD patients. Our results suggest that increased Hcy levels act as mediator of the systemic oxidative stress occurring in PD, and %CoQ10 determination might be regarded as a predictor of toxic Hcy effects. 相似文献
993.
994.
995.
BR Ito B-H Zhang EE Cable X Song JM Fujitaki DA MacKenna CE Wilker B Chi PD van Poelje DL Linemeyer MD Erion 《British journal of pharmacology》2009,156(3):454-465
Background and purpose:
Thyroid hormone receptor (TR) agonists are in clinical trials for the treatment of hypercholesterolaemia. As statins are the standard of clinical care, any new therapies must have adjunctive activity, when given in combination with statins. As already known for the statins, the cholesterol lowering effect of TR activation involves increased expression of the low-density lipoprotein receptor. Using animal models, we tested whether TR activation would have additive cholesterol lowering activity in the presence of effective doses of a statin.Experimental approach:
We evaluated the activity of a liver-targeted prodrug, MB07811, of a novel TH receptor β agonist, MB07344, as monotherapy and in combination with atorvastatin in rabbits, dogs and monkeys.Key results:
In rabbits, MB07344 (i.v.) decreased total plasma cholesterol (TPC) comparable to that achieved with a maximally effective dose of atorvastatin (p.o.). The addition of MB07344 to atorvastatin resulted in a further decrease in TPC. Similarly, the addition of MB07811 (p.o.) to atorvastatin treatment decreased TPC beyond the level achieved with either agent as monotherapy. In dogs and monkeys, atorvastatin and MB07811 were administered as monotherapy or in combination. Consistent with the rabbit studies, the combination treatment caused a greater decrease in TPC than either MB07811 or atorvastatin administered as monotherapy.Conclusions and implications:
We conclude that the effects of MB07811 and atorvastatin in lowering cholesterol are additive in animals. These results would encourage and support the demonstration of similarly improved efficacy of combination versus monotherapy with such agents in the clinic. 相似文献996.
CE Van Hove C Van der Donckt AG Herman H Bult P Fransen 《British journal of pharmacology》2009,158(3):920-930
Background and purpose:
Reduction of intracellular calcium ([Ca2+]i) in smooth muscle cells (SMCs) is an important mechanism by which nitric oxide (NO) dilates blood vessels. We investigated whether modes of Ca2+ mobilization during SMC contraction influenced NO efficacy.Experimental approach:
Isometric contractions by depolarization (high potassium, K+) or α-adrenoceptor stimulation (phenylephrine), and relaxations by acetylcholine chloride (ACh), diethylamine NONOate (DEANO) and glyceryl trinitrate (GTN) and SMC [Ca2+]i (Fura-2) were measured in aortic segments from C57Bl6 mice.Key results:
Phenylephrine-constricted segments were more sensitive to endothelium-derived (ACh) or exogenous (DEANO, GTN) NO than segments contracted by high K+ solutions. The greater sensitivity of phenylephrine-stimulated segments was independent of the amount of pre-contraction, the source of NO or the resting potential of SMCs. It coincided with a significant decrease of [Ca2+]i, which was suppressed by sarcoplasmic reticulum (SR) Ca2+ ATPase (SERCA) inhibition, but not by soluble guanylyl cylase (sGC) inhibition. Relaxation of K+-stimulated segments did not parallel a decline of [Ca2+]i. However, stimulation (BAY K8644) of L-type Ca2+ influx diminished, while inhibition (nifedipine, 1–100 nM) augmented the relaxing capacity of NO.Conclusions and implications:
In mouse aorta, NO induced relaxation via two pathways. One mechanism involved a non-cGMP-dependent stimulation of SERCA, causing Ca2+ re-uptake into the SR and was prominent when intracellular Ca2+ was mobilized. The other involved sGC-stimulated cGMP formation, causing relaxation without changing [Ca2+]i, presumably by desensitizing the contractile apparatus. This pathway seems related to L-type Ca2+ influx, and L-type Ca2+ channel blockers increase the vasodilator efficacy of NO. 相似文献997.
CE Riera C Menozzi-Smarrito M Affolter S Michlig C Munari F Robert H Vogel SA Simon J le Coutre 《British journal of pharmacology》2009,157(8):1398-1409
Background and purpose:
Oily extracts of Sichuan and Melegueta peppers evoke pungent sensations mediated by different alkylamides [mainly hydroxy-α-sanshool (α-SOH)] and hydroxyarylalkanones (6-shogaol and 6-paradol). We assessed how transient receptor potential ankyrin 1 (TRPA1) and TRP vanilloid 1 (TRPV1), two chemosensory ion channels, participate in these pungent sensations.Experimental approach:
The structure–activity relationships of these molecules on TRPA1 and TRPV1 was measured by testing natural and synthetic analogues using calcium and voltage imaging on dissociated dorsal root ganglia neurons and human embryonic kidney 293 cells expressing the wild-type channels or specific cysteine mutants using glutathione trapping as a model to probe TRPA1 activation. In addition, using Trpv1 knockout mice, the compounds'' aversive responses were measured in a taste brief-access test.Key results:
For TRPA1 activation, the cis C6 double bond in the polyenic chain of α-SOH was critical, whereas no structural specificity was required for activation of TRPV1. Both 6-shogaol and 6-paradol were found to activate TRPV1 and TRPA1 channels, whereas linalool, an abundant terpene in Sichuan pepper, activated TRPA1 but not TRPV1 channels. Alkylamides and 6-shogaol act on TRPA1 by covalent bonding whereas none of these compounds activated TRPV1 through such interactions. Finally, TRPV1 mutant mice retained sensitivity to 6-shogaol but were not responsive to α-SOH.Conclusions and implications:
The pungent nature of components of Sichuan and Melegueta peppers was mediated via interactions with TRPA1 and TRPV1 channels and may explain the aversive properties of these compounds. 相似文献998.
BN Smith S Bevan C Vance P Renwick P Wilkinson C Proukakis F Squitieri A Berardelli TT Warner E Reid and CE Shaw 《Clinical genetics》2009,75(5):485-489
Mutation of the atlastin gene ( SPG3A ) is responsible for ∼10% of autosomal dominant hereditary spastic paraplegia (AD-HSP) cases. The goal of this study was to identify novel disease causing atlastin mutations. Atlastin nucleotide variations were detected by direct sequencing of all 14 exons in 70 autosomal dominant (AD), 16 single sibship and 14 sporadic spastic paraplegia patients. Six mis-sense mutations (four of which were novel) were identified in six unrelated AD-HSP kindreds in exons 4, 7 and 8 of the atlastin gene. One kindred with a novel mutation showed variability in clinical phenotype and age of onset. Mutations are predicted to decrease GTPase activity, cause morphological abnormalities of the endoplasmic reticulum and prevent maturation of the Golgi complex resulting in impaired vesicle trafficking. Our study significantly adds to the spectrum of mutations and clinical phenotype of SPG3A . We advocate that all spastin mutation negative AD-HSP kindreds should be screened for pathogenic atlastin mutations regardless of age of onset or phenotypic complexity. 相似文献
999.
G. Orlando P. Di Cocco M. D'Angelo K. Clemente A. Famulari F. Pisani 《Transplantation proceedings》2010,42(4):1011-1013
The objective of regenerative medicine (RM) and Tissue Engineering (TE) is to create living functional tissues to repair or replace tissues or organ functions. This field holds the promise of regenerating damaged tissues and organs in the body. It has the potential to solve the problems of organ shortage and of toxicities deriving from life-long immunosuppression. In fact, cells in the regenerated organ would match those of the patient, from whom they would normally be derived. In the past decade, RM/TE has achieved striking results which are of interest to the transplant community. However, major roadblocks on the avenue to full success include the need for a deeper understanding of cell biology and of interactions with the extracellular matrix. We are presently not able to grow and expand cells indefinitely and safely in various scenarios where RM/TE may be indicated. The production of adequately vascularized scaffolds to optimize nutrients and oxygen delivery, assessment of the viability and function of the cells in the bioengineered construct, and the costs remain areas of scientific research. 相似文献
1000.
MA Momoh MU Adikwu CE Ibezim KC Ofokansi AA Attama 《Asian Pacific journal of tropical medicine》2010,3(6):458-460
ObjectiveTo investigate the characteristics of PEGylated mucin and its potential usage.MethodsMucin was extracted from giant African land snails and PEGylated mucin was prepared with different ratios of PEG 2000-Mwt and mucin (1 : 1, 0 : 1, 2 : 1, 1 : 3 and 3 : 1 to form batch A-E) using solvent technique. The physicochemical properties of mucin were identified and the solubility of mucin was assessed. The thermal properties of PEGylated mucin were measured by differential scanning calorimetry (DSC).ResultsCarbohydrates, proteins and trace amounts of fats were present in snail mucin. The mucin powder was water-soluble at 30°C and more water-soluble at 35°C, but not soluble; in acetone, ethanol, 0.1 M NaOH, 0.1M H2SO4 and 0.1 NH4OH was water-soluble. The melting point Tm ranged from 58.58 °C to 61.17 °C, crystallization temperature Tc 37.08 °C to 39.83 °C, and glass transition temperature Tg 126.85 °C to 138.39 °C. The variation in Tm, Tc, and Tg with the composition in the PEGylaton showed that an interaction between PEG and mucin occured.ConclusionsThis result can serve as a basis for further evaluation of the PEGylation method and be used for drug delivery. 相似文献