全文获取类型
收费全文 | 861篇 |
免费 | 32篇 |
国内免费 | 11篇 |
专业分类
耳鼻咽喉 | 1篇 |
基础医学 | 159篇 |
临床医学 | 13篇 |
内科学 | 26篇 |
神经病学 | 459篇 |
特种医学 | 3篇 |
外科学 | 5篇 |
综合类 | 64篇 |
眼科学 | 4篇 |
药学 | 145篇 |
中国医学 | 25篇 |
出版年
2023年 | 2篇 |
2022年 | 5篇 |
2021年 | 11篇 |
2020年 | 9篇 |
2019年 | 8篇 |
2018年 | 10篇 |
2017年 | 8篇 |
2016年 | 26篇 |
2015年 | 15篇 |
2014年 | 20篇 |
2013年 | 35篇 |
2012年 | 34篇 |
2011年 | 56篇 |
2010年 | 55篇 |
2009年 | 47篇 |
2008年 | 44篇 |
2007年 | 48篇 |
2006年 | 53篇 |
2005年 | 37篇 |
2004年 | 38篇 |
2003年 | 37篇 |
2002年 | 34篇 |
2001年 | 30篇 |
2000年 | 14篇 |
1999年 | 24篇 |
1998年 | 18篇 |
1997年 | 18篇 |
1996年 | 13篇 |
1995年 | 13篇 |
1994年 | 14篇 |
1993年 | 14篇 |
1992年 | 12篇 |
1991年 | 10篇 |
1990年 | 10篇 |
1989年 | 16篇 |
1988年 | 12篇 |
1987年 | 10篇 |
1986年 | 17篇 |
1985年 | 19篇 |
1984年 | 7篇 |
1983年 | 1篇 |
排序方式: 共有904条查询结果,搜索用时 0 毫秒
21.
22.
N. Kintz G.M. Petzinger G. Akopian S. Ptasnik C. Williams M.W. Jakowec J.P. Walsh 《Journal of neuroscience research》2013,91(11):1492-1507
The α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic‐acid‐type glutamate receptor (AMPAR) plays a critical role in modulating experience‐dependent neuroplasticity, and alterations in AMPAR expression may underlie synaptic dysfunction and disease pathophysiology. Using the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) mouse model of dopamine (DA) depletion, our previous work showed exercise increases total GluA2 subunit expression and the contribution of GluA2‐containing channels in MPTP mice. The purpose of this study was to determine whether exercise‐dependent changes in AMPAR expression after MPTP are specific to the striatopallidal (D2R) or striatonigral (D1R) medium spiny neuron (MSN) striatal projection pathways. Drd2‐eGFP‐BAC transgenic mice were used to delineate differences in AMPAR expression between striatal D2R‐MSNs and D1R‐MSNs. Striatal AMPAR expression was assessed by immunohistochemical (IHC) staining, Western immunoblotting (WB) of preparations enriched for postsynaptic density (PSD), and alterations in the current–voltage relationship of MSNs. We found DA depletion results in the emergence of GluA2‐lacking AMPARs selectively in striatopallidal D2R‐MSNs and that exercise reverses this effect in MPTP mice. Exercise‐induced changes in AMPAR channels observed after DA depletion were associated with alterations in GluA1 and GluA2 subunit expression in postsynaptic protein, D2R‐MSN cell surface expression, and restoration of corticostriatal plasticity. Mechanisms regulating experience‐dependent changes in AMPAR expression may provide innovative therapeutic targets to increase the efficacy of treatments for basal ganglia disorders, including Parkinson's disease. © 2013 Wiley Periodicals, Inc. 相似文献
23.
24.
Ruili Wang Ying Yang Hui Wang Ya He Chen Li 《Clinical and experimental pharmacology & physiology》2020,47(3):372-382
MicroRNAs (miRNAs) have been shown to have complicated implications in the pathogenesis of Parkinson's disease (PD). However, the role of miR-29c and the underlying mechanism in the development of PD remain not well understood. In this work, the MPTP-treated mice or MPP+-intoxicated SH-SY5Y cells were established as an in vivo or in vitro PD model. Then the specific agomir of miR-29c was employed to examine its biological function on PD progress. We found that miR-29c was down-expressed but SP1 was high-expressed in substantia nigra pars compacta (SNpc) of MPTP-induced PD mice. Overexpression of miR-29c attenuated dopaminergic neuron loss and α-synuclein accumulation in SNpc of PD mice. Furthermore, the increments of pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) and TUNEL-positive apoptotic cells in MPTP-treated mice were ameliorated by miR-29c. Similarly, in SH-SY5Y cell models of PD, we also found that miR-29c inhibited inflammatory cytokine production, reduced apoptotic rate and suppressed pro-apoptotic regulator activity. In addition, the increased expression of SP1 in PD models was found to be inhibited by miR-29c. Luciferase reporter assay confirmed that SP1 was complementary with miR-29c. Knockdown of SP1 with siRNA restored α-synuclein accumulation, inflammation and apoptosis in MPP+-induced SH-SY5Y cells. Collectively, this current work presents that miR-29c may directly target SP1 to protect against the neuroinflammatory and apoptotic responses in PD, providing a potential biomarker for PD diagnosis and treatment. 相似文献
25.
Chen JF Sonsalla PK Pedata F Melani A Domenici MR Popoli P Geiger J Lopes LV de Mendonça A 《Progress in neurobiology》2007,83(5):310-331
This review summarizes recent developments that have contributed to understand how adenosine receptors, particularly A2A receptors, modulate brain injury in various animal models of neurological disorders, including Parkinson's disease (PD), stroke, Huntington's disease (HD), multiple sclerosis, Alzheimer's disease (AD) and HIV-associated dementia. It is clear that extracellular adenosine acting at adenosine receptors influences the functional outcome in a broad spectrum of brain injuries, indicating that A2A Rs may modulate some general cellular processes to affect neuronal cells death. Pharmacological, neurochemical and molecular/genetic approaches to the complex actions of A2A receptors in different cellular elements suggest that A2A receptor activation can be detrimental or protective after brain insults, depending on the nature of brain injury and associated pathological conditions. An interesting concept that emerges from these studies is A2A R's ability to fine tune neuronal and glial functions to produce neuroprotective effects. While the data presented here clearly highlight the complexity of using adenosinergic agents therapeutically in PD and other neurodegenerative disorders and point out many areas for further inquiry, they also confirm that adenosine receptor ligands, particularly A2A receptor ligands, have many promising characteristics that encourage the pursuit of their therapeutic potential. 相似文献
26.
Postural control is integrated in all facets of motor commands. The role of cortico-subcortical pathways underlying postural control, including cerebellum and its afferents (climbing, mossy, and noradrenergic fibers), basal ganglia, motor thalamus, and parieto-frontal neocortex has been identified in animal models, notably through the brain lesion technique in rats and in mice with spontaneous and induced mutations. These studies are complemented by analyses of the factors underlying postural deficiencies in patients with cerebellar atrophy. With the gene deletion technique in mice, specific genes expressed in cerebellum encoding glutamate receptors (Grid2 and Grm1) and other molecules (Prkcc, Cntn6, Klf9, Syt4, and En2) have also been shown to affect postural control. In addition, transgenic mouse models of the synucleinopathies and of Huntington's disease cause deficiencies of motor coordination resembling those of patients with basal ganglia damage. 相似文献
27.
Kaikai Hu Xiaohui Chen Wuya Chen Lingkun Zhang Jian Li Jialin Ye Yuxiao Zhang Li Zhang Chu-Hua Li Liang Yin Yan-Qing Guan 《Nanomedicine : nanotechnology, biology, and medicine》2018,14(4):1123-1136
Parkinson’s disease (PD) is second most common neurodegenerative disorder worldwide. Although drugs and surgery can relieve the symptoms of PD, these therapies are incapable of fundamentally treating the disease. For PD patients, over-expression of α-synuclein (SNCA) leads to the death of dopaminergic neurons. This process can be prevented by suppressing SNCA over-expression through RNA interference. Here, we successfully synthesized gold nanoparticles (GNP) composites (CTS@GNP-pDNA-NGF) via the combination of electrostatic adsorption and photochemical immobilization, which could load plasmid DNA (pDNA) and target specific cell types. GNP was transfected into cells via endocytosis to inhibiting the apoptosis of PC12 cells and dopaminergic neurons. Simultaneously, GNP composites are also used in PD models in vivo, and it can successfully cross the blood-brain barrier by contents of GNP in the mice brain. In general, all the works demonstrated that GNP composites have good therapeutic effects for PD models in vitro and in vivo. 相似文献
28.
目的通过对深低温停循环大鼠海马线粒体通透性转换孔(MPTP)开闭情况的研究,从亚细胞水平探讨深低温脑保护的机制。方法取成年SD大鼠33只,3只作为供血动物,剩余30只随机分为深低温停循环组(n=10)、常温停循环组(n=10)、正常对照组(n=10)。采用闭胸式体外插管法建立大鼠体外循环模型。其后采用断头取脑法迅速取出大鼠双侧海马组织,提取线粒体后应用蛋白印记法测量线粒体内细胞色素C(CytC)研究MPTP的开闭情况。结果常温停循环组的MPTP较正常对照组、深低温停循环组的开放明显增加(P<0.05);正常对照组的MPTP开放较深低温停循环组的开放少(P<0.05)。结论缺血缺氧可导致MPTP开放;深低温可抑制MPTP开放,保证了细胞的正常代谢活动从而起到脑保护的作用。 相似文献
29.
目的探讨猕猴双侧慢性不可逆性帕金森病(PD)模型的制作方法。方法 4只猕猴分别采用不同剂量(0.1 mg/kg/d和0.4 mg/kg/d)和不同频率(每天一次和隔天一次)及不同次数皮下注射1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)制作PD模型,注射MPTP前后观察行为学表现并进行非人类灵长类PD评分量表(PPRS)评分。结果猕猴注射MPTP一段时间后开始出现PD症状,主要表现为倦怠、迟缓;继续给药PD症状会出现进行性快速加重导致后续动物因进食困难而死亡;若过早停止给药,则导致PD模型不稳定,动物症状可自愈。采用剂量为0.1 mg/kg/d的MPTP连续皮下注射14 d后,猕猴出现中度PD症状(PPRS评分为6~8分)时,改隔日注射一次,共4次,猕猴出现不可逆性PD症状,且可自主摄食并长期存活,是一个成功的模型。结论适量皮下注射MPTP可制作猕猴慢性、不可逆性、双侧PD模型,其更接近人PD的临床特征,且无需鼻饲喂养可长期存活。 相似文献
30.
《Parkinsonism & related disorders》2014,20(11):1119-1123
Nicotinic acetylcholine receptor (nAChR)-mediated signaling has been implicated in levodopa (l-Dopa)-induced dyskinesias (LID). This study investigated the novel selective α7 nAChR partial agonist (R)-3-(6-ρ-Tolyl-pyridin-3-yloxy)-1-aza-bicyclo(2.2.2)octane (AQW051) for its antidyskinetic activity in l-Dopa-treated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned cynomolgus monkeys. Six MPTP monkeys were repeatedly treated with l-Dopa to develop reproducible dyskinesias. AQW051 (2, 8, and 15 mg/kg) administered 1 h before l-Dopa treatment did not affect their parkinsonian scores or locomotor activity, but did significantly extend the duration of the l-Dopa antiparkinsonian response, by 30 min at the highest AQW051 dose (15 mg/kg). Dyskinesias were significantly reduced for the total period of l-Dopa effect following treatment with 15 mg/kg; achieving a reduction of 60% in median values. Significant reductions in 1 h peak dyskinesia scores and maximal dyskinesias were also observed with AQW051 (15 mg/kg). To understand the exposure–effect relationship and guide dose selection in clinical trials, plasma concentration-time data for the 15 mg/kg AQW051 dose were collected from three of the MPTP monkeys in a separate pharmacokinetic experiment. No abnormal behavioral or physiological effects were reported following AQW051 treatment. Our results show that AQW051 at a high dose can reduce LID without compromising the benefits of l-Dopa and extend the duration of the l-Dopa antiparkinsonian response in MPTP monkeys. This supports the clinical testing of α7 nAChR agonists to modulate LID and extend the duration of the therapeutic effect of l-Dopa. 相似文献