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Carola Rotermund Felicia M. Truckenmüller Heinrich Schell Philipp J. Kahle 《Journal of neurochemistry》2014,131(6):848-858
Parkinson's disease (PD) and diabetes belong to the most common neurodegenerative and metabolic syndromes, respectively. Epidemiological links between these two frequent disorders are controversial. The neuropathological hallmarks of PD are protein aggregates composed of amyloid‐like fibrillar and serine‐129 phosphorylated (pS129) α‐synuclein (AS). To study if diet‐induced obesity could be an environmental risk factor for PD‐related α‐synucleinopathy, transgenic (TG) mice, expressing the human mutant A30P AS in brain neurons, were subjected after weaning to a lifelong high fat diet (HFD). The TG mice became obese and glucose‐intolerant, as did the wild‐type controls. Upon aging, HFD significantly accelerated the onset of the lethal locomotor phenotype. Coinciding with the premature movement phenotype and death, HFD accelerated the age of onset of brainstem α‐synucleinopathy as detected by immunostaining with antibodies against pathology‐associated pS129. Amyloid‐like neuropathology was confirmed by thioflavin S staining. Accelerated onset of neurodegeneration was indicated by Gallyas silver‐positive neuronal dystrophy as well as astrogliosis. Phosphorylation of the activation sites of the pro‐survival signaling intermediate Akt was reduced in younger TG mice after HFD. Thus, diet‐induced obesity may be an environmental risk factor for the development of α‐synucleinopathies. The molecular and cellular mechanisms remain to be further elucidated.
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Aritri Bir Oishimaya Sen Shruti Anand Vineet Kumar Khemka Priyanjalee Banerjee Roberto Cappai Arghyadip Sahoo Sasanka Chakrabarti 《Journal of neurochemistry》2014,131(6):868-877
This study has shown that purified recombinant human α‐synuclein (20 μM) causes membrane depolarization and loss of phosphorylation capacity of isolated purified rat brain mitochondria by activating permeability transition pore complex. In intact SHSY5Y (human neuroblastoma cell line) cells, lactacystin (5 μM), a proteasomal inhibitor, causes an accumulation of α‐synuclein with concomitant mitochondrial dysfunction and cell death. The effects of lactacystin on intact SHSY5Y cells are, however, prevented by knocking down α‐synuclein expression by specific siRNA. Furthermore, in wild‐type (non‐transfected) SHSY5Y cells, the effects of lactacystin on mitochondrial function and cell viability are also prevented by cyclosporin A (1 μM) which blocks the activity of the mitochondrial permeability transition pore. Likewise, in wild‐type SHSY5Y cells, typical mitochondrial poison like antimycin A (50 nM) produces loss of cell viability comparable to that of lactacystin (5 μM). These data, in combination with those from isolated brain mitochondria, strongly suggest that intracellularly accumulated α‐synuclein can interact with mitochondria in intact SHSY5Y cells causing dysfunction of the organelle which drives the cell death under our experimental conditions. The results have clear implications in the pathogenesis of sporadic Parkinson's disease.
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目的:研究张家口市大气颗粒物对慢性阻塞性肺疾病(COPD)的影响,并分析大气颗粒物对不同特征人群的影响。方法:从张家口市医保办公室获取张家口市2013年1月1日-2015年12月31日两家三甲医院COPD患者的住院病历资料,从中国环境监测总站网站获取大气污染物的监测数据,从张家口市气象局获取气象资料。建立广义相加模型(GAM),在控制长期趋势、星期几效应和温湿度影响后,应用条件Logitic回归方法评估PM_(2.5)、PM_(10)对COPD住院人次的影响。根据患者不同特征(性别、年龄、季节)进行分层分析,评估颗粒物污染的高危人群。结果:研究纳入两家三甲医院,共1984例住院COPD患者,其中男性患者1258例(63.4%)、女性患者726例(36.6%),≥75岁患者678例(34.2%),60~75岁患者936例(47.2%)、芨60岁患者370例(18.6%)。2013-2015年PM_(2.5)、PM_(10)年均浓度分别为[(36.54±20.34)μg/m~3、(84.37±52.54)μg/m~3],[(34.50±27.08)μg/m~3、(78.43±69.78)μg/m~3],[(32.04±21.35)μg/m~3、(75.46±50.02)μg/m~3],两者在移动平均滞后3d时,对COPD的影响最大,即PM_(2.5)每增加10μg/m~3,COPD住院人次增加1.90%(95%CI:1.002-1.033,P0.05),PM_(10)每增加10μg/m~3,COPD住院人次增加2.10%(95%CI:1.005-1.045,P0.05)。分层分析结果显示:PM_(2.5)、PM_(10)每升高10μg/m~3,女性COPD患者住院人次增加1.09%、1.14%,差异具有统计学意义(P0.05);≥75岁患者,COPD住院人次增加1.03%、0.99%,差异具有统计学意义(P0.05);而年龄芨60岁、60~75岁、男性以及季节分层分析中,PM_(2.5)、PM_(10)浓度与COPD住院人次无统计学意义(P0.05)。结论:颗粒物污染会增加COPD住院率,≥75岁的老年患者及女性患者更敏感。 相似文献
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经过多年探索,对肝脏疾病的研究已取得重大进展,但其发病机制复杂,目前仍未完全阐明。长链非编码RNA(long noncoding RNA,lnc RNA)是非编码RNA中的一种,不具有蛋白编码功能。研究发现,lnc RNA参与调控多种肝脏疾病的生理和病理过程,能在表观遗传、转录和转录后水平发挥重要的调节作用,提示我们lnc RNA可能成为一个新的治疗突破口。本文针对当前lnc RNA在肝疾病中的功能及作用机制进行综述。首先介绍了lnc RNA的功能,再将计算机与生物学相结合概括lnc RNA的四个研究步骤,包括筛选、鉴定、预测及验证,重点阐述lnc RNA与肝纤维化、肝硬化、肝癌及肝移植的近期研究成果,并进一步探讨未来lnc RNA在肝病中的研究方向和应用前景。充分了解肝病的研究现状以及与肝病发生发展有关的lnc RNA分子和生物学功能,为后续研究肝病的机制和治疗提供理论依据和借鉴。 相似文献
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Circulating long non‐coding RNAs NRON and MHRT as novel predictive biomarkers of heart failure 下载免费PDF全文
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Celia van der Merwe Ben Loos Chrisna Swart Craig Kinnear Franclo Henning Lize van der Merwe Komala Pillay Nolan Muller Dan Zaharie Lize Engelbrecht Jonathan Carr Soraya Bardien 《Biochemical and biophysical research communications》2014
Parkinson’s disease (PD), defined as a neurodegenerative disorder, is characterized by the loss of dopaminergic neurons in the substantia nigra in the midbrain. Loss-of-function mutations in the parkin gene are a major cause of autosomal recessive, early-onset PD. Parkin has been implicated in the maintenance of healthy mitochondria, although previous studies show conflicting findings regarding mitochondrial abnormalities in fibroblasts from patients harboring parkin-null mutations. The aim of the present study was to determine whether South African PD patients with parkin mutations exhibit evidence for mitochondrial dysfunction. Fibroblasts were cultured from skin biopsies obtained from three patients with homozygous parkin-null mutations, two heterozygous mutation carriers and two wild-type controls. Muscle biopsies were obtained from two of the patients. The muscle fibers showed subtle abnormalities such as slightly swollen mitochondria in focal areas of the fibers and some folding of the sarcolemma. Although no differences in the degree of mitochondrial network branching were found in the fibroblasts, ultrastructural abnormalities were observed including the presence of electron-dense vacuoles. Moreover, decreased ATP levels which are consistent with mitochondrial dysfunction were observed in the patients’ fibroblasts compared to controls. Remarkably, these defects did not manifest in one patient, which may be due to possible compensatory mechanisms. These results suggest that parkin-null patients exhibit features of mitochondrial dysfunction. Involvement of mitochondria as a key role player in PD pathogenesis will have important implications for the design of new and more effective therapies. 相似文献
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Hongxu Wu Shifang Yang Xiaojie Wu Junling Zhao Jianping Zhao Qin Ning Yongjian Xu Jungang Xie 《Biochemical and biophysical research communications》2014
Interleukin-33 is a newly described member of the interleukin-1 family. Recent research suggests that IL-33 is increased in lungs and plays a critical role in chronic airway inflammation in cigarette smoke-induced chronic obstructive pulmonary disease (COPD) mice. To determine the role of IL-33 in systemic inflammation, we induced COPD mice models by passive cigarette smoking and identified the IL-33 expression in bronchial endothelial cells and peripheral blood mononuclear cells (PBMCs) of them. After isolation, PBMCs were cultured and stimulated in vitro. We measured expressions of interleukin-6 and interleukin-8 in PBMCs in different groups. The expression of IL-33 in bronchial endothelial cells and PBMCs of COPD mice were highly expressed. Stimulated by cigarette smoke extract (CSE), the expression of IL-6 and IL-8 were induced and enhanced by IL-33. PBMCs of COPD mice produced more IL-6 and IL-8 stimulated by CSE and IL-33. Expression of IL-6 and IL-8 were decreased when stimulated by IL-33 together with soluble ST2. The mRNA production of ST2 in IL-33 stimulated PBMCs was increased. Being pretreated with several kinds of MAPK inhibitors, the secretions of IL-6 and IL-8 in PBMCs did not decrease except for the p38 MAPK inhibitor. We found that IL-33 could induce and enhance the expression of IL-6 and IL-8 in PBMCs of COPD mice via p38 MAPK pathway, and it is a promoter of the IL-6 and IL-8 production in systemic inflammation in COPD mice. 相似文献