全文获取类型
收费全文 | 2572篇 |
免费 | 192篇 |
国内免费 | 123篇 |
专业分类
耳鼻咽喉 | 6篇 |
儿科学 | 12篇 |
妇产科学 | 14篇 |
基础医学 | 688篇 |
口腔科学 | 27篇 |
临床医学 | 141篇 |
内科学 | 371篇 |
皮肤病学 | 35篇 |
神经病学 | 540篇 |
特种医学 | 49篇 |
外科学 | 177篇 |
综合类 | 261篇 |
预防医学 | 72篇 |
眼科学 | 65篇 |
药学 | 204篇 |
中国医学 | 60篇 |
肿瘤学 | 165篇 |
出版年
2024年 | 4篇 |
2023年 | 13篇 |
2022年 | 20篇 |
2021年 | 38篇 |
2020年 | 38篇 |
2019年 | 49篇 |
2018年 | 48篇 |
2017年 | 64篇 |
2016年 | 54篇 |
2015年 | 86篇 |
2014年 | 102篇 |
2013年 | 202篇 |
2012年 | 138篇 |
2011年 | 164篇 |
2010年 | 137篇 |
2009年 | 128篇 |
2008年 | 156篇 |
2007年 | 161篇 |
2006年 | 133篇 |
2005年 | 150篇 |
2004年 | 170篇 |
2003年 | 123篇 |
2002年 | 109篇 |
2001年 | 106篇 |
2000年 | 90篇 |
1999年 | 88篇 |
1998年 | 74篇 |
1997年 | 53篇 |
1996年 | 60篇 |
1995年 | 34篇 |
1994年 | 33篇 |
1993年 | 29篇 |
1992年 | 8篇 |
1991年 | 9篇 |
1990年 | 5篇 |
1989年 | 5篇 |
1988年 | 3篇 |
1987年 | 1篇 |
1986年 | 1篇 |
1985年 | 1篇 |
排序方式: 共有2887条查询结果,搜索用时 15 毫秒
1.
Shoichi Sasaki 《Neuropathology》1993,13(3):185-192
I briefly review spheroids observed in the anterior horns of the spinal cord in amyotrophic lateral sclerosis (ALS). Spheroids are argentophilic bodies more than 20 μm in diameter. Recently, some connections between the proximal axonal swellings including spheroids and the perikarya have been reported in some ALS patients with a short clinical course or mild depletion of anterior horn neurons. Most of the cell bodies directly connected with the axonal swellings appear normal, and spheroids are considered to be one of the hallmarks of the early histological changes in this disorder. Spheroids are strongly positive with anti-phosphorylated neurofilament antibody, and are also positive with calcitonin gene-related peptide and anti-peripherin antibody. Some spheroids are immunostained with anti-synaptophysin antibody and anti-ubiquitin antibody. Spheroids are not immunostained with anti-phosphorylated tau antibody, or high molecular weight microtubule associated proteins. Electron microscopically, spheroids are usually composed of densely packed accumulation of 10 nm neurofilaments with a variety of orientations, plus vesicles, dense bodies and mitochondria. When the swellings of the initial segment is relatively pronounced, the undercoating is obscured and the neurofilaments become interwoven in some parts. In the first internode of the myelinated axons, as the swellings become larger, the neurofilaments lose their parallel orientation and become intermingled. Large accumulation of neurofilaments resembling spheroids in the perikarya of large anterior horn cells suggests that spheroids could be derived not only from the axon including the proximal portion, but also from the perikarya. Structures apparently identical to axonal spheroids are observed at the light and electron microscopic levels in the proximal portion of axons of anterior horn cells in animal models intoxicated with β, β'-iminodipropionitrile (IDPN), or with aluminum, in hereditary canine spinal muscular atrophy (HCSMA). The pathogenetic mechanism is probably associated with an impairment in slow axonal transport which particularly affects the neurofilaments in IDPN and aluminum intoxication. Impairment of slow axonal transport of neurofilaments also plays an important role in the pathogenesis of ALS. The average diameter of even normalappearing initial segment is larger in ALS than in the controls. The perikarya connected with the swollen proximal axons and their dendrites almost always appear normal. These findings suggest that the slow axonal transport of neurofilaments is probably impaired in this portion of the axon at an early stage in ALS as well as animal models for human ALS. However, techniques to analyze slow axonal transport in humans still remain tobe developed. Recently, overexpression of neurofilament subunits in transgenic mice produces a condition resembling ALS. The transgenic model may offer an interesting perspective not only for testing therapeutic strategies but also for investigating in a systematic way the various genetic and environment factors controlling the onset and progression of the disease and might yield new insights on the etiology of ALS. 相似文献
2.
目的利用MR显微成像技术研究阿尔茨海默病转基因小鼠老年斑的沉积情况。方法2只17个月龄阿尔茨海默病转基因[V717I]小鼠和2只野生型小鼠,行活体T2WI,然后对照影像定位结果进行组织学切片及免疫组织化学染色。观察T2WI中老年斑的沉积情况以及其与免疫组织化学染色结果的对应关系。结果转基因小鼠T2WI上显示大脑皮层和海马区可见点状低信号,且部分低信号可以和组织学切片所显示的老年斑相对应;野生型小鼠T2WI未见明显的低信号,免疫组织化学染色也未见到染色阳性的斑块。结论MR显微成像技术检测老年斑的沉积是可行的,且可用来特异性地诊断阿尔茨海默病。 相似文献
3.
R W Tennant 《Environmental and molecular mutagenesis》1991,18(4):322-323
The development of transgenic mouse lines with target genes that are suitable for tissue-specific mutagenesis studies is an important contribution to the field of environmental mutagenesis. These models can accommodate many of the questions relating to metabolism, distribution and relative potency of mutagens as well as providing a more comprehensive system for the identification of mutagens. However, the lesions that the field has learned about methods, development and validation from the use of in vitro systems must be applied to the development and validation of transgenic models. 相似文献
4.
Central nervous system (CNS) progenitor cells transiently proliferate in the embryonic neural tube and give rise to neurons and glial cells. A characteristic feature of the CNS progenitor cells is expression of the intermediate filament nestin and it was previously shown that the rat nestin second intron functions as an enhancer, directing gene expression to CNS progenitor cells. In this report we characterize the nestin enhancer in further detail. Cloning and sequence analysis of the rat and human nestin second introns revealed local domains of high sequence similarity in the 3' portion of the introns. Transgenic mice were generated with the most conserved 714 bp in the 3' portion of the intron, or with the complete, 1852 bp, human second intron, coupled to the reporter gene lacZ. The two constructs gave a very similar nestin-like expression pattern, indicating that the important control elements reside in the 714 bp element. Expression was observed starting in embryonic day (E)7.5 neural plate, and at E10.5 CNS progenitor cells throughout the neural tube expressed lacZ. At E12.5, lacZ expression was more restricted and confined to proliferating regions in the neural tube. An interesting difference, compared to the rat nestin second intron, was that the human intron at E10.5 mediated lacZ expression also in early migrating neural crest cells, which is a site of endogenous nestin expression. In conclusion, these data show that a relatively short, evolutionarily conserved region is sufficient to control gene expression in CNS progenitor cells, but that the same region differs between rodents and primates in its capacity to control expression in neural crest cells. 相似文献
5.
Models of Parkinson's disease. 总被引:2,自引:0,他引:2
Parkinson's disease (PD) is a heterogenous disease likely to be caused by more than one specific aetiological factor. In rare familial cases of PD with similar clinical features to the idiopathic form of the disease, the underlying genetic cause has been identified. These PD-associated genes have been manipulated to create animal and cell culture models of the disease that have helped to further our understanding of the pathogenesis of PD, particularly concerning causes of the selective loss of dopaminergic neurons at the molecular level. In addition, these models will aid the future development of rational therapeutic strategies. This study briefly reviews toxin-induced models and the genetics of PD. It focuses on recently developed animal models of PD, as well as in vitro approaches to model the disease. 相似文献
6.
Adipose tissues differentiated by adipose-derived stem cells harvested from transgenic mice 总被引:2,自引:1,他引:1
Objective: To induce adipocyte differentiation in vitro by adipose-derived stromal cells (ASCs) harvested from transgenic mice with green fluorescent protein (GFP) and assess the possibility of constructing adipose tissues via attachment of ASCs to typeⅡcollagen scaffolds. Methods: Inguinal fat pads from GFP transgenic mice were digested by enzymes for isolation of ASCs (primary culture). After expansion to three passages of ASCs, the cells were incubated in an adipogenic medium for two weeks, and the adipocyte differentiation by ASCs in vitro was assessed by morphological observation and Oil Red O staining. Then they were attached to collagen scaffolds and co-cultured for 12 hours, followed by hypodermic implantation to the dorsal skin of nude mice for 2 months. The newly-formed tissues were detected by HE staining. Results: The cultured primary stem cells were fibroblast-like and showed active proliferation. After being incubated in an adipocyte differentiation medium, the lipid droplets in the cytoplasm accumulated gradually and finally developed into mature adipocytes, which showed positive in Oil Red O staining. A 0. 5-cm3 new tissue clot was found under the dorsal skin of the nude mice and it was confirmed as mature adipose tissues by fluorescent observation and HE staining. Conclusions: ASCs can successfully differentiate adipose tissues into mature adipocytes, which exhibit an adipocyte-like morphology and express as intracytoplasmic lipid droplets. It is an efficient model of adipose tissues engineered with ASCs and type I collagen scaffolds. 相似文献
7.
Disrupted-In-Schizophrenia-1 (DISC1) is a promising candidate gene for schizophrenia (SZ) and bipolar disorder (BP), but its basic biology remains to be elucidated. Accumulating genetic evidence supports that DISC1 is associated with some aspects of cognitive functions relevant to SZ and BP. Here, we provide a summary of the current updates in biological studies of DISC1. Disrupted-In-Schizophrenia-1, preferentially expressed in the forebrain, has multiple isoforms with potential posttranslational modifications. Disrupted-In-Schizophrenia-1 protein occurs in multiple subcellular compartments, which include the centrosome, microtubule fractions, postsynaptic densities, actin cytoskeletal fractions, the mitochondria, and the nucleus. Recent studies have clarified that DISC1 mediates at least centrosome-dynein cascade and cyclic adenosine monophosphate (cAMP) signaling. Furthermore, both cytogenetic and cell biological studies consistently suggest that an overall loss of DISC1 function (either haploinsufficiency or dominant-negative, or both) may be associated with SZ and BP. On the basis of these findings, production of DISC1 genetically engineered mice is proposed as a promising animal model for SZ and BP. Several groups are currently generating DISC1 mice and starting to characterize them. In this review, the advantages and disadvantages of each animal model are discussed. 相似文献
8.
目的构建在视网膜组织特异性表达的人血管内皮生长因子(VEGF)165基因。方法用聚合酶链反应(PCR)方法从BLAB/C鼠全基因组扩增能在视网膜组织特异性表达的rho启动子,经限制性内切酶纯化后克隆于质粒pcDNA3.1+-VEGF165中,建立重组质粒pcDNA3.1+-rho-VEGF165,通过限制性内切酶酶切分析及PCR鉴定筛选出正确重组质粒pcDNA3.1+-rho-VEGF165,由jetPEI介导转染人视网膜色素上皮细胞和人脐静脉内皮细胞,并通过免疫组织化学染色以及绘制细胞生长曲线检测在人视网膜色素上皮细胞和人脐静脉内皮细胞中VEGF蛋白的表达。结果在人视网膜色素上皮细胞中,重组质粒pcDNA3.1+-rho-VEGF165比质粒pcDNA3.1+-rho-VEGF165的VEGF蛋白表达强,在人脐静脉内皮细胞,两者的表达量无明显差别。结论pcDNA3.1+-rho-VEGF165载体的构建为进一步研究VEGF在视网膜新生血管形成中的致病机理提供基础材料,并为进一步建立视网膜特异性表达VEGF转基因鼠模型建立了基础。(中华眼底病杂志,2005,21:106-109) 相似文献
9.
Clonal deletion and anergy are two major mechanisms of self-tolerance. However, the molecular mechanisms underlying clonal deletion and anergy, as well as the threshold of TCR affinity/avidity required for these processes, are not known. Expression of the V beta 8.1 TCR correlates with the reactivity of the T cells to the minor lymphocyte stimulating locus-1a (Mls-1a) and T cells expressing this TCR are deleted in the thymus of Mls-1a mice. Similarly, in TCR V beta 8.1 transgenic mice, the number of CD4+CD8-T cells is reduced in Mls-1a mice. However, small numbers of CD4+CD8-T cells remain in the periphery of adult Mls-1a transgenic mice. We have generated T cell clones from TCR V beta 8.1 transgenic mice by stimulation of lymph node T cells with C57BL/6 alloantigens. Interestingly, CD4+CD8-V beta 8.1+ clones isolated from the transgenic mice of Mls-1a background responded to the self-antigen Mls-1a, to which they did not respond in primary assay. Reactive patterns of the clones were compared with clones derived from Mls-1b mice. Proliferation and cytokine production of the clones from Mls-1a mice to the self-antigen Mls-1a were generally reduced when compared with clones from Mls-1b mice. More importantly, T cell clones from Mls-1a mice required more Mls-1a antigen for their activation, and were more susceptible to the inhibitory effects of anti-CD4 antibody on the proliferative responses to Mls-1a than those from Mls-1b mice. These results suggest that the T cell receptor on clones derived from Mls-1a mice have functional but reduced affinity/avidity for self-antigen Mls-1a. 相似文献