全文获取类型
收费全文 | 3038篇 |
免费 | 170篇 |
国内免费 | 17篇 |
专业分类
耳鼻咽喉 | 19篇 |
儿科学 | 22篇 |
妇产科学 | 20篇 |
基础医学 | 461篇 |
口腔科学 | 129篇 |
临床医学 | 198篇 |
内科学 | 728篇 |
皮肤病学 | 104篇 |
神经病学 | 262篇 |
特种医学 | 49篇 |
外科学 | 489篇 |
综合类 | 10篇 |
预防医学 | 80篇 |
眼科学 | 116篇 |
药学 | 301篇 |
中国医学 | 33篇 |
肿瘤学 | 204篇 |
出版年
2023年 | 20篇 |
2022年 | 20篇 |
2021年 | 55篇 |
2020年 | 20篇 |
2019年 | 46篇 |
2018年 | 68篇 |
2017年 | 52篇 |
2016年 | 46篇 |
2015年 | 55篇 |
2014年 | 60篇 |
2013年 | 86篇 |
2012年 | 136篇 |
2011年 | 142篇 |
2010年 | 76篇 |
2009年 | 56篇 |
2008年 | 121篇 |
2007年 | 151篇 |
2006年 | 145篇 |
2005年 | 158篇 |
2004年 | 132篇 |
2003年 | 135篇 |
2002年 | 125篇 |
2001年 | 115篇 |
2000年 | 127篇 |
1999年 | 103篇 |
1998年 | 42篇 |
1997年 | 27篇 |
1996年 | 38篇 |
1995年 | 23篇 |
1994年 | 35篇 |
1992年 | 74篇 |
1991年 | 70篇 |
1990年 | 53篇 |
1989年 | 67篇 |
1988年 | 54篇 |
1987年 | 43篇 |
1986年 | 43篇 |
1985年 | 44篇 |
1984年 | 42篇 |
1983年 | 19篇 |
1982年 | 21篇 |
1981年 | 17篇 |
1979年 | 29篇 |
1978年 | 20篇 |
1974年 | 16篇 |
1973年 | 18篇 |
1972年 | 16篇 |
1970年 | 16篇 |
1969年 | 17篇 |
1967年 | 20篇 |
排序方式: 共有3225条查询结果,搜索用时 375 毫秒
31.
32.
The effects of magnesium (Mg) deficiency on the coronary arteries of 27 Yorkshire swine were studied by light and electron microscopy. The experimental animals were divided into 4 groups which received the following supplements: Group I, basal ration with adequate Mg (540 mg/kg diet), Group II, basal ration with insufficient Mg (270 mg/kg diet) Group III, 10% milk powder with adequate Mg (540 mg/kg diet), Group IV, 10% milk powder with insufficient Mg (270 mg/kg diet). Serum analysis indicated that dietary low Mg supplementation decreased cholesterol levels and increased phospholipid concentrations significantly. The highest magnitude and incidence of intimal thickening were observed in the coronary arteries of Group IV (p less than 0.003). No significant intimal thickening was detected in any of the other groups. Ultrastructural studies revealed a greater frequency of degenerated cells in Group III and IV (p less than 0.01). Numerous calcifications were observed in only Group IV. These data suggest that moderate Mg deficiency can promote atherosclerosis in combination with some atherogenic diet, and that the presence of smooth muscle cell degeneration is important in order for a magnesium deficiency to exert an effect on the coronary artery of swine. 相似文献
33.
Lehmann A Katayama S Harrison C Dhut S Kitamura K McDonald N Toda T 《Genes to cells : devoted to molecular & cellular mechanisms》2004,9(5):367-382
Skp1 is a central component of the E3 ubiquitin ligase SCF (Skp1-Cullin-1-F-box). It forms an adapter bridge between Cullin-1 and the substrate-determining component, the F-box protein. In order to establish the role of Skp1, a temperature sensitive (ts) screen was carried out using mutagenic PCR (polymerase chain reaction) and 9 independent ts mutants were isolated. Mapping the mutated residues on the 3-D structure of human Skp1 suggested that the mutants would be compromised in binding to F-box proteins but not Cullin-1 (Pcu1). In order to assess the binding properties of ts Skp1, 12 F-box proteins and Pcu1 were epitope-tagged, and co-immunoprecipitation performed. This systematic analysis showed that ts Skp1 retains binding to Pcu1. However, binding to three specific F-box proteins, essential Pof1, Pof3 involved in maintaining genome integrity, and nonessential Pof10, was reduced. skp1ts cells exhibit a G2 cell cycle delay, which is attributable to activation of the DNA damage checkpoint. Intriguingly, contrary to pof3 mutants, in which this checkpoint is required for survival, checkpoint abrogation in skp1(ts) suppresses a G2 delay and furthermore almost rescues the ts phenotype. The activation mechanism of the DNA damage checkpoint therefore differs between pof3Delta and skp1(ts), implicating a novel role for Skp1 in the checkpoint-signalling cascade. 相似文献
34.
AIMS: The isolation of various genes that are expressed in a region specific manner is considered useful for research in molecular pathology. In situ hybridisation (ISH) was used in a screening procedure to isolate these genes efficiently, using colon cancer as a model. METHODS: Suppression subtractive hybridisation (SSH) between colon cancer tissue samples and corresponding non-cancerous tissues was performed. Genes showing high expression in the cancers were selected using macro-DNA array analysis. As a final screening procedure, conventional ISH was performed to isolate genes expressed specifically in colon cancers. RESULTS: Sixty nine clones were selected by SSH and macro-DNA array analyses. These clones were then analysed by ISH to examine their expression patterns. ISH screening revealed that all the clones screened showed more intense signals in colon cancers than in non-cancerous tissues. Among them, RACK 1, which is a protein kinase C receptor and a homologue of the G protein beta subunit, was expressed intensely in colon cancer cells. RACK 1 expression was evaluated in multiple samples by ISH, and the results confirmed that RACK 1 was universally overexpressed in cells of all 11 colon cancers examined. CONCLUSIONS: Many genes, including RACK 1, expressed in colon cancer cells can be isolated efficiently by this method, and their precise expression pattern can be evaluated. These results indicate that ISH is an excellent technique for systemic screening of genes expressed in a region specific manner. 相似文献
35.
Yohtaro Numachi Sumiko Yoshida Motoyasu Yamashita Ko Fujiyama Shigenobu Toda Hiroo Matsuoka Yasushi Kajii Toru Nishikawa 《Neuroscience letters》2007
Methamphetamine is a potent and indirect dopaminergic agonist which can cause chronic brain dysfunctions including drug abuse, drug dependence and drug-induced psychosis. Methamphetamine is known to trigger molecular mechanisms involved in associative learning and memory, and thereby alter patterns of synaptic connectivity. The persistent risk of relapse in methamphetamine abuse, dependence and psychosis may be caused by such alterations in synaptic connectivity. EphA5 receptors constitute large families of tyrosine kinase receptor and are expressed almost exclusively in the nervous system, especially in the limbic structures. Recent studies suggest EphA5 to be important in the topographic projection, development, and plasticity of limbic structures, and to be involved in dopaminergic neurotransmission. We used in situ hybridization to examine whether methamphetamine alters EphA5 mRNA expression in the brains of adult male Wister rats. EphA5 mRNA was widely distributed in the medial frontal cortex, cingulate cortex, piriform cortex, hippocampus, habenular nucleus and amygdala. Compared to baseline expression at 0 h, EphA5 mRNA was significantly decreased (by 20%) in the medial frontal cortex at 24 h, significantly increased (by 30%) in the amygdala at 9 and 24 h, significantly but transiently decreased (by 30%) in the habenular nucleus at 1 h after a single injection of methamphetamine. Methamphetamine did not change EphA5 mRNA expression in the cingulate cortex, piriform cortex or hippocampus. Our results that methamphetamine altered EphA5 mRNA expression in rat brain suggest methamphetamine could affect patterns of synaptic connectivity, which might be responsible for methamphetamine-induced chronic brain dysfunctions. 相似文献
36.
Nagai Y Fujikake N Ohno K Higashiyama H Popiel HA Rahadian J Yamaguchi M Strittmatter WJ Burke JR Toda T 《Human molecular genetics》2003,12(11):1253-1259
Polyglutamine (polyQ) diseases are a growing class of inherited neurodegenerative diseases including Huntington's disease, which are caused by abnormal expansions of the polyQ stretch in each unrelated disease protein. The expanded polyQ stretch is thought to confer toxic properties on the disease proteins through alteration of their conformation leading to pathogenic protein-protein interactions including oligomerization and/or aggregation. Hypothesizing that molecules with selective binding affinity to the expanded polyQ stretch may interfere with the pathogenic properties, we previously identified Polyglutamine Binding Peptide 1 (QBP1) from combinatorial peptide phage display libraries. We show here that a tandem repeat of the inhibitor peptide QBP1, (QBP1)(2), significantly suppresses polyQ aggregation and polyQ-induced neurodegeneration in the compound eye of Drosophila polyQ disease models, which express the expanded polyQ protein under the eye specific promoter. Most importantly, (QBP1)(2) expression dramatically rescues premature death of flies expressing the expanded polyQ protein in the nervous system, resulting in the dramatic increase of the median life span from 5.5 to 52 days. These results suggest that QBP1 can prevent polyQ-induced neurodegeneration in vivo. We propose that QBP1 prevents polyQ oligomerization and/or aggregation either by altering the toxic conformation of the expanded polyQ stretch, or by simply competing with the expanded polyQ stretches for binding to other expanded polyQ proteins. The peptide inhibitor QBP1 is a promising candidate with great potential as a therapeutic molecule against the currently untreatable polyQ diseases. 相似文献
37.
Unsu Jung Jason E Foley Andreas A Erdmann Yoko Toda Todd Borenstein Jacopo Mariotti Daniel H Fowler 《Biology of blood and marrow transplantation》2006,12(9):905-918
Rapamycin prevention of murine graft-versus-host disease (GVHD) is associated with a shift toward Th2- and Tc2-type cytokines. Recently, we found that use of rapamycin during ex vivo donor Th2 cell generation enhances the ability of adoptively transferred Th2 cells to prevent murine GVHD. In this study, using a method, without antigen-presenting cells, of T-cell expansion based on CD3,CD28 costimulation, we evaluated whether (1) rapamycin preferentially promotes the generation of Th2/Tc2 cells relative to Th1/Tc1 cells, (2) rapamycin-generated T-cell subsets induce cytokine skewing after allogeneic bone marrow transplantation (BMT), and (3) such in vivo cytokine skewing is sensitive to post-BMT rapamycin therapy. Contrary to our hypothesis, rapamycin did not preferentially promote Th2/Tc2 cell polarity, because rapamycin-generated Th1/Tc1 cells secreted type I cytokines (interleukin [IL]-2 and interferon-gamma) did not secrete type II cytokines (IL-4, IL-5, IL-10, or IL-13) and mediated fasL-based cytolysis. Rapamycin influenced T-cell differentiation, because each of the Th1, Th2, Tc1, and Tc2 subsets generated in rapamycin had increased expression of the central-memory T-cell marker, L-selectin (CD62L). Rapamycin-generated Th1/Tc1 and Th2/Tc2 cells were not anergic but instead had increased expansion after costimulation in vitro, increased expansion in vivo after BMT, and maintained full capacity to skew toward type I or II cytokines after BMT, respectively; further, rapamycin-generated Th1/Tc1 cells mediated increased lethal GVHD relative to control Th1/Tc1 cells. Rapamycin therapy after BMT in recipients of rapamycin-generated Th1/Tc1 cells greatly reduced Th1/Tc1 cell number, greatly reduced type I cytokines, and reduced lethal GVHD; in marked contrast, rapamycin therapy in recipients of rapamycin-generated Th2/Tc2 cells nominally influenced the number of Th2/Tc2 cells in vivo and did not abrogate post-BMT type II cytokine skewing. In conclusion, ex vivo and in vivo usage of rapamycin may be used to modulate the post-BMT balance of Th1/Tc1 and Th2/Tc2 cell subsets. 相似文献
38.
39.
Minoru Takagi Richard T. Parmley Francis R. Denys Hiroshi Yagasaki Yoshihisa Toda 《Anatomical record (Hoboken, N.J. : 2007)》1984,208(2):149-158
Proteoglycans (PGs) as well as sulfated glycosaminoglycans (GAGs) are closely associated with cartilage calcification. An inner zone of endoskeletal tesserae of sharks is composed of a unique calcified hyaline cartilage. Initial calcification can be seen in the cartilage close to the inner zone. We have ultrastructurally examined shark, Triakis scyllia, noncalcifying, calcifying, and calcified cartilage using the tannic acid-ferric chloride (TA-Fe), the high iron diamine (HID), and the HID-thiocarbohydrazide-silver proteinate (HID-TCH-SP) methods for localization of sulfated complex carbohydrates. In noncalcifying cartilage, TA-Fe and HID strongly stained matrix granules which were round, ovoid, elongated, or irregularly shaped and presumably represented PG monomers. The size and staining intensity of the reactive matrix granules progressively decreased in calcifying cartilage toward the calcification front of the calcified cartilage. Similarly, a progressive decrease in the size of the HID-TCH-SP stain deposits in the matrix granules was observed in the calcifying cartilage close to the calcification front and was interpreted as a decrease in length of sulfate containing GAG chains. In the calcified cartilage, the highly calcified areas were often localized in the calcification front and contained few or no small HID-TCH-SP stain deposits, whereas the weakly calcified regions contained more stain deposits. These results indicate that partial and complete degradation of sulfated GAGs and/or PGs may be a requisite for calcification of shark cartilage. 相似文献
40.
Takahashi T; Kuniyasu Y; Toda M; Sakaguchi N; Itoh M; Iwata M; Shimizu J; Sakaguchi S 《International immunology》1998,10(12):1969-1980
Elimination of CD25+ T cells, which constitute 5-10% of peripheral CD4+ T
cells in normal naive mice, leads to spontaneous development of various
autoimmune diseases. These immunoregulatory CD25+CD4+ T cells are naturally
unresponsive (anergic) in vitro to TCR stimulation, and, upon stimulation,
suppress proliferation of CD25-CD4+ T cells and CD8+ T cells. The antigen
concentration required for stimulating CD25+CD4+ T cells to exert
suppression is much lower than that required for stimulating CD25-CD4+ T
cells to proliferate. The suppression, which results in reduced IL-2
production by CD25-CD4+ T cells, is dependent on cellular interactions on
antigen-presenting cells (and not mediated by far-reaching or long-lasting
humoral factors or apoptosis-inducing signals) and antigen non-specific in
its effector phase. Addition of high doses of IL-2 or anti-CD28 antibody to
the in vitro T cell stimulation culture not only breaks the anergic state
of CD25+CD4+ T cells, but also abrogates their suppressive activity
simultaneously. Importantly, the anergic/suppressive state of CD25+CD4+ T
cells appeared to be their basal default condition, since removal of IL-2
or anti-CD28 antibody from the culture milieu allows them to revert to the
original anergic/suppressive state. Furthermore, transfer of such
anergy/suppression-broken T cells from normal mice produces various
autoimmune diseases in syngeneic athymic nude mice. These results taken
together indicate that one aspect of immunologic self-tolerance is
maintained by this unique CD25+CD4+ naturally anergic/suppressive T cell
population and its functional abnormality directly leads to the development
of autoimmune disease.
相似文献