全文获取类型
收费全文 | 28866篇 |
免费 | 1572篇 |
国内免费 | 768篇 |
专业分类
耳鼻咽喉 | 198篇 |
儿科学 | 627篇 |
妇产科学 | 473篇 |
基础医学 | 4208篇 |
口腔科学 | 711篇 |
临床医学 | 2115篇 |
内科学 | 4373篇 |
皮肤病学 | 594篇 |
神经病学 | 2219篇 |
特种医学 | 626篇 |
外国民族医学 | 4篇 |
外科学 | 2796篇 |
综合类 | 3237篇 |
现状与发展 | 3篇 |
一般理论 | 4篇 |
预防医学 | 1970篇 |
眼科学 | 332篇 |
药学 | 3221篇 |
6篇 | |
中国医学 | 895篇 |
肿瘤学 | 2594篇 |
出版年
2023年 | 233篇 |
2022年 | 524篇 |
2021年 | 705篇 |
2020年 | 618篇 |
2019年 | 1371篇 |
2018年 | 1298篇 |
2017年 | 857篇 |
2016年 | 601篇 |
2015年 | 702篇 |
2014年 | 1200篇 |
2013年 | 1355篇 |
2012年 | 1200篇 |
2011年 | 1483篇 |
2010年 | 1188篇 |
2009年 | 1127篇 |
2008年 | 1144篇 |
2007年 | 1182篇 |
2006年 | 1025篇 |
2005年 | 876篇 |
2004年 | 765篇 |
2003年 | 769篇 |
2002年 | 677篇 |
2001年 | 654篇 |
2000年 | 599篇 |
1999年 | 510篇 |
1998年 | 347篇 |
1997年 | 295篇 |
1996年 | 227篇 |
1995年 | 200篇 |
1994年 | 172篇 |
1993年 | 115篇 |
1992年 | 136篇 |
1991年 | 99篇 |
1990年 | 97篇 |
1989年 | 86篇 |
1988年 | 64篇 |
1987年 | 75篇 |
1985年 | 594篇 |
1984年 | 762篇 |
1983年 | 603篇 |
1982年 | 731篇 |
1981年 | 748篇 |
1980年 | 572篇 |
1979年 | 587篇 |
1978年 | 365篇 |
1977年 | 341篇 |
1976年 | 380篇 |
1975年 | 336篇 |
1974年 | 245篇 |
1973年 | 245篇 |
排序方式: 共有10000条查询结果,搜索用时 31 毫秒
981.
Sucrose, extracellular polysaccharide, and glucosyltransferases (GTFs) are key factors in sucrose-dependent adhesion and play important roles in the process of severe early-childhood caries (S-ECC). However, whether sucrose concentration regulates gtf expression, extracellular polysaccharide synthesis, and sucrose-dependent adhesion is related to the different genotypes of S. mutans isolated from ECC in children and still needs to be investigated. In this study, 52 strains of S. mutans were isolated from children with S-ECC and caries-free (CF) children. Water-insoluble glucan (WIG) synthesis was detected by the anthrone method, adhesion capacity by the turbidimetric method, and expression of gtf by RT-PCR in an in vitro model containing 1%–20% sucrose. The genotypes of S. mutans were analyzed by AP-PCR. The results showed that WIG synthesis, adhesion capacity, and gtf expression increased significantly when the sucrose concentration was from 1% to 10%. WIG synthesis and gtfB as well as gtfC expression of the 1% and 5% groups were significantly lower than those of the 10% and 20% groups (p < 0.05). There were no significant differences between the 10% and 20% groups. The fingerprints of S. mutans detected from individuals in the S-ECC group exhibited a significant difference in diversity compared with those from CF individuals (p < 0.05). Further, the expression of gtfB and gtfC in the S-ECC group was significantly different among the 1- to 5-genotype groups (p < 0.05). It can be concluded that sucrose-dependent adhesion might be related to the diversity of genotypes of S. mutans, and the 10% sucrose level can be seen as a “turning point” and essential factor for the prevention of S-ECC. 相似文献
982.
Tetrandrine, a constituent of Chinese herb Stephania tetrandra, causes cell death in prostate cancer, but the molecular mechanisms leading to apoptosis is not known. Here we demonstrated that tetrandrine selectively inhibits the growth of prostate cancer PC3 and DU145 cells compared to normal prostate epithelial PWR-1E cells. Tetrandrine-induced cell death in prostate cancer cells is caused by reactive oxygen species (ROS)-mediated activation of c-Jun NH2-terminal kinase (JNK1/2). JNK1/2-mediated proteasomal degradation of c-FLIPL/S and Bcl2 proteins are key events in the sensitization of prostate cancer cells to Fas- and mitochondria-mediated apoptosis by tetrandrine. Tetrandrine-induced JNK1/2 activation caused the translocation of Bax to mitochondria by disrupting its association with Bcl2 which was accompanied by collapse of mitochondrial membrane potential (MMP), cytosolic release of cytochrome c and Smac, and apoptotic cell death. Additionally, tetrandrine-induced JNK1/2 activation increased the phosphorylation of Bcl2 at Ser70 and facilitated its degradation via the ubiquitin-mediated proteasomal pathway. In parallel, tetrandrine-mediated ROS generation also caused the induction of ligand-independent Fas-mediated apoptosis by activating procaspase-8 and Bid cleavage. Inhibition of procaspase-8 activation attenuated the cleavage of Bid, loss of MMP and caspase-3 activation suggest that tetrandrine-induced Fas-mediated apoptosis is associated with the mitochondrial pathway. Furthermore, most of the signaling effects of tetrandrine on apoptosis were significantly attenuated in the presence of antioxidant N-acetyl-l-cysteine, thereby confirming the involvement of ROS in these events. In conclusion, the results of the present study indicate that tetrandrine-induced apoptosis in prostate cancer cells is initiated by ROS generation and that both intrinsic and extrinsic pathway contributes to cell death. 相似文献
983.
The vascular endothelium is specifically sensitive to oxidative stress, and this is one of the mechanisms that causes widespread endothelial dysfunction in most cardiovascular diseases and disorders. Protection against reactive oxygen species (ROS)-mediated oxidative damage via antioxidant mechanisms is essential for tissue maintenance and shows therapeutic potential for patients suffering from cardiovascular and metabolic disorders. Salvianolic acid B (SalB), a natural bioactive component known from Traditional Chinese Medicine, has been reported to exert cellular protection in various types of cells. However, the underlying mechanisms involved are not fully understood. Here, we showed that SalB significantly promoted the migratory and tube formation abilities of human bone marrow derived-endothelial progenitor cells (BM-EPCs) in vitro, and substantially abrogated hydrogen peroxide (H2O2)-induced cell damage. SalB down-regulated Nox4 and eNOS, as well as nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase expression upon H2O2 induction that in turn prevents oxidative-induced endothelial dysfunction. Moreover, SalB suppressed the Bax/Bcl-xL ratio and caspase-3 activation after H2O2 induction. Furthermore, our results provide mechanistic evidence that activation of the mTOR/p70S6K/4EBP1 pathways is required for both SalB-mediated angiogenic and protective effects against oxidative stress-induced cell injury in BM-EPCs. Suppression of MKK3/6-p38 MAPK-ATF2 and ERK1/2 signaling pathways by SalB significantly protected BM-EPCs against cell injury caused by oxidative stress via reduction of intracellular ROS levels and apoptosis. Taken together, by providing a mechanistic insight into the modulation of redox states in BM-EPCs by SalB, we suggest that SalB has a strong potential of being a new proangiogenic and cytoprotective therapeutic agent with applications in the field of endothelial injury-mediated vascular diseases. 相似文献
984.
985.
Yubo Tang Corina Vater Angela Jacobi Cornelia Liebers Xuenong Zou Maik Stiehler 《British journal of pharmacology》2014,171(9):2440-2456
Background and Purpose
With the increase of age, increased susceptibility to apoptosis and senescence may contribute to proliferative and functional impairment of endothelial progenitor cells (EPCs). The aim of this study was to investigate whether salidroside (SAL) can induce angiogenic differentiation and inhibit oxidative stress-induced apoptosis in bone marrow-derived EPCs (BM-EPCs), and if so, through what mechanism.Experimental Approach
BM-EPCs were isolated and treated with different concentrations of SAL for up to 4 days. Cell proliferation, migration and tube formation ability were detected by DNA content quantification, transwell assay and Matrigel-based angiogenesis assay. Gene and protein expression were assessed by qRT-PCR and Western blot respectively.Key Results
Treatment with SAL promoted cellular proliferation and angiogenic differentiation of BM-EPCs, and increased VEGF and NO secretion, which in turn mediated the enhanced angiogenic differentiation of BM-EPCs. Furthermore, SAL significantly attenuated hydrogen peroxide (H2O2)-induced cell apoptosis, reduced the intracellular level of reactive oxygen species and restored the mitochondrial membrane potential of BM-EPCs. Moreover, SAL stimulated the phosphorylation of Akt, mammalian target of rapamycin and p70 S6 kinase, as well as ERK1/2, which is associated with cell migration and capillary tube formation. Additionally, SAL reversed the phosphorylation of JNK and p38 MAPK induced by H2O2 and suppressed the changes in the Bax/Bcl-xL ratio observed after stimulation with H2O2.Conclusions and Implications
These findings identify novel mechanisms that regulate EPC function and suggest that SAL has therapeutic potential as a new agent to enhance vasculogenesis as well as protect against oxidative endothelial injury. 相似文献986.
987.
Large molecule therapeutics (MW > 1000 daltons) are not expected to enter the cell and thus have reduced potential to interact directly with DNA or related physiological processes. Genotoxicity studies are therefore not relevant and typically not required for large molecule therapeutic candidates. Regulatory guidance supports this approach; however there are examples of marketed large molecule therapeutics where sponsors have conducted genotoxicity studies. A retrospective analysis was performed on genotoxicity studies of United States FDA approved large molecule therapeutics since 1998 identified through the Drugs@FDA website. This information was used to provide a data-driven rationale for genotoxicity evaluations of large molecule therapeutics. Fifty-three of the 99 therapeutics identified were tested for genotoxic potential. None of the therapeutics tested showed a positive outcome in any study except the peptide glucagon (GlucaGen®) showing equivocal in vitro results, as stated in the product labeling. Scientific rationale and data from this review indicate that testing of a majority of large molecule modalities do not add value to risk assessment and support current regulatory guidance. Similarly, the data do not support testing of peptides containing only natural amino acids. Peptides containing non-natural amino acids and small molecules in conjugated products may need to be tested. 相似文献
988.
We have demonstrated for the first time the mechanism underlying ROS-mediated mitochondria-dependent apoptotic cell death triggered by isoegomaketone (IK) treatment in melanoma cells. We showed that IK induced apoptotic cell death and tumor growth inhibition using tissue culture and in vivo models of B16 melanoma. Furthermore, we observed that IK effectively induced apoptotic cell death, including sub-G1 contents up-regulation, nuclei condensation, DNA fragmentation, and caspase activation in B16 melanoma cells. Pretreatment with caspase inhibitor increased the survival rate of IK-treated B16 cells, implying that caspases play a role in IK-induced apoptosis. Furthermore, IK treatment generated ROS in melanoma cells. We also determined whether or not IK-induced cell death is due to ROS production in B16 cells. N-acetyl cysteine (NAC) inhibitedIK-induced Bcl-2 family-mediated apoptosis. This result indicates that IK-induced apoptosis involves ROS generation as well as up-regulation of Bax and Bcl-2 expression, leading to release of cytochrome c and AIF. Our data suggest that IK inhibits growth and induces apoptosis in melanoma cells via activation of ROS-mediated caspase-dependent and -independent pathways. 相似文献
989.
990.
Caffeine is one of the most researched food components, with the vast majority of dietary contributions coming from beverage consumption; however, there is little population-level data on caffeine intakes in the U.S. This study estimated the caffeine intakes of the U.S. population using a comprehensive beverage survey, the Kantar Worldpanel Beverage Consumption Panel. A nationally representative sample of 37,602 consumers (aged ⩾ 2 years) of caffeinated beverages completed 7-day diaries which facilitated the development of a detailed database of caffeine values to assess intakes. Results showed that 85% of the U.S. population consumes at least one caffeinated beverage per day. The mean (±SE) daily caffeine intake from all beverages was 165 ± 1 mg for all ages combined. Caffeine intake was highest in consumers aged 50–64 years (226 ± 2 mg/day). The 90th percentile intake was 380 mg/day for all ages combined. Coffee was the primary contributor to caffeine intakes in all age groups. Carbonated soft drinks and tea provided a greater percentage of caffeine in the younger (<18 years) age groups. The percentage of energy drink consumers across all age groups was low (⩽10%). These data provide a current perspective on caffeinated beverage consumption patterns and caffeine intakes in the U.S. population. 相似文献