全文获取类型
收费全文 | 344篇 |
免费 | 26篇 |
国内免费 | 12篇 |
专业分类
儿科学 | 4篇 |
妇产科学 | 4篇 |
基础医学 | 49篇 |
口腔科学 | 3篇 |
临床医学 | 15篇 |
内科学 | 67篇 |
皮肤病学 | 2篇 |
神经病学 | 16篇 |
外科学 | 8篇 |
综合类 | 22篇 |
预防医学 | 7篇 |
眼科学 | 1篇 |
药学 | 149篇 |
中国医学 | 7篇 |
肿瘤学 | 28篇 |
出版年
2023年 | 5篇 |
2022年 | 3篇 |
2021年 | 14篇 |
2020年 | 8篇 |
2019年 | 3篇 |
2018年 | 7篇 |
2017年 | 10篇 |
2016年 | 12篇 |
2015年 | 15篇 |
2014年 | 22篇 |
2013年 | 18篇 |
2012年 | 32篇 |
2011年 | 25篇 |
2010年 | 25篇 |
2009年 | 18篇 |
2008年 | 26篇 |
2007年 | 17篇 |
2006年 | 18篇 |
2005年 | 15篇 |
2004年 | 12篇 |
2003年 | 14篇 |
2002年 | 10篇 |
2001年 | 7篇 |
2000年 | 6篇 |
1999年 | 1篇 |
1998年 | 1篇 |
1997年 | 1篇 |
1996年 | 3篇 |
1995年 | 4篇 |
1993年 | 1篇 |
1992年 | 1篇 |
1991年 | 1篇 |
1990年 | 2篇 |
1989年 | 3篇 |
1988年 | 2篇 |
1985年 | 2篇 |
1984年 | 1篇 |
1983年 | 1篇 |
1981年 | 4篇 |
1980年 | 2篇 |
1979年 | 3篇 |
1977年 | 2篇 |
1976年 | 2篇 |
1975年 | 1篇 |
1973年 | 1篇 |
1970年 | 1篇 |
排序方式: 共有382条查询结果,搜索用时 15 毫秒
1.
Cross-sectional areas and lactate dehydrogenase activity were determined of separate muscle fibres of mouse rectus femoris muscle in both ventral and dorsal parts of the muscle. The lactate dehydrogenase activity was measured quantitatively by microscope photometry using a tetrazolium staining in absence or presence of either vitamin K3 or phenazine methosulfate. If the observations are restricted to a relatively small area of the muscle cross section, one can distinguish categorically narrow ("red") and broad ("white) fibres with average values for cross sectional area and LDH content that depend on the part of the muscle chosen (higher LDH and smaller area in ventral part). However, if these data from the different parts or from the whole muscle are added together, no categorical distinction between the fibre types is allowed. On the basis of the observations a categorical division of muscle fibres within relatively large muscle areas or in a whole muscle is rather dubious. A relation is suggested between the subjective impression of different muscle fibre types in a field of observation with the number of motorunits present in that field. 相似文献
2.
3.
4.
Takeo Shimo Naoki Ashizawa Koji Matsumoto Takashi Nakazawa Osamu Nagata 《Toxicological sciences》2005,87(1):267-276
The possible mechanism of the underlying nephropathy found in the rat toxicity study of FYX-051, a xanthine oxidoreductase inhibitor, was investigated. Rats received oral treatment of either 1 or 3 mg/kg of FYX-051, with and without citrate for four weeks to elucidate whether nephropathy could be caused by materials deposited in the kidney. Furthermore, analysis of the renal deposits in rats was also performed. Consequently, interstitial nephritis comprising interstitial inflammatory cell infiltration, dilatation, basophilia and epithelial necrosis of renal tubules and collecting ducts, deposits in renal tubules and collecting ducts, and so forth was seen in six of the eight rats and in all eight rats in the 1 and 3 mg/kg FYX-051 alone groups, respectively, with the intensity in the 3 mg/kg group being moderate to severe. In the simultaneous treatment with citrate group, however, no alterations were observed in the kidney, except for minimal interstitial nephritis in one instance in the 3 mg/kg FYX-051 + citrate group along with an increased urinary pH, leading to an increase in xanthine solubility. Analysis of intrarenal deposits showed that the entity would be composed of xanthine crystals. The present study, therefore, showed that nephropathy in rats occurring after the administration of FYX-051 was a secondary change caused by xanthine crystals being deposited in the kidney, and no other causes could be implicated in this kidney lesion. 相似文献
5.
Role of pharmacogenomics and pharmacodynamics in the treatment of acute lymphoblastic leukaemia 总被引:1,自引:0,他引:1
Pharmacodynamic studies have been used to establish the relationships between the administered dosage and the concentration of drugs and metabolites in the blood or tissues and that between these concentrations and pharmacological effects. Polymorphisms in the genes that encode drug-metabolizing enzymes, drug transporters and drug targets can affect a person's response to therapy and may affect the development of de novo or therapy-related leukaemias. The burgeoning field of pharmacogenomics elucidates inherited differences in drug metabolism and treatment response. Increasingly, pharmacodynamic and pharmacogenomic studies are being used to individualize therapy to enhance efficacy and reduce toxicity. 相似文献
6.
Mohammad Abu-Odeh Zaidoun Salah Christoph Herbel Thomas G. Hofmann Rami I. Aqeilan 《Proceedings of the National Academy of Sciences of the United States of America》2014,111(44):E4716-E4725
Genomic instability is a hallmark of cancer. The WW domain-containing oxidoreductase (WWOX) is a tumor suppressor spanning the common chromosomal fragile site FRA16D. Here, we report a direct role of WWOX in DNA damage response (DDR) and DNA repair. We show that Wwox deficiency results in reduced activation of the ataxia telangiectasia-mutated (ATM) checkpoint kinase, inefficient induction and maintenance of γ-H2AX foci, and impaired DNA repair. Mechanistically, we show that, upon DNA damage, WWOX accumulates in the cell nucleus, where it interacts with ATM and enhances its activation. Nuclear accumulation of WWOX is regulated by its K63-linked ubiquitination at lysine residue 274, which is mediated by the E3 ubiquitin ligase ITCH. These findings identify a novel role for the tumor suppressor WWOX and show that loss of WWOX expression may drive genomic instability and provide an advantage for clonal expansion of neoplastic cells.Genomic instability is a common characteristic of human cancers. The DNA damage response (DDR) maintains the integrity of the genome in response to DNA damage. DDR is a complex signaling process that results in cell cycle arrest followed by either DNA repair or apoptosis if the DNA damage is too extensive to be repaired (1–3). Key mammalian damage response sensors are ataxia telangiectasia-mutated (ATM), ATM and Rad3-related, and DNA-dependent PKs (4, 5). Disruption of the DDR machinery in human cells leads to genomic instability and an increased risk of cancer progression (6, 7).The WW domain-containing oxidoreductase (WWOX) gene spans the common fragile site (CFS) FRA16D (8, 9). Genomic alterations affecting the WWOX locus have been reported in several types of cancer and include homozygous and hemizygous deletions (10–13). Ectopic expression of WWOX in WWOX-negative cancer cells attenuates cell growth and suppresses tumor growth in immunocompromised mice (10, 11, 14). Importantly, targeted ablation of Wwox in mice results in higher incidence of spontaneous lesions resembling osteosarcomas and lung and mammary tumors (14–16). These findings suggest WWOX as a tumor suppressor. The WWOX protein contains two N-terminal WW domains mediating WWOX interaction with PP(proline)x(amino acid)Y(tyrosine)-containing proteins (11, 17) and a central short-chain deyhdrogenase/reductase domain that has been proposed to function in steroidogenesis (18). Recent characterization of WWOX domains revealed that they interact, mainly through the WW1 domain, with multiprotein networks (3). The mechanism by which WWOX suppresses tumorigenicity is, however, not well-known.In vitro, CFSs are defined as gaps or breaks on metaphase chromosomes that occur in cells treated with inhibitors of DNA replication (19, 20). In vivo, CFSs are preferential targets of replication stress in preneoplastic lesions (21), and emerging evidence suggests that they represent early warning sensors for DNA damage (22–24). Both genetic and epigenetic factors are thought to regulate the fragility of CFS (25, 26). Recent profiling studies of CFS provide evidence that the functional fragility of CFS is tissue-specific (27–29). High-throughput genomic analyses of 3,131 cancer specimens (12) and 746 cancer cell lines (13) have recently identified large deletions in CFSs, including the FRA16D/WWOX locus. Although these deletions have been linked to the presence of DNA replication stress (30), the molecular function of gene products of CFSs, including the WWOX protein, is poorly understood. Here, we identify a direct role of WWOX in the DDR and show that the WWOX gene product functions as a modulator of the DNA damage checkpoint kinase ATM. 相似文献
7.
Katarzyna Walkiewicz Andres S. Benitez Cardenas Christine Sun Colin Bacorn Gerda Saxer Yousif Shamoo 《Proceedings of the National Academy of Sciences of the United States of America》2012,109(52):21408-21413
In principle, evolutionary outcomes could be largely predicted if all of the relevant physicochemical variants of a particular protein function under selection were known and integrated into an appropriate physiological model. We have tested this principle by generating a family of variants of the tetracycline resistance protein TetX2 and identified the physicochemical properties most correlated with organismal fitness. Surprisingly, small changes in the Km(MCN), less than twofold, were sufficient to produce highly successful adaptive mutants over clinically relevant drug concentrations. We then built a quantitative model directly relating the in vitro physicochemical properties of the mutant enzymes to the growth rates of bacteria carrying a single chromosomal copy of the tet(X2) variants over a wide range of minocycline (MCN) concentrations. Importantly, this model allows the prediction of enzymatic properties directly from cellular growth rates as well as the physicochemical-fitness landscape of TetX2. Using experimental evolution and deep sequencing to monitor the allelic frequencies of the seven most biochemically efficient TetX2 mutants in 10 independently evolving populations, we showed that the model correctly predicted the success of the two most beneficial variants tet(X2)T280A and tet(X2)N371I. The structure of the most efficient variant, TetX2T280A, in complex with MCN at 2.7 Å resolution suggests an indirect effect on enzyme kinetics. Taken together, these findings support an important role for readily accessible small steps in protein evolution that can, in turn, greatly increase the fitness of an organism during natural selection. 相似文献
8.
9.
目的 探讨大鼠液压冲击伤后水肿脑组织核因子2相关因子2(nuclear factor erythroid-2-related factor 2,Nrf2)、血红素氧化酶-1(heme oxygenase-1,HO-1)和磷酸酰胺腺嘌呤二核苷酸醌氧化还原酶-1(NADPH quinineoxidoreductase-1,NQO-1)的表达变化及其意义.方法 成年雄性SD大鼠56只制作液压冲击颅脑损伤模型,术后1h、6h、12 h、24 h、3d、7d用干湿质量法测定脑组织含水量,Westernblot测定Nrf2胞浆、胞核蛋白以及HO-1、NQO-1蛋白;用实时荧光定量PCR测定Nrf2 mRNA表达.结果 自冲击伤后6h,脑组织含水量开始增加,24h达高峰,持续至3d,然后开始下降(P<0.05).组织学观察印证了脑水肿趋势.Western blot检测结果显示胞浆Nrf2蛋白于伤后12 h开始持续降低,而胞核Nrf2蛋白则于1h开始升高,24 h达到高峰,3d时降低,7d后明显降低,但仍高于NC组(P<0.05).HO-1和NQO-1蛋白表达与胞核Nrf2蛋白趋势一致.实时荧光定量PCR显示TBI组术后各时间点Nrf2 mRNA表达水平无明显变化(P>0.05).结论 液压冲击伤后出现核因子Nrf2转位激活,可能通过上调HO-1、NQO-1蛋白表达发挥神经保护作用. 相似文献
10.
Kazuomi Kario Masafumi Nishizawa Mari Kiuchi Arihiro Kiyosue Fumishi Tomita Hiroshi Ohtani Yasuhisa Abe Hideyo Kuga Satoshi Miyazaki Takatoshi Kasai Makiko Hongou Takanori Yasu Jin Kuramochi Yoshihiro Fukumoto Satoshi Hoshide Ichiro Hisatome 《Journal of clinical hypertension (Greenwich, Conn.)》2021,23(2):334
Elevated serum uric acid is a cardiovascular risk factor in patients with hypertension, even when blood pressure (BP) is well controlled. Xanthine oxidoreductase inhibitors (XORi) reduce serum uric acid levels and have several other potential effects. This multicenter, randomized, open‐label study compared the effects of two XORi, topiroxostat and febuxostat, on arterial stiffness, uric acid levels, and BP in hypertensive patients with hyperuricemia. Patients received topiroxostat 40–160 mg/day or febuxostat 10–60 mg/day, titrated to maintain serum uric acid <6 mg/dl, for 24 weeks. The primary endpoint was change in the cardio‐ankle vascular index (CAVI) from baseline to 24 weeks. There were no significant changes in CAVI from baseline to 24 weeks (from 9.13 to 9.16 [feboxustat] and 8.98 to 9.01 [topiroxostat]). Compared with baseline, there were significant reductions in serum uric acid (–2.9 and –2.5 mg/dl; both p < 0.001) and morning home systolic BP (–3.6 and –5.1 mm Hg; both p < 0.01) after 24 weeks'' treatment with febuxostat and topiroxostat. BP decreased to the greatest extent in the subgroup of patients with uncontrolled blood pressure at baseline. Topiroxostat, but not febuxostat, significantly decreased plasma xanthine oxidoreductase activity versus baseline. The urinary albumin‐creatinine ratio (UACR) decreased significantly from baseline to 24 weeks with topiroxostat (–20.8%; p = 0.021), but not febuxostat (–8.8%; p = 0.362). In conclusion, neither topiroxostat nor febuxostat had any significant effects on arterial stiffness over 24 weeks'' treatment. 相似文献