全文获取类型
收费全文 | 380篇 |
免费 | 47篇 |
国内免费 | 1篇 |
专业分类
儿科学 | 14篇 |
妇产科学 | 10篇 |
基础医学 | 50篇 |
口腔科学 | 5篇 |
临床医学 | 58篇 |
内科学 | 147篇 |
皮肤病学 | 2篇 |
神经病学 | 14篇 |
特种医学 | 21篇 |
外科学 | 61篇 |
综合类 | 11篇 |
预防医学 | 15篇 |
药学 | 7篇 |
肿瘤学 | 13篇 |
出版年
2019年 | 3篇 |
2018年 | 29篇 |
2017年 | 17篇 |
2016年 | 6篇 |
2015年 | 4篇 |
2014年 | 13篇 |
2013年 | 13篇 |
2012年 | 11篇 |
2011年 | 14篇 |
2010年 | 13篇 |
2009年 | 13篇 |
2008年 | 15篇 |
2007年 | 5篇 |
2006年 | 13篇 |
2005年 | 13篇 |
2004年 | 7篇 |
2003年 | 12篇 |
2002年 | 9篇 |
2001年 | 8篇 |
2000年 | 6篇 |
1999年 | 10篇 |
1998年 | 13篇 |
1997年 | 16篇 |
1996年 | 8篇 |
1995年 | 7篇 |
1994年 | 4篇 |
1993年 | 12篇 |
1992年 | 12篇 |
1991年 | 7篇 |
1990年 | 8篇 |
1989年 | 8篇 |
1988年 | 7篇 |
1987年 | 13篇 |
1986年 | 10篇 |
1985年 | 12篇 |
1984年 | 6篇 |
1983年 | 7篇 |
1982年 | 3篇 |
1981年 | 5篇 |
1980年 | 2篇 |
1979年 | 6篇 |
1978年 | 3篇 |
1977年 | 2篇 |
1975年 | 4篇 |
1974年 | 2篇 |
1973年 | 3篇 |
1972年 | 2篇 |
1971年 | 3篇 |
1970年 | 2篇 |
1969年 | 2篇 |
排序方式: 共有428条查询结果,搜索用时 0 毫秒
31.
Membrane permeabilization by Listeria monocytogenes phosphatidylinositol-specific phospholipase C is independent of phospholipid hydrolysis and cooperative with listeriolysin O. 总被引:4,自引:0,他引:4 下载免费PDF全文
H Goldfine C Knob D Alford J Bentz 《Proceedings of the National Academy of Sciences of the United States of America》1995,92(7):2979-2983
We have examined potential cooperative interactions of Listeria monocytogenes phosphatidylinositol-specific phospholipase C (PI-PLC) and listeriolysin O (LLO), a pore-forming hemolysin, in a liposome lysis assay. Large unilamellar vesicles, approximately 0.1 micron in diameter, encapsulating the fluorescent probe calcein, were treated with PI-PLC or LLO at pH 6.0, and each was capable of causing dye release. With phosphatidylcholine/phosphatidylinositol/cholesterol liposomes at 0.1 microM lipid, minimal release of dye was observed on addition of 80 pM LLO or 7 nM PI-PLC. Addition of the two proteins together produced rapid dye release. Unexpectedly, essentially identical results were obtained with phosphatidylcholine/cholesterol liposomes. Thus, the effect of PI-PLC did not depend on lipid hydrolysis. Both proteins also released inulin (M(r) 5200) from liposomes. Membrane permeabilization was not accompanied by membrane fusion. Very little dye release from phosphatidylcholine/phosphatidylinositol/cholesterol liposomes was seen with PI-PLC from Bacillus thuringiensis, and addition of this enzyme to LLO produced no additional dye release; however PI-PLC from L. monocytogenes cooperated with perfringolysin O from Clostridium perfringens. PI-PLC from L. monocytogenes and LLO bind to phosphatidylcholine/cholesterol liposomes, and the rate of binding of each protein was not influenced by the presence of the other. These data support a postulated accessory role for PI-PLC with LLO in lysing the primary phagosome of a macrophage. 相似文献
32.
33.
34.
35.
36.
Ryan CJ Zavodovskaya M Youngren JF Campbell M Diamond M Jones J Shiry L Allan G Maddux BA Goldfine ID 《The Prostate》2008,68(11):1232-1240
BACKGROUND: Nordihydroguaiaretic acid (NDGA) is an inhibitor of the IGF-1 receptor (IGF-1R) in breast and other cancers, and concomitantly inhibits tumor growth both in cultured cells and animals. The current study evaluates the effect of NDGA on the androgen-stimulated growth of human prostate cancer cells. METHODS: LAPC-4 prostate cancer cells in tissue culture were androgen starved for 3 days, 1 nM dihydrotestosterone (DHT) and other androgens were then added for up to 7 days, and cell proliferation measured. IGF-1R protein expression was measured by Western blot, and IGF-1R mRNA expression by quantitative PCR. IGF-1R receptor kinase activation was measured by ELISA. RESULTS: After 7 days, LAPC-4 growth was doubled by 1 nM DHT. NDGA had a rapid effect to inhibit IGF-1R autophosphorylation induced by IGF-1. DHT increased the expression of IGF-1R protein and mRNA levels. Maximal IGF-1R protein levels were observed 3 days after the addition of androgen. In addition, NDGA, at 10 microM or less, inhibited DHT-induced proliferation in both cells grown in plates and cells grown in soft agar. Androgen receptor (AR) studies by FRET revealed that NDGA had no conformational effects on the AR in response to ligand. CONCLUSIONS: NDGA blocks the DHT-induced growth of LAPC-4 prostate cancer cells by several mechanisms including rapid inhibition of the IGF-1R kinase, and a dose-dependent inhibition of androgen stimulation of IGF-1R expression. Clinical studies of this agent will determine its efficacy in the setting of androgen-dependent prostate cancer. 相似文献
37.
Ryan CJ Haqq CM Simko J Nonaka DF Chan JM Weinberg V Small EJ Goldfine ID 《Urologic oncology》2007,25(2):134-140
PURPOSE: The insulin-like growth factor (IGF)-1 receptor is currently being targeted in clinical trials in prostate cancer. Despite this targeting, there are conflicting data on the presence of this receptor in human tumor samples, largely because of differences in technique. MATERIALS AND METHODS: Immunohistochemistry was used to determine the presence of IGF-1 receptor in frozen normal prostate and prostate cancer specimens. Clinical and pathologic parameters were correlated with IGF-1 receptor intensity and frequency of staining. Only 2-3+ staining on a scale of 0-3 was considered positive in this evaluation. RESULTS: IGF-1 receptor was expressed in normal prostate epithelium in 6 of 6 patients without cancer and in morphologically normal epithelium adjacent to tumor cells in 21 of 22 patients with cancer studied. IGF-1 receptor was present in the prostate tumor epithelium of 28 of 28 primary tumors, 3 of 5 locally recurrent androgen-independent tumors, and in 4 of 5 metastatic lymph nodes. Stromal staining patterns were positive in 2 of 28 specimens near benign epithelium compared to 19 of 30 specimens of stroma surrounding tumor epithelium (P < 0.0001, Fisher exact test). Stroma adjacent to Gleason grade >or=7 tumors showed higher intensity staining than that adjacent to lower grade tumors (P < 0.001). Expression of the closely related insulin receptor did not show expression in either normal or cancer epithelium, or in adjacent stroma. CONCLUSIONS: This study using frozen tissue shows widespread IGF-1 receptor expression in normal prostate, prostate cancers, and metastases. These data support investigations into IGF-1 receptor as a therapeutic target in prostate cancer. 相似文献
38.
Physiological concentrations of cholecystokinin stimulate amino acid-induced insulin release in humans 总被引:3,自引:0,他引:3
R J Rushakoff I D Goldfine J D Carter R A Liddle 《The Journal of clinical endocrinology and metabolism》1987,65(3):395-401
After a meal, hormones released from the gut potentiate insulin release. This study was undertaken to determine if physiological concentrations of plasma cholecystokinin (CCK) stimulate insulin secretion in man. Employing a specific CCK bioassay, postprandial CCK levels were determined in normal subjects. Ingestion of a mixed liquid meal stimulated an increase in circulating CCK from a mean fasting level of 0.9 +/- 0.2 (SEM) pmol/L to a mean peak level of 7.1 +/- 1.1 pmol/L within 10 min of feeding. After 30 min the mean CCK level fell to 3.5 pmol/L and remained elevated for the remainder of the 90-min experiment. Eight subjects underwent 40-min infusions of either arginine (15 g), mixed amino acids (15 g), or glucose (30 g) with or without the simultaneous infusion of CCK-8. Since CCK-8 has full biological potency, this form was chosen for infusion to reproduce total CCK bioactivity in plasma. CCK-8 was infused at rates of 12 or 24 pmol/kg X h, producing steady state plasma CCK levels of 4.5 +/- 0.7 and 8.2 +/- 1.1 pmol/L, respectively, spanning the range of normal postprandial levels. CCK alone had no effect on insulin, glucose, or glucagon levels. Administration of arginine alone stimulated insulin from a mean basal level of 12.8 +/- 1.3 microU/mL to a peak level of 41.3 +/- 5.4 microU/mL. Infusion of CCK at 12 and 24 pmol/kg X h augmented arginine-stimulated insulin levels to peaks of 62.5 +/- 13.9 and 63.0 +/- 4.0 microU/mL, respectively. Moreover, CCK nearly doubled the total amount of insulin secreted during the arginine infusion. A similar potentiation of glucagon release was found with both doses of CCK. In addition, infusion of a mixture of amino acids with and without concomitant CCK infusions revealed that CCK potentiated the insulin release induced by mixed amino acids. In contrast to the potent effect of CCK on amino acid-induced insulin release, infusions of CCK together with glucose caused no enhancement of glucose-stimulated insulin release. These results demonstrate that physiological concentrations of CCK potentiate amino acid (but not glucose)-induced insulin secretion in man. These data suggest, therefore, that CCK may have a role in man as a modulator of insulin release. 相似文献
39.
40.
Mutagenesis of Active-Site Histidines of Listeria monocytogenes Phosphatidylinositol-Specific Phospholipase C: Effects on Enzyme Activity and Biological Function 下载免费PDF全文
Listeria monocytogenes, a gram-positive facultative intracellular pathogen, produces two distinct phospholipases C. PC-PLC, encoded by plcB, is a broad-range phospholipase, whereas PI-PLC, encoded by plcA, is specific for phosphatidylinositol. It was previously shown that PI-PLC plays a role in efficient escape of L. monocytogenes from the primary phagosome. To further understand the function of PI-PLC in intracellular growth, site-directed mutagenesis of plcA was performed. Two potential active-site histidine residues were mutated independently to alanine, serine, and phenylalanine. With the exception of the activity of the enzyme containing H38F, which was unstable, the PI-PLC enzyme activities of culture supernatants containing each mutant enzyme were <1% of wild-type activity. In addition, the levels of expression of the mutant PI-PLC proteins were equivalent to wild-type expression. Derivatives of L. monocytogenes containing these specific plcA mutations were found to have phenotypes similar to that of the plcA deletion strain in an assay for escape from the primary vacuole, in intracellular growth in a murine macrophage cell line, and in a plaquing assay for cell-to-cell spread. Thus, catalytic activity of PI-PLC is required for all its intracellular functions. 相似文献