全文获取类型
收费全文 | 468篇 |
免费 | 44篇 |
出版年
2023年 | 2篇 |
2022年 | 9篇 |
2021年 | 7篇 |
2020年 | 18篇 |
2019年 | 15篇 |
2018年 | 13篇 |
2017年 | 5篇 |
2016年 | 15篇 |
2015年 | 31篇 |
2014年 | 28篇 |
2013年 | 51篇 |
2012年 | 43篇 |
2011年 | 41篇 |
2010年 | 24篇 |
2009年 | 19篇 |
2008年 | 30篇 |
2007年 | 27篇 |
2006年 | 19篇 |
2005年 | 13篇 |
2004年 | 18篇 |
2003年 | 20篇 |
2002年 | 17篇 |
2001年 | 4篇 |
2000年 | 1篇 |
1999年 | 5篇 |
1998年 | 6篇 |
1997年 | 2篇 |
1996年 | 5篇 |
1995年 | 3篇 |
1994年 | 2篇 |
1993年 | 2篇 |
1992年 | 4篇 |
1991年 | 1篇 |
1990年 | 2篇 |
1989年 | 1篇 |
1988年 | 1篇 |
1986年 | 1篇 |
1984年 | 1篇 |
1976年 | 1篇 |
1973年 | 1篇 |
1971年 | 1篇 |
1963年 | 2篇 |
1926年 | 1篇 |
排序方式: 共有512条查询结果,搜索用时 15 毫秒
51.
Marjan Shafaati Natalia Mast Olof Beck Rima Nayef Gun Young Heo Linda Bj?rkhem-Bergman Dieter Lütjohann Ingemar Bj?rkhem Irina A. Pikuleva 《Journal of lipid research》2010,51(2):318-323
Cholesterol 24S-hydroxylase (CYP46A1) is of key importance for cholesterol homeostasis in the brain. This enzyme seems to be resistant toward most regulatory factors and at present no drug effects on its activity have been described. The crystal structures of the substrate-free and substrate-bound CYP46A1 were recently determined (Mast et al., Crystal structures of substrate-bound and substrate-free cytochrome P450 46A1, the principal cholesterol hydroxylase in the brain. Proc. Natl. Acad. Sci. USA. 2008. 105: 9546–9551). These structural studies suggested that ligands other than sterols can bind to CYP46A1. We show here that the antifungal drug voriconazole binds to the enzyme in vitro and inhibits CYP46A1-mediated cholesterol 24-hydroxylation with a Ki of 11 nM. Mice treated with daily intraperitoneal injections of voriconazole for 5 days had high levels of voriconazole in the brain and significantly reduced brain levels of 24S-hydroxycholesterol. The levels of squalene, lathosterol, and HMG-CoA reductase mRNA were reduced in the brain of the voriconazole-treated animals as well, indicating a reduced cholesterol synthesis. Most of this effect may be due to a reduced utilization of cholesterol by CYP46A1. One of the side-effects of voriconazole is visual disturbances. Because CYP46A1 is also expressed in the neural retina, we discuss the possibility that the inhibition of CYP46A1 by voriconazole contributes to these visual disturbances. 相似文献
52.
Mohammad‐Bagher Ebrahim‐Habibi Mehriar Amininasab Azadeh Ebrahim‐Habibi Marjan Sabbaghian Mohsen Nemat‐Gorgani 《Biopolymers》2010,93(10):854-865
Formation of toxic amyloid structures is believed to be associated with various late‐onset neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. The fact that many proteins in addition to those that are associated with clinical conditions have the potential to form amyloid fibrils in vitro provides opportunities for studying the fundamentals of protein aggregation and amyloid formation in model systems. Accordingly, considerable interest and effort has been directed toward developing small molecules to inhibit the formation of fibrillar assemblies and their associated toxicities. In the present study, we investigated the inhibitory effect of crocin and safranal, two principal components of saffron, on fibrillation of apo‐α‐lactalbumin (a‐α‐LA), used as a model protein, under amyloidogenic conditions. In the absence of any ligand, formation of soluble oligomers became evident after 18 h of incubation, followed by subsequent appearance of mature fibrils. Upon incubation with crocin or safranal, while transition phase to monomeric beta structures was not significantly affected, formation of soluble oligomers and following fibrillar assemblies were inhibited. While both safranal and crocin had the ability to bind to hydrophobic patches provided in the intermediate structures, and thereby inhibit protein aggregation, crocin was found more effective, possibly due to its simultaneous hydrophobic and hydrophilic character. Cell viability assay indicated that crocin could diminish toxicity while safranal act in reverse order. © 2010 Wiley Periodicals, Inc. Biopolymers 93: 854–865, 2010. 相似文献
53.
Niessen RC Sijmons RH Ou J Olthof SG Osinga J Ligtenberg MJ Hogervorst FB Weiss MM Tops CM Hes FJ de Bock GH Buys CH Kleibeuker JH Hofstra RM 《Human genetics》2006,119(1-2):206-211
Biallelic germline mutations of MUTYH—a gene encoding a base excision repair protein—are associated with an increased susceptibility of colorectal cancer. Whether
monoallelic MUTYH mutations also increase cancer risk is not yet clear, although there is some evidence suggesting a slight increase of risk.
As the MUTYH protein interacts with the mismatch repair (MMR) system, we hypothesised that the combination of a monoallelic
MUTYH mutation with an MMR gene mutation increases cancer risk. We therefore investigated the prevalence of monoallelic MUTYH mutations in carriers of a germline MMR mutation: 40 carriers of a truncating mutation (group I) and 36 of a missense mutation
(group II). These patients had been diagnosed with either colorectal or endometrial cancer. We compared their MUTYH mutation frequencies with those observed in a group of 134 Dutch colorectal and endometrial cancer patients without an MMR
gene mutation (0.7%) and those reported for Caucasian controls (1.5%). In group I one monoallelic MUTYH mutation was found (2.5%). In group II five monoallelic germline MUTYH mutations were found (14%), four of them in MSH6 missense mutation carriers (20%). Of all patients with an MMR gene mutation, only those with a missense mutation showed a
significantly higher frequency of (monoallelic) MUTYH mutations than the Dutch cancer patients without MMR gene mutations (P=0.002) and the published controls (P=0.001). These results warrant further study to test the hypothesis of mutations in MMR genes (in particular MSH6) and MUTYH acting together to increase cancer risk. 相似文献
54.
Gholivand K Mojahed F Salehi M Naderi-Manesh H Khajeh K 《Journal of enzyme inhibition and medicinal chemistry》2006,21(5):521-525
Two novel structurally related phosphoramidate compounds, 1 and 2, with likely beta-diketone system were synthesized and characterized by 1H, 13C, 31P NMR, IR spectroscopy and elemental analysis. Compound 2 exhibited a 31P NMR signal which was significantly shielded (8 ppm) relative to compound 1. Determination of human erythrocyte acetylcholinesterase (hAChE) inhibitory activity was carried out according to Ellman's modified kinetic method and the IC50 values of compounds 1 and 2 were 1.567 and 2.986 mM, respectively. The k(i) values of 1 and 2 were 1.39 to 2.65 min(-1) respectively. A comparison of the bimolecular rate constant (k(i)) and IC50 values for the irreversible inhibitors 1 and 2 revealed that the oxono analogue has greater affinity for hAChE than the thiono compound. Furthermore effects of two conventional oximes paralidoxime (A) and obidoxime (B) on reactivation of the inhibited hAChE were studied but low reactivity was shown by both the oximes. 相似文献
55.
Boerma M 《Radiation research》2012,178(1):1-6
Radiation-induced heart disease (RIHD) is a serious side effect of radiotherapy for intrathoracic and chest wall tumors. The threshold dose for development of clinically significant RIHD is believed to be lower than previously assumed. Therefore, research into mechanisms of RIHD has gained substantial momentum. RIHD becomes clinically apparent ten to fifteen years after radiation exposure. Chronic manifestations of RIHD include accelerated atherosclerosis, cardiomyopathy, and valve abnormalities. Reducing exposure of the heart during radiotherapy is the only known method of preventing RIHD, and there are no approaches to reverse RIHD once it occurs. We use a combination of pharmacological and genetic animal models to determine biological mechanisms of RIHD. Major technological advances in small animal research have made this type of study more valuable. The long-term goal of this work is to identify targets for intervention in RIHD, thereby enhancing the efficacy and safety of thoracic radiotherapy. 相似文献
56.
S Saberi M Douraghi K Azadmanesh MA Shokrgozar H Zeraati ME Hosseini MA Mohagheghi M Parsaeian M Mohammadi 《Helicobacter》2012,17(5):350-357
Background and Aims: Helicobacter pylori is a highly diverse pathogen, which encounters epithelial cells as the initial defense barrier during its lifelong infection. The structure of epithelial cells can be disrupted through cleavage of microfilaments. Cytokeratin 18 (CK18) is an intermediate filament, the cleavage of which is considered an early event during apoptosis following activation of effector caspases. Methods: Helicobacter pylori strains were isolated from 76 dyspeptic patients. cagA 3’ variable region and CagA protein status were analyzed by PCR and western blotting, respectively. Eight hours post‐co‐culture of AGS cells with different H. pylori strains, flow cytometric analysis was performed using M30 monoclonal antibody specific to CK18 cleavage‐induced neo‐epitope. Results: Higher rates of CK18 cleavage were detected during co‐culture of AGS cells with H. pylori strains bearing greater numbers of cagA EPIYA‐C and multimerization (CM) motifs. On the other hand, H. pylori strains with greater numbers of EPIYA‐B relative to EPIYA‐C demonstrated a decrease in CK18 cleavage rate. Thus, H. pylori‐mediated cleavage of CK18 appeared proportional to the number of CagA EPIYA‐C and CM motifs, which seemed to be downplayed in the presence of EPIYA‐B motifs. Conclusions: Our observation associating the heterogeneity of cagA variants with the potential of H. pylori strains in the induction of CK18 cleavage as an early indication of apoptosis in gastric epithelial cells supports the fact that apoptosis may be a type‐specific trait. However, additional cagA‐targeted experiments are required to clearly identify the role of EPIYA and CM motifs in apoptosis and/or the responsible effector molecules. 相似文献
57.
Gochuico BR Huizing M Golas GA Scher CD Tsokos M Denver SD Frei-Jones MJ Gahl WA 《Molecular medicine (Cambridge, Mass.)》2012,18(1):56-64
Pulmonary fibrosis develops in Hermansky-Pudlak syndrome (HPS) types 1 and 4. Limited information is available about lung disease in HPS type 2 (HPS-2), which is characterized by abnormal function of the adaptor protein-3 (AP-3) complex. To define lung disease in HPS-2, one child and two adults with HPS-2 were evaluated at the National Institutes of Health on at least two visits, and another child was evaluated at the University of Texas Health Science Center San Antonio. All four subjects with HPS-2 had findings of interstitial lung disease (ILD) on a high-resolution computed tomography scan of the chest. The predominant feature was ground glass opacification. Subject 1, a 14-year-old male, and subject 4, a 4-year-old male, had severe ILD, pulmonary fibrosis, secondary pulmonary hypertension and recurrent lung infections. Lung biopsy performed at 20 months of age in subject 1 revealed interstitial fibrosis and prominent type II pneumocyte hyperplasia without lamellar body enlargement. Subject 2, a 27-year-old male smoker, had mild ILD. Subject 3, a 22-year-old male nonsmoker and brother of subject 2, had minimal ILD. Severe impairment of gas exchange was found in subjects 1 and 4 and not in subjects 2 or 3. Plasma concentrations of transforming growth factor-β1 and interleukin-17A correlated with severity of HPS-2 ILD. These data show that children and young adults with HPS-2 and functional defects of the AP-3 complex are at risk for ILD and pulmonary fibrosis. 相似文献
58.
The objective of this study was to evaluate the efficiency of Scolothrips longicornis Priesner (Thysanoptera: Thripidae) as a biocontrol agent of Schizotetranychus smirnovi Wainstein (Acari: Tetranychidae), a key pest of almond trees in the southwest of Iran. To achieve a strategy for the control of this pest, it is important to understand foraging behavior (Functional response, switching, and prey-stage preference) of S. longicornis. The predator exhibited a type III functional response when it was offered S. smirnovi protonymphs at seven densities (2, 4, 8, 16, 32 .64 and 128). Based on the random predator equation, the estimated attack rate (a), handling time (Th), and maximum rate of predation were 0.0048 h?1, 0.4816 h, and 49.84 per day, respectively. Using the Murdoch's model, switching behavior was observed in S. longicornis. The predator switched from one stage when it becomes rare to another more abundant stage. S. longicornis fed on all stages but preferred S. smirnovi larvae and protonymphs. The results of this study revealed that S. longicornis could be used in the integrated management of S. smirnovi. However, further field studies are needed to verify this hypothesis. 相似文献
59.
Background
Evidence based and gender specific knowledge about sickness absence following coronary revascularisation is lacking. The objective was to investigate sickness absence after a first coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) among women and men in a national Swedish study.Materials and Methods
All patients 30–63 years of age, who underwent a first CABG (n = 22,985, 16% women) or PCI (40,891, 22% women) in Sweden between 1994 and 2006 were included. Information on sickness absence, co-morbidity, and other patient characteristics was obtained from national registers. Long-term sickness absence (LTSA) was defined as >180 and >90 sick-leave days in the first sick-leave spell following CABG and PCI, respectively. Prevalence ratio (PR) and 95% confidence interval (CI) of LTSA were calculated.Findings
LTSA followed the interventions in 41% and 36% for CABG and PCI patients, respectively. Women had more often LTSA compared with men, (CABG PR = 1.23: 95% CI 1.19–1.28 and PCI PR = 1.19; 95% CI 1.16–1.23). A history of sickness absence the year before the intervention increased the risk for LTSA after the intervention in both genders. Among women, older age, or being self employed or unemployed was associated with a lower risk for LTSA. Among men previous cardiovascular disease, diabetes and low socio-economic position increased the risk. During the observation period, there was no change in sickness absence rates among PCI patients but an increase among CABG patients adjusting for patient characteristics.Conclusion
This national study covering a 13-year period shows that long-term sickness absence following coronary revascularisation is common in Sweden, especially among women, and is associated with socio-economic position, co-morbidity, and sickness absence during the year before the intervention. Gender specific scientific knowledge about use and effects of sickness absence following coronary revascularisation is warranted for the patients, the treating physicians, the healthcare sector, and the society. 相似文献60.
ABSTRACT: BACKGROUND: Chronic gastritis, peptic ulcer disease, and gastric cancer have been shown to be related toinfection with Helicobacter pylori (H. pylori). Two major virulence factors of H. pylori,CagA and VacA, have been associated with these sequelae of the infection. In this study, totalDNA was isolated from gastric biopsy specimens to assess the cagA and vacA genotypes. RESULTS: Variations in H. pylori cagA EPIYA motifs and the mosaic structure of vacA s/m/i/dayregions were analysed in 155 H. pylori-positive gastric biopsies from 71 individuals usingPCR and sequencing. Analysis of a possible association between cagA and vacA genotypesand gastroduodenal pathogenesis was made by logistic regression analysis. We found that H. pylori strains with variation in the number of cagA EPIYA motif variants present in the samebiopsy correlated with peptic ulcer, while occurrence of two or more EPIYA-C motifs wasassociated with atrophy in the gastric mucosa. No statistically significant relation betweenvacA genotypes and gastroduodenal pathogenesis was observed. CONCLUSIONS: The results of this study indicate that cagA genotypes may be important determinants in thedevelopment of gastroduodenal sequelae of H. pylori infection. In contrast to other studies,vacA genotypes were not related to disease progression or outcome. In order to fullyunderstand the relations between cagA, vacA and gastroduodenal pathogenesis, themechanisms by which CagA and VacA act and interact need to be further investigated. 相似文献