全文获取类型
收费全文 | 1588篇 |
免费 | 81篇 |
出版年
2023年 | 10篇 |
2022年 | 14篇 |
2021年 | 38篇 |
2020年 | 26篇 |
2019年 | 39篇 |
2018年 | 57篇 |
2017年 | 47篇 |
2016年 | 62篇 |
2015年 | 96篇 |
2014年 | 95篇 |
2013年 | 152篇 |
2012年 | 155篇 |
2011年 | 141篇 |
2010年 | 77篇 |
2009年 | 73篇 |
2008年 | 90篇 |
2007年 | 77篇 |
2006年 | 77篇 |
2005年 | 46篇 |
2004年 | 46篇 |
2003年 | 65篇 |
2002年 | 46篇 |
2001年 | 8篇 |
2000年 | 8篇 |
1999年 | 12篇 |
1998年 | 8篇 |
1997年 | 11篇 |
1996年 | 7篇 |
1995年 | 10篇 |
1994年 | 5篇 |
1993年 | 6篇 |
1992年 | 9篇 |
1991年 | 9篇 |
1990年 | 7篇 |
1989年 | 6篇 |
1988年 | 4篇 |
1987年 | 8篇 |
1986年 | 2篇 |
1985年 | 3篇 |
1984年 | 3篇 |
1983年 | 3篇 |
1982年 | 1篇 |
1981年 | 2篇 |
1980年 | 1篇 |
1979年 | 1篇 |
1978年 | 1篇 |
1977年 | 2篇 |
1976年 | 1篇 |
1967年 | 1篇 |
1965年 | 1篇 |
排序方式: 共有1669条查询结果,搜索用时 468 毫秒
31.
Ivana Šagud Nikolina Maček Hrvat Ana Grgičević Tena Čadež Josipa Hodak Milena Dragojević 《Journal of enzyme inhibition and medicinal chemistry》2013,28(1):460-467
Abstract The enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are primary targets in attenuating the symptoms of neurodegenerative diseases. Their inhibition results in elevated concentrations of the neurotransmitter acetylcholine which supports communication among nerve cells. It was previously shown for trans-4/5-arylethenyloxazole compounds to have moderate AChE and BChE inhibitory properties. A preliminary docking study showed that elongating oxazole molecules and adding a new NH group could make them more prone to bind to the active site of both enzymes. Therefore, new trans-amino-4-/5-arylethenyl-oxazoles were designed and synthesised by the Buchwald-Hartwig amination of a previously synthesised trans-chloro-arylethenyloxazole derivative. Additionally, naphthoxazole benzylamine photoproducts were obtained by efficient photochemical electrocyclization reaction. Novel compounds were tested as inhibitors of both AChE and BChE. All of the compounds exhibited binding preference for BChE over AChE, especially for trans-amino-4-/5-arylethenyl-oxazole derivatives which inhibited BChE potently (IC50 in µM range) and AChE poorly (IC50?100?µM). Therefore, due to the selectivity of all of the tested compounds for binding to BChE, these compounds could be applied for further development of cholinesterase selective inhibitors.
- HIGHLIGHTS
-
Series of oxazole benzylamines were designed and synthesised
-
The tested compounds showed binding selectivity for BChE
-
Naphthoxazoles were more potent AChE inhibitors
32.
Ivana A. Cavello Roque A. Hours Natalia L. Rojas Sebastián F. Cavalitto 《Process Biochemistry》2013,48(5-6):972-978
A keratinolytic serine protease secreted by Purpureocillium lilacinum (formerly Paecilomyces lilacinus) upon culture in a basal medium containing 1% (w/v) hair waste as carbon and nitrogen source was purified and characterized. After purification the keratinase was resolved by SDS-PAGE as a homogeneus protein band of molecular mass 37.0 kDa. The extracellular keratinase of P. lilacinum was characterized by its appreciable stability over a broad pH range (from 4.0 to 9.0), and up to 65 °C, along with its strong inhibition by phenylmethylsulphonyl fluoride among the protease inhibitors tested (98.2% of inhibition), thus suggesting its nature as a serine protease. The enzyme was active and stable in the presence of organic solvents such as dimethylsulfoxide, methanol, and isopropanol; certain surfactants such as Triton X-100, sodium dodecylsulfate, and Tween 85; and bleaching agents such as hydrogen peroxide. These biochemical characteristics suggest the potential use of this enzyme in numerous industrial applications. 相似文献
33.
Živan Gojkovic Ines Garbayo-Nores Veronica Gómez-Jacinto Tamara García-Barrera José-Luis Gómez-Ariza Ivana Márová Carlos Vílchez-Lobato 《Process Biochemistry》2013,48(8):1235-1241
This article describes the enrichment of the fresh-water green microalga Chlorella sorokiniana in selenomethionine (SeMet). The microalga was cultivated in a 2.2 L glass-vessel photobioreactor, in a culture medium supplemented with selenate (SeO42?) concentrations ranging from 5 to 50 mg L?1. Although selenate exposure lowered culture viability, C. sorokiniana grew well at all tested selenate concentrations, however cultures supplemented with 50 mg L?1 selenate did not remain stable at steady state. A suitable selenate concentration in fresh culture medium for continuous operation was determined, which allowed stable long-term cultivation at steady state and maximal SeMet productivity. In order to do that, the effect of dilution rate on biomass productivity, viability and SeMet content of C. sorokiniana at several selenate concentrations were determined in the photobioreactor. A maximal SeMet productivity of 21 μg L?1 day?1 was obtained with 40 mg L?1 selenate in the culture medium. Then a continuous cultivation process at several dilution rates was performed at 40 mg L?1 selenate obtaining a maximum of 246 μg L?1 day?1 SeMet at a low dilution rate of 0.49 day?1, calculated on total daily effluent volume. This paper describes for the first time an efficient long-term continuous cultivation of C. sorokiniana for the production of biomass enriched in the high value amino acid SeMet, at laboratory scale. 相似文献
34.
Ivana Sreckovic Ruth Birner-Gruenberger Britta Obrist Tatjana Stojakovic Hubert Scharnagl Michael Holzer Monika Scholler Sonia Philipose Gunther Marsche Uwe Lang Gernot Desoye Christian Wadsack 《Biochimica et Biophysica Acta (BBA)/Molecular and Cell Biology of Lipids》2013,1831(4):737-746
In human high-density lipoprotein (HDL) represents the major cholesterol carrying lipoprotein class in cord blood, while cholesterol is mainly carried by low-density lipoprotein in maternal serum. Additionally, to carrying cholesterol, HDL also associates with a range of proteins as cargo. We tested the hypothesis that fetal HDL carries proteins qualitatively and quantitatively different from maternal HDL. These differences then contribute to distinct HDL functionality in both circulations. Shotgun proteomics and biochemical analyses were used to assess composition/function of fetal and maternal HDL isolated from uncomplicated human pregnancies at term of gestation. The pattern of analyzed proteins that were statistically elevated in fetal HDL (apoE, proteins involved in coagulation, transport processes) suggests a particle characteristic for the light HDL2 sub-fraction. In contrast, proteins that were enriched in maternal HDL (apoL, apoF, PON1, apoD, apoCs) have been described almost exclusively in the dense HDL3 fraction and relevant to its anti-oxidative function and role in innate immunity. Strikingly, PON1 mass and activity were 5-fold lower (p < 0.01) in the fetus, which was accompanied by attenuation of anti-oxidant capacity of fetal HDL. Despite almost equal quantity of CETP in maternal and fetal HDL, its enzymatic activity was 55% lower (p < 0.001) in the fetal circulation, whereas LCAT activity was not altered. These findings indicate that maternally derived HDL differs from fetal HDL with respect to its proteome, size and function. Absence of apoA-1, apoL and PON1 on fetal HDL is associated with decreased anti-oxidative properties together with deficiency in innate immunity collectively indicating distinct HDLs in fetuses. 相似文献
35.
Svetlana Dashevskaya Ruth Horn Ivana Chudobova Stefan Schillberg Sol Maiam Rivera Vélez Teresa Capell Paul Christou 《Molecular breeding : new strategies in plant improvement》2013,32(2):463-484
Plants adapt to abiotic stress by undergoing diverse biochemical and physiological changes that involve hormone-dependent signaling pathways. The effects of plant hormones can be mimicked by exogenous chemical regulators such as herbicide safeners, which not only enhance stress tolerance but also confer hormetic benefits such as increased vigor and yield. In this study, rice plants growing in normal and saline soils were exposed to abscisic acid (ABA), the safener cyprosulfamide or both compounds together. We found that cyprosulfamide, either alone or in combination with ABA, protected the plants from salinity stress and induced vigorous growth, including the formation of new tillers and early flowering. Proteomic analysis identified several proteins that were induced by stress and/or the chemical treatments, including the late embryogenesis abundant protein OsLEA3, a putative mitochondrial translocase and a putative fumarylacetoacetate hydrolase. The corresponding genes were induced by stress and/or the individual chemical treatments, but expression dropped back when the stress was removed. However, the combination of ABA and cyprosulfamide prolonged the expression of all three genes beyond the stress period, and allowed the plants to maintain their enhanced growth characteristics. These data support a model involving cooperation between the cyprosulfamide and ABA signaling pathways. Accordingly, it was found that cyprosulfamide induces ABA synthesis more robustly than salinity stress, allowing the two regulators to converge on certain downstream target genes. We discuss the impact of our results on current models for the hormonal regulation of stress response pathways in rice and other plants. 相似文献
36.
37.
Neurodegenerative diseases are associated with misfolding and deposition of specific proteins, either intra or extracellularly in the nervous system. Advanced glycation end products (AGEs) originate from different molecular species that become glycated after exposure to sugars. Several proteins implicated in neurodegenerative diseases have been found to be glycated in vivo and the extent of glycation is related to the pathologies of the patients. Although it is now accepted that there is a direct correlation between AGEs formation and the development of neurodegenerative diseases, several questions still remain unanswered: whether glycation is the triggering event or just an additional factor acting on the aggregation pathway. To this concern, in the present study we have investigated the effect of glycation on the aggregation pathway of the amyloidogenic W7FW14F apomyoglobin. Although this protein has not been related to any amyloid disease, it represents a good model to resemble proteins that intrinsically evolve toward the formation of amyloid aggregates in physiological conditions. We show that D-ribose, but not D-glucose, rapidly induces the W7FW14F apomyoglobin to generate AGEs in a time-dependent manner and protein ribosylation is likely to involve lysine residues on the polypeptide chain. Ribosylation of the W7FW14F apomyoglobin strongly affects its aggregation kinetics producing amyloid fibrils within few days. Cytotoxicity of the glycated aggregates has also been tested using a cell viability assay. We propose that ribosylation in the W7FW14F apomyoglobin induces the formation of a cross-link that strongly reduces the flexibility of the H helix and/or induce a conformational change that favor fibril formation. These results open new perspectives for AGEs biological role as they can be considered not only a triggering factor in amyloidosis but also a player in later stages of the aggregation process. 相似文献
38.
Petronella Anbeek Ivana I?gum Britt J. M. van Kooij Christian P. Mol Karina J. Kersbergen Floris Groenendaal Max A. Viergever Linda S. de Vries Manon J. N. L. Benders 《PloS one》2013,8(12)
Purpose
Volumetric measurements of neonatal brain tissues may be used as a biomarker for later neurodevelopmental outcome. We propose an automatic method for probabilistic brain segmentation in neonatal MRIs.Materials and Methods
In an IRB-approved study axial T1- and T2-weighted MR images were acquired at term-equivalent age for a preterm cohort of 108 neonates. A method for automatic probabilistic segmentation of the images into eight cerebral tissue classes was developed: cortical and central grey matter, unmyelinated and myelinated white matter, cerebrospinal fluid in the ventricles and in the extra cerebral space, brainstem and cerebellum. Segmentation is based on supervised pixel classification using intensity values and spatial positions of the image voxels. The method was trained and evaluated using leave-one-out experiments on seven images, for which an expert had set a reference standard manually. Subsequently, the method was applied to the remaining 101 scans, and the resulting segmentations were evaluated visually by three experts. Finally, volumes of the eight segmented tissue classes were determined for each patient.Results
The Dice similarity coefficients of the segmented tissue classes, except myelinated white matter, ranged from 0.75 to 0.92. Myelinated white matter was difficult to segment and the achieved Dice coefficient was 0.47. Visual analysis of the results demonstrated accurate segmentations of the eight tissue classes. The probabilistic segmentation method produced volumes that compared favorably with the reference standard.Conclusion
The proposed method provides accurate segmentation of neonatal brain MR images into all given tissue classes, except myelinated white matter. This is the one of the first methods that distinguishes cerebrospinal fluid in the ventricles from cerebrospinal fluid in the extracerebral space. This method might be helpful in predicting neurodevelopmental outcome and useful for evaluating neuroprotective clinical trials in neonates. 相似文献39.
Viera Kajabova Bozena Smolkova Iveta Zmetakova Katarina Sebova Tomas Krivulcik Vladimir Bella Karol Kajo Katarina Machalekova Ivana Fridrichova 《Translational oncology》2013,6(3):297-IN5
The aim of this study was to investigate the relationship between the promoter methylation in five cancer-associated genes and clinicopathologic features for identification of molecular markers of tumor metastatic potential and hormone therapy response efficiency in breast cancer. The methylation levels in paraffin-embedded tumor tissues, plasma, and blood cells from 151 sporadic breast cancer patients and blood samples of 50 controls were evaluated by quantitative multiplex methylation-specific polymerase chain reaction. DNA methylation of RAS-association domain family member 1 (RASSF1A), estrogen receptor 1 (ESR1), cadherin 1, type 1, E-cadherin (CDH1), TIMP metallopeptidase inhibitor 3 (TIMP3) and spleen tyrosine kinase (SYK) genes was detected in the tumors of 124, 19, 15, 15, and 6 patients with mean levels of 48.45%, 3.81%, 2.36%, 27.55%, and 10.81%, respectively. Plasma samples exhibited methylation in the same genes in 25, 10, 15, 17, and 3 patients with levels of 22.54%, 17.20%, 22.87%, 31.93%, and 27.42%, respectively. Cumulative methylation results confirmed different spectra in tumor and plasma samples. Simultaneous methylation in tumors and plasma were shown in less than 17% of patients. RASSF1A methylation levels in tumor samples statistically differ according to tumor size (P = .029), estrogen receptor (ER) and progesterone receptor (PR) status (P = .000 and P = .004), and immunohistochemical subtype (P = .000). Moreover, the positive correlation was found between RASSF1A methylation levels and percentage of cancer cells expressing ER and PR. The direct relationship between RASSF1A promoter methylation and expression of ER could aid the prognosis of hormonal therapy response. 相似文献
40.
Maria Cecilia Rey Moreno Karma C. Fussell Sibylle Gröters Steffen Schneider Volker Strauss Stefan Stinchcombe Ivana Fegert Mariana Veras Bennard van Ravenzwaay 《Birth defects research. Part B, Developmental and reproductive toxicology》2013,98(3):208-221
Epoxiconazole (CAS‐No. 133855‐98‐8) was recently shown to cause both a marked depletion of maternal estradiol blood levels and a significantly increased incidence of late fetal mortality when administered to pregnant rats throughout gestation (GD 7–18 or 21); estradiol supplementation prevented this epoxiconazole effect in rats (Stinchcombe et al., 2013), indicating that epoxiconazole‐mediated estradiol depletion is a critical key event for induction of late fetal resorptions in rats. For further elucidation of the mode of action, the placentas from these modified prenatal developmental toxicity experiments with 23 and 50 mg/kg bw/d epoxiconazole were subjected to a detailed histopathological examination. This revealed dose‐dependent placental degeneration characterized by cystic dilation of maternal sinuses in the labyrinth, leading to rupture of the interhemal membrane. Concomitant degeneration occurred in the trophospongium. Both placentas supporting live fetuses and late fetal resorptions were affected; the highest degree of severity was observed in placentas with late resorptions. Placental degeneration correlated with a severe decline in maternal serum estradiol concentration. Supplementation with 0.5 and 1.0 μg of the synthetic estrogen estradiol cyclopentylpropionate per day reduced the severity of the degeneration in placentas with live fetuses. The present study demonstrates that both the placental degeneration and the increased incidence of late fetal resorptions are due to decreased levels of estrogen, since estrogen supplementation ameliorates the former and abolishes the latter. Birth Defects Res (Part B) 98:208–221, 2013. © 2013 Wiley Periodicals, Inc. 相似文献