全文获取类型
收费全文 | 498篇 |
免费 | 24篇 |
出版年
2023年 | 1篇 |
2022年 | 6篇 |
2021年 | 12篇 |
2020年 | 13篇 |
2019年 | 6篇 |
2018年 | 12篇 |
2017年 | 9篇 |
2016年 | 16篇 |
2015年 | 18篇 |
2014年 | 23篇 |
2013年 | 33篇 |
2012年 | 42篇 |
2011年 | 42篇 |
2010年 | 27篇 |
2009年 | 18篇 |
2008年 | 29篇 |
2007年 | 34篇 |
2006年 | 33篇 |
2005年 | 37篇 |
2004年 | 24篇 |
2003年 | 19篇 |
2002年 | 17篇 |
2001年 | 7篇 |
2000年 | 11篇 |
1999年 | 5篇 |
1998年 | 4篇 |
1996年 | 1篇 |
1995年 | 2篇 |
1994年 | 1篇 |
1993年 | 2篇 |
1992年 | 1篇 |
1991年 | 1篇 |
1990年 | 1篇 |
1986年 | 2篇 |
1985年 | 1篇 |
1984年 | 1篇 |
1983年 | 1篇 |
1981年 | 1篇 |
1980年 | 1篇 |
1978年 | 1篇 |
1976年 | 2篇 |
1974年 | 1篇 |
1973年 | 1篇 |
1969年 | 1篇 |
1961年 | 2篇 |
排序方式: 共有522条查询结果,搜索用时 187 毫秒
91.
Marion Gay Pascal Carato Mathilde Coevoet Nicolas Renault Paul-Emmanuel Larchanché Amélie Barczyk Saïd Yous Luc Buée Nicolas Sergeant Patricia Melnyk 《Bioorganic & medicinal chemistry》2018,26(8):2151-2164
The chloroquinoline scaffold is characteristic of anti-malarial drugs such as chloroquine (CQ) or amodiaquine (AQ). These drugs are also described for their potential effectiveness against prion disease, HCV, EBV, Ebola virus, cancer, Parkinson or Alzheimer diseases. Amyloid precursor protein (APP) metabolism is deregulated in Alzheimer’s disease. Indeed, CQ modifies amyloid precursor protein (APP) metabolism by precluding the release of amyloid-beta peptides (Aβ), which accumulate in the brain of Alzheimer patients to form the so-called amyloid plaques. We showed that AQ and analogs have similar effects although having a higher cytotoxicity. Herein, two new series of compounds were synthesized by replacing 7-chloroquinolin-4-amine moiety of AQ by 2-aminomethylaniline and 2-aminomethylphenyle moieties. Their structure activity relationship was based on their ability to modulate APP metabolism, Aβ release, and their cytotoxicity similarly to CQ. Two compounds 15a, 16a showed interesting and potent effect on the redirection of APP metabolism toward a decrease of Aβ peptide release (in the same range compared to AQ), and a 3–10-fold increased stability of APP carboxy terminal fragments (CTFα and AICD) without obvious cellular toxicity at 100?µM. 相似文献
92.
Previous studies demonstrated reduced weight of abdominal white adipose tissue depots and of carcass fat in capsaicin-desensitized (Cap-Des) rats up to 8 months after treatment. The objective of the present study was to find out whether aging-associated obesity and hyperplasia of retroperitoneal white adipose tissue was prevented in older (13.5 month old) Cap-Des rats, one year after treatment with Cap (done when they were 1.5 months old). The prevalence of obesity is known to increase in rats by this age. Abdominal white adipose tissue depots weighed less in old Cap-Des rats, both epididymal (9% less) and retroperitoneal (30% less). The number of mature white adipocytes was 28% less in the retroperitoneal depot but was not significantly different in the epididymal depot. Adipocyte size was not different. Carcass fat was less, both total and as percent of body weight. Food intake was normal for their reduced body size. The exponential increase in retroperitoneal white adipose tissue weight characteristic of aging rats that are becoming obese was virtually absent in Cap-Des rats. We conclude that lack of function of capsaicin-sensitive afferent autonomic nerves, known to be destroyed in Cap-Des rats, results in an alteration in energy balance conducive to leanness. We suggest that the attenuated age-associated increase in circulating CGRP (derived mainly from capsaicin-sensitive nerves) in the Cap-Des rat results in a lower degree of aging-associated insulin-resistance, hence in a lesser degree of obesity. 相似文献
93.
Yaroslav G. Gurskiy David G. Garbuz Nataliya V. Soshnikova Aleksey N. Krasnov Alexei Deikin Vladimir F. Lazarev Dmitry Sverchinskyi Boris A. Margulis Olga G. Zatsepina Vadim L. Karpov Svetlana N. Belzhelarskaya Evgenia Feoktistova Sofia G. Georgieva Michael B. Evgen’ev 《Cell stress & chaperones》2016,21(6):1055-1064
The production of major human heat shock protein Hsp70 (HSPA1A) in a eukaryotic expression system is needed for testing and possible medical applications. In this study, transgenic mice were produced containing wild-type human Hsp70 allele in the vector providing expression in the milk. The results indicated that human Hsp70 was readily expressed in the transgenic animals but did not apparently preserve its intact structure and, hence, it was not possible to purify the protein using conventional isolation techniques. It was suggested that the protein underwent glycosylation in the process of expression, and this quite common modification for proteins expressed in the milk complicated its isolation. To check this possibility, we mutated all presumptive sites of glycosylation and tested the properties of the resulting modified Hsp70 expressed in E. coli. The investigation demonstrated that the modified protein exhibited all beneficial properties of the wild-type Hsp70 and was even superior to the latter for a few parameters. Based on these results, a transgenic mouse strain was obtained which expressed the modified Hsp70 in milk and which was easy to isolate using ATP columns. Therefore, the developed construct can be explored in various bioreactors for reliable manufacture of high quality, uniform, and reproducible human Hsp70 for possible medical applications including neurodegenerative diseases and cancer. 相似文献
94.
95.
96.
97.
We investigated the role of the ATP-sensitive potassium channel opener pinacidil and blocker glibenclamide on guinea pig liver
mitochondrial function, and a possible significance of pinacidil in the pharmacological treatment during myocardium dystrophy.
First, a series of experiments was performed to determine the effect of pinacidil and glibenclamide on mitochondrial oxygen
consumption. We found that pinacidil increased the rate of mitochondrial respiration for FAD-generated substrate (succinate
oxidation), but was most effective for α-ketoglutarate oxidation with enhancement of respiratory control ratio. Oxidation of FAD-generated substrate inhibited efficiency
of phosphorylation for α-ketoglutarate oxidation in pinacidil-treated animals. Glibenclamide decreased the rate of respiration with the lowest value
of efficiency of phosphorylation, especially for α-ketoglutarate oxidation. A second series of experiments was performed to determine the effects of pinacidil and glibenclamide
on oxidative phosphorylation during adrenaline-induced myocardium dystrophy. The increase in respiratory control ratio and
efficiency of phosphorylation for α-ketoglutarate oxidation was greater than for succinate oxidation in mitochondria of pinacidil-pretreated animals during myocardium
dystrophy. Inhibitory analysis with malonate suggested that endogenous succinate increased oxidation of NADH-generated substrates
in mitochondria. Pinacidil is mainly involved in the adrenaline-induced alterations of mitochondrial function due to elevation
of phosphorylation efficiency for α-ketoglutarate oxidation and a decreased level of lipid peroxidation. 相似文献
98.
Caenorhabditis elegans integrates food and reproductive signals in lifespan determination 总被引:1,自引:0,他引:1
Dietary restriction extends lifespan and inhibits reproduction in many species. In Caenorhabditis elegans, inhibiting reproduction by germline removal extends lifespan. Therefore, we asked whether the effect of dietary restriction on lifespan might proceed via changes in the activity of the germline. We found that dietary restriction could increase the lifespan of animals lacking the entire reproductive system. Thus, dietary restriction can extend lifespan independently of any reproductive input. However, dietary restriction produced little or no increase in the long lifespan of animals that lack germ cells. Thus, germline removal and dietary restriction may potentially activate lifespan-extending pathways that ultimately converge on the same downstream longevity mechanisms. In well-fed animals, the somatic reproductive tissues are generally completely required for germline removal to extend lifespan. We found that this was not the case in animals subjected to dietary restriction. In addition, in these animals, loss of the germline could either further lengthen lifespan or shorten lifespan, depending on the genetic background. Thus, nutrient levels play an important role in determining how the reproductive system influences longevity. 相似文献
99.
Roux C Chai F Ollivier N Ochsenbein A Winter S Melnyk O Hildebrand HF 《Biomolecular engineering》2007,24(5):549-554
In orthopaedics and cardiovascular surgery, titanium has become the metal of choice, due to its excellent mechanical properties and biocompatibility. In many surgical operations, chemicals and/or biomolecules (such as antibiotics or growth factors) are used in conjunction with prostheses, so as to avoid or stimulate targeted biological events. Often, immobilization instead of release of such molecules is preferred to optimize their effects, thus avoiding ectopic transformations. A versatile method for the functionalization of pure Ti is shown here, which allows the covalent immobilization of polypeptides. In order to avoid the hydrolysable Ti-O-Si bond found in directly silanized Ti, we use organic/inorganic silica colloids, derived from commercially available 25 nm Ludox silica nanoparticles. Prior to deposition onto Ti-Cp, the silica nanoparticles are functionalized by a propylsemicarbazide moiety by silanization. After spin-coating onto the Ti substrates, the colloids were shown by SEM to form a uniform layer, and to be very strongly adsorbed; the reactivity of the supported semicarbazide (Sc) functionalities being maintained. Chemoselective reaction of semicarbazide groups on the surface with aldehyde moieties present on the polypeptide of interest was chosen in this work due to its efficiency, to its compatibility with the proteinogenic amino acids and in particular cystein and to the use of mild experimental conditions. Aldehyde groups are also easily introduced onto polypeptides by synthesis, oxidation of N-terminal Ser residue or polysaccharide moieties of glycoproteins. Biological assays with MC3T3-E1 osteoblasts revealed an excellent cytocompatibility as shown by the assessment of cell viability, vitality and morphology. 相似文献
100.