全文获取类型
收费全文 | 647篇 |
免费 | 41篇 |
出版年
2023年 | 3篇 |
2022年 | 13篇 |
2021年 | 15篇 |
2020年 | 13篇 |
2019年 | 14篇 |
2018年 | 24篇 |
2017年 | 16篇 |
2016年 | 14篇 |
2015年 | 29篇 |
2014年 | 39篇 |
2013年 | 36篇 |
2012年 | 48篇 |
2011年 | 46篇 |
2010年 | 32篇 |
2009年 | 17篇 |
2008年 | 27篇 |
2007年 | 25篇 |
2006年 | 37篇 |
2005年 | 20篇 |
2004年 | 21篇 |
2003年 | 23篇 |
2002年 | 16篇 |
2001年 | 7篇 |
2000年 | 7篇 |
1999年 | 5篇 |
1998年 | 7篇 |
1997年 | 3篇 |
1996年 | 3篇 |
1995年 | 7篇 |
1992年 | 11篇 |
1991年 | 10篇 |
1990年 | 11篇 |
1989年 | 7篇 |
1988年 | 3篇 |
1987年 | 5篇 |
1985年 | 6篇 |
1983年 | 6篇 |
1982年 | 4篇 |
1981年 | 3篇 |
1980年 | 7篇 |
1979年 | 8篇 |
1978年 | 4篇 |
1977年 | 2篇 |
1976年 | 4篇 |
1975年 | 2篇 |
1974年 | 5篇 |
1972年 | 2篇 |
1970年 | 2篇 |
1967年 | 4篇 |
1966年 | 2篇 |
排序方式: 共有688条查询结果,搜索用时 15 毫秒
71.
(-)-Epigallocatechin-3-gallate (EGCG), the major constituent of green tea has been reported to prevent many diseases by virtue of its antioxidant properties. The binding of EGCG with human serum albumin (HSA) has been investigated for the first time by using fluorescence, circular dichroism (CD), Fourier transform infrared (FTIR) spectroscopy, and protein-ligand docking. We observed a quenching of fluorescence of HSA in the presence of EGCG. The binding parameters were determined by a Scatchard plot and the results were found to be consistent with those obtained from a modified Stern-Volmer equation. From the thermodynamic parameters calculated according to the van't Hoff equation, the enthalpy change deltaH degrees and entropy change deltaS degrees were found to be -22.59 and 16.23 J/mol K, respectively. These values suggest that apart from an initial hydrophobic association, the complex is held together by van der Waals interactions and hydrogen bonding. Data obtained by fluorescence spectroscopy, CD, and FTIR experiments along with the docking studies suggest that EGCG binds to residues located in subdomains IIa and IIIa of HSA. Specific interactions are observed with residues Trp 214, Arg 218, Gln 221, Asn 295 and Asp 451. We have also looked at changes in the accessible surface area of the interacting residues on binding EGCG for a better understanding of the interaction. 相似文献
72.
Mahajan B Noiva R Yadava A Zheng H Majam V Mohan KV Moch JK Haynes JD Nakhasi H Kumar S 《International journal for parasitology》2006,36(9):1037-1048
In eukaryotes, the formation of protein disulfide bonds among cysteine residues is mediated by protein disulfide isomerases and occurs in the highly oxidised environment of the endoplasmic reticulum. This process is poorly understood in malaria parasites. In this paper, we report the gene isolation, sequence and phylogenetic comparisons, protein structure and thioredoxin-domain analyses of nine protein disulfide isomerases-like molecules from five species of malaria parasites including Plasmodium falciparum and Plasmodium vivax (human), Plasmodium knowlesi (simian) and Plasmodium berghei and Plasmodium yoelii (murine). Four of the studied protein disulfide isomerases belong to P. falciparum malaria and have been named PfPDI-8, PfPDI-9, PfPDI-11 and PfPDI-14, based on their chromosomal location. Among these, PfPDI-8 bears the closest similarity to a prototype PDI molecule with two thioredoxin domains (containing CGHC active sites) and a C-terminal Endoplasmic reticulum retrieval signal, SEEL. PfPDI-8 is expressed during all stages of parasite life cycle and is highly conserved (82-96% identity at amino acid level) in the other four Plasmodium species studied. Detailed biochemical analysis of PfPDI-8 revealed that this molecule is a potent oxido-reductase enzyme that facilitated the disulfide-dependent conformational folding of EBA-175, a leading malaria vaccine candidate. These studies open the avenues to understand the process of protein folding and secretory pathway in malaria parasites that in turn might aid in the production of superior recombinant vaccines and provide novel drug targets. 相似文献
73.
AKT/PKB serine threonine kinase, a critical signaling molecule promoting cell growth and survival pathways, is frequently dysregulated in many cancers. Although phosphatidylinositol-3-OH kinase (PI3K), a lipid kinase, is well characterized as a major regulator of AKT activation in response to a variety of ligands, recent studies highlight a diverse group of tyrosine (Ack1/TNK2, Src, PTK6) and serine/threonine (TBK1, IKBKE, DNAPKcs) kinases that activate AKT directly to promote its pro-proliferative signaling functions. While some of these alternate AKT activating kinases respond to growth factors, others respond to inflammatory and genotoxic stimuli. A common theme emerging from these studies is that aberrant or hyperactivation of these alternate kinases is often associated with malignancy. Consequently, evaluating the use of small molecular inhibitors against these alternate AKT activating kinases at earlier stages of cancer therapy may overcome the pressing problem of drug resistance surfacing especially in patients treated with PI3K inhibitors. 相似文献
74.
Reynolds JL Law WC Mahajan SD Aalinkeel R Nair B Sykes DE Mammen MJ Yong KT Hui R Prasad PN Schwartz SA 《Journal of immunology (Baltimore, Md. : 1950)》2012,188(8):3757-3765
Morphine is a widely abused, addictive drug that modulates immune function. Macrophages are a primary reservoir of HIV-1; therefore, they play a role in the development of this disease, as well as impact the overall course of disease progression. Galectin-1 is a member of a family of β-galactoside-binding lectins that are soluble adhesion molecules and that mediate direct cell-pathogen interactions during HIV-1 viral adhesion. Because the drug abuse epidemic and the HIV-1 epidemic are closely interrelated, we propose that increased expression of galectin-1 induced by morphine may modulate HIV-1 infection of human monocyte-derived macrophages (MDMs). In this article, we show that galectin-1 gene and protein expression are potentiated by incubation with morphine. Confirming previous studies, morphine alone or galectin-1 alone enhance HIV-1 infection of MDMs. Concomitant incubation with exogenous galectin-1 and morphine potentiated HIV-1 infection of MDMs. We used a nanotechnology approach that uses gold nanorod-galectin-1 small interfering RNA complexes (nanoplexes) to inhibit gene expression for galectin-1. We found that nanoplexes silenced gene expression for galectin-1, and they reversed the effects of morphine on galectin-1 expression. Furthermore, the effects of morphine on HIV-1 infection were reduced in the presence of the nanoplex. 相似文献
75.
76.
Mahajan K Coppola D Rawal B Chen YA Lawrence HR Engelman RW Lawrence NJ Mahajan NP 《The Journal of biological chemistry》2012,287(26):22112-22122
Androgen deprivation therapy has been the standard of care in prostate cancer due to its effectiveness in initial stages. However, the disease recurs, and this recurrent cancer is referred to as castration-resistant prostate cancer (CRPC). Radiotherapy is the treatment of choice; however, in addition to androgen independence, CRPC is often resistant to radiotherapy, making radioresistant CRPC an incurable disease. The molecular mechanisms by which CRPC cells acquire radioresistance are unclear. Androgen receptor (AR)-tyrosine 267 phosphorylation by Ack1 tyrosine kinase (also known as TNK2) has emerged as an important mechanism of CRPC growth. Here, we demonstrate that pTyr(267)-AR is recruited to the ATM (ataxia telangiectasia mutated) enhancer in an Ack1-dependent manner to up-regulate ATM expression. Mice engineered to express activated Ack1 exhibited a significant increase in pTyr(267)-AR and ATM levels. Furthermore, primary human CRPCs with up-regulated activated Ack1 and pTyr(267)-AR also exhibited significant increase in ATM expression. The Ack1 inhibitor AIM-100 not only inhibited Ack1 activity but also was able to suppress AR Tyr(267) phosphorylation and its recruitment to the ATM enhancer. Notably, AIM-100 suppressed Ack1 mediated ATM expression and mitigated the growth of radioresistant CRPC tumors. Thus, our study uncovers a previously unknown mechanism of radioresistance in CRPC, which can be therapeutically reversed by a new synergistic approach that includes radiotherapy along with the suppression of Ack1/AR/ATM signaling by the Ack1 inhibitor, AIM-100. 相似文献
77.
78.
In this report, a label-free reflectometric interference spectroscopy (RIfS) based microchip biosensor for the detection of circulating tumour cells (CTCs) is demonstrated. Highly ordered nanoporous anodic aluminium oxide (AAO) fabricated by electrochemical anodization of aluminium foil was used as the RIfS sensing platform. Biotinylated anti-EpCAM antibody that specifically binds to human cancer cells of epithelial origin such as pancreatic cancer cells (PANC-1) was covalently attached to the AAO surface through multiple surface functionalization steps. Whole blood or phosphate buffer saline spiked with low numbers of pancreatic cancer cells were successfully detected by specially designed microfluidic device incorporating an AAO RIfS sensor, without labour intensive fluorescence labelling and/or pre-enhancement process. Our results show that the developed device is capable of selectively detecting of cancer cells, within a concentrations range of 1000-100,000 cells/mL, with a detection limit of <1000 cells/mL, a response time of <5 min and sample volume of 50 μL of. The presented RIfS method shows considerable promise for translation to a rapid and cost-effective point-of-care diagnostic device for the detection of CTCs in patients with metastatic cancer. 相似文献
79.
80.
Dubey A Boukouvala F Keyvan G Hsia R Saranteas K Brone D Misra T Ierapetritou MG Muzzio FJ 《AAPS PharmSciTech》2012,13(1):231-246
A combination of analytical and statistical methods is used to improve a tablet coating process guided by quality by design
(QbD) principles. A solid dosage form product was found to intermittently exhibit bad taste. A suspected cause was the variability
in coating thickness which could lead to the subject tasting the active ingredient in some tablets. A number of samples were
analyzed using a laser-induced breakdown spectroscopy (LIBS)-based analytical method, and it was found that the main variability
component was the tablet-to-tablet variability within a lot. Hence, it was inferred that the coating process (performed in
a perforated rotating pan) required optimization. A set of designed experiments along with response surface modeling and kriging
method were used to arrive at an optimal set of operating conditions. Effects of the amount of coating imparted, spray rate,
pan rotation speed, and spray temperature were characterized. The results were quantified in terms of the relative standard
deviation of tablet-averaged LIBS score and a coating variability index which was the ratio of the standard deviation of the
tablet-averaged LIBS score and the weight gain of the tablets. The data-driven models developed based on the designed experiments
predicted that the minimum value of this index would be obtained for a 6% weight gain for a pan operating at the highest speed
at the maximum fill level while using the lowest spraying rate and temperature from the chosen parametric space. This systematic
application of the QbD-based method resulted in an enhanced process understanding and reducing the coating variability by
more than half. 相似文献