全文获取类型
收费全文 | 649篇 |
免费 | 27篇 |
国内免费 | 1篇 |
出版年
2023年 | 5篇 |
2022年 | 10篇 |
2021年 | 29篇 |
2020年 | 16篇 |
2019年 | 16篇 |
2018年 | 15篇 |
2017年 | 16篇 |
2016年 | 13篇 |
2015年 | 36篇 |
2014年 | 34篇 |
2013年 | 57篇 |
2012年 | 44篇 |
2011年 | 35篇 |
2010年 | 25篇 |
2009年 | 13篇 |
2008年 | 30篇 |
2007年 | 37篇 |
2006年 | 26篇 |
2005年 | 28篇 |
2004年 | 20篇 |
2003年 | 11篇 |
2002年 | 23篇 |
2001年 | 11篇 |
2000年 | 9篇 |
1999年 | 6篇 |
1998年 | 3篇 |
1996年 | 4篇 |
1995年 | 4篇 |
1994年 | 4篇 |
1992年 | 5篇 |
1991年 | 7篇 |
1990年 | 3篇 |
1989年 | 4篇 |
1988年 | 4篇 |
1987年 | 3篇 |
1986年 | 4篇 |
1985年 | 8篇 |
1984年 | 3篇 |
1983年 | 5篇 |
1982年 | 5篇 |
1981年 | 4篇 |
1980年 | 2篇 |
1979年 | 4篇 |
1978年 | 5篇 |
1976年 | 5篇 |
1975年 | 2篇 |
1974年 | 7篇 |
1973年 | 3篇 |
1972年 | 3篇 |
1966年 | 2篇 |
排序方式: 共有677条查询结果,搜索用时 328 毫秒
81.
The genes involved in DNA repair system play a crucial role in the protection against mutations. It has been hypothesized
that functional deficiencies in highly conserved DNA repair processes resulting from polymorphic variation may increase genetic
susceptibility to breast cancer (BC). The aim of the present study was to evaluate the association of genetic polymorphisms
in 2 DNA repair genes, XPD (Asp312Asn) and XRCC1 (A399G), with BC susceptibility. We further investigated the potential combined
effect of these DNA repair variants on BC risk. Both XPD (xeroderma pigmentosum group D) and XRCC1 (X-ray repair cross-complementing
group 1) polymorphisms were characterized in 100 BC Egyptian females and 100 healthy women who had no history of any malignancy
by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) method and PCR with confronting two-pair
primers (PCR-CTPP), using DNA from peripheral blood in a case control study. Our results revealed that the frequencies of
AA genotype of XPD codon 312 polymorphism were significantly higher in the BC patients than in the normal individuals (P ≤ 0.003), and did not observe any association between the XRCC1 Arg399Gln polymorphism and risk of developing BC. Also, no
association between both XPD Asp312Asn and XRCC1 A399G polymorphisms and the clinical characteristics of disease. Finally,
the combination of AA(XPD) + AG(XRCC1) were significantly associated with BC risk. Our results suggested that, XPD gene is
an important candidate gene for susceptibility to BC. Also, gene–gene interaction between XPD(AA) + XRCC1(AG) polymorphism
may be associated with increased risk of BC in Egyptian women. 相似文献
82.
Mekhail GM Kamel AO Awad GA Mortada ND 《International journal of biological macromolecules》2012,51(4):351-363
The purpose of this study was to develop a new therapeutic approach for atorvastatin (ATV) adopting nanostructured polymeric micelles for its controlled delivery to the cancer cells. Amphiphilic block copolymers of stearyl chitosan (SC) and sulfated stearyl chitosan (S-SC) that could self assemble to form polymeric micelles with different degree of substitution (DS) were synthesized and characterized. The synthesized chitosan derivatives were able to self assemble and form micelles encapsulating ATV with critical micellar concentrations ranging from 6.9 to 21μg/ml, drug-loading ranging from 40% to 84.1% and encapsulation efficiency ranging from 10.4% to 35%. ATV caused a significant decrease in particle size and zeta potential of both SC and S-SC micelles. Micelles encapsulating ATV exhibited a sustained release and more cytotoxic activity against MCF 7 and HCT 116 cell lines than ATV alone. The 50% cellular growth inhibition (IC50%) of the drug decreased from 10.4 to 3.7 in case of MCF 7 and from 9.4 to 3.4 in case of HCT 116 after its loading in micelles. These results indicate that SC ATV polymeric micelles can be considered as a promising system for site specific controlled delivery of ATV to tumor cells. 相似文献
83.
84.
Fatémeh Namdari Genaro Alejandro Hurtado-Escobar Nadia Abed Jér?me Trotereau Yann Fardini Etienne Giraud Philippe Velge Isabelle Virlogeux-Payant 《PloS one》2012,7(11)
The folding and insertion of β-barrel proteins in the outer membrane of Gram-negative bacteria is mediated by the BAM complex, which is composed of the outer membrane protein BamA and four lipoproteins BamB to BamE. In Escherichia coli and/or Salmonella, the BamB lipoprotein is involved in (i) β-barrel protein assembly in the outer membrane, (ii) outer membrane permeability to antibiotics, (iii) the control of the expression of T3SS which are major virulence factors and (iv) the virulence of Salmonella. In E. coli, this protein has been shown to interact directly with BamA. In this study, we investigated the structure-function relationship of BamB in order to assess whether the roles of BamB in these phenotypes were inter-related and whether they require the interaction of BamB with BamA. For this purpose, recombinant plasmids harbouring point mutations in bamB were introduced in a ΔSalmonella bamB mutant. We demonstrated that the residues L173, L175 and R176 are crucial for all the roles of BamB and for the interaction of BamB with BamA. Moreover, the results obtained with a D229A BamB variant, which is unable to immunoprecipitate BamA, suggest that the interaction of BamB with BamA is not absolutely necessary for BamB function in outer-membrane protein assembly, T3SS expression and virulence. Finally, we showed that the virulence defect of the ΔbamB mutant is not related to its increased susceptibility to antimicrobials, as the D227A BamB variant fully restored the virulence of the mutant while having a similar antibiotic susceptibility to the ΔbamB strain. Overall, this study demonstrates that the different roles of BamB are not all inter-related and that L173, L175 and R176 amino-acids are privileged sites for the design of BamB inhibitors that could be used as alternative therapeutics to antibiotics, at least against Salmonella. 相似文献
85.
Anne-Cecile Huby Panagiotis Kavvadas Carlo Alfieri Ahmed Abed Julie Toubas Maria-Pia Rastaldi Jean-Claude Dussaule Christos Chatziantoniou Christos E. Chadjichristos 《PloS one》2012,7(12)
Background
Several studies have shown that activation of the renin-angiotensin system may lead to hypertension, a major risk factor for the development of chronic kidney disease (CKD). The existing hypertension-induced CDK mouse models are quite fast and consequently away from the human pathology. Thus, there is an urgent need for a mouse model that can be used to delineate the pathogenic process leading to progressive renal disease. The objective of this study was dual: to investigate whether mice overexpressing renin could mimic the kinetics and the physiopathological characteristics of hypertension-induced renal disease and to identify cellular and/or molecular events characterizing the different steps of the progression of CKD.Methodology/Principal Findings
We used a novel transgenic strain, the RenTg mice harboring a genetically clamped renin transgene. At 3 months, heterozygous mice are hypertensive and slightly albuminuric. The expression of adhesion markers such as vascular cell adhesion molecule-1 and platelet endothelial cell adhesion molecule-1 are increased in the renal vasculature indicating initiation of endothelial dysfunction. At 5 months, perivascular and periglomerular infiltrations of macrophages are observed. These early renal vascular events are followed at 8 months by leukocyte invasion, decreased expression of nephrin, increased expression of KIM-1, a typical protein of tubular cell stress, and of several pro-fibrotic agents of the TGFβ family. At 12 months, mice display characteristic structural alterations of hypertensive renal disease such as glomerular ischemia, glomerulo- and nephroangio-sclerosis, mesangial expansion and tubular dilation.Conclusions/Significance
The RenTg strain develops CKD progressively. In this model, endothelial dysfunction is an early event preceding the structural and fibrotic alterations which ultimately lead to the development of CKD. This model can provide new insights into the mechanisms of chronic renal failure and help to identify new targets for arresting and/or reversing the development of the disease. 相似文献86.
Rojkovicova T Mechref Y Starkey JA Wu G Bell RL McBride WJ Novotny MV 《Journal of chromatography. B, Analytical technologies in the biomedical and life sciences》2008,863(2):206-214
A method to determine the catecholamine content in putamen (CPU) and midbrain (MB) regions of the brain of alcohol-preferring rats (P) is presented with a focus on the low-level detection of S,R-salsolinol, a metabolite of dopamine and a putative alcoholism marker. The developed strategy allows both quantitative profiling of related catecholamines and the enantiomeric separation and quantification of the S- and R-salsolinol isomers and their ratios. The described LC/MS strategy simplifies the current methodology that typically employs GC-MS by eliminating the need for derivatization. The data also suggest an increase in the non-enzymatic formation of salsolinol as a consequence of ethanol exposure. 相似文献
87.
In 2000, a severe outbreak of phytoplasma-caused disease in Limonium spp. flowers devastated the industry in Israel; insecticides were not able to knock down and kill leafhopper vectors before they could transmit the pathogen. Nonchoice laboratory studies were conducted to determine the effect of UV-absorbing plastics on the movement of leafhoppers toward light; UV-absorbing plastic significantly reduced leafhopper movement. In choice trials conducted in sunlight, significantly more leafhoppers moved into the cage covered with regular plastic as opposed to the cage covered with UV-absorbing plastic. Field studies were conducted to determine at what height leafhoppers enter 2.5-3-m high walk-in tunnels; the majority enter the tunnels low to the ground, up to 1 m. Finally, field studies were conduced to compare leafhopper population levels in walk-in tunnels covered with UV-absorbing plastic or screening, and with ventilation holes at different heights above the ground. Elevated ventilation holes and UV-absorbing tunnel covering significantly reduced Orosius orientalis entrance into tunnels. Ramifications of these finding for leafhopper control are discussed. 相似文献
88.
Characterization of oxidized low-density lipoprotein-induced hormesis-like effects in osteoblastic cells 总被引:1,自引:0,他引:1
Hamel P Abed E Brissette L Moreau R 《American journal of physiology. Cell physiology》2008,294(4):C1021-C1033
Epidemiological studies indicate that patients suffering from atherosclerosis are predisposed to develop osteoporosis. Atherogenic determinants such as oxidized low-density lipoprotein (oxLDL) particles have been shown both to stimulate the proliferation and promote apoptosis of bone-forming osteoblasts. Given such opposite responses, we characterized the oxLDL-induced hormesis-like effects in osteoblasts. Biphasic 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reductive activity responses were induced by oxLDL where low concentrations (10–50 µg/ml) increased and high concentrations (from 150 µg/ml) reduced the MTT activity. Cell proliferation stimulation by oxLDL partially accounted for the increased MTT activity. No alteration of mitochondria mass was noticed, whereas low concentrations of oxLDL induced mitochondria hyperpolarization and increased the cellular levels of reactive oxygen species (ROS). The oxLDL-induced MTT activity was not related to intracellular ROS levels. OxLDL increased NAD(P)H-associated cellular fluorescence and flavoenzyme inhibitor diphenyleneiodonium reduced basal and oxLDL-induced MTT activity, suggesting an enhancement of NAD(P)H-dependent cellular reduction potential. Low concentrations of oxLDL reduced cellular thiol content and increased metallothionein expression, suggesting the induction of compensatory mechanisms for the maintenance of cell redox state. These concentrations of oxLDL reduced osteoblast alkaline phosphatase activity and cell migration. Our results indicate that oxLDL particles cause hormesis-like response with the stimulation of both proliferation and cellular NAD(P)H-dependent reduction potential by low concentrations, whereas high concentrations lead to reduction of MTT activity associated with the cell death. Given the effects of low concentrations of oxLDL on osteoblast functions, oxLDL may contribute to the impairment of bone remodeling equilibrium. osteoblasts; atherosclerosis; oxysterol 相似文献
89.
90.
Seed development has emerged as an important area of research in plant development. Recent research has highlighted the divergent reproductive strategies of the male and female genomes and interaction between genetic and epigenetic control mechanisms. Isolation of genes involved in embryo and endosperm development is leading to an understanding of the regulation of these processes at the molecular level. A thorough grasp of these processes will not only illuminate an important area of plant development but will also have an impact on agronomy by helping to facilitate food production. An understanding of seed development is also likely to clarify the molecular mechanisms of apomixis, a fascinating process of asexual seed production present in many plants. 相似文献