全文获取类型
收费全文 | 591篇 |
免费 | 69篇 |
专业分类
660篇 |
出版年
2023年 | 3篇 |
2022年 | 16篇 |
2021年 | 20篇 |
2020年 | 2篇 |
2019年 | 7篇 |
2018年 | 11篇 |
2017年 | 11篇 |
2016年 | 27篇 |
2015年 | 32篇 |
2014年 | 39篇 |
2013年 | 25篇 |
2012年 | 55篇 |
2011年 | 43篇 |
2010年 | 30篇 |
2009年 | 28篇 |
2008年 | 41篇 |
2007年 | 30篇 |
2006年 | 19篇 |
2005年 | 21篇 |
2004年 | 23篇 |
2003年 | 17篇 |
2002年 | 5篇 |
2001年 | 15篇 |
2000年 | 15篇 |
1999年 | 17篇 |
1998年 | 9篇 |
1997年 | 6篇 |
1996年 | 3篇 |
1995年 | 8篇 |
1994年 | 2篇 |
1993年 | 7篇 |
1992年 | 10篇 |
1991年 | 5篇 |
1990年 | 4篇 |
1989年 | 4篇 |
1988年 | 3篇 |
1987年 | 4篇 |
1986年 | 2篇 |
1985年 | 4篇 |
1984年 | 2篇 |
1983年 | 5篇 |
1982年 | 7篇 |
1981年 | 2篇 |
1979年 | 2篇 |
1978年 | 3篇 |
1977年 | 3篇 |
1975年 | 2篇 |
1974年 | 2篇 |
1973年 | 2篇 |
1961年 | 1篇 |
排序方式: 共有660条查询结果,搜索用时 15 毫秒
41.
Jessica AB van Nies Rute B Marques Stella Trompet Zuzana de Jong Fina AS Kurreeman Rene EM Toes J Wouter Jukema Tom WJ Huizinga Annette HM van der Helm-van Mil 《Arthritis research & therapy》2010,12(2):R38
Introduction
Recently an association between a genetic variation in TRAF1/C5 and mortality from sepsis or cancer was found in rheumatoid arthritis (RA). The most prevalent cause of death, cardiovascular disease, may have been missed in that study, since patients were enrolled at an advanced disease stage. Therefore, we used an inception cohort of RA patients to investigate the association between TRAF1/C5 and cardiovascular mortality, and replicate the findings on all-cause mortality. As TRAF1/C5 associated mortality may not be restricted to RA, we also studied a large cohort of non-RA patients. 相似文献42.
Intervention with mesenchymal stem cells (MSCs) represents a promising therapeutic tool in treatment-refractory autoimmune
diseases. A new report by Schurgers and colleagues in a previous issue of Arthritis Research & Therapy sheds novel mechanistic insight into the pathways employed by MSCs to suppress T-cell proliferation in vitro, but, at the same time, indicates that MSCs do not influence T-cell reactivity and the disease course in an in vivo arthritis model. Such discrepancies between the in vitro and in vivo effects of potent cellular immune modulators should spark further research and should be interpreted as a sign of caution
for the in vitro design of MSC-derived interventions in the setting of human autoimmune diseases. 相似文献
43.
Skurla CP Perera A Towe CT Robertson PR Healy JL Kane RR 《Journal of biomechanics》2007,40(1):220-224
Visible light combined with naphthalimides has previously been shown to catalyze formation of physical bonds in avascular meniscal tissue. The first objective was to modify the existing in vitro testing method (i.e., adhesion testing using lap-jointed slices) to gain more sensitivity in detecting relative bonding strengths among candidate bonding agents. A repeated measures experimental design (RMED) was used to account for variability in properties among bovine menisci and was achieved by testing all treatments/controls on slices from each meniscus. Additionally, to make the method more clinically relevant in modeling a bucket-handle tear, the bovine meniscal slices were cut with collagen fibers parallel to the test slice's length. Peak stress was greater for the complete treatment group (light plus naphthalimide) than for the control or incomplete treatment groups (light only or napthalimide only). The second objective was to perform concentration and photoactivation time dose-response studies. In the concentration dose-response study, peak stress was greater for all treatments when compared with the control but not different among treatment groups; however, there was a trend of increased bonding strength with increased concentration. In the photoactivation time dose-response study, peak stress was greater for all treatments when compared with the control and greater for the 3-min treatment vs. the 6- and 9-min treatments. Peak stress was not different between the longer treatments. The RMED provided increased reproducibility and statistical sensitivity for detecting differences among treatments and will be used to test candidate bonding agents prior to in vivo testing. 相似文献
44.
Wickramarachchi T Illeperuma RJ Perera L Bandara S Holm I Longacre S Handunnetti SM Udagama-Randeniya PV 《International journal for parasitology》2007,37(2):199-208
We report here, for the first time, a comparison of naturally acquired antibody responses to the 42 and 19 kDa C-terminal processing products of Plasmodium vivax Merozoite Surface Protein-1 assayed by ELISA using p42 and p19 baculovirus-derived recombinant proteins, respectively. Test populations comprised patients with microscopy confirmed acute P. vivax infections from two regions endemic for vivax malaria where low transmission and unstable malaria conditions prevail, and a non-endemic urban area, in Sri Lanka. The antibody prevalence to the two proteins, both at the individual and population levels, tend to respond more to p42 than to p19 in all test areas, where >14% of individuals preferentially recognized p42, compared with <2% for p19. In patients with no previous exposure to malaria, 21% preferentially recognized p42, whereas none exclusively recognized p19. A significantly lower prevalence of anti-p19 IgM, but not anti-p42 IgM, was observed among residents from endemic areas compared with their non-endemic counterparts. Individuals from both endemic areas produced significantly less anti-p19 IgM compared with anti-p42 IgM. IgG1 was the predominant IgG isotype for both antigens in all individuals. With increasing exposure to malaria in both endemic areas, anti-p19 antibody responses were dominated by the functionally important IgG1 and IgG3 isotypes, with a concurrent reduction in IgM that was lacking in the non-endemic residents. This antibody switch was also reflected for PvAMA-1 as we previously reported with the identical battery of sera. In contrast, the antibody switch for p42 was restricted to endemic residents with more extensive exposure. These results suggest that an IgM-dominated antibody response against the p42 polymorphic region in endemic residents may interfere with the development of an IgG-dominated "protective" isotype shift to p19, that may complicate vaccine development. 相似文献
45.
Admixture in Mexico City: implications for admixture mapping of Type 2 diabetes genetic risk factors
Martinez-Marignac VL Valladares A Cameron E Chan A Perera A Globus-Goldberg R Wacher N Kumate J McKeigue P O'Donnell D Shriver MD Cruz M Parra EJ 《Human genetics》2007,120(6):807-819
Admixture mapping is a recently developed method for identifying genetic risk factors involved in complex traits or diseases
showing prevalence differences between major continental groups. Type 2 diabetes (T2D) is at least twice as prevalent in Native
American populations as in populations of European ancestry, so admixture mapping is well suited to study the genetic basis
of this complex disease. We have characterized the admixture proportions in a sample of 286 unrelated T2D patients and 275
controls from Mexico City and we discuss the implications of the results for admixture mapping studies. Admixture proportions
were estimated using 69 autosomal ancestry-informative markers (AIMs). Maternal and paternal contributions were estimated
from geographically informative mtDNA and Y-specific polymorphisms. The average proportions of Native American, European and,
West African admixture were estimated as 65, 30, and 5%, respectively. The contributions of Native American ancestors to maternal
and paternal lineages were estimated as 90 and 40%, respectively. In a logistic model with higher educational status as dependent
variable, the odds ratio for higher educational status associated with an increase from 0 to 1 in European admixture proportions
was 9.4 (95%, credible interval 3.8–22.6). This association of socioeconomic status with individual admixture proportion shows
that genetic stratification in this population is paralleled, and possibly maintained, by socioeconomic stratification. The
effective number of generations back to unadmixed ancestors was 6.7 (95% CI 5.7–8.0), from which we can estimate that genome-wide
admixture mapping will require typing about 1,400 evenly distributed AIMs to localize genes underlying disease risk between
populations of European and Native American ancestry. Sample sizes of about 2,000 cases will be required to detect any locus
that contributes an ancestry risk ratio of at least 1.5. 相似文献
46.
Yang Shu Zachary S. Breitbach Milan K. Dissanayake Sirantha Perera Joseph M. Aslan Nagham Alatrash Frederick M. MacDonnell Daniel W. Armstrong 《Chirality》2015,27(1):64-70
The enantiomeric separation of 21 ruthenium (II) polypyridyl complexes was achieved with a novel class of cyclofructan‐based chiral stationary phases (CSPs) in the polar organic mode. Aromatic derivatives on the chiral selectors proved to be essential for enantioselectivity. The R‐napthylethyl carbamate functionalized cyclofructan 6 (LARIHC CF6‐RN) column proved to be the most effective overall, while the dimethylphenyl carbamate cyclofructan 7 (LARIHC CF7‐DMP) showed complementary selectivity. A combination of acid and base additives was necessary for optimal separations. The retention factor vs. acetonitrile/methanol ratio plot showed a U‐shaped retention curve, indicating that different interactions take place at different polar organic solvent compositions. The separation results indicated that π–π interactions, steric effects, and hydrogen bonding contribute to the enantiomeric separation of ruthenium (II) polypyridyl complexes with cyclofructan chiral stationary phases in the polar organic mode. Chirality 27:64–70, 2015. © 2014 Wiley Periodicals, Inc. 相似文献
47.
Bahareh Honarparvar Sachin A Pawar Cláudio Nahum Alves Jer?nimo Lameira Glenn EM Maguire José Rogério A Silva Thavendran Govender Hendrik G Kruger 《Journal of biomedical science》2015,22(1)
Background
Novel pentacycloundecane (PCU)-lactone-CO-EAIS peptide inhibitors were designed, synthesized, and evaluated against wild-type C-South African (C-SA) HIV-1 protease. Three compounds are reported herein, two of which displayed IC50 values of less than 1.00 μM. A comparative MM-PB(GB)SA binding free energy of solvation values of PCU-lactam and lactone models and their enantiomers as well as the PCU-lactam-NH-EAIS and lactone-CO-EAIS peptide inhibitors and their corresponding diastereomers complexed with South African HIV protease (C-SA) was performed. This will enable us to rationalize the considerable difference between inhibitory concentration (IC50) of PCU-lactam-NH-EAIS and PCU-lactone-CO-EAIS peptides.Results
The PCU-lactam model exhibited more negative calculated binding free energies of solvation than the PCU-lactone model. The same trend was observed for the PCU-peptide inhibitors, which correspond to the experimental activities for the PCU-lactam-NH-EAIS peptide (IC50 = 0.076 μM) and the PCU-lactone-CO-EAIS peptide inhibitors (IC50 = 0.850 μM). Furthermore, a density functional theory (DFT) study on the natural atomic charges of the nitrogen and oxygen atoms of the three PCU-lactam, PCU-lactim and PCU-lactone models were performed using natural bond orbital (NBO) analysis. Electrostatic potential maps were also used to visualize the electron density around electron-rich regions. The asymmetry parameter (η) and quadrupole coupling constant (χ) values of the nitrogen and oxygen nuclei of the model compounds were calculated at the same level of theory. Electronic molecular properties including polarizability and electric dipole moments were also calculated and compared. The Gibbs theoretical free solvation energies of solvation (∆Gsolv) were also considered.Conclusions
A general trend is observed that the lactam species appears to have a larger negative charge distribution around the heteroatoms, larger quadrupole constant, dipole moment and better solvation energy, in comparison to the PCU-lactone model. It can be argued that these characteristics will ensure better eletronic interaction between the lactam and the receptor, corresponding to the observed HIV protease activities in terms of experimental IC50 data.Electronic supplementary material
The online version of this article (doi:10.1186/s12929-015-0115-5) contains supplementary material, which is available to authorized users. 相似文献48.
Suzanne Donn John A. Kirkegaard Geetha Perera Alan E. Richardson Michelle Watt 《Environmental microbiology》2015,17(3):610-621
The gap between current average global wheat yields and that achievable through best agronomic management and crop genetics is large. This is notable in intensive wheat rotations which are widely used. Expectations are that this gap can be reduced by manipulating soil processes, especially those that involve microbial ecology. Cross‐year analysis of the soil microbiome in an intensive wheat cropping system revealed that rhizosphere bacteria changed much more than the bulk soil community. Dominant factors influencing populations included binding to roots, plant age, site and planting sequence. We demonstrated evolution of bacterial communities within the field rhizosphere. Early in the season, communities tightly bound to the root were simplest. These increased in diversity with plant age and senescence. Loosely bound communities also increased in diversity from vegetative to reproductive plant stages but were more stable than those tightly bound to roots. Planting sequence and, to a lesser extent, wheat genotype also significantly affected rhizosphere bacteria. Plasticity in the rhizosphere generated from crop root system management and genetics offers promise for manipulating the soil ecology of intense cereal systems. Analyses of soil microbiomes for the purpose of developing agronomic benefit should include roots as well as soil loosely adhered to the roots, and the bulk soil. 相似文献
49.
Suurmond J Dorjée AL Boon MR Knol EF Huizinga TW Toes RE Schuerwegh AJ 《Arthritis research & therapy》2011,13(5):R150
Introduction
Mast cells have been implicated to play a functional role in arthritis, especially in autoantibody-positive disease. Among the cytokines involved in rheumatoid arthritis (RA), IL-17 is an important inflammatory mediator. Recent data suggest that the synovial mast cell is a main producer of IL-17, although T cells have also been implicated as prominent IL-17 producers as well. We aimed to identify IL-17 expression by mast cells and T cells in synovium of arthritis patients. 相似文献50.
We recently reported a chemical genetic method for generating bivalent inhibitors of protein kinases. This method relies on the use of the DNA repair enzyme O(6)-alkylguanine-DNA alkyltransferase (AGT) to display an ATP-competitive inhibitor and a ligand that targets a secondary binding domain. With this method potent and selective inhibitors of the tyrosine kinases SRC and ABL were identified. Here, we dissect the molecular determinants of the potency and selectivity of these bivalent ligands. Systematic analysis of ATP-competitive inhibitors with varying linker lengths revealed that SRC and ABL have differential sensitivities to ligand presentation. Generation of bivalent constructs that contain ligands with differential affinities for the ATP-binding sites and SH3 domains of SRC and ABL demonstrated the modular nature of inhibitors based on the AGT scaffold. Furthermore, these studies revealed that the interaction between the SH3 domain ligand and the kinase SH3 domain is the major selectivity determinant amongst closely-related tyrosine kinases. Finally, the potency of bivalent inhibitors against distinct phospho-isoforms of SRC was determined. Overall, these results provide insight into how individual ligands can be modified to provide more potent and selective bivalent inhibitors of protein kinases. 相似文献