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81.
Jan-Patrick Stellmann Klarissa Hanja Stürner Kim Lea Young Susanne Siemonsen Tim Friede Christoph Heesen 《PloS one》2015,10(2)
BackgroundGadolinium-enhancing (GD+) lesions and T2 lesions are MRI outcomes for phase-2 treatment trials in relapsing-remitting Multiple Sclerosis (RRMS). Little is known about predictors of lesion development and regression-to-the-mean, which is an important aspect in early baseline-to-treatment trials.ObjectivesTo quantify regression-to-the-mean and identify predictors of MRI lesion development in placebo cohorts.Methods21 Phase-2 and Phase-3 trials were identified by a systematic literature research. Random-effects meta-analyses were performed to estimate development of T2 and GD+ after 6 months (phase-2) or 2 years (phase-3). Predictors of lesion development were evaluated with mixed-effect meta-regression.ResultsThe mean number of GD+-lesions per scan was similar after 6 months (1.19, 95%CI: 0.87-1.51) and 2 years (1.19, 95%CI: 1.00-1.39). 39% of the patients were without new T2-lesion after 6 month and 19% after 2 years (95%CI: 12-25%). Mean number of baseline GD+-lesions was the best predictor for new lesions after 6 months.ConclusionBaseline GD-enhancing lesions predict evolution of Gd- and T2 lesions after 6 months and might be used to control for regression to the mean effects. Overall, proof-of-concept studies with a baseline to treatment design have to face a regression to 1.2 GD+lesions per scan within 6 months. 相似文献
82.
Christian Thaler Tobias Faizy Jan Sedlacik Brigitte Holst Jan-Patrick Stellmann Kim Lea Young Christoph Heesen Jens Fiehler Susanne Siemonsen 《PloS one》2015,10(12)
Background
Magnetic Resonance Imaging (MRI) is an established tool in diagnosing and evaluating disease activity in Multiple Sclerosis (MS). While clinical-radiological correlations are limited in general, hypointense T1 lesions (also known as Black Holes (BH)) have shown some promising results. The definition of BHs is very heterogeneous and depends on subjective visual evaluation.Objective
We aimed to improve clinical-radiological correlations by defining BHs using T1 relaxation time (T1-RT) thresholds to achieve best possible correlation between BH lesion volume and clinical disability.Method
40 patients with mainly relapsing-remitting MS underwent MRI including 3-dimensional fluid attenuated inversion recovery (FLAIR), magnetization-prepared rapid gradient echo (MPRAGE) before and after Gadolinium (GD) injection and double inversion-contrast magnetization-prepared rapid gradient echo (MP2RAGE) sequences. BHs (BHvis) were marked by two raters on native T1-weighted (T1w)-MPRAGE, contrast-enhancing lesions (CE lesions) on T1w-MPRAGE after GD and FLAIR lesions (total-FLAIR lesions) were detected separately. BHvis and total-FLAIR lesion maps were registered to MP2RAGE images, and the mean T1-RT were calculated for all lesion ROIs. Mean T1 values of the cortex (CTX) were calculated for each patient. Subsequently, Spearman rank correlations between clinical scores (Expanded Disability Status Scale and Multiple Sclerosis Functional Composite) and lesion volume were determined for different T1-RT thresholds.Results
Significant differences in T1-RT were obtained between all different lesion types with highest T1 values in visually marked BHs (BHvis: 1453.3±213.4 ms, total-FLAIR lesions: 1394.33±187.38 ms, CTX: 1305.6±35.8 ms; p<0.05). Significant correlations between BHvis/total-FLAIR lesion volume and clinical disability were obtained for a wide range of T1-RT thresholds. The highest correlation for BHvis and total-FLAIR lesion masks were found at T1-RT>1500 ms (Expanded Disability Status Scale vs. lesion volume: rBHvis = 0.442 and rtotal-FLAIR = 0.497, p<0.05; Multiple Sclerosis Functional Composite vs. lesion volume: rBHvis = -0.53 and rtotal-FLAIR = -0.627, p<0.05).Conclusion
Clinical-radiological correlations in MS patients are increased by application of T1-RT thresholds. With the short acquisition time of the MP2RAGE sequences, quantitative T1 maps could be easily established in clinical studies. 相似文献83.
Valeria Sabaj Mario Galindo Daniela Silva Lea Sandoval Juan C. Rodríguez 《Molecular biology reports》2010,37(6):2927-2933
Toxoplasma gondii is one of the most successful protozoan parasites given its ability to manipulate the immune system and establish a chronic infection. It is a parasite with a significant impact on human health, mainly in immunocompromised patients. In Europe and North America, only a few clonal genotypes (I, II and III) seem to be responsible for the vast majority of Toxoplasma infections. Surface antigen 2 gene (SAG2) has been extensively used for genotyping T. gondii isolates. The analysis of this locus reveals that in Northern hemisphere, human disease causing isolates are mainly type II, whereas T. gondii isolated from different animals are both type II and III. Since the immune response depends on parasite genotype, it seems relevant to characterize parasites producing human toxoplasmosis in different geographical areas. The growing information about the prevalent T. gondii genotypes in South America mostly refers to domestic animals. This is the first report of genetic characterization of T. gondii isolates from clinical samples in Chile, South America. All the samples analyzed corresponded to SAG2 type I isolates, and they differ from classic SAG2 type I by genetic polymorphisms. This study contributes to the scarce available information on T. gondii at South America, and reinforces an emerging concept suggesting that SAG2 type I, rather than II, parasites are a frequent cause of clinical toxoplasmosis in this continent. 相似文献
84.
Sang Hoon Jeong Jae Hwan Kim Sang Min Yi Jin Ho Kim Kui Lea Park Sang Wook Son 《Biochemical and biophysical research communications》2010,394(3):612-615
Quantum dots (QDs) are rapidly emerging as an important class of nanoparticles (NPs) with potential applications in medicine. However, little is known about penetration of QDs through human skin. This study investigated skin penetration of QDs in both in vivo and in vitro human skin. Using the tape stripping method, this study demonstrates for the first time that QDs can actually penetrate through the stratum corneum (SC) of human skin. Transmission electron microscope (TEM) and energy diverse X-ray (EDX) analysis showed accumulation of QDs in the SC of a human skin equivalent model (HSEM) after dermal exposure to QDs. These findings suggest possible transdermal absorption of QDs after dermal exposure over a relatively long period of time. 相似文献
85.
Guilliams M Oldenhove G Noel W Hérin M Brys L Loi P Flamand V Moser M De Baetselier P Beschin A 《Journal of immunology (Baltimore, Md. : 1950)》2007,179(5):2748-2757
Tolerance to African trypanosomes requires the production of IFN-gamma in the early stage of infection that triggers the development of classically activated macrophages controlling parasite growth. However, once the first peak of parasitemia has been controlled, down-regulation of the type 1 immune response has been described. In this study, we have evaluated whether regulatory T cells (Tregs) contribute to the limitation of the immune response occurring during Trypanosoma congolense infection and hereby influence the outcome of the disease in trypanotolerant C57BL/6 host. Our data show that Foxp3+ Tregs originating from the naturally occurring Treg pool expanded in the spleen and the liver of infected mice. These cells produced IL-10 and limited the production of IFN-gamma by CD4+ and CD8+ effector T cells. Tregs also down-regulated classical activation of macrophages resulting in reduced TNF-alpha production. The Treg-mediated suppression of the type 1 inflammatory immune response did not hamper parasite clearance, but was beneficial for the host survival by limiting the tissue damages, including liver injury. Collectively, these data suggest a cardinal role for naturally occurring Tregs in the development of a trypanotolerant phenotype during African trypanosomiasis. 相似文献
86.
87.
Glutamate in plants: metabolism, regulation, and signalling 总被引:10,自引:0,他引:10
Glutamate occupies a central position in amino acid metabolism in plants. The acidic amino acid is formed by the action of glutamate synthase, utilizing glutamine and 2-oxoglutarate. However, glutamate is also the substrate for the synthesis of glutamine from ammonia, catalysed by glutamine synthetase. The alpha-amino group of glutamate may be transferred to other amino acids by the action of a wide range of multispecific aminotransferases. In addition, both the carbon skeleton and alpha-amino group of glutamate form the basis for the synthesis of gamma-aminobutyric acid, arginine, and proline. Finally, glutamate may be deaminated by glutamate dehydrogenase to form ammonia and 2-oxoglutarate. The possibility that the cellular concentrations of glutamate within the plant are homeostatically regulated by the combined action of these pathways is examined. Evidence that the well-known signalling properties of glutamate in animals may also extend to the plant kingdom is reviewed. The existence in plants of glutamate-activated ion channels and their possible relationship to the GLR gene family that is homologous to ionotropic glutamate receptors (iGluRs) in animals are discussed. Glutamate signalling is examined from an evolutionary perspective, and the roles it might play in plants, both in endogenous signalling pathways and in determining the capacity of the root to respond to sources of organic N in the soil, are considered. 相似文献
88.
Exploring the binding sites of the haloalkane dehalogenase DhlA from Xanthobacter autotrophicus GJ10 总被引:1,自引:0,他引:1
The catalytic site of haloalkane dehalogenase DhlA is buried more than 10 A from the protein surface. While potential access channels to this site have been reported, the precise mechanism of substrate import and product export is still unconfirmed. We used computational methods to examine surface pockets and their putative roles in ligand access to and from the catalytic site. Computational solvent mapping moves small organic molecule as probes over the protein surface in order to identify energetically favorable sites, that is, regions that tend to bind a variety of molecules. The mapping of three DhlA structures identifies seven such regions, some of which have been previously suggested to be involved in the binding and the import/export of substrates or products. These sites are the active site, the putative entrance of the channel leading to the active site, two pockets that bind Br- ions, a pocket in the slot region, and two additional sites between the main domain and the cap of DhlA. We also performed mapping and free energy analysis of the DhlA structures using the substrate, 1,2-dichloroethane, and halide ions as probes. The findings were compared to crystallographic data and to results obtained by CAVER, a program developed for finding routes from protein clefts and cavities to the surface. Solvent mapping precisely reproduced all three Br- binding sites identified by protein crystallography and the openings to four channels found by CAVER. The analyses suggest that (i) the active site has the highest affinity for the substrate molecule, (ii) the substrate initially binds at the entrance of the main tunnel, (iii) the site Br2, close to the entrance, is likely to serve as an intermediate binding site in product export, (iv) the site Br3, induced in the structure at high concentrations of Br-, could be part of an auxiliary route for product release, and (v) three of the identified sites are likely to be entrances of water-access channels leading to the active site. For comparison, we also mapped haloalkane dehalogenases DhaA and LinB, both of which contain significantly larger and more solvent accessible binding sites than DhlA. The mapping of DhaA and LinB places the majority of probes in the active site, but most of the other six regions consistently identified in DhlA were not observed, suggesting that the more open active site eliminates the need for intermediate binding sites for the collision complex seen in DhlA. 相似文献
89.
Franciskovich JB Masters JJ Weber WW Klimkowski VJ Chouinard M Sipes PR Johnson LM Snyder DW Chastain MK Craft TJ Towner RD Gifford-Moore DS Froelich LL Smallwood JK Foster RS Smith GF Liebeschuetz JW Murray CW Young SC 《Bioorganic & medicinal chemistry letters》2007,17(24):6910-6913
Several P4 domain derivatives of the general d-phenylglycinamide-based scaffold (2) were synthesized and evaluated for their ability to bind to the serine protease factor Xa. Some of the more potent compounds were evaluated for their anticoagulant effects in vitro. A select subset containing various P1 indole constructs was further evaluated for their pharmacokinetic properties after oral administration to rats. 相似文献
90.
Clinal variation in traits often reflects climatic adaptation; in Drosophila melanogaster clinal variation provides an opportunity to link variation in chromosomal inversions, microsatellite loci and various candidate genes to adaptive variation in traits. We undertook association studies with crosses from a single population of D. melanogaster from eastern Australia to investigate the association between genetic markers and traits showing clinal variation. By genotyping parents and phenotyping offspring, we minimized genotyping costs but had the power to detect association between markers and quantitative traits. Consistent with prior studies, we found strong associations between the clinal chromosomal inversion In(3R)Payne and markers within it, as well as among these markers. We also found an association between In(3L)Payne and one marker located within this inversion. Of the five predicted associations between markers and traits, four were detected (increased heat, decreased cold resistance and body size with the heat shock gene hsr-omega S, increased cold resistance with the inversion In(3L)Payne), while one was not detected (heat resistance and the heat shock gene hsp68). In a set of eight exploratory tests, we detected one positive association (between hsp23a and heat resistance) but no associations of heat resistance with alleles at the hsp26, hsp83, Desat 2, alpha-Gpdh, hsp70 loci, while cold resistance was not associated with Frost and Dca loci. These results confirm interactions between hsr-omega and thermal resistance, as well as between In(3L)Payne and cold resistance, but do not provide evidence for associations between thermal responses and alleles at other clinically varying marker genes. 相似文献