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851.
852.
D Robin Taylor Piush Mandhane Justina M Greene Robert J Hancox Sue Filsell Christene R McLachlan Avis J Williamson Jan O Cowan Andrew D Smith Malcolm R Sears 《Respiratory research》2007,8(1):82-9
Background
Exhaled nitric oxide (FENO) measurements are used as a surrogate marker for eosinophilic airway inflammation. However, many constitutional and environmental factors affect FENO, making it difficult to devise reference values. Our aim was to evaluate the relative importance of factors affecting FENO in a well characterised adult population.Methods
Data were obtained from 895 members of the Dunedin Multidisciplinary Health and Development Study at age 32. The effects of sex, height, weight, lung function indices, smoking, atopy, asthma and rhinitis on FENO were explored by unadjusted and adjusted linear regression analyses.Results
The effect of sex on FENO was both statistically and clinically significant, with FENO levels approximately 25% less in females. Overall, current smoking reduced FENO up to 50%, but this effect occurred predominantly in those who smoked on the day of the FENO measurement. Atopy increased FENO by 60%. The sex-related differences in FENO remained significant (p < 0.001) after controlling for all other significant factors affecting FENO.Conclusion
Even after adjustment, FENO values are significantly different in males and females. The derivation of reference values and the interpretation of FENO in the clinical setting should be stratified by sex. Other common factors such as current smoking and atopy also require to be taken into account. 相似文献853.
Liz Stevenson Erik Laursen Graeme J. Cowan Betty Bandoh Lea Barfod David R. Cavanagh Gregers R. Andersen Lars Hviid 《PLoS pathogens》2015,11(7)
Rosetting, the adhesion of Plasmodium falciparum-infected erythrocytes to uninfected erythrocytes, involves clonal variants of the parasite protein P. falciparum erythrocyte membrane protein 1 (PfEMP1) and soluble serum factors. While rosetting is a well-known phenotypic marker of parasites associated with severe malaria, the reason for this association remains unclear, as do the molecular details of the interaction between the infected erythrocyte (IE) and the adhering erythrocytes. Here, we identify for the first time a single serum factor, the abundant serum protease inhibitor α2-macroglobulin (α2M), which is both required and sufficient for rosetting mediated by the PfEMP1 protein HB3VAR06 and some other rosette-mediating PfEMP1 proteins. We map the α2M binding site to the C terminal end of HB3VAR06, and demonstrate that α2M can bind at least four HB3VAR06 proteins, plausibly augmenting their combined avidity for host receptors. IgM has previously been identified as a rosette-facilitating soluble factor that acts in a similar way, but it cannot induce rosetting on its own. This is in contrast to α2M and probably due to the more limited cross-linking potential of IgM. Nevertheless, we show that IgM works synergistically with α2M and markedly lowers the concentration of α2M required for rosetting. Finally, HB3VAR06+ IEs share the capacity to bind α2M with subsets of genotypically distinct P. falciparum isolates forming rosettes in vitro and of patient parasite isolates ex vivo. Together, our results are evidence that P. falciparum parasites exploit α2M (and IgM) to expand the repertoire of host receptors available for PfEMP1-mediated IE adhesion, such as the erythrocyte carbohydrate moieties that lead to formation of rosettes. It is likely that this mechanism also affects IE adhesion to receptors on vascular endothelium. The study opens opportunities for broad-ranging immunological interventions targeting the α2M—(and IgM-) binding domains of PfEMP1, which would be independent of the host receptor specificity of clinically important PfEMP1 antigens. 相似文献
854.
Andrew J. Holland Rita M. Reis Sherry Niessen Cláudia Pereira Douglas A. Andres H. Peter Spielmann Don W. Cleveland Arshad Desai Reto Gassmann 《Molecular biology of the cell》2015,26(10):1845-1856
The clinical interest in farnesyltransferase inhibitors (FTIs) makes it important to understand how these compounds affect cellular processes involving farnesylated proteins. Mitotic abnormalities observed after treatment with FTIs have so far been attributed to defects in the farnesylation of the outer kinetochore proteins CENP-E and CENP-F, which are involved in chromosome congression and spindle assembly checkpoint signaling. Here we identify the cytoplasmic dynein adaptor Spindly as an additional component of the outer kinetochore that is modified by farnesyltransferase (FTase). We show that farnesylation of Spindly is essential for its localization, and thus for the proper localization of dynein and its cofactor dynactin, to prometaphase kinetochores and that Spindly kinetochore recruitment is more severely affected by FTase inhibition than kinetochore recruitment of CENP-E and CENP-F. Molecular replacement experiments show that both Spindly and CENP-E farnesylation are required for efficient chromosome congression. The identification of Spindly as a new mitotic substrate of FTase provides insight into the causes of the mitotic phenotypes observed with FTase inhibitors. 相似文献
855.
Microsupercapacitors: Lithographically Integrated Microsupercapacitors for Compact,High Performance,and Designable Energy Circuits (Adv. Energy Mater. 18/2015) 下载免费PDF全文
856.
Brulois KF Chang H Lee AS Ensser A Wong LY Toth Z Lee SH Lee HR Myoung J Ganem D Oh TK Kim JF Gao SJ Jung JU 《Journal of virology》2012,86(18):9708-9720
Efficient genetic modification of herpesviruses such as Kaposi's sarcoma-associated herpesvirus (KSHV) has come to rely on bacterial artificial chromosome (BAC) technology. In order to facilitate this approach, we generated a new KSHV BAC clone, called BAC16, derived from the rKSHV.219 virus, which stems from KSHV and Epstein-Barr virus-coinfected JSC1 primary effusion lymphoma (PEL) cells. Restriction enzyme and complete sequencing data demonstrate that the KSHV of JSC1 PEL cells showed a minimal level of sequence variation across the entire viral genome compared to the complete genomic sequence of other KSHV strains. BAC16 not only stably propagated in both Escherichia coli and mammalian cells without apparent genetic rearrangements, but also was capable of robustly producing infectious virions (~5 × 10(7)/ml). We also demonstrated the utility of BAC16 by generating deletion mutants of either the K3 or K5 genes, whose products are E3 ligases of the membrane-associated RING-CH (MARCH) family. While previous studies have shown that individual expression of either K3 or K5 results in efficient downregulation of the surface expression of major histocompatibility complex class I (MHC-I) molecules, we found that K5, but not K3, was the primary factor critical for the downregulation of MHC-I surface expression during KSHV lytic reactivation or following de novo infection. The data presented here demonstrate the utility of BAC16 for the generation and characterization of KSHV knockout and mutant recombinants and further emphasize the importance of functional analysis of viral genes in the context of the KSHV genome besides the study of individual gene expression. 相似文献
857.
Kaposi's sarcoma-associated herpesvirus (KSHV) establishes long-term latent infection in humans and can cause cancers in endothelial and B cells. A functioning immune system is vital for restricting viral proliferation and preventing KSHV-dependent neoplasms. While natural killer (NK) lymphocytes are known to target virus-infected cells for destruction, their importance in the anti-KSHV immune response is not currently understood. Activating receptors on NK cells recognize ligands on target cells, including the uncharacterized ligand(s) for NKp44, termed NKp44L. Here we demonstrate that several NK ligands are affected when KSHV-infected cells are induced to enter the lytic program. We performed a screen of most of the known KSHV genes and found that the product of the ORF54 gene could downregulate NKp44L. The ORF54-encoded protein is a dUTPase; however, dUTPase activity is neither necessary nor sufficient for the downregulation of NKp44L. In addition, we find that ORF54 can also target proteins of the cytokine receptor family and the mechanism of downregulation involves perturbation of membrane protein trafficking. The ORF54-related proteins of other human herpesviruses do not possess this activity, suggesting that the KSHV homolog has evolved a novel immunoregulatory function and that the NKp44-NKp44L signaling pathway contributes to antiviral immunity. 相似文献
858.
He X Galpin JD Tropak MB Mahuran D Haselhorst T von Itzstein M Kolarich D Packer NH Miao Y Jiang L Grabowski GA Clarke LA Kermode AR 《Glycobiology》2012,22(4):492-503
There is a clear need for efficient methods to produce protein therapeutics requiring mannose-termination for therapeutic efficacy. Here we report on a unique system for production of active human lysosomal acid β-glucosidase (glucocerebrosidase, GCase, EC 3.2.1.45) using seeds of the Arabidopsis thaliana complex-glycan-deficient (cgl) mutant, which are deficient in the activity of N-acetylglucosaminyl transferase I (EC 2.4.1.101). Gaucher disease is a prevalent lysosomal storage disease in which affected individuals inherit mutations in the gene (GBA1) encoding GCase. A gene cassette optimized for seed expression was used to generate the human enzyme in seeds of the cgl (C5) mutant, and the recombinant GCase was mainly accumulated in the apoplast. Importantly, the enzymatic properties including kinetic parameters, half-maximal inhibitory concentration of isofagomine and thermal stability of the cgl-derived GCase were comparable with those of imiglucerase, a commercially available recombinant human GCase used for enzyme replacement therapy in Gaucher patients. N-glycan structural analyses of recombinant cgl-GCase showed that the majority of the N-glycans (97%) were mannose terminated. Additional purification was required to remove ~15% of the plant-derived recombinant GCase that possessed potentially immunogenic (xylose- and/or fucose-containing) N-glycans. Uptake of cgl-derived GCase by mouse macrophages was similar to that of imiglucerase. The cgl seed system requires no addition of foreign (non-native) amino acids to the mature recombinant GCase protein, and the dry transgenic seeds represent a stable repository of the therapeutic protein. Other strategies that may completely prevent plant-like complex N-glycans are discussed, including the use of a null cgl mutant. 相似文献
859.
This investigation sought to examine the contributions of exercise and nutrient replenishment on in vivo regulation of the
insulin-like growth factor-I (IGF-I) axis components. Eight college-aged males completed three high-intensity interval training
(HIIT) protocols followed by three post-exercise nutritional protocols: (1) placebo (EX); (2) carbohydrate only (CHO); and
(3) essential amino acid/carbohydrate (EAA/CHO). Samples were analyzed for growth hormone (GH), free IGF-I, IGFBP-1, IGFBP-2,
insulin, hematocrit, hemoglobin, serum leucine, matrix metalloproteinase-9 (MMP-9) proteolytic activity, and presence of IGFBP-3
protease activity. No evidence for IGFBP-3 proteolysis was observed. Significant increases in [free IGF-I] and [leucine] were
observed in the EAA/CHO group only. Significant differences were noted in [IGFBP-1] and [IGFBP-2] across conditions. Significant
increases in [GH] and MMP-9 activity were observed in all groups. These results indicate that post-exercise macronutrient
ratio is a determinant of [free IGF-I], [IGFBP-1 and -2] and may play a role in modulating the IGF-I axis in vivo. 相似文献
860.
Ali AH Cowan AB Gregory JS Aspden RM Meakin JR 《Computer methods in biomechanics and biomedical engineering》2012,15(2):167-172
The 2D shape of the lumbar spine in the sagittal plane can be determined from lordosis angles measured between the corresponding end-plates of the vertebral bodies or by using an active shape model (ASM) of the vertebral body outline. The ASM was previously shown to be a more efficient and reliable method, but its accuracy has not been assessed. The aim of this study was to determine the accuracy of an ASM for characterising lumbar spine shape and compare this to conventional measurements. Images of 25 different lumbar spine shapes were generated and measured, using both methods, by three independent observers. The accuracy of the ASM, determined from lordosis angles predicted by the model, was found to be better than conventional measurements. 相似文献