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121.
In addition to being associated with severe degenerative diseases, amyloids show exceptional mechanical properties including great strength, sturdiness and elasticity. However, thus far physical models that explain these properties remain elusive, and our understanding of molecular deformation and failure mechanisms of individual amyloid fibrils is limited. Here we report a series of molecular dynamics simulations, carried out to analyze the mechanical response of two-fold symmetric Aβ(1–40) amyloid fibrils, twisted protein nanofilaments consisting of a H-bonded layered structure. We find a correlation of the mechanical behavior with chemical and nanostructural rearrangements of the fibril during compressive and tensile deformation, showing that the density of H-bonds varies linearly with the measured strain. Further, we find that both compressive and tensile deformation is coupled with torsional deformation, which is manifested in a strong variation of the interlayer twist angle that is found to be proportional to both the applied stress and measured strain. In both compression and tension we observe an increase of the Young's modulus from 2.34 GPa (for less than 0.1% strain in compression and 0.2% strain in tension), to 12.43 GPa for compression and 18.05 GPa for tension. The moduli at larger deformation are in good agreement with experimental data, where values in the range of 10–20 GPa have been reported. Our studies confirm that amyloids feature a very high stiffness, and elucidate the importance of the chemical and structural rearrangements of the fibrils during deformation. 相似文献
122.
123.
Ausiello CM Fedele G Palazzo R Spensieri F Ciervo A Cassone A 《Microbes and infection / Institut Pasteur》2006,8(3):714-720
Infection, in particular by Chlamydia pneumoniae (Cp), has been associated with atherosclerosis and coronary heart disease. Immune reactions to heat shock proteins (HSPs) have been advocated to link infection to atherosclerosis and its acute sequelae based on molecular mimicry with host HSPs. We have here evaluated the role played by recombinant Cp-HSP60 and Cp-HSP10 for their ability to induce maturation of human monocyte-derived dendritic cells (MDDC) and T cell polarization. Cp-HSP60, but not Cp-HSP10, induced a strong MDCC maturation, as assessed by the expression of co-stimulatory molecules and other markers. Secretion of regulatory cytokines and enhancement of antigen presenting ability of mature (m)MDDC toward a clear T helper (Th) 1 pattern were also induced by Cp-HSP60. An analysis of the IL-12 cytokine family demonstrated that Cp-HSP60-matured MDDC were able to express p35 and p40 mRNA subunits to form IL-12, and p19 and p40 subunits to form IL-23. Thus, preferential Th1 polarization of immune response induced by Cp-HSP60-matured MDDC appears to be due to the concomitant expression of IL-12 and IL-23. Our data suggest that Cp-HSP60-matured DC may contribute to T-cell mediated immunopathology of atherosclerosis via a chronic stimulation of Th1 immune responses. 相似文献
124.
Ausiello CM Cerquetti M Fedele G Spensieri F Palazzo R Nasso M Frezza S Mastrantonio P 《Microbes and infection / Institut Pasteur》2006,8(11):2640-2646
Clostridium difficile, an etiological agent of most cases of antibiotic-associated diarrhea, exerts its pathological action mainly by the activity of toxin A and toxin B. Less known is the role that S-layer proteins (SLPs), predominant surface components of the bacterium, may play in pathogenesis. Here, we evaluate the ability of SLPs to modulate the function of human monocytes and dendritic cells (DC) and to induce inflammatory and regulatory cytokines, influencing the natural and adaptive immune response. To this aim, SLPs were extracted from the clinical isolate C253 and characterized for their effects on immune cells. SLPs induced the release of elevated amounts of interleukin (IL)-1β and IL-6 pro-inflammatory cytokines by resting monocytes, induced maturation of human monocyte-derived DC (MDDC), and enhanced proliferation of allogeneic T cells. C253-SLP-treated MDDC also secreted large amounts of IL-10 and IL-12p70 and induced a mixed Th1/Th2 orientation of immune response in naïve CD4 T cells. In conclusion, C. difficile SLPs may contribute to the pathogenicity of the bacterium by perturbing the fine balance of inflammatory and regulatory cytokines. These data are of interest also in the light of the possible use of SLPs in a multicomponent vaccine against C. difficile infections for high-risk patients. 相似文献
125.
126.
Pettinari C Caruso F Zaffaroni N Villa R Marchetti F Pettinari R Phillips C Tanski J Rossi M 《Journal of inorganic biochemistry》2006,100(1):58-69
Novel 4-acylpyrazolon-5-ato-dihalotin(IV) complexes, [Q2SnX2], (X = F, Cl, Br or I); HQ = HQ(CHPh2) (1,2-dihydro-3-methyl-1-phenyl-4-(2,2-diphenylacetyl)pyrazol-5-one), HQ(Bn) (1,2-dihydro-3-methyl-1-phenyl-4-(2-phenylacetyl)pyrazol-5-one) or HQ(CF3,py) (4-(2,2,2-trifluoroacetyl)-1,2-dihydro-3-methyl-1-(pyridin-2-yl)pyrazol-5-one) have been synthesized and characterized by spectroscopic (IR, 1H, 13C, 19F and 119Sn NMR, electrospray ionisation mass spectrometry (ESI-MS)), analytical and structural methods (X-ray and density functional theory). 119Sn chemical shifts depend on the nature of the halides bonded to tin. Isomer conversion, detected in solution by NMR spectroscopy, is related to the acyl moiety bulkiness while the cis(Cl)-cis(acyl)-trans(pyrazolonato) scheme is found in the solid state. The in vitro antiproliferative tests of three derivatives on three human melanoma cell lines (JR8, SK-MEL-5, MEL501) and two melanoma cell clones (2/21 and 2/60) show dose-dependent decrease of cell proliferation in all cell lines. The activity correlates with the nature of the substituent on position 1 of pyrazole, decreasing in the order pyridyl>Ph>methyl. The activity for (Q(CF3,py))2SnCl2 on the SK-MEL-5 cell line is IC50 = 50 microM. 相似文献
127.
During 1999–2001 the chemical composition and fluxes were measured in rainfall, throughfall, soil solution and stream water
in a remote forested site in the Italian Alps. The analysis of temporal patterns revealed the differential behaviour of nitrogen
and sulphur and suggested that different mechanisms controlled their flux. No important changes in sulphate concentration
and fluxes emerged as the solution passed through the various components of the forest ecosystem, and temporal variations
of SO4 in the soil solution and stream were likely driven by the physical process of dilution. The availability of nitrate and ammonia,
by contrast, was drastically reduced as throughfall water entered the soil and passed through the mineral layers, irrespective
of season. The calculated hydrochemical budget based on throughfall and soil solution N fluxes revealed that ~80% N retention
in the forest soil, corresponding to 12 kg ha−1 yr−1, despite a relatively high N deposition loading (15 kg ha−1 yr−1). Most of the leached nitrogen (90%) was in the organic form. Indicators of the N status of this ecosystem, such as C/N ratio
in solid and solution phase of the soil and N foliage content as well as land use history were examined. Despite the strong
N retention in the forested part of the catchment, the stream water N–NO3 levels were consistently above 10 μg l−1 suggesting that the Val Masino catchment as a whole was less efficient in processing atmospheric N inputs. This contrasting
N behaviour illustrates the role of landscape features, such as the soil cover and vegetation type, that is characteristic
of an alpine catchment. 相似文献
128.
129.
Coecke S Ahr H Blaauboer BJ Bremer S Casati S Castell J Combes R Corvi R Crespi CL Cunningham ML Elaut G Eletti B Freidig A Gennari A Ghersi-Egea JF Guillouzo A Hartung T Hoet P Ingelman-Sundberg M Munn S Janssens W Ladstetter B Leahy D Long A Meneguz A Monshouwer M Morath S Nagelkerke F Pelkonen O Ponti J Prieto P Richert L Sabbioni E Schaack B Steiling W Testai E Vericat JA Worth A 《Alternatives to laboratory animals : ATLA》2006,34(1):49-84
130.
Willmann R Pun S Stallmach L Sadasivam G Santos AF Caroni P Fuhrer C 《The EMBO journal》2006,25(17):4050-4060
Stabilization and maturation of synapses are important for development and function of the nervous system. Previous studies have implicated cholesterol-rich lipid microdomains in synapse stabilization, but the underlying mechanisms remain unclear. We found that cholesterol stabilizes clusters of synaptic acetylcholine receptors (AChRs) in denervated muscle in vivo and in nerve-muscle explants. In paralyzed muscles, cholesterol triggered maturation of nerve sprout-induced AChR clusters into pretzel shape. Cholesterol treatment also rescued a specific defect in AChR cluster stability in cultured src(-/-);fyn(-/-) myotubes. Postsynaptic proteins including AChRs, rapsyn, MuSK and Src-family kinases were strongly enriched in lipid microdomains prepared from wild-type myotubes. Microdomain disruption by cholesterol-sequestering methyl-beta-cyclodextrin disassembled AChR clusters and decreased AChR-rapsyn interaction and AChR phosphorylation. Amounts of microdomains and enrichment of postsynaptic proteins into microdomains were decreased in src(-/-);fyn(-/-) myotubes but rescued by cholesterol treatment. These data provide evidence that cholesterol-rich lipid microdomains and SFKs act in a dual mechanism in stabilizing the postsynapse: SFKs enhance microdomain-association of postsynaptic components, whereas microdomains provide the environment for SFKs to maintain interactions and phosphorylation of these components. 相似文献