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141.
Stefano Crosignani Marc Missotten Christophe Cleva Ruggero Dondi Yann Ratinaud Yves Humbert Ashis Baran Mandal Agnès Bombrun Christine Power André Chollet Amanda Proudfoot 《Bioorganic & medicinal chemistry letters》2010,20(12):3614-3617
The discovery of a novel series of CXCR3 antagonists is described. Starting from an HTS positive, iterative optimization gave potent compounds (IC50 15 nM in a chemotaxis assay). The strategy employed to improve the metabolic stability of these derivatives is described. 相似文献
142.
Johanna E. Bischof Charles E. Spritzer Adam M. Caputo Mark E. Easley James K. DeOrio James A. Nunley Louis E. DeFrate 《Journal of biomechanics》2010,43(13):2561-2566
Damage to the anterior talofibular ligament (ATFL) and cacaneofibular ligament (CFL) during an ankle sprain may be linked to the development of osteoarthritis. Although altered tibiotalar kinematics have been demonstrated, the effects of lateral ankle instability (LAI) on in vivo cartilage strains have not been described. We hypothesized that peak cartilage strains increase, and the location is shifted in patients with ATFL injuries. We used 3-D MRI models and biplanar fluoroscopy to evaluate in vivo cartilage contact strains in seven patients with unilateral LAI. Subjects had chronic unilateral ATFL injury or combined ATFL and CFL injury, and were evaluated with increasing load while stepping onto a force plate. Peak cartilage strain and the location of the peak strain were measured using the contralateral normal ankle as a control. Ankles with LAI demonstrated significantly increased peak strain when compared with ATFL-intact controls. For example, at 100% body weight, peak strain was 29±8% on the injured side compared to 21±5% on the intact side. The position of peak strain on the injured ankle also showed significant anterior translation and medial translation. At 100% body weight, the location of peak strain in the injured ankle translated anteriorly by 15.5±7.1 mm and medially by 12.9±4.3 mm relative to the intact ankle. These changes correspond to the region of clinically observed osteoarthritis. Chronic LAI, therefore, may contribute to the development of tibiotalar cartilage degeneration due to altered cartilage strains. 相似文献
143.
Alessia Calzolari Luigi Maria Larocca Silvia Deaglio Veronica Finisguerra Alessandra Boe Carla Raggi Lucia Ricci-Vitani Francesco Pierconti Fabio Malavasi Ruggero De Maria Ugo Testa Roberto Pallini 《Translational oncology》2010,3(2):123-134
Under physiological conditions, transferrin receptor 2 (TfR2) is expressed in the liver and its balance is related to the cell cycle rather than to intracellular iron levels. We recently showed that TfR2 is highly expressed in glioblastoma cell lines. Here, we demonstrate that, in these cells, TfR2 appears to localize in lipid rafts, induces extracellular signal-regulated kinase 1/2 phosphorylation after transferrin binding, and contributes to cell proliferation, as shown by RNA silencing experiments. In vitro hypoxic conditions induce a significant TfR2 up-regulation, suggesting a role in tumor angiogenesis. As assessed by immunohistochemistry, the level of TfR2 expression in astrocytic tumors is related to histologic grade, with the highest expression observed in glioblastomas. The level of TfR2 expression represents a favorable prognostic factor, which is associated with the higher sensitivity to temozolomide of TfR2-positive tumor cells in vitro. The endothelial cells of glioblastoma vasculature also stain for TfR2, whereas those of the normal brain vessels do not. Importantly, TfR2 is expressed by the subpopulation of glioblastoma cells with properties of cancer-initiating cells. TfR2-positive glioblastoma cells retain their TfR2 expression on xenografting in immunodeficient mice. In conclusion, our observations demonstrate that TfR2 is a neoantigen for astrocytomas that seems attractive for developing target therapies. 相似文献
144.
Lupi A Della Torre S Campari E Tenni R Cetta G Rossi A Forlino A 《The FEBS journal》2006,273(23):5466-5478
Prolidase is a Mn(2+)-dependent dipeptidase that cleaves imidodipeptides containing C-terminal proline or hydroxyproline. In humans, a lack of prolidase activity causes prolidase deficiency, a rare autosomal recessive disease, characterized by a wide range of clinical outcomes, including severe skin lesions, mental retardation, and infections of the respiratory tract. In this study, recombinant prolidase was produced as a fusion protein with an N-terminal histidine tag in eukaryotic and prokaryotic hosts and purified in a single step using immobilized metal affinity chromatography. The enzyme was characterized in terms of activity against different substrates, in the presence of various bivalent ions, in the presence of the strong inhibitor Cbz-Pro, and at different temperatures and pHs. The recombinant enzyme with and without a tag showed properties mainly indistinguishable from those of the native prolidase from fibroblast lysate. The protein yield was higher from the prokaryotic source, and a detailed long-term stability study of this enzyme at 37 degrees C was therefore undertaken. For this analysis, an 'on-column' digestion of the N-terminal His tag by Factor Xa was performed. A positive effect of Mn(2+) and GSH in the incubation mixture and high stability of the untagged enzyme are reported. Poly(ethylene glycol) and glycerol had a stabilizing effect, the latter being the more effective. In addition, no significant degradation was detected after up to 6 days of incubation with cellular lysate. Generation of the prolidase in Escherichia coli, because of its high yield, stability, and similarity to native prolidase, appears to be the best approach for future structural studies and enzyme replacement therapy. 相似文献
145.
We examined the effect of ionizable residues at positions flanking the hydrophobic core of helix-forming polyLeu peptides upon helix-helix interactions within model membrane vesicles composed of dioleoylphosphatidylcholine. The peptides studied were flanked on both the N and C termini either by two Lys (K(2)-flanked peptide), one Lys plus one Asp (DK-flanked peptide), or one Lys plus three Asp (KD(3)-flanked peptide). The fluorescence of a Trp residue positioned at the center of the hydrophobic sequence was used to evaluate peptide behavior. As judged by the concentration dependence of the maximum wavelength of Trp emission, there was significant oligomerization of the KD(3)- and DK-flanked peptides, but not the K(2)-flanked peptide, at neutral pH. At neutral pH mixtures of K(2)- and KD(3)-flanked peptides associated with each other, but mixtures of the K(2)- and DK-flanked peptides did not. Oligomerization by the DK- and KD(3)-flanked peptides decreased under low pH conditions in which the Asp residues were protonated. Additional experiments showed that at neutral pH the KD(3)-flanked peptide showed an increased tendency to oligomerize when as little as 10-15 mol % of an anionic lipid, phosphatidylglycerol, was present. The behavior of the other peptides was not strongly influenced by phosphatidylglycerol. These results can largely be explained by modulation of helix-helix interactions via electrostatic interactions involving the helix-flanking ionizable residues. Such interactions may influence membrane protein folding. The self-association of anionic KD(3)-flanked peptides suggests that additional interactions involving charged residues also can modulate helix-helix association. 相似文献
146.
The karyotype of Histiodraco velifer from the Antartic Ocean was analyzed using various banding methods and in situ hybridization with a telomeric probe. A male and a female had a diploid set of 46 chromosomes (6 submetacentric + 40 acrocentric, FN = 52); the nucleolar organizer was CMA3-positive and was located on the short arm of a medium-sized submetacentric pair. All chromosomes stained uniformly with DAPI, whereas C-banding revealed heterochromatic blocks that were mostly located centromerically and telomerically and were resistant to ALUI digestion. The substantial identity of the karyotype of H. velifer with that of the other artedidraconids investigated so far suggests that chromosome changes must have played a less than significant role in the speciation among the lineages of this fish family endemic to Antarctica. 相似文献
147.
The aim of this paper was to study the effect of the granulate properties and tablet compression force on disintegrating force
behavior in order to investigate the capability of the disintegrating force to characterize tablets that have the same composition
but were manufactured in different conditions. Several tablets containing spironolactone in the external or internal granulated
mixture of calcium carbonate and maize starch differing in particle size distribution, were prepared at 3 compression levels.
The force developed by tablets during water uptake and disintegration was measured and plotted versus time. The curves obtained
were analyzed by the Weibull equation in order to calculate the parameters characterizing the tablet disintegration kinetics.
The disintegrating force time parameter, the maximum force developed, and the area under the curve were determined. In general,
the reduction of time parameter value and/or the increase in maximum force developed corresponded to an acceleration in tablet
disintegration. In addition, the area under the force curve increased in stronger tablets, monitoring in a sensitive way the
tablet structural changes introduced by compression force. The results showed that the disintegrating force measurement can
detect small changes in the structure of the tablet that cannot be discriminated by pharmacopoeia tests. The effect of manufacturing,
in particular compression force, on tablet properties was quantified by the parameters of disintegrating force kinetics. 相似文献
148.
149.
Retrotransposons have shaped eukaryotic genomes for millions of years. To analyze the consequences of human L1 retrotransposition, we developed a genetic system to recover many new L1 insertions in somatic cells. Forty-two de novo integrants were recovered that faithfully mimic many aspects of L1s that accumulated since the primate radiation. Their structures experimentally demonstrate an association between L1 retrotransposition and various forms of genetic instability. Numerous L1 element inversions, extra nucleotide insertions, exon deletions, a chromosomal inversion, and flanking sequence comobilization (called 5' transduction) were identified. In a striking number of integrants, short identical sequences were shared between the donor and the target site's 3' end, suggesting a mechanistic model that helps explain the structure of L1 insertions. 相似文献
150.