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71.
Felista L. Tansi Ronny Rüger Ansgar M. Kollmeier Markus Rabenhold Frank Steiniger Roland E. Kontermann Ulf K. Teichgraeber Alfred Fahr Ingrid Hilger 《Biochimica et Biophysica Acta (BBA)/General Subjects》2018,1862(6):1389-1400
Background
Endoglin (CD105) is overexpressed on tumor cells and tumor vasculatures, making it a potential target for diagnostic imaging and therapy of different neoplasms. Therefore, studies on nanocarrier systems designed for endoglin-directed diagnostic and drug delivery purposes would expose the feasibility of targeting endoglin with therapeutics.Methods
Liposomes carrying high concentrations of a near-infrared fluorescent dye in the aqueous interior were prepared by the lipid film hydration and extrusion procedure, then conjugated to single chain antibody fragments either selective for murine endoglin (termed mEnd-IL) or directed towards human endoglin (termed hEnd-IL). A combination of Dynamic Light Scattering, electron microscopy, cell binding and uptake assays, confocal microscopy and in vivo fluorescence imaging of mice bearing xenografted human breast cancer and human fibrosarcoma models were implemented to elucidate the potentials of the liposomes.Results
The mEnd-IL and hEnd-IL were highly selective for the respective murine- and human endoglin expressing cells in vitro and in vivo. Hence, the hEnd-IL bound distinctly to the tumor cells and enabled suitable fluorescence imaging of the tumors, whereas the mEnd-IL bound the tumor vasculature, but also to the liver, kidney and lung vasculature of mice.Conclusions
The work highlights key differences between targeting vascular (murine) and neoplastic (human) endoglin in animal studies, and suggests that the hEnd-IL can serve as a delivery system that targets human endoglin overexpressed in pathological conditions.General significance
The endoglin-targeting liposomes presented herewith represent strategic tools for the future implementation of endoglin-directed neoplastic and anti-angiogenic therapies. 相似文献72.
N-aryl-piperidine-4-carboxamides as a novel class of potent inhibitors of MALT1 proteolytic activity
Achim Schlapbach Laszlo Revesz Carole Pissot Soldermann Thomas Zoller Catherine H. Régnier Frédéric Bornancin Thomas Radimerski Jutta Blank Ansgar Schuffenhauer Martin Renatus Paulus Erbel Samu Melkko Richard Heng Oliver Simic Ralf Endres Markus Wartmann Jean Quancard 《Bioorganic & medicinal chemistry letters》2018,28(12):2153-2158
Starting from a weak screening hit, potent and selective inhibitors of the MALT1 protease function were elaborated. Advanced compounds displayed high potency in biochemical and cellular assays. Compounds showed activity in a mechanistic Jurkat T cell activation assay as well as in the B-cell lymphoma line OCI-Ly3, which suggests potential use of MALT1 inhibitors in the treatment of autoimmune diseases as well as B-cell lymphomas with a dysregulated NF-κB pathway. Initially, rat pharmacokinetic properties of this compound series were dominated by very high clearance which could be linked to amide cleavage. Using a rat hepatocyte assay a good in vitro-in vivo correlation could be established which led to the identification of compounds with improved PK properties. 相似文献
73.
74.
Ansgar Hakvoort Matthias Haselbach Joachim Wegener Dirk Hoheisel Hans-Joachim Galla 《Journal of neurochemistry》1998,71(3):1141-1150
Abstract: The influence of culture conditions on the development of normal characteristics of the choroid plexus epithelium has been investigated in vitro with respect to polarity, barrier properties, transport, and secretory activity. Withdrawal of serum supplement in the culture medium of cells grown on filters caused morphologically visible changes by an increased trimming of microvilli at the apical membrane side, which is accompanied by an increased expression of the Na+ ,K+ -ATPase. Moreover cells under serum-free conditions exhibit structural changes in tight junctional zonula occludens protein-1 (ZO-1) organization, a reduced permeability, and a drastically increased electrical resistance from 150 Ω· cm2 in the presence of serum to 1,500 Ω· cm2 after serum withdrawal. Under these conditions, cell monolayers are able to build up a transcellular proton gradient and to secrete fluid into the upper (apical) filter compartment, which is accompanied by a polarized secretion of proteins like transthyretin. Active transport of the dyes fluorescein and phenol red by the organic anion transporter is found to be driven by the Na+ ,K+ -ATPase. We come to the conclusion that removal of serum favors the differentiation process of the plexus epithelium in vitro, which brings the cell culture model closer to the physiological situation in vivo. We present preliminary evidence that epidermal growth factor may be one component in serum preventing the proper in vitro differentiation. 相似文献
75.
76.
Eugenia M. del Pino Herbert Steinbeisser Ansgar Hofmann Christine Dreyer Margarita Campos Michael F. Trendelenburg 《Differentiation; research in biological diversity》1986,32(1):24-33
Abstract. The dissimilarities between oocytes of the eggbrooding frog, Gastrotheca riobambae , and Xenopus laevis suggest that oogenesis is modified according to the mode of reproduction. Oocytes of G. riobambae are large, yolky, and measure about 3 mm in diameter. In spite of the large oocyte size of Gastrotheca , the amplification of ribosomal genes, the number of nucleoli, and the amount of 18S and 28S rRNA are lower than in Xenopus oocytes. In Gastrotheca , the lower RNA content of oocytes is associated with a slow rate of development. A prolonged period of development is possible due to the protection given by the maternal pouch. 相似文献
77.
78.
We developed a general approach that allows unnatural amino acids with diverse physicochemical and biological properties to be genetically encoded in mammalian cells. A mutant Escherichia coli aminoacyl-tRNA synthetase (aaRS) is first evolved in yeast to selectively aminoacylate its tRNA with the unnatural amino acid of interest. This mutant aaRS together with an amber suppressor tRNA from Bacillus stearothermophilus is then used to site-specifically incorporate the unnatural amino acid into a protein in mammalian cells in response to an amber nonsense codon. We independently incorporated six unnatural amino acids into GFP expressed in CHO cells with efficiencies up to 1 mug protein per 2 x 10(7) cells; mass spectrometry confirmed a high translational fidelity for the unnatural amino acid. This methodology should facilitate the introduction of biological probes into proteins for cellular studies and may ultimately facilitate the synthesis of therapeutic proteins containing unnatural amino acids in mammalian cells. 相似文献
79.
80.
Buchstaller HP Eggenweiler HM Sirrenberg C Grädler U Musil D Hoppe E Zimmermann A Schwartz H März J Bomke J Wegener A Wolf M 《Bioorganic & medicinal chemistry letters》2012,22(13):4396-4403
Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential molecular therapeutic agents for the treatment of cancer. Here we describe the identification of novel small molecular weight inhibitors of Hsp90 using a fragment based approach. Fragments were selected by docking, tested in a biochemical assay and the confirmed hits were crystallized. Information gained from X-ray structures of these fragments and other chemotypes was used to drive the fragment evolution process. Optimization of these high μM binders resulted in 3-benzylindazole derivatives with significantly improved affinity and anti-proliferative effects in different human cancer cell lines. 相似文献