全文获取类型
收费全文 | 255篇 |
免费 | 24篇 |
出版年
2022年 | 2篇 |
2021年 | 2篇 |
2017年 | 3篇 |
2016年 | 4篇 |
2015年 | 4篇 |
2014年 | 6篇 |
2013年 | 10篇 |
2012年 | 15篇 |
2011年 | 12篇 |
2010年 | 14篇 |
2009年 | 11篇 |
2008年 | 12篇 |
2007年 | 12篇 |
2006年 | 13篇 |
2005年 | 13篇 |
2004年 | 8篇 |
2003年 | 10篇 |
2002年 | 9篇 |
2001年 | 9篇 |
2000年 | 11篇 |
1999年 | 21篇 |
1998年 | 7篇 |
1997年 | 7篇 |
1996年 | 3篇 |
1995年 | 5篇 |
1994年 | 8篇 |
1993年 | 5篇 |
1992年 | 5篇 |
1991年 | 6篇 |
1990年 | 4篇 |
1989年 | 4篇 |
1988年 | 2篇 |
1987年 | 6篇 |
1985年 | 1篇 |
1984年 | 8篇 |
1983年 | 1篇 |
1977年 | 1篇 |
1973年 | 1篇 |
1970年 | 1篇 |
1966年 | 1篇 |
1963年 | 1篇 |
1961年 | 1篇 |
排序方式: 共有279条查询结果,搜索用时 15 毫秒
101.
alpha-Aminoisobutyric acid (AIB) is a nonmetabolized amino acid analogue of alanine, which at low (muM) concentrations acts as a tracer for amino acid movements. At high concentrations (mM), it competitively inhibits membrane transport and metabolism of protein amino acids and acts as a systemic translocated inhibitor of mycelial extension in fungi. AIB can control mycelial spread of the basidiomycete Serpula lacrymans, the cause of brown rot of wood in buildings. However, it is not known how effectively the inhibitor is distributed throughout the mycelium. Realistically heterogeneous microcosms, in which the fungus grew across nutritionally inert sand to colonize discrete wood resources, were used to investigate patterns of inhibition and translocation following local application of AIB. At a 0.1 M concentration, locally applied AIB caused immediate arrest of extension throughout the whole mycelium, maintained for a 6-week experimental period. The dynamics of translocation of subtoxic amounts of [1-(14)C]AIB ([(14)C]AIB) were mapped by photon-counting scintillation imaging in conjunction with destructive harvest to establish the velocity, direction, and rate of translocation and the extent of [(14)C]AIB reallocation accompanying the invasion of fresh wood. Locally applied [(14)C]AIB was distributed throughout complex mycelial networks within 2 h of application, becoming localized in growing margins by 12 h. Encounter with a fresh wood resource triggered a widespread response, causing withdrawal of [(14)C]AIB from throughout the network, accompanied by accumulation in the newly colonized wood and associated mycelium. The results are discussed in the context of nutrient dynamics in wood decomposer fungi and the mechanism of the amino acid reallocation response. 相似文献
102.
Vadim Bernard-Gauthier Anne Mahringer Matthew Vesnaver Gert Fricker Ralf Schirrmacher 《Bioorganic & medicinal chemistry letters》2017,27(12):2771-2775
NTRK1/2/3 fusions have recently been characterized as low incidence oncogenic alterations across various tumor histologies. Tyrosine kinase inhibitors (TKIs) of the tropomyosin receptor kinase family TrkA/B/C (encoded by NTRK1/2/3) are showing promises in the clinic for the treatment of cancer patients whose diseases harbor NTRK tumor drivers. We describe herein the development of [18F]QMICF ([18F]-(R)-9), a quinazoline-based type-II pan-Trk radiotracer with nanomolar potencies for TrkA/B/C (IC50 = 85–650 nM) and relevant TrkA fusions including TrkA-TPM3 (IC50 = 162 nM). Starting from a racemic FLT3 (fms like tyrosine kinase 3) inhibitor lead with off-target TrkA activity ((±)-6), we developed and synthesized the fluorinated derivative (R)-9 in three steps and 40% overall chemical yield. Compound (R)-9 displays a favorable selectivity profile on a diverse set of kinases including FLT3 (>37-fold selectivity for TrkB/C). The mesylate precursor 16 required for the radiosynthesis of [18F]QMICF was obtained in six steps and 36% overall yield. The results presented herein support the further exploration of [18F]QMICF for imaging of Trk fusions in vivo. 相似文献
103.
Crystal structure of avian carboxypeptidase D domain II: a prototype for the regulatory metallocarboxypeptidase subfamily.
下载免费PDF全文
![点击此处可从《The EMBO journal》网站下载免费的PDF全文](/ch/ext_images/free.gif)
F X Gomis-Rüth V Companys Y Qian L D Fricker J Vendrell F X Avilés M Coll 《The EMBO journal》1999,18(21):5817-5826
The crystal structure of domain II of duck carboxypeptidase D, a prohormone/propeptide processing enzyme integrated in a three repeat tandem in the natural system, has been solved, constituting a prototype for members of the regulatory metallocarboxypeptidase subfamily. It displays a 300 residue N-terminal alpha/beta-hydrolase subdomain with overall topological similarity to and general coincidence of the key catalytic residues with the archetypal pancreatic carboxypeptidase A. However, numerous significant insertions/deletions in segments forming the funnel-like access to the active site explain differences in specificity towards larger protein substrates or inhibitors. This alpha/beta-hydrolase subdomain is followed by a C-terminal 80 residue beta-sandwich subdomain, unique for these regulatory metalloenzymes and topologically related to transthyretin and sugar-binding proteins. The structure described here establishes the fundamentals for a better understanding of the mechanism ruling events such as prohormone processing and will enable modelling of regulatory carboxypeptidases as well as a more rational design of inhibitors of carboxypeptidase D. 相似文献
104.
Daniela C. Tradowsky Heide Fier Jessica Becker Anne C. Boehmer Ruth Herberz Nadine Fricker Sandra Barth Philipp Wahle Stefanie Nowak Heiko Reutter Rudolf H. Reich Carola Lauster Bert Braumann Thomas Kreusch Alexander Hemprich Bernd Pötzsch Per Hoffmann Franz‐Josef Kramer Michael Knapp Christoph Lange Markus M. Nöthen Kerstin U. Ludwig 《Birth defects research. Part A, Clinical and molecular teratology》2012,94(11):925-933
105.
Carboxypeptidase A6 (CPA6) is an extracellular matrix-bound metallocarboxypeptidase (CP) that has been implicated in Duane syndrome, a neurodevelopmental disorder in which the lateral rectus extraocular muscle is not properly innervated. Consistent with a role in Duane syndrome, CPA6 is expressed in a number of chondrocytic and nervous tissues during embryogenesis. To better characterize the enzymatic function and specificity of CPA6 and to compare this with other CPs, CPA6 was expressed in HEK293 cells and purified. Kinetic parameters were determined using a panel of synthetic carboxypeptidase substrates, indicating a preference of CPA6 for large hydrophobic C-terminal amino acids and only very weak activity toward small amino acids and histidine. A quantitative peptidomics approach using a mixture of peptides representative of the neuropeptidome allowed the characterization of CPA6 preferences at the P1 substrate position and suggested that small and acidic P1 residues significantly inhibit CPA6 cleavage. Finally, a comparison of available kinetic data for CPA enzymes shows a gradient of specificity across the subfamily, from the very restricted specificity of CPA2 to the very broad activity of CPA4. Structural data and modeling for all CPA/B subfamily members suggests the structural basis for the unique specificities observed for each member of the CPA/B subfamily of metallocarboxypeptidases. 相似文献
106.
A. de Fraissinette M. Kolopp I. Schiller G. Fricker C. Gammert A. Pospischil J. Vonderscher F. Richter 《Cell biology and toxicology》1995,11(5):295-301
Anin vitro human nasal model was developed as a tool to study the local tolerabiliity of nasal powder forms using excised nasal mucosa in a diffusion chamber. The suitability of this model was tested using Sandostatin® (SMS) an octapeptide analog of somatostatin, as a reference drug enhanced by Avicel® (microcrystalline cellulose) or lactose (100 mesh). The standard nasal spray vehicle was taken as a harmless control and 1% chenodeoxycholate (CDC) as a harmful control in terms of local tolerability. The extent of peptide permeation was determined by measuring SMS concentration in the receiving chamber. The labeling of SMS was detected by immunoperoxidase staining on cross sections. The local tolerability for all tested forms was assessed by histopathological examination and scanning electron microscopy. The apparent permeation coefficient allowed us to rank the absorption of the tested drug forms as Avicel > spray=lactose>1%CDC. For all formulations, SMS was detected in the epithelium. No changes of the nasal mucosa could be observed with Avicel, lactose or nasal spray vehicle in the presence or absence of SMS. 1%CDC with or without drug showed an immediate destruction of the nasal epithelium. The validation of thisin vitro model using human nasal mucosa will be further discussed as a tool for assessing the local tolerability of intranasally applied test substances.Abbreviations CDC
chenodeoxycholate
- SMS
Sandostatin® or octreotide 相似文献
107.
The incidence of 'thermophilic' campylobacters in foods and environmental samples has been studied over a two-year period. Of 781 environmental samples, 529 (67%) were found to contain campylobacters, and campylobacters were isolated from 835 (39%) of 2116 food samples. Sewage was almost always contaminated with campylobacters (96.6% of samples) and of the food samples both poultry (55.5%) and offal (47.0%) were commonly contaminated. Determination of the heat-stable serotypes of all strains isolated from these sources and of 921 strains isolated from human faeces showed that there was a wide distribution of serotypes in most types of sample. Serotype Pen 2 was the commonest type found in human faeces (18.9%) and it was also commonest in offal (21.3%), beef (40.0%), sewage (17.7%) and was the third commonest type in poultry. A comparison of culture media and conditions for optimal production of both cytotoxic and cytotonic enterotoxins showed that Brucella Broth incubated under microaerobic conditions for 24 h at 42 degrees C was suitable for both toxins. Detection of cytotoxic activity was most sensitive using HeLa cells. The sensitivities of two ELISA systems and a Chinese Hamster Ovary tissue culture assay for detection of cytotonic enterotoxin were comparable. Not all strains isolated from cases of enteritis in human beings produced toxin; 23.1% produced cytotonic enterotoxin and 17.5% produced cytotoxin. There was no correlation between serotype and toxin production. The wide distribution of campylobacters, indistinguishable from those isolated from cases of enteritis in human beings, leads us to conclude that simplistic statements suggesting that one particular type of food is primarily responsible for cases of human disease should not be made. 相似文献
108.
Carboxypeptidase E (CPE) is a carboxypeptidase B-like enzyme involved in the biosynthesis of numerous peptide hormones and neurotransmitters. A sensitive assay for CPE and other carboxypeptidase B-like enzymes has been developed using 125I-acetyl-Tyr-Ala-Arg (125I-AcYAR) as the substrate. This peptide is poorly soluble in ethyl acetate whereas the product of carboxypeptidase B-like enzymatic activity (125I-AcYA) can be quantitatively extracted with this solvent, allowing the rapid separation of product from substrate. This radiometric assay can detect less than 1 pg of either CPE or carboxypeptidase B. For CPE, the assay with 125I-AcYAR is approximately 1000 times more sensitive than a fluorescent assay using dansyl-Phe-Ala-Arg (dans-FAR), and 6000 times more sensitive than a spectrophotometric assay using hippuryl-Arg (hipp-R). CPE hydrolyzes the three substrates with Kcat values of 16 s-1 for AcYAR, 13 s-1 for dans-FAR, and 8.5 s-1 for hipp-R. The Km values for CPE with AcYAR (28 microM) and dans-FAR (34 microM) are similar, and are much lower than the Km with hipp-R (400 microM). Thus, the primary reason for the increased sensitivity of the 125I-AcYAR assay over the fluorescent assay is not a result of kinetic differences but is due to the detection limit of iodinated product (10(-15) mol), compared to the fluorescent product (5 x 10(-11) mol). Applications of this rapid and sensitive radiometric assay to detect CPE in cultured cells and in subcellular fractions of the pituitary are described. 相似文献
109.
Structural characterization of the rat carboxypeptidase-E gene. 总被引:7,自引:0,他引:7
Y K Jung C J Kunczt R K Pearson J E Dixon L D Fricker 《Molecular endocrinology (Baltimore, Md.)》1991,5(9):1257-1268
110.
Uptake of phosphatidylserine-containing liposomes by liver sinusoidal endothelial cells in the serum-free perfused rat liver 总被引:2,自引:0,他引:2
We studied the kinetics of hepatic uptake of liposomes during serum-free recirculating perfusion of rat livers. Liposomes consisted of phosphatidylcholine, cholesterol and phosphatidylserine in a 6:4:0 or a 3:4:3 molar ratio and were radiolabelled with [3H]cholesteryl oleyl ether. The negatively charged liposomes were taken up to a 10-fold higher extent than the neutral ones. Hepatic uptake of fluorescently labelled liposomes was examined by fluorescence microscopy. The neutral liposomes displayed a typical Kupffer cell distribution pattern, in addition to weak diffuse staining of the parenchyma, while the negatively charged liposomes showed a characteristic sinusoidal lining pattern, consistent with an endothelial localization. In addition, scattered Kupffer cell staining was distinguished as well as diffuse parenchymal fluorescence. The mainly endothelial localisation of the negatively charged liposomes was confirmed by determining radioactivity in endothelial and Kupffer cells isolated following a 1-h perfusion. Perfusion in the presence of polyinosinic acid, an inhibitor of scavenger receptor activity, reduced the rate of uptake of the negatively charged liposomes twofold, indicating the involvement of this receptor in the elimination mechanism. These results are compatible with earlier in vitro studies on liposome uptake by isolated endothelial cells and Kupffer cells, which showed that in the absence of serum also endothelial cells in situ are able to take up massive amounts of negatively charged liposomes. The present results emphasize that the high in vitro endothelial cell uptake in the absence of serum from earlier observations was not an artifact induced by the cell isolation procedure. 相似文献