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931.
Klingler O Matter H Schudok M Bajaj SP Czech J Lorenz M Nestler HP Schreuder H Wildgoose P 《Bioorganic & medicinal chemistry letters》2003,13(8):1463-1467
Selective inhibition of coagulation factor VIIa has recently gained attraction as interesting approach towards antithrombotic treatment. Using parallel synthesis supported by structure-based design and X-ray crystallography, we were able to identify a novel series of amidinophenylurea derivatives with remarkable affinity for factor VIIa. The most potent compound displays a K(i) value of 23 nM for factor VIIa. 相似文献
932.
Hubschwerlen C Specklin JL Baeschlin DK Borer Y Haefeli S Sigwalt C Schroeder S Locher HH 《Bioorganic & medicinal chemistry letters》2003,13(23):4229-4233
Oxazolidinone-quinolone hybrids, which combine the pharmacophores of a quinolone and an oxazolidinone, were synthesised and shown to be active against a variety of susceptible and resistant Gram-positive and Gram-negative bacteria. The nature of the spacer greatly influences the antibacterial activity by directing the mode of action, that is quinolone- and/or oxazolidinone-like activity. The best compounds in this series have a balanced dual mode of action and overcome all types of resistance, including resistance to quinolones and linezolid, in clinically relevant Gram-positive pathogens. 相似文献
933.
Schirrmacher E Schirrmacher R Thews O Dillenburg W Helisch A Wessler I Buhl R Höhnemann S Buchholz HG Bartenstein P Machulla HJ Rösch F 《Bioorganic & medicinal chemistry letters》2003,13(16):2687-2692
The (18)F-labeled beta2-adrenergic receptor ligand (R,R)(S,S) 5-(2-(2-[4-(2-[(18)F]fluoroethoxy)phenyl]-1-methylethylamino)-1-hydroxyethyl)-benzene-1,3-diol, a derivative of the original highly selective racemic fenoterol, was synthesized in an overall radiochemical yield of 20% after 65 min with a radiochemical purity higher than 98%. The specific activity was in the range of 50-60 GBq/micromol. In vitro testing of the non-radioactive fluorinated fenoterol derivative with isolated guinea pig trachea was conducted to obtain an IC(50) value of 60 nM. Preliminary ex vivo organ distribution and in vivo experiments with positron emission tomography (PET) on guinea pigs were performed to study the biodistribution as well as the displacement of the radiotracer to prove specific binding to the beta2-receptor. 相似文献
934.
Luther Hans Peter Podlowski Svenia Schulze Wolfgang Morwinski Rosemarie Buchwalow Igor Baumann Gert Luther Hans Peter 《Molecular and cellular biochemistry》2001,224(1-2):69-79
Three 1AR subtypes have been cloned so far and are designated as 1a, 1b, and 1d. Organspecific distribution pattern and subtype-specific effects are known but not fully understood. To address a cell-type specific expression pattern in the heart we investigated expression pattern of 1AR subtypes on RNA and proteinlevel in heart tissue, cultured cardiomyocytes and nonmyocytes of the rat. Each 1ARsubtype mRNA was present in neonatal and adult rat heart culture but the relative distribution pattern was significantly different. While the 1aAR subtype is preferentially expressed in adult cardiomyocytes, the 1bAR subtype was preferentially expressed in the nonmyocyte cell fraction. The RTPCR results were confirmed by Westernblotting (1b) and immunocytochemical studies. Incubation with an 1agonist (phenylephrine) for 72 h led to a significant reduction of the 1bAR in neonatal heart cell culture on both mRNA and protein level. In contrast, incubation with an 1antagonist (prazosin) induced a 1.6 fold upregulation of the 1aAR mRNA without significant effects on radioligand binding and functional assay. The results indicate a distribution pattern of the 1AR subtype which is specific for cell type and ontogeny of the rat heart and may be regulated by adrenergic agents. 相似文献
935.
Distinct apoptotic phenotypes induced by radiation and ceramide in both p53-wild-type and p53-mutated lymphoblastoid cells 总被引:1,自引:0,他引:1
Shi YQ Wuergler FE Blattmann H Crompton NE 《Radiation and environmental biophysics》2001,40(4):301-308
The tumour suppressor gene p53 and the intracellular signalling molecule ceramide have both been shown to play crucial roles
in the induction of apoptosis by ionising radiation. In this study we examined whether p53 and ceramide are involved in independent
signal pathways, inducing different types of apoptosis. TK6 (p53wt/wt) and WTK1 (p53mut/mut) lymphoblastoid cells were treated with ionising radiation or N-acetyl-d-sphingosine (C2-ceramide). Flow cytometry and fluorescence microscopy studies were performed to characterise the time kinetics and morphological
features of induced apoptosis. Ceramide- and radiation-induced apoptotic cells display characteristic differences in morphology
and DNA staining and ceramide-induced apoptosis is expressed much faster than radiation-induced apoptosis. Radiation-induced
apoptosis is p53-dependent and ceramide-induced apoptosis is p53-independent. The p53 pathway and the ceramide pathway are
two independent signal pathways leading to distinct types of apoptosis. Since p53 is very often dysfunctional in tumour cells,
modifying the ceramide pathway is a promising strategy to increase tumour sensitivity to radiation and other anticancer agents.
Received: 19 April 2001 / Accepted: 15 October 2001 相似文献
936.
Bischof MG Bernroider E Ludwig C Kurzemann S Kletter K Waldhäusl W Roden M 《Hormone research》2001,56(5-6):151-158
OBJECTIVES: The aim of this study was to examine hormonal counterregulation during insulin-induced hypoglycemia in type-1 diabetic patients during long-term near normoglycemic insulin therapy and intensive clinical care. METHODS: Type-1 diabetic patients (age 35.3 +/- 2 years, body mass index 22.8 +/- 1 kg x m(-2), mean diabetes duration 13.6 (11-17 years), mean HbA1c during the last year 6.6 +/- 0.1%) and nondiabetic subjects were studied during (0-120 min) and after (120-240 min) hypoglycemic (3.05 mmol/l) hyperinsulinemic (approximately 330 pmol/l) clamp tests. RESULTS: During hypoglycemia peak plasma concentrations of glucagon (199 +/- 16 vs. 155 +/- 11 ng/l, p < 0.05), epinephrine (4,514 +/- 644 vs. 1,676 +/- 513 pmol/l, p < 0.001), norepinephrine (2.21 +/- 0.14 vs. 1.35 +/- 0.19 nmol/l, p < 0.01) and cortisol (532 +/- 44 vs. 334 +/- 61 nmol/l) were reduced in the diabetic patients. Plasma lactate did not change from baseline values (0.51 +/- 0.06 mmol/l) in diabetic but doubled in healthy subjects (1.13 +/- 0.111 mmol/l, p < 0.001 vs. control). During the posthypoglycemic recovery period plasma concentrations of free fatty acids were higher in diabetic patients at 240 min (1.34 +/- 0.12 vs. 2.01 +/- 0.23 mmol/l, p < 0.05). CONCLUSION: Despite long-term near physiologic insulin substitution and the low incidence of hypoglycemia, hormonal hypoglycemia counterregulation was impaired in type-1 diabetic patients after a diabetes duration of more than 10 years. 相似文献
937.
A primer set was designed for the specific detection of methanotrophic bacteria in forest soils by PCR. The primer sequences
were derived from highly conservative regions of the pmoA gene, encoding the α-subunit of the particulate methane monooxygenase present in all methanotrophs. In control experiments
with genomic DNA from a collection of different type I, II, and X methanotrophs, it could be demonstrated that the new primers
were specific for members of the genera Methylosinus, Methylocystis, Methylomonas, Methylobacter, and Methylococcus. To test the suitability of the new primers for the detection of particulate methane monooxygenase (pMMO) containing methanotrophs
in environmental samples we used DNA extracts from an acid spruce forest soil. For simple and rapid purification of the DNA
extracts, the samples were separated by electrophoresis on a low-melting-point agarose gel. This allowed us to efficiently
separate the DNA from coextracted humic acids. The DNA from the melted agarose gel was ready for use in PCR reactions. In
PCR reactions with DNA from the Ah soil layer, products of the correct size were amplified by PCR by use of the new primers.
By sequencing of cloned PCR products, it could be confirmed that the PCR products represented partial sequences with strong
similarity to the pmoA gene. The sequence was most related to the pmoA sequence of a type II methanotroph strain isolated from the Ah layer of the investigated soils.
Received: 1 September 2000 / Accepted: 2 October 2000 相似文献
938.
Glycoproteins, as a class of biomolecules, exhibit much more heterogeneous structures than non-glycosylated proteins. They present a challenging area of research. Model glycoproteins with well-defined protein and carbohydrate structures are helpful in the search for high-resolution methods for the separation of glycoproteins. Neoglycoproteins, maltose-modified chymotrypsin and lactose-modified chymotrypsin, were synthesised by modifying chymotrypsin with maltose and lactose, respectively, using the reductive amination method. Boronate chromatography was applied to isolate the neoglycoproteins from non-glycosylated substances. The use of Tris–HCl as a shielding reagent during the boronate chromatography proved to be efficient in eliminating unwanted interactions between the boronate ligand and the peptide backbone of chymotrypsin. The retention time of neoglycoproteins on the boronate column was increased with increasing the degree of modification. 相似文献
939.
In this technical note we describe the setup and application of automated sample preparation and usage of flow-through NMR equipment for the characterization of ligand binding on proteins. In addition, we focus on the perspectives of automated analysis of 2D HSQC spectra to identify changes in patterns indicative for ligand binding or changes of sample conditions. In this context we discuss a combination of statistical and non-statistical data analysis. 相似文献
940.
Phenology in central Europe – differences and trends of spring phenophases in urban and rural areas 总被引:5,自引:0,他引:5
Roetzer T Wittenzeller M Haeckel H Nekovar J 《International journal of biometeorology》2000,44(2):60-66
In order to examine the impacts of both large-scale and small-scale climate changes (urban climate effect) on the development
of plants, long-term observations of four spring phenophases from ten central European regions (Hamburg, Berlin, Cologne,
Frankfurt, Munich, Prague, Vienna, Zurich, Basle and Chur) were analysed. The objective of this study was to identify and
compare the differences in the starting dates of the pre-spring phenophases, the beginning of flowering of the snowdrop (Galanthus nivalis) and forsythia (Forsythia sp.), and of the full-spring phenophases, the beginning of flowering of the sweet cherry (Prunus avium) and apple (Malus domestica), in urban and rural areas. The results indicate that, despite regional differences, in nearly all cases the species studied
flower earlier in urbanised areas than in the corresponding rural areas. The forcing in urban areas was about 4 days for the
pre-spring phenophases and about 2 days for the full-spring phenophases. The analysis of trends for the period from 1951 to
1995 showed tendencies towards an earlier flowering in all regions, but only 22% were significant at the 5% level. The trends
for the period from 1980 to 1995 were much stronger for all regions and phases: the pre-spring phenophases on average became
earlier by 13.9 days/decade in the urban areas and 15.3 days/decade in the rural areas, while the full-spring phenophases
were 6.7 days earlier/decade in the urban areas and 9.1 days/decade earlier in the rural areas. Thus rural areas showed a
higher trend towards an earlier flowering than did urban areas for the period from 1980 to 1995. However, these trends, especially
for the pre-spring phenophases, turned out to be extremely variable.
Received: 21 October 1999 / Revised: 5 April 2000 / Accepted: 25 April 2000 相似文献