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981.
Andreas Lerchner Rainer Machauer Claudia Betschart Siem Veenstra Heinrich Rueeger Clive McCarthy Marina Tintelnot-Blomley Anne-Lise Jaton Sabine Rabe Sandrine Desrayaud Albert Enz Matthias Staufenbiel Paolo Paganetti Jean-Michel Rondeau Ulf Neumann 《Bioorganic & medicinal chemistry letters》2010,20(2):603-607
A series of macrocyclic peptidic BACE-1 inhibitors was designed. While potency on BACE-1 was rather high, the first set of compounds showed poor brain permeation and high efflux in the MDRI–MDCK assay. The replacement of the secondary benzylamino group with a phenylcyclopropylamino group maintained potency on BACE-1, while P-glycoprotein-mediated efflux was significantly reduced and brain permeation improved. Several compounds from this series demonstrated acute reduction of Aβ in human APP-wildtype transgenic (APP51/16) mice after oral administration. 相似文献
982.
Rémy C. Lemoine Ann C. Petersen Lina Setti Jutta Wanner Andreas Jekle Gabrielle Heilek André deRosier Changhua Ji Pamela Berry David Rotstein 《Bioorganic & medicinal chemistry letters》2010,20(2):704-708
Replacement of a secondary amide with an N-acyl or N-sulfonyl gem-disubstituted azacyle in a series of CCR5 antagonists led to the identification of compounds with excellent in vitro HIV antiviral activity and increased intrinsic membrane permeability. 相似文献
983.
984.
Marcus Lettau Jennifer Pieper Alyn Gerneth Beate Lengl‐Janßen Matthias Voss Andreas Linkermann Hendrik Schmidt Christoph Gelhaus Matthias Leippe Dieter Kabelitz Ottmar Janssen 《Protein science : a publication of the Protein Society》2010,19(4):658-669
Nck is a ubiquitously expressed, primarily cytosolic adapter protein consisting of one SH2 domain and three SH3 domains. It links receptor and nonreceptor tyrosine kinases to actin cytoskeleton reorganizing proteins. In T lymphocytes, Nck is a crucial component of signaling pathways for T cell activation and effector function. It recruits actin remodeling proteins to T cell receptor (TCR)‐associated activation clusters and thereby initiates changes in cell polarity and morphology. Moreover, Nck is crucial for the TCR‐induced mobilization of secretory vesicles to the cytotoxic immunological synapse. To identify the interactome of Nck in human T cells, we performed a systematic screen for interaction partners in untreated or pervanadate‐treated cells. We used GST fusion proteins containing full length Nck, the combined SH3 domains or the individual SH3 and SH2 domains to precipitate putative Nck interactors from cellular lysates. Protein bands were excised from gels, processed by tryptic in‐gel digestion and analyzed by mass spectrometry. Using this approach, we confirmed previously established interactions (e.g., with Slp76, CD3ε, WASP, and WIPF1) and identified several novel putative Nck‐binding proteins. We subsequently verified the SH2 domain binding to the actin‐binding protein HIP55 and to FYB/ADAP, and the SH3‐mediated binding to the nuclear proteins SFPQ/NONO. Using laser scanning microscopy, we provide new evidence for a nuclear localization of Nck in human T cells. Our data highlight the fundamental role of Nck in the TCR‐to‐cytoskeleton crosstalk and point to yet unknown nuclear functions of Nck also in T lymphocytes. 相似文献
985.
986.
987.
988.
Tomasz Borowski Valentin Georgiev Per E. M. Siegbahn 《Journal of molecular modeling》2010,16(11):1673-1677
Catalytic cycle intermediates of a representative extradiol dioxygenase, homoprotocatechuate 2,3-dioxygenase (HPCD), have
recently been characterized in crystallo by Kovaleva and Lipscomb. The structures of the identified species indicate that
the process of inserting oxygen into the catechol ring occurs stepwise, and involves an Fe(II)-alkylperoxo intermediate and
its O–O cleavage product: a gem diol species. In general, these findings corroborate the results of our previous computational
studies; however, the fact that the gem diol species is stable enough to be observed in the crystal form seems to be at odds
with the computational mechanistic data, which suggest that this intermediate should very readily and spontaneously convert
to the epoxide species. The key question then becomes what is actually observed in the X-ray experiments. Here we report additional
computational studies undertaken with the hope of clarifying this issue. The results obtained for active site models hosting
both the native and the alternative (4-sulfonylcatechol) substrate indicate that the stability of the gem diol species is
substantially increased if an electron and a proton are added. If this occurs somehow, the lifetime of the intermediate should
be sufficient to observe it. 相似文献
989.
Andreas Zahn Sabine Bauer Eva Kriner Jennifer Holzhaider 《European Journal of Wildlife Research》2010,56(3):395-400
We radio-tracked Myotis emarginatus in Upper Bavaria, Germany to identify the key-foraging habitats and to enable an adequate habitat management for this endangered species. The studied females foraged at a distance of up to 8.1 km around their colony roost. The average distance of the foraging area was 3.7 km, where 70% of foraging areas were located within a distance of 5 km and 90% within 6 km of the nurseries. Moreover, these bats spent about 75% of their foraging time within 5 km and 85% within a 6-km radius. To reach the foraging areas, the bats usually used riparian woodlands, hedges and tree lines as flight paths. Specifically, 46.9% of the foraging areas were located in forests, 24.5% in cow sheds, 18.4% in riparian woodlands along streams and 10.2% in fields, villages, orchards, hedges and groves on open land. On average, the bats foraged in forests for 56.2% of the time, during which habitat allocation was possible. In cow sheds the percentage was 29.2%, in riparian deciduous woodland 11.5% and in the other habitats 3.1%. Within forests M. emarginatus avoided foraging in spruce monocultures. Pure stands of spruce covered 45% of the total forest area, but only 10% of the foraging areas were located in this forest type. Deciduous forests on the other hand were much more common as foraging sites (40% versus 11%). Therefore, the availability of native deciduous forest and of fly-infested stables within a radius of 6 km around the colony roosts should be the focus of conservation concepts for M. emarginatus. 相似文献
990.
Alexandros A. Karamanlidis Elena Drosopoulou Miguel de Gabriel Hernando Lazaros Georgiadis Lambros Krambokoukis Stavri Pllaha Andreas Zedrosser Zacharias Scouras 《European Journal of Wildlife Research》2010,56(5):693-702
One difficulty in the conservation of endangered wildlife is the lack of reliable information on its status. This lack of
knowledge can often be attributed to financial and logistic constraints as well as the lack of trained personnel to collect
data. We test a simple method to study bears in the southern Balkans by inspecting power poles, which are used by bears for
marking and rubbing purposes. We created a network of barbed-wire fitted poles for the collection of hair samples, evenly
distributed throughout six study areas. During 87 sampling sessions in the main study area, we collected 191 samples and identified
six microsatellite loci that were variable enough for individual bear identification. The most and best-quality hair samples
were collected during the mating period, and DNA was most successfully extracted from samples remaining <4 weeks in the field.
In the six study areas, we identified 47 bears. An advantage of using power poles for hair sampling is their availability
and accessibility; no bait is required, and the network can be easily set up. A drawback may be an unequal capture probability
of sex and age classes of bears. Despite this limitation, using power poles proved to be a simple and cheap method for the
noninvasive genetic study of bears that did not require any prior knowledge on habitat use and activity patterns. The method
is suitable for large-scale surveys to estimate distribution and relative densities of bears and could also be applied for
studying other species. 相似文献