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991.
Orain D Ofner S Koller M Carcache DA Froestl W Allgeier H Rasetti V Nozulak J Mattes H Soldermann N Floersheim P Desrayaud S Kallen J Lingenhoehl K Urwyler S 《Bioorganic & medicinal chemistry letters》2012,22(2):996-999
A new set of quinazolinedione sulfonamide derivatives as competitive AMPA receptor antagonist with improved properties compared to 1 is disclosed. By modulating physico-chemical properties, compound 29 was identified with a low ED(50) of 5.5mg/kg in an animal model of anticonvulsant activity after oral dosage. 相似文献
992.
Martínez González S Hernández AI Varela C Rodríguez-Arístegui S Lorenzo M Rodríguez A Rivero V Martín JI Saluste CG Ramos-Lima F Cendón E Cebrián D Aguirre E Gomez-Casero E Albarrán M Alfonso P García-Serelde B Oyarzabal J Rabal O Mulero F Gonzalez-Granda T Link W Fominaya J Barbacid M Bischoff JR Pizcueta P Pastor J 《Bioorganic & medicinal chemistry letters》2012,22(10):3460-3466
Phosphoinositide-3-kinase (PI3K) is an important target for cancer therapeutics due to the deregulation of this signaling pathway in a wide variety of human cancers. Herein, we describe the optimization of imidazo [1,2-a] pyrazines, which allow us to identify compound 14 (ETP-46321), with potent biochemical and cellular activity and good pharmacokinetic properties (PK) after oral dosing. ETP-46321 PK/PD studies showed time dependent downregulation of AKT(Ser473) phosphorylation, which correlates with compound levels in tumor tissue and demonstrating to be efficacious in a GEMM mouse tumor model driven by a K-Ras(G12V) oncogenic mutation. Treatment with ETP-46321 resulted in significant tumor growth inhibition. 相似文献
993.
S Martínez González AI Hernández C Varela M Lorenzo F Ramos-Lima E Cendón D Cebrián E Aguirre E Gomez-Casero MI Albarrán P Alfonso B García-Serelde G Mateos J Oyarzabal O Rabal F Mulero T Gonzalez-Granda W Link J Fominaya M Barbacid JR Bischoff P Pizcueta C Blanco-Aparicio J Pastor 《Bioorganic & medicinal chemistry letters》2012,22(16):5208-5214
Phosphoinositide-3-kinases (PI3K) are a family of lipid kinases mediating numerous cell processes such as proliferation, migration and differentiation. PI3K is an important target for cancer therapeutics due to the deregulation of this signaling pathway in a wide variety of human cancers. Herein, we describe the rapid identification of ETP-46992, within 2-aminocarbonyl imidazo [1,2-a] pyrazine series, with suitable pharmacokinetic (PK) properties that allows the establishment of mechanism of action and efficacy in vivo studies. ETP-46992 showed tumor growth inhibition in a GEMM mouse tumor model driven by a K-Ras(G12V) oncogenic mutation and in tumor xenograft models with PI3K pathway deregulated (BT474). 相似文献
994.
Multitrophic effects of experimental changes in plant diversity on cavity-nesting bees, wasps, and their parasitoids 总被引:1,自引:0,他引:1
Plant diversity changes can impact the abundance, diversity, and functioning of species at higher trophic levels. We used an experimental gradient in grassland plant diversity ranging from 1 to 16 plant species to study multitrophic interactions among plants, cavity-nesting bees and wasps, and their natural enemies, and analysed brood cell density, insect diversity (species richness), and bee and wasp community similarity over two consecutive years. The bee and wasp communities were more similar among the high (16 species) diversity plots than among plots of the lower diversity levels (up to 8 species), and a more similar community of bees and wasps resulted in a more similar community of their parasitoids. Plant diversity, which was closely related to flower diversity, positively and indirectly affected bee diversity and the diversity of their parasitoids via increasing brood cell density of bees. Increasing plant diversity directly led to higher wasp diversity. Parasitism rates of bees and wasps (hosts) were not affected by plant diversity, but increased with the diversity of their respective parasitoids. Decreases in parasitism rates of bees arose from increasing brood cell density of bees (hosts), whereas decreasing parasitism rates of wasps arose from increasing wasp diversity (hosts). In conclusion, decreases in plant diversity propagated through different trophic levels: from plants to insect hosts to their parasitoids, decreasing density and diversity. The positive relationship between plant diversity and the community similarity of higher trophic levels indicates a community-stabilising effect of high plant diversity. 相似文献
995.
Jochen Krüger Wolfgang W. Gettmann 《Der Zoologische Garten (in deutscher Sprache / in German)》2012,81(5-6):275-296
The oral examination of a five and half years old Asian Small-Clawed Otter (Aonyx cinerea) showed the accumulation of tartar and two complicated tooth fractures. The tartar has been removed with an ultrasonic device. The fractured molar of the mandibula has been extracted and the damaged canine tooth of the maxilla has been treated by an endodontic procedure. Half a year later the x-ray control of the canine tooth indicated a stop of the periapical reactions. 相似文献
996.
Thomas Dejaco Wolfgang Arthofer H. David Sheets Florian M. Steiner 《Zoologischer Anzeiger》2012,251(4):307-316
Accurate species delimitation is fundamental for many fields of biology. Although a wide range of evolutionary-biological patterns are known to promote failure in species delimitation when any single information source is considered, the majority of species characterisations are still based on single disciplines. Using Alpine jumping bristletails we here showcase the establishment of morphological and molecular tools for multi-source species delimitation in a taxonomically problematic arthropod group and stress its advantages over single-discipline approaches. Once sound species delimitations have been achieved, Alpine jumping bristletails will be available as a prime model system for addressing questions related to the emergence of endemism and parthenogenesis. 相似文献
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Heterozygosity-fitness correlations in zebra finches: microsatellite markers can be better than their reputation 总被引:1,自引:0,他引:1
Forstmeier W Schielzeth H Mueller JC Ellegren H Kempenaers B 《Molecular ecology》2012,21(13):3237-3249
Numerous studies have reported associations between heterozygosity in microsatellite markers and fitness-related traits (heterozygosity-fitness correlations, HFCs). However, it has often been questioned whether HFCs reflect general inbreeding depression, because a small panel of microsatellite markers does not reflect very well an individual's inbreeding coefficient (F) as calculated from a pedigree. Here, we challenge this prevailing view. Because of chance events during Mendelian segregation, an individual's realized proportion of the genome that is identical by descent (IBD) may substantially deviate from the pedigree-based expectation (i.e. F). This Mendelian noise may result in a weak correlation between F and multi-locus heterozygosity, but this does not imply that multi-locus heterozygosity is a bad estimator of realized IBD. We examined correlations between 11 fitness-related traits measured in up to 1192 captive zebra finches and three measures of inbreeding: (i) heterozygosity across 11 microsatellite markers, (ii) heterozygosity across 1359 single-nucleotide polymorphism (SNP) markers and (iii) F, based on a 5th-generation pedigree. All 11 phenotypic traits showed positive relationships with measures of heterozygosity, especially traits that are most closely related to fitness. Remarkably, the small panel of microsatellite markers produced equally strong HFCs as the large panel of SNP markers. Both marker-based approaches produced stronger correlations with phenotypes than the pedigree-based F, and this did not seem to result from the shortness of our pedigree. We argue that a small panel of microsatellites with high allelic richness may better reflect an individual's realized IBD than previously appreciated, especially in species like the zebra finch, where much of the genome is inherited in large blocks that rarely experience cross-over during meiosis. 相似文献