ABSTRACT
Phylogeographic patterns in large mammals result from natural environmental factors and anthropogenic effects, which in some cases include domestication. The grey wolf was once widely distributed across the Holarctic, but experienced phylogeographic shifts and demographic declines during the Holocene. In the 19th-20th centuries, the species became extirpated from large parts of Europe due to direct extermination and habitat loss. We reconstructed the evolutionary history of the extinct Western European wolves based on the mitogenomic composition of 78 samples from France (Neolithic-20th century) in the context of other populations of wolves and dogs worldwide. We found a close genetic similarity of French wolves from ancient, medieval and recent populations, which suggests the long-term continuity of maternal lineages. MtDNA haplotypes of the French wolves showed large diversity and fell into two main haplogroups of modern Holarctic wolves. Our worldwide phylogeographic analysis indicated that haplogroup W1, which includes wolves from Eurasia and North America, originated in Northern Siberia. Haplogroup W2, which includes only European wolves, originated in Europe ~35 kya and its frequency was reduced during the Holocene due to an expansion of haplogroup W1 from the east. Moreover, we found that dog haplogroup D, currently restricted to Europe and the Middle East, was nested within the wolf haplogroup W2. This suggests European origin of haplogroup D, probably as a result of an ancient introgression from European wolves. Our results highlight the dynamic evolutionary history of European wolves during the Holocene, with a partial lineage replacement and introgressive hybridization with local dog populations.
Subject(s)
Wolves , Dogs , Animals , Wolves/genetics , Phylogeny , Biological Evolution , Phylogeography , France , Haplotypes/genetics , DNA, Mitochondrial/geneticsABSTRACT
In an effort to identify new pharmacological inhibitors of disease-relevant protein kinases with increased potency and selectivity, we synthesized and evaluated new 5-substituted indirubins. The effects of 34 indirubin derivatives on CDK1/cyclin B, CDK5/p25, and GSK-3, as well as on SH-SY5Y human neuroblastoma cell survival, were investigated.
Subject(s)
CDC2-CDC28 Kinases/antagonists & inhibitors , Glycogen Synthase Kinase 3/antagonists & inhibitors , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Animals , Cell Line, Tumor , Cell Survival/drug effects , Humans , Indoles/chemical synthesis , Indoles/chemistry , Indoles/pharmacology , Molecular Structure , Molecular Weight , Protein Kinase Inhibitors/chemistry , Starfish , Stereoisomerism , Structure-Activity Relationship , SwineABSTRACT
The interest of microwaves in drug discovery and multi-step synthesis is exposed with the aim of describing our strategy. These studies are connected with our work on the synthesis of original heterocyclic compounds with potential pharmaceutical value. Reactions in the presence of solvent and solvent-free synthesis can be realised under a variety of conditions; for some of these selected results are given, and where available, results from comparison with the same solvent-free conditions but with classical heating are given.
