Gastropod mollusks have been used for over 2500 years to produce the "Tyrian purple" dye made famous by the Phoenicians. This dye is constituted of mixed bromine-substituted indigo and indirubin isomers. Among these, the new natural product 6-bromoindirubin and its synthetic, cell-permeable derivative, 6-bromoindirubin-3'-oxime (BIO), display remarkable selective inhibition of glycogen synthase kinase-3 (GSK-3). Cocrystal structure of GSK-3beta/BIO and CDK5/p25/indirubin-3'-oxime were resolved, providing a detailed view of indirubins' interactions within the ATP binding pocket of these kinases. BIO but not 1-methyl-BIO, its kinase inactive analog, also inhibited the phosphorylation on Tyr276/216, a GSK-3alpha/beta activation site. BIO but not 1-methyl-BIO reduced beta-catenin phosphorylation on a GSK-3-specific site in cellular models. BIO but not 1-methyl-BIO closely mimicked Wnt signaling in Xenopus embryos. 6-bromoindirubins thus provide a new scaffold for the development of selective and potent pharmacological inhibitors of GSK-3.

Glycogen synthase kinase 3b (GSK3b) is a serine/ threonine kinase involved in insulin, growth factor and Wnt signalling. In Wnt signalling, GSK3b is recruited to a multiprotein complex via interaction with axin, where it hyperphosphorylates b-catenin, marking it for ubiquitylation and destruction. We have now determined the crystal structure of GSK3b in complex with a minimal GSK3b-binding segment of axin, at 2.4 A Ê resolution. The structure con®rms the co-localization of the binding sites for axin and FRAT in the C-terminal domain of GSK3b, but reveals signi®cant differences in the interactions made by axin and FRAT, mediated by conformational plasticity of the 285±299 loop in GSK3b. Detailed comparison of the axin and FRAT GSK3b complexes allows the generation of highly speci®c mutations, which abrogate binding of one or the other. Quantitative analysis suggests that the interaction of GSK3b with the axin scaffold enhances phosphorylation of b-catenin by >20 000-fold.

For thousands of years the Eurasian steppes have been a centre of human migrations and cultural change. Here we sequence the genomes of 137 ancient humans (about 1× average coverage), covering a period of 4,000 years, to understand the population history of the Eurasian steppes after the Bronze Age migrations. We find that the genetics of the Scythian groups that dominated the Eurasian steppes throughout the Iron Age were highly structured, with diverse origins comprising Late Bronze Age herders, European farmers and southern Siberian hunter-gatherers. Later, Scythians admixed with the eastern steppe nomads who formed the Xiongnu confederations, and moved westward in about the second or third century BC, forming the Hun traditions in the fourth-fifth century AD, and carrying with them plague that was basal to the Justinian plague. These nomads were further admixed with East Asian groups during several short-term khanates in the Medieval period. These historical events transformed the Eurasian steppes from being inhabited by Indo-European speakers of largely West Eurasian ancestry to the mostly Turkic-speaking groups of the present day, who are primarily of East Asian ancestry.

Glycogen synthase kinase 3 beta (GSK3 beta) plays a key role in insulin and Wnt signaling, phosphorylating downstream targets by default, and becoming inhibited following the extracellular signaling event. The crystal structure of human GSK3 beta shows a catalytically active conformation in the absence of activation-segment phosphorylation, with the sulphonate of a buffer molecule bridging the activation-segment and N-terminal domain in the same way as the phosphate group of the activation-segment phospho-Ser/Thr in other kinases. The location of this oxyanion binding site in the substrate binding cleft indicates direct coupling of P+4 phosphate-primed substrate binding and catalytic activation, explains the ability of GSK3 beta to processively hyperphosphorylate substrates with Ser/Thr pentad-repeats, and suggests a mechanism for autoinhibition in which the phosphorylated N terminus binds as a competitive pseudosubstrate with phospho-Ser 9 occupying the P+4 site.

Validated measures are needed for assessing resilience in conflict settings. An Arabic version of the Child and Youth Resilience Measure (CYRM) was developed and tested in Jordan. Following qualitative work, surveys were implemented with male/female, refugee/nonrefugee samples (N = 603, 11–18 years). Confirmatory factor analyses tested three‐factor structures for 28‐ and 12‐item CYRMs and measurement equivalence across groups. CYRM‐12 showed measurement reliability and face, content, construct (comparative fit index = .92–.98), and convergent validity. Gender‐differentiated item loadings reflected resource access and social responsibilities. Resilience scores were inversely associated with mental health symptoms, and for Syrian refugees were unrelated to lifetime trauma exposure. In assessing individual, family, and community‐level dimensions of resilience, the CYRM is a useful measure for research and practice with refugee and host‐community youth.