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.

BackgroundStrengthening the evidence base for humanitarian interventions that provide psychosocial support to war‐affected youth is a key priority. We tested the impacts of an 8‐week programme of structured activities informed by a profound stress attunement (PSA) framework (Advancing Adolescents), delivered in group‐format to 12–18 year‐olds in communities heavily affected by the Syrian crisis. We included both Syrian refugee and Jordanian youth.MethodsWe followed an experimental design, comparing treatment youth and wait‐list controls over two programme implementation cycles, randomizing to study arm in cycle 2 (ClinicalTrials.gov ID: NCT03012451). We measured insecurity, distress, mental health difficulties, prosocial behaviour and post‐traumatic stress symptoms at three time‐points: baseline (n = 817 youth; 55% Syrian, 43% female), postintervention (n = 463; 54% Syrian, 47% female), and follow‐up (n = 212, 58% Syrian, 43% female). Regression models assessed: prospective intervention impacts, adjusting for baseline scores, trauma exposure, age, and gender; differential impacts across levels of trauma exposure and activity‐based modality; and sustained recovery 1 year later. We analysed cycle‐specific and cycle‐pooled data for youth exclusively engaged in Advancing Adolescents and for the intent‐to‐treat sample.ResultsWe found medium to small effect sizes for all psychosocial outcomes, namely Human Insecurity (β = −7.04 (95% CI: −10.90, −3.17), Cohen's d = −0.4), Human Distress (β = −5.78 (−9.02, −2.54), d = −0.3), and Perceived Stress (β = −1.92 (−3.05, −0.79), d = −0.3); and two secondary mental health outcomes (AYMH: β = −3.35 (−4.68, −2.02), d = −0.4; SDQ: β = −1.46 (−2.42, −0.50), d = −0.2). We found no programme impacts for prosocial behaviour or post‐traumatic stress reactions. Beneficial impacts were stronger for youth with exposure to four trauma events or more. While symptoms alleviated for both intervention and control groups over time, there were sustained effects of the intervention on Human Insecurity.ConclusionsFindings strengthen the evidence base for mental health and psychosocial programming for a generation affected by conflict and forced displacement. We discuss implications for programme implementation and evaluation research.

Glycogen synthase kinase-3 (GSK-3) is a key component of several signaling pathways including those regulated by Wnt and insulin ligands. Specificity in GSK-3 signaling is thought to involve interactions with scaffold proteins that localize GSK-3 regulators and substrates. This report shows that GSK-3 forms a low affinity homodimer that is disrupted by binding to Axin and Frat. Based on the crystal structure of GSK-3, we have used surface-scanning mutagenesis to identify residues that differentially affect GSK-3 interactions. Mutations that disrupt Frat and Axin cluster at the dimer interface explaining their effect on homodimer formation. Loss of the Axin binding site blocks the ability of dominant negative GSK-3 to cause axis duplication in Xenopus embryos. The Axin binding site is conserved within all GSK-3 proteins, and its loss affects both cell motility and gene expression in the nonmetazoan, Dictyostelium. Surprisingly, we find no genetic interaction between a nonAxin-binding GSK-3 mutant and T-cell factor activity, arguing that Axin interactions alone cannot explain the regulation of T-cell factor-mediated gene expression.

Submucosal glands are abundant ‫ف(‬ 1 gland/mm 2 ) secretory structures in the tracheobronchial airways of the human lung. Because submucosal glands express antibacterial proteins, it has been proposed that they contribute to lung defense. However, this concept is challenged by the fact that mice do not have submucosal glands in their bronchial airways, yet are quite resistant to bacterial lung infection. The contribution of airway submucosal glands to host defense is also debated as a pathophysiologic component of cystic fibrosis lung disease. Here, we asked whether submucosal glands protect airways against bacterial infection. By comparing tracheal xenograft airways with and without glands, we found that the presence of glands enhanced bacterial killing in vivo and by airway secretions in vitro. Moreover, immunodepletion studies suggested that lysozyme is a major antibacterial component secreted by submucosal glands. These studies provide evidence that submucosal glands are a major source of antibacterials critical for maintaining sterile airways.