Suppressed recombination rate in 6VS/6AL translocation region carrying the Pm21 locus introgressed from Haynaldia villosa into hexaploid wheat

Pm21 is an effective gene for powdery mildew resistance transferred from Haynaldia villosa into common wheat cultivars. No virulence against this gene has been detected so far. A set of 42 powdery mildew isolates collected in Israel and tested in the current study also revealed no virulence against this gene. Pm21 was previously reported to be located on the short arm of 6VS/6AL translocation chromosome. We constructed a high-density genetic map of chromosome 6A, consisting of 28 PCR markers and the Pm21 gene. A comparison with previously published genetic maps of wheat chromosome 6A revealed that the recombination rate in the 6VS/6AL translocation region was poor. We assume that suppressed recombination caused by the alien H. villosa genetic material is the most reasonable explanation for the tight genetic linkage and the inadequacy between the Pm21 genetic map and the Pm21 physical map of 6A. A large number of sequence-tag sites (STS) and simple sequence repeat markers, which co-segregate with or are closely linked to the Pm21 gene, and the conversion of three resistance gene analog markers into new STS markers, provide a reliable and easy-to-use molecular tool for marker-assisted selection of Pm21 in wheat breeding programs. An additional gene, Pm31, previously reported to be derived from Triticum dicoccoides, was mapped into a similar genomic location to Pm21. Screening of the parental lines and the mapping population with Pm21 diagnostic markers clearly confirmed that the donor line of Pm31 is H. villosa and not T. dicoccoides. Therefore, we conclude that Pm21 and Pm31 refer to the same gene, derived from H. villosa, and that the designation of Pm31 as a new Pm gene was erroneous.     

Networks of neuronal genes affected by common and rare variants in autism spectrum disorders

Autism spectrum disorders (ASD) are neurodevelopmental disorders with phenotypic and genetic heterogeneity. Recent studies have reported rare and de novo mutations in ASD, but the allelic architecture of ASD remains unclear. To assess the role of common and rare variations in ASD, we constructed a gene co-expression network based on a widespread survey of gene expression in the human brain. We identified modules associated with specific cell types and processes. By integrating known rare mutations and the results of an ASD genome-wide association study (GWAS), we identified two neuronal modules that are perturbed by both rare and common variations. These modules contain highly connected genes that are involved in synaptic and neuronal plasticity and that are expressed in areas associated with learning and memory and sensory perception. The enrichment of common risk variants was replicated in two additional samples which include both simplex and multiplex families. An analysis of the combined contribution of common variants in the neuronal modules revealed a polygenic component to the risk of ASD. The results of this study point toward contribution of minor and major perturbations in the two sub-networks of neuronal genes to ASD risk.     

Novel racemosin B derivatives as new therapeutic agents for aggressive breast cancer

Carbazole derivatives show anti-cancer activity and are of great interest for drug development. In this study, we synthesized and analyzed several new alkylamide derivatives of racemocin B, a natural indolo[3,2-a]carbazole molecule originally isolated from the green alga Caulerpa racemose. Several alkylamide derivatives were found to exhibit moderate to strong growth inhibition against human breast cancer cell lines. They induced G2/M cell cycle arrest and apoptosis in the aggressive triple-negative breast cancer cell line MDA-MB-231. Among these derivatives, compound 25 with the lowest IC₅₀ induced cell death by suppressing autophagy. This was accompanied by inhibition of autophagic flux and accumulation of autophagy protein 1 light chain 3, LC3II, and p62. The novel alkylamide derivative offers a potential new treatment for human breast cancer.     

Self-segregation of myelin membrane lipids in model membranes

Rapid conduction of nerve impulses requires coating of axons by myelin sheaths, which are multilamellar, lipid-rich membranes produced by oligodendrocytes in the central nervous system. To act as an insulator, myelin has to form a stable and firm membrane structure. In this study, we have analyzed the biophysical properties of myelin membranes prepared from wild-type mice and from mouse mutants that are unable to form stable myelin. Using C-Laurdan and fluorescence correlation spectroscopy, we find that lipids are tightly organized and highly ordered in myelin isolated from wild-type mice, but not from shiverer and ceramide synthase 2 null mice. Furthermore, only myelin lipids from wild-type mice laterally segregate into physically distinct lipid phases in giant unilamellar vesicles in a process that requires very long chain glycosphingolipids. Taken together, our findings suggest that oligodendrocytes exploit the potential of lipids to self-segregate to generate a highly ordered membrane for electrical insulation of axons.