Chromosome-level organization of the regulatory genome in the Drosophila nervous system.

Previous studies have identified topologically associating domains (TADs) as basic units of genome organization. We present evidence of a previously unreported level of genome folding, where distant TAD pairs, megabases apart, interact to form meta-domains. Within meta-domains, gene promoters and structural intergenic elements present in distant TADs are specifically paired. The associated genes encode neuronal determinants, including those engaged in axonal guidance and adhesion. These long-range associations occur in a large fraction of neurons but support transcription in only a subset of neurons. Meta-domains are formed by diverse transcription factors that are able to pair over long and flexible distances. We present evidence that two such factors, GAF and CTCF, play direct roles in this process. The relative simplicity of higher-order meta-domain interactions in Drosophila, compared with those previously described in mammals, allowed the demonstration that genomes can fold into highly specialized cell-type-specific scaffolds that enable megabase-scale regulatory associations.

Binding modes of potential anti-prion phytochemicals to PrPC structures in silico.

BACKGROUND: Prion diseases involve the conversion of a normal, cell-surface glycoprotein (PrPC) into a misfolded pathogenic form (PrPSc). One possible strategy to inhibit PrPSc formation is to stabilize the native conformation of PrPC and interfere with the conversion of PrPC to PrPSc. Many compounds have been shown to inhibit the conversion process, however, no promising drugs have been identified to cure prion diseases. OBJECTIVE: This study aims to identify potential anti-prion compounds from plant phytochemicals by integrating traditional ethnobotanical knowledge with modern in silico drug design approaches. MATERIALS AND METHODS: In the current study medicinal phytochemicals were docked with swapped and non-swapped crystal structures of PrPCin silico to identify potential anti-prions to determine their binding modes and interactions. RESULTS: Eleven new phytochemicals were identified based on their binding energies and pharmacokinetic properties. The binding sites and interactions of the known and new anti-prion compounds are similar, and differences in binding modes occur in structures with very subtle differences in side chain conformations. Binding of these compounds poses steric hindrance to neighbouring molecules. Residues shown to be associated with the inhibition of PrPC to PrPSc conversion form interactions with most of the compounds. CONCLUSION: Identified compounds might act as potent inhibitors of PrPC to PrPSc conversion. These might be attractive candidates for the development of novel anti-prion therapy although further tests in vitro cell cultures and in vivo mouse models are needed to confirm these findings.