Discovery of a series of potent arylthiadiazole H(3) antagonists

A series of 2-piperidinopiperidine-5-arylthiadiazoles was synthesized and subjected to a structure-activity relationship (SAR) investigation. The potency of this series was improved to the single digit nanomolar range. The key analogs were shown to be free of P450 issues, and they also maintained good ex vivo activity and brain penetration.     

Influence of landscape structure on endemic cicadas in New Zealand kiwifruit orchards

• 1 The endemic cicada species Amphipsalta cingulata (Fabricius) and Amphipsalta zelandica (Boisduval) are pests of New Zealand kiwifruit.
• 2 We determined the abundance of A. cingulata and A. zelandica by counting final‐instar exuviae in a block of ‘Hayward’ kiwifruit, the dominant cultivar, on each of 70 blocks on separate orchards in the Bay of Plenty, New Zealand.
• 3 We used a geographic information system and fragstats to generate predictive variables describing landscape structure in four nested landscapes ranging in size between 6.25 and 400 ha for each site. Other variables described the physical characteristics of the site and management practices. Data were analyzed by boosted regression trees, a method that combines the advantages of regression trees and machine learning.
• 4 The most influential variables differed for each species. Modified coastal landscapes with high densities of ‘Hayward’ kiwifruit were most favourable for A. cingulata. For A. zelandica, favourable landscapes contained significant areas of native forest. The 12 most influential variables accounted for 51% and 46% of the total influence of all variables measured for A. cingulata and A. zelandica, respectively.
• 5 Landscape structure was more influential than insecticide use and local site factors. Despite the apparent low vagility of cicadas, landscape structure at relatively large scales of ≥25 ha was influential for both A. cingulata and A. zelandica. The ability to use a wide range of hosts within the production landscape may account for this pattern. Key variables need to be confirmed by identifying the same patterns in other landscapes.

     

Over‐expression of specific HvCslF cellulose synthase‐like genes in transgenic barley increases the levels of cell wall (1,3;1,4)‐β‐d‐glucans and alters their fine structure

Cell walls in commercially important cereals and grasses are characterized by the presence of (1,3;1,4)‐β‐d ‐glucans. These polysaccharides are beneficial constituents of human diets, where they can reduce the risk of hypercholesterolemia, type II diabetes, obesity and colorectal cancer. The biosynthesis of cell wall (1,3;1,4)‐β‐d ‐glucans in the Poaceae is mediated, in part at least, by the cellulose synthase‐like CslF family of genes. Over‐expression of the barley CslF6 gene under the control of an endosperm‐specific oat globulin promoter results in increases of more than 80% in (1,3;1,4)‐β‐d ‐glucan content in grain of transgenic barley. Analyses of (1,3;1,4)‐β‐d ‐glucan fine structure indicate that individual CslF enzymes might direct the synthesis of (1,3;1,4)‐β‐d ‐glucans with different structures. When expression of the CslF6 transgene is driven by the Pro35S promoter, the transgenic lines have up to sixfold higher levels of (1,3;1,4)‐β‐d ‐glucan in leaves, but similar levels as controls in the grain. Some transgenic lines of Pro35S:CslF4 also show increased levels of (1,3;1,4)‐β‐d ‐glucans in grain, but not in leaves. Thus, the effects of CslF genes on (1,3;1,4)‐β‐d ‐glucan levels are dependent not only on the promoter used, but also on the specific member of the CslF gene family that is inserted into the transgenic barley lines. Altering (1,3;1,4)‐β‐d ‐glucan levels in grain and vegetative tissues will have potential applications in human health, where (1,3;1,4)‐β‐d ‐glucans contribute to dietary fibre, and in tailoring the composition of biomass cell walls for the production of bioethanol from cereal crop residues and grasses.     

Epigenetic regulation of cell type-specific expression patterns in the human mammary epithelium

Differentiation is an epigenetic program that involves the gradual loss of pluripotency and acquisition of cell type-specific features. Understanding these processes requires genome-wide analysis of epigenetic and gene expression profiles, which have been challenging in primary tissue samples due to limited numbers of cells available. Here we describe the application of high-throughput sequencing technology for profiling histone and DNA methylation, as well as gene expression patterns of normal human mammary progenitor-enriched and luminal lineage-committed cells. We observed significant differences in histone H3 lysine 27 tri-methylation (H3K27me3) enrichment and DNA methylation of genes expressed in a cell type-specific manner, suggesting their regulation by epigenetic mechanisms and a dynamic interplay between the two processes that together define developmental potential. The technologies we developed and the epigenetically regulated genes we identified will accelerate the characterization of primary cell epigenomes and the dissection of human mammary epithelial lineage-commitment and luminal differentiation.