Synthesis of Nuclearly-Modified Cephalosporin Antibiotics

Approaches are described towards synthesis of 1-hydroxy-1-carba-cephalosporin (1), a chemically interesting nuclearly modified cephalosporin analogue which may possess potent antibiotic activity. Approaches to a bicyclic tetrahydropyridine (27), potentially convertible into carbacephem (1), are also discussed. Oxygenated 1-carbacephems (95) and (97) have been prepared via a route employing the reaction between imines and a ketene precursor to give beta-lactams. The 1alpha-isomer (95) exhibited weak antibiotic properties

Convergent genetic and expression data implicate immunity in Alzheimer's disease

Background Late–onset Alzheimer's disease (AD) is heritable with 20 genes showing genome wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease we extended these genetic data in a pathway analysis. Methods The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. Results ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (p = 3.27×10-12 after multiple testing correction for pathways), regulation of endocytosis (p = 1.31×10-11), cholesterol transport (p = 2.96 × 10-9) and proteasome-ubiquitin activity (p = 1.34×10-6). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected p 0.002 – 0.05). Conclusions The immune response, regulation of endocytosis, cholesterol transport and protein ubiquitination represent prime targets for AD therapeutics