BACKGROUND: Guanfacine is a alpha2A adrenergic receptor agonist approved for treating attention deficit hyperactivity disorder (ADHD). It is thought to act via postsynaptic receptors in the prefrontal cortex, modulating executive functions including the regulation of attention. Attention is affected early in Alzheimer's disease (AD), and this may relate to pathological changes within the locus coeruleus, the main source of noradrenergic pathways within the brain. Given that cholinergic pathways, also involved in attention, are disrupted in AD, the combination of noradrenergic and cholinergic treatments may have a synergistic effect on symptomatic AD. The primary objective of the NorAD trial is to evaluate the change in cognition with 12 weeks of treatment of extended-release guanfacine (GXR) against a placebo as a combination therapy with cholinesterase inhibitors in participants with mild to moderate Alzheimer's disease. METHODS/DESIGN: NorAD is a 3-month, single-centre, randomised, double-blind, placebo-controlled, phase III trial of extended-release guanfacine (GXR) in participants with mild to moderate Alzheimer's disease. A total of 160 participants will be randomised to receive either daily guanfacine or placebo in combination with approved cholinesterase treatment for 12 weeks. The primary outcome is the change in cognition, as measured by the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), from baseline to follow-up in the treatment group compared to the placebo group. Secondary outcomes include the change in additional cognitive measures of attention (Tests of Attention: Trails A and B, digit-symbol substitution, Test of Everyday Attention and CANTAB-RVP), neuropsychiatric symptoms (Neuropsychiatric Inventory), caregiver burden (Zarit Burden Interview) and activities of daily living (Alzheimer's Disease Co-operative Study - Activities of Daily Living Inventory). From July 2020, observation of change following cessation of treatment is also being assessed. DISCUSSION: There is strong evidence for early noradrenergic dysfunction in Alzheimer's disease. The NorAD trial aims to determine whether guanfacine, a noradrenergic alpha-2 agonist, improves attention and cognition when used in addition to standard cholinergic treatment. TRIAL REGISTRATION: ClinicalTrials.gov NCT03116126 . Registered on 14 April 2017 EudraCT: 2016-002598-36.
Comparative analysis of multiple genomes in a phylogenetic framework dramatically improves the precision and sensitivity of evolutionary inference, producing more robust results than single-genome analyses can provide. The genomes of 12 Drosophila species, ten of which are presented here for the first time (sechellia, simulans, yakuba, erecta, ananassae, persimilis, willistoni, mojavensis, virilis and grimshawi), illustrate how rates and patterns of sequence divergence across taxa can illuminate evolutionary processes on a genomic scale. These genome sequences augment the formidable genetic tools that have made Drosophila melanogaster a pre-eminent model for animal genetics, and will further catalyse fundamental research on mechanisms of development, cell biology, genetics, disease, neurobiology, behaviour, physiology and evolution. Despite remarkable similarities among these Drosophila species, we identified many putatively non-neutral changes in protein-coding genes, non-coding RNA genes, and cis-regulatory regions. These may prove to underlie differences in the ecology and behaviour of these diverse species.
Title: Genetic architecture of the polyketide synthases for methymycin and pikromycin series macrolides Xue Y, Wilson D, Sherman DH Ref: Gene, 245:203, 2000 : PubMed
The methymycin and pikromycin series of antibiotics are structurally related macrolides produced by several Streptomyces species, including Streptomyces venezuelae ATCC 15439, which produces both 12-membered ring macrolides methymycin, neomethymycin, and 14-membered ring macrolides pikromycin and narbomycin. Cloning and sequencing of the biosynthetic gene clusters for these macrolides from three selected Streptomyces strains revealed a common genetic architecture of their polyketide synthases (PKSs). Unlike PKS clusters of other 14-membered ring macrolides such as erythromycin and oleandomycin, each of the pikromycin series producers harbors a six module PKS cluster, in which modules 5 and 6 are encoded on two separate proteins instead of one bimodular protein, as well as a thioesterase II gene immediately downstream of the main PKS gene. The results shed new light on the evolution of modular PKSs and provide further evidence on the regulation of methymycin and pikromycin production in S. venezuelae ATCC 15439.
Title: Demonstration of the catalytic roles and evidence for the physical association of type I fatty acid synthases and a polyketide synthase in the biosynthesis of aflatoxin B1 Watanabe CM, Wilson D, Linz JE, Townsend CA Ref: Chemical Biology, 3:463, 1996 : PubMed
BACKGROUND: Aflatoxin B1 (compound 5. ) is a potent environmental carcinogen produced by certain Aspergillus species. Its first stable biosynthetic precursor is the anthraquinone norsolorinic acid (compound 3. ), which accumulates in the Aspergillus mutant strain NOR-1. Biochemical and genetic evidence suggest that this metabolite is synthesized in vivo by a specialized pair of fatty acid synthases (FAS-1 and FAS-2) and a separately transcribed polyketide synthase (PKS-A). RESULTS: The N-acetylcysteamine (NAC) thioester of hexanoic acid was shown to efficiently support the biosynthesis of norsolorinic acid (compound 3. ) in the NOR-1 strain. In contrast, the mutants Dis-1 and Dis-2, which are derived from NOR-1 by insertional inactivation of fas-1, produced unexpectedly low amounts of norsolorinic acid in the presence of hexanoylNAC. Controls eliminated defects in the parent strain or enhancement of degradative beta-oxidation activity as an explanation for the low level of production. Southern blots and restriction mapping of Dis-1 and Dis-2 suggested normal levels of expression of the PKS-A and FAS-2 proteins should be observed because the genes encoding these proteins are not physically altered by disruption of fas-1. CONCLUSIONS: The impaired ability of Dis-1 and Dis-2, harboring modified FAS-1 enzymes, to carry out norsolorinic acid synthesis implies the need for FAS-1 (and possibly also FAS-2) to physically associate with the PKS before biosynthesis can begin. The failure of the unaffected PKS alone to be efficiently primed by hexanoylNAC, and the presumed requirement for at least one of the FAS proteins to bind and transfer the C6 unit to the PKS, is in contrast to behavior widely believed to occur for type I PKSs.
