14 research outputs found
Extrinsic primary afferent signalling in the gut
Visceral sensory neurons activate reflex pathways that control gut function and also give rise to important sensations, such as fullness, bloating, nausea, discomfort, urgency and pain. Sensory neurons are organised into three distinct anatomical pathways to the central nervous system (vagal, thoracolumbar and lumbosacral). Although remarkable progress has been made in characterizing the roles of many ion channels, receptors and second messengers in visceral sensory neurons, the basic aim of understanding how many classes there are, and how they differ, has proven difficult to achieve. We suggest that just five structurally distinct types of sensory endings are present in the gut wall that account for essentially all of the primary afferent neurons in the three pathways. Each of these five major structural types of endings seems to show distinctive combinations of physiological responses. These types are: 'intraganglionic laminar' endings in myenteric ganglia; 'mucosal' endings located in the subepithelial layer; 'muscular–mucosal' afferents, with mechanosensitive endings close to the muscularis mucosae; 'intramuscular' endings, with endings within the smooth muscle layers; and 'vascular' afferents, with sensitive endings primarily on blood vessels. 'Silent' afferents might be a subset of inexcitable 'vascular' afferents, which can be switched on by inflammatory mediators. Extrinsic sensory neurons comprise an attractive focus for targeted therapeutic intervention in a range of gastrointestinal disorders.Australian National Health and Medical Research Counci
Influence of composition and ionizing radiation on kinetics of reduction of mixed CdO-ZnO oxides with hydrogen
Discovery of GS-9669, a thumb site II non-nucleoside inhibitor of NS5B for the treatment of genotype 1 chronic hepatitis C infection
Investigation of thiophene-2-carboxylic acid HCV NS5B site II inhibitors, guided by measurement of cell culture medium binding, revealed the structure-activity relationships for intrinsic cellular potency. The pharmacokinetic profile was enhanced through incorporation of heterocyclic ethers on the N-alkyl substituent. Hydroxyl groups were incorporated to modulate protein binding. Intrinsic potency was further improved through enantiospecific introduction of an olefin in the N-acyl motif, resulting in the discovery of the phase 2 clinical candidate GS-9669. The unexpected activity of this compound against the clinically relevant NS5B M423T mutant, relative to the wild type, was shown to arise from both the N-alkyl substituent and the N-acyl group. 2013 American Chemical Societ
Preparation of branched polystyrene using atom transfer radical polymerization techniques and protection-deprotection chemistry
Investigation on the catalytic activity of doped low-percentage oxide catalysts Mn/ZnO obtained from oxalate precursor
CdS-sensitized ZnO nanorod arrays coated with TiO2 layer for visible light photoelectrocatalysis
Discovery of GS-9669, a Thumb Site II Non-Nucleoside Inhibitor of NS5B for the Treatment of Genotype 1 Chronic Hepatitis C Infection
Investigation
of thiophene-2-carboxylic acid HCV NS5B site II inhibitors, guided
by measurement of cell culture medium binding, revealed the structure–activity
relationships for intrinsic cellular potency. The pharmacokinetic
profile was enhanced through incorporation of heterocyclic ethers
on the <i>N</i>-alkyl substituent. Hydroxyl groups were
incorporated to modulate protein binding. Intrinsic potency was further
improved through enantiospecific introduction of an olefin in the <i>N</i>-acyl motif, resulting in the discovery of the phase 2
clinical candidate GS-9669. The unexpected activity of this compound
against the clinically relevant NS5B M423T mutant, relative to the
wild type, was shown to arise from both the <i>N</i>-alkyl
substituent and the <i>N</i>-acyl group