Early identification of a ward-based outbreak of using prospective multilocus sequence type-based Oxford Nanopore genomic surveillance.

Objective: To describe an outbreak of sequence type (ST)2 infection (CDI) detected by a recently implemented multilocus sequence type (MLST)-based prospective genomic surveillance system using Oxford Nanopore Technologies (ONT) sequencing.

Setting: Hemato-oncology ward of a public tertiary referral centre.

Methods: From February 2022, we began prospectively sequencing all isolated from inpatients at our institution on the ONT MinION device, with the output being an MLST.

Identification and Optimization of RNA-Splicing Modulators as Huntingtin Protein-Lowering Agents for the Treatment of Huntington's Disease.

Huntington's disease (HD) is caused by an expanded CAG trinucleotide repeat in exon 1 of the huntingtin () gene. We report the design of a series of pre-mRNA splicing modulators that lower huntingtin (HTT) protein, including the toxic mutant huntingtin (mHTT), by promoting insertion of a pseudoexon containing a premature termination codon at the exon 49-50 junction. The resulting transcript undergoes nonsense-mediated decay, leading to a reduction of mRNA transcripts and protein levels.

Developing HDAC4-Selective Protein Degraders To Investigate the Role of HDAC4 in Huntington's Disease Pathology.

Huntington's disease (HD) is a lethal autosomal dominant neurodegenerative disorder resulting from a CAG repeat expansion in the huntingtin () gene. The product of translation of this gene is a highly aggregation-prone protein containing a polyglutamine tract >35 repeats (mHTT) that has been shown to colocalize with histone deacetylase 4 (HDAC4) in cytoplasmic inclusions in HD mouse models. Genetic reduction of HDAC4 in an HD mouse model resulted in delayed aggregation of mHTT, along with amelioration of neurological phenotypes and extended lifespan.

Discovery of GSK251: A Highly Potent, Highly Selective, Orally Bioavailable Inhibitor of PI3Kδ with a Novel Binding Mode.

Optimization of a previously reported lead series of PI3Kδ inhibitors with a novel binding mode led to the identification of a clinical candidate compound (GSK251). Removal of an embedded Ames-positive heteroaromatic amine by reversing a sulfonamide followed by locating an interaction with Trp760 led to a highly selective compound . Further optimization to avoid glutathione trapping, to enhance potency and selectivity, and to optimize an oral pharmacokinetic profile led to the discovery of compound (GSK215) that had a low predicted daily dose (45 mg, b.

Structure-Based Exploration of Selectivity for ATM Inhibitors in Huntington's Disease.

Our group has recently shown that brain-penetrant ataxia telangiectasia-mutated (ATM) kinase inhibitors may have potential as novel therapeutics for the treatment of Huntington's disease (HD). However, the previously described pyranone-thioxanthenes (e.g.

Genetic Engineering of Streptomyces coelicolor A3(2) for the Enantioselective Reduction of Unnatural beta-Keto-Ester Substrates.

Potential "reagents" for the enantioselective reduction, and other biotransformations, of beta-keto-esters result from the genetic engineering of Streptomyces coelicolor A3(2). For example, incubation of the N-acetylcysteamine thioester 1 with the recombinant strain CH999/pIJ5675 followed by treatment with MeOH/HCl gave the lactone 2 as essentially a single enantiomer.