Downregulation of monocyte miRNAs: implications for immune dysfunction and disease severity in drug-resistant tuberculosis

Monocyte miRNAs govern both protective and pathological responses during tuberculosis (TB) through their differential expression and emerged as potent targets for biomarker discovery and host-directed therapeutics. Thus, this study examined the miRNA profile of sorted monocytes across the TB disease spectrum [drug-resistant TB (DR-TB), drug-sensitive TB (DS-TB), and latent TB] and in healthy individuals (HC) to understand the underlying pathophysiology and their regulatory mechanism

Inhibition of telomerase: an in silico study

Telomeres are DNA-protein structures at the ends of linear chromosomes essential for the maintenance of genomic stability. Telomerase activity is non-existent in the majority of normal cells but is activated in 80-85% of tumour cell lines in essentially all types of cancer. This enzyme functions in cancer cells by maintaining the integrity of the telomeric ends rendering the cells ‘immortal’. The recognition of telomerase as a possible target for the treatment of cancer 20 years ago has stimulated a tremendous amount of research in this area. However, the binding modes and detailed inhibitory mechanisms of most classes of telomerase inhibitors are currently unknown. At present, there are no pharmaceuticals on the market that target telomeres or telomerase, albeit some compounds are undergoing clinical trials. This study was conducted to use pharmacophore models to (i) predict the binding modes of existing telomerase inhibitors and (ii) to use the information obtained in discovering novel telomerase inhibitors. In the first results chapter, the following types of training sets were used in inhibitor binding site studies by generating quantitative and common feature pharmacophores: nucleoside inhibitors, non-nucleoside inhibitors and a group of bisindoles. Based on the datasets, pharmacophore models were built using the Discovery Studio 3.5 software. The pharmacophore models were first refined, and then validated. Once the models were finalised, they were compared against each other in various ways to find hints regarding binding sites. The bisindoles whose mechanism of action was unknown were compared against the non-nucleoside inhibitor pharmacophores. A hypothetical model of binding sites was derived based on the clues obtained through the pharmacophore models. In the second results chapter, the pharmacophore models were used in database searching with the aim to retrieve novel telomerase inhibitors. The hits were filtered and evaluated using different methods and the top compounds were then tested in vitro using telospot and direct assays. The hits selected from the first search using only one database were not active. The search was then refined and two databases were searched, and hits again filtered, evaluated and tested. In the third results chapter, G-quadruplex stabilisers, which inhibit the action of telomerase by binding to the G-quadruplex structure formed by telomeres, were also analysed and pharmacophore models generated. Quantitative, common feature, complex based and structure based pharmacophores were explored for this type of inhibitors, and the hits from database searches evaluated using docking methods

Parathyroid allotransplantation to treat post-thyroidectomy hypoparathyroidism: A review of case studies

10.1016/j.surge.2020.06.008SURGEON-JOURNAL OF THE ROYAL COLLEGES OF SURGEONS OF EDINBURGH AND IRELAND193183-19