Karlsson Lyng (banjodraw02)

Antibiotic resistance has been highlighted by international organizations, including World Health Organization, World Bank and United Nations, as one of the most relevant global health problems. Classical approaches to study this problem have focused in infected humans, mainly at hospitals. Nevertheless, antibiotic resistance can expand through different ecosystems and geographical allocations, hence constituting a One-Health, Global-Health problem, requiring specific integrative analytic tools. Antibiotic resistance evolution and transmission are multilayer, hierarchically organized processes with several elements (from genes to the whole microbiome) involved. However, their study has been traditionally gene-centric, each element independently studied. The development of robust-economically affordable whole genome sequencing approaches, as well as other -omic techniques as transcriptomics and proteomics, is changing this panorama. check details These technologies allow the description of a system, either a cell or a microbiome as a whole, overcoming the problems associated with gene-centric approaches. We are currently at the time of combining the information derived from -omic studies to have a more holistic view of the evolution and spread of antibiotic resistance. This synthesis process requires the accurate integration of -omic information into computational models that serve to analyse the causes and the consequences of acquiring AR, fed by curated databases capable of identifying the elements involved in the acquisition of resistance. In this review, we analyse the capacities and drawbacks of the tools that are currently in use for the global analysis of AR, aiming to identify the more useful targets for effective corrective interventions.Phosphate and tensin homolog on chromosome ten (PTEN) germline mutations are associated with an overarching condition known as PTEN hamartoma tumor syndrome. Clinical phenotypes associated with this syndrome range from macrocephaly and autism spectrum disorder to Cowden syndrome, which manifests as multiple noncancerous tumor-like growths (hamartomas), and an increased predisposition to certain cancers. It is unclear, however, the basis by which mutations might lead to these very diverse phenotypic outcomes. Here we show that, by considering the molecular consequences of mutations in PTEN on protein structure and function, we can accurately distinguish PTEN mutations exhibiting different phenotypes. Changes in phosphatase activity, protein stability, and intramolecular interactions appeared to be major drivers of clinical phenotype, with cancer-associated variants leading to the most drastic changes, while ASD and non-pathogenic variants associated with more mild and neutral changes, respectively. Importantly, we show via saturation mutagenesis that more than half of variants of unknown significance could be associated with disease phenotypes, while over half of Cowden syndrome mutations likely lead to cancer. These insights can assist in exploring potentially important clinical outcomes delineated by PTEN variation.The OleA enzyme is distinct amongst thiolase enzymes in binding two long (≥C8) acyl chains into structurally-opposed hydrophobic channels, denoted A and B, to carry out a non-decarboxylative Claisen condensation reaction and initiate the biosynthesis of membrane hydrocarbons and β-lactone natural products. OleA has now been identified in hundreds of diverse bacteria via bioinformatics and high-throughput screening using p-nitrophenyl alkanoate esters as surrogate substrates. In the present study, p-nitrophenyl esters were used to probe the reaction mechanism of OleA and shown to be incorporated into Claisen condensation products for the first time. p-Nitrophenyl alkanoate substrates alone were shown not to undergo Claisen condensation, but co-incubation of p-nitrophenyl esters and CoA thioesters produced mixed Claisen products. Mixed product reactions were shown to init