SLC6A14, a Pivotal Actor on Cancer Stage: When Function Meets Structure

SLC6A14 (ATB0,+) is a sodium- and chloride-dependent neutral and dibasic amino acid transporter that regulates the distribution of amino acids across cell membranes. The transporter is overexpressed in many human cancers characterized by an increased demand for amino acids; as such, it was recently acknowledged as a novel target for cancer therapy. The knowledge on the molecular mechanism of SLC6A14 transport is still limited, but some elegant studies on related transporters report the involvement of the 12 transmembrane \u3b1-helices in the transport mechanism, and describe structural rearrangements mediated by electrostatic interactions with some pivotal gating residues. In the present work, we constructed a SLC6A14 model in outward-facing conformation via homology modeling and used molecular dynamics simulations to predict amino acid residues critical for substrate recognition and translocation. We docked the proteinogenic amino acids and other known substrates in the SLC6A14 binding site to study both gating regions and the exposed residues involved in transport. Interestingly, some of these residues correspond to those previously identified in other LeuT-fold transporters; however, we could also identify a novel relevant residue with such function. For the first time, by combined approaches of molecular docking and molecular dynamics simulations, we highlight the potential role of these residues in neutral amino acid transport. This novel information unravels new aspects of the human SLC6A14 structure-function relationship and may have important outcomes for cancer treatment through the design of novel inhibitors of SLC6A14-mediated transport

Predictors of efficacy in depression prevention programmes. Meta-analysis

Item does not contain fulltextBackground Worldwide, 340 million people are affected by depression, with high comorbid, social and economic costs. Aims To identify potential predictors of effect in prevention programmes. Method A meta-analysis was made of 69 programmes to reduce depression or depressive symptoms. Results The weighted mean effect size of 0.22 was effective for different age groups and different levels of risk, and in reducing risk factors and depressive or psychiatric symptoms.Programmes with larger effect sizes were multi-component, included competence techniques, had more than eight sessions, had sessions 60–90 60–90 min long, had a high quality of research design and were delivered by a health care provider in targeted programmes. Older people benefited from social support, whereas behavioural methods were detrimental. Conclusions An 11% improvement in depressive symptoms can be achieved through prevention programmes. Single trial evaluations should ensure high quality of the research design and detailed reporting of results and potential predictors