The capabilities approach: fostering contexts for enhancing mental health and wellbeing across the globe

Concerted efforts have been made in recent years to achieve equity and equality in mental health for all people across the globe. This has led to the emergence of Global Mental Health as an area of study and practice. The momentum that this has created has contributed to the development, implementation and evaluation of services for priority mental disorders in many low- and middle-income countries. This paper discusses two related issues that may be serving to limit the success of mental health initiatives across the globe, and proposes potential solutions to these issues. First, there has been a lack of sophistication in determining what constitutes a ‘good outcome’ for people experiencing mental health difficulties. Even though health is defined and understood as a state of ‘wellbeing’ and not merely an absence of illness, mental health interventions tend to narrowly focus on reducing symptoms of mental illness. The need to also focus more broadly on enhancing subjective wellbeing is highlighted. The second limitation relates to the lack of an overarching theoretical framework guiding efforts to reduce inequalities and inequities in mental health across the globe. This paper discusses the potential impact that the Capabilities Approach (CA) could have for addressing both of these issues. As a framework for human development, the CA places emphasis on promoting wellbeing through enabling people to realise their capabilities and engage in behaviours that they subjectively value. The utilization of the CA to guide the development and implementation of mental health interventions can help Global Mental Health initiatives to identify sources of social inequality and structural violence that may impede freedom and individuals’ opportunities to realise their capabilities

Dealiasing techniques for high-order spectral element methods on regular and irregular grids

High-order methods are becoming increasingly attractive in both academia and industry, especially in the context of computational fluid dynamics. However, before they can be more widely adopted, issues such as lack of robustness in terms of numerical stability need to be addressed, particularly when treating industrial-type problems where challenging geometries and a wide range of physical scales, typically due to high Reynolds numbers, need to be taken into account. One source of instability is aliasing effects which arise from the nonlinearity of the underlying problem. In this work we detail two dealiasing strategies based on the concept of consistent integration. The first uses a localised approach, which is useful when the nonlinearities only arise in parts of the problem. The second is based on the more traditional approach of using a higher quadrature. The main goal of both dealiasing techniques is to improve the robustness of high order spectral element methods, thereby reducing aliasing-driven instabilities. We demonstrate how these two strategies can be effectively applied to both continuous and discontinuous discretisations, where, in the latter, both volumetric and interface approximations must be considered. We show the key features of each dealiasing technique applied to the scalar conservation law with numerical examples and we highlight the main differences in terms of implementation between continuous and discontinuous spatial discretisations

The phytocannabinoid, Δ(9) -tetrahydrocannabivarin, can act through 5-HT1 A receptors to produce antipsychotic effects

Funded by: •GW Pharmaceuticals Acknowledgements: The authors wish to thank Mrs Lesley Stevenson for technical support and Dr John Raymond, Dr Keith Parker and Dr Ethan Russo for providing human 5-HT1A CHO cells. This research was supported by a grant from GW Pharmaceuticals to M. G. C. and R. G. P.Peer reviewedPostprin

Multiphoton Absorption of Myoglobin–Nitric Oxide Complex: Relaxation by D-NEMD of a Stationary State

ABSTRACT: The photodissociation and geminate recombination of nitric oxide in myoglobin, under continuous illumination, is modeled computationally. The relaxation of the photon energy into the protein matrix is also considered in a single simulation scheme that mimics a complete experimental setup. The dynamic approach to non-equilibrium molecular dynamics is used, starting from a steady state, to compute its relaxation to equilibrium. Simulations are conducted for the native form of sperm whale myoglobin and for two other mutants, V68W and L29F, illustrating a fair diversity of spatial and temporal geminate recombination processes. Energy flow to the heme and immediate protein environment provide hints to allostery. In particular, a pathway of energy flow between the heme and the FG loop is illustrated. Although the simulations were conducted for myoglobin only, the thermal fluctuations of the FG corner are in agreement with the large structural shifts of FG during the allosteric transition of tetrameric hemoglobin

Possible routes of animal exposure to cadmium and cadmium compounds and induced effects: a review

A retrospective analysis about cadmium and cadmium compounds teratogenicity, toxicity and carcinogenicity was carried out on literature basis, up to date, reviewed according to animal species, routes of exposure, acute and chronic response to different dosages via gastrointestinal or inhalatory uptake, target organs and apparatus. Some recent updates from experimental trials were also comparatively considered

Cadmium in cephalopod molluscs: implications for public health.

Cadmium concentrations were measured in the flesh and hepatopancreas (digestive gland) of 1,392 specimens of different species of cephalopod molluscs (broadtail squid, spider octopus, curled octopus, horned octopus, elegant cuttlefish, and pink cuttlefish) to determine whether maximum levels fixed by the European Commission were exceeded. In all species, mean cadmium concentrations were higher in hepatopancreas than in flesh. Large differences among the different species were also observed. Pink cuttlefish and spider octopus had the highest concentrations for both flesh (spider octopus, 0.77 microg g(-1); pink cuttlefish, 0.87 microg g(-1)) and hepatopancreas (spider octopus, 9.65 microg g(-1); pink cuttlefish, 18.03 microg g(-1)), and the lowest concentrations were encountered in broadtail squid (flesh, 0.13 microg g(-1); hepatopancreas, 2.48 microg g(-1)). The other species had intermediate concentrations of 0.20 to 0.30 microg g(-1) in flesh and 5.46 to 8.01 microg g(-1) in hepatopancreas. Concentrations exceeding the limit proposed by the European Commission (1.00 microg g(-1)) were observed in 44.4 and 40.0% of flesh samples of spider octopus and pink cuttlefish, respectively. The estimated weekly intake, 0.09 to 0.66 microg/kg body weigh, was below the provisional tolerable weekly intake set by the World Health Organization

Coral distribution and bleaching vulnerability areas in Southwestern Atlantic under ocean warming

Global climate change is a major threat to reefs by increasing the frequency and severity of coral bleaching events over time, reducing coral cover and diversity. Ocean warming may cause shifts in coral communities by increasing temperatures above coral’s upper thermal limits in tropical regions, and by making extratropical regions (marginal reefs) more suitable and potential refugia. We used Bayesian models to project coral occurrence, cover and bleaching probabilities in Southwestern Atlantic and predicted how these probabilities will change under a high-emission scenario (RCP8.5). By overlapping these projections, we categorized areas that combine high probabilities of coral occurrence, cover and bleaching as vulnerability-hotspots. Current coral occurrence and cover probabilities were higher in the tropics (1°S–20°S) but both will decrease and shift to new suitable extratropical reefs (20°S–27°S; tropicalization) with ocean warming. Over 90% of the area present low and mild vulnerability, while the vulnerability-hotspots represent ~ 3% under current and future scenarios, but include the most biodiverse reef complex in South Atlantic (13°S–18°S; Abrolhos Bank). As bleaching probabilities increase with warming, the least vulnerable areas that could act as potential refugia are predicted to reduce by 50%. Predicting potential refugia and highly vulnerable areas can inform conservation actions to face climate change.Postprint2,92

CO-TARGETING OF ONCOGENIC AND DEATH RECEPTORS PATHWAYS IN HUMAN MELANOMA:PRE-CLINICAL RATIONALE FOR A PRO-APOPTOTIC AND ANTI-ANGIOGENIC STRATEGY

INTRODUCTION: Resistance to cell death is one of the well-known hallmarks of cancer. Metastatic melanoma is an aggressive disease whose treatment has significantly improved thanks to the recent development of either target-specific or immune-modulating agents. Since the FDA approval of the BRAFV600E inhibitor Vemurafenib in 2011, several other inhibitors, targeting relevant oncogenic signaling pathways (i.e. the MEK/ERK or the PI3K/Akt/mTOR pathways) have been used to treat melanoma patients. However intrinsic or acquired resistance limits the efficacy of these compounds, with relapses in most of the patients within 6 months. Therefore, there is an immediate necessity for new therapeutic strategies to face this issue, and one option could be represented by combinatorial treatments associating different anti-tumor agents able to target not only tumor cells but also to counteract pro-tumoral mechanisms in melanoma microenvironment. HYPOTHESIS: Our goal was to obtain pre-clinical evidence for the efficacy of an anti-tumor approach based on the combination of MEK, PI3K inhibitors and TRAIL; building upon the hypothesis that these agents should: 1) be able to overcome melanoma intrinsic resistance to programmed cell death by the concomitant targeting of both the extrinsic (mainly through TRAIL activity) and the intrinsic (mainly due to the activity of MEK and PI3K pathway inhibitors) apoptosis pathways; 2) be able to promote an anti-angiogenic effect combining the well-known vascular disrupting activity of TRAIL and the effects of inhibition of pro-angiogenic pathways in tumor and in tumor-associated vasculature due to targeting of ERK and AKT cascades. METHODS: A large panel of patient-derived melanoma cell lines was used to test the in vitro efficacy of the association between AZD6244/Selumetinib (a MEK1/2 inhibitor), the dual PI3K/mTOR inhibitor BEZ235, and soluble TRAIL. Chou-Talalay drug interaction analysis was used to determine Combination Indexes and Fraction Affected values for all the possible combinations of anti-tumor agents. Whole-genome gene expression profiling, flow cytometry experiments, western blot analysis, proteomic arrays and ELISAs were used to clarify the mechanism behind the synergy shown for the AZD6244+TRAIL and AZD6244+BEZ235+TRAIL associations. Moreover, xenografts in SCID mice were used to confirm the in vivo efficacy and mechanism of action of the combination between the MEK inhibitor and TRAIL, using tumor growth rates and immunohistochemistry on tumor nodules to evaluate effects of the association. Human Umbilical Vein Endothelial Cells (HUVEC) were chosen to model the endothelial-melanoma cell interaction in order to analyze its effects on response to the combinatorial treatment, both in terms of apoptosis induction and endothelial differentiation/activation status RESULTS: While half of the melanoma cell lines we tested were resistant to the death receptor ligand TRAIL, several were susceptible either to AZD6244 or to BEZ235, evidencing independent susceptibility profiles to these drugs and setting the rationale for their association. The combination of the MEK inhibitor, with or without the PI3K/mTOR inhibitor, and TRAIL achieved synergistic anti-tumor activity in 20/21 melanoma cell lines tested, including tumors resistant to either one of the agents. Mechanistically, an increment in induction of caspase-dependent cell death and of mitochondrial depolarization was evidenced for the association, and a significant modulation of key regulators of extrinsic and intrinsic apoptosis pathways including c-FLIP, BIM, BAX, clusterin, Mcl-1 and several IAP family members was confirmed. Moreover, silencing experiments defined Apollon downmodulation as a central event for the promotion of the melanoma apoptotic response to our combinatorial treatments. SCID mice bearing melanoma xenografts were treated with the MEK inhibitor and TRAIL, alone or in combination, obtaining a more significant tumor growth inhibition by the combinatorial treatment, with no detectable adverse events on mice body weight and tissue histology. TUNEL staining on tissues sections indicated also in vivo an increased promotion of tumor apoptosis, which was associated with suppression of several pro-angiogenic molecules like HIF1\uf061, VEGF\uf061, IL-8 and TGF1\uf062\uf020as well as a marked reduction in CD31 positive cells. Furthermore, initial results on HUVECs pointed at a possible effect of the interaction between endothelial and melanoma cells, affecting responsiveness of HUVECs to combinatorial treatments, as documented by increased endothelial cell apoptosis, in response to MEK inhibitor and TRAIL treatment, after co-culture with melanoma cells. The modulatory effect of melanoma on endothelial cells was evidenced not only by \u201cactivation\u201d markers (upregulation of ICAM-1/CD54) but also the \u201cdifferentiation\u201d status of endothelial cells, indicated by increased alpha-SMA levels, reduction in the expression of vascular cadherin CD144 and downmodulation of the endothelial marker CD31. CONCLUSIONS: Results of this work suggest that concomitant targeting of melanoma oncogenic signaling pathways and the TRAIL receptor cascade can not only overcome in vitro tumor resistance to different anti-tumor agents, but can also have in vivo effects on tumor microenvironment, promoting pro-apoptotic effects and inhibition of tumor angiogenesis. Moreover, this could be associated to a modulation of endothelium responsiveness to anti tumor agents by direct interaction with melanoma cells