Autoethnographic Reflections on Mental Distress and Medication Management: Conceptualising Biomedical and Recovery Models of Mental Health.

This article uses autoethnography to explore the author's lived experiences of mental distress and how she has conceptualised and explained these symptoms to herself using both the biomedical and recovery models of care. Autoethnography is a process of personal reflection that enables connection between the personal and the political. Experiences of mental distress are recounted alongside the decision to reduce medication. This personal experience is then explored in the context of limited evidence base on the effectiveness of reducing medication and the situation in which prescribers often feel reluctant to recommend and support service users in these choices. Shared decision-making in medication management is introduced which is an approach which draws on the models of recovery and co-production challenging traditional biomedical approaches which locate the prescriber as expert. Moreover, the radical service user led model is highlighted, within which, the Hearing Voices Network and Open Dialogue offer alternative approaches which promote co-production and empowerment. The author connects the personal to the political and reflects on her dual identity as an expert-by-experience and social work academic. She details how she has drawn on biomedical explanations to describe her distress yet has been challenged by the recovery model throughout her journey of recovery. She concludes that her own position, in identifying herself as an academic and expert-by-experience is an important step in challenging notions of expertise and approaches to mental health care.

Exploring the Efficacy of an Online Training Programme to Introduce Mental Health Recovery to Carers.

Family carers often support people with mental ill-health, however, there is a dearth of research on the importance of recovery to mental health carers. This article describes the delivery and qualitative evaluation of an online training programme on recovery to a group of eleven carers. The participants considered their understanding of the meaning of recovery, differentiating between its personal and clinical nature. They highlighted the importance of carer involvement in the service users' professional support, alongside the need for carers to participate more widely in service development. Finally, the participants found the training useful in enabling them to recognise their own needs in a caring journey, particularly valuing its delivery by a service user and carer trainer. This study is limited by the small number of participants in this programme; however, this series of connected studies suggests its potential to be rolled out more widely, possibly embedded in Recovery Colleges.

At the Crossroads of Life and Death: The Proteins That Influence Cell Fate Decisions.

When a cell is damaged, it must decide how to respond. As a consequence of a variety of stresses, cells can induce well-regulated programmes such as senescence, a persistent proliferative arrest that limits their replication. Alternatively, regulated programmed cell death can be induced to remove the irreversibly damaged cells in a controlled manner. These programmes are mainly triggered and controlled by the tumour suppressor protein p53 and its complex network of effectors, but how it decides between these wildly different responses is not fully understood. This review focuses on the key proteins involved both in the regulation and induction of apoptosis and senescence to examine the key events that determine cell fate following damage. Furthermore, we examine how the regulation and activity of these proteins are altered during the progression of many chronic diseases, including cancer.

Experiences of Being Cared-For: The Perspective of an Expert-by-Experience in Mental Health.

It is difficult to understand what it feels like for people with mental ill-health to be cared-for and supported by family members; this experience is often little-explored. Narratives about caring have been increasingly written alongside first-person accounts of recovery, however, there is a dearth of literature written to gain the perspective of being cared-for because of mental distress. Thus, using autoethnography, I present three critical incidents occurring at different points in my recovery to enable exploration of experiences of being cared-for. Firstly, a critical incident at the point of acute unwellness is introduced, secondly an incident during a consultation with a health professional is highlighted, and finally a moment of transition when embarking on an independent life with my husband-to-be is described. I use autoethnography to connect "the autobiographical and personal to the cultural, social, and political". I consider how the identity of a carer is continually negotiated in a relationship with the service user in both the "private" and the "public" worlds during recovery. I reflect on how professionals can support both service users and carers in a triangle of care, by providing information and support, alongside promoting the development of independence and agency for the service user whilst in the caring relationship. Finally, I introduce a service model which promotes a family network approach to empower the service user, and highlight training programs on recovery that enable carers. I conclude by suggesting the potential of both approaches to support carers to promote the recovery of the service user.

Shared Decision-Making: An Autoethnography About Service User Perspectives in Making Choices About Mental Health Care and Treatment.

Shared decision-making (SDM) between mental health medication prescribers and service users is a central pillar in the recovery approach, because it supports people experiencing mental ill-health to explore their care and treatment options to promote their well-being and to enable clinicians to gain knowledge of the choices the service user prefers. SDM is receiving increasing recognition both in the delivery of physical and mental health services; and as such, is of significance to current practice. As an expert-by-experience with over 30 years of receiving mental health treatment, I have made many choices about taking medication and accessing other forms of support. The experiences of SDM have been variable over my career as a service user: both encounters when I have felt utterly disempowered and interactions when I have led decision-making process based on my expertise-by-experience. In this article, I recount two experiences of exploring care and treatment options: firstly, a discharge planning meeting; and secondly, the choice to take medication over the long-term, despite the side effects. The article will explore both opportunities and barriers to effective shared decision-making, as well as skills and processes to facilitate this approach. The need to balance power between service users and professionals in this interaction is highlighted, including the need to respect expertise built on lived experience, alongside that of clinical expertise. This narrative is framed within an autoethnographic approach which allows me to contextualize my personal experiences in the wider environment of mental health care and support.

Exorcising memories of internalised stigma: The demons of lived experience.

Public stigma and self-stigma impact negatively on the lives of people with mental health issues. Many people in society stereotype and discriminate against people with mental ill-health, and often this negative process of marginalisation is internalised by people with lived experiences. Thus, this negative internalisation leads to the development of self-stigma. In this article, I reflect on my own experiences of shame and self-stigma as a person with mental ill-health socially bullied by peers from my community and social groups. I present a personal narrative of both public and self-stigmatisation which I hope will enable me to exorcise memories of internalised stigma, which are encountered as my demons of lived experience. Using reflexivity, a process used widely in health and social care fields, I consider how social bullying shattered my fragile confidence, self-esteem, and self-efficacy in the early days of my recovery; the impact of associative stigma on family members is also explored. Following this, the potential to empower people who experience shame and stigma is explored alongside effective anti-stigma processes which challenge discrimination. I connect the concept of recovery with the notion of empowerment, both of which emphasise the importance of agency and self-efficacy for people with mental ill-health. Finally, I consider how the concepts of empowerment and recovery can challenge both the public stigma held by peers in the community and the self-stigma of those with lived experiences.

Cryo-EM structural analysis of FADD:Caspase-8 complexes defines the catalytic dimer architecture for co-ordinated control of cell fate.

Regulated cell death is essential in development and cellular homeostasis. Multi-protein platforms, including the Death-Inducing Signaling Complex (DISC), co-ordinate cell fate via a core FADD:Caspase-8 complex and its regulatory partners, such as the cell death inhibitor c-FLIP. Here, using electron microscopy, we visualize full-length procaspase-8 in complex with FADD. Our structural analysis now reveals how the FADD-nucleated tandem death effector domain (tDED) helical filament is required to orientate the procaspase-8 catalytic domains, enabling their activation via anti-parallel dimerization. Strikingly, recruitment of c-FLIPS into this complex inhibits Caspase-8 activity by altering tDED triple helix architecture, resulting in steric hindrance of the canonical tDED Type I binding site. This prevents both Caspase-8 catalytic domain assembly and tDED helical filament elongation. Our findings reveal how the plasticity, composition and architecture of the core FADD:Caspase-8 complex critically defines life/death decisions not only via the DISC, but across multiple key signaling platforms including TNF complex II, the ripoptosome, and RIPK1/RIPK3 necrosome.

Targeting cell death signalling in cancer: minimising 'Collateral damage'.

Targeting apoptosis for the treatment of cancer has become an increasingly attractive strategy, with agents in development to trigger extrinsic apoptosis via TRAIL signalling, or to prevent the anti-apoptotic activity of BCL-2 proteins or inhibitor of apoptosis (IAP) proteins. Although the evasion of apoptosis is one of the hallmarks of cancer, many cancers have intact apoptotic signalling pathways, which if unblocked could efficiently kill cancerous cells. However, it is becoming increasing clear that without a detailed understanding of both apoptotic and non-apoptotic signalling, and the key proteins that regulate these pathways, there can be dose-limiting toxicity and adverse effects associated with their modulation. Here we review the main apoptotic pathways directly targeted for anti-cancer therapy and the unforeseen consequences of their modulation. Furthermore, we highlight the importance of an in-depth mechanistic understanding of both the apoptotic and non-apoptotic functions of those proteins under investigation as anti-cancer drug targets and outline some novel approaches to sensitise cancer cells to apoptosis, thereby improving the efficacy of existing therapies when used in combination with novel targeted agents.

BMX Negatively Regulates BAK Function, Thereby Increasing Apoptotic Resistance to Chemotherapeutic Drugs.

The ability of chemotherapeutic agents to induce apoptosis, predominantly via the mitochondrial (intrinsic) apoptotic pathway, is thought to be a major determinant of the sensitivity of a given cancer to treatment. Intrinsic apoptosis, regulated by the BCL2 family, integrates diverse apoptotic signals to determine cell death commitment and then activates the nodal effector protein BAK to initiate the apoptotic cascade. In this study, we identified the tyrosine kinase BMX as a direct negative regulator of BAK function. BMX associates with BAK in viable cells and is the first kinase to phosphorylate the key tyrosine residue needed to maintain BAK in an inactive conformation. Importantly, elevated BMX expression prevents BAK activation in tumor cells treated with chemotherapeutic agents and is associated with increased resistance to apoptosis and decreased patient survival. Accordingly, BMX expression was elevated in prostate, breast, and colon cancers compared with normal tissue, including in aggressive triple-negative breast cancers where BMX overexpression may be a novel biomarker. Furthermore, BMX silencing potentiated BAK activation, rendering tumor cells hypersensitive to otherwise sublethal doses of clinically relevant chemotherapeutic agents. Our finding that BMX directly inhibits a core component of the intrinsic apoptosis machinery opens opportunities to improve the efficacy of existing chemotherapy by potentiating BAK-driven cell death in cancer cells.

Resistance to UV-induced apoptosis by ß-HPV5 E6 involves targeting of activated BAK for proteolysis by recruitment of the HERC1 ubiquitin ligase.

UV exposure is the main etiological agent in the development of non-melanoma skin cancer (NMSC), but mounting evidence suggests a co-factorial role for ß-genus HPV types early in tumor initiation or progression. UV damage initiates an apoptotic response, driven at the mitochondrial level by BCL-2 family proteins, that eliminates damaged cells that may accumulate deleterious mutations and acquire tumorigenic properties. BAK is a pro-apoptotic BCL-2 protein that functions ultimately to form pores that permeabilize the mitochondrial outer membrane, thereby committing a cell to death, a process involving changes in BAK phosphorylation and conformation. The E6 protein of ß-type HPV5 signals BAK for proteasomal degradation, a function that confers protection from UV-induced apoptosis. We find that HPV5 E6 does not constitutively target BAK for proteolysis, but targets the latter stages of BAK activation, following changes in phosphorylation and conformation. A mutational analysis identified the lysine residue on BAK required for proteolysis, and a functional siRNA screen identified the HECT domain E3 ubiquitin ligase HERC1 as being required for E6-mediated BAK degradation. We show that HERC1 interacts with BAK in E6-expressing cells that have been damaged by UV, and provide evidence that the interaction of HERC1 with BAK requires access to a hydrophobic surface on BAK that binds BH3 domains of BCL-2 proteins. We also show that HERC1 contains a putative BH3 domain that can bind to BAK. These findings reveal a specific and unique mechanism used by the HPV5 E6 protein to target BAK.

Blockade of the BAK hydrophobic groove by inhibitory phosphorylation regulates commitment to apoptosis.

The BCL-2 family protein BAK is a key regulator of mitochondrial apoptosis. BAK activation first involves N-terminal conformational changes that lead to the transient exposure of the BAK BH3 domain that then inserts into a hydrophobic groove on another BAK molecule to form symmetric dimers. We showed recently that post-translational modifications are important in the regulation of BAK conformational change and multimerization, with dephosphorylation at tyrosine 108 constituting an initial step in the BAK activation process. We now show that dephosphorylation of serine 117 (S117), located in the BAK hydrophobic groove, is also critical for BAK activation to proceed to completion. Phosphorylation of BAK at S117 has two important regulatory functions: first, it occludes the binding of BH3-containing peptides that bind to BAK causing activation and cytochrome c release from mitochondria; second, it prevents BAK-BH3:BAK-Groove interactions that nucleate dimer formation for subsequent multimerization. Hence, BH3-mediated BAK conformational change and subsequent BAK multimerization for cytochrome c release and cell death is intimately linked to, and dependent on, dephosphorylation at S117. Our study reveals important novel mechanistic and structural insights into the temporal sequence of events governing the process of BAK activation in commitment to cell death and how they are regulated.

Intra-individual and inter-individual variation in breath alcohol pharmacokinetics: The effect of food on absorption.

Eight male and 8 female subjects underwent serial breath alcohol concentration (BrAC) measurements in the fasting state, following a snack of crisps and following a light meal. BrAC versus time curves were constructed for each subject and the values of peak BrAC (C(max)), theoretical (extrapolated) BrAC at zero time (C(0)), time taken to reach peak (T(max)) and rate of elimination (ß) were recorded directly from the curves. In all subjects values of C(0) extrapolated from the post-meal BrAC-time curves were significantly lower than in the fasting and snack fed states. Since Widmark factor (W.F.) is inversely proportional to C(0), values of WF calculated from extrapolated C(0) after a meal were spuriously high. WF obtained from the fasting BrAC-time curves were usually only slightly higher than those calculated by the Forrest mathematical method. C(max) was highest in fasting subjects (mean 30.5, range 22.5-42µg/100ml) and lowest after a meal (mean 21.4, range 13.5-32µg/100ml). T(max) was shortest after a meal and also remarkably consistent (mean 22, range 17-50min). 'Overshoot' was seen in most fasting subjects within about 40min of consuming alcohol. Elimination of alcohol from breath was slightly lower after a meal (mean 5.4, range 3.9-8.5µg/100ml/h) than after either fasting (mean 6, range 4.7-7.3µg/100ml/h) or a snack (mean 6, range 4.4-8.8µg/100ml/h). The availability of alcohol for absorption (as a percentage of the predicted value) was almost complete after fasting or a snack but after a meal was reduced to only 66% in females and 71% in males. The practical significance of this much reduced peak BrAC after food occurs in relation to forward or back calculations and cases involving post-accident drinking ("the hip flask" defence) as ingestion of a meal before or with alcohol is a common social situation which may complicate BAC estimation in some medico-legal cases.

"Licensed to kill": tyrosine dephosphorylation and Bak activation.

The genomes of multi-cellular organisms are under constant assault from a host of environmental agents. The efficient elimination of cells harbouring damage is essential to avoid the accumulation of deleterious changes that may promote tumorigenesis. Consequently, a complex and elaborate series of damage responses have evolved to either ensure that correct repair of the DNA has been carried out, or alternatively, to initiate programmes that result in the ablation of the damaged cell. Apoptosis is recognized as both a fast an efficient way of disposing of damaged or unwanted cells before they accumulate changes that may result in the acquisition of neoplastic autonomy. The mitochondrial apoptotic pathway relies upon two effector proteins of the Bcl2 family, Bax and Bak, that when activated form pores in the outer mitochondrial membrane that release cytochrome c and other apoptogenic factors. We have recently shown that the initiation of Bak activation is controlled by dephosphorylation. In particular, we found that a specific tyrosine dephosphorylation was required for Bak activation to proceed, and that tyrosine phosphatases may serve to integrate apoptotic signals that culminate in Bak dephosphorylation. Here, we discuss these findings and present additional data underlining the importance of dephosphorylation in the Bak activation process, and how the modulation of Bak phosphorylation status may be modified to enhance cell killing.

Tyrosine dephosphorylation is required for Bak activation in apoptosis.

Activation of the cell-death mediator Bak commits a cell to mitochondrial apoptosis. The initial steps that govern Bak activation are poorly understood. To further clarify these pivotal events, we have investigated whether post-translational modifications of Bak impinge on its activation potential. In this study, we report that on apoptotic stimulation Bak undergoes dephosphorylation at tyrosine residue 108 (Y108), a critical event that is necessary but not sufficient for Bak activation, but is required both for early exposure of the occluded N-terminal domain and multimerisation. RNA interference (RNAi) screening identified non-receptor tyrosine phosphatases (PTPNs) required for Bak dephosphorylation and apoptotic induction through chemotherapeutic agents. Specifically, modulation of PTPN5 protein expression by siRNA and overexpression directly affected both Bak-Y108 phosphorylation and the initiation of Bak activation. We further show that MEK/ERK signalling directly affects Bak phosphorylation through inhibition of PTPN5 to promote cell survival. We propose a model of Bak activation in which the regulation of Bak dephosphorylation constitutes the initial step in the activation process, which reveals a previously unsuspected mechanism controlling the initiation of mitochondrial apoptosis.