A psychometric evaluation of the Defence Style Questionnaire-40 in a UK forensic patient population

Psychological defence mechanisms have been considered important personality processes in the onset, maintenance and recovery of mental disorders. More recently, their application to understanding presenting problems and as potential outcome indicators for forensic patients has been recommended. However, to date there have been no investigations into the reliability and factor structure of defence mechanism assessments for this population. The current study investigated the factor structure, internal consistency and test-retest reliability of the Defence Style Questionnaire-40 (DSQ) for 160 adult male UK forensic patients. The three-factor model of defences proposed by the DSQ-40 developers was not confirmed in the study sample. Reliability indices of the three factors indicated that the Immature factor was the most ‘acceptable’ in terms of internal consistency. Test-retest reliability coefficients ranged from .70 to .91. A revised three-factor structure that closely corresponds to the original validation study is recommended following an exploratory factor analysis. The findings are compared with previous reliability and factor analytic evaluations of the DSQ-40, and recommendations for its use with forensic patients are discussed

Investigating the ATP13A2 (PARK9) and a- Synuclein inter-relationship in Parkinson’s Disease

Parkinson’s disease (PD) is a progressive, neurodegenerative disease characterised by the intra-neuronal aggregation of the a-Synuclein protein, which impairs cellular functions promoting neurodegeneration. The deposition of aggregated a-Synuclein progresses through the brain in a stereotypical manner. The dopaminergic neurons of the SNpc are most susceptible to neurodegeneration in PD and their loss underlies motor symptoms including resting tremor and bradykinesia. Current treatments only temporarily alleviate motor symptoms and do not slow or stop disease progression, highlighting the need for disease-modifying therapies. This thesis focuses on ATP13A2, a probable cation transporting ATPase, whose loss of function causes familial PD and overexpression rescues a-Synuclein cytotoxicity in vitro. This study discovered that two alternatively spliced isoforms of ATP13A2 (T2 and T3) are being mistakenly used interchangeably in the published literature and that ATP13A2-T3 is the actual suppressor of a-Syn toxicity. Isoform specific investigations revealed that ATP13A2-T2 and ATP13A2-T3 were localised to distinct subcellular compartments within the late endosomal system, suggesting that they impact different cellular pathways. Additionally, ATP13A2-T3, but not ATP13A2-T2, showed partial localisation with Rab7L1 which is known to be part of an interaction network of familial PD genes and to be reduced in the brains of idiopathic PD patients, thus strengthening the links between ATP13A2-T3 and PD.One aim was to undertake in vivo studies investigating the relationship between ATP13A2 and a-Synuclein. Lentiviral-mediated ATP13A2-T3 overexpression in the SNpc ofa-Syn transgenic mice ameliorated several a-Syn-dependent phenotypes, validating ATP13A2-T3 as a therapeutic target. Investigating ATP13A2 knockout in the context of a-Syn transgenic mice aimed to provide insight into how the loss of ATP13A2 may contribute to PD progression. Surprisingly, ATP13A2 loss also suppressed a-Syn-dependent phenotypes. ATP13A2 expression levels modulate the extracellular release of a-Syn suggesting that ATP13A2 may affect the cell-to-cell transmission of a-Syn in the progression of PD. ATP13A2 loss caused increased SNpc pathology when using an in vivo model of PD progression. Subsequent in vitro studies into this mechanism determined that ATP13A2-/- neurons are more sensitive to exogenous a-Syn, likely due to lysosomal impairments that may also affect their rate of -Syn externalisation

Local integrin activation in pancreatic β cells targets insulin secretion to the vasculature

The extracellular matrix (ECM) critically affects β cell functions via integrin activation. But whether these ECM actions drive the spatial organization of β cells, as they do in epithelial cells, is unknown. Here, we show that within islets of Langerhans, focal adhesion activation in β cells occurs exclusively where they contact the capillary ECM (vascular face). In cultured β cells, 3D mapping shows enriched insulin granule fusion where the cells contact ECM-coated coverslips, which depends on β1 integrin receptor activation. Culture on micro-contact printed stripes of E-cadherin and fibronectin shows that β cell contact at the fibronectin stripe selectively activates focal adhesions and enriches exocytic machinery and insulin granule fusion. Culture of cells in high glucose, as a model of glucotoxicity, abolishes granule targeting. We conclude that local integrin activation targets insulin secretion to the islet capillaries. This mechanism might be important for islet function and may change in disease. Pancreatic β cells are polarized within islets by unknown mechanisms. Gan et al. show that ECM contact at the vascular face of pancreatic β cells triggers local integrin β1-dependent focal adhesion activation, which orientates the cells and directs targeting of insulin granule fusion to this region

Strengthening mental health research outcomes through genuine partnerships with young people with lived or living experience: A pilot evaluation study

Abstract Background Despite increasing support for stakeholder inclusion in research, there is limited evaluative research to guide safe (i.e., youth‐friendly) and meaningful (i.e., non‐tokenistic) partnerships with young people with lived experience of mental ill‐health in research. This paper describes a pilot evaluation and iterative design of a Youth Lived Experience Working Group (LEWG) protocol that was established by the Youth Mental Health and Technology team at The University of Sydney's Brain and Mind Centre, based on the results of two studies. Methods Study one consisted of a pilot evaluation of the extent to which youth partners felt empowered to contribute, to qualitatively explore how LEWG processes could be improved. Youth partners completed online surveys, and results were shared over two LEWG meetings in 2021 to empower youth partners to collectively identify actions of positive change regarding LEWG processes. These meetings were audio‐recorded and transcripts were subsequently coded using thematic analysis. Study two assessed whether LEWG processes and proposed improvements were acceptable and feasible from the perspective of academic researchers via an online survey in 2022. Results Quantitative and qualitative data collected from nine youth partners and 42 academic researchers uncovered initial learnings regarding facilitators, motivators, and barriers to partnering with young people with lived experience in research. Implementing clear processes for youth partners and academic researchers on effective partnership strategies, providing training opportunities for youth partners to develop research skills, and providing regular updates on how youth partner contributions led to research outcomes were identified as key facilitators. Conclusions This pilot study provides insight into a growing international field on how to optimise participatory processes so that researchers and young people with lived experience can be better supported and engaged to make meaningful contributions to mental health research. We argue that more transparency is needed around participatory research processes so that partnerships with young people with lived experience are not merely tokenistic. Consumer Contributions Our study has also been approved by and reflects the concepts and priorities of our youth lived experience partners and lived experience researchers, all of whom are authors of this paper

ATP13A2 (PARK9) protein levels are reduced in brain tissue of cases with Lewy bodies

Background: ATP13A2 (PARK9) loss of function mutations are a genetic cause of an early-onset form of Parkinson’s disease (PD), with in vitro studies showing that ATP13A2 deficits lead to lysosomal and mitochondrial dysfunction and α-synuclein accumulation, while elevated ATP13A2 expression reduces α-synuclein toxicity. The three human brain tissue studies assessing changes in ATP13A2 expression in PD produced divergent results; mRNA is increased while protein levels were observed to be either increased or decreased. This apparent conflict in protein levels might have arisen from examining Lewy body disease cases with coexisting Alzheimer-type pathologies.To assess whether ATP13A2 levels in Lewy body disease are modified by Alzheimer-type β-amyloid deposition, we evaluated cases of pure PD and pure dementia with Lewy bodies (DLB) for changes in ATP13A2, α-synuclein and β-amyloid protein levels in cortical regions with and without Lewy bodies.Results: In all Lewy body disease cases, we identified decreased ATP13A2 protein levels that correlated with increases in both α-synuclein and β-amyloid. Partial colocalization was observed between ATP13A2 and α-synuclein in Lewy bodies, whereas ATP13A2 did not colocalize with pathological β-amyloid deposition.Conclusions: Our data show that patients with Lewy body diseases have an overall deficit in ATP13A2 protein levels, with the remaining protein being more insoluble and partially redistributing towards Lewy bodies. This supports the concept that increasing ATP13A2 levels may offer potential therapeutic benefits to patients with Lewy body diseases

SARS-CoV-2 infection of African green monkeys results in mild respiratory disease discernible by PET/CT imaging and shedding of infectious virus from both respiratory and gastrointestinal tracts.

Vaccines are urgently needed to combat the global coronavirus disease 2019 (COVID-19) pandemic, and testing of candidate vaccines in an appropriate non-human primate (NHP) model is a critical step in the process. Infection of African green monkeys (AGM) with a low passage human isolate of SARS-CoV-2 by aerosol or mucosal exposure resulted in mild clinical infection with a transient decrease in lung tidal volume. Imaging with human clinical-grade 18F-fluoro-2-deoxy-D-glucose positron emission tomography (18F-FDG PET) co-registered with computed tomography (CT) revealed pulmonary lesions at 4 days post-infection (dpi) that resolved over time. Infectious virus was shed from both respiratory and gastrointestinal (GI) tracts in all animals in a biphasic manner, first between 2-7 dpi followed by a recrudescence at 14-21 dpi. Viral RNA (vRNA) was found throughout both respiratory and gastrointestinal systems at necropsy with higher levels of vRNA found within the GI tract tissues. All animals seroconverted simultaneously for IgM and IgG, which has also been documented in human COVID-19 cases. Young AGM represent an species to study mild/subclinical COVID-19 disease and with possible insights into live virus shedding. Future vaccine evaluation can be performed in AGM with correlates of efficacy being lung lesions by PET/CT, virus shedding, and tissue viral load