Functional analysis of the CD8[beta] polypeptide and its role in T cell differentiation

The CD8 molecule is a cell surface glycoprotein that is expressed predominantly on class I MHC-restricted T cells. CD8 is expressed as a disulphide-linked a heterodimer on the surface of thymocytes and peripheral T cells. Much of the work establishing the role of CD8 as a coreceptor has concentrated on CD8a, which interacts with the a3 region of MHC class I molecules and intracellularly with the protein tyrosine kinase p56lck. Recently an important role for the CD8β chain in thymic development and antigen responsiveness has been suggested. Previous biochemical analysis of the CD8β chain has shown that there is a decrease in the sialylation of O-linked sugars during T cell maturation and on T cell activation. The alteration in sialic acid levels is specific for the CD8β chain, and is predicted to occur within the connective peptide region, between the external and transmembrane domains. Glycosylation analysis of the CD8 complex from thymocytes and resting T cells show the O-glycans have a core 1 structure with sialic acid joined in the a2-6 linkage to galNAc. On activation the O-glycans appear to become hyposialylated and change their core structure, influenced by changes in the O-glycan biosynthetic pathway. To examine the role of the connecting peptide region of CD8β, transgenic CD8βa Hinge mice have been constructed with a hybrid molecule in which the connecting peptide region of CD8β has been exchanged with the corresponding region of CD8a. The transgenic mice were backcrossed onto the CD8β knockout to allow the role of the hybrid molecule to be studied in the absence of the endogenous CD8β molecule. The CD8βaH transgenic mice show a partial block in T cell differentiation subsequent to the double positive stage in the thymus which results in reduced CD8 T cell numbers in the periphery. This phenotype seems to mirror the phenotype of the CD8β knockout suggesting the hybrid molecule was unable to restore CD8β function in these mice. Biochemical analysis of the transgenic mice shows the hinge region of the CD8βaH molecule is more heavily glycosylated than either CD8β or CD8a. Two additional polypeptides, of 14kD and 26kD molecular weight, were shown to associate with the CD8 complex. The 14kD molecule is a novel polypeptide which associates with CD8 complex in thymocytes and resting T lymphocytes, but not activated T lymphocytes. The presence of the molecule was thought to be linked to the changes in glycosylation of CD8β, but was found to co-precipitate with the CD8 complex from CD8β-deficient mice, suggesting that it does not associate with CD8β. The 26kD molecule was found only within the cell and was not present in CD8β-deficient mice. It is thought that this novel polypeptide may be involved in the developmentally regulated transport of CD8, since in the absence of CD8β and p26 a block in the cellular transport of CD8 was found with a build up of partially glycosylated precursors held in the ER. These results suggest CD8[beta] has a role in T cell differentiation and that part of its function may be mediated through the glycosylated hinge region, which may have a unique role within the TCR/MHC complex

Obstetric complications as a risk factor for bipolar affective disorder: Comparison with matched non-psychiatric controls

Background Family studies have consistently shown that the morbid risk of bipolar affective disorder (BP) in the relatives of BP probands is higher compared with that of the general population. However, concordance rates of less than 100% in identical twins indicate that in addition to genetic factors, environmental factors must contribute to the aetiology of BP. One environmental factor found to be associated with the subsequent development of several psychiatric illnesses is obstetric complications (OCs). A systematic review of OCs as a risk factor for the development of BP found that there was insufficient data to support the hypothesis that OCs are a risk factor for BP and thus more rigorous systematic studies with large enough sample sizes to avoid a type II error are required. Aims To determine whether OCs are more common in individuals with BP compared to matched non-psychiatric controls. Hypotheses 1. More individuals with BP will have experienced OCs compared to matched controls. 2. Individuals with BP will have experienced a greater number of OCs compared to matched controls Method The methodology of this study involved linking the Scottish Morbidity Records (SMR) held at Information Statistics Division Scotland. The psychiatric inpatients register (SMR4) was used to identify all individuals born in Scotland between 1969 and 1974 who were subsequently admitted in Scotland with a diagnosis of BP. A link was established between this register and the maternity inpatient and day case register (SMR2) which provided all relevant obstetric information and a matched control for each for the BP probands. A case-control comparison was carried out for the prevalence of each pregnancy, labour, delivery and neonatal complication and the mean number of complications experienced in each period. Results A similar number of cases and controls had experienced OCs and the mean number of complications experienced by individuals in each group did not differ. A case control comparison of the individual obstetric events recorded on SMR2 however indicated that mothers of females with BP had significantly more previous pregnancies (1.8, sd 2.0 vs. 1.4, sd 1.5) and therefore a significantly higher parity (1.6, sd 1.9 vs. 1.2, sd 1.4) than mothers of controls. Further analysis of this variable indicated that the female offspring of mothers with a parity of three or more were at significantly increased risk of BP (OR 2.2, 95% Cl 1.3-3.9). Furthermore the offspring of mothers who had had more than one x-ray during their pregnancy were at increased risk of BP (OR 4.2, 95% Cl 1.2-14.7). Comparison of the mean birthweight of each diagnostic group indicated that the male probands were significantly smaller at birth (3282 grams vs. 3398 grams) however low birth weight (<2500 grams) did not significantly increase the risk of BP (OR 1.6, 95% Cl 0.7-3.4). Conclusion This large prospective study failed to support the hypotheses that significantly more individuals with BP experienced OCs and that the mean number of OCs experienced by the individuals with BP was significantly greater. The principal research implication of this study is the need for more systematic studies reporting on the frequency of specific OCs in addition to reporting the number of subjects in each group who experienced any definite OCs

Guided self-help cognitive behavioural therapy for depression in primary care : a randomised controlled trial

Peer reviewedPublisher PD

The Saliency of Gestural Misinformation in the Perception of a Violent Crime

This is the accepted manuscript version of the following article: Daniel J. gurney, Louise R. Ellis & Emily Vardn-Hynard, ‘The saliencey of gestural misinformation in the perception of a violent crime’, Psychology, Crime & Law, Vol. 22(7): 651-665, first published online 18 April 2016. The version of record is available online via doi: http://dx.doi.org/10.1080/1068316X.2016.1174860 Published by Taylor & Francis Online.Recent research has revealed that misinformation from gestures can influence eyewitness memory. However, while the effects of verbal influence have been shown to have major impacts on prosecution, gestural misinformation is yet to demonstrate misinformation effects to this extent. To investigate the salience of suggestions provided nonverbally, and how these compare to those made verbally, two experiments were conducted. In Experiment 1, participants watched footage of a crime scene and were presented with one of two types of gestures during questioning that suggested different interpretations of the crime. The results confirmed that the gestures influenced responses with participants altering their interpretation of the crime according to the information gestured to them. Experiment 2 built on this to investigate how comparable this gestural influence was to verbal influence. The results revealed that gestural misinformation caused participants to alter their interpretation of the crime and elicited the same effects as verbal misinformation. Additionally, participants were less likely to have felt misled from gestures as they were from speech. These results reveal new insights into the strength of gestural misinformation and show that, despite their subtle nature in communication, gestures can exert a powerful influence in eyewitness interviews.Peer reviewedFinal Accepted Versio

The differential regulation of Lck kinase phosphorylation sites by CD45 is critical for T cell receptor signaling responses

SummaryThe molecular mechanisms whereby the CD45 tyrosine phosphatase (PTPase) regulates T cell receptor (TCR) signaling responses remain to be elucidated. To investigate this question, we have reconstituted CD45 (encoded by Ptprc)-deficient mice, which display severe defects in thymic development, with five different expression levels of transgenic CD45RO, or with mutant PTPase null or PTPase-low CD45R0. Whereas CD45 PTPase activity was absolutely required for the reconstitution of thymic development, only 3% of wild-type CD45 activity restored T cell numbers and normal cytotoxic T cell responses. Lowering the CD45 expression increased CD4 lineage commitment. Peripheral T cells with very low activity of CD45 phosphatase displayed reduced TCR signaling, whereas intermediate activity caused hyperactivation of CD4+ and CD8+ T cells. These results are explained by a rheostat mechanism whereby CD45 differentially regulates the negatively acting pTyr-505 and positively acting pTyr-394 p56lck tyrosine kinase phosphorylation sites. We propose that high wild-type CD45 expression is necessary to dephosphorylate p56lck pTyr-394, suppressing CD4 T+ cell lineage commitment and hyperactivity

Articulating Value in Cooperative Housing: International and Methodological Review

Housing cooperatives are a growing presence in Australia’s housing system, providing a diversity of housing forms to a variety of household types across the income spectrum, typically serving low- and moderate-income households. International evidence shows that housing cooperatives can provide a range of housing from very low price points through to market rate in both non-urban and urban contexts. The research presented in this report reviewed a selection of international cooperative housing sectors in addition to the Australian context, with two aims: 1. Compile the current evidence for the social and financial benefits of housing cooperatives, to develop a framework to assess this in Australia; and, 2. Identify preliminary issues regarding the growth and diversification of housing cooperatives in Australia

Policing Hate Crime: Exploring the Issue with a Cohort of Sworn Police Officers

Globally, there has been a trend in rising levels of hate crime that scholars have argued is reflective of significant social problems within society. Research into hate crime has typically focused on the police and their subsequent response to this crime type, with many findings reporting that the police are racist, homophobic and Islamophobic, to name but a few. However, existing research seldom captures the insights and experiences of sworn police officers, as much of the data is gathered from third parties. This paper presents the empirical findings from a Delphi study conducted with one police force in Australia, sampling sworn New South Wales (NSW) police officers between October 2020 and October 2021. The findings focus on four overarching areas: defining hate crime, perpetrators of hate crime, victims of hate crime, and responses to hate crime. These themes capture the perspectives of NSW police officers in relation to operational and organisational practice in respect of hate crime. Drawing on a Delphi method, the research outlines police perceptions of the nature of hate crime, as well as capturing how hate crime can be effectively reported, recorded, and responded to. Conclusions and implications are considered. These include the requirement for a clearer definition and targeted education strategies aimed at improving knowledge and understanding relating to hate crime. Future directions include the development of a standardised approach to reporting, recording, and responding to hate crime

Evaluation of the Reducing Reoffending Change Fund

The independent evaluation of the Reducing Reoffending Change Fund (RRCF) assessed the extent to which the Public Social Partnership (PSP) model delivers effective mentoring services that reduce the risk of reoffending and support reintegration, and concluded that there is a strong case for the continuation and expansion of mentoring services

Evaluation of the Reducing Reoffending Change Fund: Research Findings

This report presents the findings of an independent evaluation of the Reducing Reoffending Change Fund (RRCF). This was undertaken by Ipsos MORI Scotland between September 2013 and November 2015. The aim of the evaluation was to provide a comprehensive assessment of the extent to which the Public Social Partnership (PSP) model delivers effective mentoring services that reduce the risk of reoffending and support reintegration. The report concludes that mentoring is an effective approach which helps mentees to learn and implement constructive, non-criminal ways of addressing problems in their lives and to reduce risk factors associated with offending behaviour, and that there is a strong case for the continuation and expansion of mentoring services