Cellular expression, trafficking, and function of two isoforms of human ULBP5/RAET1G

Background: The activating immunoreceptor NKG2D is expressed on Natural Killer (NK) cells and subsets of T cells. NKG2D contributes to anti-tumour and anti-viral immune responses in vitro and in vivo. The ligands for NKG2D in humans are diverse proteins of the MIC and ULBP/RAET families that are upregulated on the surface of virally infected cells and tumours. Two splicing variants of ULBP5/RAET1G have been cloned previously, but not extensively characterised. Methodology/Principal Findings: We pursue a number of approaches to characterise the expression, trafficking, and function of the two isoforms of ULBP5/RAET1G. We show that both transcripts are frequently expressed in cell lines derived from epithelial cancers, and in primary breast cancers. The full-length transcript, RAET1G1, is predicted to encode a molecule with transmembrane and cytoplasmic domains that are unique amongst NKG2D ligands. Using specific anti-RAET1G1 antiserum to stain tissue microarrays we show that RAET1G1 expression is highly restricted in normal tissues. RAET1G1 was expressed at a low level in normal gastrointestinal epithelial cells in a similar pattern to MICA. Both RAET1G1 and MICA showed increased expression in the gut of patients with celiac disease. In contrast to healthy tissues the RAET1G1 antiserum stained a wide variety or different primary tumour sections. Both endogenously expressed and transfected RAET1G1 was mainly found inside the cell, with a minority of the protein reaching the cell surface. Conversely the truncated splicing variant of RAET1G2 was shown to encode a soluble molecule that could be secreted from cells. Secreted RAET1G2 was shown to downregulate NKG2D receptor expression on NK cells and hence may represent a novel tumour immune evasion strategy. Conclusions/Significance: We demonstrate that the expression patterns of ULBP5RAET1G are very similar to the well-characterised NKG2D ligand, MICA. However the two isoforms of ULBP5/RAET1G have very different cellular localisations that are likely to reflect unique functionality

The dopamine D2/D3 receptor agonist quinpirole increases checking-like behaviour in an operant observing response task with uncertain reinforcement: a novel possible model of OCD.

Excessive checking is a common, debilitating symptom of obsessive-compulsive disorder (OCD). In an established rodent model of OCD checking behaviour, quinpirole (dopamine D2/3-receptor agonist) increased checking in open-field tests, indicating dopaminergic modulation of checking-like behaviours. We designed a novel operant paradigm for rats (observing response task (ORT)) to further examine cognitive processes underpinning checking behaviour and clarify how and why checking develops. We investigated i) how quinpirole increases checking, ii) dependence of these effects on D2/3 receptor function (following treatment with D2/3 receptor antagonist sulpiride) and iii) effects of reward uncertainty. In the ORT, rats pressed an 'observing' lever for information about the location of an 'active' lever that provided food reinforcement. High- and low-checkers (defined from baseline observing) received quinpirole (0.5mg/kg, 10 treatments) or vehicle. Parametric task manipulations assessed observing/checking under increasing task demands relating to reinforcement uncertainty (variable response requirement and active-lever location switching). Treatment with sulpiride further probed the pharmacological basis of long-term behavioural changes. Quinpirole selectively increased checking, both functional observing lever presses (OLPs) and non-functional extra OLPs (EOLPs). The increase in OLPs and EOLPs was long-lasting, without further quinpirole administration. Quinpirole did not affect the immediate ability to use information from checking. Vehicle and quinpirole-treated rats (VEH and QNP respectively) were selectively sensitive to different forms of uncertainty. Sulpiride reduced non-functional EOLPs in QNP rats but had no effect on functional OLPs. These data have implications for treatment of compulsive checking in OCD, particularly for serotonin-reuptake-inhibitor treatment-refractory cases, where supplementation with dopamine receptor antagonists may be beneficial

A large-scale test of the relationship between procrastination and performance using learning analytics

Many studies have found a relationship between students’ self-reported procrastination and their grades. Few studies have used learning analytic data as a behavioural measure of procrastination in order to predict performance, and there is no systematic research on how this relationship may differ across assessments or disciplines. In this study we analyse nine years’ worth of institutional electronic submission records, a total of 73,608 assignment submissions, to examine the relationship between submission time and grades across assignments, students, courses, and disciplines in higher education. A significant negative relationship was found overall, with students who submitted closer to the deadline obtaining lower grades, however the size of the relationship was negligible, accounting for less than 1% of the variance in grades. The relationship varied significantly depending on student, assignment, course, and discipline

“My Values Keep Me Well… Would They Help Other People?”: A Thematic Analysis Exploring the Values and Values-Based Behaviours of People Facing Severe and Multiple Disadvantage

Individuals facing Severe and Multiple Disadvantage (SMD) have experience of at least three of the following: homelessness, substance use, mental illness, offending, and domestic violence. There is a push towards providing better support for people facing SMD and yet little research on what the “best” support looks like. Values motivate behaviour across various contexts, and helping an individual identify their values can lead to greater enactment of positive behavioural change. This study aimed to identify and explore the values of people facing SMD, the barriers and facilitators to enacting these values, and the perceived helpfulness of service provision in encouraging values-based behaviour or change. Twelve participants took part in semi-structured interviews. Reflexive thematic analysis resulted in four themes: values are idiosyncratic and interconnected; the benefits of value identification and enactment; the risks and challenges of value identification and enactment; and the relationship between values and support. Results offer preliminary evidence for the potential use of values in providing helpful, person-centered support for people facing SMD. Values work could arguably be integrated into any level of support for those facing SMD to support values-based living and change. Further research on the use and efficacy of values-focused interventions in SMD is needed

“My Values Keep Me Well… Would They Help Other People?”: A Thematic Analysis Exploring the Values and Values-Based Behaviours of People Facing Severe and Multiple Disadvantage

Individuals facing Severe and Multiple Disadvantage (SMD) have experience of at least three of the following: homelessness, substance use, mental illness, offending, and domestic violence. There is a push towards providing better support for people facing SMD and yet little research on what the “best” support looks like. Values motivate behaviour across various contexts, and helping an individual identify their values can lead to greater enactment of positive behavioural change. This study aimed to identify and explore the values of people facing SMD, the barriers and facilitators to enacting these values, and the perceived helpfulness of service provision in encouraging values-based behaviour or change. Twelve participants took part in semi-structured interviews. Reflexive thematic analysis resulted in four themes: values are idiosyncratic and interconnected; the benefits of value identification and enactment; the risks and challenges of value identification and enactment; and the relationship between values and support. Results offer preliminary evidence for the potential use of values in providing helpful, person-centered support for people facing SMD. Values work could arguably be integrated into any level of support for those facing SMD to support values-based living and change. Further research on the use and efficacy of values-focused interventions in SMD is needed. </p

Animal models of obsessive-compulsive spectrum disorders

Obsessive-compulsive disorder (OCD) and related conditions (trichotillomania, pathological skin-picking, pathological nail-biting) are common and disabling. Current treatment approaches fail to help a significant proportion of patients. Multiple tiers of evidence link these conditions with underlying dysregulation of particular cortico-subcortical circuitry and monoamine systems, which represent targets for treatment. Animal models designed to capture aspects of these conditions are critical for several reasons. First, they help in furthering our understanding of neuroanatomical and neurochemical underpinnings of the obsessive-compulsive (OC) spectrum. Second, they help to account for the brain mechanisms by which existing treatments (pharmacotherapy, psychotherapy, deep brain stimulation) exert their beneficial effects on patients. Third, they inform the search for novel treatments. This article provides a critique of key animal models for selected OC spectrum disorders, beginning with initial work relating to anxiety, but moving on to recent developments in domains of genetic, pharmacological, cognitive, and ethological models. We find that there is a burgeoning literature in these areas with important ramifications, which are considered, along with salient future lines of research.</p

Baseline characteristics, management practices, and in-hospital outcomes of patients hospitalized with acute coronary syndromes in the Global Registry of Acute Coronary Events (GRACE)

Acute coronary syndrome (ACS) represents a heterogenous spectrum of conditions. The Global Registry of Acute Coronary Events (GRACE) describes the epidemiology, management, and outcomes of patients with ACS. Data were collected from 11,543 patients enrolled in 14 countries. Of these patients, 30% had ST-segment elevation myocardial infarction (STEMI), 25% had non-ST-segment elevation myocardial infarction (NSTEMI), 38% had unstable angina pectoris, and 7% had other cardiac or noncardiac diagnoses. Over half of these patients (53%) were >/=65 years old. Reperfusion therapy was used in 62% of patients with STEMI. Percutaneous coronary intervention was performed in 40% of these subjects during the index admission. Intravenous glycoprotein IIb/IIIa blockers were used in 23%, 20%, and 7% of patients with STEMI, NSTEMI, and unstable angina, respectively (STEMI vs NSTEMI, p = 0.0018, and for either group vs unstable angina,