An evaluation of the Cygnet parenting support programme for parents of children with autism spectrum conditions

Parents of children on the autistic spectrum often struggle to understand the condition and, related to this, manage their child’s behaviour. Cygnet is a parenting intervention which aims to help parents address these difficulties, consequently improving parenting confidence. It is widely used in the United Kingdom (UK). Despite this, there have been few evaluations. This paper reports a small-scale pragmatic evaluation of Cygnet as it was routinely delivered in two English cities. A non-randomised controlled study of outcomes for parents (and their children) was conducted. Data regarding intervention fidelity and delivery costs were also collected. Parents either attending, or waiting to attend, Cygnet were recruited (intervention group: IG, n=35; comparator group: CG, n=32). Parents completed standardised measures of child behaviour and parenting sense of competence pre- and post-intervention, and at three-month follow-up (matched time points for CG). Longer-term outcomes were measured for the IG. IG parents also set specific child behaviour goals. Typically, the programme was delivered as specified by the manual. Attending Cygnet was associated with significant improvements in parenting satisfaction and the specific child behaviour goals. Findings regarding other outcomes were equivocal and further evaluation is required. We conclude that Cygnet is a promising intervention for parents of children with autism in terms of, at least, some outcomes

Overexpression of cdk4 and cyclinD1 triggers greater expansion of neural stem cells in the adult mouse brain

Inducible alterations in expression of cyclinD1 and cdk4 in the adult mouse hippocampus allow temporal control and manipulation of neurogenesis

Mechanism-Based Screen for G1/S Checkpoint Activators Identifies a Selective Activator of EIF2AK3/PERK Signalling

Human cancers often contain genetic alterations that disable G1/S checkpoint control and loss of this checkpoint is thought to critically contribute to cancer generation by permitting inappropriate proliferation and distorting fate-driven cell cycle exit. The identification of cell permeable small molecules that activate the G1/S checkpoint may therefore represent a broadly applicable and clinically effective strategy for the treatment of cancer. Here we describe the identification of several novel small molecules that trigger G1/S checkpoint activation and characterise the mechanism of action for one, CCT020312, in detail. Transcriptional profiling by cDNA microarray combined with reverse genetics revealed phosphorylation of the eukaryotic initiation factor 2-alpha (EIF2A) through the eukaryotic translation initiation factor 2-alpha kinase 3 (EIF2AK3/PERK) as the mechanism of action of this compound. While EIF2AK3/PERK activation classically follows endoplasmic reticulum (ER) stress signalling that sets off a range of different cellular responses, CCT020312 does not trigger these other cellular responses but instead selectively elicits EIF2AK3/PERK signalling. Phosphorylation of EIF2A by EIF2A kinases is a known means to block protein translation and hence restriction point transit in G1, but further supports apoptosis in specific contexts. Significantly, EIF2AK3/PERK signalling has previously been linked to the resistance of cancer cells to multiple anticancer chemotherapeutic agents, including drugs that target the ubiquitin/proteasome pathway and taxanes. Consistent with such findings CCT020312 sensitizes cancer cells with defective taxane-induced EIF2A phosphorylation to paclitaxel treatment. Our work therefore identifies CCT020312 as a novel small molecule chemical tool for the selective activation of EIF2A-mediated translation control with utility for proof-of-concept applications in EIF2A-centered therapeutic approaches, and as a chemical starting point for pathway selective agent development. We demonstrate that consistent with its mode of action CCT020312 is capable of delivering potent, and EIF2AK3 selective, proliferation control and can act as a sensitizer to chemotherapy-associated stresses as elicited by taxanes

Deterministic Effects Propagation Networks for reconstructing protein signaling networks from multiple interventions

<p>Abstract</p> <p>Background</p> <p>Modern gene perturbation techniques, like RNA interference (RNAi), enable us to study effects of targeted interventions in cells efficiently. In combination with mRNA or protein expression data this allows to gain insights into the behavior of complex biological systems.</p> <p>Results</p> <p>In this paper, we propose Deterministic Effects Propagation Networks (DEPNs) as a special Bayesian Network approach to reverse engineer signaling networks from a combination of protein expression and perturbation data. DEPNs allow to reconstruct protein networks based on combinatorial intervention effects, which are monitored via changes of the protein expression or activation over one or a few time points. Our implementation of DEPNs allows for latent network nodes (i.e. proteins without measurements) and has a built in mechanism to impute missing data. The robustness of our approach was tested on simulated data. We applied DEPNs to reconstruct the <it>ERBB </it>signaling network in <it>de novo </it>trastuzumab resistant human breast cancer cells, where protein expression was monitored on Reverse Phase Protein Arrays (RPPAs) after knockdown of network proteins using RNAi.</p> <p>Conclusion</p> <p>DEPNs offer a robust, efficient and simple approach to infer protein signaling networks from multiple interventions. The method as well as the data have been made part of the latest version of the R package "nem" available as a supplement to this paper and via the Bioconductor repository.</p

Co-Depletion of Cathepsin B and uPAR Induces G0/G1 Arrest in Glioma via FOXO3a Mediated p27Kip1 Upregulation

Cathepsin B and urokinase plasminogen activator receptor (uPAR) are both known to be overexpressed in gliomas. Our previous work and that of others strongly suggest a relationship between the infiltrative phenotype of glioma and the expression of cathepsin B and uPAR. Though their role in migration and adhesion are well studied the effect of these molecules on cell cycle progression has not been thoroughly examined.Cathepsin B and uPAR single and bicistronic siRNA plasmids were used to downregulate these molecules in SNB19 and U251 glioma cells. FACS analysis and BrdU incorporation assay demonstrated G0/G1 arrest and decreased proliferation with the treatments, respectively. Immunoblot and immunocyto analysis demonstrated increased expression of p27(Kip1) and its nuclear localization with the knockdown of cathepsin B and uPAR. These effects could be mediated by alphaVbeta3/PI3K/AKT/FOXO pathway as observed by the decreased alphaVbeta3 expression, PI3K and AKT phosphorylation accompanied by elevated FOXO3a levels. These results were further confirmed with the increased expression of p27(Kip1) and FOXO3a when treated with Ly294002 (10 microM) and increased luciferase expression with the siRNA and Ly294002 treatments when the FOXO binding promoter region of p27(Kip1) was used. Our treatment also reduced the expression of cyclin D1, cyclin D2, p-Rb and cyclin E while the expression of Cdk2 was unaffected. Of note, the Cdk2-cyclin E complex formation was reduced significantly.Our study indicates that cathepsin B and uPAR knockdown induces G0/G1 arrest by modulating the PI3K/AKT signaling pathway and further increases expression of p27(Kip1) accompanied by the binding of FOXO3a to its promoter. Taken together, our findings provide molecular mechanism for the G0/G1 arrest induced by the downregulation of cathepsin B and uPAR in SNB19 and U251 glioma cells

Multiple Mechanisms for E2F Binding Inhibition by Phosphorylation of the Retinoblastoma Protein C-Terminal Domain

The retinoblastoma proteinC-terminal domain (RbC) is necessary for the tumor suppressor protein's activities in growth suppression and E2F transcription factor inhibition. Cyclin-dependent kinase phosphorylation of RbC contributes to Rb inactivation and weakens the Rb-E2F inhibitory complex. Here we demonstratetwo mechanisms for how RbC phosphorylation inhibits E2F binding. We find that phosphorylation of S788 and S795 weakens the direct association between the N-terminal portion of RbC (RbC(N)) and the marked-box domains of E2F and its heterodimerization partner DP. Phosphorylation of these sites and S807/S811 also induces an intramolecular association between RbC and the pocket domain,which overlaps with the site of E2F transactivation domain binding. Areduction in E2F binding affinity occurs with S788/S795 phosphorylation that is additive with the effects of phosphorylation at other sites, and we propose a structural mechanism that explains this additivity. We find that different Rb phosphorylation events have distinct effects on activating E2F family members, which suggests a novel mechanism for how Rb may differentially regulate E2F activities

Meta-cognitive beliefs about worry and pain catastrophising as mediators between neuroticism and pain behaviour

© 2015 The Australian Psychological SocietyBackground: The present study explored the relationship between neuroticism, meta-cognitive beliefs about worry, pain catastrophising, and pain behaviour. Methods: A non-clinical convenience sample of 308 participants completed the following four measures in this cross-sectional study: Neo Five-Factor Inventory, Meta-Cognitions Questionnaire 30, Pain Catastrophising Scale, and the Pain Behaviour Checklist. Results: A multiple-step multiple mediator analysis was employed to test a model in which (1) positive meta-cognitive beliefs about worry would mediate the relationship between neuroticism and pain catastrophising and (2) negative meta-cognitive beliefs about worry would mediate the relationship between pain catastrophising and self-reported pain behaviour. We also hypothesised that the combined effects of meta-cognitive beliefs about worry and pain catastrophising on self-reported pain behaviour would be independent of neuroticism. Results supported the proposed structure with pain catastrophising and meta-cognitive beliefs about worry mediating fully the effect of neuroticism on self-reported pain behaviour. Conclusions: These findings identify, for the first time in the literature, a link between meta-cognitive beliefs about worry and both self-reported pain behaviour and pain catastrophising. The implications of these findings are discussed. This is an electronic version of an article published in Spada, MM and Gay, H and Nikčevic, AV and Fernie, BA and Caselli, G (2016) Meta-cognitive beliefs about worry and pain catastrophising as mediators between neuroticism and pain behaviour. Clinical Psychologist, 20 (3). pp. 138-146. DOI 10.1111/cp.1208