170 research outputs found
Experiences of mindfulness training in living with rheumatic disease: an interpretative phenomenological analysis
This study examined experiences of Mindfulness training for 5 adults living with Rheumatic Disease. Focus group data was used to explore the experience and impact of Mindfulness training in participants aged between 46 and 69 diagnosed with Psoriatic Arthritis, Fibromyalgia or Rheumatoid Arthritis. All participants had completed an 8-week Mindfulness-Based Stress Reduction Programme (MBSR) 6 months prior to the study. Interpretative Phenomenological Analysis produced two themes: âresponding to painâ and âpsychological well-beingâ. All participants spoke similarly and with enthusiasm, reflecting the strength of the impact of Mindfulness upon the daily lives of these individuals. Methodological limitations are considered along with clinical applications and suggestions for future research. The findings from this study reinforce the outcomes of previous research and indicate that Mindfulness has potential to improve the health and well-being of individuals living with Rheumatic Disease
National Evaluation of the Capacity Building Programme in English Local Government: Evaluation of the National Programmes: Annex 2: Evaluation of the National Programmes
The report is one of a series of outputs from the national evaluation of the CBP, being undertaken by a team of researchers at the Policy Research Institute (PRI) at Leeds Metropolitan University and the Cities Research Unit at the University of West of England. The Capacity Building Programme for local government was launched in 2003 as a joint Department for Communities and Local Government (DCLG) / Local Government Association (LGA) initiative to support capacity building and improvement activities within local authorities in England. The evaluation of the Capacity Building Programme has been underway since late 2004. A scoping phase was conducted until May 2005, including a short evaluation of the Pilot Programmes. The main phase of the evaluation commenced in September 2005 and encompassed four main phases (see Section 1.3: p10)
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Baseline T cell dysfunction by single cell network profiling in metastatic breast cancer patients.
BackgroundWe previously reported the results of a multicentric prospective randomized trial of chemo-refractory metastatic breast cancer patients testing the efficacy of two doses of TGFβ blockade during radiotherapy. Despite a lack of objective responses to the combination, patients who received a higher dose of TGFβ blocking antibody fresolimumab had a better overall survival when compared to those assigned to lower dose (hazard ratio of 2.73, pâ=â0.039). They also demonstrated an improved peripheral blood mononuclear cell (PBMC) counts and increase in the CD8 central memory pool. We performed additional analysis on residual PBMC using single cell network profiling (SCNP).MethodsThe original trial randomized metastatic breast cancer patients to either 1 or 10âmg/kg of fresolimumab, every 3âweeks for 5âcycles, combined with radiotherapy to a metastatic site at week 1 and 7 (22.5âGy given in 3 doses of 7.5âGy). Trial immune monitoring results were previously reported. In 15 patients with available residual blood samples, additional functional studies were performed, and compared with data obtained in parallel from seven healthy female donors (HD): SCNP was applied to analyze T cell receptor (TCR) modulated signaling via CD3 and CD28 crosslinking and measurement of evoked phosphorylation of AKT and ERK in CD4 and CD8 T cell subsets defined by PD-1 expression.ResultsAt baseline, a significantly higher level of expression (pâ<â0.05) of PD-L1 was identified in patient monocytes compared to HD. TCR modulation revealed dysfunction of circulating T-cells in patient baseline samples as compared to HD, and this was more pronounced in PD-1+ cells. Treatment with radiotherapy and fresolimumab did not resolve this dyfunctional signaling. However, in vitro PD-1 blockade enhanced TCR signaling in patient PD-1+ T cells and not in PD-1- T cells or in PD-1+ T cells from HD.ConclusionsFunctional T cell analysis suggests that baseline T cell functionality is hampered in metastatic breast cancer patients, at least in part mediated by the PD-1 signaling pathway. These preliminary data support the rationale for investigating the possible beneficial effects of adding PD-1 blockade to improve responses to TGFβ blockade and radiotherapy.Trial registrationNCT01401062
Palmitoylation of human proteinase-activated receptor-2 differentially regulates receptor-triggered ERK1/2 activation, calcium signalling and endocytosis
hPAR2 (human proteinase-activated receptor-2) is a member of the novel family of proteolytically activated GPCRs (G-protein-coupled receptors) termed PARs (proteinase-activated receptors). Previous pharmacological studies have found that activation of hPAR2 by mast cell tryptase can be regulated by receptor N-terminal glycosylation. In order to elucidate other post-translational modifications of hPAR2 that can regulate function, we have explored the functional role of the intracellular cysteine residue Cys361. We have demonstrated, using autoradiography, that Cys361 is the primary palmitoylation site of hPAR2. The hPAR2C361A mutant cell line displayed greater cell-surface expression compared with the wt (wild-type)-hPAR2-expressing cell line. hPAR2C361A also showed a decreased sensitivity and efficacy (intracellular calcium signalling) towards both trypsin and SLIGKV. In stark contrast, hPAR2C361A triggered greater and more prolonged ERK (extracellular-signal-regulated kinase) phosphorylation compared with that of wt-hPAR2 possibly through Gi, since pertussis toxin inhibited the ability of this receptor to activate ERK. Finally, flow cytometry was utilized to assess the rate and extent of receptor internalization following agonist challenge. hPAR2C361A displayed faster internalization kinetics following trypsin activation compared with wt-hPAR2, whereas SLIGKV had a negligible effect on internalization for either receptor. In conclusion, palmitoylation plays an important role in the regulation of PAR2 expression, agonist sensitivity, desensitization and internalization
Palmitoylation and membrane cholesterol stabilize Îź-opioid receptor homodimerization and G protein coupling
<p>Abstract</p> <p>Background</p> <p>A cholesterol-palmitoyl interaction has been reported to occur in the dimeric interface of the β<sub>2</sub>-adrenergic receptor crystal structure. We sought to investigate whether a similar phenomenon could be observed with Ο-opioid receptor (OPRM1), and if so, to assess the role of cholesterol in this class of G protein-coupled receptor (GPCR) signaling.</p> <p>Results</p> <p>C3.55(170) was determined to be the palmitoylation site of OPRM1. Mutation of this Cys to Ala did not affect the binding of agonists, but attenuated receptor signaling and decreased cholesterol associated with the receptor signaling complex. In addition, both attenuation of receptor palmitoylation (by mutation of C3.55[170] to Ala) and inhibition of cholesterol synthesis (by treating the cells with simvastatin, a HMG-CoA reductase inhibitor) impaired receptor signaling, possibly by decreasing receptor homodimerization and Gιi2 coupling; this was demonstrated by co-immunoprecipitation, immunofluorescence colocalization and fluorescence resonance energy transfer (FRET) analyses. A computational model of the OPRM1 homodimer structure indicated that a specific cholesterol-palmitoyl interaction can facilitate OPRM1 homodimerization at the TMH4-TMH4 interface.</p> <p>Conclusions</p> <p>We demonstrate that C3.55(170) is the palmitoylation site of OPRM1 and identify a cholesterol-palmitoyl interaction in the OPRM1 complex. Our findings suggest that this interaction contributes to OPRM1 signaling by facilitating receptor homodimerization and G protein coupling. This conclusion is supported by computational modeling of the OPRM1 homodimer.</p
Identification and Preliminary Characterization of a Chitinase Gene in the Autographa californica Nuclear Polyhedrosis Virus Genome
AbstractA functional chitinase gene (chiA) has been identified in the genome of the Autographa californica nuclear polyhedrosis virus (AcMNPV). It is expressed in the late phase of virus replication in insect cells. High levels of both endo- and exochitinase activity were detected by 12 hr p.i. and remained stable throughout infection. An AcMNPV chiA protein-specific antibody was prepared using recombinant material prepared in bacteria. This was used to demonstrate that a product of approximately 58 kDa was synthesised in virus-infected cells. Immunofluorescence analysis of virus-infected cells showed that most chitinase was located in the cytoplasm. Primer extension analysis of mRNA from AcMNPV-infected cells confirmed that transcription initiated from a baculovirus late start site (TAAG), 14 nucleotides upstream from the putative translation initiation codon. The predicted protein sequence of the AcMNPV chiA shares extensive sequence similarity with chitinases from bacteria and, in particular, the Serratia marcescens chitinase A (60.5% identical residues). Phylogenetic analyses indicate that AcMNPV, or an ancestral baculovirus, acquired the chitinase gene from a bacterium via horizontal gene transfer
Costs and benefits of processivity in enzymatic degradation of recalcitrant polysaccharides
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