‘Small Project, Big Difference’: capacity building through a national volunteering fund : An Evaluation of The Department of Health’s Health and Social Care Volunteering Fund

This article reports the findings of a mixed methods evaluation study on the impact of a national fund to support volunteering as a mechanism to achieve health and social goals, within the Department of Health’s Volunteering Fund Programme (HSCVF). This paper adds understanding of the mechanisms through which government organisations can build VSCE organisational capacity to support volunteers. Firstly, the programme increased capacity via resource mobilisation to enhance volunteer recruitment, secondly it strengthened voluntary, community and social enterprise (VCSE) organisations through linkages and finally the programme supported development and learning. The HSCVF impacted upon both volunteering projects and host organisations to produce a range of positive outcomes that were particularly marked in smaller organisations: ‘small project, big difference’. Successful community capacity building can result from programmes such as HSCVF, with this paper contributing to the evidence base by detailing the processes through which this occurred

Modeling the evolution space of breakage fusion bridge cycles with a stochastic folding process

Breakage-Fusion-Bridge cycles in cancer arise when a broken segment of DNA is duplicated and an end from each copy joined together. This structure then 'unfolds' into a new piece of palindromic DNA. This is one mechanism responsible for the localised amplicons observed in cancer genome data. The process has parallels with paper folding sequences that arise when a piece of paper is folded several times and then unfolded. Here we adapt such methods to study the breakage-fusion-bridge structures in detail. We firstly consider discrete representations of this space with 2-d trees to demonstrate that there are 2^(n(n-1)/2) qualitatively distinct evolutions involving n breakage-fusion-bridge cycles. Secondly we consider the stochastic nature of the fold positions, to determine evolution likelihoods, and also describe how amplicons become localised. Finally we highlight these methods by inferring the evolution of breakage-fusion-bridge cycles with data from primary tissue cancer samples

The effect of the systemic inflammatory response on plasma vitamin 25 (OH) D concentrations adjusted for albumin

<b>Aim</b><p></p> To examine the relationship between plasma 25(OH)D, CRP and albumin concentrations in two patient cohorts.<p></p> <b>Methods</b><p></p> 5327 patients referred for nutritional assessment and 117 patients with critical illness were examined. Plasma 25 (OH) D concentrations were measured using standard methods. Intra and between assay imprecision was <10%.<p></p> <b>Result</b><p></p> In the large cohort, plasma 25 (OH) D was significantly associated with CRP (rs = −0.113, p<0.001) and albumin (rs = 0.192, p<0.001). 3711 patients had CRP concentrations ≤10 mg/L; with decreasing albumin concentrations ≥35, 25–34 and <25 g/l, median concentrations of 25 (OH) D were significantly lower from 35 to 28 to 14 nmol/l (p<0.001). This decrease was significant when albumin concentrations were reduced between 25–34 g/L (p<0.001) and when albumin <25 g/L (p<0.001). 1271 patients had CRP concentrations between 11–80 mg/L; with decreasing albumin concentrations ≥35, 25–34 and <25 g/l, median concentrations of 25 (OH) D were significantly lower from 31 to 24 to 19 nmol/l (p<0.001). This decrease was significant when albumin concentration were 25–34 g/L (p<0.001) and when albumin <25 g/L (p<0.001). 345 patients had CRP concentrations >80 mg/L; with decreasing albumin concentrations ≥35, 25–34 and <25 g/l, median concentrations of 25 (OH) D were not significantly altered varying from 19 to 23 to 23 nmol/l. Similar relationships were also obtained in the cohort of patients with critical illness.<p></p> <b>Conclusion</b><p></p> Plasma concentrations of 25(OH) D were independently associated with both CRP and albumin and consistent with the systemic inflammatory response as a major confounding factor in determining vitamin D status.<p></p&gt

Regulation of Thromboxane Receptor Signaling at Multiple Levels by Oxidative Stress-Induced Stabilization, Relocation and Enhanced Responsiveness

Thromboxane A(2) (TxA(2)) is a major, unstable arachidonic acid metabolite, and plays a key role in normal physiology and control of vascular tone. The human thromboxane receptor (TPβ), expressed in COS-7 cells, is located predominantly in the endoplasmic reticulum (ER). Brief hydrogen peroxide exposure increases the efficiency of translocation of TPβ from the ER into the Golgi complex, inducing maturation and stabilization of TPβ. However, the ultimate fate of this post-ER TPβ pool is not known, nor is its capacity to initiate signal transduction. Here we specifically assessed if functional TPβ was transported to the plasma membrane following H(2)O(2) exposure.We demonstrate, by biotinylation and confocal microscopy, that exposure to H(2)O(2) results in rapid delivery of a cohort of TPβ to the cell surface, which is stable for at least eight hours. Surface delivery is brefeldin A-sensitive, indicating that translocation of this receptor cohort is from internal pools and via the Golgi complex. H(2)O(2) treatment results in potentiation of the increase to intracellular calcium concentrations in response to TPβ agonists U46619 and 8-iso PGF(2α) and also in the loss of ligand-dependent receptor internalization. Further there is increased responsiveness to a second application of the agonist. Finally we demonstrate that the effect of H(2)O(2) on stimulating surface delivery is shared with the FP prostanoid receptor but not the EP3 or EP4 receptors.In summary, brief exposure to H(2)O(2) results in an immediate and sustained increase in the surface pool of thromboxane receptor that is capable of mediating a persistent hyper-responsiveness of the cell and suggests a highly sophisticated mechanism for rapidly regulating thromboxane signaling

Inhaled nitric oxide alleviates hyperoxia suppressed phosphatidylcholine synthesis in endotoxin-induced injury in mature rat lungs

BACKGROUND: We investigated efficacy of inhaled nitric oxide (NO) in modulation of metabolism of phosphatidylcholine (PC) of pulmonary surfactant and in anti-inflammatory mechanism of mature lungs with inflammatory injury. METHODS: Healthy adult rats were divided into a group of lung inflammation induced by i.v. lipopolysaccharides (LPS) or a normal control (C) for 24 h, and then exposed to: room air (Air), 95% oxygen (O), NO (20 parts per million, NO), both O and NO (ONO) as subgroups, whereas [(3)H]-choline was injected i.v. for incorporation into PC of the lungs which were processed subsequently at 10 min, 4, 8, 12 and 24 h, respectively, for measurement of PC synthesis and proinflammatory cytokine production. RESULTS: LPS-NO subgroup had the lowest level of labeled PC in total phospholipids and disaturated PC in bronchoalveolar lavage fluid and lung tissue (decreased by 46–59%), along with the lowest activity of cytidine triphosphate: phosphocholine cytidylyltransferase (-14–18%) in the lungs, compared to all other subgroups at 4 h (p < 0.01), but not at 8 and 12 h. After 24-h, all LPS-subgroups had lower labeled PC than the corresponding C-subgroups (p < 0.05). LPS-ONO had higher labeled PC in total phospholipids and disaturated PC, activity of cytidylyltransferase, and lower activity of nuclear transcription factor-κB and expression of proinflammatory cytokine mRNA, than that in the LPS-O subgroup (p < 0.05). CONCLUSION: In LPS-induced lung inflammation in association with hyperoxia, depressed PC synthesis and enhanced proinflammatory cytokine production may be alleviated by iNO. NO alone only transiently suppressed the PC synthesis as a result of lower activity of cytidylyltransferase

The politics of heroes through the prism of popular heroism

This is the author accepted manuscript. The final version is available from Palgrave Macmillan via the DOI in this record.In modern day Britain, the discourse of national heroification is routinely utilised by politicians, educationalists and cultural industry professionals, whilst also being a popular concept to describe deserving ‘do-gooders’ who contribute to British society in a myriad of ways. We argue that although this heroification discourse is enacted as a discursive device of encouraging politically and morally desirable behaviour, it is dissociated from the largely under-explored facets of contemporary popular heroism. To compensate for this gap, this paper explores public preferences for heroes using survey data representative of British adults. This analysis demonstrates a conceptual stretching in the understanding of heroism, and allows identifying age- and gender-linked dynamics which effect public choices of heroes. In particular, we demonstrate that age above all determines the preference for having a hero, but does not explain preferences for specific hero-types. The focus on gender illustrates that the landscape of popular heroism reproduces a male-dominated bias which exists in the wider political and cultural heroification discourse. Simultaneously, our study shows that if national heroification discourse in Britain remains male-centric, the landscape of popular heroism is characterised by a gendered trend towards privatisation of heroes being particularly prominent amongst women. In the conclusion, this paper argues for a conceptual revision and re-gendering of the national heroification discourse as a step towards both empirically grounded, and age- and gender-sensitive politics of heroes and heroines.AHR

Maternal depression is associated with DNA methylation changes in cord blood T lymphocytes and adult hippocampi

Depression affects 10-15% of pregnant women and has been associated with preterm delivery and later developmental, behavioural and learning disabilities. We tested the hypothesis that maternal depression is associated with DNA methylation alterations in maternal T lymphocytes, neonatal cord blood T lymphocytes and adult offspring hippocampi. Genome-wide DNA methylation of CD3+ T lymphocytes isolated from 38 antepartum maternal and 44 neonatal cord blood samples were analyzed using Illumina Methylation 450 K microarrays. Previously obtained methylation data sets using methylated DNA immunoprecipitation and array-hybridization of 62 postmortem hippocampal samples of adult males were re-analyzed to test associations with history of maternal depression. We found 145 (false discovery rate (FDR) q<0.05) and 2520 (FDR q<0.1) differentially methylated CG-sites in cord blood T lymphocytes of neonates from the maternal depression group as compared with the control group. However, no significant DNA methylation differences were detected in the antepartum maternal T lymphocytes of our preliminary data set. We also detected 294 differentially methylated probes (FDR q<0.1) in hippocampal samples associated with history of maternal depression. We observed a significant overlap (P=0.002) of 33 genes with changes in DNA methylation in T lymphocytes of neonates and brains of adult offspring. Many of these genes are involved in immune system functions. Our results show that DNA methylation changes in offspring associated with maternal depression are detectable at birth in the immune system and persist to adulthood in the brain. This is consistent with the hypothesis that system-wide epigenetic changes are involved in life-long responses to maternal depression in the offspring. © 2015 Translational Psychiatry

X-Linked thrombocytopenia causing mutations in WASP (L46P and A47D) impair T cell chemotaxis

BACKGROUND: Mutation in the Wiskott-Aldrich syndrome Protein (WASP) causes Wiskott-Aldrich syndrome (WAS), X-linked thrombocytopenia (XLT) and X-linked congenital neutropenia (XLN). The majority of missense mutations causing WAS and XLT are found in the WH1 (WASP Homology) domain of WASP, known to mediate interaction with WIP (WASP Interacting Protein) and CIB1 (Calcium and Integrin Binding). RESULTS: We analyzed two WASP missense mutants (L46P and A47D) causing XLT for their effects on T cell chemotaxis. Both mutants, WASP(R)(L46P) and WASP(R)(A47D) (S1-WASP shRNA resistant) expressed well in Jurkat(WASP-KD) T cells (WASP knockdown), however expression of these two mutants did not rescue the chemotaxis defect of Jurkat(WASP-KD) T cells towards SDF-1α. In addition Jurkat(WASP-KD) T cells expressing these two WASP mutants were found to be defective in T cell polarization when stimulated with SDF-1α. WASP exists in a closed conformation in the presence of WIP, however both the mutants (WASP(R)(L46P) and WASP(R)(A47D)) were found to be in an open conformation as determined in the bi-molecular complementation assay. WASP protein undergoes proteolysis upon phosphorylation and this turnover of WASP is critical for T cell migration. Both the WASP mutants were found to be stable and have reduced tyrosine phosphorylation after stimulation with SDF-1α. CONCLUSION: Thus our data suggest that missense mutations WASP(R)(L46P) or WASP(R)(A47D) affect the activity of WASP in T cell chemotaxis probably by affecting the turnover of the protein. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12929-014-0091-1) contains supplementary material, which is available to authorized users

Hypoxia-Induced Invadopodia Formation Involves Activation of NHE-1 by the p90 Ribosomal S6 Kinase (p90RSK)

The hypoxic and acidic microenvironments in tumors are strongly associated with malignant progression and metastasis, and have thus become a central issue in tumor physiology and cancer treatment. Despite this, the molecular links between acidic pH- and hypoxia-mediated cell invasion/metastasis remain mostly unresolved. One of the mechanisms that tumor cells use for tissue invasion is the generation of invadopodia, which are actin-rich invasive plasma membrane protrusions that degrade the extracellular matrix. Here, we show that hypoxia stimulates the formation of invadopodia as well as the invasive ability of cancer cells. Inhibition or shRNA-based depletion of the Na+/H+ exchanger NHE-1, along with intracellular pH monitoring by live-cell imaging, revealed that invadopodia formation is associated with alterations in cellular pH homeostasis, an event that involves activation of the Na+/H+ exchange rate by NHE-1. Further characterization indicates that hypoxia triggered the activation of the p90 ribosomal S6 kinase (p90 RSK), which resulted in invadopodia formation and site-specific phosphorylation and activation of NHE-1. This study reveals an unsuspected role of p90RSK in tumor cell invasion and establishes p90RS kinase as a link between hypoxia and the acidic microenvironment of tumors