Connected Growth: developing a framework to drive inclusive growth across a city-region

This ‘in perspective’ piece addresses the (re-)positioning of civil society within new structures of city-region governance within Greater Manchester (GM). This follows on from the processes of devolution, which have given the Greater Manchester City-Region (GMCR) a number of new powers. UK devolution, to date, has been largely focused upon engendering agglomerated economic growth at the city-region scale. Within GMCR, devolution for economic development has sat alongside the devolution of health and social care (unlike any other city-region in the UK) as well. Based on stakeholder mapping and semi-structured interviews with key actors operating across the GMCR, the paper illustrates how this has created a number of significant tensions and opportunities for civil society actors, as they have sought to contest a shifting governance framework. The paper, therefore, calls for future research to carefully consider how civil society groups are grappling with devolution; both contesting and responding to devolution. This is timely given the shifting policy and political discourse towards the need to deliver more socially-inclusive city-regions

Putting you in the picture: using visual imagery in social work supervision

The literature on social work supervision has consistently documented the impact of the work on the health and wellbeing of individual practitioners and the tensions they experience when mediating organisational demands with the needs of service users. Simultaneously, the quality and content of social work supervision has become increasingly vulnerable to both local and global systemic issues impacting on the profession. It is timely to explore effective short term, self-regulatory methods of support based on short/simple training for professionals. These can be used as a means of complementing and enriching their current supervision experiences and practice. We describe such a method involving an arts-based intervention in which five groups of social work professionals in England (n=30) were invited to explore guided imagery as a tool for reflecting on a challenge or dilemma arising in their everyday practice. Evaluation data was captured from the participants’ pre-workshop questionnaire; visual analyses of the images generated and the social workers narratives and post-workshop evaluation. We discuss the potential application of using visual imagery as a tool to bridge gaps in supervision practice and as a simple pedagogic tool for promoting contemplative processes of learning. Visual imagery can be used to strengthen social workers integration of different demands with their emotional supports and coping strategies

Simulated steady-state fluxes and concentrations in the mFAO model.

<p><b>(A)</b> The effect of cytosolic palmitoyl-CoA concentration ([palmitoyl-CoA]_CYT) on the steady-state flux. The steady-state uptake flux of palmitoyl-CoA (J_uptake) is plotted (calculated as the steady-state flux of palmitoyl-carnitine through CACT, i.e. the uptake of palmitoyl-carnitine into the mitochondria), in contrast to van Eunen <i>et al</i>. 2013 [<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1005461#pcbi.1005461.ref008" target="_blank">8</a>] in which the NADH flux was plotted. The two are uniquely linked with the latter being 7-fold higher. <b>(B)</b> The steady-state concentrations of free CoA (identical to data from [<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1005461#pcbi.1005461.ref008" target="_blank">8</a>]), the sum of all intermediate CoA esters, the sum of all C4- and C6 CoA esters and the subset of C4- and C6 CoA esters (new results). <b>(C-D)</b> Distribution of steady-state fluxes (J) of different chain-length substrates through MTP and MCKAT, respectively. Only the chain lengths which are converted by these enzymes (cf. <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1005461#pcbi.1005461.g001" target="_blank">Fig 1</a>) are included.</p

Time course of key short-chain reaction rates and regulation of the MCKAT-C4 reaction.

<p><b>(A)</b> Time course of the reaction rates of MCKAT for its C6 and C4 substrates (vMCKATC6 and vMCKATC4, respectively) and of the summed activities of SCAD and MCAD on their C4 substrate (vMCADC4 + vSCADC4) after a sudden upshift of [palmitoyl-CoA]_CYT from 0.1 to 60 μM. <b>(B)</b> Time course of regulatory metabolite contributions to vMCKATC4 after a sudden [palmitoyl-CoA]_CYT increase from 0.1 to 60 μM.</p

Elucidating the mechanism of flux decline.

<p><b>1.</b> Upon substrate overload with cytosolic palmitoyl-CoA, MCKAT’s ketoacyl-CoA substrates start to accumulate. <b>2.</b> The unfavourable equilibrium constant of the preceding enzyme, medium/short-chain hydroxyacyl-CoA dehydrogenase, works as an amplifier, leading to the accumulation of upstream CoA esters, including acyl-CoA esters. <b>3.</b> These acyl-CoA esters are at the same time products of MCKAT and inhibit its already low activity further. <b>4.</b> Finally, the accumulation of CoA esters leads to a sequestration of free CoA. CoA being a cofactor for MCKAT, its sequestration limited the MCKAT activity even further, thus completing the vicious cycle. <b>5</b>. Since CoA is also a substrate for distant enzymes (such as MTP), it efficiently communicates the ‘traffic jam’ at MCKAT to the entire pathway.</p

The role of the short-chain branch.

<p><b>(A)</b> Steady-state flux versus [palmitoyl-CoA]_CYT in the published model (black line), a model without any enzymatic promiscuity (black dashed line, reproducing results from [<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1005461#pcbi.1005461.ref008" target="_blank">8</a>] as a reference), a model without promiscuity of MCKAT (green line), and finally a model with only promiscuity of MCKAT, but not of any of the other enzymes (purple line). <b>(B)</b> The flux control coefficients in the original model as a function of [palmitoyl-CoA]_CYT. Only enzymes with a substantial contribution are included; for a complete set of flux control coefficients, see figure A in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1005461#pcbi.1005461.s002" target="_blank">S2 Fig</a>. <b>(C-D)</b> Top 15 flux response coefficients with the highest absolute values at 25 μM (C) and 60 μM (D) of [palmitoyl-CoA]_CYT. The parameters <i>p</i> for which the flux response coefficient was calculated is indicated on the Y-axis. Dark grey bars represent CPT1-related parameters, pink bars represent M/SCHAD-related parameters, purple bars represent MCKAT-related parameters and the light blue bar represents a crotonase-related parameter. <b>(E)</b> Flux response coefficient of [NAD⁺]/[NADH] () partitioned in contributions of individual NAD⁺-dependent reactions at 5 palmitoyl-CoA concentrations according to . (cf. <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1005461#pcbi.1005461.e009" target="_blank">Eq 4</a>). The contributions of M/SCHAD reactions C8-C16 to were negligible and therefore not shown in the legend.</p

Schematic representation of the modelled mFAO pathway in rat.

<p>Metabolites in blue are fixed parameters, while other metabolites are free variables. The sum of variable CoA esters and free CoA is a conserved moiety. Green: enzymes participating in the carnitine cycle; purple: enzymes participating in the short-chain branch; grey: enzymes participating in the medium-and long-chain branch. All processes are reversible and the size of the arrowheads indicates the net direction of the flux. This model is exactly the same as published before [<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1005461#pcbi.1005461.ref008" target="_blank">8</a>], without modifications.</p

Regulation of key reactions by their substrates and products.

<p><b>(A-F)</b> Relative average absolute contribution, i.e. , of metabolites to the transition from the steady state at 0.1 μM to the indicated concentration of palmitoyl-CoA, calculated for vMCKATC6 (panel A), vMCKATC4 (panel B), vMCADC6 (panel C), vSCADC4 (panel D), vMPTC8 (panel E), vCPT2C16 (panel F).</p

Gene expression for cecal SCFA transport, hepatic gluconeogenesis and glycolysis and hepatic fatty acid synthesis and oxidation for the different guar gum groups.

<p>Mct-1, Monocarboxylate transporter 1; Smct-1, sodium-coupled monocarboxylate transporter 1; Pepck, phosphoenolpyruvate carboxykinase; G6Pase, glucose 6-phosphatase; PC, pyruvate carboxylase; HK, hexokinase; PK, pyruvate kinase; Fasn, fatty acid synthase; Acc1, acetyl-CoA carboxylase 1; Acc2, acetyl-CoA carboxylase 2; Elovl6, fatty acid elongase 6; Cpt-1a, carnitine palmitoyltransferase 1a; Mcad, medium-chain acyl coA dehydrogenase; Lcad, long-chain acyl coA dehydrogenase; Aox, acyl-CoA oxidase.</p><p>Data represent means ± SEM for n = 7–8. When groups have a different superscript <i>a</i>, <i>b</i> or <i>c</i> associated, the results differ significantly between them (at least p<0.05).</p><p>Gene expression for cecal SCFA transport, hepatic gluconeogenesis and glycolysis and hepatic fatty acid synthesis and oxidation for the different guar gum groups.</p

<i>In vivo</i> SCFA uptake fluxes correlate inversely with metabolic syndrome markers.

<p>Correlation of acetate, propionate and butyrate host uptake fluxes with body weight (A), AW/BW (B), hepatic triglycerides (C) and HOMA-IR (D). The Spearman's correlation coefficient was calculated and the significance level was set at p<0.05.</p