Complexity and physical activity policy: considerations for theory and practice.

Background: Complex systems perspectives have been increasingly adopted to address physical inactivity. Within this, myriad policy actions are deemed important for supporting population physical activity and creating so-called ‘active systems.’ I argue that complexity and systems-thinking have, prior to this thesis, predominantly been applied uncritically and with insufficient consideration of the agents who influence, and are influenced by, the complexity of the physical activity policy environment. There is the need to connect different strands of research, specifically in relation to physical activity policy, evidence-informed Public Health, and complexity. Aim: My research aimed to critically assess the understanding and application of complexity theories as a basis for evidence-informed physical activity policy efforts. Specifically, I sought to interrogate the suitability of complexity theories for influencing, developing and implementing physical activity policies; identify conditions that enable more effective complex systems approaches to physical activity policy and programmes; and in doing so, extend understanding concerning complexity theories and their application. Theory and methods: Central to my theoretical position has been a reflexive process in which I have located myself within the wider physical activity and Public Health research landscape, and crucially the system I seek to change. This thesis is underpinned by a complex realist ontology, and epistemologically I draw on the notion of different lenses of evidence about policy issues. Methodologically, I employed qualitative and action-orientated methods to explore individuals’ agency and experiences of the physical activity policy system. My own observations and experiences are discussed through a theoretical pluralism. Study 1: I explored the processes, values and experiences of physical activity policy-makers in UK national government, in relation to complexity, and how they sought to foster system change. I conducted 10 semi-structured interviews. Three overarching themes were constructed and emphasised that while the idea of complex systems permeated the physical activity sector, uncertainty as to the meaning of complexity and its implications may preclude its application in ways that enhance physical activity policies and programmes. I highlight problematic practices and identify potentially important mechanisms to support system change. Study 2: This study was originally a preliminary component of an action research project that was curtailed by the SARS-Cov-2 pandemic. Through five in-depth semi-structured interviews, I examined how local partnerships can be used more effectively to improve the implementation of national physical activity policies. Specifically, I extended knowledge by providing a critical reflection on system leadership, demonstrating how it is enabled and strengthened, how it links to implementation, and how changes in systemic practices and cultures can be stimulated in the physical activity policy domain. Study 3: This study responded to outstanding gaps in the evidence, in particular the ongoing uncertainty around the practical applications of complexity theories and systems perspectives. In-keeping with my intended action-orientated approach, I convened a workshop with 19 international experts (from research, policy and practice) to critically reflect on my previous research, drawing attention to issues of conceptual purity and discord between the theory and practice of complexity in the physical activity policy domain. Thereafter, the workshop explored how to optimise the application of complex systems approaches to physical activity policy, by focusing on the action of knowledge mobilisers. Analysis led to the creation of four propositions for advancing complexity theories and systems-based approaches, which set out important considerations concerning the how, when, and why of applying these perspectives. Concluding remarks: The general discussion is presented not as a line in the sand, but as both an advancement on previous thinking, and reflection on these and empirical contributions that remain a work in progress. Specifically, I set out current conceptualisations of complexity theories as they pertain to physical activity policy, and discuss considerations for future practice. I conclude by arguing that a reorientation of efforts across research, policy and practice toward agency, mobilisation and application of complex systems perspectives in physical activity policy settings will strengthen collective impact

Critical Role of FLRT1 Phosphorylation in the Interdependent Regulation of FLRT1 Function and FGF Receptor Signalling

Background Fibronectin leucine rich transmembrane (FLRT) proteins have dual properties as regulators of cell adhesion and potentiators of fibroblast growth factor (FGF) mediated signalling. The mechanism by which the latter is achieved is still unknown and is the subject of this investigation. Principal Findings Here we show that FLRT1 is a target for tyrosine phosphorylation mediated by FGFR1 and implicate a non-receptor Src family kinase (SFK). We identify the target tyrosine residues in the cytoplasmic domain of FLRT1 and show that these are not direct substrates for Src kinase suggesting that the SFK may exert effects via potentiation of FGFR1 kinase activity. We show that whilst FLRT1 expression results in a ligand-dependent elevation of MAP kinase activity, a mutant version of FLRT1, defective as an FGFR1 kinase substrate (Y3F-FLRT1), has the property of eliciting ligand-independent chronic activation of the MAP kinase pathway which is suppressed by pharmacological inhibition of either FGFR1 or Src kinase. Functional investigation of FGFR1 and FLRT1 signalling in SH-SY5Y neuroblastoma cells reveals that FLRT1 alone acts to induce a multi-polar phenotype whereas the combination of FLRT1 and FGFR activation, or expression of Y3F-FLRT1, acts to induce neurite outgrowth via MAPK activation. Similar results were obtained in a dendrite outgrowth assay in primary hippocampal neurons. We also show that FGFR1, FLRT1 and activated Src are co-localized and this complex is trafficked toward the soma of the cell. The presence of Y3F-FLRT1 rather than FLRT1 resulted in prolonged localization of this complex within the neuritic arbour. Conclusions This study shows that the phosphorylation state of FLRT1, which is itself FGFR1 dependent, may play a critical role in the potentiation of FGFR1 signalling and may also depend on a SFK-dependent phosphorylation mechanism acting via the FGFR. This is consistent with an ‘in vivo’ role for FLRT1 regulation of FGF signalling via SFKs. Furthermore, the phosphorylation-dependent futile cycle mechanism controlling FGFR1 signalling is concurrently crucial for regulation of FLRT1-mediated neurite outgrowth

Dial M(RF) for myogenesis

The transcriptional regulatory network that controls the determination and differentiation of skeletal muscle cells in the embryo has at its core the four myogenic regulatory factors (MRFs) Myf5, MyoD, Mrf4 and MyoG. These basic helix–loop–helix transcription factors act by binding, as obligate heterodimers with the ubiquitously expressed E proteins, to the E-box sequence CANNTG. While all skeletal muscle cells have the same underlying function their progenitors arise at many sites in the embryo and it has become apparent that the upstream activators of the cascade differ in these various populations so that it can be switched on by a variety of inductive signals, some of which act by initiating transcription, some by maintaining it. The application of genome-wide approaches has provided important new information as to how the MRFs function to activate the terminal differentiation programme and some of these data provide significant mechanistic insights into questions which have exercised the field for many years. We also consider the emerging roles played by micro-RNAs in the regulation of both upstream activators and terminal differentiation genes.Peer reviewe

Guilt, shame and expressed emotion in carers of people with long-term mental health difficulties:a systematic review

Expressed emotion (EE) is a global index of familial emotional climate, whose primary components are emotional over-involvement (EOI) and critical comments (CC)/hostility. There is a strong theoretical rationale for hypothesising that carers’ guilt and shame may be differentially associated with their EOI and CC/hostility respectively. This systematic review investigates the magnitude of these theorised associations in carers of people with long-term mental health difficulties. Electronic searches (conducted in May 2016 across Medline, CINAHL, Embase, PsycINFO and ProQuest) were supplemented with iterative hand searches. Ten papers, reporting data from eight studies, were included. Risk of bias was assessed using a standardised checklist. Relevant data were extracted and synthesised narratively. EOI was positively associated with both guilt and shame, whereas CC/hostility was positively associated with shame. The strength of associations varied depending on whether or not guilt and shame were assessed within the context of the caring relationship. Based on these data, an argument can be made for the refinement, development and evaluation of systemic and individual interventions designed to target carers’ guilt and shame. However, more research is needed to clarify the strength of these associations and their direction of effect before firm conclusions can be drawn

The Carnegie Hubble Program

We present an overview of and preliminary results from an ongoing comprehensive program that has a goal of determining the Hubble constant to a systematic accuracy of 2%. As part of this program, we are currently obtaining 3.6 micron data using the Infrared Array Camera (IRAC) on Spitzer, and the program is designed to include JWST in the future. We demonstrate that the mid-infrared period-luminosity relation for Cepheids at 3.6 microns is the most accurate means of measuring Cepheid distances to date. At 3.6 microns, it is possible to minimize the known remaining systematic uncertainties in the Cepheid extragalactic distance scale. We discuss the advantages of 3.6 micron observations in minimizing systematic effects in the Cepheid calibration of the Hubble constant including the absolute zero point, extinction corrections, and the effects of metallicity on the colors and magnitudes of Cepheids. We are undertaking three independent tests of the sensitivity of the mid-IR Cepheid Leavitt Law to metallicity, which when combined will allow a robust constraint on the effect. Finally, we are providing a new mid-IR Tully-Fisher relation for spiral galaxies

A BAC transgenic analysis of the Mrf4/Myf5 locus reveals interdigitated elements that control activation and maintenance of gene expression during muscle development

The muscle-specific transcription factors Myf5 and Mrf4 are two of the four myogenic regulatory factors involved in the transcriptional cascade responsible for skeletal myogenesis in the vertebrate embryo. Myf5 is the first of these four genes to be expressed in the mouse. We have previously described discrete enhancers that drive Myf5 expression in epaxial and hypaxial somites, branchial arches and central nervous system, and argued that additional elements are required for proper expression (Summerbell, D., Ashby, P.R., Coutelle, O., Cox, D., Yee, S.P. and Rigby, P.W.J. (2000) Development 127, 3745-3757). We have now investigated the transcriptional regulation of both Myf5 and Mrf4 using bacterial artificial chromosome transgenesis. We show that a clone containing Myf5 and 140 kb of upstream sequences is sufficient to recapitulate the known expression patterns of both genes. Our results confirm and reinforce the conclusion of our earlier studies, that Myf5 expression is regulated differently in each of a considerable number of populations of muscle progenitors, and they begin to illuminate the evolutionary origins of this complex regulation. We further show that separate elements are involved in the activation and maintenance of expression in the various precursor populations, reflecting the diversity of the signals that control myogenesis. Mrf4 expression requires at least four elements, one of which may be shared with Myf5, providing a possible explanation for the linkage of these genes throughout vertebrate phylogeny. Further complexity is revealed by the demonstration that elements which control Mrf4 and Myf5 are embedded in an unrelated neighbouring gene.J. J. C. was supported by a Research Training Fellowship from the Medical Research Council (UK), which also paid for this work.Peer reviewe

Chandra Reveals Heavy Obscuration and Circumnuclear Star Formation in Seyfert 2 Galaxy NGC 4968

We present the Chandra imaging and spectral analysis of NGC 4968, a nearby (z = 0.00986) Seyfert 2 galaxy. We discover extended ($\sim$1 kpc) X-ray emission in the soft band (0.5 - 2 keV) that is neither coincident with the narrow line region nor the extended radio emission. Based on spectral modeling, it is linked to on-going star formation ($\sim$2.6-4 M_{\sun} yr$^{-1}$). The soft emission at circumnuclear scales (inner $\sim$400 pc) originates from hot gas, with kT $\sim$ 0.7 keV, while the most extended thermal emission is cooler (kT $\sim$ 0.3 keV). We refine previous measurements of the extreme Fe K$\alpha$ equivalent width in this source (EW = 2.5$^{+2.6}_{-1.0}$ keV), which suggests the central engine is completely embedded within Compton-thick levels of obscuration. Using physically motivated models fit to the Chandra spectrum, we derive a Compton-thick column density ($N_{\rm H} > 1.25\times10^{24}$ cm$^{-2}$) and an intrinsic hard (2-10 keV) X-ray luminosity of $\sim$3-8$\times 10^{42}$ erg s$^{-1}$ (depending on the presumed geometry of the obscurer), which is over two orders of magnitude larger than that observed. The large Fe K$\alpha$ EW suggests a spherical covering geometry, which could be confirmed with X-ray measurements above 10 keV. NGC 4968 is similar to other active galaxies that exhibit extreme Fe K$\alpha$ EWs (i.e., $>$2 keV) in that they also contain ongoing star formation. This work supports the idea that gas associated with nuclear star formation may increase the covering factor of the enshrouding gas and play a role in obscuring AGN.Comment: 11 pages, 8 figures, 4 tables. Accepted for publication in Ap