Genomic analysis of the role of transcription factor C/EBPδ in the regulation of cell behaviour on nanometric grooves

C/EBPδ is a tumour suppressor transcription factor that induces gene expression involved in suppressing cell migration. Here we investigate whether C/EBPδ-dependent gene expression also affects cell responses to nanometric topology. We found that ablation of the C/EBPδ gene in mouse embryonal fibroblasts (MEFs) decreased cell size, adhesion and cytoskeleton spreading on 240 nm and 540 nm nanometric grooves. ChIP-SEQ and cDNA microarray analyses demonstrated that many binding sites for C/EBPδ, and the closely related C/EBPβ, exist throughout the mouse genome and control the upregulation or downregulation of many adjacent genes. We also identified a group of C/EBPδ-dependent, trans-regulated genes, whose promoters contained no C/EBPδ binding sites and yet their activity was regulated in a C/EBPδ-dependent manner. These genes include signalling molecules (e.g. SOCS3), cytoskeletal components (Tubb2, Krt16 and Krt20) and cytoskeletal regulators (ArhGEF33 and Rnd3) and are possibly regulated by cis-regulated diffusible mediators, such as IL6. Of particular note, SOCS3 was shown to be absolutely required for efficient cell spreading and contact guidance on 240 nm and 540 nm nanometric grooves. C/EBPδ is therefore involved in the complex regulation of multiple genes, including cytoskeletal components and signalling mediators, which influence the nature of cell interactions with nanometric topology

Community experiences of organised crime in Scotland

The research explored community experiences of serious organised crime in Scotland (SOC). The report provides information on the nature and extent of the impact of SOC on everyday life in the community, as well as offering suggestions for policy development. The study sought to answer the following questions: 1)What are the relationships that exist between SOC and communities in Scotland? 2)What are the experiences and perceptions of residents, stakeholders and organisations of the scope and nature of SOC within their local area? and 3)How does SOC impact on community wellbeing, and to what extent can the harms associated with SOC be mitigated

Suspected cancer (part 2—adults): visual overview of updated NICE guidance

This is the final version of the article. Available from the publisher via the DOI in this record.See part 1 – children and young adults www.bmj.com/ content/350/bmj.h3036This is one of a series of BMJ summaries of new guidelines based on the best available evidence; they highlight important recommendations for clinical practice, especially where uncertainty or controversy exists

Suspected cancer (part 1 - Children and young adults): Visual overview of updated NICE guidance

This is the final version of the article. Available from BMJ Publishing Group via the DOI in this record

Experimental demonstration of ray-rotation sheets

We have built microstructured sheets that rotate, on transmission, the direction of light rays by an arbitrary, but fixed, angle around the sheet normal. These ray-rotation sheets comprise two pairs of confocal lenticular arrays. In addition to rotating the direction of transmitted light rays, our sheets also offset ray position sideways on the scale of the diameter of the lenticules. If this ray offset is sufficiently small so that it cannot be resolved, our ray-rotation sheets appear to perform generalized refraction

Role of angiopoietin-like protein 3 in sugar-induced dyslipidemia in rhesus macaques: suppression by fish oil or RNAi.

Angiopoietin-like protein 3 (ANGPTL3) inhibits lipid clearance and is a promising target for managing cardiovascular disease. Here we investigated the effects of a high-sugar (high-fructose) diet on circulating ANGPTL3 concentrations in rhesus macaques. Plasma ANGPTL3 concentrations increased ∼30% to 40% after 1 and 3 months of a high-fructose diet (both P < 0.001 vs. baseline). During fructose-induced metabolic dysregulation, plasma ANGPTL3 concentrations were positively correlated with circulating indices of insulin resistance [assessed with fasting insulin and the homeostatic model assessment of insulin resistance (HOMA-IR)], hypertriglyceridemia, adiposity (assessed as leptin), and systemic inflammation [C-reactive peptide (CRP)] and negatively correlated with plasma levels of the insulin-sensitizing hormone adropin. Multiple regression analyses identified a strong association between circulating APOC3 and ANGPTL3 concentrations. Higher baseline plasma levels of both ANGPTL3 and APOC3 were associated with an increased risk for fructose-induced insulin resistance. Fish oil previously shown to prevent insulin resistance and hypertriglyceridemia in this model prevented increases of ANGPTL3 without affecting systemic inflammation (increased plasma CRP and interleukin-6 concentrations). ANGPTL3 RNAi lowered plasma concentrations of ANGPTL3, triglycerides (TGs), VLDL-C, APOC3, and APOE. These decreases were consistent with a reduced risk of atherosclerosis. In summary, dietary sugar-induced increases of circulating ANGPTL3 concentrations after metabolic dysregulation correlated positively with leptin levels, HOMA-IR, and dyslipidemia. Targeting ANGPTL3 expression with RNAi inhibited dyslipidemia by lowering plasma TGs, VLDL-C, APOC3, and APOE levels in rhesus macaques

Conceptualisations of children’s wellbeing at school: the contribution of recognition theory

A large study in Australian schools aimed to elucidate understandings of ‘wellbeing’ and of factors in school life that contribute to it. Students and teachers understood wellbeing primarily, and holistically, in terms of interpersonal relationships, in contrast to policy documents which mainly focused on ‘problem areas’ such as mental health. The study also drew on recognition theory as developed by the social philosopher Axel Honneth. Results indicate that recognition theory may be useful in understanding wellbeing in schools, and that empirical research in schools may give rise to further questions regarding theory

Cardiac hypertrophy is inhibited by a local pool of cAMP regulated by phosphodiesterase 2

Rationale: Chronic elevation of 3'-5'-cyclic adenosine monophosphate (cAMP) levels has been associated with cardiac remodelling and cardiac hypertrophy. However, enhancement of particular aspects of cAMP/protein kinase A (PKA) signalling appears to be beneficial for the failing heart. cAMP is a pleiotropic second messenger with the ability to generate multiple functional outcomes in response to different extracellular stimuli with strict fidelity, a feature that relies on the spatial segregation of the cAMP pathway components in signalling microdomains. Objective: How individual cAMP microdomains impact on cardiac pathophysiology remains largely to be established. The cAMP-degrading enzymes phosphodiesterases (PDEs) play a key role in shaping local changes in cAMP. Here we investigated the effect of specific inhibition of selected PDEs on cardiac myocyte hypertrophic growth. Methods and Results: Using pharmacological and genetic manipulation of PDE activity we found that the rise in cAMP resulting from inhibition of PDE3 and PDE4 induces hypertrophy whereas increasing cAMP levels via PDE2 inhibition is anti-hypertrophic. By real-time imaging of cAMP levels in intact myocytes and selective displacement of PKA isoforms we demonstrate that the anti-hypertrophic effect of PDE2 inhibition involves the generation of a local pool of cAMP and activation of a PKA type II subset leading to phosphorylation of the nuclear factor of activated T cells (NFAT). Conclusions: Different cAMP pools have opposing effects on cardiac myocyte cell size. PDE2 emerges as a novel key regulator of cardiac hypertrophy in vitro and in vivo and its inhibition may have therapeutic applications

Community Experiences of Serious Organised Crime in Scotland

This summary sets out key findings from a research project that aimed to explore the community experiences of serious organised crime ( SOC) in Scotland. The study sought to answer the following questions: 1) What are the relationships that exist between SOC and communities in Scotland? 2) What are the experiences and perceptions of residents, stakeholders and organisations of the scope and nature of SOC within their local area? and 3) How does SOC impact on community wellbeing, and to what extent can the harms associated with SOC be mitigated? The work involved in-depth qualitative research, to understand both direct and indirect forms of harm. Key points pertaining to the research and its results are as follows: - The study involved the selection of three community case study sites based on a typology of ' SOC-affected' communities. These sites were based in varying urban and semi-urban settings. - The impact of SOC at a more 'diffuse' national level was explored via research in a range of smaller case study sites and via interviews with national stakeholders. This included a consideration of SOC impacts in rural and remote areas, and on populations that were not concentrated in any defined geographic community. - The case study areas were selected on the basis of pre-existing academic and policy literature, an initial set of interviews with key experts, and on the basis of aggregated and anonymised intelligence summaries provided by Police Scotland. - 188 individuals participated in the study, which mostly involved semi-structured qualitative interviews, but also a small number of focus groups, unstructured interviews and observational research. Interviews were conducted with residents, local businesses, service providers, community groups, and national organisations, as well as with a small number of individuals with lived experience of SOC. - Interviews comprised of questions about: the relationship between SOC and communities; the experiences and perceptions of residents and local service providers as to the nature and extent of SOC; and the impact of SOC on community wellbeing. - Preliminary findings were presented back to a sub-sample of 33 community residents and representatives, across three of the case study areas, through a feedback method called 'co-inquiry'. This involved the organisation of events designed to assess the integrity of the findings, and elicit reflections on the implications of the findings for potential actions