Systems science for developing policy to improve physical activity, the Caribbean.

The World Health Organization (WHO) Global Action Plan on Physical Activity recommends adopting a systems approach to implementing and tailoring actions according to local contexts. We held group model-building workshops with key stakeholders in the Caribbean region to develop a causal loop diagram to describe the system driving the increasing physical inactivity in the region and envision the most effective ways of intervening in that system to encourage and promote physical activity. We used the causal loop diagram to inform how the WHO Global Action Plan on Physical Activity might be adapted to a local context. Although the WHO recommendations aligned well with our causal loop diagram, the diagram also illustrates the importance of local context in determining how interventions should be coordinated and implemented. Some interventions included creating safe physical activity spaces for both sexes, tackling negative attitudes to physical activity in certain contexts, including in schools and workplaces, and improving infrastructure for active transport. The causal loop diagram may also help understand how policies may be undermined or supported by key actors or where policies should be coordinated. We demonstrate how, in a region with a high level of physical inactivity and low resources, applying systems thinking with relevant stakeholders can help the targeted adaptation of global recommendations to local contexts

Public health benefits of strategies to reduce greenhouse-gas emissions: overview and implications for policy makers

This Series has examined the health implications of policies aimed at tackling climate change. Assessments of mitigation strategies in four domains-household energy, transport, food and agriculture, and electricity generation-suggest an important message: that actions to reduce greenhouse-gas emissions often, although not always, entail net benefits for health. In some cases, the potential benefits seem to be substantial. This evidence provides an additional and immediate rationale for reductions in greenhouse-gas emissions beyond that of climate change mitigation alone. Climate change is an increasing and evolving threat to the health of populations worldwide. At the same time, major public health burdens remain in many regions. Climate change therefore adds further urgency to the task of addressing international health priorities, such as the UN Millennium Development Goals. Recognition that mitigation strategies can have substantial benefits for both health and climate protection offers the possibility of policy choices that are potentially both more cost effective and socially attractive than are those that address these priorities independently

Molecular characterisation of canine osteosarcoma in high risk breeds

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. Dogs develop osteosarcoma (OSA) and the disease process closely resembles that of human OSA. OSA has a poor prognosis in both species and disease-free intervals and cure rates have not improved in recent years. Gene expression in canine OSAs was compared with non-tumor tissue utilising RNA sequencing, validated by qRT-PCR and immunohistochemistry (n = 16). Polymorphic polyglutamine (polyQ) tracts in the androgen receptor (AR/NR3C4) and nuclear receptor coactivator 3 (NCOA3) genes were investigated in control and OSA patients using polymerase chain reaction (PCR), Sanger sequencing and fragment analysis (n = 1019 Rottweilers, 379 Irish Wolfhounds). Our analysis identified 1281 significantly differentially expressed genes (>2 fold change, p < 0.05), specifically 839 lower and 442 elevated gene expression in osteosarcoma (n = 3) samples relative to non-malignant (n = 4) bone. Enriched pathways and gene ontologies were identified, which provide insight into the molecular pathways implicated in canine OSA. Expression of a subset of these genes (SLC2A1, DKK3, MMP3, POSTN, RBP4, ASPN) was validated by qRTPCR and immunohistochemistry (MMP3, DKK3, SLC2A1) respectively. While little variation was found in the NCOA3 polyQ tract, greater variation was present in both polyQ tracts in the AR, but no significant associations in length were made with OSA. The data provides novel insights into the molecular mechanisms of OSA in high risk breeds. This knowledge may inform development of new prevention strategies and treatments for OSA in dogs and supports utilising spontaneous OSA in dogs to improve understanding of the disease in people

The global diet and activity research (GDAR) network: a global public health partnership to address upstream NCD risk factors in urban low and middle-income contexts.

BACKGROUND: Non-communicable diseases (NCDs) are the leading cause of death globally. While upstream approaches to tackle NCD risk factors of poor quality diets and physical inactivity have been trialled in high income countries (HICs), there is little evidence from low and middle-income countries (LMICs) that bear a disproportionate NCD burden. Sub-Saharan Africa and the Caribbean are therefore the focus regions for a novel global health partnership to address upstream determinants of NCDs. PARTNERSHIP: The Global Diet and Activity research Network (GDAR Network) was formed in July 2017 with funding from the UK National Institute for Health Research (NIHR) Global Health Research Units and Groups Programme. We describe the GDAR Network as a case example and a potential model for research generation and capacity strengthening for others committed to addressing the upstream determinants of NCDs in LMICs. We highlight the dual equity targets of research generation and capacity strengthening in the description of the four work packages. The work packages focus on learning from the past through identifying evidence and policy gaps and priorities, understanding the present through adolescent lived experiences of healthy eating and physical activity, and co-designing future interventions with non-academic stakeholders. CONCLUSION: We present five lessons learned to date from the GDAR Network activities that can benefit other global health research partnerships. We close with a summary of the GDAR Network contribution to cultivating sustainable capacity strengthening and cutting-edge policy-relevant research as a beacon to exemplify the need for such collaborative groups

Implications of COVID-19 control measures for diet and physical activity, and lessons for addressing other pandemics facing rapidly urbanising countries.

At the time of writing, it is unclear how the COVID-19 pandemic will play out in rapidly urbanising regions of the world. In these regions, the realities of large overcrowded informal settlements, a high burden of infectious and non-communicable diseases, as well as malnutrition and precarity of livelihoods, have raised added concerns about the potential impact of the COVID-19 pandemic in these contexts. COVID-19 infection control measures have been shown to have some effects in slowing down the progress of the pandemic, effectively buying time to prepare the healthcare system. However, there has been less of a focus on the indirect impacts of these measures on health behaviours and the consequent health risks, particularly in the most vulnerable. In this current debate piece, focusing on two of the four risk factors that contribute to >80% of the NCD burden, we consider the possible ways that the restrictions put in place to control the pandemic, have the potential to impact on dietary and physical activity behaviours and their determinants. By considering mitigation responses implemented by governments in several LMIC cities, we identify key lessons that highlight the potential of economic, political, food and built environment sectors, mobilised during the pandemic, to retain health as a priority beyond the context of pandemic response. Such whole-of society approaches are feasible and necessary to support equitable healthy eating and active living required to address other epidemics and to lower the baseline need for healthcare in the long term

A synopsis of the Ordovician System in its birthplace - Britain and Ireland

Rock successions in Britain and Ireland, and more especially those in North Wales, were instrumental in the founding and naming of the Ordovician System, and the Anglo-Welsh series established both initially and subsequently were used widely as a standard for Ordovician chronostratigraphy. Although now largely superseded in the global scheme of series and stages, they retain their local and regional importance. The Ordovician System in Britain and Ireland documents the history of a segment of the Earth's crust that incorporated opposing peri-Gondwanan and peri-Laurentian/Laurentian margins of the Iapetus Ocean during its closure, and is accordingly complex. The complexity arises from the volcanic and tectonic processes that accompanied oceanic closure coupled with the effects of eustatic sea-level changes, including the far-field effects of the Late Ordovician glaciation. For the past three decades, Ordovician successions in Britain and Ireland have been discussed in terms of terranes. Here we review Ordovician successions in each terrane, incorporating the results of recent research and correlating those successions via biostratigraphical schemes and radiometric dates to the global Ordovician series and stages

Clinical and molecular significance of the RNA m6A methyltransferase complex in prostate cancer

N6-methyladenosine (m6A) is the most abundant internal mRNA modification and is dynamically regulated through distinct protein complexes that methylate, demethylate, and/or interpret the m6A modification. These proteins, and the m6A modification, are involved in the regulation of gene expression, RNA stability, splicing and translation. Given its role in these crucial processes, m6A has been implicated in many diseases, including in cancer development and progression. Prostate cancer (PCa) is the most commonly diagnosed non-cutaneous cancer in men and recent studies support a role for m6A in PCa. Despite this, the literature currently lacks an integrated analysis of the expression of key components of the m6A RNA methyltransferase complex, both in PCa patients and in well-established cell line models. For this reason, this study used immunohistochemistry and functional studies to investigate the mechanistic and clinical significance of the METTL3, METTL14, WTAP and CBLL1 components of the m6A methyltransferase complex in PCa specimens and cell lines. Expression of METTL3 and CBLL1, but not METTL14 and WTAP, was associated with poorer PCa patient outcomes. Expression of METTL3, METTL14, WTAP and CBLL1 was higher in PCa cells compared with non-malignant prostate cells, with the highest expression seen in castrate-sensitive, androgen-responsive PCa cells. Moreover, in PCa cell lines, expression of METTL3 and WTAP was found to be androgen-regulated. To investigate the mechanistic role(s) of the m6A methyltransferase complex in PCa cells, short hairpin RNA (shRNA)-mediated knockdown coupled with next generation sequencing was used to determine the transcriptome-wide roles of METTL3, the catalytic subunit of the m6A methyltransferase complex. Functional depletion of METTL3 resulted in upregulation of the androgen receptor (AR), together with 134 AR-regulated genes. METTL3 knockdown also resulted in altered splicing, and enrichment of cell cycle, DNA repair and metabolic pathways. Collectively, this study identified the functional and clinical significance of four essential m6A complex components in PCa patient specimens and cell lines for the first time. Further studies are now warranted to determine the potential therapeutic relevance of METTL3 inhibitors in development to treat leukaemia to benefit patients with PCa

The KDM5B and KDM1A lysine demethylases cooperate in regulating androgen receptor expression and signalling in prostate cancer

Histone H3 lysine 4 (H3K4) methylation is key epigenetic mark associated with active transcription and is a substrate for the KDM1A/LSD1 and KDM5B/JARID1B lysine demethylases. Increased expression of KDM1A and KDM5B is implicated in many cancer types, including prostate cancer (PCa). Both KDM1A and KDM5B interact with AR and promote androgen regulated gene expression. For this reason, there is great interested in the development of new therapies targeting KDM1A and KDM5B, particularly in the context of castrate resistant PCa (CRPC), where conventional androgen deprivation therapies and androgen receptor signalling inhibitors are no longer effective. As there is no curative therapy for CRPC, new approaches are urgently required to suppress androgen signalling that prevent, delay or reverse progression to the castrate resistant state. While the contribution of KDM1A to PCa is well established, the exact contribution of KDM5B to PCa is less well understood. However, there is evidence that KDM5B is implicated in numerous pro-oncogenic mechanisms in many different types of cancer, including the hypoxic response, immune evasion and PI3/AKT signalling. Here we elucidate the individual and cooperative functions of KDM1A and KDM5B in PCa. We show that KDM5B mRNA and protein expression is elevated in localised and advanced PCa. We show that the KDM5 inhibitor, CPI-455, impairs androgen regulated transcription and alternative splicing. Consistent with the established role of KDM1A and KDM5B as AR coregulators, we found that individual pharmacologic inhibition of KDM1A and KDM5 by namoline and CPI-455 respectively, impairs androgen regulated transcription. Notably, combined inhibition of KDM1A and KDM5 downregulates AR expression in CRPC cells. Furthermore, combined KDM1A and KDM5 inhibition impairs PCa cell proliferation and invasion more than individual inhibition of KDM1A and KDM5B. Collectively our study has identified individual and cooperative mechanisms involving KDM1A and KDM5 in androgen signalling in PCa. Our findings support the further development of KDM1A and KDM5B inhibitors to treat advanced PCa. Further work is now required to confirm the therapeutic feasibility of combined inhibition of KDM1A and KDM5B as a novel therapeutic strategy for targeting AR positive CRPC