Elevated O-GlcNAc levels activate epigenetically repressed genes and delay mouse ES cell differentiation without affecting naive to primed cell transition

The differentiation of mouse embryonic stem (ES) cells is controlled by the interaction of multiple signaling pathways, typically mediated by post-translational protein modifications. The addition of O-linked N-acetylglucosamine (O-GlcNAc) to serine and threonine residues of nuclear and cytoplasmic proteins is one such modification (O-GlcNAcylation), whose function in ES cells is only now beginning to be elucidated. Here we demonstrate that the specific inhibition of O-GlcNAc hydrolase (Oga) causes increased levels of protein O-GlcNAcylation and impairs differentiation of mouse ES cells both in serum-free monolayer and in embryoid bodies (EBs). Use of reporter cell lines demonstrates that Oga inhibition leads to a reduction in the number of Sox1-expressing neural progenitors generated following induction of neural differentiation, as well as maintained expression of the ES cell marker Oct4 (Pou5f1). In EBs expression of mesodermal and endodermal markers is also delayed. However, the transition of naïve cells to primed pluripotency indicated by Rex1 (Zfp42), Nanog, Esrrb and Dppa3 downregulation and Fgf5 upregulation remains unchanged. Finally, we demonstrate that increased O-GlcNAcylation results in upregulation of genes normally epigenetically silenced in ES cells, supporting the emerging role for this protein modification in the regulation of histone modifications and DNA methylation. Stem Cells 2014

Geographical distance and reduced access to palliative radiotherapy: Systematic Review and Meta-Analysis

Background. Palliative radiotherapy (PRT) is an effective way of reducing symptoms caused by advanced incurable cancer. Several studies have investigated factors that contribute to inequalities in access to PRT; distance to a radiotherapy centre has been identified as one potential barrier.Aim. To assess whether there is an association between distance to a radiotherapy centre and utilisation rates of PRT in adults with cancer.Methods. A systematic review and meta-analysis protocol was registered in the PROSPERO database (CRD42020190772). MEDLINE, EMBASE, CINAHL and APA-PsycINFO were searched for relevant papers up to 28 February 2021.Results. Twenty-one studies were included. Twelve studies focused on whether patients with incurable cancer received PRT, as part of their treatment package. Pooled results reported that living ≥50 km vs <50 km from the radiotherapy centre was associated with a reduced likelihood of receiving PRT (OR 0.84 (95%CI 0.80, 0.88)). Nine focused on distance from the radiotherapy centre and compared single-fraction (SF) versus multiple-fraction PRT, indicating that patients living further away were more likely to receive SF. Pooled results comparing ≥50 km versus <50 km showed increased odds of receiving SF for those living ≥50 km (OR 1.48 (95%CI 1.26,1.75)).Conclusion. Patients living further away from radiotherapy centres were less likely to receive PRT and those who received PRT were more likely to receive SF PRT, providing some evidence of inequalities in access to PRT treatment based on proximity to centres providing radiotherapy. Further research is needed to understand whether these inequalities are influenced by clinical referral patterns or by patients unwilling or unable to travel longer distances

Pituitary Lesions, Obesity, and Mesenteric Lipomas in Insulin-Resistant Horses

The aim of the current study was to identify associations between pituitary lesions, body condition scores, and mesenteric lipomas in horses with insulin resistance. Necropsy examinations were performed following euthanasia in 30 adult horses designated as insulin resistant (n = 11) or insulin sensitive (n = 19). Insulin sensitivity was determined using the insulin-modified frequently sampled intravenous glucose tolerance test and resting insulin concentrations. At necropsy, mesenteric lipomas were measured. The pituitary and adrenal glands, pancreas, and liver were evaluated histologically; pituitary glands were scored based on published criteria. Insulin-resistant horses had significantly higher pituitary scores (p = 0.0035) and body condition scores (p = 0.0001), even when adjusting for age, and a greater frequency of mesenteric lipomas (p = 0.014) and greater lipoma area (p = 0.0332) than insulin-sensitive horses. Regardless of insulin status, horses with pituitary scores ≥3 (diffuse hyperplasia; n = 25) had higher body condition scores (p = 0.0313) and a greater frequency of mesenteric lipomas (p \u3c 0.0002) than those with lower pituitary scores. High body condition score was not correlated to an increased frequency of mesenteric lipomas. Detection of higher pituitary scores in insulin-resistant horses suggested an association between insulin resistance and pituitary morphology. Horses in the insulin-resistant group and those with high pituitary scores had higher body condition scores and a greater frequency of mesenteric lipomas. These horses might be at increased risk for lipoma-associated colic

History in schools and the problem of 'the nation'

The article examines the enduring popularity of a form of school history which is based predominantly on the idea that the transmission of a positive story about the national past will inculcate in young people a sense of loyalty to the state; a reassuring and positive sense of identity and belonging; and a sense of social solidarity with fellow citizens. England is one of the countries which has to at least some extent moved away from this model of school history; but the past few years have seen suggestions for a move back to a history curriculum which focuses predominantly on the transmission of ‘Our Island Story’; and which presents a positive rendering of that story. The history curriculum in England is currently under review; and public pronouncements by politicians; academic historians and newspaper editorials suggest strong pressures towards a restoration of what is often termed ‘traditional’ school history; which was prevalent in English schools before the advent of what has been termed ‘New history’ in the 1970s. The paper questions some of the arguments which have been put forward in order to justify a return to a history curriculum based on a positive and unproblematic narrative of the national story and suggests that such a course of action is based on some unexamined assumptions and a limited understanding of pedagogy and learning. The final section of the paper outlines several weaknesses and flaws in the arguments for reverting to a traditional (i.e. ‘nation-based’ and celebratory) form of school history; and some of the dangers inherent in such a project

Review of UK microgeneration. Part 1 : policy and behavioural aspects

A critical review of the literature relating to government policy and behavioural aspects relevant to the uptake and application of microgeneration in the UK is presented. Given the current policy context aspiring to zero-carbon new homes by 2016 and a variety of minimum standards and financial policy instruments supporting microgeneration in existing dwellings, it appears that this class of technologies could make a significant contribution to UK energy supply and low-carbon buildings in the future. Indeed, achievement of a reduction in greenhouse gas emissions by 80% (the UK government's 2050 target) for the residential sector may entail substantial deployment of microgeneration. Realisation of the large potential market for microgeneration relies on a variety of inter-related factors such as microeconomics, behavioural aspects, the structure of supporting policy instruments and well-informed technology development. This article explores these issues in terms of current and proposed policy instruments in the UK. Behavioural aspects associated with both initial uptake of the technology and after purchase are also considered

Lipoprotein biosynthesis as a target for anti-Wolbachia treatment of filarial nematodes

<p>Abstract</p> <p>Background</p> <p>Lymphatic filariasis and onchocerciasis are debilitating diseases caused by filarial nematodes. Disease pathogenesis is induced by inflammatory responses following the death of the parasite. <it>Wolbachia </it>endosymbionts of filariae are potent inducers of innate and adaptive inflammation and bacterial lipoproteins have been identified as the ligands that bind toll-like receptors (TLR) 2 and TLR6. Lipoproteins are important structural and functional components of bacteria and therefore enzymes involved in <it>Wolbachia </it>lipoprotein biosynthesis are potential chemotherapeutic targets.</p> <p>Results</p> <p>Globomycin, a signal peptidase II (LspA) inhibitor, has activity against Gram-negative bacteria and a putative <it>lspA </it>gene has been identified from the <it>Wolbachia </it>genome of <it>Brugia malayi </it>(<it>w</it>Bm). The amino acids required for function are strictly conserved and functionality was verified by complementation tests in a temperature-sensitive <it>Escherichia coli lspA </it>mutant. Also, transformation of wild type <it>E. coli </it>with <it>Wolbachia lspA </it>conferred significant globomycin resistance. A cell-based screen has been developed utilizing a <it>Wolbachia</it>-containing <it>Aedes albopictus </it>cell line to assay novel compounds active against <it>Wolbachia</it>. Globomycin was screened using this assay, which resulted in a dose-dependent reduction in <it>Wolbachia </it>load. Furthermore, globomycin was also effective in reducing the motility and viability of adult <it>B. malayi in vitro</it>.</p> <p>Conclusions</p> <p>These studies validate lipoprotein biosynthesis as a target in an organism for which no genetic tools are available. Further studies to evaluate drugs targeting this pathway are underway as part of the A-WOL drug discovery and development program.</p

Wearable Technology Supported Home Rehabilitation Services in Rural Areas:– Emphasis on Monitoring Structures and Activities of Functional Capacity Handbook

The sustainability of modern healthcare systems is under threat. – the ageing of the population, the prevalence of chronic disease and a need to focus on wellness and preventative health management, in parallel with the treatment of disease, pose significant social and economic challenges. The current economic situation has made these issues more acute. Across Europe, healthcare expenditure is expected to rice to almost 16% of GDP by 2020. (OECD Health Statistics 2018). Coupled with a shortage of qualified personnel, European nations are facing increasing challenges in their ability to provide better-integrated and sustainable health and social services. The focus is currently shifting from treatment in a care center to prevention and health promotion outside the care institute. Improvements in technology offers one solution to innovate health care and meet demand at a low cost. New technology has the potential to decrease the need for hospitals and health stations (Lankila et al., 2016. In the future the use of new technologies – including health technologies, sensor technologies, digital media, mobile technology etc. - and digital services will dramatically increase interaction between healthcare personnel and customers (Deloitte Center for Health Solutions, 2015a; Deloitte Center for Health Solutions 2015b). Introduction of technology is expected to drive a change in healthcare delivery models and the relationship between patients and healthcare providers. Applications of wearable sensors are the most promising technology to aid health and social care providers deliver safe, more efficient and cost-effective care as well as improving people’s ability to self-manage their health and wellbeing, alert healthcare professionals to changes in their condition and support adherence to prescribed interventions. (Tedesco et al., 2017; Majumder et al., 2017). While it is true that wearable technology can change how healthcare is monitored and delivered, it is necessary to consider a few things when working towards the successful implementation of this new shift in health care. It raises challenges for the healthcare systems in how to implement these new technologies, and how the growing amount of information in clinical practice, integrates into the clinical workflows of healthcare providers. Future challenges for healthcare include how to use the developing technology in a way that will bring added value to healthcare professionals, healthcare organizations and patients without increasing the workload and cost of the healthcare services. For wearable technology developers, the challenge will be to develop solutions that can be easily integrated and used by healthcare professionals considering the existing constraints. This handbook summarizes key findings from clinical and laboratory-controlled demonstrator trials regarding wearables to assist rehabilitation professionals, who are planning the use of wearable sensors in rehabilitation processes. The handbook can also be used by those developing wearable sensor systems for clinical work and especially for use in hometype environments with specific emphasis on elderly patients, who are our major health care consumers