Getting lost in the matrix? On how the characteristics and arrangement of linear landscape elements influence ecological connectivity

Acknowledgements We would like to thank the Natural Environment Research Council and Natural England for providing the funding to conduct this study. We are also indebted to the work of Greta Bocedi in developing the RangeShifter platform prior to its implementation in this study. Funding This research was supported by the Natural Environment Research Council (NERC) [Grant No. NE/P009697/1]. Support was also received from Natural England (https://www.gov.uk/government/organisations/natural-england).Peer reviewedPublisher PD

A cascade Suzuki-Miyaura/Diels-Alder protocol : exploring the bifunctional utility of vinyl Bpin

Funding: Industrial CASE studentship awarded from EPSRC and GlaxoSmithKline. The authors thank the EPSRC, GlaxoSmithKline, and the University of St Andrews for studentship funding (DLC), and the University of St Andrews and the EPSRC UK National Mass Spectrometry Facility at Swansea University for analyses.Cascade reactions are an important strategy in reaction design, allowing streamlining of chemical synthesis. Here we report a cascade Suzuki-Miyaura/Diels-Alder reaction, employing vinyl Bpin as a bifunctional reagent in two distinct roles: as an organoboron nucleophile for cross- coupling and as a Diels-Alder dienophile. Merging these two reactions enables a rapid and operationally simple synthesis of functionalized carbocycles in good yield. The effect of the organoboron subtype on Diels- Alder regioselectivity was investigated and post-synthetic modifications were carried out on a model substrate. The potential for a complementary Heck/Diels-Alder process was also assessed.PostprintPeer reviewe

Health First: An evidence-based alcohol strategy for the UK

Alcohol is taken for granted in the UK today. It is easy to get hold of, increasingly affordable, advertised everywhere and accepted by many as an integral part of daily life. Yet, despite this, the great majority of the population recognise the harm that alcohol causes. They believe that drinking damages health, drives anti social behaviour, harms children and families and creates huge costs for the NHS and the Police. They are right. Every year in the UK, there are thousands of deaths and over a million hospital admissions related to drinking. More than two in five (44%) violent crimes are committed under the influence of alcohol, as are 37% of domesti c violence incidents. One fifth of all violent crime occurs in or near pubs and clubs and 45% of adults avoid town centres at night because of drunken behaviour. The personal, social and economic cost of alcohol has been estimated to be up to £55bn for England and £7.5bn for Scotland. None of this should be taken for granted. The impact of drinking on public health and community safety is so great that radical steps are needed to change our relationship with alcohol. We need to imagine a society where low or no alcohol consumpti on is the norm, drunkenness is socially unacceptable and town centres are safe and welcoming places for everyone to use. Our vision is for a safer, healthier and happier world where the harm caused by alcohol is minimised. This vision is achievable. But only if we tackle the primary drivers of alcohol consumption. The evidence is clear: the most effective way to reduce the harm from alcohol is to reduce the affordability, availability and attractiveness of alcohol products. It is not enough to limit the damage once people are drunk, dependent, ill or dying. We need to intervene earlier in order to reduce consumption across the entire population. The tools are available. The ‘four Ps' of the marketing mix - price, product, promotion and place - are used by alcohol producers and retailers to increase their sales of alcohol. They can also be used by government to reduce alcohol sales, alcohol consumption and alcohol-related harm. Alcohol taxes are an effective public health measure as they raise prices and suppress demand. However, if they do not keep pace with both inflation and incomes, alcohol products will become more affordable over time. This has been the case in the UK. Deep discounting by retailers has also driven down the price of alcohol and encouraged heavy drinkers to maintain dangerous levels of consumption. These problems need to be tackled by a combinati on of more effective fiscal policy and controls on pricing and discounting. Alcohol products are an extraordinary anomaly. Unlike most food products, they are both remarkably harmful and excepti onally lightly regulated. As with other toxic products, the product label ought to communicate the content of the product and the risks of its consumpti on. Regulation should drive out products that appeal to young people while also incentivising the development and sale of lower strength products. The pervasive marketing of alcohol products in the UK is indefensible. Current restrictions are woefully inadequate: children and young people are regularly exposed to alcohol adverti sing in both old and new media. Only a complete ban on all alcohol advertising and sponsorship will make a lasting diff erence. Licensing practice in the UK is out of date. The focus on pubs and bars has allowed shops and supermarkets to become the dominant players in alcohol sales. Consequently, alcohol is now more available than it has ever been. This has driven pre-loading: getting drunk on cheap, shop-bought alcohol before heading out to late-opening night life. Licensing must focus on public health and seek to control the overall availability of alcohol as well as the effects of drunkenness. Beyond these populati on-level approaches, many more targeted measures are needed to reduce alcohol-related harm. Early interventi on by health and social care professionals is an important and underexploited opportunity to prevent problems developing. Stronger drink driving measures are also required. All these measures are needed. Together, they provide a template for an integrated and comprehensive strategy to tackle the harm from alcohol in the UK.Additional co-authors: Gerry McElwee, Dr Kieran Moriarty CBE, Dr Robin Purshouse, Dr Peter Rice, Alison Rogers, George Roycroft , Chit Selvarajah, Don Shenker, Eric Appleby, Dr Nick Sheron, and Colin Shevill

Vacuolar ATPase Is a Possible Therapeutic Target in Acute Myeloid Leukemia: Focus on Patient Heterogeneity and Treatment Toxicity

Vacuolar ATPase (V-ATPase) is regarded as a possible target in cancer treatment. It is expressed in primary acute myeloid leukemia cells (AML), but the expression varies between patients and is highest for patients with a favorable prognosis after intensive chemotherapy. We therefore investigated the functional effects of two V-ATPase inhibitors (bafilomycin A1, concanamycin A) for primary AML cells derived from 80 consecutive patients. The V-ATPase inhibitors showed dose-dependent antiproliferative and proapoptotic effects that varied considerably between patients. A proteomic comparison of primary AML cells showing weak versus strong antiproliferative effects of V-ATPase inhibition showed a differential expression of proteins involved in intracellular transport/cytoskeleton functions, and an equivalent phosphoproteomic comparison showed a differential expression of proteins that regulate RNA processing/function together with increased activity of casein kinase 2. Patients with secondary AML, i.e., a heterogeneous subset with generally adverse prognosis and previous cytotoxic therapy, myeloproliferative neoplasia or myelodysplastic syndrome, were characterized by a strong antiproliferative effect of V-ATPase inhibition and also by a specific mRNA expression profile of V-ATPase interactome proteins. Furthermore, the V-ATPase inhibition altered the constitutive extracellular release of several soluble mediators (e.g., chemokines, interleukins, proteases, protease inhibitors), and increased mediator levels in the presence of AML-supporting bone marrow mesenchymal stem cells was then observed, especially for patients with secondary AML. Finally, animal studies suggested that the V-ATPase inhibitor bafilomycin had limited toxicity, even when combined with cytarabine. To conclude, V-ATPase inhibition has antileukemic effects in AML, but this effect varies between patients.publishedVersio

Rapid mechanosensitive migration and dispersal of newly divided mesenchymal cells aid their recruitment into dermal condensates

Embryonic mesenchymal cells are dispersed within an extracellular matrix but can coalesce to form condensates with key developmental roles. Cells within condensates undergo fate and morphological changes and induce cell fate changes in nearby epithelia to produce structures including hair follicles, feathers, or intestinal villi. Here, by imaging mouse and chicken embryonic skin, we find that mesenchymal cells undergo much of their dispersal in early interphase, in a stereotyped process of displacement driven by 3 hours of rapid and persistent migration followed by a long period of low motility. The cell division plane and the elevated migration speed and persistence of newly born mesenchymal cells are mechanosensitive, aligning with tissue tension, and are reliant on active WNT secretion. This behaviour disperses mesenchymal cells and allows daughters of recent divisions to travel long distances to enter dermal condensates, demonstrating an unanticipated effect of cell cycle subphase on core mesenchymal behaviour

Incidence and phenotypes of childhood-onset genetic epilepsies:a prospective population-based national cohort

Epilepsy is common in early childhood. In this age group it is associated with high rates of therapy-resistance, and with cognitive, motor, and behavioural comorbidity. A large number of genes, with wide ranging functions, are implicated in its aetiology, especially in those with therapy-resistant seizures. Identifying the more common single-gene epilepsies will aid in targeting resources, the prioritization of diagnostic testing and development of precision therapy. Previous studies of genetic testing in epilepsy have not been prospective and population-based. Therefore, the population-incidence of common genetic epilepsies remains unknown. The objective of this study was to describe the incidence and phenotypic spectrum of the most common single-gene epilepsies in young children, and to calculate what proportion are amenable to precision therapy. This was a prospective national epidemiological cohort study. All children presenting with epilepsy before 36 months of age were eligible. Children presenting with recurrent prolonged (>10 min) febrile seizures; febrile or afebrile status epilepticus (>30 min); or with clusters of two or more febrile or afebrile seizures within a 24-h period were also eligible. Participants were recruited from all 20 regional paediatric departments and four tertiary children’s hospitals in Scotland over a 3-year period. DNA samples were tested on a custom-designed 104-gene epilepsy panel. Detailed clinical information was systematically gathered at initial presentation and during follow-up. Clinical and genetic data were reviewed by a multidisciplinary team of clinicians and genetic scientists. The pathogenic significance of the genetic variants was assessed in accordance with the guidelines of UK Association of Clinical Genetic Science (ACGS). Of the 343 patients who met inclusion criteria, 333 completed genetic testing, and 80/333 (24%) had a diagnostic genetic finding. The overall estimated annual incidence of single-gene epilepsies in this well-defined population was 1 per 2120 live births (47.2/100 000; 95% confidence interval 36.9–57.5). PRRT2 was the most common single-gene epilepsy with an incidence of 1 per 9970 live births (10.0/100 000; 95% confidence interval 5.26–14.8) followed by SCN1A: 1 per 12 200 (8.26/100 000; 95% confidence interval 3.93–12.6); KCNQ2: 1 per 17 000 (5.89/100 000; 95% confidence interval 2.24–9.56) and SLC2A1: 1 per 24 300 (4.13/100 000; 95% confidence interval 1.07–7.19). Presentation before the age of 6 months, and presentation with afebrile focal seizures were significantly associated with genetic diagnosis. Single-gene disorders accounted for a quarter of the seizure disorders in this cohort. Genetic testing is recommended to identify children who may benefit from precision treatment and should be mainstream practice in early childhood onset epilepsy

Ferumoxytol-enhanced magnetic resonance imaging methodology and normal values at 1.5 and 3T

Background: Ultrasmall superparamagnetic particles of iron oxide (USPIO)-enhanced magnetic resonance imaging (MRI) can detect tissue-resident macrophage activity and identify cellular inflammation. Clinical studies using this technique are now emerging. We aimed to report a range of normal R2* values at 1.5 and 3 T in the myocardium and other tissues following ferumoxytol administration, outline the methodology used and suggest solutions to commonly encountered analysis problems. Methods: Twenty volunteers were recruited: 10 imaged each at 1.5 T and 3 T. T2* and late gadolinium enhanced (LGE) MRI was conducted at baseline with further T2* imaging conducted approximately 24 h after USPIO infusion (ferumoxytol, 4 mg/kg). Regions of interest were selected in the myocardium and compared to other tissues. Results: Following administration, USPIO was detected by changes in R2* from baseline (1/T2*) at 24 h in myocardium, skeletal muscle, kidney, liver, spleen and blood at 1.5 T, and myocardium, kidney, liver, spleen, blood and bone at 3 T (p < 0.05 for all). Myocardial changes in R2* due to USPIO were 26.5 ± 7.3 s-1 at 1.5 T, and 37.2 ± 9.6 s-1 at 3 T (p < 0.0001 for both). Tissues showing greatest ferumoxytol enhancement were the reticuloendothelial system: the liver, spleen and bone marrow (216.3 ± 32.6 s-1, 336.3 ± 60.3 s-1, 69.9 ± 79.9 s-1; p < 0.0001, p < 0.0001, p = ns respectively at 1.5 T, and 275.6 ± 69.9 s-1, 463.9 ± 136.7 s-1, 417.9 ± 370.3 s-1; p < 0.0001, p < 0.0001, p < 0.01 respectively at 3 T). Conclusion: Ferumoxytol-enhanced MRI is feasible at both 1.5 T and 3 T. Careful data selection and dose administration, along with refinements to echo-time acquisition, post-processing and analysis techniques are essential to ensure reliable and robust quantification of tissue enhancement