Virtual Roman Leicester (VRL): An interactive Computer Model of a Romano-British City

This paper describes the background, development and use of a new Virtual Reality (VR) model of the built fabric of Roman Leicester (Ratae Corieltauvo-rum) which has been based upon direct archaeologi-cal evidence, literary evidence and comparisons with the remains of similar Romano-British cities. It forms the conclusion of the first stage of a larger ongoing collaborative research project to create an inhabited virtual Romano-British world populated by interact-ing avatars programmed using a novel form of artifi-cial intelligence (AI) to have a range of Romano-British morals and values for the purposes of examin-ing resultant emergent behaviors and societal devel-opment. Virtual Roman Leicester (VRL) has been created in a popular games engine to allow real-time exploration by real world users and has a multiplat-form capability to also examine issues surrounding the use of Virtual Reality for public outreach and the wider understanding of cultural heritage. Here we focus firstly upon issues surrounding the interpreta-tion of the archaeological evidence and its extrapola-tion into full buildings (using a technique we call architectural forensics), secondly upon technical is-sues concerning importation of ancient land surface terrain and thirdly upon aspects of initial user expe-rience following an extensive public exhibition of the model

Adding Another Dimension to Small Satellite Constellations

Satellite constellations for Earth Observation almost invariably use duplicates of the same satellites to provide higher temporal resolution or greater coverage. The value of Big Data applications often depend on the fusing of different sensor information. If instead constellation satellites are equipped with a variety of sensors, these can be configured to provide more complex data products. Flexibility and in orbit rearrangement can create a range of systems that can be configured on-demand to address a range of new applications. Small satellites and sensor capability have only recently advanced far enough to make such a systems financially viable. Key challenges in such systems are optimising the composition of the constellation with different sensors or capabilities in addressing different applications, and developing methods for fusing non-contemporaneous information to build capabilities that can only be achieved through a distributed system

DMC3 and Carbonite-1: Two Sides of Small Satellites

Launched in July 2015, the DMC3 constellation was designed with a “smallsat mentality” and represents the coming of age of small satellites for Earth Observation, offering performance that until a few years ago could only be found in satellites costing ten or twenty times more. The low cost of the individual satellites made it possible to deploy a constellation of 3 spacecraft, for daily global access, without any compromises in performance, at a fraction of the price of equivalent single EO satellites. The constellation started generating data 10 days after launch and has been in regular operation since the last quarter of 2015 and some results are presented in this paper. On the same launch as DMC3, SSTL deployed a prototype “video from space” satellite. Designed and built in under 8 months, Carbonite-1 demonstrated the use of very fast, low cost techniques to design and build satellites for “super-constellations”. In this paper, results from Carbonite-1 are presented and we undertake a discussion on the merits of DMC3 versus Carbonite-1 and what they offer to the EO community. We also discuss the future evolution of the DMC3 spacecraft design (the SSTL-300 S1) as well as the future plans for Carbonite

Prolonged treatment of genetically obese mice with conjugated linoleic acid improves glucose tolerance and lowers plasma insulin concentration: possible involvement of PPAR activation

BACKGROUND: Studies in rodents and some studies in humans have shown that conjugated linoleic acid (CLA), especially its trans-10, cis-12 isomer, reduces body fat content. However, some but not all studies in mice and humans (though none in rats) have found that CLA promotes insulin resistance. The molecular mechanisms responsible for these effects are unclear, and there are conflicting reports on the effects of CLA on peroxisomal proliferator-activated receptor-γ (PPARγ) activation and expression. We have conducted three experiments with CLA in obese mice over three weeks, and one over eleven weeks. We have also investigated the effects of CLA isomers in PPARγ and PPARα reporter gene assays. RESULTS: Inclusion of CLA or CLA enriched with its trans-10, cis-12 isomer in the diet of female genetically obese (lep(ob)/lep(ob)) mice for up to eleven weeks reduced body weight gain and white fat pad weight. After two weeks, in contrast to beneficial effects obtained with the PPARγ agonist rosiglitazone, CLA or CLA enriched with its trans-10, cis-12 isomer raised fasting blood glucose and plasma insulin concentrations, and exacerbated glucose tolerance. After 10 weeks, however, CLA had beneficial effects on glucose and insulin concentrations. At this time, CLA had no effect on the plasma TNFα concentration, but it markedly reduced the plasma adiponectin concentration. CLA and CLA enriched with either isomer raised the plasma triglyceride concentration during the first three weeks, but not subsequently. CLA enriched with its trans-10, cis-12 isomer, but not with its cis-9, trans-11 isomer, stimulated PPARγ-mediated reporter gene activity; both isomers stimulated PPARα-mediated reporter gene activity. CONCLUSIONS: CLA initially decreased but subsequently increased insulin sensitivity in lep(ob)/lep(ob )mice. Activation of both PPARγ and PPARα may contribute to the improvement in insulin sensitivity. In the short term, however, another mechanism, activated primarily by trans-10, cis-12-CLA, which probably leads to reduced adipocyte number and consequently reduced plasma adiponectin concentration, may decrease insulin sensitivity

Development of the Observation Schedule for Children with Autism-Anxiety, Behaviour and Parenting (OSCA-ABP): A New Measure of Child and Parenting Behavior for Use with Young Autistic Children.

Co-occurring emotional and behavioral problems (EBPs) frequently exist in young autistic children. There is evidence based on parental report that parenting interventions reduce child EBPs. More objective measures of child EBPs should supplement parent reported outcomes in trials. We describe the development of a new measure of child and parenting behavior, the Observation Schedule for Children with Autism-Anxiety, Behaviour and Parenting (OSCA-ABP). Participants were 83 parents/carers and their 4-8-year-old autistic children. The measure demonstrated good variance and potential sensitivity to change. Child and parenting behavior were reliably coded among verbal and minimally verbal children. Associations between reports from other informants and observed behavior showed the measure had sufficient convergent validity. The measure has promise to contribute to research and clinical practice in autism mental health beyond objective measurement in trials

A novel group parenting intervention to reduce emotional and behavioural difficulties in young autistic children:protocol for the Autism Spectrum Treatment and Resilience pilot randomised controlled trial

INTRODUCTION: The majority of young autistic children display impairing emotional and behavioural difficulties that contribute to family stress. There is some evidence that behavioural parenting interventions are effective for reducing behavioural difficulties in autistic children, with less evidence assessing change in emotional difficulties. Previous trials have tended to use unblinded parent-report measures as primary outcomes and many do not employ an active control, limiting the conclusions that can be drawn. METHODS AND ANALYSIS: The Autism Spectrum Treatment and Resilience study is a pilot randomised controlled trial (RCT) testing the specific effect of a 12-week group parenting intervention (Predictive Parenting) on primary and secondary outcomes, in comparison to an attention control condition consisting of psychoeducation parent groups. Following a feasibility study to test research procedures and the interventions, the pilot RCT participants include 60 parents of autistic children aged 4-8 years who are randomised to Predictive Parenting versus the attention control. Measures are administered at baseline and post intervention to assess group differences in child and parent outcomes, costs and service use and adverse events. The primary outcome is an objective measure of child behaviours that challenge during interactions with their parent and a researcher. The trial aims to provide data on recruitment, retention, completion of measures and acceptability of the intervention and research protocol, in addition to providing a preliminary indication of potential efficacy and establishing an effect size that could be used to power a larger-scale efficacy trial. We will also provide preliminary estimates of the cost-effectiveness of the interventions. ETHICS AND DISSEMINATION: Ethical approval was granted from NHS Camden and Kings Cross Research Ethics Committee (ref: 16/LO/1769) along with NHS R&D approval from South London and Maudsley, Guy's and St Thomas', and Croydon Health Services NHS Trusts. The findings will be disseminated through publication in peer-reviewed journals and presentations at conferences. TRIAL REGISTRATION NUMBER: ISRCTN91411078

Mycobacterium tuberculosis whole genome sequencing and protein structure modelling provides insights into anti-tuberculosis drug resistance.

BACKGROUND: Combating the spread of drug resistant tuberculosis is a global health priority. Whole genome association studies are being applied to identify genetic determinants of resistance to anti-tuberculosis drugs. Protein structure and interaction modelling are used to understand the functional effects of putative mutations and provide insight into the molecular mechanisms leading to resistance. METHODS: To investigate the potential utility of these approaches, we analysed the genomes of 144 Mycobacterium tuberculosis clinical isolates from The Special Programme for Research and Training in Tropical Diseases (TDR) collection sourced from 20 countries in four continents. A genome-wide approach was applied to 127 isolates to identify polymorphisms associated with minimum inhibitory concentrations for first-line anti-tuberculosis drugs. In addition, the effect of identified candidate mutations on protein stability and interactions was assessed quantitatively with well-established computational methods. RESULTS: The analysis revealed that mutations in the genes rpoB (rifampicin), katG (isoniazid), inhA-promoter (isoniazid), rpsL (streptomycin) and embB (ethambutol) were responsible for the majority of resistance observed. A subset of the mutations identified in rpoB and katG were predicted to affect protein stability. Further, a strong direct correlation was observed between the minimum inhibitory concentration values and the distance of the mutated residues in the three-dimensional structures of rpoB and katG to their respective drugs binding sites. CONCLUSIONS: Using the TDR resource, we demonstrate the usefulness of whole genome association and convergent evolution approaches to detect known and potentially novel mutations associated with drug resistance. Further, protein structural modelling could provide a means of predicting the impact of polymorphisms on drug efficacy in the absence of phenotypic data. These approaches could ultimately lead to novel resistance mutations to improve the design of tuberculosis control measures, such as diagnostics, and inform patient management

Genomic Epidemiology of Complex, Multispecies, Plasmid-Borne bla KPC Carbapenemase in Enterobacterales in the United Kingdom from 2009 to 2014.

Carbapenem resistance in Enterobacterales is a public health threat. Klebsiella pneumoniae carbapenemase (encoded by alleles of the bla KPC family) is one of the most common transmissible carbapenem resistance mechanisms worldwide. The dissemination of bla KPC historically has been associated with distinct K. pneumoniae lineages (clonal group 258 [CG258]), a particular plasmid family (pKpQIL), and a composite transposon (Tn4401). In the United Kingdom, bla KPC has represented a large-scale, persistent management challenge for some hospitals, particularly in North West England. The dissemination of bla KPC has evolved to be polyclonal and polyspecies, but the genetic mechanisms underpinning this evolution have not been elucidated in detail; this study used short-read whole-genome sequencing of 604 bla KPC-positive isolates (Illumina) and long-read assembly (PacBio)/polishing (Illumina) of 21 isolates for characterization. We observed the dissemination of bla KPC (predominantly bla KPC-2; 573/604 [95%] isolates) across eight species and more than 100 known sequence types. Although there was some variation at the transposon level (mostly Tn4401a, 584/604 [97%] isolates; predominantly with ATTGA-ATTGA target site duplications, 465/604 [77%] isolates), bla KPC spread appears to have been supported by highly fluid, modular exchange of larger genetic segments among plasmid populations dominated by IncFIB (580/604 isolates), IncFII (545/604 isolates), and IncR (252/604 isolates) replicons. The subset of reconstructed plasmid sequences (21 isolates, 77 plasmids) also highlighted modular exchange among non-bla KPC and bla KPC plasmids and the common presence of multiple replicons within bla KPC plasmid structures (>60%). The substantial genomic plasticity observed has important implications for our understanding of the epidemiology of transmissible carbapenem resistance in Enterobacterales for the implementation of adequate surveillance approaches and for control

WSB-1 regulates the metastatic potential of hormone receptor negative breast cancer

© 2018 Cancer Research UK. Background: Metastatic spread is responsible for the majority of cancer-associated deaths. The tumour microenvironment, including hypoxia, is a major driver of metastasis. The aim of this study was to investigate the role of the E3 ligase WSB-1 in breast cancer biology in the context of the hypoxic tumour microenvironment, particularly regarding metastatic spread. Methods: In this study, WSB-1 expression was evaluated in breast cancer cell lines and patient samples. In silico analyses were used to determine the impact of WSB-1 expression on distant metastasis-free survival (DMFS) in patients, and correlation between WSB1 expression and hypoxia gene expression signatures. The role of WSB-1 on metastasis promotion was evaluated in vitro and in vivo. Results: High WSB1 expression was associated with decreased DMFS in ER-breast cancer and PR-breast cancer patients. Surprisingly, WSB1 expression was not positively correlated with known hypoxic gene expression signatures in patient samples. Our study is the first to show that WSB-1 knockdown led to decreased metastatic potential in breast cancer hormone receptor-negative models in vitro and in vivo. WSB-1 knockdown was associated with decreased metalloproteinase (MMP) activity, vascular endothelial growth factor (VEGF) secretion, and angiogenic potential. Conclusions: Our data suggests that WSB-1 may be an important regulator of aggressive metastatic disease in hormone receptor-negative breast cancer. WSB-1 could therefore represent a novel regulator and therapeutic target for secondary breast cancer in these patients

Chronic Activation of γ2 AMPK Induces Obesity and Reduces β Cell Function.

Despite significant advances in our understanding of the biology determining systemic energy homeostasis, the treatment of obesity remains a medical challenge. Activation of AMP-activated protein kinase (AMPK) has been proposed as an attractive strategy for the treatment of obesity and its complications. AMPK is a conserved, ubiquitously expressed, heterotrimeric serine/threonine kinase whose short-term activation has multiple beneficial metabolic effects. Whether these translate into long-term benefits for obesity and its complications is unknown. Here, we observe that mice with chronic AMPK activation, resulting from mutation of the AMPK γ2 subunit, exhibit ghrelin signaling-dependent hyperphagia, obesity, and impaired pancreatic islet insulin secretion. Humans bearing the homologous mutation manifest a congruent phenotype. Our studies highlight that long-term AMPK activation throughout all tissues can have adverse metabolic consequences, with implications for pharmacological strategies seeking to chronically activate AMPK systemically to treat metabolic disease