A Simulator Program for Evaluating and Improving the Nottingham Muse Architecture.

This paper describes the modelling and simulation of the Nottingham MUSE (MUltiple Stream Evaluator) machine. MUSE is a data flow machine capable of supporting structured parallel computation. The simulator described in this paper was designed to enable alterations, improvements and additions to be made to the prototype MUSE architecture. The stages through which the model has progressed, and the implementation details of this model as a program, are discussed. The validation experiments are explained, and future plans for alterations and modifications to the basic model are suggested

Study design of 'FRIENDS for Life': process and effect evaluation of an indicated school-based prevention programme for childhood anxiety and depression

Background: Anxiety disorders and depression are highly prevalent in children and affect their current and future functioning. 'FRIENDS for Life' is a cognitive-behavioural programme teaching children skills to cope more effectively with feelings of anxiety and depression. Although 'FRIENDS for Life' is increasingly being implemented at Dutch schools, its effectiveness as a preventive intervention in Dutch schools has never been investigated. The aim of the study is to evaluate the effectiveness of 'FRIENDS for Life' as an indicated school-based prevention programme for children with early or mild signs of anxiety or depression. Methods/Design. This study is a controlled trial with one pre-intervention and three post-intervention measurements (directly after, and 6 and 12 months after the end of the programme). The study sample consists of children aged 10-12 years (grades 6, 7 and 8 of Dutch primary schools), who show symptoms of anxiety or depressive disorder. Data are collected through self-report, teacher report and peer nomination. A process evaluation is conducted to investigate programme integrity (whether the programme has been executed according to protocol) and to evaluate children's and parents' opinions about 'FRIENDS for Life' using online focus groups and interviews. Discussion. The present study will provide insight into the effectiveness of 'FRIENDS for Life' as an indicated school-based prevention programme for children with early or mild signs of anxiety or depression

Stakeholder narratives on trypanosomiasis, their effect on policy and the scope for One Health

Background This paper explores the framings of trypanosomiasis, a widespread and potentially fatal zoonotic disease transmitted by tsetse flies (Glossina species) affecting both humans and livestock. This is a country case study focusing on the political economy of knowledge in Zambia. It is a pertinent time to examine this issue as human population growth and other factors have led to migration into tsetse-inhabited areas with little historical influence from livestock. Disease transmission in new human-wildlife interfaces such as these is a greater risk, and opinions on the best way to manage this are deeply divided. Methods A qualitative case study method was used to examine the narratives on trypanosomiasis in the Zambian policy context through a series of key informant interviews. Interviewees included key actors from international organisations, research organisations and local activists from a variety of perspectives acknowledging the need to explore the relationships between the human, animal and environmental sectors. Principal Findings Diverse framings are held by key actors looking from, variously, the perspectives of wildlife and environmental protection, agricultural development, poverty alleviation, and veterinary and public health. From these viewpoints, four narratives about trypanosomiasis policy were identified, focused around four different beliefs: that trypanosomiasis is protecting the environment, is causing poverty, is not a major problem, and finally, that it is a Zambian rather than international issue to contend with. Within these narratives there are also conflicting views on the best control methods to use and different reasoning behind the pathways of response. These are based on apparently incompatible priorities of people, land, animals, the economy and the environment. The extent to which a One Health approach has been embraced and the potential usefulness of this as a way of reconciling the aims of these framings and narratives is considered throughout the paper. Conclusions/Significance While there has historically been a lack of One Health working in this context, the complex, interacting factors that impact the disease show the need for cross-sector, interdisciplinary decision making to stop rival narratives leading to competing actions. Additional recommendations include implementing: surveillance to assess under-reporting of disease and consequential under-estimation of disease risk; evidence-based decision making; increased and structurally managed funding across countries; and focus on interactions between disease drivers, disease incidence at the community level, and poverty and equity impacts

Mechanisms of Adaptation from a Multiple to a Single Step Recovery Strategy following Repeated Exposure to Forward Loss of Balance in Older Adults

When released from an initial, static, forward lean angle and instructed to recover with a single step, some older adults are able to meet the task requirements, whereas others either stumble or fall. The purpose of the present study was to use the concept of margin of stability (MoS) to investigate balance recovery responses in the anterior-posterior direction exhibited by older single steppers, multiple steppers and those that are able to adapt from multiple to single steps following exposure to repeated forward loss of balance. One hundred and fifty-one healthy, community dwelling, older adults, aged 65–80 years, participated in the study. Participants performed four trials of the balance recovery task from each of three initial lean angles. Balance recovery responses in the anterior-posterior direction were quantified at three events; cable release (CR), toe-off (TO) and foot contact (FC), for trials performed at the intermediate lean angle. MoS was computed as the anterior-posterior distance between the forward boundary of the Base of Support (BoS) and the vertical projection of the velocity adjusted centre of mass position (XCoM). Approximately one-third of participants adapted from a multiple to a single step recovery strategy following repeated exposure to the task. MoS at FC for the single and multiple step trials in the adaptation group were intermediate between the exclusively single step group and the exclusively multiple step group, with the single step trials having a significant, 3.7 times higher MoS at FC than the multiple step trials. Consistent with differences between single and multiple steppers, adaptation from multiple to single steps was attributed to an increased BoS at FC, a reduced XCoM at FC and an increased rate of BoS displacement from TO to FC. Adaptations occurred within a single test session and suggest older adults that are close to the threshold of successful recovery can rapidly improve dynamic stability following repeated exposure to a forward loss of balance

Resistance to natural and synthetic gene drive systems

Scientists are rapidly developing synthetic gene drive elements intended for release into natural populations. These are intended to control or eradicate disease vectors and pests, or to spread useful traits through wild populations for disease control or conservation purposes. However, a crucial problem for gene drives is the evolution of resistance against them, preventing their spread. Understanding the mechanisms by which populations might evolve resistance is essential for engineering effective gene drive systems. This review summarizes our current knowledge of drive resistance in both natural and synthetic gene drives. We explore how insights from naturally occurring and synthetic drive systems can be integrated to improve the design of gene drives, better predict the outcome of releases and understand genomic conflict in general

Beta-lactam-induced immediate hypersensitivity reactions: A genome-wide association study of a deeply phenotyped cohort

Background β-lactam antibiotics are associated with a variety of immune-mediated or hypersensitivity reactions, including immediate (Type I) reactions mediated by antigen-specific IgE. Objective To identify genetic predisposing factors for immediate reactions to β-lactam antibiotics. Methods Patients with a clinical history of immediate hypersensitivity reactions to either penicillins or cephalosporins, which were immunologically confirmed, were recruited from allergy clinics. A genome-wide association study (GWAS) was conducted on 662 patients (the discovery cohort) with a diagnosis of immediate hypersensitivity and the main finding was replicated in a cohort of 98 Spanish cases, recruited using the same diagnostic criteria as the discovery cohort. Results GWAS identified rs71542416 within the Class II HLA region as the top hit (P = 2x10-14); this was in linkage disequilibrium with HLA-DRB1*10:01 (OR = 2.93 P = 5.4x10-7) and HLA-DQA1*01:05 (OR=2.93, P=5.4x10-7). Haplotype analysis identified that HLA-DRB1*10:01 was a risk factor even without the HLA-DQA1*01:05 allele. The association with HLA-DRB1*10:01 was replicated in another cohort, with the meta-analysis of the discovery and replication cohorts showing that HLA-DRB1*10:01 increased the risk of immediate hypersensitivity at a genome-wide level (OR = 2.96 P=4.1x10-9). No association with HLA-DRB1*10:01 was identified in 268 patients with delayed hypersensitivity reactions to β-lactams. Conclusion HLA-DRB1*10:01 predisposed to immediate hypersensitivity reactions to penicillins. Further work to identify other predisposing HLA and non-HLA loci is required. Clinical implications This novel insight into the mechanisms of immediate reactions associated with penicillins may be of use in risk stratifying patients where penicillin cannot be excluded as an etiological agent

A Small Peptide Modeled after the NRAGE Repeat Domain Inhibits XIAP-TAB1-TAK1 Signaling for NF-κB Activation and Apoptosis in P19 Cells

In normal growth and development, apoptosis is necessary to shape the central nervous system and to eliminate excess neurons which are not required for innervation. In some diseases, however, apoptosis can be either overactive as in some neurodegenerative disorders or severely attenuated as in the spread of certain cancers. Bone morphogenetic proteins (BMPs) transmit signals for regulating cell growth, differentiation, and apoptosis. Responding to BMP receptors stimulated from BMP ligands, neurotrophin receptor-mediated MAGE homolog (NRAGE) binds and functions with the XIAP-TAK1-TAB1 complex to activate p38MAPK and induces apoptosis in cortical neural progenitors. NRAGE contains a unique repeat domain that is only found in human, mouse, and rat homologs that we theorize is pivotal in its BMP MAPK role. Previously, we showed that deletion of the repeat domain inhibits apoptosis, p38MAPK phosphorylation, and caspase-3 cleavage in P19 neural progenitor cells. We also showed that the XIAP-TAB1-TAK1 complex is dependent on NRAGE for IKK-α/β phosphorylation and NF-κB activation. XIAP is a major inhibitor of caspases, the main executioners of apoptosis. Although it has been shown previously that NRAGE binds to the RING domain of XIAP, it has not been determined which NRAGE domain binds to XIAP. Here, we used fluorescence resonance energy transfer (FRET) to determine that there is a strong likelihood of a direct interaction between NRAGE and XIAP occurring at NRAGE's unique repeat domain which we also attribute to be the domain responsible for downstream signaling of NF-κB and activating IKK subunits. From these results, we designed a small peptide modeled after the NRAGE repeat domain which we have determined inhibits NF-κB activation and apoptosis in P19 cells. These intriguing results illustrate that the paradigm of the NRAGE repeat domain may hold promising therapeutic strategies in developing pharmaceutical solutions for combating harmful diseases involving excessive downstream BMP signaling, including apoptosis

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment