Measurements of 12C(→γ,pp) photon asymmetries for Eγ= 200–450 MeV

The 12C (→γ ,pp) reaction has been studied in the photon energy range 200-450 MeV at the Mainz microtron MAMI-C, where linearly polarised photons were energy-tagged using the Glasgow-Mainz Tagged Photon Spectrometer and protons were detected in the Crystal Ball detector. The photon asymmetry Σ has been measured over a wider Eγ range than previous measurements. The strongest asymmetries were found at low missing energies where direct emission of nucleon pairs is expected. Cuts on the difference in azimuthal angles of the two ejected protons increased the magnitude of the observed asymmetries. At low missing energies the Σ data exhibit a strong angular dependence, similar to deuteron photodisintegration

Blood and islet phenotypes indicate immunological heterogeneity in type 1 diabetes

This is an author-created, uncopyedited electronic version of an article accepted for publication in Diabetes. The American Diabetes Association (ADA), publisher of Diabetes, is not responsible for any errors or omissions in this version of the manuscript or any version derived from it by third parties. The definitive publisher-authenticated version is available in Diabetes in print and online at http://diabetes.diabetesjournals.orgThe erratum to this article is available in ORE at http://hdl.handle.net/10871/40335Studies in type 1 diabetes indicate potential disease heterogeneity, notably in the rate of β-cell loss, responsiveness to immunotherapies, and, in limited studies, islet pathology. We sought evidence for different immunological phenotypes using two approaches. First, we defined blood autoimmune response phenotypes by combinatorial, multiparameter analysis of autoantibodies and autoreactive T-cell responses in 33 children/adolescents with newly diagnosed diabetes. Multidimensional cluster analysis showed two equal-sized patient agglomerations characterized by proinflammatory (interferon-γ-positive, multiautoantibody-positive) and partially regulated (interleukin-10-positive, pauci-autoantibody-positive) responses. Multiautoantibody-positive nondiabetic siblings at high risk of disease progression showed similar clustering. Additionally, pancreas samples obtained post mortem from a separate cohort of 21 children/adolescents with recently diagnosed type 1 diabetes were examined immunohistologically. This revealed two distinct types of insulitic lesions distinguishable by the degree of cellular infiltrate and presence of B cells that we termed "hyper-immune CD20Hi" and "pauci-immune CD20Lo." Of note, subjects had only one infiltration phenotype and were partitioned by this into two equal-sized groups that differed significantly by age at diagnosis, with hyper-immune CD20Hi subjects being 5 years younger. These data indicate potentially related islet and blood autoimmune response phenotypes that coincide with and precede disease. We conclude that different immunopathological processes (endotypes) may underlie type 1 diabetes, carrying important implications for treatment and prevention strategies.JDRFNational Institute for Health Research (NIHR) Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust and King’s College LondonEuropean Union (EU FP7) award - Persistent Virus Infection in Diabetes Network Study Group (PEVNET)EU FP7 Large-Scale Focused Collaborative Research Project on Natural Immunomodulators as Novel Immunotherapies for Type 1 Diabetes (NAIMIT)EU FP7 Large-Scale Focused Collaborative Research Project on β-cell preservation through antigen-specific immunotherapy in Type 1 Diabetes: Enhanced Epidermal Antigen Delivery Systems (EE-ASI)National Institutes of Health (NIH)National Institute of Diabetes and Digestive and Kidney DiseasesNational Institute of Allergy and Infectious DiseasesEunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNational Center for Research ResourcesGeneral Clinical Research CenterAmerican Diabetes Association (ADA

To respond or not to respond - a personal perspective of intestinal tolerance

For many years, the intestine was one of the poor relations of the immunology world, being a realm inhabited mostly by specialists and those interested in unusual phenomena. However, this has changed dramatically in recent years with the realization of how important the microbiota is in shaping immune function throughout the body, and almost every major immunology institution now includes the intestine as an area of interest. One of the most important aspects of the intestinal immune system is how it discriminates carefully between harmless and harmful antigens, in particular, its ability to generate active tolerance to materials such as commensal bacteria and food proteins. This phenomenon has been recognized for more than 100 years, and it is essential for preventing inflammatory disease in the intestine, but its basis remains enigmatic. Here, I discuss the progress that has been made in understanding oral tolerance during my 40 years in the field and highlight the topics that will be the focus of future research

Alterations in the gut microbiome implicate key taxa and metabolic pathways across inflammatory arthritis phenotypes

Musculoskeletal diseases affect up to 20% of adults worldwide. The gut microbiome has been implicated in inflammatory conditions, but large-scale metagenomic evaluations have not yet traced the routes by which immunity in the gut affects inflammatory arthritis. To characterize the community structure and associated functional processes driving gut microbial involvement in arthritis, the Inflammatory Arthritis Microbiome Consortium investigated 440 stool shotgun metagenomes comprising 221 adults diagnosed with rheumatoid arthritis, ankylosing spondylitis, or psoriatic arthritis and 219 healthy controls and individuals with joint pain without an underlying inflammatory cause. Diagnosis explained about 2% of gut taxonomic variability, which is comparable in magnitude to inflammatory bowel disease. We identified several candidate microbes with differential carriage patterns in patients with elevated blood markers for inflammation. Our results confirm and extend previous findings of increased carriage of typically oral and inflammatory taxa and decreased abundance and prevalence of typical gut clades, indicating that distal inflammatory conditions, as well as local conditions, correspond to alterations to the gut microbial composition. We identified several differentially encoded pathways in the gut microbiome of patients with inflammatory arthritis, including changes in vitamin B salvage and biosynthesis and enrichment of iron sequestration. Although several of these changes characteristic of inflammation could have causal roles, we hypothesize that they are mainly positive feedback responses to changes in host physiology and immune homeostasis. By connecting taxonomic alternations to functional alterations, this work expands our understanding of the shifts in the gut ecosystem that occur in response to systemic inflammation during arthritis

Biological and engineering impacts of climate on slopes -learning from full-scale

ABSTRACT: Our climate is set to change significantly over the next century; future change is likely to have a serious effect on UK slopes. The scenario of hotter drier summers, followed by more intense periods of rainfall has the potential to reduce stability by increasing degradation mechanisms and/or increasing positive pore water pressure generation. There is evidence that the scenario of more intense rainfall is already having an impact on the UK slopes. However, there is also potential for stability to be improved through the generation of greater suctions during longer periods of drought. Newcastle, Southampton, Belfast, Durham and Loughborough Universities have all been carrying out research into the impacts of climate and vegetation on embankment and cut slope stability. These five Universities, along with international partners in Canada, Singapore, China, South Africa, France and Portugal, are conducting a collaboration programme the aim of which is to link research groups undertaking full-scale monitoring of slopes to improve the understanding of the complex interaction between climate, vegetation and clay soils. This paper presents results of current full scale infrastructure slope monitoring and model development at the involved universities and plans for future collaborations

Innate recognition of bacteria in human milk is mediated by a milk-derived highly expressed pattern recognition receptor, soluble CD14.

Published versio

A realist evaluation of a physical activity participation intervention for children and youth with disabilities: What works, for whom, in what circumstances, and how?

Background: The need to identify strategies that facilitate involvement in physical activity for children and youth with disabilities is recognised as an urgent priority. This study aimed to describe the association between context, mechanisms and outcome(s) of a participation-focused physical activity intervention to understand what works, in what conditions, and how. Methods: This study was designed as a realist evaluation. Participant recruitment occurred through purposive and theoretical sampling of children and parents participating in the Local Environment Model intervention at Beitostolen Healthsports Centre in Norway. Ethnographic methods comprising participant observation, interviews, and focus groups were employed over 15 weeks in the field. Data analysis was completed using the context-mechanism-outcome framework of realist evaluation. Context-mechanism-outcome connections were generated empirically from the data to create a model to indicate how the program activated mechanisms within the program context, to enable participation in physical activity. Results: Thirty one children with a range of disabilities (mean age 12y 6 m (SD 2y 2 m); 18 males) and their parents (n=44; 26 mothers and 18 fathers) participated in the study. Following data synthesis, a refined program theory comprising four context themes, five mechanisms, and six outcomes, were identified. The mechanisms (choice, fun, friends, specialised health professionals, and time) were activated in a context that was safe, social, learning-based and family-centred, to elicit outcomes across all levels of the International Classification of Functioning, Disability and Health. Conclusions: The interaction of mechanisms and context as a whole facilitated meaningful outcomes for children and youth with disabilities, and their parents. Whilst optimising participation in physical activity is a primary outcome of the Local Environment Model, the refined program theory suggests the participation-focused approach may act as a catalyst to promote a range of outcomes. Findings from this study may inform future interventions attempting to enable participation in physical activity for children and youth with disabilities

Interleukin-10 Overexpression Promotes Fas-Ligand-Dependent Chronic Macrophage-Mediated Demyelinating Polyneuropathy

BACKGROUND:Demyelinating polyneuropathy is a debilitating, poorly understood disease that can exist in acute (Guillain-Barré syndrome) or chronic forms. Interleukin-10 (IL-10), although traditionally considered an anti-inflammatory cytokine, has also been implicated in promoting abnormal angiogenesis in the eye and in the pathobiology of autoimmune diseases such as lupus and encephalomyelitis. PRINCIPAL FINDINGS:Overexpression of IL-10 in a transgenic mouse model leads to macrophage-mediated demyelinating polyneuropathy. IL-10 upregulates ICAM-1 within neural tissues, promoting massive macrophage influx, inflammation-induced demyelination, and subsequent loss of neural tissue resulting in muscle weakness and paralysis. The primary insult is to perineural myelin followed by secondary axonal loss. Infiltrating macrophages within the peripheral nerves demonstrate a highly pro-inflammatory signature. Macrophages are central players in the pathophysiology, as in vivo depletion of macrophages using clodronate liposomes reverses the phenotype, including progressive nerve loss and paralysis. Macrophage-mediate demyelination is dependent on Fas-ligand (FasL)-mediated Schwann cell death. SIGNIFICANCE:These findings mimic the human disease chronic idiopathic demyelinating polyneuropathy (CIDP) and may also promote further understanding of the pathobiology of related conditions such as acute idiopathic demyelinating polyneuropathy (AIDP) or Guillain-Barré syndrome