Expression-Based Genome-Wide Association Study Links Vitamin D-Binding Protein With Autoantigenicity in Type 1 Diabetes.

Type 1 diabetes (T1D) is caused by autoreactive T cells that recognize pancreatic islet antigens and destroy insulin-producing β-cells. This attack results from a breakdown in tolerance for self-antigens, which is controlled by ectopic antigen expression in the thymus and pancreatic lymph nodes (PLNs). The autoantigens known to be involved include a set of islet proteins, such as insulin, GAD65, IA-2, and ZnT8. In an attempt to identify additional antigenic proteins, we performed an expression-based genome-wide association study using microarray data from 118 arrays of the thymus and PLNs of T1D mice. We ranked all 16,089 protein-coding genes by the likelihood of finding repeated differential expression and the degree of tissue specificity for pancreatic islets. The top autoantigen candidate was vitamin D-binding protein (VDBP). T-cell proliferation assays showed stronger T-cell reactivity to VDBP compared with control stimulations. Higher levels and frequencies of serum anti-VDBP autoantibodies (VDBP-Abs) were identified in patients with T1D (n = 331) than in healthy control subjects (n = 77). Serum vitamin D levels were negatively correlated with VDBP-Ab levels in patients in whom T1D developed during the winter. Immunohistochemical localization revealed that VDBP was specifically expressed in α-cells of pancreatic islets. We propose that VDBP could be an autoantigen in T1D

Human-robot collaboration in manufacturing: Quantitative evaluation of predictable, convergent joint action

New industrial robotic systems that operate in the same physical space as people highlight the emerging need for robots that can integrate seamlessly into human group dynamics. In this paper we build on our prior investigation, which evaluates the convergence of a robot computational teaming model and a human teammate's mental model, by computing the entropy rate of the Markov chain. We present and analyze the six out of thirty-six human trials where the human participant switched execution strategies while working with the robot. We conduct a post-hoc analysis of this dataset and show that the entropy rate appears to be sensitive to changes in the human strategy and reflects the resulting increase in uncertainty about the human next actions. We propose that these results provide first support that entropy rate may be used as a component of dynamic risk assessment, to generate risk-aware robot motions and action selections

Premature subclinical atherosclerosis in children and young adults with juvenile idiopathic arthritis.:A review considering preventive measures

Many studies show that Juvenile Idiopathic Arthritis (JIA) is associated with early subclinical signs of atherosclerosis. Chronic inflammation per se may be an important driver but other known risk factors, such as dyslipidemia, hypertension, insulin insensitivity, a physically inactive lifestyle, obesity, and tobacco smoking may also contribute substantially. We performed a systematic review of studies through the last 20 years on early signs of subclinical atherosclerosis in children and adolescents with JIA with the purpose of investigating whether possible risk factors, other than inflammation, were considered. We found 13 descriptive cross sectional studies with healthy controls, one intervention study and two studies on adults diagnosed with JIA. Only one study addressed obesity, and physical activity (PA) has only been assessed in one study on adults with JIA and only by self-reporting. This is important as studies on PA in children with JIA have shown that most patients are less physically active than their healthy peers, and as physical inactivity in several large studies of normal schoolchildren is found to be associated with increased clustering of risk factors for cardiovascular disease. It is thus possible that an inactive lifestyle in patients with JIA is an important contributor to development of the subclinical signs of atherosclerosis seen in children with JIA, and that promotion of an active lifestyle in childhood and adolescence may diminish the risk for premature atherosclerotic events in adulthood

Overexpression of IL-1α in Skin Differentially Modulates the Immune Response to Scarification with Vaccinia Virus

Transepidermal inoculation of vaccinia virus (VV), or scarification, has been used effectively for the induction of specific and long-lasting immunity to smallpox and is superior to other routes of immunization. Scarification of individuals with atopic skin disease or immune deficiency, however, can lead to persistent viral replication and result in significant morbidity and mortality. These effects of scarification presumably reflect the unique immunological properties of skin and the immune cells resident in, or recruited to, the site of inoculation. To explore these phenomena, we utilized transgenic mice engineered to overexpress IL-1α, a critical mediator of cutaneous inflammation, in the epidermis. Following scarification with VV, both transgenic and wild-type mice develop local pox. At high doses of VV, IL-1α transgenic mice recruited immune cells to the inoculation site more rapidly and demonstrated enhanced T-cell and humoral immune responses. At limiting doses, however, IL-1α transgenic mice could effectively control virus replication without formation of pox lesions or activation of a memory response. This study suggests that IL-1 might be useful as an adjuvant to enhance antiviral immunity and promote safer vaccination strategies; however, understanding the balance of IL-1 effects on innate and adaptive immune functions will be critical to achieve optimal results

TGF-β Suppresses β-Catenin-Dependent Tolerogenic Activation Program in Dendritic Cells

The mechanisms that underlie the critical dendritic cell (DC) function in maintainance of peripheral immune tolerance are incompletely understood, although the β-catenin signaling pathway is critical for this role. The molecular details by which β-catenin signaling is regulated in DCs are unknown. Mechanical disruption of murine bone marrow-derived DC (BMDC) clusters activates DCs while maintaining their tolerogenic potential and this activation is associated with β-catenin signaling, providing a useful model with which to explore tolerance-associated β-catenin signaling in DCs. In this report, we demonstrate novel molecular features of the signaling events that control DC activation in response to mechanical stimulation. Non-canonical β-catenin signaling is an essential component of this tolerogenic activation and is modulated by adhesion molecules, including integrins. This unique β-catenin-dependent signaling pathway is constitutively active at low levels, suggesting that mechanical stimulation is not necessarily required for induction of this unique activation program. We additionally find that the immunomodulatory cytokine TGF-β antagonizes β-catenin in DCs, thereby selectively suppressing signaling associated with tolerogenic DC activation while having no impact on LPS-induced, β-catenin-independent immunogenic activation. These findings provide new molecular insight into the regulation of a critical signaling pathway for DC function in peripheral immune tolerance

Tailored second line therapy in asthmatic children with the arginine-16 genotype

The arginine-16 beta-2 receptor genotype confers increased susceptibility to exacerbations in asthmatic children taking regular long acting beta-2 agonists. We therefore evaluated using montelukast as an alternative to salmeterol as tailored second line asthma controller therapy in children expressing this susceptible genotype. 62 persistent asthmatic children with the homozygous arginine-16 genotype were randomized to receive salmeterol 50ug bid or montelukast 5/10mg od as add on to inhaled fluticasone for 1 year. School absences (the primary outcome) were reduced with montelukast arm compared to salmeterol: difference in score = 0.40 (95%CI 0.07-0.87) p=0.005. Albuterol use was also reduced with montelukast compared with salmeterol: difference in score = 0.47 (95%CI 0.16-0.79) p<0.0001. Greater improvements occurred in both symptom and quality of life scores with montelukast vs salmeterol, while there was no difference in FEV1. Montelukast may be suitable as tailored second line controller therapy instead of salmeterol in asthmatic children expressing the susceptible arginine-16 genotype - moving towards a personalised medicine approach to management