Circulating beta cell-specific CD8(+) T cells restricted by high-risk HLA class I molecules show antigen experience in children with and at risk of type 1 diabetes

In type 1 diabetes (T1D), autoreactive cytotoxic CD8(+) T cells are implicated in the destruction of insulin-producing beta cells. The HLA-B*3906 and HLA-A*2402 class I genes confer increased risk and promote early disease onset, suggesting that CD8(+) T cells that recognize peptides presented by these class I molecules on pancreatic beta cells play a pivotal role in the autoimmune response. We examined the frequency and phenotype of circulating preproinsulin (PPI)-specific and insulin B (InsB)-specific CD8(+) T cells in HLA-B*3906(+) children newly diagnosed with T1D and in high-risk HLA-A*2402(+) children before the appearance of disease-specific autoantibodies and before diagnosis of T1D. Antigen-specific CD8(+) T cells were detected using human leucocyte antigen (HLA) class I tetramers and flow cytometry was used to assess memory status. In HLA-B*3906(+) children with T1D, we observed an increase in PPI5-12-specific transitional memory CD8(+) T cells compared to non-diabetic, age- and HLA-matched subjects. Furthermore, PPI5-12-specific CD8(+) T cells in HLA-B*3906(+) children with T1D showed a significantly more antigen-experienced phenotype compared to polyclonal CD8(+) T cells. In longitudinal samples from high-risk HLA-A*2402(+) children, the percentage of terminal effector cells within the InsB(15-24)-specific CD8(+) T cells was increased before diagnosis relative to samples taken before the appearance of autoantibodies. This is the first study, to our knowledge, to report HLA-B*3906-restricted autoreactive CD8(+) T cells in T1D. Collectively, our results provide evidence that beta cell-reactive CD8(+) T cells restricted by disease-associated HLA class I molecules display an antigen-experienced phenotype and acquire enhanced effector function during the period leading to clinical diagnosis, implicating these cells in driving disease.Peer reviewe

Simulations of Aerodynamic Damping for MEMS Resonators

Aerodynamic damping for MEMS resonators is studied based on the numerical solution of Boltzmann-ESBGK equation. A compact model is then developed based on numerical simulations for a wide range of Knudsen numbers. The damping predictions are compared with both Reynold equation based models and several sets of experimental data. It has been found that the structural damping is dominant at low pressures (high Knudsen numbers). For cases with small length-to-width ratios and large vibration amplitudes, the threedimensionality effects must be taken into account. Finally, an uncertainty quantification approach based on the probability transformation method has been applied to assess the influence of pressure and geometric uncertainties. The output probability density functions (PDF) of the damping ratio has been studied for various input PDF of beam geometry and ambient pressure

Circulating metabolites in progression to islet autoimmunity and type 1 diabetes

Aims/hypothesis: Metabolic dysregulation may precede the onset of type 1 diabetes. However, these metabolic disturbances and their specific role in disease initiation remain poorly understood. In this study, we examined whether children who progress to type 1 diabetes have a circulatory polar metabolite profile distinct from that of children who later progress to islet autoimmunity but not type 1 diabetes and a matched control group.Methods: We analysed polar metabolites from 415 longitudinal plasma samples in a prospective cohort of children in three study groups: those who progressed to type 1 diabetes; those who seroconverted to one islet autoantibody but not to type 1 diabetes; and an antibody-negative control group. Metabolites were measured using two-dimensional GC high-speed time of flight MS.Results: In early infancy, progression to type 1 diabetes was associated with downregulated amino acids, sugar derivatives and fatty acids, including catabolites of microbial origin, compared with the control group. Methionine remained persistently upregulated in those progressing to type 1 diabetes compared with the control group and those who seroconverted to one islet autoantibody. The appearance of islet autoantibodies was associated with decreased glutamic and aspartic acids.Conclusions/interpretation: Our findings suggest that children who progress to type 1 diabetes have a unique metabolic profile, which is, however, altered with the appearance of islet autoantibodies. Our findings may assist with early prediction of the disease.</p

Quantifying the utility of islet autoantibody levels in the prediction of type 1 diabetes in children

Aims/hypothesis: The aim of this study was to explore the utility of islet autoantibody (IAb) levels for the prediction of type 1 diabetes in autoantibody-positive children.Methods: Prospective cohort studies in Finland, Germany, Sweden and the USA followed 24,662 children at increased genetic or familial risk of developing islet autoimmunity and diabetes. For the 1403 who developed IAbs (523 of whom developed diabetes), levels of autoantibodies against insulin (IAA), glutamic acid decarboxylase (GADA) and insulinoma-associated antigen-2 (IA-2A) were harmonised for analysis. Diabetes prediction models using multivariate logistic regression with inverse probability censored weighting (IPCW) were trained using 10-fold cross-validation. Discriminative power for disease was estimated using the IPCW concordance index (C index) with 95% CI estimated via bootstrap.Results: A baseline model with covariates for data source, sex, diabetes family history, HLA risk group and age at seroconversion with a 10-year follow-up period yielded a C index of 0.61 (95% CI 0.58, 0.63). The performance improved after adding the IAb positivity status for IAA, GADA and IA-2A at seroconversion: C index 0.72 (95% CI 0.71, 0.74). Using the IAb levels instead of positivity indicators resulted in even better performance: C index 0.76 (95% CI 0.74, 0.77). The predictive power was maintained when using the IAb levels alone: C index 0.76 (95% CI 0.75, 0.76). The prediction was better for shorter follow-up periods, with a C index of 0.82 (95% CI 0.81, 0.83) at 2 years, and remained reasonable for longer follow-up periods, with a C index of 0.76 (95% CI 0.75, 0.76) at 11 years. Inclusion of the results of a third IAb test added to the predictive power, and a suitable interval between seroconversion and the third test was approximately 1.5 years, with a C index of 0.78 (95% CI 0.77, 0.78) at 10 years follow-up.Conclusions/interpretation: Consideration of quantitative patterns of IAb levels improved the predictive power for type 1 diabetes in IAb-positive children beyond qualitative IAb positivity status.</p

Different vulnerability indicators for psychosis and their neuropsychological characteristics in the Northern Finland 1986 Birth Cohor

This study is one of very few that has investigated the neuropsychological functioning of both familial and clinical high risk subjects for psychosis. Participants (N = 164) were members of the Northern Finland 1986 Birth Cohort in the following four groups: familial risk for psychosis (n = 62), clinical risk for psychosis (n = 20), psychosis (n = 13), and control subjects (n = 69). The neurocognitive performance of these groups was compared across 19 cognitive variables. The two risk groups did not differ significantly from controls, but differed from the psychosis group in fine motor function. Neuropsychological impairments were not evident in a non-help-seeking high-risk sample

Role of the electro-thermo-mechanical multiple coupling on the operation of RF microswitch

A phenomenological approach is proposed to identify some effects occurring within the structure of the microswitch conceived for radio frequency application. This microsystem is operated via a nonlinear electromechanical action imposed by the applied voltage. Unfortunately, it can be affected by residual stress, due to the microfabrication process, therefore axial and flexural behaviors are strongly coupled. This coupling increases the actuation voltage required to achieve the so-called ‘‘pull-in'' condition. Moreover, temperature may strongly affect strain and stress distributions, respectively. Environmental temperature, internal dissipation of material, thermo-elastic and Joule effects play different roles on the microswitch flexural isplacement. Sometimes buckling phenomenon evenly occurs. Literature show that all those issues make difficult an effective computation of ‘‘pull-in'' and ‘‘pull-out'' voltages for evenly distinguishing the origin of some failures detected in operation. Analysis, numerical methods and experiments are applied to an industrial test case to investigate step by step the RF-microswitch operation. Multiple electro-hermomechanical coupling is first modeled to have a preliminary and comprehensive description of the microswitch behavior and of its reliability. ‘‘Pull-in'' and ‘‘pull-out'' tests are then performed to validate the proposed models and to find suitable criteria to design the RF-MEM

The social affordances of flashpacking: exploring the mobility nexus of travel and communication

The proliferation of digital devices and online social media and networking technologies has altered the backpacking landscape in recent years. Thanks to the ready availability of online communication, travelers are now able to stay in continuous touch with friends, family and other travelers while on the move. This article introduces the practice of ‘flashpacking’ to describe this emerging trend and interrogates the patterns of connection and disconnection that become possible as corporeal travel and social technologies converge. Drawing on the concepts of ‘assemblages’ and ‘affordances’, we outline several aspects of this new sociality: virtual mooring, following, collaborating, and (dis)connecting. The conclusion situates this discussion alongside broader questions about the shifting nature of social life in an increasingly mobile and mediated world and suggests directions for future research at the intersection of tourism and technology