2,790 research outputs found
Stochastic Domain Wall-Magnetic Tunnel Junction Artificial Neurons for Noise-Resilient Spiking Neural Networks
The spatiotemporal nature of neuronal behavior in spiking neural networks
(SNNs) make SNNs promising for edge applications that require high energy
efficiency. To realize SNNs in hardware, spintronic neuron implementations can
bring advantages of scalability and energy efficiency. Domain wall (DW) based
magnetic tunnel junction (MTJ) devices are well suited for probabilistic neural
networks given their intrinsic integrate-and-fire behavior with tunable
stochasticity. Here, we present a scaled DW-MTJ neuron with voltage-dependent
firing probability. The measured behavior was used to simulate a SNN that
attains accuracy during learning compared to an equivalent, but more
complicated, multi-weight (MW) DW-MTJ device. The validation accuracy during
training was also shown to be comparable to an ideal leaky integrate and fire
(LIF) device. However, during inference, the binary DW-MTJ neuron outperformed
the other devices after gaussian noise was introduced to the Fashion-MNIST
classification task. This work shows that DW-MTJ devices can be used to
construct noise-resilient networks suitable for neuromorphic computing on the
edge.Comment: 10 pages, 4 figure
Aerosol Insulin Induces Regulatory CD8 γδ T Cells That Prevent Murine Insulin-dependent Diabetes
Cellular immune hyporesponsiveness can be induced by the presentation of soluble protein antigens to mucosal surfaces. Most studies of mucosa-mediated tolerance have used the oral route of antigen delivery and few have examined autoantigens in natural models of autoimmune disease. Insulin is an autoantigen in humans and nonobese diabetic (NOD) mice with insulindependent diabetes mellitus (IDDM). When we administered insulin aerosol to NOD mice after the onset of subclinical disease, pancreatic islet pathology and diabetes incidence were both significantly reduced. Insulin-treated mice had increased circulating antibodies to insulin, absent splenocyte proliferation to the major epitope, insulin B chain amino acids 9–23, which was associated with increased IL-4 and particularly IL-10 secretion, and reduced proliferation to glutamic acid decarboxylase, another islet autoantigen. The ability of splenocytes from insulin-treated mice to suppress the adoptive transfer of diabetes to nondiabetic mice by T cells of diabetic mice was shown to be caused by small numbers of CD8 γδ T cells. These findings reveal a novel mechanism for suppressing cell-mediated autoimmune disease. Induction of regulatory CD8 γδ T cells by aerosol insulin is a therapeutic strategy with implications for the prevention of human IDDM
Immunity to self co-generates regulatory T cells
Immune responses to self are kept in check by tolerance mechanisms, including suppression by regulatory T cells (Tregs). The defective generation of Tregs specific for self-antigens may lead to autoimmune disease. We identified a novel population of human CD4^+^ Tregs, characterized by high surface expression of CD52, which is co-generated in response to autoantigen. Blood CD4^+^CD52^hi^ T cells were generated preferentially in response to low-dose autoantigen and suppressed proliferation and interferon-[gamma] production by other T cells. Depletion of resting CD4^+^CD52^hi^ T cells enhanced the T-cell response to autoantigen. CD4^+^CD52^hi^ Tregs were neither derived from nor distinguished by markers of conventional resting CD4^+^CD25^+^ Tregs. In response to the pancreatic islet autoantigens glutamic acid decarboxylase, the generation of CD4^+^CD52^hi^ Tregs was impaired in individuals with and at-risk for type 1 diabetes, compared to healthy controls and individuals with type 2 diabetes. CD4^+^CD52^hi^ Tregs co-generated to self-antigen may therefore contribute to immune homeostasis and protect against autoimmune disease
The Non-Immune RIP-kb Mouse is a Useful Host for Islet Transplantation, as the Diabetes is Spontaneous, Mild and Predictable
Chemically-induced diabetic mice and spontaneously
diabetic NOD mice have been valuable
as recipients for experimental islet transplantation.
However, their maintenance often
requires parenteral insulin. Diabetogenic chemicals
can be cytotoxic to the host’s immune system
and to other organs some of which are
often used as the transplant site. Procurement
of diabetic cohorts in the NOD mouse is problematic
due to variability in the age of disease
onset. We show that RIP-Kb mice, which spontaneously
develop non-immune diabetes due to
over-expression of the H-2Kb heavy chain in
beta cells, offer many advantages as islet transplant
recipients. Diabetes is predictable with a
relatively narrow range of onset (4 wk) and
blood glucose levels (23.0± 4.0 mmol/l for 39
males at 6 weeks of age). The diabetes is mild enough so that most diabetic mice can be maintained
to 40 weeks of age without parenteral
insulin. This consistency of diabetes avails that
outcomes of intervention can be interpreted
with confidence
Recommended from our members
An Antibody-Based Leukocyte-Capture Microarray for the Diagnosis of Systemic Lupus Erythematosus
The diagnosis of Systemic Lupus Erythematosus (SLE) is challenging due to its heterogeneous clinical presentation and the lack of robust biomarkers to distinguish it from other autoimmune diseases. Further, currently used laboratory tests do not readily distinguish active and inactive disease. Several groups have attempted to apply emerging high throughput profiling technologies to diagnose and monitor SLE. Despite showing promise, many are expensive and technically challenging for routine clinical use. The goal of this work is to develop a better diagnostic and monitoring tool for SLE. We report a highly customisable antibody microarray that consists of a duplicate arrangement of 82 antibodies directed against surface antigens on peripheral blood mononuclear cells (PMBCs). This high-throughput array was used to profile SLE patients (n = 60) with varying disease activity, compared to healthy controls (n = 24), patients with rheumatoid arthritis (n = 25), and other autoimmune diseases (n = 28). We used a computational algorithm to calculate a score from the entire microarray profile and correlated it with SLE disease activity. Our results demonstrate that leukocyte-capture microarray profiles can readily distinguish active SLE patients from healthy controls (AUROC = 0.84). When combined with the standard laboratory tests (serum anti-dsDNA, complements C3 and C4), the microarrays provide significantly increased discrimination. The antibody microarrays can be enhanced by the addition of other markers for potential application to the diagnosis and stratification of SLE, paving the way for the customised and accurate diagnosis and monitoring of SLE
The Rising Incidence of Type 1 Diabetes Is Accounted for by Cases With Lower-Risk Human Leukocyte Antigen Genotypes
OBJECTIVE—The rising incidence of type 1 diabetes has been attributed to environment, implying a lesser role for genetic susceptibility. However, the rise could be accounted for by either more cases with classic high-risk genes or by cases with other risk genes. Separately, for any degree of genetic susceptibility, age at presentation may decrease in a permissive environment. To examine these possibilities, human leukocyte antigen (HLA) class II DRB1 genes known to confer risk for type 1 diabetes were analyzed in relation to year of birth and age at diagnosis over the last five decades
Beta cell function in type 1 diabetes determined from clinical and fasting biochemical variables
AIMS/HYPOTHESIS:
Beta cell function in type 1 diabetes is commonly assessed as the average plasma C-peptide concentration over 2 h following a mixed-meal test (CPAVE). Monitoring of disease progression and response to disease-modifying therapy would benefit from a simpler, more convenient and less costly measure. Therefore, we determined whether CPAVE could be reliably estimated from routine clinical variables.
METHODS:
Clinical and fasting biochemical data from eight randomised therapy trials involving participants with recently diagnosed type 1 diabetes were used to develop and validate linear models to estimate CPAVE and to test their accuracy in estimating loss of beta cell function and response to immune therapy.
RESULTS:
A model based on disease duration, BMI, insulin dose, HbA1c, fasting plasma C-peptide and fasting plasma glucose most accurately estimated loss of beta cell function (area under the receiver operating characteristic curve [AUROC] 0.89 [95% CI 0.87, 0.92]) and was superior to the commonly used insulin-dose-adjusted HbA1c (IDAA1c) measure (AUROC 0.72 [95% CI 0.68, 0.76]). Model-estimated CPAVE (CPEST) reliably identified treatment effects in randomised trials. CPEST, compared with CPAVE, required only a modest (up to 17%) increase in sample size for equivalent statistical power.
CONCLUSIONS/INTERPRETATION:
CPEST, approximated from six variables at a single time point, accurately identifies loss of beta cell function in type 1 diabetes and is comparable to CPAVE for identifying treatment effects. CPEST could serve as a convenient and economical measure of beta cell function in the clinic and as a primary outcome measure in trials of disease-modifying therapy in type 1 diabetes
Evidence That Nasal Insulin Induces Immune Tolerance to Insulin in Adults With Autoimmune Diabetes
OBJECTIVE: Insulin in pancreatic β-cells is a target of autoimmunity in type 1 diabetes. In the NOD mouse model of type 1 diabetes, oral or nasal administration of insulin induces immune tolerance to insulin and protects against autoimmune diabetes. Evidence for tolerance to mucosally administered insulin or other autoantigens is poorly documented in humans. Adults with recent-onset type 1 diabetes in whom the disease process is subacute afford an opportunity to determine whether mucosal insulin induces tolerance to insulin subsequently injected for treatment. RESEARCH DESIGN AND METHODS: We randomized 52 adults with recent-onset, noninsulin-requiring type 1 diabetes to nasal insulin or placebo for 12 months. Fasting blood glucose and serum C-peptide, glucagon-stimulated serum C-peptide, and serum antibodies to islet antigens were monitored three times monthly for 24 months. An enhanced ELISpot assay was used to measure the T-cell response to human proinsulin. RESULTS: β-Cell function declined by 35% overall, and 23 of 52 participants (44%) progressed to insulin treatment. Metabolic parameters remained similar between nasal insulin and placebo groups, but the insulin antibody response to injected insulin was significantly blunted in a sustained manner in those who had received nasal insulin. In a small cohort, the interferon-γ response of blood T-cells to proinsulin was suppressed after nasal insulin. CONCLUSIONS: Although nasal insulin did not retard loss of residual β-cell function in adults with established type 1 diabetes, evidence that it induced immune tolerance to insulin provides a rationale for its application to prevent diabetes in at-risk individuals
Genome-wide analysis reveals no evidence of trans chromosomal regulation of mammalian immune development.
It has been proposed that interactions between mammalian chromosomes, or transchromosomal interactions (also known as kissing chromosomes), regulate gene expression and cell fate determination. Here we aimed to identify novel transchromosomal interactions in immune cells by high-resolution genome-wide chromosome conformation capture. Although we readily identified stable interactions in cis, and also between centromeres and telomeres on different chromosomes, surprisingly we identified no gene regulatory transchromosomal interactions in either mouse or human cells, including previously described interactions. We suggest that advances in the chromosome conformation capture technique and the unbiased nature of this approach allow more reliable capture of interactions between chromosomes than previous methods. Overall our findings suggest that stable transchromosomal interactions that regulate gene expression are not present in mammalian immune cells and that lineage identity is governed by cis, not trans chromosomal interactions
- …