Extrapolation Method for System Reliability Assessment: A New Scheme

The present paper presents a new scheme for probability integral solution for system reliability analysis, which takes basis in the approaches by Naess et al. (2009) and Bucher (2009). The idea is to evaluate the probability integral by extrapolation, based on a sequence of MC approximations of integrals with scaled domains. The performance of this class of approximation depends on the approach applied for the scaling and the functional form utilized for the extrapolation. A scheme for this task is derived here taking basis in the theory of asymptotic solutions to multi-normal probability integrals. The scheme is extended so that it can be applied to cases where the asymptotic property may not be valid and/or the random variables are not normally distributed. The performance of the scheme is investigated by four principal series and parallel systems and some practical examples. The results indicate that the proposed scheme is efficient and adds to generality for this class of approximations for probability integrals. </jats:p

Amelioration of diabetes in NOD by additive Aire

Tissue-specific autoimmune diseases are assumed to arise through malfunction of two checkpoints for immune tolerance: defective elimination of autoreactive T cells in the thymus and activation of these T cells by corresponding autoantigens in the periphery. However, evidence for this model and the outcome of such alterations in each or both of the tolerance mechanisms have not been sufficiently investigated. We studied these issues by expressing human AIRE (huAIRE) as a modifier of tolerance function in NOD mice wherein the defects of thymic and peripheral tolerance together cause type I diabetes (T1D). Additive huAIRE expression in the thymic stroma had no major impact on the production of diabetogenic T cells in the thymus. In contrast, huAIRE expression in peripheral antigen-presenting cells (APCs) rendered the mice resistant to T1D, while maintaining other tissue-specific autoimmune responses and antibody production against an exogenous protein antigen, because of the loss of Xcr1+ dendritic cells, an essential component for activating diabetogenic T cells in the periphery. These results contrast with our recent demonstration that huAIRE expression in both the thymic stroma and peripheral APCs resulted in the paradoxical development of muscle-specific autoimmunity. Our results reveal that tissue-specific autoimmunity is differentially controlled by a combination of thymic function and peripheral tolerance, which can be manipulated by expression of huAIRE/Aire in each or both of the tolerance mechanisms

Three cases of myxofibroma.

Myxofibroma is a rare tumor. Three cases of myxofibroma, each of which developed at the right mandibular ramus, mandibular anterior tooth region, are presented. Myxofibroma developing in the mandibular ramus region is rare, and there has been only one case reported so far in Japan.</p

A NEW LOOK AT TRANSCRIPTIONAL REGULATION BY AIRE IN mTECs

The deficiency of Aire, a transcriptional regulator whose defect results in the development of autoimmunity, is associated with reduced expression of tissue-restricted self-Ags (TRAs) in medullary thymic epithelial cells (mTECs). Although the mechanisms underlying Aire-dependent expression of TRAs need to be explored, the physical identification of the target(s) of Aire has been hampered by the low and promiscuous expression of TRAs. We have tackled this issue by engineering mice with augmented Aire expression. Integration of the transcriptomic data from Aire-augmented and Aire-deficient mTECs revealed that a large proportion of so-called Aire-dependent genes, including those of TRAs, may not be direct transcriptional targets downstream of Aire. Rather, Aire induces TRA expression indirectly through controlling the heterogeneity of mTECs, as revealed by single-cell analyses. In contrast, Ccl25 emerged as a canonical target of Aire, and we verified this both in vitro and in vivo. Our approach has illuminated the Aire’s primary targets while distinguishing them from the secondary targets

A case of mesenchymoma in the oral cavity clinically resembling a large pleomorphic adenoma.

A report is made of a 52-year-old male whose main complaint was a painless tumor at the right side of the palate resulting in speech disturbance. He was diagnosed as a case of what Stout called benign mesenchymoma. Some discussion is also made of the tumor pathology in terms of genetic factors, predirective sites, age range, sex differences and therapy.</p

Paradoxical development of polymyositis-like autoimmunity through augmented expression of autoimmune regulator (AIRE)

Autoimmunity is prevented by the function of the autoimmune regulator [AIRE (Aire in mice)], which promotes the expression of a wide variety of tissue-restricted antigens (TRAs) from medullary thymic epithelial cells (mTECs) and from a subset of peripheral antigen-presenting cells (APCs). We examined the effect of additive expression of human AIRE (huAIRE) in a model of autoimmune diabetes in NOD mice. Unexpectedly, we observed that mice expressing augmented AIRE/Aire developed muscle-specific autoimmunity associated with incomplete maturation of mTECs together with impaired expression of Aire-dependent TRAs. This led to failure of deletion of autoreactive T cells together with dramatically reduced production of regulatory T cells in the thymus. In peripheral APCs, expression of costimulatory molecules was augmented. We suggest that levels of Aire expression need to be tightly controlled for maintenance of immunological tolerance. Our results also highlight the importance of coordinated action between central tolerance and peripheral tolerance under the common control of Aire