Aod1, the immunoregulatory locus controlling abrogation of tolerance in neonatal thymectomy-induced autoimmune ovarian dysgenesis, maps to mouse chromosome 16.

Mice thymectomized at three days of age (D3Tx) develop during adulthood a variety of organ-specific autoimmune diseases, including autoimmune ovarian dysgenesis (AOD). The phenotypic spectrum of AOD is characterized by the development of anti-ovarian autoantibodies, oophoritis, and atrophy. The D3Tx model of AOD is unique in that disease induction depends exclusively on perturbation of the normal developing immune system, is T-cell-mediated, and is strain specific. For example, D3Tx A/J mice are highly susceptible to AOD, whereas C57BL/6J mice are resistant. After D3Tx, self ovarian antigens, expressed at physiological levels, trigger an autoimmune response capable of eliciting disease. The D3Tx model provides, therefore, the opportunity to focus on the mechanisms of self-tolerance that are relevant to disease pathogenesis. Previous studies indicate that the principal mechanisms involved in AOD susceptibility are genetically controlled and govern developmental processes associated with the induction and maintenance of peripheral tolerance. We report here the mapping of the Aod1 locus to mouse chromosome 16 within a region encoding several loci of immunologic relevance, including scid, Igl1, VpreB, Igll, Igl1r, Mtv6 (Mls-3), Ly-7, Ifnar, and Ifgt.

Evidence for a role of endothelin 1 and protein kinase C in nitroglycerin tolerance.

We sought to examine mechanisms responsible for increased vasoconstriction that occurs during development of nitroglycerin tolerance. Rabbits were treated for 3 days with nitroglycerin patches (0.4 mg/hr), and their aortic segments were studied in organ chambers. This treatment resulted in attenuated in vitro relaxations to nitroglycerin and increased contractile sensitivity to angiotensin II, serotonin, phenylephrine, KCl, and a direct activator of protein kinase C, the phorbol ester phorbol 12,13-dibutyrate. The protein kinase C antagonists calphostin C (100 nM) and staurosporine (10 nM) corrected the hypersensitivity to constrictors in tolerant vessels, yet had minimal effects on constrictions in control vessels. Paradoxically, constrictions caused by endothelin 1 were decreased in nitrate-tolerant vessels. Immunocytochemical analysis revealed intense endothelin 1-like and big endothelin 1-like immunoreactivity in the media of nitroglycerin-tolerant but not of control aortas. The enhanced vasoconstriction to angiotensin II, serotonin, KCl, and phenylephrine could be mimicked in normal vessels by addition of subthreshold concentrations of endothelin 1, and this effect was prevented by calphostin C. We propose that increased autocrine production of endothelin 1 in nitrate tolerance sensitizes vascular smooth muscle to a variety of vasoconstrictors through a protein kinase C-mediated mechanism.

High fat diet-induced hyperglycemia: prevention by low level expression of a glucose transporter (GLUT4) minigene in transgenic mice.

High-fat intake leading to obesity contributes to the development of non-insulin-dependent diabetes mellitus (NIDDM, type 2). Similarly, mice fed a high-fat (safflower oil) diet develop defective glycemic control, hyperglycemia, and obesity. To assess the effect of a modest increase in the expression of GLUT4 (the insulin-responsive glucose transporter) on impaired glycemic control caused by fat feeding, transgenic mice harboring a GLUT4 minigene were fed a high-fat diet. Low-level tissue-specific (heart, skeletal muscle, and adipose tissue) expression of the GLUT4 minigene in transgenic mice prevented the impairment of glycemic control and accompanying hyperglycemia, but not obesity, caused by fat feeding. Thus, a small increase (< or = 2-fold) in the tissue level of GLUT4 prevents a primary symptom of the diabetic state in a mouse model, suggesting a possible target for intervention in the treatment of NIDDM.

Selective SWIFT-R. A Flexible Software-Based Technique for Soft Error Mitigation in Low-Cost Embedded Systems

Commercial off-the-shelf microprocessors are the core of low-cost embedded systems due to their programmability and cost-effectiveness. Recent advances in electronic technologies have allowed remarkable improvements in their performance. However, they have also made microprocessors more susceptible to transient faults induced by radiation. These non-destructive events (soft errors), may cause a microprocessor to produce a wrong computation result or lose control of a system with catastrophic consequences. Therefore, soft error mitigation has become a compulsory requirement for an increasing number of applications, which operate from the space to the ground level. In this context, this paper uses the concept of selective hardening, which is aimed to design reduced-overhead and flexible mitigation techniques. Following this concept, a novel flexible version of the software-based fault recovery technique known as SWIFT-R is proposed. Our approach makes possible to select different registers subsets from the microprocessor register file to be protected on software. Thus, design space is enriched with a wide spectrum of new partially protected versions, which offer more flexibility to designers. This permits to find the best trade-offs between performance, code size, and fault coverage. Three case studies have been developed to show the applicability and flexibility of the proposal.

Fault tolerant embedded systems design by multi-objective optimization

The design of fault tolerant systems is gaining importance in large domains of embedded applications where design constrains are as important as reliability. New software techniques, based on selective application of redundancy, have shown remarkable fault coverage with reduced costs and overheads. However, the large number of different solutions provided by these techniques, and the costly process to assess their reliability, make the design space exploration a very difficult and time-consuming task. This paper proposes the integration of a multi-objective optimization tool with a software hardening environment to perform an automatic design space exploration in the search for the best trade-offs between reliability, cost, and performance. The first tool is commanded by a genetic algorithm which can simultaneously fulfill many design goals thanks to the use of the NSGA-II multi-objective algorithm. The second is a compiler-based infrastructure that automatically produces selective protected (hardened) versions of the software and generates accurate overhead reports and fault coverage estimations. The advantages of our proposal are illustrated by means of a complex and detailed case study involving a typical embedded application, the AES (Advanced Encryption Standard).

Efficient Mitigation of Data and Control Flow Errors in Microprocessors

The use of microprocessor-based systems is gaining importance in application domains where safety is a must. For this reason, there is a growing concern about the mitigation of SEU and SET effects. This paper presents a new hybrid technique aimed to protect both the data and the control-flow of embedded applications running on microprocessors. On one hand, the approach is based on software redundancy techniques for correcting errors produced in the data. On the other hand, control-flow errors can be detected by reusing the on-chip debug interface, existing in most modern microprocessors. Experimental results show an important increase in the system reliability even superior to two orders of magnitude, in terms of mitigation of both SEUs and SETs. Furthermore, the overheads incurred by our technique can be perfectly assumable in low-cost systems.

Intimate partner violence among women in Spain: the impact of regional-level male unemployment and income inequality

Background: Intimate partner violence (IPV) against women is a complex worldwide public health problem. There is scarce research on the independent effect on IPV exerted by structural factors such as labour and economic policies, economic inequalities and gender inequality. Objective: To analyse the association, in Spain, between contextual variables of regional unemployment and income inequality and individual women’s likelihood of IPV, independently of the women’s characteristics. Method: We conducted multilevel logistic regression to analyse cross-sectional data from the 2011 Spanish Macrosurvey of Gender-based Violence which included 7898 adult women. The first level of analyses was the individual women’ characteristics and the second level was the region of residence. Results: Of the survey participants, 12.2% reported lifetime IPV. The region of residence accounted for 3.5% of the total variability in IPV prevalence. We determined a direct association between regional male long-term unemployment and IPV likelihood (P = 0.007) and between the Gini Index for the regional income inequality and IPV likelihood (P < 0.001). Women residing in a region with higher gender-based income discrimination are at a lower likelihood of IPV than those residing in a region with low gender-based income discrimination (odds ratio = 0.64, 95% confidence intervals: 0.55–0.75). Conclusions: Growing regional unemployment rates and income inequalities increase women’s likelihood of IPV. In times of economic downturn, like the current one in Spain, this association may translate into an increase in women’s vulnerability to IPV.

The Revision of the Insurance Mediation Rules at EU Level and its Impact on Consumer Protection

The European Commission has put forward a new proposal for a directive on insurance mediation which should provide for significant changes in practices of selling insurance products and guarantee enhanced level of consumer protection. This proposal accompanies other regulatory initiatives in the insurance sector, all of them pursuing three main objectives: firstly, a strengthened insurance supervision with convergent supervisory standards at EU level; secondly, a better risk management of insurance companies; and thirdly a greater protection of policyholders. All these initiatives contribute to the EU programme on consumer protection and herald a new approach to EU insurance regulation and supervision. However, while the new supervisory rules are a direct response to the financial crisis and shortcomings of crossborder cooperation between national supervisors, the plans for the revision of insurance mediation rules were conceived much earlier due to scandals with mis-selling of insurance products in the United States and some EU Member States. This article will focus entirely on the Commission’s initiative in the consumer mediation area and the aspects of insurance supervision and risk management will be dealt with in separate articles.

Fault diagnosis of an automotive suspension system

With the development of the embedded application and driving assistance systems, it becomes relevant to develop parallel mechanisms in order to check and to diagnose these new systems. In this thesis we focus our research on one of this type of parallel mechanisms and analytical redundancy for fault diagnosis of an automotive suspension system. We have considered a quarter model car passive suspension model and used a parameter estimation, ARX model, method to detect the fault happening in the damper and spring of system. Moreover, afterward we have deployed a neural network classifier to isolate the faults and identifies where the fault is happening. Then in this regard, the safety measurements and redundancies can take into the effect to prevent failure in the system. It is shown that The ARX estimator could quickly detect the fault online using the vertical acceleration and displacement sensor data which are common sensors in nowadays vehicles. Hence, the clear divergence is the ARX response make it easy to deploy a threshold to give alarm to the intelligent system of vehicle and the neural classifier can quickly show the place of fault occurrence.

Increased mononuclear cell activation and apoptosis early after human liver transplantation is associated with a reduced frequency of acute rejection

Experimental models of orthotopic liver transplantation (OLT) have shown that the very early events post-OLT are critical in distinguishing immunogenic and tolerogenic reactions. In rodents, increased leukocyte apoptosis and cytokine expression have been demonstrated in tolerogenic strain combinations. Information from human OLT recipients is less abundant. The aim of this study was to determine the amount of early leukocyte activation and apoptosis following human OLT, and to correlate this with subsequent rejection status. Peripheral blood mononuclear cells (PBMC) were isolated from 76 patients undergoing OLT - on the day prior, 5 hrs after reperfusion (day 0), and 18-24 hrs post-OLT (day 1). The mean level of apoptotic PBMCs on post OLT day 1 was higher than healthy recipients (0.9% +/- 0.2 vs. 0.2% +/- 0.1, p = 0.013). Apoptosis was greater in nonrejecting (NR) (1.1% +/- 0.3) compared with acutely-rejecting (R) (0.3% +/- 0.1, p = 0.021) patients. On day 1, PBMC from NR patients had increased expression of IFN-gamma (p = 0.006), IL-10 (p = 0.016), and CD40 ligand (p = 0.02) compared with R. Donor cell chimerism on day 1 did not differ between the groups indicating that this was unlikely to account for increased PBMC apoptosis in the NR group. Interestingly, the level of chimerism on day 0 was significantly higher in NR (3.8% +/- 0.6) compared with R (1.2% +/- 0.4, p = 0.004) patients and there was a close correlation between chimerism on day 0 and cytokine expression on day 1. These results imply that similar mechanisms are occurring in the human liver to promote graft acceptance as in the experimental models of liver transplantation and suggest that strategies that promote liver transplant acceptance in rodents might be applicable to humans.

A continent of plant defense peptide diversity: Cyclotides in Australian Hybanthus (Violaceae)

Cyclotides are plant-derived miniproteins that have the unusual features of a head-to-tail cyclized peptide backbone and a knotted arrangement of disulfide bonds. It had been postulated that they might be an especially large family of host defense agents, but this had not yet been tested by field data on cyclotide variation in wild plant populations. In this study, we sampled Australian Hybanthus (Violaceae) to gain an insight into the level of variation within populations, within species, and between species. A wealth of cyclotide diversity was discovered: at least 246 new cyclotides are present in the 11 species sampled, and 26 novel sequences were characterized. A new approach to the discovery of cyclotide sequences was developed based on the identification of a conserved sequence within a signal sequence in cyclotide precursors. The number of cyclotides in the Violaceae is now estimated to be >9000. Cyclotide physicochemical profiles were shown to be a useful taxonomic feature that reflected species and their morphological relationships. The novel sequences provided substantial insight into the tolerance of the cystine knot framework in cyclotides to amino acid substitutions and will facilitate protein engineering applications of this framework.

Dynamic rupture in a 3-D particle-based simulation of a rough planar fault

An appreciation of the physical mechanisms which cause observed seismicity complexity is fundamental to the understanding of the temporal behaviour of faults and single slip events. Numerical simulation of fault slip can provide insights into fault processes by allowing exploration of parameter spaces which influence microscopic and macroscopic physics of processes which may lead towards an answer to those questions. Particle-based models such as the Lattice Solid Model have been used previously for the simulation of stick-slip dynamics of faults, although mainly in two dimensions. Recent increases in the power of computers and the ability to use the power of parallel computer systems have made it possible to extend particle-based fault simulations to three dimensions. In this paper a particle-based numerical model of a rough planar fault embedded between two elastic blocks in three dimensions is presented. A very simple friction law without any rate dependency and no spatial heterogeneity in the intrinsic coefficient of friction is used in the model. To simulate earthquake dynamics the model is sheared in a direction parallel to the fault plane with a constant velocity at the driving edges. Spontaneous slip occurs on the fault when the shear stress is large enough to overcome the frictional forces on the fault. Slip events with a wide range of event sizes are observed. Investigation of the temporal evolution and spatial distribution of slip during each event shows a high degree of variability between the events. In some of the larger events highly complex slip patterns are observed.

Effect of nutrition level and diets on creatinine excretion by sheep

In this experiment, creatinine (C) excretion by sheep was measured when they were fed different diets at different levels of intake. Creatinine excretion was not affected by the level of feed intake or the addition of salt to lucerne-based diets. However, differences between individual animals were significant. Creatinine excretion was significantly affected by diets, which were formulated by combining different amounts of lucerne chaff, oaten chaff and sorghum. It was also found that there were significant diurnal changes in the ratios of purine derivatives to creatinine (PD:C) in 3 hourly urine samples when the animals were fed either once or twice daily, but the average value for the PD:C ratio of any two urine samples taken 12 h apart was close to the daily mean. The results of this experiment suggest that if separate determination of the creatinine excretion by individual animals is made and the average value of the ratio of PD:C in two spot urine samples taken 12 h apart is used to predict PD excretion by spot urine sampling, microbial nitrogen flow can be estimated more accurately than when a fixed value of creatinine excretion is used for all animals and only a single urine sample is taken. (c) 2005 Elsevier B.V. All rights reserved.

Downregulation of IgE antibody and allergic responses in the lung by epidermal biolistic microparticle delivery

Background: Biolistic injections provide a needle-free delivery of antigen-laden microparticles to the epithelium. The precision of the injection preferentially targets the Langerhans cell network, which, although ideal for vaccination, might not be suitable for the downregulation of immune responses in immunotherapy. Objective: We sought to determine the ability of biolistic injection of antigen into the epithelium of sensitized mice to inhibit IgE antibody and lung inflammatory responses produced by further exposure to antigen. Methods: Mice were sensitized by means of a needle injection of ovalbumin (OVA) in alum and given a series of biolistic injections of OVA or vehicle control, followed by a boost of OVA in alum. Serum IgE and IgG antibodies were measured before and after the boost. The mice were then challenged intranasally, and the infiltration of inflammatory cells was measured by means of bronchoalveolar lavage. Airway reactivity of the challenged mice was measured by examining responses to methacholine with forced oscillatory techniques. Results: Biolistic injection of OVA into the dorsal skin of sensitized mice markedly inhibited IgE and IgG1 antibody responses induced by boosting. IgG2a antibody responses were reduced rather than stimulated. The eosinophilic inflammation in the bronchoalveolar lavage fluid induced by intranasal challenge was also markedly inhibited. Lung hyperreactivity showed an initial increase and then a decrease of responsiveness to methacholine, with elastance returning to the level of unsensitized mice. Biolistic injection into the buccal epithelium was also inhibitory. Conclusions: Biolistic injection of allergen inhibited the boosting of IgE antibody and eosinophilic lung inflammatory responses without inducing TO immunity.

Parallel 3D Simulation of a Fault Gouge using the Lattice Solid Model

Despite the insight gained from 2-D particle models, and given that the dynamics of crustal faults occur in 3-D space, the question remains, how do the 3-D fault gouge dynamics differ from those in 2-D? Traditionally, 2-D modeling has been preferred over 3-D simulations because of the computational cost of solving 3-D problems. However, modern high performance computing architectures, combined with a parallel implementation of the Lattice Solid Model (LSM), provide the opportunity to explore 3-D fault micro-mechanics and to advance understanding of effective constitutive relations of fault gouge layers. In this paper, macroscopic friction values from 2-D and 3-D LSM simulations, performed on an SGI Altix 3700 super-cluster, are compared. Two rectangular elastic blocks of bonded particles, with a rough fault plane and separated by a region of randomly sized non-bonded gouge particles, are sheared in opposite directions by normally-loaded driving plates. The results demonstrate that the gouge particles in the 3-D models undergo significant out-of-plane motion during shear. The 3-D models also exhibit a higher mean macroscopic friction than the 2-D models for varying values of interparticle friction. 2-D LSM gouge models have previously been shown to exhibit accelerating energy release in simulated earthquake cycles, supporting the Critical Point hypothesis. The 3-D models are shown to also display accelerating energy release, and good fits of power law time-to-failure functions to the cumulative energy release are obtained.