Nasal administration of glutamate decarboxylase (GAD65) peptides induces Th2 responses and prevents murine insulin-dependent diabetes.

We previously demonstrated that a spontaneous Th1 response against glutamate decarboxylase (GAD65) arises in NOD mice at four weeks in age and subsequently T cell autoimmunity spreads both intramolecularly and intermolecularly. Induction of passive tolerance to GAD65, through inactivation of reactive T cells before the onset of autoimmunity, prevented determinant spreading and the development of insulin-dependent diabetes mellitus (IDDM). Here, we examined whether an alternative strategy, designed to induce active tolerance via the engagement of Th2 immune responses to GAD65, before the spontaneous onset of autoimmunity, could inhibit the cascade of Th1 responses that lead to IDDM. We observed that a single intranasal administration of GAD65 peptides to 2-3-wk-old NOD mice induced high levels of IgG1 antibodies to GAD65. GAD65 peptide treated mice displayed greatly reduced IFN gamma responses and increased IL-5 responses to GAD65, confirming the diversion of the spontaneous GAD65 Th1 response toward a Th2 phenotype. Consistent with the induction of an active tolerance mechanism, splenic CD4+ (but not CD8+) T cells from GAD65 peptide-treated mice, inhibited the adoptive transfer of IDDM to NOD-scid/scid mice. This active mechanism not only inhibited the development of proliferative T cell responses to GAD65, it also limited the expansion of autoreactive T cell responses to other beta cell antigens (i.e., determinant spreading). Finally, GAD65 peptide treatment reduced insulitis and long-term IDDM incidence. Collectively, these data suggest that the nasal administration of GAD65 peptides induces a Th2 cell response that inhibits the spontaneous development of autoreactive Th1 responses and the progression of beta cell autoimmunity in NOD mice

Are goal states represented during kinematic imitation?

A number of studies have shown that observation of another person's actions can modulate one's own actions, such as when 2 individuals cooperate in order to complete a joint task. However, little is known about whether or not direct matching of specific movements is modulated by the goals of the actions observed. In a series of 7 experiments, we employed an action observation paradigm in which 2 coactors sat opposite each other and took turns to reach out to targets presented on a shared workspace. Importantly, coactors performed either the same goal at the reached-to location or a different goal. Although results consistently showed that the reaching action of 1 individual slows the observer's reaching action to the same spatial location, the effect was not modulated according to the adopted goals of coactors. These findings challenge the notion that the processes involved in the imitation of specific movements code for the action goals of those movements

Hierarchy and Feedback in the Evolution of the E. coli Transcription Network

The E.coli transcription network has an essentially feedforward structure, with, however, abundant feedback at the level of self-regulations. Here, we investigate how these properties emerged during evolution. An assessment of the role of gene duplication based on protein domain architecture shows that (i) transcriptional autoregulators have mostly arisen through duplication, while (ii) the expected feedback loops stemming from their initial cross-regulation are strongly selected against. This requires a divergent coevolution of the transcription factor DNA-binding sites and their respective DNA cis-regulatory regions. Moreover, we find that the network tends to grow by expansion of the existing hierarchical layers of computation, rather than by addition of new layers. We also argue that rewiring of regulatory links due to mutation/selection of novel transcription factor/DNA binding interactions appears not to significantly affect the network global hierarchy, and that horizontally transferred genes are mainly added at the bottom, as new target nodes. These findings highlight the important evolutionary roles of both duplication and selective deletion of crosstalks between autoregulators in the emergence of the hierarchical transcription network of E.coli.Comment: to appear in PNA

Combining semi-automated image analysis techniques with machine learning algorithms to accelerate large scale genetic studies

Background: Genetic analyses of plant root system development require large datasets of extracted architectural traits. To quantify such traits from images of root systems, researchers often have to choose between automated tools (that are prone to error and extract only a limited number of architectural traits) or semi-automated ones (that are highly time consuming). Findings: We trained a Random Forest algorithm to infer architectural traits from automatically-extracted image descriptors. The training was performed on a subset of the dataset, then applied to its entirety. This strategy allowed us to (i) decrease the image analysis time by 73% and (ii) extract meaningful architectural traits based on image descriptors. We also show that these traits are sufficient to identify Quantitative Trait Loci that had previously been discovered using a semi-automated method. Conclusions: We have shown that combining semi-automated image analysis with machine learning algorithms has the power to increase the throughput in large scale root studies. We expect that such an approach will enable the quantification of more complex root systems for genetic studies. We also believe that our approach could be extended to other area of plant phenotyping

Human monoclonal islet specific autoantibodies share features of islet cell and 64 kDa antibodies

The first human monoclonal islet cell antibodies of the IgG class (MICA 1-6) obtained from an individual with Type 1 (insulin-dependent) diabetes mellitus were cytoplasmic islet cell antibodies selected by the indirect immunofluorescence test on pancreas sections. Surprisingly, they all recognized the 64 kDa autoantigen glutamate decarboxylase. In this study we investigated which typical features of cytoplasmic islet cell antibodies are represented by these monoclonals. We show by double immunofluorescence testing that MICA 1-6 stain pancreatic beta cells which is in agreement with the beta-cell specific expression of glutamate decarboxylase. In contrast an islet-reactive IgM monoclonal antibody obtained from a pre-diabetic individual stained all islet cells but lacked the tissue specificity of MICA 1-6 and must therefore be considered as a polyreactive IgM-antibody. We further demonstrate that MICA 1-6 revealed typical features of epitope sensitivity to biochemical treatment of the target tissue which has been demonstrated for islet cell antibodies, and which has been used to argue for a lipid rather than a protein nature of target antigens. Our results provide direct evidence that the epitopes recognized by the MICA are destroyed by methanol/chloroform treatment but reveal a high stability to Pronase digestion compared to proinsulin epitopes. Conformational protein epitopes in glutamate decarboxylase therefore show a sensitivity to biochemical treatment of sections such as ganglioside epitopes. MICA 1-6 share typical features of islet cell and 64 kDa antibodies and reveal that glutamate decarboxylase-reactive islet cell antibodies represent a subgroup of islet cell antibodies present in islet cell antibody-positive sera

A diffusion-based quantification technique for assessment of sacroiliitis in adolescents with enthesitis-related arthritis

OBJECTIVE: To investigate the use of a quantitative diffusion-weighted imaging (DWI) tool for measuring inflammation of the sacroiliac joints (SIJs) in enthesitis-related arthritis (ERA). METHODS: A retrospective study was performed with institutional review board approval. Subjects were adolescents who had undergone MRI of the SIJs since January 2010. 10 patients with a clinical diagnosis of ERA and 10 controls with a clinical diagnosis of mechanical back pain were assessed. Axial T1 weighted, short tau inversion recovery (STIR) and DWI (b-values 0, 50, 100, 300 and 600 mm(2) s(-1)) images were acquired. Apparent diffusion coefficient (ADC) maps were generated using a monoexponential fit. On each of four slices, two to three linear regions-of-interest were placed on each joint. Normalized ADC (nADC) values were defined as joint ADC divided by a reference ADC derived from normal sacral bone. STIR images were scored using a modification of an established technique. The correlation between nADC values and STIR scores was evaluated using Spearman's rank correlation. RESULTS: Mean nADC values were significantly higher in cases than in controls (p = 0.0015). There was a strong correlation between STIR scores and nADC values (R = 0.85). CONCLUSION: ADC values are significantly increased in inflamed SIJs compared with controls. There is a good correlation between this diffusion-based method and STIR scores of inflammation. ADVANCES IN KNOWLEDGE: We have described and provisionally validated a method for quantifying the severity of inflammation in the SIJs in ERA using ADC measurements. This method is quick, is reproducible and could potentially be automated

Semisolid processing characteristics of AM series Mg alloys by rheo-diecasting

The official published version of this Article can be found at the link below - Copyright @ 2006 ASM InternationalAn investigation has been made into the solidification behavior and microstructural evolution of AM50, AM70, and AM90 alloys during rheo-diecasting, their processibility, and the resulting mechanical properties. It was found that solidification of AM series alloys under intensive melt shearing in the unique twin-screw slurry maker during rheo-diecasting gave rise to numerous spheroidal primary magnesium (Mg) particles that were uniformly present in the microstructure. As a result, the network of the beta-Mg17Al12 phase was consistently interrupted by these spheroidal and ductile particles. Such a microstructure reduced the obstacle of deformation and the harmfulness of the beta-Mg17Al12 network on ductility, and therefore improved the ductility of rheo-diecast AM alloys. It was shown that, even with 9 wt pct Al, the elongation of rheo-diecast AM90 still achieved (9 +/- 1.2) pct. Rheodiecasting thus provides an attractive processing route for upgrading the alloy specification of AM series alloys by increasing the aluminum (Al) content while ensuring ductility. Assessment of the processibility of AM series alloys for semisolid processing showed that high Al content AM series alloys are more suitable for rheo-diecasting than low Al content alloys, because of the lower sensitivity of solid fraction to temperature, the lower liquidus temperature, and the smaller interval between the semisolid processing temperature and the complete solidification temperature.This work is supported by the EPSR

Views and experiences of hepatitis C testing and diagnosis among people who inject drugs: Systematic review of qualitative research

Background: Many developed countries are facing a major challenge to improve identification of individuals acutely and chronically infected with hepatitis C virus (HCV) infection. We explored the views and experiences of people who inject drugs (PWID) in relation to HCV testing, and diagnosis through a review and synthesis of qualitative research. Methods: Based on the thematic synthesis of qualitative research. Searches were conducted in 14 databases and supplemented by reference checking, hand searching of selected journals, and searches of relevant websites. Studies of any qualitative design that examined the views and experiences of, and attitudes towards, HCV testing and diagnosis among PWID or practitioners involved in their care were included. Key themes and sub-themes were systematically coded according to the meaning and content of the findings of each study which proceeded to the preparation of a narrative account of the synthesis. Results: 28 qualitative studies were identified. We identified a number of overarching descriptive themes in the literature, finding overall that PWID hold complex and differing views and experiences of testing and diagnosis. Three major themes emerged: missed opportunities for the provision of information and knowledge; shifting priorities between HCV testing and other needs; and testing as unexpected and routine. Evidence of missed opportunities for the provision of knowledge and information about HCV were clear, contributing to delays in seeking testing and providing a context to poor experiences of diagnosis. Influenced by the nature of their personal circumstances, perceptions of the risk associated with HCV and the prioritisation of other needs acted both to encourage and discourage the uptake of HCV testing. Undergoing HCV testing as part of routine health assessment, and an unawareness of being testing was common. An unexpected positive diagnosis exacerbated anxiety and confusion. Conclusions: This review has identified that there are modifiable factors that affect the uptake of HCV testing and experiences of HCV diagnosis among PWID. Intervention development should focus on addressing these factors. There is a need for further research that engages PWID from a diverse range of populations to identify interventions, strategies and approaches that they consider valuable