Swaran Singh, China-South Asia: Issues, Equations, Policies. Boquérat Gilles, Grare Frédéric, India, China, Russia. Intricacies of an Asian Triangle.

Swaran Singh is currently one of India’s most active researchers in the field of contemporary Chinese strategic studies. This work presents an overall view of the political and strategic issues affecting the relations between China and its South-East Asian neighbours. The first part, entitled Issues, identifies the main points of friction which have arisen between China and these neighbours, around the questions of Tibet, the Kashmir entanglement, and the struggle for influence in the Indian ..

Swaran Singh, China-South Asia : Issues, Equations, Policies / Boquérat Gilles, Grare Frédéric (éds.), India, China, Russia. Intricacies of an Asian Triangle

Swaran Singh est, en Inde, l’un des chercheurs les plus actifs dans le domaine des études stratégiques sur la Chine contemporaine. Il offre dans cet ouvrage une vue d’ensemble des problématiques politiques et stratégiques qui marquent le rapport de la Chine à ses voisins d’Asie du Sud. La première partie de l’ouvrage (Issues) identifie les principaux points de tensions qui se sont successivement noués entre la Chine et son voisinage sud-asiatique, autour de la question tibétaine, de l’imbrogl..

Swaran Singh, China-South Asia: Issues, Equations, Policies. Boquérat Gilles, Grare Frédéric, India, China, Russia. Intricacies of an Asian Triangle.

Swaran Singh is currently one of India’s most active researchers in the field of contemporary Chinese strategic studies. This work presents an overall view of the political and strategic issues affecting the relations between China and its South-East Asian neighbours. The first part, entitled Issues, identifies the main points of friction which have arisen between China and these neighbours, around the questions of Tibet, the Kashmir entanglement, and the struggle for influence in the Indian ..

Eczéma allergique de contact : Comment ré-induire une tolérance ?

L’eczéma allergique de contact est une dermatose inflammatoire fréquente, due à l’activation de lymphocytes T (LT) CD8+ cytotoxiques spécifiques d’haptènes en contact avec la peau. Les LT CD4+ sont, quant à eux, doués d’une fonction régulatrice et tolérogène, puisqu’ils limitent l’inflammation cutanée chez les patients (régulation) et préviennent le développement des LT effecteurs chez les individus sains (tolérance) : l’eczéma correspond donc à une rupture de la tolérance immunitaire aux haptènes présents dans l’environnement quotidien. Plusieurs sous-populations de LT CD4+ régulateurs (LT reg), parmi lesquelles celle des LT CD4+CD25+ naturels, sont impliquées dans la tolérance et la régulation de l’eczéma, via la production des cytokines immunosuppressives IL-10 (interleukine-10) et TGFβ (transforming growth factor β). Les travaux en cours ont pour objectif de ré-induire une tolérance immunitaire dans l’eczéma, soit en améliorant les méthodes existantes d’induction de tolérance aux haptènes (tolérance orale, tolérance à faibles doses, immunothérapie spécifique, tolérance induite par les rayons ultraviolets), soit en développant de nouvelles molécules capables d’activer les LT reg. Plus généralement, les données issues de ces travaux devraient pouvoir être appliquées au traitement des maladies auto-immunes ou allergiques, caractérisées par un déficit fonctionnel ou quantitatif en Ltreg à l’origine d’une rupture de la tolérance aux auto-antigènes ou aux allergènes de l’environnement.Allergic contact dermatitis (ACD) is a skin inflammatory disease mediated by activation of CD8+ cytotoxic T cells specific for haptens in contact with the skin. CD4+ T cells behave as both regulatory and tolerogenic cells since they down-regulate the skin inflammation in patients with ACD (regulation) and prevent the developement of eczema (tolerance) in normal individuals. Thus, ACD corresponds to a breakdown of immune tolerance to haptens in contact with the skin. Several regulatory CD4+ T cell subsets (Treg), especially CD4+CD25+ natural Treg cells, are involved in immunological tolerance and regulation to haptens through the production of the immunosuppressive cytokines IL-10 and TGF-β. Ongoing strategies to re-induce immune tolerance to haptens in patients with eczema include improvement of existing methods of tolerance induction (oral tolerance, low dose tolerance, allergen-specific immunotherapy, UV-induced tolerance) as well as development of new drugs able to activate IL-10 producing Treg cells in vivo. Ongoing and future progress in this area will open up new avenues for treatment of eczema and more generally autoimmune and allergic diseases resulting from a breakdown of tolerance to autoantigens and allergens, respectively

Regression of melanoma metastases after immunotherapy is associated with activation of antigen presentation and interferon-mediated rejection genes

We present the results of a comparative gene expression analysis of 15 metastases (10 regressing and 5 progressing) obtained from 2 melanoma patients with mixed response following different forms of immunotherapy. Whole genome transcriptional analysis clearly indicate that regression of melanoma metastases is due to an acute immune rejection mediated by the upregulation of genes involved in antigen presentation and interferon mediated response (STAT-1/IRF-1) in all the regressing metastases from both patients. In contrast, progressing metastases showed low transcription levels of genes involved in these pathways. Histological analysis showed T cells and HLA-DR positive infiltrating cells in the regressing but not in the progressing metastases. Quantitative expression analysis of HLA-A,B and C genes on microdisected tumoral regions indicate higher HLA expression in regressing than in progressing metastases. The molecular signature obtained in melanoma rejection appeared to be similar to that observed in other forms of immune-mediated tissue-specific rejection such as allograft, pathogen clearance, graft versus host or autoimmune disease, supporting the immunological constant of rejection. We favor the idea that the major factor determining the success or failure of immunotherapy is the nature of HLA Class I alterations in tumor cells and not the type of immunotherapy used. If the molecular alteration is reversible by the immunotherapy, the HLA expression will be upregulated and the lesion will be recognized and rejected. In contrast, if the defect is structural the MHC Class I expression will remain unchanged and the lesion will progress.Fondo de Investigaciones Sanitarias (FIS). Grant Numbers: CP03/0111, PI 08/1265. Proyecto de investigacion MEC I + D. Grant Numbers: SAF 2007-63262, SAF 2010-20273. Red Genomica del Cancer. Grant Number: RETIC RD 06/020. Plan Andaluz de Investigacion. Grant Numbers: CTS 143, CTS-695. Proyectos de Excelencia. Grant Numbers: CTS-03952, CVI-04740. Integrated European Cancer Immunotherapy. Grant Numbers: OJ2004/C158, 518234

Chronic itch development in sensory neurons requires BRAF signaling pathways

Chronic itch, or pruritus, is associated with a wide range of skin abnormalities. The mechanisms responsible for chronic itch induction and persistence remain unclear. We developed a mouse model in which a constitutively active form of the serine/threonine kinase BRAF was expressed in neurons gated by the sodium channel Nav1.8 (BRAF(Nav1.8) mice). We found that constitutive BRAF pathway activation in BRAF(Nav1.8) mice results in ectopic and enhanced expression of a cohort of itch-sensing genes, including gastrin-releasing peptide (GRP) and MAS-related GPCR member A3 (MRGPRA3), in nociceptors expressing transient receptor potential vanilloid 1 (TRPV1). BRAF(Nav1.8) mice showed de novo neuronal responsiveness to pruritogens, enhanced pruriceptor excitability, and heightened evoked and spontaneous scratching behavior. GRP receptor expression was increased in the spinal cord, indicating augmented coding capacity for itch subsequent to amplified pruriceptive inputs. Enhanced GRP expression and sustained ERK phosphorylation were observed in sensory neurons of mice with allergic contact dermatitis– or dry skin–elicited itch; however, spinal ERK activation was not required for maintaining central sensitization of itch. Inhibition of either BRAF or GRP signaling attenuated itch sensation in chronic itch mouse models. These data uncover RAF/MEK/ERK signaling as a key regulator that confers a subset of nociceptors with pruriceptive properties to initiate and maintain long-lasting itch sensation

Mutations in TRAF3IP1/IFT54 reveal a new role for IFT proteins in microtubule stabilization

Ciliopathies are a large group of clinically and genetically heterogeneous disorders caused by defects in primary cilia. Here we identified mutations in TRAF3IP1 (TNF Receptor-Associated Factor Interacting Protein 1) in eight patients from five families with nephronophthisis (NPH) and retinal degeneration, two of the most common manifestations of ciliopathies. TRAF3IP1 encodes IFT54, a subunit of the IFT-B complex required for ciliogenesis. The identified mutations result in mild ciliary defects in patients but also reveal an unexpected role of IFT54 as a negative regulator of microtubule stability via MAP4 (microtubule-associated protein 4). Microtubule defects are associated with altered epithelialization/polarity in renal cells and with pronephric cysts and microphthalmia in zebrafish embryos. Our findings highlight the regulation of cytoplasmic microtubule dynamics as a role of the IFT54 protein beyond the cilium, contributing to the development of NPH-related ciliopathies

The Ginzburg-Landau Theory of Type II superconductors in magnetic field

Thermodynamics of type II superconductors in electromagnetic field based on the Ginzburg - Landau theory is presented. The Abrikosov flux lattice solution is derived using an expansion in a parameter characterizing the "distance" to the superconductor - normal phase transition line. The expansion allows a systematic improvement of the solution. The phase diagram of the vortex matter in magnetic field is determined in detail. In the presence of significant thermal fluctuations on the mesoscopic scale (for example in high $T_{c}$ materials) the vortex crystal melts into a vortex liquid. A quantitative theory of thermal fluctuations using the lowest Landau level approximation is given. It allows to determine the melting line and discontinuities at melt, as well as important characteristics of the vortex liquid state. In the presence of quenched disorder (pinning) the vortex matter acquires certain "glassy" properties. The irreversibility line and static properties of the vortex glass state are studied using the "replica" method. Most of the analytical methods are introduced and presented in some detail. Various quantitative and qualitative features are compared to experiments in type II superconductors, although the use of a rather universal Ginzburg - Landau theory is not restricted to superconductivity and can be applied with certain adjustments to other physical systems, for example rotating Bose - Einstein condensate.Comment: 60 pages, 15 figures, accepted for publication in Review of Modern Physic

Prevention of Diabetes in NOD Mice by Repeated Exposures to a Contact Allergen Inducing a Sub-Clinical Dermatitis

BACKGROUND: Type 1 diabetes is an autoimmune disease, while allergic contact dermatitis although immune mediated, is considered an exposure driven disease that develops due to epicutaneous contact with reactive low-molecular chemicals. The objective of the present study was to experimentally study the effect of contact allergens on the development of diabetes in NOD mice. As the link between contact allergy and diabetes is yet unexplained we also examined the effect of provocation with allergens on Natural Killer T (NKT) cells, since involvement of NKT cells could suggest an innate connection between the two diseases. METHOD: NOD mice 4 weeks of age were exposed, on the ears, to two allergens, p-phenylenediamine and 2,4-dinitrochlorobenzene respectively, to investigate the diabetes development. The mice were followed for a maximum of 32 weeks, and they were either repeatedly exposed to the allergens or only sensitized a week after arrival. The stimulation of NKT cells by the two allergens were additionally studied in C57BL/6 mice. The mice were sensitized and two weeks later provocated with the allergens. The mice were subsequently euthanized at different time points after the provocation. RESULTS: It was found that repeated application of p-phenylenediamine reduced the incidence of diabetes compared to application with water (47% vs. 93%, P = 0.004). Moreover it was shown that in C57BL/6 mice both allergens resulted in a slight increment in the quantity of NKT cells in the liver. Application of the allergens at the same time resulted in an increased number of NKT cells in the draining auricular lymph node, and the increase appeared to be somewhat allergen specific as the accumulation was stronger for p-phenylenediamine. CONCLUSION: The study showed that repeated topical application on the ears with a contact allergen could prevent the development of diabetes in NOD mice. The contact allergens gave a non-visible, sub-clinical dermatitis on the application site. The preventive effect on diabetes may be due to stimulation of peripheral NKT cells, as shown for provocation with p-phenylenediamine in the C57BL/6 mouse. This epicutaneous procedure may lead to new strategies in prevention of type 1 diabetes in humans