Reconciling leptogenesis with observable mu --> e gamma rates

We perform a detailed analysis of thermal leptogenesis in the framework of seesaw models which approximately conserve lepton number. These models are known to allow for large Yukawa couplings and a low seesaw scale in agreement with neutrino mass constraints, and hence to lead to large lepton flavour violating rates that can be probed experimentally. Although large Yukawa couplings lead to (inverse) decay rates much larger than the Hubble expansion rate, we show that the leptogenesis washout induced is generically small if the mass splitting between the right-handed neutrinos is small enough. As a result, large lepton flavour violating rates are compatible with successful leptogenesis. We emphasize that this scenario does not require any particular flavour structure. A small splitting is natural and radiatively stable in this context because it is protected by the lepton number symmetry.Comment: One section added, a few equations and sentences rewritten, references added, results unchange

Touch of chemokines

Chemoattractant cytokines or chemokines constitute a family of structurally related proteins found in vertebrates, bacteria, or viruses. So far, 48 chemokine genes have been identified in humans, which bind to around 20 chemokine receptors These receptors belong to the seven transmembrane G-protein-coupled receptor family. Chemokines and their receptors were originally studied for their role in cellular trafficking of leukocytes during inflammation and immune surveillance. It is now known that they exert different functions under physiological conditions such as homeostasis, development, tissue repair, and angiogenesis but also under pathological disorders including tumorigenesis, cancer metastasis, inflammatory, and autoimmune diseases. Physicochemical properties of chemokines and chernokine receptors confer the ability to homo- and hetero-oligornerize. Many efforts are currently performed in establishing new therapeutically compounds able to target the chemokine/chemokine receptor system. In this review, we are interested in the role of chemokines in inflammatory disease and leukocyte trafficking with a focus on vascular inflammatory diseases, the operating synergism, and the emerging therapeutic approaches of chemokines

A Static Analyzer for Large Safety-Critical Software

We show that abstract interpretation-based static program analysis can be made efficient and precise enough to formally verify a class of properties for a family of large programs with few or no false alarms. This is achieved by refinement of a general purpose static analyzer and later adaptation to particular programs of the family by the end-user through parametrization. This is applied to the proof of soundness of data manipulation operations at the machine level for periodic synchronous safety critical embedded software. The main novelties are the design principle of static analyzers by refinement and adaptation through parametrization, the symbolic manipulation of expressions to improve the precision of abstract transfer functions, the octagon, ellipsoid, and decision tree abstract domains, all with sound handling of rounding errors in floating point computations, widening strategies (with thresholds, delayed) and the automatic determination of the parameters (parametrized packing)

An original SERPINA3 gene cluster: Elucidation of genomic organization and gene expression in the Bos taurus 21q24 region

<p>Abstract</p> <p>Background</p> <p>The superfamily of <b><it>ser</it></b>ine <b><it>p</it></b>roteinase <b><it>in</it></b>hibitors (serpins) is involved in numerous fundamental biological processes as inflammation, blood coagulation and apoptosis. Our interest is focused on the SERPINA3 sub-family. The major human plasma protease inhibitor, α1-antichymotrypsin, encoded by the <it>SERPINA3 </it>gene, is homologous to genes organized in clusters in several mammalian species. However, although there is a similar genic organization with a high degree of sequence conservation, the reactive-centre-loop domains, which are responsible for the protease specificity, show significant divergences.</p> <p>Results</p> <p>We provide additional information by analyzing the situation of <it>SERPINA3 </it>in the bovine genome. A cluster of eight genes and one pseudogene sharing a high degree of identity and the same structural organization was characterized. Bovine <it>SERPINA3 </it>genes were localized by radiation hybrid mapping on 21q24 and only spanned over 235 Kilobases. For all these genes, we propose a new nomenclature from <it>SERPINA3-1 </it>to <it>SERPINA3-8</it>. They share approximately 70% of identity with the human <it>SERPINA3 </it>homologue. In the cluster, we described an original sub-group of six members with an unexpected high degree of conservation for the reactive-centre-loop domain, suggesting a similar peptidase inhibitory pattern. Preliminary expression analyses of these bovSERPINA3s showed different tissue-specific patterns and diverse states of glycosylation and phosphorylation. Finally, in the context of phylogenetic analyses, we improved our knowledge on mammalian SERPINAs evolution.</p> <p>Conclusion</p> <p>Our experimental results update data of the bovine genome sequencing, substantially increase the bovSERPINA3 sub-family and enrich the phylogenetic tree of serpins. We provide new opportunities for future investigations to approach the biological functions of this unusual subset of serine proteinase inhibitors.</p

Successful Leptogenesis in SO(10) Unification with a Left-Right Symmetric Seesaw Mechanism

We study thermal leptogenesis in a broad class of supersymmetric SO(10) models with a left-right symmetric seesaw mechanism, taking into account flavour effects and the contribution of the next-to-lightest right-handed neutrino supermultiplet. Assuming M_D = M_u and a normal hierarchy of light neutrino masses, we show that four out of the eight right-handed neutrino mass spectra reconstructed from low-energy neutrino data can lead to successful leptogenesis with a reheating temperature in the (10^9 - 10^10) GeV range. In the remaining four solutions, leptogenesis is dominated by N_2 decays, as in the type I seesaw case. We find that some of these spectra can generate the observed baryon asymmetry for reheating temperatures above 10^10 GeV, in contrast to the type I case. Together with flavour effects, an accurate description of charged fermion masses turns out to be a crucial ingredient in the analysis.Comment: 32 pages, 23 figures. v2: 2 comments [below Eq. (53) and at the end of the conclusions] and 1 reference added, typos corrected. Version to be published in Nucl. Phys.

Recent discovery of Paranthura japonica Richardson, 1909 (Crustacea: Isopod: Paranthuridae) in European marine waters (Arcachon Bay, Bay of Biscay)

The Asiatic isopod Paranthura japonica Richardson, 1909 was collected in 2007 in Arcachon Bay (SW France), where the species occurs in a variety of habitats, both in the intertidal and at shallow depths. This species, native to the Sea of Japan, may have been accidentally introduced in Arcachon Bay with oyster transfers or as fouling on ship hulls

Chemokines and galectins form heterodimers to modulate inflammation

Chemokines and galectins are simultaneously upregulated and mediate leukocyte recruitment during inflammation. Until now, these effector molecules have been considered to function independently. Here, we tested the hypothesis that they form molecular hybrids. By systematically screening chemokines for their ability to bind galectin‐1 and galectin‐3, we identified several interacting pairs, such as CXCL12 and galectin‐3. Based on NMR and MD studies of the CXCL12/galectin‐3 heterodimer, we identified contact sites between CXCL12 β‐strand 1 and Gal‐3 F‐face residues. Mutagenesis of galectin‐3 residues involved in heterodimer formation resulted in reduced binding to CXCL12, enabling testing of functional activity comparatively. Galectin‐3, but not its mutants, inhibited CXCL12‐induced chemotaxis of leukocytes and their recruitment into the mouse peritoneum. Moreover, galectin‐3 attenuated CXCL12‐stimulated signaling via its receptor CXCR4 in a ternary complex with the chemokine and receptor, consistent with our structural model. This first report of heterodimerization between chemokines and galectins reveals a new type of interaction between inflammatory mediators that can underlie a novel immunoregulatory mechanism in inflammation. Thus, further exploration of the chemokine/galectin interactome is warranted

A genomic rearrangement resulting in a tandem duplication is associated with split hand-split foot malformation 3 (SHFM3) at 10q24

Split hand-split foot malformation (SHFM) is characterized by hypoplasia/aplasia of the central digits with fusion of the remaining digits. SHFM is usually an autosomal dominant condition and at least five loci have been identified in humans. Mutation analysis of the DACTYLIN gene, suspected to be responsible for SHFM3 in chromosome 10q24, was conducted in seven SHFM patients. We screened the coding region of DACTYLIN by single-strand conformation polymorphism and sequencing, and found no point mutations. However, Southern, pulsed field gel electrophoresis and dosage analyses demonstrated a complex rearrangement associated with a ∼0.5 Mb tandem duplication in all the patients. The distal and proximal breakpoints were within an 80 and 130 kb region, respectively. This duplicated region contained a disrupted extra copy of the DACTYLIN gene and the entire LBX1 and β-TRCP genes, known to be involved in limb development. The possible role of these genes in the SHFM3 phenotype is discusse

Identification of a non-canonical chemokine-receptor pathway suppressing regulatory T cells to drive atherosclerosis

CCL17 is produced by conventional dendritic cells, signals through CCR4 on regulatory T (Treg) cells and drives atherosclerosis by suppressing Treg functions through yet undefined mechanisms. Here we show that conventional dendritic cells from CCL17-deficient mice display a pro-tolerogenic phenotype and transcriptome that is not phenocopied in mice lacking its cognate receptor CCR4. In the plasma of CCL17-deficient mice, CCL3 was the only decreased cytokine/chemokine. We found that CCL17 signaled through CCR8 as an alternate high-affinity receptor, which induced CCL3 expression and suppressed Treg functions in the absence of CCR4. Genetic ablation of CCL3 and CCR8 in CD4+ T cells reduced CCL3 secretion, boosted FoxP3+ Treg numbers and limited atherosclerosis. Conversely, CCL3 administration exacerbated atherosclerosis and restrained Treg differentiation. In symptomatic versus asymptomatic human carotid atheroma, CCL3 expression was increased, whereas FoxP3 expression was reduced. Together, we identified a non-canonical chemokine pathway whereby CCL17 interacts with CCR8 to yield a CCL3-dependent suppression of atheroprotective Treg cells. Doring, van der Vorst, Yan, Neideck et al. present a non-canonical chemokine pathway involving CCL17 signaling through CCR8, which induces CCL3 expression independent of CCR4 and suppresses the functions of atheroprotective Treg cells

Tissue Tropism and Target Cells of NSs-Deleted Rift Valley Fever Virus in Live Immunodeficient Mice

Rift Valley fever, caused by a member of the Bunyaviridae family, has spread during recent years to most sub-Saharan African countries, in Egypt and in the Arabian peninsula. The virus can be transmitted by insect vectors or by direct contacts with infectious tissues. The analysis of virus replication and dissemination in laboratory animals has been hampered by the need to euthanize sufficient numbers of animals and to assay appropriate organs at various time points after infection to evaluate the viral replication. By following the bioluminescence and fluorescence of Rift Valley fever viruses expressing light reporters, we were able to track the real-time dissemination of the viruses in live immunodeficient mice. We showed that the first infected organs were the thymus, spleen and liver, but the liver rapidly became the main location of viral replication. Phagocytes also appeared as important targets, and their systemic depletion by use of clodronate liposomes decreased the number of viruses in the blood, delayed the viral dissemination and prolonged the survival of the infected mice