Genomic investigations of unexplained acute hepatitis in children

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children

Phosphorylation of serine 11 and serine 92 as new positive regulators of human snail1 function: Potential involvement of casein kinase-2 and the cAMP-activated kinase protein kinase A

10 páginas, 8 figuras.-- et al.Snail1 is a major factor for epithelial-mesenchymal transition (EMT), an important event in tumor metastasis and in other pathologies. Snail1 is tightly regulated at transcriptional and posttranscriptional levels. Control of Snail1 protein stability and nuclear export by GSK3 beta phosphorylation is important for Snail1 functionality. Stabilization mechanisms independent of GSK3 beta have also been reported, including interaction with LOXL2 or regulation of the COP9 signalosome by inflammatory signals. To get further insights into the role of Snail1 phosphorylation, we have performed an in-depth analysis of in vivo human Snail1 phosphorylation combined with mutational studies. We identify new phosphorylation sites at serines 11, 82, and 92 and confirmed previously suggested phosphorylations at serine 104 and 107. Serines 11 and 92 participate in the control of Snail1 stability and positively regulate Snail1 repressive function and its interaction with mSin3A corepressor. Furthermore, serines 11 and 92 are required for Snail1-mediated EMT and cell viability, respectively. PKA and CK2 have been characterized as the main kinases responsible for in vitro Snail1 phosphorylation at serine 11 and 92, respectively. These results highlight serines 11 and 92 as new players in Snail1 regulation and suggest the participation of CK2 and PKA in the modulation of Snail1 functionality.This work was supported by the EU and the Spanish Ministry of Science and Innovation (MRTN-CT-2004-005428, SAF2007-06351, Consolider Ingenio CDS2007-00017 grants to AC) and Fundación Mutua Madrileña. M.McP. was supported by the EU Marie Curie program, P.O. is supported by a FPI fellowship from the Spanish Ministry of Science and Innovation.Peer reviewe

Search for Supersymmetry in pp Collisions at 7 TeV in Events with Jets and Missing Transverse Energy

A search for supersymmetry with R-parity conservation in proton-proton collisions at a centre-of-mass energy of 7 TeV is presented. The data correspond to an integrated luminosity of 35 inverse picobarns collected by the CMS experiment at the LHC. The search is performed in events with jets and significant missing transverse energy, characteristic of the decays of heavy, pair-produced squarks and gluinos. The primary background, from standard model multijet production, is reduced by several orders of magnitude to a negligible level by the application of a set of robust kinematic requirements. With this selection, the data are consistent with the standard model backgrounds, namely t t-bar, W + jet and Z + jet production, which are estimated from data control samples. Limits are set on the parameters of the constrained minimal supersymmetric extension of the standard model. These limits extend those set previously by experiments at the Tevatron and LEP colliders.A search for supersymmetry with R-parity conservation in proton–proton collisions at a centre-of-mass energy of 7 TeV is presented. The data correspond to an integrated luminosity of 35 pb−1 collected by the CMS experiment at the LHC. The search is performed in events with jets and significant missing transverse energy, characteristic of the decays of heavy, pair-produced squarks and gluinos. The primary background, from standard model multijet production, is reduced by several orders of magnitude to a negligible level by the application of a set of robust kinematic requirements. With this selection, the data are consistent with the standard model backgrounds, namely tt¯ , W + jet and Z + jet production, which are estimated from data control samples. Limits are set on the parameters of the constrained minimal supersymmetric extension of the standard model. These limits extend those set previously by experiments at the Tevatron and LEP colliders.A search for supersymmetry with R-parity conservation in proton-proton collisions at a centre-of-mass energy of 7 TeV is presented. The data correspond to an integrated luminosity of 35 inverse picobarns collected by the CMS experiment at the LHC. The search is performed in events with jets and significant missing transverse energy, characteristic of the decays of heavy, pair-produced squarks and gluinos. The primary background, from standard model multijet production, is reduced by several orders of magnitude to a negligible level by the application of a set of robust kinematic requirements. With this selection, the data are consistent with the standard model backgrounds, namely t t-bar, W + jet and Z + jet production, which are estimated from data control samples. Limits are set on the parameters of the constrained minimal supersymmetric extension of the standard model. These limits extend those set previously by experiments at the Tevatron and LEP colliders

Measurement of Dijet Angular Distributions and Search for Quark Compositeness in pp Collisions at sqrts=7sqrt{s} = 7 TeV

Dijet angular distributions are measured over a wide range of dijet invariant masses in pp collisions at sqrt(s) = 7 TeV, at the CERN LHC. The event sample, recorded with the CMS detector, corresponds to an integrated luminosity of 36 inverse picobarns. The data are found to be in good agreement with the predictions of perturbative QCD, and yield no evidence of quark compositeness. With a modified frequentist approach, a lower limit on the contact interaction scale for left-handed quarks of Lambda = 5.6 TeV is obtained at the 95% confidence level