Modification of an aggressive model of Alport Syndrome reveals early differences in disease pathogenesis due to genetic background

The link between mutations in collagen genes and the development of Alport Syndrome has been clearly established and a number of animal models, including knock-out mouse lines, have been developed that mirror disease observed in patients. However, it is clear from both patients and animal models that the progression of disease can vary greatly and can be modifed genetically. We have identifed a point mutation in Col4a4 in mice where disease is modifed by strain background, providing further evidence of the genetic modifcation of disease symptoms. Our results indicate that C57BL/6J is a protective background and postpones end stage renal failure from 7 weeks, as seen on a C3H background, to several months. We have identifed early diferences in disease progression, including expression of podocyte-specifc genes and podocyte morphology. In C57BL/6J mice podocyte efacement is delayed, prolonging normal renal function. The slower disease progression has allowed us to begin dissecting the pathogenesis of murine Alport Syndrome in detail. We fnd that there is evidence of diferential gene expression during disease on the two genetic backgrounds, and that disease diverges by 4 weeks of age. We also show that an infammatory response with increasing MCP-1 and KIM-1 levels precedes loss of renal function

SETD2 haploinsufficiency for microtubule methylation is an early driver of genomic instability in renal cell carcinoma

Loss of the short arm of chromosome 3 (3p) occurs early in >95% of clear cell renal cell carcinoma (ccRCC). Nearly ubiquitous 3p loss in ccRCC suggests haploinsufficiency for 3p tumor suppressors as early drivers of tumorigenesis. We previously reported methyltransferase SETD2, which trimethylates H3 histones on lysine 36 (H3K36me3) and is located in the 3p deletion, to also trimethylate microtubules on lysine 40 (aTubK40me3) during mitosis, with aTubK40me3 required for genomic stability. We now show that monoallelic, Setd2-deficient cells retaining H3K36me3, but not aTubK40me3, exhibit a dramatic increase in mitotic defects and micronuclei count, with increased viability compared with biallelic loss. In SETD2-inactivated human kidney cells, rescue with a pathogenic SETD2 mutant deficient for microtubule (aTubK40me3), but not histone (H3K36me3) methylation, replicated this phenotype. Genomic instability (micronuclei) was also a hallmark of patient-derived cells from ccRCC. These data show that the SETD2 tumor suppressor displays a haploinsufficiency phenotype disproportionately impacting microtubule methylation and serves as an early driver of genomic instability. Significance: Loss of a single allele of a chromatin modifier plays a role in promoting oncogenesis, underscoring the growing relevance of tumor suppressor haploinsufficiency in tumorigenesis

Extension of Earth-Moon libration point orbits with solar sail propulsion

This paper presents families of libration point orbits in the Earth-Moon system that originate from complementing the classical circular restricted three-body problem with a solar sail. Through the use of a differential correction scheme in combination with a continuation on the solar sail induced acceleration, families of Lyapunov, halo, vertical Lyapunov, Earth-centred, and distant retrograde orbits are created. As the solar sail circular restricted three-body problem is non-autonomous, a constraint defined within the differential correction scheme ensures that all orbits are periodic with the Sun’s motion around the Earth-Moon system. The continuation method then starts from a classical libration point orbit with a suitable period and increases the solar sail acceleration magnitude to obtain families of orbits that are parametrised by this acceleration. Furthermore, different solar sail steering laws are considered (both in-plane and out-of-plane, and either fixed in the synodic frame or fixed with respect to the direction of sunlight), adding to the wealth of families of solar sail enabled libration point orbits presented. Finally, the linear stability properties of the generated orbits are investigated to assess the need for active orbital control. It is shown that the solar sail induced acceleration can have a positive effect on the stability of some orbit families, especially those at the L2 point, but that it most often (further) destabilises the orbit. Active control will therefore be needed to ensure long-term survivability of these orbits

Context, Complexity and Contestation: Birmingham's Agreed Syllabuses for Religious Education since the 1970s

publication-status: AcceptedThis is an Author's Original Manuscript of an article whose final and definitive form, the Version of Record, has been published in the Journal of Beliefs and Values, September 2011. Available online at: http://www.tandfonline.com/ or DOI: 10.1080/13617672.2011.600823The present article offers an historical perspective on the 1975, 1995 and 2007 Birmingham Agreed Syllabuses for Religious Education. It draws upon historical evidence uncovered as part of ‘The hidden history of curriculum change in religious education in English schools, 1969–1979’ project, and curriculum history theories, especially David Labaree’s observations about the distance between the ‘rhetorical’ and ‘received’ curricula. We argue that, contrary to the existing historiography, curriculum change in religious education (RE) has been evolutionary not revolutionary. Multiple reasons are posited to explain this, not least among which is the capacity and agency of teachers. Furthermore, we argue that ongoing debates about the nature and purpose of RE, as exemplified in the Birmingham context, reflect the multiple expectations that religious educators and other stakeholders had, and continue to have, of the curriculum subject. These debates contribute to the inertia evident in the implementation of RE curriculum reforms. A consciousness of the history of RE enables curriculum contestations to be contextualised and understood, and, thereby, provides important insights which can be applied to ongoing and future debates and developments

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types

Observation of a new chi_b state in radiative transitions to Upsilon(1S) and Upsilon(2S) at ATLAS

The chi_b(nP) quarkonium states are produced in proton-proton collisions at the Large Hadron Collider (LHC) at sqrt(s) = 7 TeV and recorded by the ATLAS detector. Using a data sample corresponding to an integrated luminosity of 4.4 fb^-1, these states are reconstructed through their radiative decays to Upsilon(1S,2S) with Upsilon->mu+mu-. In addition to the mass peaks corresponding to the decay modes chi_b(1P,2P)->Upsilon(1S)gamma, a new structure centered at a mass of 10.530+/-0.005 (stat.)+/-0.009 (syst.) GeV is also observed, in both the Upsilon(1S)gamma and Upsilon(2S)gamma decay modes. This is interpreted as the chi_b(3P) system.Comment: 5 pages plus author list (18 pages total), 2 figures, 1 table, corrected author list, matches final version in Physical Review Letter

Search for displaced vertices arising from decays of new heavy particles in 7 TeV pp collisions at ATLAS

We present the results of a search for new, heavy particles that decay at a significant distance from their production point into a final state containing charged hadrons in association with a high-momentum muon. The search is conducted in a pp-collision data sample with a center-of-mass energy of 7 TeV and an integrated luminosity of 33 pb^-1 collected in 2010 by the ATLAS detector operating at the Large Hadron Collider. Production of such particles is expected in various scenarios of physics beyond the standard model. We observe no signal and place limits on the production cross-section of supersymmetric particles in an R-parity-violating scenario as a function of the neutralino lifetime. Limits are presented for different squark and neutralino masses, enabling extension of the limits to a variety of other models.Comment: 8 pages plus author list (20 pages total), 8 figures, 1 table, final version to appear in Physics Letters

Reducing heterotic M-theory to five dimensional supergravity on a manifold with boundary

This paper constructs the reduction of heterotic $M$-theory in eleven dimensions to a supergravity model on a manifold with boundary in five dimensions using a Calabi-Yau three-fold. New results are presented for the boundary terms in the action and for the boundary conditions on the bulk fields. Some general features of dualisation on a manifold with boundary are used to explain the origin of some topological terms in the action. The effect of gaugino condensation on the fermion boundary conditions leads to a `twist' in the chirality of the gravitino which can provide an uplifting mechanism in the vacuum energy to cancel the cosmological constant after moduli stabilisation.Comment: 16 pages, RevTe

Search for direct production of charginos and neutralinos in events with three leptons and missing transverse momentum in √s = 7 TeV pp collisions with the ATLAS detector

A search for the direct production of charginos and neutralinos in final states with three electrons or muons and missing transverse momentum is presented. The analysis is based on 4.7 fb−1 of proton–proton collision data delivered by the Large Hadron Collider and recorded with the ATLAS detector. Observations are consistent with Standard Model expectations in three signal regions that are either depleted or enriched in Z-boson decays. Upper limits at 95% confidence level are set in R-parity conserving phenomenological minimal supersymmetric models and in simplified models, significantly extending previous results

Measurement of the inclusive isolated prompt photon cross-section in pp collisions at sqrt(s)= 7 TeV using 35 pb-1 of ATLAS data

A measurement of the differential cross-section for the inclusive production of isolated prompt photons in pp collisions at a center-of-mass energy sqrt(s) = 7 TeV is presented. The measurement covers the pseudorapidity ranges |eta|<1.37 and 1.52<=|eta|<2.37 in the transverse energy range 45<=E_T<400GeV. The results are based on an integrated luminosity of 35 pb-1, collected with the ATLAS detector at the LHC. The yields of the signal photons are measured using a data-driven technique, based on the observed distribution of the hadronic energy in a narrow cone around the photon candidate and the photon selection criteria. The results are compared with next-to-leading order perturbative QCD calculations and found to be in good agreement over four orders of magnitude in cross-section.Comment: 7 pages plus author list (18 pages total), 2 figures, 4 tables, final version published in Physics Letters