Genomic catastrophes frequently arise in esophageal adenocarcinoma and drive tumorigenesis

Oesophageal adenocarcinoma (EAC) incidence is rapidly increasing in Western countries. A better understanding of EAC underpins efforts to improve early detection and treatment outcomes. While large EAC exome sequencing efforts to date have found recurrent loss-offunction mutations, oncogenic driving events have been underrepresented. Here we use a combination of whole-genome sequencing (WGS) and single-nucleotide polymorphism-array profiling to show that genomic catastrophes are frequent in EAC, with almost a third (32%, n¼40/123) undergoing chromothriptic events. WGS of 22 EAC cases show that catastrophes may lead to oncogene amplification through chromothripsis-derived double-minute chromosome formation (MYC and MDM2) or breakage-fusion-bridge (KRAS, MDM2 and RFC3). Telomere shortening is more prominent in EACs bearing localized complex rearrangements. Mutational signature analysis also confirms that extreme genomic instability in EAC can be driven by somatic BRCA2 mutations. These findings suggest that genomic catastrophes have a significant role in the malignant transformation of EAC

Bristol Deaf Memories: archives, nostalgia and the loss of community space in the deaf community in Bristol

This is the author accepted manuscript. The final version is available from Taylor & Francis via the DOI in this record.The deaf community in the UK has undergone major changes in recent years, which has uprooted it from its traditional foundations, the deaf club and deaf residential school. This article examines the effect of the closure of the deaf club in Bristol, a city in the South West of England, which resulted in the loss of an important community place and spaces for deaf people in the city. We discuss, with a strong focus on methodology, a community event celebrating Bristol’s deaf heritage organised by the research team which utilised archive materials, including archived actuality footage, this article draws on interview data elicited from participants in that event to explore the meanings connected to space and place in both past and present by the deaf community in Bristol. Concepts of the rhizome and the smooth and striated spaces of Deleuze and Guattari were found to be useful models with which to engage with the contemporary struggles of the deaf community for community recognition and organisation. We also suggest an online mapping application which enables the practice of rhizomatic cartography could be a way forward in preserving the deaf heritage and history of the city.This research was funded by the Arts and Humanities Research Council, grant number AH/M009203/

Amine functionalization of cholecyst-derived extracellular matrix with generation 1 PAMAM dendrimer

This document is the unedited author's version of a Submitted Work that was subsequently accepted for publication in Biomacromolecules, copyright © American Chemical Society after peer review. To access the final edited and published work, see http://pubs.acs.org/doi/pdf/10.1021/bm701055k.A method to functionalize cholecyst-derived extracellular matrix (CEM) with free amine groups was established in an attempt to improve its potential for tethering of bioactive molecules. CEM was incorporated with Generation-1 polyamidoamine (G1 PAMAM) dendrimer by using N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide and N-hydroxysuccinimide cross-linking system. The nature of incorporation of PAMAM dendrimer was evaluated using shrink temperature measurements, Fourier transform infrared (FTIR) assessment, ninhydrin assay, and swellability. The effects of PAMAM incorporation on mechanical and degradation properties of CEM were evaluated using a uniaxial mechanical test and collagenase degradation assay, respectively. Ninhydrin assay and FTIR assessment confirmed the presence of increasing free amine groups with increasing quantity of PAMAM in dendrimer-incorporated CEM (DENCEM) scaffolds. The amount of dendrimer used was found to be critical in controlling scaffold degradation, shrink temperature, and free amine content. Cell culture studies showed that fibroblasts seeded on DENCEM maintained their metabolic activity and ability to proliferate in vitro. In addition, fluorescence cell staining and scanning electron microscopy analysis of cell-seeded DENCEM showed preservation of normal fibroblast morphology and phenotype

Robust, gapped, flat bands at half-filling in the minimal model of the superconducting metal-organic framework, Cu-BHT

The superconducting metal-organic framework Cu-BHT forms a kagome lattice with metals at the vertices and ligands along the bonds. We show that a tight-binding model with metal and ligand sites on this lattice yields five flat topological bands (FTBs), three of which are partially occupied at half-filling, with large gaps between them and all other bands. Long-range hopping induces curvature in the FTBs but leaves them flatter and more isolated than those in twisted bilayer graphene. Thus, framework materials are ideal materials for exploring flat band physics at high electronic densities.Comment: 5 pages, 3 figure

Dual targeting of p53 and c-MYC selectively eliminates leukaemic stem cells

e Glasgow and Manchester Experimental Cancer Medicine Centres (ECMC), which are funded by CR-UK and the Chief Scientist’s Office (Scotland). We acknowledge the funders who have contributed to this work: MRC stratified medicine infrastructure award (A.D.W.), CR-UK C11074/A11008 (F.P., L.E.M.H., T.L.H., A.D.W.); LLR08071 (S.A.A., E.C.); LLR11017 (M.C.); SCD/04 (M.C.); LLR13035 (S.A.A., K.D., A.D.W., and A.P.); LLR14005 (M.T.S., D.V.); KKL690 (L.E.P.); KKL698 (P.B.); LLR08004 (A.D.W., A.P. and A.J.W.); MRC CiC (M.E.D.); The Howat Foundation (FACS support); Friends of Paul O’Gorman (K.D. and FACS support); ELF 67954 (S.A.A.); BSH start up fund (S.A.A.); MR/K014854/1 (K.D.)

A Multilaboratory Comparison of Calibration Accuracy and the Performance of External References in Analytical Ultracentrifugation

Analytical ultracentrifugation (AUC) is a first principles based method to determine absolute sedimentation coefficients and buoyant molar masses of macromolecules and their complexes, reporting on their size and shape in free solution. The purpose of this multi-laboratory study was to establish the precision and accuracy of basic data dimensions in AUC and validate previously proposed calibration techniques. Three kits of AUC cell assemblies containing radial and temperature calibration tools and a bovine serum albumin (BSA) reference sample were shared among 67 laboratories, generating 129 comprehensive data sets. These allowed for an assessment of many parameters of instrument performance, including accuracy of the reported scan time after the start of centrifugation, the accuracy of the temperature calibration, and the accuracy of the radial magnification. The range of sedimentation coefficients obtained for BSA monomer in different instruments and using different optical systems was from 3.655 S to 4.949 S, with a mean and standard deviation of (4.304 ± 0.188) S (4.4%). After the combined application of correction factors derived from the external calibration references for elapsed time, scan velocity, temperature, and radial magnification, the range of s-values was reduced 7-fold with a mean of 4.325 S and a 6-fold reduced standard deviation of ± 0.030 S (0.7%). In addition, the large data set provided an opportunity to determine the instrument-to-instrument variation of the absolute radial positions reported in the scan files, the precision of photometric or refractometric signal magnitudes, and the precision of the calculated apparent molar mass of BSA monomer and the fraction of BSA dimers. These results highlight the necessity and effectiveness of independent calibration of basic AUC data dimensions for reliable quantitative studies

Gate control of Mott metal-insulator transition in a 2D metal-organic framework

Strong electron-electron Coulomb interactions in materials can lead to a vast range of exotic many-body quantum phenomena, including Mott metal-insulator transitions, magnetic order, quantum spin liquids, and unconventional superconductivity. These many-body phases are strongly dependent on band occupation and can hence be controlled via the chemical potential. Flat electronic bands in two-dimensional (2D) and layered materials such as the kagome lattice, enhance strong electronic correlations. Although theoretically predicted, correlated-electron phases in monolayer 2D metal-organic frameworks (MOFs) - which benefit from efficient synthesis protocols and tunable properties - with a kagome structure have not yet been realised experimentally. Here, we synthesise a 2D kagome MOF comprised of 9,10-dicyanoanthracene molecules and copper atoms on an atomically thin insulator, monolayer hexagonal boron nitride (hBN) on Cu(111). Scanning tunnelling microscopy (STM) and spectroscopy reveal an electronic energy gap of ~200 meV in this MOF, consistent with dynamical mean-field theory predictions of a Mott insulating phase. By tuning the electron population of kagome bands, via either template-induced (via local work function variations of the hBN/Cu(111) substrate) or tip-induced (via the STM probe) gating, we are able to induce Mott metal-insulator transitions in the MOF. These findings pave the way for devices and technologies based on 2D MOFs and on electrostatic control of many-body quantum phases therein.Comment: 19 pages, 4 figure

Membrane Biophysics Define Neuron and Astrocyte Progenitors in the Neural Lineage

Neural stem and progenitor cells (NSPCs) are heterogeneous populations of self-renewing stem cells and more committed progenitors that differentiate into neurons, astrocytes, and oligodendrocytes. Accurately identifying and characterizing the different progenitor cells in this lineage has continued to be a challenge for the field. We found previously that populations of NSPCs with more neurogenic progenitors (NPs) can be distinguished from those with more astrogenic progenitors (APs) by their inherent biophysical properties, specifically the electrophysiological property of whole cell membrane capacitance, which we characterized with dielectrophoresis (DEP). Here, we hypothesize that inherent electrophysiological properties are sufficient to define NPs and APs and test this by determining whether isolation of cells solely by these properties specifically separates NPs and APs. We found NPs and APs are enriched in distinct fractions after separation by electrophysiological properties using DEP. A single round of DEP isolation provided greater NP enrichment than sorting with PSA-NCAM, which is considered an NP marker. Additionally, cell surface N-linked glycosylation was found to significantly affect cell fate-specific electrophysiological properties, providing a molecular basis for the cell membrane characteristics. Inherent plasma membrane biophysical properties are thus sufficient to define progenitor cells of differing fate potential in the neural lineage, can be used to specifically isolate these cells, and are linked to patterns of glycosylation on the cell surface. STEM CELLS 2014;32:706–71