Base Excision Repair Of Dna In Human Cells: The Apurinic/apyrimidinic Intermediate

Base excision repair of DNA and factors that affect DNA incision in human cells were considered in this study.;Treatment of alkylated HeLa cells with 3-aminobenzamide, and inhibitor of poly(ADP-ribose) polymerase, increased the number of DNA strand breaks but did not slow down their rejoining by DNA repair. Therefore, an increase in DNA incision, not a decrease in ligation, results from the inhibition of poly(ADP-ribose) polymerase in alkylated cells. This is consistent with recent findings by others that suggest that repair-patch frequency is increased in alkylated cells when polyADP-ribosylation is inhibited.;Apurinic/apyrimidinic (AP) sites were measured in HeLa cells by digestion of cellular DNA with Escherichia coli endonuclease IV, an AP-specific endonuclease, prior to alkaline elution. The absence of non-specific endonuclease activity allowed endonuclease IV-sensitive AP sites to be detected with the sensitivity of conventional alkaline elution. Cells that were alkylated with dimethylsulfate, but not benzo(a)pyrene diol epoxide, contained AP sites that were repaired along with DNA single-strand breaks during a post-alkylation recovery period. In addition, alkali-labile sites (that become single-strand breaks in the presence of alkali) other than AP sites were resolved in dimethylsulfate-treated cells by comparing the rate of elution of endonuclease IV-digested DNA at pH 12.1 and pH 12.6. Alkali-labile sites were also observed in benzo(a)pyrene diol epoxide-treated cells. However, these alkali-labile sites were not sensitive to endonuclease IV, and hence are not AP sites.;According to the base excision repair model, the sequential action of DNA glycosylases and AP endonucleases is thought to initiate the repair of DNA base damage. This model was tested in {dollar}\gamma{dollar}-irradiated HeLa cells by endonuclease IV-coupled alkaline elution. AP sites were detected as a transient DNA repair intermediate in {dollar}\gamma{dollar}-irradiated cells. This approach illuminated the operation of base excision repair in human cells by demonstrating the transit of ionizing radiation-induced base lesions, most of which are unknown, through this pathway

The relationship between Central Nervous System morphometry changes and key symptoms in Crohn’s disease

Alterations in grey matter volume (GMV) and cortical thickness (CT) in Crohn’s disease (CD) patients has been previously documented. However, the findings are inconsistent, and not a true representation of CD burden, as only CD patients in remission have been studied thus far. We investigate alterations in brain morphometry in patients with active CD and those in remission, and study relationships between brain structure and key symptoms of fatigue, abdominal pain, and extraintestinal manifestations (EIM).Magnetic Resonance Imaging brain scans were collected in 89 participants; 34 CD participants with active disease, 13 CD participants in remission and 42 healthy controls (HCs); Voxel based morphometry (VBM) assessed GMV and white matter volume (WMV), and surface-based analysis assessed cortical thickness (CT).We show a significant reduction in global cerebrospinal fluid (CSF) volume in CD participants compared with HCs, as well as, a reduction in regional GMV, WMV and CT in the left precentral gyrus (motor cortex), and an increase in GMV in the frontal brain regions in CD compared with HCs. Atrophy of the supplementary motor area (SMA) was associated with greater fatigue in CD. We also show alterations in brain structure in multiple regions in CD associated with abdominal pain and extraintestinal inflammations (EIMs).These brain structural alterations likely reflect neuroplasticity to a chronic systemic inflammatory response, abdominal pain, EIMs and fatigue. These findings will aid our understanding of the cross-linking between chronic inflammation, brain structural changes and key unexplained CD symptomatology like fatigue

Collision, Collusion and Coincidence: Pop Art’s Fairground Parallel

This article looks at parallel methods, motivations and modes of consumption between formative British pop art and British fairground art. I focus on two strands, the emergent critical work of the Independent Group and the school of artists based at the Royal College of Art under the nominal leadership of Peter Blake. I use iconographical and iconological methods to compare the content of the art, and then examine how pop art tried to create both a critical and playful distancing from established rules and practices of the artistic canon. I focus on non-institutional cultural groupings and diffuse production and consumption models

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

The Artist in the Library

Through the course of this paper I seek to intertwine a story of my own creative relationship with libraries with accounts of artists’ work, including the work of my students. My goal is to articulate the ways in which artists work with, in, and on libraries and in doing this to define features of a library aesthetic. It is impossible, writing in London in 2016, to ignore the dire context for UK public libraries. Reductions in local government funding have resulted in widespread disregard by local authorities to their responsibilities under the 1964 Public Libraries and Museums Act – their statutory duty to provide a ‘comprehensive and efficient library service for all persons to make use thereof’. (Culture, Media and Sport Committee 2012, online) Cuts to library services continue apace [{note}]1. Writers, poets, artists and authors add their pleas to the protests against closures [{note}]2, but go largely unheeded. The idea of defining a library aesthetic might seem futile in the face of this austerity drive, but through my analysis of such an aesthetic, I hope to explore the potential of artworks to highlight and extend our understanding of its possibilities

Atmospheric conditions during the Arctic Clouds in Summer Experiment (ACSE): Contrasting open-water and sea-ice surfaces during melt and freeze-up seasons

The Arctic Clouds in Summer Experiment (ACSE) was conducted during summer and early autumn 2014, providing a detailed view of the seasonal transition from ice melt into freeze-up. Measurements were taken over both ice-free and ice-covered surfaces near the ice edge, offering insight into the role of the surface state in shaping the atmospheric conditions. The initiation of the autumn freeze-up was related to a change in air mass, rather than to changes in solar radiation alone; the lower atmosphere cooled abruptly, leading to a surface heat loss. During melt season, strong surface inversions persisted over the ice, while elevated inversions were more frequent over open water. These differences disappeared during autumn freeze-up, when elevated inversions persisted over both ice-free and ice-covered conditions. These results are in contrast to previous studies that found a well-mixed boundary layer persisting in summer and an increased frequency of surface-based inversions in autumn, suggesting that knowledge derived from measurements taken within the pan-Arctic area and on the central ice pack does not necessarily apply closer to the ice edge. This study offers an insight into the atmospheric processes that occur during a crucial period of the year; understanding and accurately modeling these processes is essential for the improvement of ice-extent predictions and future Arctic climate projections

Genome-wide Association Analysis Identifies 14 New Risk Loci for Schizophrenia

Schizophrenia is a heritable disorder with substantial public health impact. We conducted a multi-stage genome-wide association study (GWAS) for schizophrenia beginning with a Swedish national sample (5,001 cases, 6,243 controls) followed by meta-analysis with prior schizophrenia GWAS (8,832 cases, 12,067 controls) and finally by replication of SNPs in 168 genomic regions in independent samples (7,413 cases, 19,762 controls, and 581 trios). In total, 22 regions met genome-wide significance (14 novel and one previously implicated in bipolar disorder). The results strongly implicate calcium signaling in the etiology of schizophrenia, and include genome-wide significant results for CACNA1C and CACNB2 whose protein products interact. We estimate that ∼8,300 independent and predominantly common SNPs contribute to risk for schizophrenia and that these collectively account for most of its heritability. Common genetic variation plays an important role in the etiology of schizophrenia, and larger studies will allow more detailed understanding of this devastating disorder