Associative and Spatial Relationships in Thesaurus-based Retrieval

The OASIS (Ontologically Augmented Spatial Information System) project explores terminology systems for thematic and spatial access in digital library applications. A prototype implementation uses data from the Royal Commission on the Ancient and Historical Monuments of Scotland, together with the Getty AAT and TGN thesauri. This paper describes its integrated spatial and thematic schema and discusses novel approaches to the application of thesauri in spatial and thematic semantic distance measures. Semantic distance measures can underpin interactive and automatic query expansion techniques by ranking lists of candidate terms. We first illustrate how hierarchical spatial relationships can be used to provide more flexible retrieval for queries incorporating place names in applications employing online gazetteers and geographical thesauri. We then employ a set of experimental scenarios to investigate key issues affecting use of the associative (RT) thesaurus relationships in semantic distance measures. Previous work has noted the potential of RTs in thesaurus search aids but the problem of increased noise in result sets has been emphasised. Specialising RTs allows the possibility of dynamically linking RT type to query context. Results presented in this paper demonstrate the potential for filtering on the context of the RT link and on subtypes of RT relationships

Population health and the economy: Mortality and the Great Recession in Europe

We analyze the evolution of mortality‐based health indicators in 27 European countries before and after the start of the Great Recession. We find that in the countries where the crisis has been particularly severe, mortality reductions in 2007–2010 were considerably bigger than in 2004–2007. Panel models adjusted for space‐invariant and time‐invariant factors show that an increase of 1 percentage point in the national unemployment rate is associated with a reduction of 0.5% (p < .001) in the rate of age‐adjusted mortality. The pattern of mortality oscillating procyclically is found for total and sex‐specific mortality, cause‐specific mortality due to major causes of death, and mortality for ages 30–44 and 75 and over, but not for ages 0–14. Suicides appear increasing when the economy decelerates—countercyclically—but the evidence is weak. Results are robust to using different weights in the regression, applying nonlinear methods for detrending, expanding the sample, and using as business cycle indicator gross domestic product per capita or employment‐to‐population ratios rather than the unemployment rate. We conclude that in the European experience of the past 20 years, recessions, on average, have beneficial short‐term effects on mortality of the adult population.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142224/1/hec3495_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142224/2/hec3495.pd

Do semantic standards lack quality? : a survey among 34 semantic standards

The adoption of standards to improve interoperability in the automotive, aerospace, shipbuilding and other sectors could save billions. While interoperability standards have been created for a number of industries, problems persist, suggesting a lack of quality of the standards themselves. The issue of semantic standard quality is not often addressed. In this research we take a closer look at the quality of semantics standards, development processes, and survey the current state of the quality of semantic standards by means of a questionnaire that was sent to standards developers. This survey looked at 34 semantic standards, and it shows that the quality of semantic standards for inter-organizational interoperability can be improved. Improved standards may advance interoperability in networked business. Improvement of semantic standards requires transparency of their quality. Although many semantic standard development organisations already have quality assurance in place, this research shows that they could benefit from a quality measuring instrument

MSH2/MSH6 Complex Promotes Error-Free Repair of AID-Induced dU:G Mispairs as well as Error-Prone Hypermutation of A:T Sites

Mismatch repair of AID-generated dU:G mispairs is critical for class switch recombination (CSR) and somatic hypermutation (SHM) in B cells. The generation of a previously unavailable Msh2−/−Msh6−/− mouse has for the first time allowed us to examine the impact of the complete loss of MutSα on lymphomagenesis, CSR and SHM. The onset of T cell lymphomas and the survival of Msh2−/−Msh6−/− and Msh2−/−Msh6−/−Msh3−/− mice are indistinguishable from Msh2−/− mice, suggesting that MSH2 plays the critical role in protecting T cells from malignant transformation, presumably because it is essential for the formation of stable MutSα heterodimers that maintain genomic stability. The similar defects on switching in Msh2−/−, Msh2−/−Msh6−/− and Msh2−/−Msh6−/−Msh3−/− mice confirm that MutSα but not MutSβ plays an important role in CSR. Analysis of SHM in Msh2−/−Msh6−/− mice not only confirmed the error-prone role of MutSα in the generation of strand biased mutations at A:T bases, but also revealed an error-free role of MutSα when repairing some of the dU:G mispairs generated by AID on both DNA strands. We propose a model for the role of MutSα at the immunoglobulin locus where the local balance of error-free and error-prone repair has an impact in the spectrum of mutations introduced during Phase 2 of SHM

Pharmacological levels of withaferin A (Withania somnifera) trigger clinically relevant anticancer effects specific to triple negative breast cancer cells

Withaferin A (WA) isolated from Withania somnifera (Ashwagandha) has recently become an attractive phytochemical under investigation in various preclinical studies for treatment of different cancer types. In the present study, a comparative pathway-based transcriptome analysis was applied in epithelial-like MCF-7 and triple negative mesenchymal MDA-MB-231 breast cancer cells exposed to different concentrations of WA which can be detected systemically in in vivo experiments. Whereas WA treatment demonstrated attenuation of multiple cancer hallmarks, the withanolide analogue Withanone (WN) did not exert any of the described effects at comparable concentrations. Pathway enrichment analysis revealed that WA targets specific cancer processes related to cell death, cell cycle and proliferation, which could be functionally validated by flow cytometry and real-time cell proliferation assays. WA also strongly decreased MDA-MB-231 invasion as determined by single-cell collagen invasion assay. This was further supported by decreased gene expression of extracellular matrix-degrading proteases (uPA, PLAT, ADAM8), cell adhesion molecules (integrins, laminins), pro-inflammatory mediators of the metastasis-promoting tumor microenvironment (TNFSF12, IL6, ANGPTL2, CSF1R) and concomitant increased expression of the validated breast cancer metastasis suppressor gene (BRMS1). In line with the transcriptional changes, nanomolar concentrations of WA significantly decreased protein levels and corresponding activity of uPA in MDA-MB-231 cell supernatant, further supporting its anti-metastatic properties. Finally, hierarchical clustering analysis of 84 chromatin writer-reader-eraser enzymes revealed that WA treatment of invasive mesenchymal MDA-MB-231 cells reprogrammed their transcription levels more similarly towards the pattern observed in non-invasive MCF-7 cells. In conclusion, taking into account that sub-cytotoxic concentrations of WA target multiple metastatic effectors in therapy-resistant triple negative breast cancer, WA-based therapeutic strategies targeting the uPA pathway hold promise for further (pre)clinical development to defeat aggressive metastatic breast cancer

TEAD and YAP regulate the enhancer network of human embryonic pancreatic progenitors.

The genomic regulatory programmes that underlie human organogenesis are poorly understood. Pancreas development, in particular, has pivotal implications for pancreatic regeneration, cancer and diabetes. We have now characterized the regulatory landscape of embryonic multipotent progenitor cells that give rise to all pancreatic epithelial lineages. Using human embryonic pancreas and embryonic-stem-cell-derived progenitors we identify stage-specific transcripts and associated enhancers, many of which are co-occupied by transcription factors that are essential for pancreas development. We further show that TEAD1, a Hippo signalling effector, is an integral component of the transcription factor combinatorial code of pancreatic progenitor enhancers. TEAD and its coactivator YAP activate key pancreatic signalling mediators and transcription factors, and regulate the expansion of pancreatic progenitors. This work therefore uncovers a central role for TEAD and YAP as signal-responsive regulators of multipotent pancreatic progenitors, and provides a resource for the study of embryonic development of the human pancreas

Anti-cancer effects and mechanism of actions of aspirin analogues in the treatment of glioma cancer

INTRODUCTION: In the past 25 years only modest advancements in glioma treatment have been made, with patient prognosis and median survival time following diagnosis only increasing from 3 to 7 months. A substantial body of clinical and preclinical evidence has suggested a role for aspirin in the treatment of cancer with multiple mechanisms of action proposed including COX 2 inhibition, down regulation of EGFR expression, and NF-κB signaling affecting Bcl-2 expression. However, with serious side effects such as stroke and gastrointestinal bleeding, aspirin analogues with improved potency and side effect profiles are being developed. METHOD: Effects on cell viability following 24 hr incubation of four aspirin derivatives (PN508, 517, 526 and 529) were compared to cisplatin, aspirin and di-aspirin in four glioma cell lines (U87 MG, SVG P12, GOS – 3, and 1321N1), using the PrestoBlue assay, establishing IC50 and examining the time course of drug effects. RESULTS: All compounds were found to decrease cell viability in a concentration and time dependant manner. Significantly, the analogue PN517 (IC50 2mM) showed approximately a twofold increase in potency when compared to aspirin (3.7mM) and cisplatin (4.3mM) in U87 cells, with similar increased potency in SVG P12 cells. Other analogues demonstrated similar potency to aspirin and cisplatin. CONCLUSION: These results support the further development and characterization of novel NSAID derivatives for the treatment of glioma

Modulation of enhancer looping and differential gene targeting by Epstein-Barr virus transcription factors directs cellular reprogramming

Epstein-Barr virus (EBV) epigenetically reprogrammes B-lymphocytes to drive immortalization and facilitate viral persistence. Host-cell transcription is perturbed principally through the actions of EBV EBNA 2, 3A, 3B and 3C, with cellular genes deregulated by specific combinations of these EBNAs through unknown mechanisms. Comparing human genome binding by these viral transcription factors, we discovered that 25% of binding sites were shared by EBNA 2 and the EBNA 3s and were located predominantly in enhancers. Moreover, 80% of potential EBNA 3A, 3B or 3C target genes were also targeted by EBNA 2, implicating extensive interplay between EBNA 2 and 3 proteins in cellular reprogramming. Investigating shared enhancer sites neighbouring two new targets (WEE1 and CTBP2) we discovered that EBNA 3 proteins repress transcription by modulating enhancer-promoter loop formation to establish repressive chromatin hubs or prevent assembly of active hubs. Re-ChIP analysis revealed that EBNA 2 and 3 proteins do not bind simultaneously at shared sites but compete for binding thereby modulating enhancer-promoter interactions. At an EBNA 3-only intergenic enhancer site between ADAM28 and ADAMDEC1 EBNA 3C was also able to independently direct epigenetic repression of both genes through enhancer-promoter looping. Significantly, studying shared or unique EBNA 3 binding sites at WEE1, CTBP2, ITGAL (LFA-1 alpha chain), BCL2L11 (Bim) and the ADAMs, we also discovered that different sets of EBNA 3 proteins bind regulatory elements in a gene and cell-type specific manner. Binding profiles correlated with the effects of individual EBNA 3 proteins on the expression of these genes, providing a molecular basis for the targeting of different sets of cellular genes by the EBNA 3s. Our results therefore highlight the influence of the genomic and cellular context in determining the specificity of gene deregulation by EBV and provide a paradigm for host-cell reprogramming through modulation of enhancer-promoter interactions by viral transcription factors

Seroprevalence of Toxoplasma gondii infection among veterinary staff in Ontario, Canada (2002): Implications for teratogenic risk

BACKGROUND: Toxoplasma gondii infection is embryotoxic in humans. It is mainly transmitted through raw/undercooked meat and ingestion of oocysts in cat feces. There remains controversy about the actual risk of cats transmitting the disease to humans. Our primary objective was to determine the seroprevalence of T. gondii antibody among veterinary staff, to ascertain whether they have an increased risk through occupational exposure. Our secondary objective was to examine their practices regarding cats, toxoplasma infection, and pregnancy. METHODS: Veterinary staff attending the 2002 Annual Ontario Veterinary Medical Association Conference were invited to discuss their toxoplasma seroprevalence. Interested attendees completed a questionnaire and a physician drew blood samples to determine T. gondii titres using the ELISA IgG test. RESULTS: We collected 161 completed questionnaires, and 141 blood samples. There were 20 (14.2%, CI95%:8.4–19.9%) reactive titres among the veterinarian staff (80% females aged 30–45). All were regularly exposed to cats, washed their hands when in contact and few wore gloves routinely. CONCLUSIONS: These findings of low positive rates may be used to reassure veterinary staff that their exposure to cats does not appear to increase their risk of contracting toxoplasma infection and that pregnant women are not at an increased risk by owning a cat