Clustering of Epigenetic Methylation and Oxidative Damage: Effects on Duplex DNA Solution Structure, Thermodynamic Stability and Local Dynamics

All known living organisms use DNA to store genetic templates used for development, proper function and reproduction. The structural integrity of DNA is therefore of extreme importance and cellular machinery continuously regulates our DNA either through addition of covalent molecules to regulate the transcription of genes or the removal of DNA lesions propagating from the exposure to reactive molecules. One of the most common DNA lesions, 8-oxoguanine (8OG), is a prominent, pro-mutagenic DNA adduct present at a baseline level from consistent generation of reactive oxygen species through oxidative metabolism or at greater concentrations through exposure to ionizing radiation and other toxins. Its mutagenic potential is attributed to its ability in the syn- conformation, to mimic thymine during DNA replication, resulting in a mispair with adenine. In contrast, 5-methylcytosine (5MC), occurs from the covalent addition of a methyl group to a cytosine base by a DNA methyltransferase. 5MC acts as an epigenetic gene regulator, often found densely packed within CpG islands upstream of transcriptionally inactive genes. It can be estimated that each human diploid cell contains hundreds of CpG dinucleotides undergoing active methylation while also harboring 8OG. Previous results obtained by Kasymov et al, showed reduced endonuclease activity by hOGG1 for substrates containing 5MC adjacent and cross strand from 8OG. In addition, the work presented by Maltseva et al, conveyed that the enzymatic methylation rates by maintenance DNA methyltransferases were severely impacted when 8OG is adjacent to the methylation target. These results prompted us to investigate the clustering of these two modifications in greater detail. We present the results of solution NMR structure determination, thermodynamic stability analysis and molecular dynamics simulations on the DNA sequence 5’-d(CGCGAATTCGCG)-3’ with clustered 5MC and 8OG in CpG dinucleotides. NMR spectroscopy and restrained molecular dynamics were used to refine the structure of 11 DNA duplexes containing different methylation and oxidation patterns. The results reveal that 8OG induces local unwinding 5’ to itself and 31P chemical shifts indicate an increase in the BII phosphate backbone conformation 3’ relative to 8OG. Melting temperatures of the duplexes was shown to decrease with the addition of 8OG in all contexts. Surprisingly, the addition of 5MC in two separate instances led to lower Tm values of already oxidized DNA samples. 1D-1H NMR linewidths indicate 8OG increases the base dynamics while incorporation of 5MC leads to a stabilizing effect. Our results indicate that addition of 8OG to a fully-methylated CpG induces a sequence dependent stabilizing effect. Molecular dynamics trajectories were analyzed for BI/BII phosphate conformation populations, conformational flexibility and local dynamics. Comparison of helical geometries and backbone angles indicated that our MD simulations accurately and reliably reproduced our NMR structures within one standard deviation. Principal component analysis was carried out to highlight the most dominant modes of motion for CpG sites with clustered 5MC and 8OG. Particularly, we report significant differences in concerted atomic displacements, with the 8OG:5MC base pair displaying the greatest dynamic effects

A framework for deriving semantic web services

Web service-based development represents an emerging approach for the development of distributed information systems. Web services have been mainly applied by software practitioners as a means to modularize system functionality that can be offered across a network (e.g., intranet and/or the Internet). Although web services have been predominantly developed as a technical solution for integrating software systems, there is a more business-oriented aspect that developers and enterprises need to deal with in order to benefit from the full potential of web services in an electronic market. This ‘ignored’ aspect is the representation of the semantics underlying the services themselves as well as the ‘things’ that the services manage. Currently languages like the Web Services Description Language (WSDL) provide the syntactic means to describe web services, but lack in providing a semantic underpinning. In order to harvest all the benefits of web services technology, a framework has been developed for deriving business semantics from syntactic descriptions of web services. The benefits of such a framework are two-fold. Firstly, the framework provides a way to gradually construct domain ontologies from previously defined technical services. Secondly, the framework enables the migration of syntactically defined web services toward semantic web services. The study follows a design research approach which (1) identifies the problem area and its relevance from an industrial case study and previous research, (2) develops the framework as a design artifact and (3) evaluates the application of the framework through a relevant scenario

The Fermi GBM Gamma-Ray Burst Spectral Catalog: Four Years Of Data

In this catalog we present the updated set of spectral analyses of GRBs detected by the Fermi Gamma-Ray Burst Monitor (GBM) during its first four years of operation. It contains two types of spectra, time-integrated spectral fits and spectral fits at the brightest time bin, from 943 triggered GRBs. Four different spectral models were fitted to the data, resulting in a compendium of more than 7500 spectra. The analysis was performed similarly, but not identically to Goldstein et al. 2012. All 487 GRBs from the first two years have been re-fitted using the same methodology as that of the 456 GRBs in years three and four. We describe, in detail, our procedure and criteria for the analysis, and present the results in the form of parameter distributions both for the observer-frame and rest-frame quantities. The data files containing the complete results are available from the High-Energy Astrophysics Science Archive Research Center (HEASARC).Comment: Accepted for publication in ApJ

Scientific Futures for a Rhetoric of Science: "We do this and they do that?" A Junior-Senior Scholar Session, RSA 2018, Minneapolis, Minnesota, USA; 1 June 2018

Growing attention to a rift between epistemology and ontology, between words and things, sets new challenges and invigorations for a Rhetoric of Science that traditionally aims to “analyze and evaluate the persuasive communications of scientists” (Ceccarelli, 2017, para 6). Rhetoricians confront a vibrant, new intellectual space where scholars across disciplines are seeking to better account for bodies and moving to “include the materiality of our ambient environs” in their analyses (Rickert, 2013, p. x). The question, in light of material expansions, is what is a Rhetoric of Science, and what are its futures? In response to the Rhetoric Society of America’s 2018 conference call for junior and senior scholars to discuss “major developments in rhetorical studies,” we offer a Feyerabendian innovation-meets-dogma performative session: the junior scholar, representing innovation, argues that Rhetoric of Science must move aggressively beyond a study of texts and scientific language to account for continuous technological, social, and biological entanglements; specifically, to expand the field’s practices to include neuro-cognitive approaches and other forms of experiment. The senior scholar, representing dogma, expresses caution, arguing that the domain of a Rhetoric of Science is still symbols and semiosis; specifically, that looking at “ambient rhetorics” and “entanglements” is another approach, not a foundational shift

Variable X-ray Absorption in the Seyfert 2 Galaxy Mrk 348

We present RXTE monitoring observations of the Seyfert 2 galaxy Mrk 348 spanning a 6 month period. The time-averaged spectrum in the 3-20 keV band shows many features characteristic of a Compton-thin Seyfert 2 galaxy, namely a hard underlying power-law continuum (photon index = 1.8) with heavy soft X-ray absorption (N_h ~ 10^23 cm^-2) plus measureable iron line emission (equivalent width ~ 100 eV) and, at high energy, evidence for a reflection component (R < 1). During the first half of the monitoring period the X-ray continuum flux from Mrk 348 remained relatively steady. However this was followed by a significant brightening of the source (by roughly a factor of 4) with the fastest change corresponding to a doubling of its X-ray flux on a timescale of about 20 days. The flux increase was accompanied by a marked softening of X-ray spectrum most likely attributable to a factor 3 decline in the intrinsic line-of-sight column density. In contrast the iron line and the reflection components showed no evidence of variability. These observations suggest a scenario in which the central X-ray source is surrounded by a patchy distribution of absorbing material located within about a light-week of the nucleus of Mrk 348. The random movement of individual clouds within the absorbing screen, across our line of sight, produces substantial temporal variations in the measured column density on timescales of weeks to months and gives rise to the observed X-ray spectral variability. However, as viewed from the nucleus the global coverage and typical thickness of the cloud layer remains relatively constant.Comment: 19 pages, 3 figures Accepted for publication in the Astrophysical Journa

Case acquisition from text: ontology-based information extraction with SCOOBIE for myCBR

myCBR is a freely available tool for rapid prototyping of similarity-based retrieval applications such as case-based product recommender systems. It provides easy-to-use model generation, data import, similarity modelling, explanation, and testing functionality together with comfortable graphical user interfaces. SCOOBIE is an ontology-based information extraction system, which uses symbolic background knowledge for extracting information from text. Extraction results depend on existing knowledge fragments. In this paper we show how to use SCOOBIE for generating cases from texts. More concrete we use ontologies of the Web of Data, published as so called Linked Data interlinked with myCBR’s case model. We present a way of formalising a case model as Linked Data ready ontology and connect it with other ontologies of the Web of Data in order to get richer cases

The fundamental cycle of concept construction underlying various theoretical frameworks

In this paper, the development of mathematical concepts over time is considered. Particular reference is given to the shifting of attention from step-by-step procedures that are performed in time, to symbolism that can be manipulated as mental entities on paper and in the mind. The development is analysed using different theoretical perspectives, including the SOLO model and various theories of concept construction to reveal a fundamental cycle underlying the building of concepts that features widely in different ways of thinking that occurs throughout mathematical learning

First-year Results of Broadband Spectroscopy of the Brightest Fermi-GBM Gamma-Ray Bursts

We present here our results of the temporal and spectral analysis of a sample of 52 bright and hard gamma-ray bursts (GRBs) observed with the Fermi Gamma-ray Burst Monitor (GBM) during its first year of operation (July 2008-July 2009). Our sample was selected from a total of 253 GBM GRBs based on each event peak count rate measured between 0.2 and 40MeV. The final sample comprised 34 long and 18 short GRBs. These numbers show that the GBM sample contains a much larger fraction of short GRBs, than the CGRO/BATSE data set, which we explain as the result of our (different) selection criteria and the improved GBM trigger algorithms, which favor collection of short, bright GRBs over BATSE. A first by-product of our selection methodology is the determination of a detection threshold from the GBM data alone, above which GRBs most likely will be detected in the MeV/GeV range with the Large Area Telescope (LAT) onboard Fermi. This predictor will be very useful for future multiwavelength GRB follow ups with ground and space based observatories. Further we have estimated the burst durations up to 10MeV and for the first time expanded the duration-energy relationship in the GRB light curves to high energies. We confirm that GRB durations decline with energy as a power law with index approximately -0.4, as was found earlier with the BATSE data and we also notice evidence of a possible cutoff or break at higher energies. Finally, we performed time-integrated spectral analysis of all 52 bursts and compared their spectral parameters with those obtained with the larger data sample of the BATSE data. We find that the two parameter data sets are similar and confirm that short GRBs are in general harder than longer ones.Comment: 40 pages, 11 figures, 3 tables, Submitted to Ap

The (Digital) Majesty of All Under Heaven: Affective Constitutive Rhetoric at the Hong Kong Museum of History's Multi-Media Exhibition of Terracotta Warriors

During a series of protests in Hong Kong about a leadership transition widely perceived to give Mainland China greater political influence, the Hong Kong Museum of History held a Special Exhibition of the Terracotta Warriors of Xian, China. Sponsored by "The Leisure and Cultural Service Department, " the exhibit featured the first emperor of the Qin Dynasty who ushered in "an epoch-making era in Chinese history that witnessed the unification of China" (Museum Exhibition). This essay explores the multi-media aspects of the exhibit, arguing that encounters with dramatic music and fully immersive digital experiences are examples of an embodied, affective form of constitutive rhetoric. Put differently, the museum's multi-media elements demonstrate how Maurice Charland's theory of a constitutive rhetoric can be informed by recent work on affect and can provide one point from which to engage affect theory and the "affective dimension of politics.