1,720,999 research outputs found
Machanick, Philip (Assoc Prof)
No full text Department of Computer Science (2011-present) Philip Machanick ORCID 0000-0001-6648-7032 </a
Algorithmic definitions for KLM-style defeasible disjunctive Datalog
Get PDFDatalog is a declarative logic programming language that uses classical logical reasoning as its basic form of reasoning. Defeasible reasoning is a form of non-classical reasoning that is able to deal with exceptions to general assertions in a formal manner. The KLM approach to defeasible reasoning is an axiomatic approach based on the concept of plausible inference. Since Datalog uses classical reasoning, it is currently not able to handle defeasible implications and exceptions. We aim to extend the expressivity of Datalog by incorporating KLM-style defeasible reasoning into classical Datalog. We present a systematic approach for extending the KLM properties and a well-known form of defeasible entailment: Rational Closure. We conclude by exploring Datalog extensions of less conservative forms of defeasible entailment: Relevant and Lexicographic Closure. We provide algorithmic definitions for these forms of defeasible entailment and prove that the definitions are LM-rational
Analysis of transcription factor binding specificity using ChIP-seq data.
Get PDFTranscription factors (TFs) are key regulators of gene expression whose failure has been implicated in many diseases, including cancer. They bind at various sites at different specificity depending on the prevailing cellular conditions, disease, development stage or environmental conditions of the cell. TF binding specificity is how well a TF distinguishes functional sites from potential non-functional sites to form a useful regulatory network. Owing to its role in diseases, various techniques have been used to determine TF binding specificity in vitro and in vivo, including chromatin immuno-precipitation followed by massively parallel sequencing (ChIP-seq). ChIP-seq is an in vivo technique that considers how the chromatin landscape affects TF binding. Motif enrichment analysis (MEA) tools are used to identify motifs that are over-represented in ChIP-seq peak regions. One such tool, CentriMo, finds over-represented motifs at the center since peak calling software are biased to declaring binding regions centered at the TF binding site. In this study, we investigate the use of CentriMo and other MEA tools to determine the difference in motif enrichment attributed presence of Chronic Myeloid leukemia (CML)), treatment with Interferon (IFN) and Dexamethasone (DEX) compared to control based on Fisher’s exact test; using uniform peaks ChIP-seq data generated by the ENCODE consortium. CentriMo proved to be capable. We observed differential motif enrichment of TFs with tumor promoter activity: YY1, CEBPA, Egr1, Cmyc family, Gata1 and JunD in K562 while Stat1, Irf1, and Runx1 in Gm12878. Enrichment of CTCF in Gm12878 with YY1 as the immuno-precipitated (ChIP-ed) factor and the presence of significant spacing (SpaMo analysis) of CTCF and YY1 in Gm12878 but not in K562 could show that CTCF, as a repressor, helps in maintaining the required YY1 level in a normal cell line. IFN might reduce Cmyc and the Jun family of TFs binding via the repressive action of CTCF and E2f2. We also show that the concentration of DEX treatment affects motif enrichment with 50nm being an optimum concentration for Gr binding by maintaining open chromatin via AP1 TF. This study has demonstrated the usefulness of CentriMo for TF binding specificity analysis
DDLV: A system for rational preferential reasoning for Datalog
Get PDFDatalog is a powerful language that can be used to represent explicit knowledge and compute inferences in knowledge bases. Datalog cannot, however, represent or reason about contradictory rules. This is a limitation as contradictions are often present in domains that contain exceptions. In this paper, we extend Datalog to repres- ent contradictory and defeasible information. We define an approach to efficiently reason about contradictory information in Datalog and show that it satisfies the KLM requirements for a rational consequence relation. We introduce DDLV, a defeasible Datalog reasoning system that implements this approach. Finally, we evaluate the performance of DDLV
Comparison of protein binding microarray derived and ChIP-seq derived transcription factor binding DNA motifs
Get PDFTranscription factors (TFs) are biologically important proteins that interact
with transcription machinery and bind DNA regulatory sequences to regulate
gene expression by modulating the synthesis of the messenger RNA. The
regulatory sequences comprise of short conserved regions of a specific length
called motifs . TFs have very diverse roles in different cells and play a very
significant role in development. TFs have been associated with carcinogenesis
in various tissue types, as well as developmental and hormone response
disorders. They may be responsible for the regulation of oncogenes and can be
oncogenic. Consequently, understanding TF binding and knowing the motifs to
which they bind is worthy of attention and research focus.
Various projects have made the study of TF binding their main focus;
nevertheless, much about TF binding remains confounding. Chromatin
immunoprecipitation in conjunction with deep sequencing (ChIP-seq) techniques are a popular method used to investigate DNA-TF interactions in
vivo. This procedure is followed by motif discovery and motif enrichment
analysis using relevant tools. Protein Binding Microarrays (PBMs) are an in
vitro method for investigating DNA-TF interactions. We use a motif enrichment
analysis tools (CentriMo and AME) and an empirical quality assessment tool
(Area under the ROC curve) to investigate which method yields motifs that are
a true representation of in vivo binding.
Motif enrichment analysis: On average, ChIP-seq derived motifs from the
JASPAR Core database outperformed PBM derived ones from the UniPROBE
mouse database. However, the performance of motifs derived using these two
methods is not much different from each other when using CentriMo and AME.
The E-values from Motif enrichment analysis were not too different from each
other or 0. CentriMo showed that in 35 cases JASPAR Core ChIP-seq derived
motifs outperformed UniPROBE mouse PBM derived motifs, while it was only
in 11 cases that PBM derived motifs outperformed ChIP-seq derived motifs.
AME showed that in 18 cases JASPAR Core ChIP-seq derived motifs did better,
while only it was only in 3 cases that UniPROBE motifs outperformed ChIP-seq
derived motifs. We could not distinguish the performance in 25 cases.
Empirical quality assessment: Area under the ROC curve values computations
followed by a two-sided t-test showed that there is no significant difference in
the average performances of the motifs from the two databases (with 95%
confidence, mean of differences=0.0088125 p-value= 0.4874, DF=47)
A central enrichment-based comparison of two alternative methods of generating transcription factor binding motifs from protein binding microarray data
Get PDFCharacterising transcription factor binding sites (TFBS) is an important problem in bioinformatics, since predicting binding sites has many applications such as predicting gene regulation. ChIP-seq is a powerful in vivo method for generating genome-wide putative binding regions for transcription factors (TFs). CentriMo is an algorithm that measures central enrichment of a motif and has previously been used as motif enrichment analysis (MEA) tool. CentriMo uses the fact that ChIP-seq peak calling methods are likely to be biased towards the centre of the putative binding region, at least in cases where there is direct binding. CentriMo calculates a binomial p-value representing central enrichment, based on the central bias of the binding site with the highest likelihood ratio. In cases where binding is indirect or involves cofactors, a more complex distribution of preferred binding sites may occur but, in many cases, a low CentriMo p-value and low width of maximum enrichment (about 100bp) are strong evidence that the motif in question is the true binding motif. Several other MEA tools have been developed, but they do not consider motif central enrichment. The study investigates the claim made by Zhao and Stormo (2011) that they have identified a simpler method than that used to derive the UniPROBE motif database for creating motifs from protein binding microarray (PBM) data, which they call BEEML-PBM (Binding Energy Estimation by Maximum Likelihood-PBM). To accomplish this, CentriMo is employed on 13 motifs from both motif databases. The results indicate that there is no conclusive difference in the quality of motifs from the original PBM and BEEML-PBM approaches. CentriMo provides an understanding of the mechanisms by which TFs bind to DNA. Out of 13 TFs for which ChIP-seq data is used, BEEML-PBM reports five better motifs and twice it has not had any central enrichment when the best PBM motif does. PBM approach finds seven motifs with better central enrichment. On the other hand, across all variations, the number of examples where PBM is better is not high enough to conclude that it is overall the better approach. Some TFs bind directly to DNA, some indirect or in combination with other TFs. Some of the predicted mechanisms are supported by literature evidence. This study further revealed that the binding specificity of a TF is different in different cell types and development stages. A TF is up-regulated in a cell line where it performs its biological function. The discovery of cell line differences, which has not been done before in any CentriMo study, is interesting and provides reasons to study this further
Defeasibility applied to Forrester’s paradox
Get PDFDeontic logic is a logic often used to formalise scenarios in the legal domain. Within the legal domain there are many exceptions and conflicting obligations. This motivates the enrichment of deontic logic with not only the notion of defeasibility, which allows for reasoning about exceptions, but a stronger notion of typicality that is based on defeasibility. KLM-style defeasible reasoning is a logic system that employs defeasibility while Propositional Typicality Logic (PTL) is a logic that does the same for the notion of typicality. Deontic paradoxes are often used to examine logic systems as the paradoxes provide undesirable results even if the scenarios seem intuitive. Forrester’s paradox is one of the most famous of these paradoxes. This paper shows that KLM-style defeasible reasoning and PTL can be used to represent and reason with Forrester’s paradox in such a way as to block undesirable conclusions without completely sacrificing desirable deontic properties
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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