Conformational Studies of Ortho- and Meto-Isomers and Methyl, Dimethyl, and Chloro Ortho-Substituted Analogues of Dantrolene Using Ab Initio SCF-MO Procedures

The conformation of the nitro group of nitroaromatic compounds relative to the aromatic ringsystem is suggested to affect their metabolic activation and mutagenicity. We have recently showed the nitrophenylfuran skeletal muscle relaxant, dantrolene, tobe a potent mutagen inSalmonella. Synthesis of or^o-substituted analogues of dantrolene was achieved in an effort to alter the conformation of the nitro group ina manner that willdecrease the mutagenicity. Using ab initio techniques we investigated the minimum energy conformation of the nitro group of dantrolene (/mitro) and its o-and mnitro isomers as well as the nitro group conformation of dantrolene\u27s ortho- mono- and di- substituted analogues. The most stable conformer for each isomer and analogue was found by optimizing the bond lengths and bond angles for each molecule and rotating about bonds ofinterest using the STO-3G basis set in the Gaussian-92 program at the Hartree-Fock level

A Preference-Based Approach to Backbone Computation with Application to Argumentation

The backbone of a constraint satisfaction problem consists of those variables that take the same value in all solutions. Algorithms for determining the backbone of propositional formulas, i.e., Boolean satisfiability (SAT) instances, find various real-world applications. From the knowledge representation and reasoning (KRR) perspective, one interesting connection is that of backbones and the so-called ideal semantics in abstract argumentation. In this paper, we propose a new backbone algorithm which makes use of a "SAT with preferences" solver, i.e., a SAT solver which is guaranteed to output a most preferred satisfying assignment w.r.t. a given preference over literals of the SAT instance at hand. We also show empirically that the proposed approach is specifically effective in computing the ideal semantics of argumentation frameworks, noticeably outperforming an other state-of-the-art backbone solver as well as the winning approach of the recent ICCMA 2017 argumentation solver competition in the ideal semantics track.Peer reviewe

Global haplotype partitioning for maximal associated SNP pairs

<p>Abstract</p> <p>Background</p> <p>Global partitioning based on pairwise associations of SNPs has not previously been used to define haplotype blocks within genomes. Here, we define an association index based on LD between SNP pairs. We use the Fisher's exact test to assess the statistical significance of the LD estimator. By this test, each SNP pair is characterized as associated, independent, or not-statistically-significant. We set limits on the maximum acceptable proportion of independent pairs within all blocks and search for the partitioning with maximal proportion of associated SNP pairs. Essentially, this model is reduced to a constrained optimization problem, the solution of which is obtained by iterating a dynamic programming algorithm.</p> <p>Results</p> <p>In comparison with other methods, our algorithm reports blocks of larger average size. Nevertheless, the haplotype diversity within the blocks is captured by a small number of tagSNPs. Resampling HapMap haplotypes under a block-based model of recombination showed that our algorithm is robust in reproducing the same partitioning for recombinant samples. Our algorithm performed better than previously reported models in a case-control association study aimed at mapping a single locus trait, based on simulation results that were evaluated by a block-based statistical test. Compared to methods of haplotype block partitioning, we performed best on detection of recombination hotspots.</p> <p>Conclusion</p> <p>Our proposed method divides chromosomes into the regions within which allelic associations of SNP pairs are maximized. This approach presents a native design for dimension reduction in genome-wide association studies. Our results show that the pairwise allelic association of SNPs can describe various features of genomic variation, in particular recombination hotspots.</p

Biclustering via optimal re-ordering of data matrices in systems biology: rigorous methods and comparative studies

<p>Abstract</p> <p>Background</p> <p>The analysis of large-scale data sets via clustering techniques is utilized in a number of applications. Biclustering in particular has emerged as an important problem in the analysis of gene expression data since genes may only jointly respond over a subset of conditions. Biclustering algorithms also have important applications in sample classification where, for instance, tissue samples can be classified as cancerous or normal. Many of the methods for biclustering, and clustering algorithms in general, utilize simplified models or heuristic strategies for identifying the "best" grouping of elements according to some metric and cluster definition and thus result in suboptimal clusters.</p> <p>Results</p> <p>In this article, we present a rigorous approach to biclustering, OREO, which is based on the Optimal RE-Ordering of the rows and columns of a data matrix so as to globally minimize the dissimilarity metric. The physical permutations of the rows and columns of the data matrix can be modeled as either a network flow problem or a traveling salesman problem. Cluster boundaries in one dimension are used to partition and re-order the other dimensions of the corresponding submatrices to generate biclusters. The performance of OREO is tested on (a) metabolite concentration data, (b) an image reconstruction matrix, (c) synthetic data with implanted biclusters, and gene expression data for (d) colon cancer data, (e) breast cancer data, as well as (f) yeast segregant data to validate the ability of the proposed method and compare it to existing biclustering and clustering methods.</p> <p>Conclusion</p> <p>We demonstrate that this rigorous global optimization method for biclustering produces clusters with more insightful groupings of similar entities, such as genes or metabolites sharing common functions, than other clustering and biclustering algorithms and can reconstruct underlying fundamental patterns in the data for several distinct sets of data matrices arising in important biological applications.</p

How frugal is mother nature with haplotypes?

Motivation: Inference of haplotypes from genotype data is crucial and challenging for many vitally important studies. The first, and most critical step, is the ascertainment of a biologically sound model to be optimized. Many models that have been proposed rely partially or entirely on reducing the number of unique haplotypes in the solution

The functional organization of excitatory synaptic input to place cells.

Hippocampal place cells contribute to mammalian spatial navigation and memory formation. Numerous models have been proposed to explain the location-specific firing of this cognitive representation, but the pattern of excitatory synaptic input leading to place firing is unknown, leaving no synaptic-scale explanation of place coding. Here we used resonant scanning two-photon microscopy to establish the pattern of synaptic glutamate input received by CA1 place cells in behaving mice. During traversals of the somatic place field, we found increased excitatory dendritic input, mainly arising from inputs with spatial tuning overlapping the somatic field, and functional clustering of this input along the dendrites over ~10 µm. These results implicate increases in total excitatory input and co-activation of anatomically clustered synaptic input in place firing. Since they largely inherit their fields from upstream synaptic partners with similar fields, many CA1 place cells appear to be part of multi-brain-region cell assemblies forming representations of specific locations

Assessing Similarity of Rating Distributions by Kullback-Leibler Divergence

A mixture model for ordinal data modelling (denoted CUB) has been recently proposed in literature. Specifically, ordinal data are represented by means of a discrete random variable which is a mixture of a Uniform and shifted Binomial random variables. This article proposes a testing procedure based on the Kullback-Leibler divergence in order to compare CUB models and detect similarities in the structure of judgements that raters express on set of items. © Springer-Verlag Berlin Heidelberg 2011