A Monte Carlo-based framework enhances the discovery and interpretation of regulatory sequence motifs

Abstract Background Discovery of functionally significant short, statistically overrepresented subsequence patterns (motifs) in a set of sequences is a challenging problem in bioinformatics. Oftentimes, not all sequences in the set contain a motif. These non-motif-containing sequences complicate the algorithmic discovery of motifs. Filtering the non-motif-containing sequences from the larger set of sequences while simultaneously determining the identity of the motif is, therefore, desirable and a non-trivial problem in motif discovery research. Results We describe MotifCatcher, a framework that extends the sensitivity of existing motif-finding tools by employing random sampling to effectively remove non-motif-containing sequences from the motif search. We developed two implementations of our algorithm; each built around a commonly used motif-finding tool, and applied our algorithm to three diverse chromatin immunoprecipitation (ChIP) data sets. In each case, the motif finder with the MotifCatcher extension demonstrated improved sensitivity over the motif finder alone. Our approach organizes candidate functionally significant discovered motifs into a tree, which allowed us to make additional insights. In all cases, we were able to support our findings with experimental work from the literature. Conclusions Our framework demonstrates that additional processing at the sequence entry level can significantly improve the performance of existing motif-finding tools. For each biological data set tested, we were able to propose novel biological hypotheses supported by experimental work from the literature. Specifically, in Escherichia coli, we suggested binding site motifs for 6 non-traditional LexA protein binding sites; in Saccharomyces cerevisiae, we hypothesize 2 disparate mechanisms for novel binding sites of the Cse4p protein; and in Halobacterium sp. NRC-1, we discoverd subtle differences in a general transcription factor (GTF) binding site motif across several data sets. We suggest that small differences in our discovered motif could confer specificity for one or more homologous GTF proteins. We offer a free implementation of the MotifCatcher software package at http://www.bme.ucdavis.edu/facciotti/resources_data/software/ .http://deepblue.lib.umich.edu/bitstream/2027.42/112965/1/12859_2012_Article_5570.pd

The Sunyaev-Zel'dovich Infrared Experiment: A Millimeter-wave Receiver for Cluster Cosmology

Measurements of the Sunyaev-Zel'dovich (S-Z) effect towards distant clusters of galaxies can be used to determine the Hubble constant and the radial component of cluster peculiar velocities. Determination of the cluster peculiar velocity requires the separation of the two components of the S-Z effect, which are due to the thermal and bulk velocities of the intracluster plasma. The two components can be separated practically only at millimeter (mm) wavelengths. Measurements of the S-Z effect at mm wavelengths are subject to minimal astrophysical confusion and, therefore, provide an important test of results obtained at longer wavelengths. We describe the instrument used to make the first significant detections of the S-Z effect at millimeter wavelengths. This instrument employs new filter, detector, and readout technologies to produce sensitive measurements of differential sky brightness stable on long time scales. These advances allow drift scan observations which achieve high sensitivity while minimizing common sources of systematic error.Comment: 19 pages, 15 postscript figures, LaTeX(aaspptwo.sty), ApJ(in press

Shape-based peak identification for ChIP-Seq

We present a new algorithm for the identification of bound regions from ChIP-seq experiments. Our method for identifying statistically significant peaks from read coverage is inspired by the notion of persistence in topological data analysis and provides a non-parametric approach that is robust to noise in experiments. Specifically, our method reduces the peak calling problem to the study of tree-based statistics derived from the data. We demonstrate the accuracy of our method on existing datasets, and we show that it can discover previously missed regions and can more clearly discriminate between multiple binding events. The software T-PIC (Tree shape Peak Identification for ChIP-Seq) is available at http://math.berkeley.edu/~vhower/tpic.htmlComment: 12 pages, 6 figure

Microscale sulfur cycling in the phototrophic pink berry consortia of the Sippewissett Salt Marsh

Microbial metabolism is the engine that drives global biogeochemical cycles, yet many key transformations are carried out by microbial consortia over short spatiotemporal scales that elude detection by traditional analytical approaches. We investigate syntrophic sulfur cycling in the ‘pink berry’ consortia of the Sippewissett Salt Marsh through an integrative study at the microbial scale. The pink berries are macroscopic, photosynthetic microbial aggregates composed primarily of two closely associated species: sulfide-oxidizing purple sulfur bacteria (PB-PSB1) and sulfate-reducing bacteria (PB-SRB1). Using metagenomic sequencing and 34S-enriched sulfate stable isotope probing coupled with nanoSIMS, we demonstrate interspecies transfer of reduced sulfur metabolites from PB-SRB1 to PB-PSB1. The pink berries catalyse net sulfide oxidation and maintain internal sulfide concentrations of 0–500 μm. Sulfide within the berries, captured on silver wires and analysed using secondary ion mass spectrometer, increased in abundance towards the berry interior, while δ34S-sulfide decreased from 6‰ to −31‰ from the exterior to interior of the berry. These values correspond to sulfate–sulfide isotopic fractionations (15–53‰) consistent with either sulfate reduction or a mixture of reductive and oxidative metabolisms. Together this combined metagenomic and high-resolution isotopic analysis demonstrates active sulfur cycling at the microscale within well-structured macroscopic consortia consisting of sulfide-oxidizing anoxygenic phototrophs and sulfate-reducing bacteria

Управління обізнаністю персоналу в питаннях протидії методам соціальної інженерії

Об’єкт дослідження: процес управління обізнаністю персоналу. Мета роботи: підготовка обґрунтованої методики підвищення рівня обізнаності персоналу у питаннях протидії методам соціальної інженерії. Методи дослідження: порівняння, статистичний аналіз, моделювання. У спеціальній частині досліджена теоретична база у сфері обізнаності персоналу в питаннях протидії методам соціальної інженерії. Проаналізовані загрози кібербезпеки та розглянута їх класифікація за різними ознаками. Виділено загрози кібербезпеки антропогенного характеру. З загроз антропогенного характеру виділено загрози методами соціальної інженерії. Проаналізовано методи соціальної інженерії та розглянуто існуючі методи протидії атакам соціальної інженерії. У роботі розроблено методику управління обізнаністю персоналу у питаннях протидії методам соціальної інженерії. Для цього розроблено методичні вказівки для підвищення обізнаності персоналу у питаннях протидії методам соціальної інженерії та шаблон опитувальника як метрику для аналізу рівня обізнаності персоналу у питаннях протидії методам соціальної інженерії. В економічній частині проведено розрахунок вартості розробки та впровадження методики управління обізнаністю персоналу у питаннях протидії методам соціальної інженерії і обґрунтовано її економічну доцільність. Практичне значення роботи полягає у розробці методичних вказівок для підвищення обізнаності персоналу у питаннях протидії методам соціальної інженерії, а такожу розробці опитувальника для аналізу рівня обізнаності. Наукова новизна роботи полягає у розробці методики управління обізнаністюперсоналу у питаннях протидії методам соціальної інженерії

Lucro Real x Lucro Presumido: Opção menos onerosa para uma empresa prestadora de serviços de Comunicação.

TCC (Graduação) - Universidade Federal de Santa Catarina. Centro Socioeconômico. Curso de Ciências ContábeisCada vez mais o empresário visa o maior lucro para sua empresa, com a elevada carga tributária no Brasil é necessário que o empreendedor tenha um auxilio para a tomada de suas decisões no que diz respeito à tributação. Assim o profissional contábil tem papel importante na vida da empresa, fazendo um planejamento tributário, levando em consideração os benefícios que a opção correta do regime de tributação apresenta. Atualmente existem incentivos fiscais que podem ser utilizados como dedução dos impostos a pagar, a exemplo do PAT (Programa de Alimentação do Trabalhador), que permite a dedução direta de até 4% do imposto de renda a pagar, além de poder ser utilizado nos próximos dois anos de apuração o valor que ultrapassar este limite. O Lucro Presumido é uma forma mais simples de se apurar o imposto de renda, contribuição social sobre o lucro líquido, PIS e COFINS, pois parte de uma base presumida, o que facilita sua apuração para o contador. Já o Lucro Real é a forma mais complexa dos regimes de tributação, ele necessita de uma correta escrituração contábil para apurar os valores dos impostos a serem pagos, nesse regime a base de cálculo parte do lucro real da empresa, a partir da confrontação das receitas menos as despesas do período, podendo adicionar ou excluir dessa base as receitas e despesas previstas em lei. Para constatar a opção menos onerosa para a empresa em estudo, são apresentados os devidos cálculos para demonstrar ao empresário qual a opção menos onerosa para sua empresa ao se tratar dos regimes do Lucro Real e do Lucro Presumido

Virtual patients design and its effect on clinical reasoning and student experience : a protocol for a randomised factorial multi-centre study

Background Virtual Patients (VPs) are web-based representations of realistic clinical cases. They are proposed as being an optimal method for teaching clinical reasoning skills. International standards exist which define precisely what constitutes a VP. There are multiple design possibilities for VPs, however there is little formal evidence to support individual design features. The purpose of this trial is to explore the effect of two different potentially important design features on clinical reasoning skills and the student experience. These are the branching case pathways (present or absent) and structured clinical reasoning feedback (present or absent). Methods/Design This is a multi-centre randomised 2x2 factorial design study evaluating two independent variables of VP design, branching (present or absent), and structured clinical reasoning feedback (present or absent).The study will be carried out in medical student volunteers in one year group from three university medical schools in the United Kingdom, Warwick, Keele and Birmingham. There are four core musculoskeletal topics. Each case can be designed in four different ways, equating to 16 VPs required for the research. Students will be randomised to four groups, completing the four VP topics in the same order, but with each group exposed to a different VP design sequentially. All students will be exposed to the four designs. Primary outcomes are performance for each case design in a standardized fifteen item clinical reasoning assessment, integrated into each VP, which is identical for each topic. Additionally a 15-item self-reported evaluation is completed for each VP, based on a widely used EViP tool. Student patterns of use of the VPs will be recorded. In one centre, formative clinical and examination performance will be recorded, along with a self reported pre and post-intervention reasoning score, the DTI. Our power calculations indicate a sample size of 112 is required for both primary outcomes

Geocentrism reexamined

The universe is nearly isotropic on very large scales. It is much more difficult to show that the universe is radially homogeneous (independent of distance), or equivalently, that it is isotropic about distant points. This taken as an axiom, since if it were not true, then we would occupy a preferred position. This paper considers several empirical arguments for radial homogeneity based on the cosmic microwave background (CMB). The tightest limits on inhomogeneity on the scale of the horizon are of order ten percent but will improve soon. These limits involve the Sunyaev-Zel'dovich effect in clusters of galaxies, excitation of low-energy atomic transitions, and the accurately thermal spectrum of the CMB. Weaker limits from primordial nucleosynthesis are discussed briefly.Comment: RevTeX source, 14 pages, no figs. To appear Phys Rev

A Weak Gravitational Lensing and X-ray Analysis of Abell 2163

We report on the detection of dark matter in the cluster of galaxies Abell~2163 using the weak gravitational distortion of background galaxies, and an analysis of the cluster X-ray emission. We find that while the qualitative distributions of the cluster light and the dark matter are similar -- shallow and extended, with significant substructure -- the X-ray morphology shows a more regular overall appearance. We interpret the joint lensing and X-ray observations as a signature of a merger event in the cluster. We present new ROSAT/HRI data and reanalyze ROSAT/PSPC data, accounting for the effect of a varying background to determine the best fit parameters in the $\beta$-model formalism. We combine the surface brightness fits with two determinations of the radial temperature profile to determine the total mass. Although there are slight variations in the total mass determinations introduced by the uncertainties in the $\beta$-fit, the main contributor to the error arises from the uncertainties in the temperature determinations. Even though the morphologies of the dark matter/light and X-ray gas are quite different, we find that the total mass determined from the X-ray and weak lensing estimates are consistent with each other within the $2\sigma$ error bars, with the X-ray inferred mass a factor of $\simeq 2$ larger. However, as the lensing mass estimates are differential (the surface density at any point is determined relative to the mean in a control annulus), the shallow, extended nature of the mass profile biases the lensing inferred mass downwards. We estimate the correction for this effect and find very good agreement between the corrected lensing and X-ray results. We determine the gas mass fraction and find $f_g \simeq 0.07h^{-3/2}$ at all radii and a constant mass-to-light ratio of $M/L_VComment: 30 pages, latex file. Postscript file also available at ftp://magicbean.berkeley.edu/pub/squires/a2163/a2163_paper.ps.g

Functional divergence in the role of N-linked glycosylation in smoothened signaling

The G protein-coupled receptor (GPCR) Smoothened (Smo) is the requisite signal transducer of the evolutionarily conserved Hedgehog (Hh) pathway. Although aspects of Smo signaling are conserved from Drosophila to vertebrates, significant differences have evolved. These include changes in its active sub-cellular localization, and the ability of vertebrate Smo to induce distinct G protein-dependent and independent signals in response to ligand. Whereas the canonical Smo signal to Gli transcriptional effectors occurs in a G protein-independent manner, its non-canonical signal employs Gαi. Whether vertebrate Smo can selectively bias its signal between these routes is not yet known. N-linked glycosylation is a post-translational modification that can influence GPCR trafficking, ligand responsiveness and signal output. Smo proteins in Drosophila and vertebrate systems harbor N-linked glycans, but their role in Smo signaling has not been established. Herein, we present a comprehensive analysis of Drosophila and murine Smo glycosylation that supports a functional divergence in the contribution of N-linked glycans to signaling. Of the seven predicted glycan acceptor sites in Drosophila Smo, one is essential. Loss of N-glycosylation at this site disrupted Smo trafficking and attenuated its signaling capability. In stark contrast, we found that all four predicted N-glycosylation sites on murine Smo were dispensable for proper trafficking, agonist binding and canonical signal induction. However, the under-glycosylated protein was compromised in its ability to induce a non-canonical signal through Gαi, providing for the first time evidence that Smo can bias its signal and that a post-translational modification can impact this process. As such, we postulate a profound shift in N-glycan function from affecting Smo ER exit in flies to influencing its signal output in mice