Fate of linear and supercoiled multinucleosomic templates during transcription.

Electron microscopy was used to monitor the fate of reconstituted nucleosome cores during in vitro transcription of long linear and supercoiled multinucleosomic templates by the prokaryotic T7 RNA polymerase and the eukaryotic RNA polymerase II. Transcription by T7 RNA polymerase disrupted the nucleosomal configuration in the transcribed region, while nucleosomes were preserved upstream of the transcription initiation site and in front of the polymerase. Nucleosome disruption was independent of the topology of the template, linear or supercoiled, and of the presence or absence of nucleosome positioning sequences in the transcribed region. In contrast, the nucleosomal configuration was preserved during transcription from the vitellogenin B1 promoter with RNA polymerase II in a rat liver total nuclear extract. However, the persistence of nucleosomes on the template was not RNA polymerase II-specific, but was dependent on another activity present in the nuclear extract. This was demonstrated by addition of the extract to the T7 RNA polymerase transcription reaction, which resulted in retention of the nucleosomal configuration. This nuclear activity, also found in HeLa cell nuclei, is heat sensitive and could not be substituted by nucleoplasmin, chromatin assembly factor (CAF-I) or a combination thereof. Altogether, these results identify a novel nuclear activity, called herein transcription-dependent chromatin stabilizing activity I or TCSA-I, which may be involved in a nucleosome transfer mechanism during transcription.

16q24.1 microdeletion in a premature newborn: Usefulness of array-based comparative genomic hybridization in persistent pulmonary hypertension of the newborn.

OBJECTIVE:: Report of a 16q24.1 deletion in a premature newborn, demonstrating the usefulness of array-based comparative genomic hybridization in persistent pulmonary hypertension of the newborn and multiple congenital malformations. DESIGN:: Descriptive case report. SETTING:: Genetic department and neonatal intensive care unit of a tertiary care children's hospital. INTERVENTIONS:: None. PATIENT:: We report the case of a preterm male infant, born at 26 wks of gestation. A cardiac malformation and bilateral hydronephrosis were diagnosed at 19 wks of gestation. Karyotype analysis was normal, and a 22q11.2 microdeletion was excluded by fluorescence in situ hybridization analysis. A cesarean section was performed due to fetal distress. The patient developed persistent pulmonary hypertension unresponsive to mechanical ventilation and nitric oxide treatment and expired at 16 hrs of life. MEASUREMENTS AND MAIN RESULTS:: An autopsy revealed partial atrioventricular canal malformation and showed bilateral dilation of the renal pelvocaliceal system with bilateral ureteral stenosis and annular pancreas. Array-based comparative genomic hybridization analysis (Agilent oligoNT 44K, Agilent Technologies, Santa Clara, CA) showed an interstitial microdeletion encompassing the forkhead box gene cluster in 16q24.1. Review of the pulmonary microscopic examination showed the characteristic features of alveolar capillary dysplasia with misalignment of pulmonary veins. Some features were less prominent due to the gestational age. CONCLUSIONS:: Our review of the literature shows that alveolar capillary dysplasia with misalignment of pulmonary veins is rare but probably underreported. Prematurity is not a usual presentation, and histologic features are difficult to interpret. In our case, array-based comparative genomic hybridization revealed a 16q24.1 deletion, leading to the final diagnosis of alveolar capillary dysplasia with misalignment of pulmonary veins. It emphasizes the usefulness of array-based comparative genomic hybridization analysis as a diagnostic tool with implications for both prognosis and management decisions in newborns with refractory persistent pulmonary hypertension and multiple congenital malformations.

Otimização Não Linear de Mínimos Quadrados

O problema de otimização de mínimos quadrados e apresentado como uma classe importante de problemas de minimização sem restrições. A importância dessa classe de problemas deriva das bem conhecidas aplicações a estimação de parâmetros no contexto das analises de regressão e de resolução de sistemas de equações não lineares. Apresenta-se uma revisão dos métodos de otimização de mínimos quadrados lineares e de algumas técnicas conhecidas de linearização. Faz-se um estudo dos principais métodos de gradiente usados para problemas não lineares gerais: Métodos de Newton e suas modificações incluindo os métodos Quasi-Newton mais usados (DFP e BFGS). Introduzem-se depois métodos específicos de gradiente para problemas de mínimos quadrados: Gauss-Newton e Levenberg-Larquardt. Apresenta-se uma variedade de exemplos selecionados na literatura para testar os diferentes métodos usando rotinas MATLAB. Faz-se uma an alise comparativa dos algoritmos baseados nesses ensaios computacionais que exibem as vantagens e desvantagens dos diferentes métodos.

On the throughput-WIP trade-off in queueing systems, diminishing returns and the threshold property: A linear programming approach

We present a new unifying framework for investigating throughput-WIP(Work-in-Process) optimal control problems in queueing systems,based on reformulating them as linear programming (LP) problems withspecial structure: We show that if a throughput-WIP performance pairin a stochastic system satisfies the Threshold Property we introducein this paper, then we can reformulate the problem of optimizing alinear objective of throughput-WIP performance as a (semi-infinite)LP problem over a polygon with special structure (a thresholdpolygon). The strong structural properties of such polygones explainthe optimality of threshold policies for optimizing linearperformance objectives: their vertices correspond to the performancepairs of threshold policies. We analyze in this framework theversatile input-output queueing intensity control model introduced byChen and Yao (1990), obtaining a variety of new results, including (a)an exact reformulation of the control problem as an LP problem over athreshold polygon; (b) an analytical characterization of the Min WIPfunction (giving the minimum WIP level required to attain a targetthroughput level); (c) an LP Value Decomposition Theorem that relatesthe objective value under an arbitrary policy with that of a giventhreshold policy (thus revealing the LP interpretation of Chen andYao's optimality conditions); (d) diminishing returns and invarianceproperties of throughput-WIP performance, which underlie thresholdoptimality; (e) a unified treatment of the time-discounted andtime-average cases.

Exact tests for correlation and for the slope in simple linear regressions without making assumptions

We present an exact test for whether two random variables that have known bounds on their support are negatively correlated. The alternative hypothesis is that they are not negatively correlated. No assumptions are made on the underlying distributions. We show by example that the Spearman rank correlation test as the competing exact test of correlation in nonparametric settings rests on an additional assumption on the data generating process without which it is not valid as a test for correlation.We then show how to test for the significance of the slope in a linear regression analysis that invovles a single independent variable and where outcomes of the dependent variable belong to a known bounded set.

A test of the predictive validity of non-linear QALY models using time trade-off utilities

This paper presents a test of the predictive validity of various classes ofQALY models (i.e., linear, power and exponential models). We first estimatedTTO utilities for 43 EQ-5D chronic health states and next these states wereembedded in health profiles. The chronic TTO utilities were then used topredict the responses to TTO questions with health profiles. We find that thepower QALY model clearly outperforms linear and exponential QALY models.Optimal power coefficient is 0.65. Our results suggest that TTO-based QALYcalculations may be biased. This bias can be avoided using a power QALY model.

Implementing TURF analysis through binary linear programming

This paper introduces the approach of using Total Unduplicated Reach and Frequency analysis (TURF) to design a product line through a binary linear programming model. This improves the efficiency of the search for the solution to the problem compared to the algorithms that have been used to date. The results obtained through our exact algorithm are presented, and this method shows to be extremely efficient both in obtaining optimal solutions and in computing time for very large instances of the problem at hand. Furthermore, the proposed technique enables the model to be improved in order to overcome the main drawbacks presented by TURF analysis in practice.

Restless bandits, linear programming relaxations and a primal-dual index heuristic

We develop a mathematical programming approach for the classicalPSPACE - hard restless bandit problem in stochastic optimization.We introduce a hierarchy of n (where n is the number of bandits)increasingly stronger linear programming relaxations, the lastof which is exact and corresponds to the (exponential size)formulation of the problem as a Markov decision chain, while theother relaxations provide bounds and are efficiently computed. Wealso propose a priority-index heuristic scheduling policy fromthe solution to the first-order relaxation, where the indices aredefined in terms of optimal dual variables. In this way wepropose a policy and a suboptimality guarantee. We report resultsof computational experiments that suggest that the proposedheuristic policy is nearly optimal. Moreover, the second-orderrelaxation is found to provide strong bounds on the optimalvalue.

Genomewide association study using a high-density single nucleotide polymorphism array and case-control design identifies a novel essential hypertension susceptibility locus in the promoter region of endothelial NO synthase.

Essential hypertension is a multifactorial disorder and is the main risk factor for renal and cardiovascular complications. The research on the genetics of hypertension has been frustrated by the small predictive value of the discovered genetic variants. The HYPERGENES Project investigated associations between genetic variants and essential hypertension pursuing a 2-stage study by recruiting cases and controls from extensively characterized cohorts recruited over many years in different European regions. The discovery phase consisted of 1865 cases and 1750 controls genotyped with 1M Illumina array. Best hits were followed up in a validation panel of 1385 cases and 1246 controls that were genotyped with a custom array of 14 055 markers. We identified a new hypertension susceptibility locus (rs3918226) in the promoter region of the endothelial NO synthase gene (odds ratio: 1.54 [95% CI: 1.37-1.73]; combined P=2.58 · 10(-13)). A meta-analysis, using other in silico/de novo genotyping data for a total of 21 714 subjects, resulted in an overall odds ratio of 1.34 (95% CI: 1.25-1.44; P=1.032 · 10(-14)). The quantitative analysis on a population-based sample revealed an effect size of 1.91 (95% CI: 0.16-3.66) for systolic and 1.40 (95% CI: 0.25-2.55) for diastolic blood pressure. We identified in silico a potential binding site for ETS transcription factors directly next to rs3918226, suggesting a potential modulation of endothelial NO synthase expression. Biological evidence links endothelial NO synthase with hypertension, because it is a critical mediator of cardiovascular homeostasis and blood pressure control via vascular tone regulation. This finding supports the hypothesis that there may be a causal genetic variation at this locus.

On heuristic and linear models of judgment: Mapping the demand for knowledge

Research on judgment and decision making presents a confusing picture of human abilities. For example, much research has emphasized the dysfunctional aspects of judgmental heuristics, and yet, other findings suggest that these can be highly effective. A further line of research has modeled judgment as resulting from as if linear models. This paper illuminates the distinctions in these approaches by providing a common analytical framework based on the central theoretical premise that understanding human performance requires specifying how characteristics of the decision rules people use interact with the demands of the tasks they face. Our work synthesizes the analytical tools of lens model research with novel methodology developed to specify the effectiveness of heuristics in different environments and allows direct comparisons between the different approaches. We illustrate with both theoretical analyses and simulations. We further link our results to the empirical literature by a meta-analysis of lens model studies and estimate both human andheuristic performance in the same tasks. Our results highlight the trade-off betweenlinear models and heuristics. Whereas the former are cognitively demanding, the latterare simple to use. However, they require knowledge and thus maps of when andwhich heuristic to employ.

O Primal e o Dual na programação Linear

O tema da Programação Linear, com as suas particularizações do Problema dos Transportes e do Problema da Afectação de Recursos, é hoje estudado em cursos diversos onde uma disciplina de Investigação Operacional esteja presente. Trata-se, em última análise, de um problema de cálculo de extremos condicionados, seja de máximo ou de mínimo, que apresenta características muito particulares e de grande elegância simbólica. Também os Problemas dos Transportes e da Afectação de Recursos se podem resolver como problemas de Programação Linear, através do Algoritmo Simplex, embora seja preferível o recurso a algoritmos próprios, de muitíssimo maior simplicidade: o Algoritmo dos Transportes e o Algoritmo Húngaro, respectivamente. De molde a facilitar a compreensão do que realmente está em jogo, consideram-se aqui dois casos de determinação de extremos e de extremos condicionados, mas ao nível do final do ensino secundário.

Comparação entre os métodos da transeção linear e fotográfico na avaliação de cobertura vegetal morta, sob dois métodos de preparo, após a colheita da soja

A eficácia da cobertura vegetal morta no controle da erosão pode ser avaliada através de dois indicadores principais: a porcentagem de cobertura do solo pelos resíduos culturais e sua persistência sobre a superfície ao longo do tempo. O preparo do solo, por sua vez, pode exercer influência significativa sobre esses indicadores. O trabalho foi realizado no campo, no município de Eldorado do Sul, Depressão Central do Rio Grande do Sul. Avaliou-se a persistência da cobertura vegetal morta durante um período de pousio, que foi de maio de 1989 a abril de 1990, em sucessão à cultura da soja. Os resíduos dessa cultura foram manejados sem preparo, por escarificação e por gradagem. A porcentagem de cobertura do solo pelos resíduos culturais foi quantificada pelo método fotográfico e pelo da transeção linear. A cultura da soja produziu cobertura vegetal morta em pequena quantidade e de baixa durabilidade. A distribuição dos resíduos na superfície, sem preparo do solo, foi o tratamento que possibilitou melhor correlação (R²) entre os índices de cobertura obtidos pelos dois métodos testados. Nas áreas sob gradagem ou escarificação do solo, os índices de cobertura obtidos pelo método fotográfico foram superiores aos da transeção linear, enquanto, na área sem preparo do solo, houve similaridade entre os resultados dos dois métodos.

Optimum Redundant Array Configurations for Earth Observation Aperture Synthesis Microwave Radiometers

Two-dimensional aperture synthesis radiometry is the technologyselected for ESA's SMOS mission to provide high resolution L-bandradiometric imagery. The array topology is a Y-shaped structure. Theposition and number of redundant elements to minimise instrumentdegradation in case of element failure(s) are studied.