Parsimonious Higher-Order Hidden Markov Models for Improved Array-CGH Analysis with Applications to Arabidopsis thaliana

Array-based comparative genomic hybridization (Array-CGH) is an important technology in molecular biology for the detection of DNA copy number polymorphisms between closely related genomes. Hidden Markov Models (HMMs) are popular tools for the analysis of Array-CGH data, but current methods are only based on first-order HMMs having constrained abilities to model spatial dependencies between measurements of closely adjacent chromosomal regions. Here, we develop parsimonious higher-order HMMs enabling the interpolation between a mixture model ignoring spatial dependencies and a higher-order HMM exhaustively modeling spatial dependencies. We apply parsimonious higher-order HMMs to the analysis of Array-CGH data of the accessions C24 and Col-0 of the model plant Arabidopsis thaliana. We compare these models against first-order HMMs and other existing methods using a reference of known deletions and sequence deviations. We find that parsimonious higher-order HMMs clearly improve the identification of these polymorphisms. Moreover, we perform a functional analysis of identified polymorphisms revealing novel details of genomic differences between C24 and Col-0. Additional model evaluations are done on widely considered Array-CGH data of human cell lines indicating that parsimonious HMMs are also well-suited for the analysis of non-plant specific data. All these results indicate that parsimonious higher-order HMMs are useful for Array-CGH analyses. An implementation of parsimonious higher-order HMMs is available as part of the open source Java library Jstacs (www.jstacs.de/index.php/PHHMM)

Targeting cancer cell death with a bcl-x S adenovirus

Transformation is a complex cellular process that requires several genetic abnormalities. In many cases, one of these abnormalities is an inhibition of PCD, which provides a selective advantage for tumor cells. This has been recently shown in an in vivo model, where overexpression of Bcl-x L is a crucial step in the progression from hyperplasia to neoplasia and is accompanied by a significant decrease in tumor apoptosis [56].Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46936/1/281_2004_Article_BF00787225.pd

Esofagomanometria e pHmetria esofágica de 24 h em uma ampla amostra de pacientes com manifestações respiratórias Esophageal manometry and 24-h esophageal pH-metry in a large sample of patients with respiratory symptoms

OBJETIVO: Determinar a prevalência da doença do refluxo gastroesofágico (DRGE) e avaliar o perfil motor esofágico de portadores de manifestações respiratórias encaminhados para avaliação funcional esofágica em um serviço de referência em motilidade digestiva. MÉTODOS: Foram analisados os resultados de esofagomanometria e de pHmetria esofágica de 24 h. O critério de inclusão foi a presença de sintomas respiratórios, acompanhados ou não de sintomas digestivos. RESULTADOS: Dos 1.170 pacientes incluídos no estudo, 602 (51,5%) relataram manifestações digestivas associadas às respiratórias (grupo MRD) e 568 (48,5%), apenas respiratórias (grupo MR). A asma foi diagnosticada em 142 indivíduos no grupo MR (subgrupo MR-A) e em 201 no grupo MRD (subgrupo MRD-A). Dentre os 346 casos de dismotilidade do corpo esofágico, a hipomotilidade esteve presente em 175 (14,3% e 15,6%, respectivamente, no grupos MRD e MR) e hipotonia do esfíncter esofágico inferior (EEI) em 411 (40.3% e 30,2% nos mesmos grupos, respectivamente). A hipotonia se correlacionou com DRGE. A exposição do esôfago distal ao ácido foi marcadamente anormal no período de decúbito. A prevalência de DRGE na amostra total, nos subgrupos MR-A/MRD-A e somente no subgrupo MR-A foi de 39,8%, 44,0% e 35,2%, respectivamente. CONCLUSÕES: A hipotonia do EEI foi a alteração manométrica preponderante, correlacionando-se com DRGE. Embora a DRGE foi mais evidente no grupo MRD, aproximadamente um terço dos pacientes do grupo MR apresentou DRGE (DRGE silencioso). Os achados sugerem a DRGE como possível causa extrapulmonar de sintomas respiratórios crônicos não responsivos à terapêutica convencional.<br>OBJECTIVE: To determine the prevalence of gastroesophageal reflux disease (GERD) and to evaluate the esophageal motor profile of patients with respiratory symptoms referred to a digestive motility referral center for esophageal function testing. METHODS: The results of esophageal manometry and 24-h esophageal pH-metry were analyzed.The inclusion criterion was presenting respiratory symptoms, with or without accompanying digestive symptoms. RESULTS: Of the 1,170 patients included in the study, 602 (51.5%) reported having digestive and respiratory symptoms (DRS group), and 568 (48.5%) reported having only respiratory symptoms (RS group). Asthma was diagnosed in 142 patients in the RS group (RS-A subgroup) and in 201 of those in the DRS group (DRS-A). Of the 346 cases of esophageal dysmotility, hypomotility was found in 175 (14.3% and 15.6% in the DRS and RS groups, respectively), and lower esophageal sphincter (LES) hypotonia was found in 411 (40.3% and 30.2%, respectively). Hypotonia correlated with GERD. Exposure of the distal esophagus to acid was markedly abnormal in the supine position. The prevalence of GERD in the sample as a whole, the RS-A/DRS-A subgroups and the RS-A subgroup alone was 39.8%, 44.0% and 35.2%, respectively CONCLUSIONS: Hypotonic LES was the most common abnormality and correlated with GERD. Although GERD was more evident in the DRS group, approximately one third of the patients in the RS group also presented GERD (silent GERD). The findings suggest that GERD can be an extrapulmonary cause of chronic respiratory symptoms unresponsive to conventional therapy