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1.
Ann Oncol ; 34(4): 397-409, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36709040

RESUMEN

BACKGROUND: Very young premenopausal women diagnosed with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+HER2-) early breast cancer (EBC) have higher rates of recurrence and death for reasons that remain largely unexplained. PATIENTS AND METHODS: Genomic sequencing was applied to HR+HER2- tumours from patients enrolled in the Suppression of Ovarian Function Trial (SOFT) to determine genomic drivers that are enriched in young premenopausal women. Genomic alterations were characterised using next-generation sequencing from a subset of 1276 patients (deep targeted sequencing, n = 1258; whole-exome sequencing in a young-age, case-control subsample, n = 82). We defined copy number (CN) subgroups and assessed for features suggestive of homologous recombination deficiency (HRD). Genomic alteration frequencies were compared between young premenopausal women (<40 years) and older premenopausal women (≥40 years), and assessed for associations with distant recurrence-free interval (DRFI) and overall survival (OS). RESULTS: Younger women (<40 years, n = 359) compared with older women (≥40 years, n = 917) had significantly higher frequencies of mutations in GATA3 (19% versus 16%) and CN amplifications (CNAs) (47% versus 26%), but significantly lower frequencies of mutations in PIK3CA (32% versus 47%), CDH1 (3% versus 9%), and MAP3K1 (7% versus 12%). Additionally, they had significantly higher frequencies of features suggestive of HRD (27% versus 21%) and a higher proportion of PIK3CA mutations with concurrent CNAs (23% versus 11%). Genomic features suggestive of HRD, PIK3CA mutations with CNAs, and CNAs were associated with significantly worse DRFI and OS compared with those without these features. These poor prognostic features were enriched in younger patients: present in 72% of patients aged <35 years, 54% aged 35-39 years, and 40% aged ≥40 years. Poor prognostic features [n = 584 (46%)] versus none [n = 692 (54%)] had an 8-year DRFI of 84% versus 94% and OS of 88% versus 96%. Younger women (<40 years) had the poorest outcomes: 8-year DRFI 74% versus 85% and OS 80% versus 93%, respectively. CONCLUSION: These results provide insights into genomic alterations that are enriched in young women with HR+HER2- EBC, provide rationale for genomic subgrouping, and highlight priority molecular targets for future clinical trials.


Asunto(s)
Neoplasias de la Mama , Humanos , Femenino , Anciano , Neoplasias de la Mama/tratamiento farmacológico , Receptor ErbB-2/metabolismo , Pronóstico , Genómica , Fosfatidilinositol 3-Quinasa Clase I/genética
2.
Genet Res (Camb) ; 95(1): 14-29, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-23497823

RESUMEN

Gene expression profiling using microarrays and xenograft transplants of human cancer cell lines are both popular tools to investigate human cancer. However, the undefined degree of cross hybridization between the mouse and human genomes hinders the use of microarrays to characterize gene expression of both the host and the cancer cell within the xenograft. Since an increasingly recognized aspect of cancer is the host response (or cancer-stroma interaction), we describe here a bioinformatic manipulation of the Affymetrix profiling that allows interrogation of the gene expression of both the mouse host and the human tumour. Evidence of microenvironmental regulation of epithelial mesenchymal transition of the tumour component in vivo is resolved against a background of mesenchymal gene expression. This tool could allow deeper insight to the mechanism of action of anti-cancer drugs, as typically novel drug efficacy is being tested in xenograft systems.


Asunto(s)
Biomarcadores de Tumor/genética , Transición Epitelial-Mesenquimal , Perfilación de la Expresión Génica , Neoplasias/genética , Neoplasias/patología , Animales , Biología Computacional , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones , Análisis de Secuencia por Matrices de Oligonucleótidos , Especificidad de la Especie , Trasplante Heterólogo , Microambiente Tumoral
3.
Bioinformatics ; 24(6): 759-67, 2008 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-18204055

RESUMEN

MOTIVATION: Although copy-number aberrations are known to contribute to the diversity of the human DNA and cause various diseases, many aberrations and their phenotypes are still to be explored. The recent development of single-nucleotide polymorphism (SNP) arrays provides researchers with tools for calling genotypes and identifying chromosomal aberrations at an order-of-magnitude greater resolution than possible a few years ago. The fundamental problem in array-based copy-number (CN) analysis is to obtain CN estimates at a single-locus resolution with high accuracy and precision such that downstream segmentation methods are more likely to succeed. RESULTS: We propose a preprocessing method for estimating raw CNs from Affymetrix SNP arrays. Its core utilizes a multichip probe-level model analogous to that for high-density oligonucleotide expression arrays. We extend this model by adding an adjustment for sequence-specific allelic imbalances such as cross-hybridization between allele A and allele B probes. We focus on total CN estimates, which allows us to further constrain the probe-level model to increase the signal-to-noise ratio of CN estimates. Further improvement is obtained by controlling for PCR effects. Each part of the model is fitted robustly. The performance is assessed by quantifying how well raw CNs alone differentiate between one and two copies on Chromosome X (ChrX) at a single-locus resolution (27kb) up to a 200kb resolution. The evaluation is done with publicly available HapMap data. AVAILABILITY: The proposed method is available as part of an open-source R package named aroma.affymetrix. Because it is a bounded-memory algorithm, any number of arrays can be analyzed.


Asunto(s)
Algoritmos , Inteligencia Artificial , Mapeo Cromosómico/métodos , Dosificación de Gen/genética , Perfilación de la Expresión Génica/métodos , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Sitios de Carácter Cuantitativo/genética , Secuencia de Bases , Análisis Mutacional de ADN/métodos , Cadenas de Markov , Datos de Secuencia Molecular , Reconocimiento de Normas Patrones Automatizadas/métodos , Polimorfismo de Nucleótido Simple/genética , Programas Informáticos
4.
Bioinformatics ; 24(15): 1707-14, 2008 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-18573797

RESUMEN

MOTIVATION: Analyses of EST data show that alternative splicing is much more widespread than once thought. The advent of exon and tiling microarrays means that researchers now have the capacity to experimentally measure alternative splicing on a genome wide level. New methods are needed to analyze the data from these arrays. RESULTS: We present a method, finding isoforms using robust multichip analysis (FIRMA), for detecting differential alternative splicing in exon array data. FIRMA has been developed for Affymetrix exon arrays, but could in principle be extended to other exon arrays, tiling arrays or splice junction arrays. We have evaluated the method using simulated data, and have also applied it to two datasets: a panel of 11 human tissues and a set of 10 pairs of matched normal and tumor colon tissue. FIRMA is able to detect exons in several genes confirmed by reverse transcriptase PCR. AVAILABILITY: R code implementing our methods is contributed to the package aroma.affymetrix.


Asunto(s)
Algoritmos , Mapeo Cromosómico/métodos , Bases de Datos Genéticas , Etiquetas de Secuencia Expresada , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Sitios de Empalme de ARN/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Análisis de Secuencia de ADN/métodos
5.
Genes Immun ; 9(7): 624-30, 2008 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-18650830

RESUMEN

A recent genome-wide association study (GWAS) conducted by the International Multiple Sclerosis Genetics Consortium (IMSGC) identified a number of putative MS susceptibility genes. Here we have performed a replication study in 1134 Australian MS cases and 1265 controls for 17 risk-associated single nucleotide polymorphisms (SNPs) reported by the IMSGC. Of 16 SNPs that passed quality control filters, four, each corresponding to a different non-human leukocyte antigen (HLA) gene, were associated with disease susceptibility: KIAA0350 (rs6498169) P=0.001, IL2RA (rs2104286) P=0.033, RPL5 (rs6604026) P=0.041 and CD58 (rs12044852) P=0.042. There was no association (P=0.58) between rs6897932 in the IL7R gene and the risk of MS. No interactions were detected between the replicated IMSGC SNPs and HLA-DRB1*15, gender, disease course, disease progression or age-at-onset. We used a novel Bayesian approach to estimate the extent to which our data increased or decreased evidence for association with the six most-associated IMSGC loci. These analyses indicated that even modest P-values, such as those reported here, can contribute markedly to the posterior probability of 'true' association in replication studies. In conclusion, these data provide support for the involvement of four non-HLA genes in the pathogenesis of MS, and combined with previous data, increase to genome-wide significance (P=3 x 10(-8)) evidence of an association between KIAA0350 and risk of disease.


Asunto(s)
Antígenos CD58/genética , Predisposición Genética a la Enfermedad , Subunidad alfa del Receptor de Interleucina-2/genética , Lectinas Tipo C/genética , Proteínas de Transporte de Monosacáridos/genética , Esclerosis Múltiple/genética , Proteínas Ribosómicas/genética , Adolescente , Adulto , Anciano , Australia , Estudios de Casos y Controles , Niño , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple
6.
Genes Brain Behav ; 5(1): 19-28, 2006 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-16436185

RESUMEN

Disruption of dopaminergic (DA) systems is thought to play a central role in the addictive process and in the pathophysiology of schizophrenia. Although inheritance plays an important role in the predisposition to these disorders, the genetic basis of this is not well understood. To provide additional insight, we have performed a modifier screen in mice designed to identify mutations that perturb DA homeostasis. With a genetic background sensitized by a mutation in the dopamine transporter (DAT), we used random chemical mutagenesis and screened for mutant mice with locomotor abnormalities. Four mutant lines were identified with quantitatively elevated levels of locomotor activity. Mapping of mutations in these lines identified two loci that alter activity only when dopamine levels are elevated by a DAT mutation and thus would only have been uncovered by this type of approach. One of these quantitative trait loci behaves as an enhancer of DA neurotransmission, whereas the other may act as a suppressor. In addition, we also identified three loci which are not dependent on the sensitized background but which also contribute to the overall locomotor phenotype.


Asunto(s)
Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Dopamina/metabolismo , Conducta Exploratoria/fisiología , Pruebas Genéticas , Homeostasis/genética , Actividad Motora/genética , Mutagénesis/genética , Animales , Mapeo Cromosómico , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/genética , Etilnitrosourea , Femenino , Tamización de Portadores Genéticos , Homocigoto , Masculino , Ratones , Ratones Endogámicos DBA , Ratones Noqueados , Mutágenos , Fenotipo , Sitios de Carácter Cuantitativo/genética , Distribución Aleatoria
7.
Biostatistics ; 1(1): 1-26, 2000 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-12933522

RESUMEN

We propose a general likelihood-based approach to the linkage analysis of qualitative and quantitative traits using identity by descent (IBD) data from sib-pairs. We consider the likelihood of IBD data conditional on phenotypes and test the null hypothesis of no linkage between a marker locus and a gene influencing the trait using a score test in the recombination fraction theta between the two loci. This method unifies the linkage analysis of qualitative and quantitative traits into a single inferential framework, yielding a simple and intuitive test statistic. Conditioning on phenotypes avoids unrealistic random sampling assumptions and allows sib-pairs from differing ascertainment mechanisms to be incorporated into a single likelihood analysis. In particular, it allows the selection of sib-pairs based on their trait values and the analysis of only those pairs having the most informative phenotypes. The score test is based on the full likelihood, i.e. the likelihood based on all phenotype data rather than just differences of sib-pair phenotypes. Considering only phenotype differences, as in Haseman and Elston (1972) and Kruglyak and Lander (1995), may result in important losses in power. The linkage score test is derived under general genetic models for the trait, which may include multiple unlinked genes. Population genetic assumptions, such as random mating or linkage equilibrium at the trait loci, are not required. This score test is thus particularly promising for the analysis of complex human traits. The score statistic readily extends to accommodate incomplete IBD data at the test locus, by using the hidden Markov model implemented in the programs MAPMAKER/SIBS and GENEHUNTER (Kruglyak and Lander, 1995; Kruglyak et al., 1996). Preliminary simulation studies indicate that the linkage score test generally matches or outperforms the Haseman-Elston test, the largest gains in power being for selected samples of sib-pairs with extreme phenotypes.

8.
Genetics ; 150(1): 459-72, 1998 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-9725861

RESUMEN

Ordered tetrad data yield information on chromatid interference, chiasma interference, and centromere locations. In this article, we show that the assumption of no chromatid interference imposes certain constraints on multilocus ordered tetrad probabilities. Assuming no chromatid interference, these constraints can be used to order markers under general chiasma processes. We also derive multilocus tetrad probabilities under a class of chiasma interference models, the chi-square models. Finally, we compare centromere map functions under the chi-square models with map functions proposed in the literature. Results in this article can be applied to order genetic markers and map centromeres using multilocus ordered tetrad data.


Asunto(s)
Interpretación Estadística de Datos , Modelos Genéticos , Centrómero , Distribución de Chi-Cuadrado , Cromátides
9.
Genetics ; 150(1): 473-85, 1998 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-9725862

RESUMEN

Half-tetrads, where two meiotic products from a single meiosis are recovered together, arise in different forms in a variety of organisms. Closely related to ordered tetrads, half-tetrads yield information on chromatid interference, chiasma interference, and centromere positions. In this article, for different half-tetrad types and different marker configurations, we derive the relations between multilocus half-tetrad probabilities and multilocus ordered tetrad probabilities. These relations are used to obtain equality and inequality constraints among multilocus half-tetrad probabilities that are imposed by the assumption of no chromatid interference. We illustrate how to apply these results to study chiasma interference and to map centromeres using multilocus half-tetrad data.


Asunto(s)
Interpretación Estadística de Datos , Modelos Genéticos , Animales , Cromátides , Marcadores Genéticos , Medicago sativa/genética , Trucha/genética
10.
Genetics ; 139(2): 1031-44, 1995 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-7713406

RESUMEN

In analyzing genetic linkage data it is common to assume that the locations of crossovers along a chromosome follow a Poisson process, whereas it has long been known that this assumption does not fit the data. In many organisms it appears that the presence of a crossover inhibits the formation of another nearby, a phenomenon known as "interference." We discuss several point process models for recombination that incorporate position interference but assume no chromatid interference. Using stochastic simulation, we are able to fit the models to a multilocus Drosophila dataset by the method of maximum likelihood. We find that some biologically inspired point process models incorporating one or two additional parameters provide a dramatically better fit to the data than the usual "no-interference" Poisson model.


Asunto(s)
Intercambio Genético , Modelos Genéticos , Modelos Estadísticos , Recombinación Genética , Animales , Drosophila/genética , Ligamiento Genético , Funciones de Verosimilitud , Método de Montecarlo , Procesos Estocásticos
11.
Genetics ; 142(4): 1369-77, 1996 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-8846913

RESUMEN

Various genetic map functions have been proposed to infer the unobservable genetic distance between two loci from the observable recombination fraction between them. Some map functions were found to fit data better than others. When there are more than three markers, multilocus recombination probabilities cannot be uniquely determined by the defining property of map functions, and different methods have been proposed to permit the use of map functions to analyze multilocus data. If for a given map function, there is a probability model for recombination that can give rise to it, then joint recombination probabilities can be deduced from this model. This provides another way to use map functions in multilocus analysis. In this paper we show that stationary renewal processes give rise to most of the map functions in the literature. Furthermore, we show that the interevent distributions of these renewal processes can all be approximated quite well by gamma distributions.


Asunto(s)
Mapeo Cromosómico , Modelos Genéticos
12.
Genetics ; 139(2): 1045-56, 1995 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-7713407

RESUMEN

The chi-square model (also known as the gamma model with integer shape parameter) for the occurrence of crossovers along a chromosome was first proposed in the 1940's as a description of interference that was mathematically tractable but without biological basis. Recently, the chi-square model has been reintroduced into the literature from a biological perspective. It arises as a result of certain hypothesized constraints on the resolution of randomly distributed crossover intermediates. In this paper under the assumption of no chromatid interference, the probability for any single spore or tetrad joint recombination pattern is derived under the chi-square model. The method of maximum likelihood is then used to estimate the chi-square parameter m and genetic distances among marker loci. We discuss how to interpret the goodness-of-fit statistics appropriately when there are some recombination classes that have only a small number of observations. Finally, comparisons are made between the chi-square model and some other tractable models in the literature.


Asunto(s)
Distribución de Chi-Cuadrado , Intercambio Genético , Animales , Ligamiento Genético , Humanos , Funciones de Verosimilitud , Modelos Genéticos , Modelos Estadísticos , Recombinación Genética
13.
Genetics ; 139(2): 1057-65, 1995 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-7713408

RESUMEN

The nonrandom occurrence of crossovers along a single strand during meiosis can be caused by either chromatid interference, crossover interference or both. Although crossover interference has been consistently observed in almost all organisms since the time of the first linkage studies, chromatid interference has not been as thoroughly discussed in the literature, and the evidence provided for it is inconsistent. In this paper with virtually no restrictions on the nature of crossover interference, we describe the constraints that follow from the assumption of no chromatid interference for single spore data. These constraints are necessary consequences of the assumption of no chromatid interference, but their satisfaction is not sufficient to guarantee no chromatid interference. Models can be constructed in which chromatid interference clearly exists but is not detectable with single spore data. We then extend our analysis to cover tetrad data, which permits more powerful tests of no chromatid interference. We note that the traditional test of no chromatid interference based on tetrad data does not make full use of the information provided by the data, and we offer a statistical procedure for testing the no chromatid interference constraints that does make full use of the data. The procedure is then applied to data from several organisms. Although no strong evidence of chromatid interference is found, we do observe an excess of two-strand double recombinations, i.e., negative chromatid interference.


Asunto(s)
Cromátides , Intercambio Genético , Recombinación Genética , Animales , Modelos Genéticos , Modelos Estadísticos , Esporas Fúngicas/genética
14.
Int J Parasitol ; 35(5): 523-31, 2005 Apr 30.
Artículo en Inglés | MEDLINE | ID: mdl-15826644

RESUMEN

This study is motivated by two data sets which employ a custom Plasmodium falciparum version of the Affymetrix GeneChip, containing only perfect match (PM) oligonucleotides. A PM-only chip cannot be analysed using the standard Affymetrix-supplied software. We compared the performance of three match-only algorithms on these data: the Match Only Integral Distribution (MOID) algorithm, Robust Multichip Analysis (RMA), and the Model Based Expression Index (MBEI). We validated the differential expression of several genes using quantitative reverse transcriptase-PCR. We also performed a comparison using two publicly available 'benchmarking' data sets: the Latin Square spike-in data set generated by Affymetrix, and the Gene Logic dilution series. Since we know what the true fold changes are in these special data sets, they are helpful for assessment of expression algorithms.


Asunto(s)
Algoritmos , Genes Protozoarios , Análisis de Secuencia por Matrices de Oligonucleótidos , Plasmodium falciparum/genética , Animales , Biología Computacional , Perfilación de la Expresión Génica , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Análisis de Secuencia de ADN
15.
J Acquir Immune Defic Syndr (1988) ; 6(3): 303-12, 1993 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-8450406

RESUMEN

A total of 83 HIV seroconversions occurred between 1984 and 1989 in three San Francisco cohorts of homosexual and bisexual men. A nested case-control analysis was performed to assess the risk of seroconversion associated with sexual practices. Strong associations were found with total number of intercourse partners and receptive anal intercourse. Weaker, but significant associations were found with receptive oral intercourse. Individuals reporting condom use with some partners were more likely to become infected than those reporting no condom use. Some of this difference was due to increased numbers of sexual partners among those reporting some condom use, but the association remained significant in multivariate analyses. This observation indicates there is some unmeasured risk associated with those using condoms, such as more HIV seropositive partners.


Asunto(s)
Condones , Infecciones por VIH/transmisión , Conducta Sexual , Parejas Sexuales , Estudios de Cohortes , Infecciones por VIH/epidemiología , Humanos , Masculino , Análisis Multivariante , San Francisco/epidemiología
16.
Mol Biochem Parasitol ; 118(2): 167-74, 2001 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-11738707

RESUMEN

We describe and assess the performance of the gene finding program pretty handy annotation tool (Phat) on sequence from the malaria parasite Plasmodium falciparum. Phat is based on a generalized hidden Markov model (GHMM) similar to the models used in GENSCAN, Genie and HMMgene. In a test set of 44 confirmed gene structures Phat achieves nucleotide-level sensitivity and specificity of greater than 95%, performing as well as the other P. falciparum gene finding programs Hexamer and GlimmerM. Phat is particularly useful for P. falciparum and other eukaryotes for which there are few gene finding programs available as it is distributed with code for retraining it on new organisms. Moreover, the full source code is freely available under the GNU General Public License, allowing for users to further develop and customize it.


Asunto(s)
Biología Computacional , Genes Protozoarios , Cadenas de Markov , Plasmodium falciparum/genética , Programas Informáticos , Algoritmos , Animales , Humanos , Sensibilidad y Especificidad
17.
J Comput Biol ; 4(4): 535-46, 1997.
Artículo en Inglés | MEDLINE | ID: mdl-9385544

RESUMEN

This paper proposes an algorithm for haplotype analysis based on a Monte Carlo method. Haplotype configurations are generated according to the distribution of joint haplotypes of individuals in a pedigree given their phenotype data, via a Markov chain Monte Carlo algorithm. The haplotype configuration which maximizes this conditional probability distribution can thus be estimated. In addition, the set of haplotype configurations with relatively high probabilities can also be estimated as possible alternatives to the most probable one. This flexibility enables geneticists to choose the haplotype configurations which are most reasonable to them, allowing them to include their knowledge of the data under analysis.


Asunto(s)
Algoritmos , Técnicas Genéticas , Haplotipos , Ataxia/genética , Simulación por Computador , Humanos , Leucodistrofia de Células Globoides/genética , Cadenas de Markov , Método de Montecarlo , Linaje
18.
J Comput Biol ; 7(5): 717-29, 2000.
Artículo en Inglés | MEDLINE | ID: mdl-11153095

RESUMEN

The use of transposons offers the possibility of a directed approach to DNA sequencing, where a target DNA up to about 6kb in length can be sequenced quickly and with minimal redundancy. Transposons are mobile DNA elements which can be inserted in a reasonably random fashion into the target DNA. An important part of this process is the location of the transposon insertions (known as mapping) and the selection of a sensible subset of transposons to use as priming sites for sequencing reactions. This paper presents a probabilistic method of scoring selected subsets of transposons and a graph-theoretic algorithm for selection of a subset of maximal score.


Asunto(s)
Elementos Transponibles de ADN/genética , Análisis de Secuencia de ADN/métodos , Algoritmos , Modelos Estadísticos , Análisis de Secuencia de ADN/estadística & datos numéricos
19.
J Comput Biol ; 3(3): 345-60, 1996.
Artículo en Inglés | MEDLINE | ID: mdl-8891954

RESUMEN

The relative abundance and rarity of DNA words have been recognized in previous biological studies to have implications for the regulation, repair, and evolutionary mechanisms of a genome. In this paper, we review several different measures of abundance and rarity of DNA words, including z-scores, representation ratios, and cross-ratios, that have appeared in the recent literature, and examine the concordance among them using the human cytomegalovirus genome sequence. We then rank all words of length k = 2, ..., 5 of seven herpesvirus genomes according to their abundance, as measured by one of the z-scores based upon a stationary Markov model of order k-2. Using a simple metric on the ranks of 2-words of the seven herpesvirus sequences, we construct an evolutionary tree. Several 3-words are observed to be consistently over- or underrepresented in all seven herpesviruses. Furthermore, clusters of some of the most over- and underrepresented 4- and 5-words in the genomes are identified with functional sites such as the origins of replication and regulatory signals of individual viruses.


Asunto(s)
ADN Viral/química , Herpesviridae/genética , Algoritmos , Genoma Viral , Humanos , Cadenas de Markov
20.
J Appl Physiol (1985) ; 79(5): 1615-28, 1995 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-8594022

RESUMEN

The low-temperature electron microscope, which preserves aqueous structures as solid water at liquid nitrogen temperature, was used to image the alveolar lining layer, including surfactant and its aqueous subphase, of air-filled lungs frozen in anesthetized rats at 15-cmH2O transpulmonary pressure. Lining layer thickness was measured on cross fractures of walls of the outermost subpleural alveoli that could be solidified with metal mirror cryofixation at rates sufficient to limit ice crystal growth to 10 nm and prevent appreciable water movement. The thickness of the liquid layer averaged 0.14 micron over relatively flat portions of the alveolar walls, 0.89 micron at the alveolar wall junctions, and 0.09 micron over the protruding features (9 rats, 20 walls, 16 junctions, and 146 areas), for an area-weighted average thickness of 0.2 micron. The alveolar lining layer appears continuous, submerging epithelial cell microvilli and intercellular junctional ridges; varies from a few nanometers to several micrometers in thickness, and serves to smooth the alveolar air-liquid interface in lungs inflated to zone 1 or 2 conditions.


Asunto(s)
Alveolos Pulmonares/ultraestructura , Animales , Criopreservación , Masculino , Microscopía Electrónica de Rastreo , Ratas , Ratas Sprague-Dawley
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