RESUMEN

Resumen La alineación de ADN es un proceso clave para la reconstrucción de genomas, a partir de los millones de lecturas cortas producidas por las máquinas de secuenciación paralela masiva. Tal proceso suele realizarse mediante algoritmos con elevada complejidad espacial y temporal, requiriendo varias horas para entregar los resultados, así como decenas de GB de RAM. Esto ha motivado la búsqueda de nuevos algoritmos y/o estrategias que permitan disminuir los tiempos de ejecución, mientras se utilizan recursos mínimos de memoria. En este artículo se presenta ABPSE, un nuevo alineador de ADN que combina el algoritmo de Ferragina y Manzini (o índices de FM) y el algoritmo de Myers, mediante la estrategia siembra y extiende. En la siembra, los índices de FM permiten calcular de manera rápida regiones con alta probabilidad de alineación; mientras que en la extensión, el algoritmo de Myers refina la alineación utilizando operaciones basadas en vectores de bits, calculando simultáneamente varias celdas de la matriz de programación dinámica. Los resultados muestran un 96.1% de lecturas alineadas correctamente, un factor de aceleración de 2.45x en relación a BWA-SW y un uso de memoria de apenas 7.6 GB, cuando se alinea el genoma humano completo.

Abstract DNA alignment is a key process in the assembly of genomes from the millions of short reads that are produced by massive parallel sequencing machines. Such a process is usually done by means of high spatial and temporal complexity algorithms, which takes hours to deliver the results as well as tens of GB of RAM. This has prompted the search for new algorithms and/or strategies that allow shorter runtimes, while using minimal memory footprint. In this article, we present ABPSE, a new DNA aligner that combines the Ferragina and Manzini algorithm (or FM indexes) and the Myers algorithm, by means of the seed and extend strategy. In the seeding, the FM indices allow a rapid calculation of the regions with high probability of alignment. In the extension, the Myers algorithm refines the alignment using operations based on bit vectors. It simultaneously calculates several cells of the dynamic programming matrix. The results show 96.1% of correctly aligned reads, an acceleration factor of 2.45x in relation to BWA-SW and a memory footprint of only 7.6 GB when aligning the entire human genome.

RESUMEN

Estrogen (17ß-estradiol) is essential for normal growth and differentiation in the mammary gland. In the last three decades, previous investigations have revealed that Estrogen Receptor Alpha (ERα) plays a critical role in breast cancer. More recently, observations regarding the widespread expression of ERß-like proteins in normal and neoplastic mammary tissues have suggested that ERß is also involved in the mentioned pathology. Design of new drugs both steroidal and nonsteroidal that target any of these receptors represents a promise to treat breast cancer although it remains a challenge due to the sequence similarity between their catalytic domains. In this work, we propose a new set of compounds that could effectively target the estrogen receptors ERα and ERß. These ligands were designed based on the chemical structure of the ERß-selective agonist Diarylpropionitrile (DPN). The designed ligands were submitted to in silico ADMET studies, yielding in a filtered list of ligands that showed better drug-like properties. Molecular dynamics simulations of both estrogen receptors and docking analysis were carried-out employing the designed compounds, from which two were chosen due to their promising characteristics retrieved from theoretical results (docking analysis or targeting receptor predictions). They were chemically synthetized and during the process, two precursor ligands were also obtained. These four ligands were subjected to biological studies from which it could be detected that compound mol60b dislplayed inhibitory activity and its ability to activate the transcription via an estrogenic mechanism of action was also determined. Interestinly, this observation can be related to theoretical binding free energy calculations, where the complex: ERß-mol60b showed the highest energy ΔGbind value in comparison to others.

Asunto(s)

RESUMEN

En los últimos años ha ocurrido un avance impresionante en las máquinas de secuenciación paralela masiva, también llamadas de secuenciación de siguiente generación (NGS), por ejemplo, máquinas recientes como Illumina Hiseq son capaces de generar millones de lecturas en una sola corrida. No obstante, estas tecnologías están limitadas a secuenciar solo fragmentos pequeños de material genético (entre 35 y 1100 nucleótidos), por lo que para secuenciar un genoma completo es necesario dividir la cadena, secuenciar y posteriormente ensamblar las lecturas cortas obtenidas. En este trabajo se revisan y comparan las tecnologías de secuenciación recientes, se estudia el proceso de ensamble de genomas completos y se establece formalmente el problema de la alineación. También se incluye un resumen de los principales programas de alineación y sus algoritmos que lo soportan. Finalmente, después de concluir que las tecnologías de secuenciación han superado en velocidad por un factor mayor a 10x a los programas de alineación, se revisa la aceleración Hardware como alternativa para acelerar tales programas. Este trabajo al ser una revisión integral pretende contribuir al desarrollo de investigación en el área de bioinformática en el país.

In recent years, impressive progress has occurred in the machines of massively parallel sequencing, also called of next-generation sequencing (NGS), for example, recent machines like Illumina HiSeq are capable of generating millions of reads in a single run. However, these technologies are limited to sequence only small fragments of genetic material (35 to 1100 nucleotides), so that for complete-genome sequencing, it is necessary to divide the chain, to sequence the fragments, and, subsequently, to assemble the obtained short readings. In this paper, the recent NGS sequencing technologies are reviewed and compared, analyzing the problem of sequence assembly, and formally establishing the problem of alignment. Also, it is examined the main alignment programs and the algorithms that support them. Finally, after concluding that sequencing technologies have speed that exceeds 10 times to the speed of the alignment programs, the hardware acceleration is reviewed as an alternative to accelerate these programs. This work, which is a comprehensive analysis and review, aims to contribute to the development of the research in the area of bioinformatics in the country.

Asunto(s)

RESUMEN

This is a rare case of a patient with type 1 multiple endocrine neoplasia (MEN-1) syndrome. The case is further unusual in that the glucagonoma debuted with two synchronic pancreatic masses at the time of diagnosis and with pulmonary metastases as the primary site of metastasis and not the more usual site of the liver.

Asunto(s)

RESUMEN

Phototransduction in the Drosophila retina appears to require the phosphoinositide signaling cascade following receptor/G-protein activation. Subsequent opening of membrane cationic channels causes excitation. The biochemical events underlying channel opening and regulation of sensitivity remain largely unknown. Evidence is mounting that phototransduction in Drosophila and other invertebrate species may additionally involve the second messenger, cyclic-GMP (cGMP). We report that exogenous cGMP influenced Drosophila retinal phototransduction in two ways. In whole cell tight-seal voltage-clamp experiments, membrane permeant cGMP analog, 8-bromo-cyclic-GMP (8-Br-cGMP), induced membrane currents and dramatically enhanced light-induced currents. The currents induced by 8-Br-cGMP possessed reversal potentials similar to those induced by light. The magnitudes of cGMP-induced currents exhibited marked dependence on intensity of background illumination. Potential direct or modulatory roles of cGMP in Drosophila phototransduction are discussed.

Asunto(s)

RESUMEN

Because infants of substance-abusing mothers (ISAM) have an increased risk of sudden infant death syndrome and have abnormal sleeping ventilatory patterns, we studied the effects of mild hypoxia during quiet sleep on ventilatory pattern, heart rate, and arousal in 23 healthy ISAM (mean +/- SEM: 9.0 +/- 0.49 weeks of age) and 15 healthy, similarly aged, control infants. Hypercapnic challenges were performed in six ISAM and eight control subjects. Hypoxic arousal responses were elicited by rapidly decreasing inspired oxygen tension to 80 mm Hg for 3 minutes or until arousal occurred. Failure to arouse to hypoxia occurred in the majority of infants in both groups. All infants had a fall in end-tidal carbon dioxide tension during hypoxia, suggesting that each had a hypoxic ventilatory response. However, the fall in end-tidal carbon dioxide tension was significantly less in the ISAM (mean +/- SEM: -4.0 +/- 0.3 vs -8.0 +/- 1.0 mm Hg), suggesting blunted ventilatory responses to hypoxia. Periodic breathing occurred during 9.5% of hypoxic challenges in control infants compared with 37% in ISAM (p = 0.056). Heart rates were significantly higher in the ISAM before, during, and after hypoxic challenges. Hypercapnic challenges (inspired carbon dioxide tension of 60 mm Hg for a maximum of 3 minutes) resulted in arousal in all infants; however, ISAM required a significantly longer exposure to hypercapnia before arousal (mean +/- SEM; 116 +/- 7.8 vs 79 +/- 13.9 seconds; p < 0.02). We conclude that ISAM have an impaired repertoire of protective responses to hypoxia and hypercapnia during sleep, and that this may play a role in their increased risk for sudden infant death syndrome.

Asunto(s)

RESUMEN

This paper discusses the relationship between migration and health using as a case study the problem of Acquired Immunodeficiency Syndrome (AIDS) in the Mexican-American border. The authors state that the permanent nature of migration between Mexico and the United States points to the need of binational health programs offering health education and promotion, and a greater interaction between the Mexican and the American health care systems.

Asunto(s)

RESUMEN

A population-based study was performed to determine whether substance abuse during the perinatal period may be a risk factor for sudden infant death syndrome (SIDS). The incidence of SIDS was studied in 2143 infants of substance-abusing mothers (ISAM) born in Los Angeles County during 1986 and 1987 who were reported to the Los Angeles County Department of Health Services because of a history of drug exposure or positive urine test results in the mother, infant, or both. By comparing the ISAM birth reports with records of autopsy-proven SIDS in Los Angeles County, we found 19 SIDS cases in the population of 2143 ISAM, a SIDS rate of 8.87 cases per 1000 ISAM (95% confidence interval 5.3 to 13.8). This was significantly higher than the SIDS rate for the non-ISAM general population: 396 SIDS deaths among 325,372 live births, an incidence rate of 1.22 cases per 1000 births, p less than 0.00001. The age of ISAM at death was 99 +/- 63 (mean +/- SD) days compared with 91 +/- 52 days for the non-ISAM population (not significant). The incidence of SIDS was significantly greater in male infants, during the winter months, in black infants, and in non-Hispanic white infants in the non-ISAM population. Such differences were not observed in the ISAM group. A greater incidence of symptomatic apnea was reported before SIDS for the ISAM than for the non-ISAM population (22% vs 5.4%, p = 0.022). We conclude that ISAM have a higher incidence of SIDS than the non-ISAM general population. However, it was not possible to separate maternal substance abuse from other confounding variables that may also have had an impact on SIDS risk in the ISAM group.

Asunto(s)

RESUMEN

Growth failure is a major problem in infants with bronchopulmonary dysplasia (BPD), but the cause is unknown. We studied 13 infants with BPD but without other medical problems that could contribute to growth failure at 6 months' corrected age. We measured resting oxygen consumption (Vo2), Pao2, airway resistance, specific airway conductance, and dynamic pulmonary compliance (Cdyn) by body plethysmography and growth. Growth failure was defined as height and weight less than the tenth percentile of the Babson growth curves. Vo2 in infants with growth failure and BPD was markedly elevated compared with that in control infants and infants with BPD and normal growth. Vo2 showed an inverse correlation with body weight in infants with BPD but not in control infants. Although Vo2 was inversely related to Cdyn, the total work of breathing only partially explained the increased metabolic demands of the growth failure group. We speculate that growth failure in infants with BPD is partially the result of increased metabolic demands from increased work of breathing but that other mechanisms may act to elevate the metabolic expenditure of these infants.

Asunto(s)

RESUMEN

This study in the sociology of lay knowledge seeks to conceptualize the "everyday rules" by which a patient makes choices about which practitioner should be consulted for which episode. A lay person must often choose a practitioner from among competing coteries of specialists, without having recourse to their specialized knowledge in order to classify them. The patient must develop her own typology of specialists, utilizing her own criteria. The patient becomes aware of a number of aspects of an epsiode, each of which requires a response of some sort. In the course of her interaction with a practitioner, the patient discovers that the practitioner is competent, in her perception to handle some aspects and inadequate to handle others, thereby presenting her with a particular constellation of competencies and inadequacies. When seeing different practitioners, the patient encounters vertical and horizontal conflict between the assessments offered her by each. She must decide which offers the competencies most needed and the inadequacies most tolerable. A practitioner's constellation may change over time or by episode. In order to secure the competencies she feels necessary, the patient may utilize a number of practitioners either sequentially or simultaneously, thereby functioning as an assembler of her own health care team.

Asunto(s)