Isolation and characterization of a dideoxyguanosine triphosphate-resistant mutant of human immunodeficiency virus reverse transcriptase

The appearance of drug-resistant strains of viral pathogens is a major difficulty confounding current efforts to block viral infections. The identification and analysis of mutations responsible for drug resistance can provide important clues helpful in understanding the mechanisms of resistance and in the eventual development of better therapies. We have used a direct screening method to scan libraries of mutagenized genes encoding the reverse transcriptase of human immunodeficiency virus type 1, and have recovered a variant enzyme that is resistant to the chain-terminator inhibitor 2',3'-dideoxyguanosine triphosphate. The single substitution mutation in this variant conferred broad crossresistance to a variety of other antiviral compounds currently in clinical trials. Virus carrying the mutation was fully infectious in cultured human lymphocytes. The replication of the mutant virus was highly resistant to phosphonoformic acid but did not show increased resistance to the prodrug dideoxyguanosine

Relationship Between Foveal Cone Specialization and Pit Morphology in Albinism

Purpose.Albinism is associated with disrupted foveal development, though intersubject variability is becoming appreciated. We sought to quantify this variability, and examine the relationship between foveal cone specialization and pit morphology in patients with a clinical diagnosis of albinism. Methods. We recruited 32 subjects with a clinical diagnosis of albinism. DNA was obtained from 25 subjects, and known albinism genes were analyzed for mutations. Relative inner and outer segment (IS and OS) lengthening (fovea-to-perifovea ratio) was determined from manually segmented spectral domain-optical coherence tomography (SD-OCT) B-scans. Foveal pit morphology was quantified for eight subjects from macular SD-OCT volumes. Ten subjects underwent imaging with adaptive optics scanning light ophthalmoscopy (AOSLO), and cone density was measured. Results. We found mutations in 22 of 25 subjects, including five novel mutations. All subjects lacked complete excavation of inner retinal layers at the fovea, though four subjects had foveal pits with normal diameter and/or volume. Peak cone density and OS lengthening were variable and overlapped with that observed in normal controls. A fifth hyper-reflective band was observed in the outer retina on SD-OCT in the majority of the subjects with albinism. Conclusions. Foveal cone specialization and pit morphology vary greatly in albinism. Normal cone packing was observed in the absence of a foveal pit, suggesting a pit is not required for packing to occur. The degree to which retinal anatomy correlates with genotype or visual function remains unclear, and future examination of larger patient groups will provide important insight on this issue

Sleep and Inflammation During Adolescents\u27 Transition to Young Adulthood

Purpose This study investigated the extent to which multiple sleep dimensions are associated with inflammation during adolescents\u27 transition to young adulthood, a developmental period when sleep difficulties and systemic inflammation levels are on the rise. Additionally, the moderating roles of socioeconomic status (SES) and ethnicity were explored. Methods A total of 350 Asian American, Latino, and European American youth participated at two-year intervals in wave 1 ( n = 316, M age = 16.40), wave 2 ( n = 248 including 34 new participants to refresh the sample, M age = 18.31), and wave 3 ( n = 180, M age = 20.29). Sleep duration (weekday and weekend) and variability in duration (nightly and weekday/weekend) were obtained from eight nights of wrist actigraphy. Subjective sleep quality was assessed using the Pittsburgh Sleep Quality Index. Levels of C-reactive protein (CRP), a biomarker of systemic inflammation, were assayed from dried blood spots obtained from finger pricks. Results Multilevel models demonstrated that greater weekday/weekend sleep variability and worse sleep quality were associated with higher CRP; shorter weekend duration was associated with higher CRP only at younger ages. Shorter weekday duration was associated with higher CRP only among high-SES youth, whereas greater nightly variability was associated with higher CRP only among European American youth. Conclusions Aspects of poor sleep may contribute to the rise of CRP during adolescents\u27 transition to young adulthood, especially in earlier years. In addition, some sleep-CRP associations may vary as a function of youth\u27s SES and ethnicity

Attenuation of RNA polymerase II pausing mitigates BRCA1-associated R-loop accumulation and tumorigenesis.

Most BRCA1-associated breast tumours are basal-like yet originate from luminal progenitors. BRCA1 is best known for its functions in double-strand break repair and resolution of DNA replication stress. However, it is unclear whether loss of these ubiquitously important functions fully explains the cell lineage-specific tumorigenesis. In vitro studies implicate BRCA1 in elimination of R-loops, DNA-RNA hybrid structures involved in transcription and genetic instability. Here we show that R-loops accumulate preferentially in breast luminal epithelial cells, not in basal epithelial or stromal cells, of BRCA1 mutation carriers. Furthermore, R-loops are enriched at the 5' end of those genes with promoter-proximal RNA polymerase II (Pol II) pausing. Genetic ablation of Cobra1, which encodes a Pol II-pausing and BRCA1-binding protein, ameliorates R-loop accumulation and reduces tumorigenesis in Brca1-knockout mouse mammary epithelium. Our studies show that Pol II pausing is an important contributor to BRCA1-associated R-loop accumulation and breast cancer development

Effects of Acyclovir and IVIG on Behavioral Outcomes after HSV1 CNS Infection

Herpes simplex virus 1 (HSV) encephalitis (HSE) has serious neurological complications, involving behavioral and cognitive impairments that cause significant morbidity and a reduced quality of life. We showed that HSE results from dysregulated central nervous system (CNS) inflammatory responses. We hypothesized that CNS inflammation is casually involved in behavioral abnormalities after HSE and that treatment with ACV and pooled human immunoglobulin (IVIG), an immunomodulatory drug, would improve outcomes compared to mice treated with phosphate buffered saline (PBS) or ACV alone. Anxiety levels were high in HSV-infected PBS and ACV-treated mice compared to mice treated with ACV + IVIG, consistent with reports implicating inflammation in anxiety induced by lipopolysaccharide (LPS) or stress. Female, but not male, PBS-treated mice were cognitively impaired, and unexpectedly, ACV was protective, while the inclusion of IVIG surprisingly antagonized ACV’s beneficial effects. Distinct serum proteomic profiles were observed for male and female mice, and the antagonistic effects of ACV and IVIG on behavior were paralleled by similar changes in the serum proteome of ACV- and ACV + IVIG-treated mice. We conclude that inflammation and other factors mediate HSV-induced behavioral impairments and that the effects of ACV and IVIG on behavior involve novel mechanisms

Learning Styles: a Step Forward in its Conceptualization and Diagnosis. (Depending on the Learning Styles of Alonso, Gallego and Honey, 1994)

RESUMEN: El resumen/ del artículo publicado en la REA nº3 Vol. 3 Abril (2009) lo finalizábamos exponiendo que "las propuestas, como tal, son quizá incompletas e imperfectas pero estos adjetivos las otorga, desde una crítica constructiva, el reto de complementarlas, mejorarlas y avanzar en la relación y un mayor ajuste entre la enseñanza y el aprendizaje". En este artículo, presentamos los avances en cuanto a la conceptualización y diagnóstico de los EE.EE definidos a partir de los comportamientos de enseñanza de los docentes. Hemos definido cada uno de los Estilos y re-construido el instrumento "Cuestionario de Estilos de Enseñanza CEE" Martínez (2002), para no diagnosticar contrastando pares de Estilos, como se había realizado en la publicación anteriormente citada, sino, para valorar cada uno en sí mismo. Desde el reconocimiento, aporte y el respeto, consideramos adoptar el formato del CHAEA Alonso, Gallego y Honey (1994) para favorecer el tratamiento estadístico y facilitar el contraste de resultados. El instrumento ha sido puesto en campo y está validado en cuanto a contenido y estadísticos.ABSTRACT: The abstract of the article published in the REA N. 3 Vol 3 April (2009) ended maybe the proposals, such as, are incomplete and imperfect but from constructive critical, these adjectives give them the challenge of complement, improve and advance toward better fit between teaching and learning In this paper, we present the advances about conceptualization and diagnose of EE.EE according to teaching behaviors of teachers.We have defined each of the styles and re-built the instrument "Teaching Styles Questionnaire EEC" (Martinez, 2002). The aim has been discovered the ontrast styles pairs and assess each one.We have gone in for CHAEA format (Alonso, Gallego and Honey, 1994) to encourage and facilitate the statistical contrast results. The instrument has been developed and is validated in terms of content and statistical. Key Words: Teaching, teaching behaviorsL earning, teaching styles