Specific binding of the methyl binding domain protein 2 at the BRCA1-NBR2 locus

The methyl-CpG binding domain (MBD) proteins are key molecules in the interpretation of DNA methylation signals leading to gene silencing. We investigated their binding specificity at the constitutively methylated region of a CpG island containing the bidirectional promoter of the Breast cancer predisposition gene 1, BRCA1, and the Near BRCA1 2 (NBR2) gene. In HeLa cells, quantitative chromatin immunoprecipitation assays indicated that MBD2 is associated with the methylated region, while MeCP2 and MBD1 were not detected at this locus. MBD2 depletion (∼90%), mediated by a transgene expressing a small interfering RNA (siRNA), did not induce MeCP2 or MBD1 binding at the methylated area. Furthermore, the lack of MBD2 at the BRCA1-NBR2 CpG island is associated with an elevated level of NBR2 transcripts and with a significant reduction of induced-DNA-hypomethylation response. In MBD2 knockdown cells, transient expression of a Mbd2 cDNA, refractory to siRNA-mediated decay, shifted down the NBR2 mRNA level to that observed in unmodified HeLa cells. Variations in MBD2 levels did not affect BRCA1 expression despite its stimulation by DNA hypomethylation. Collectively, our data indicate that MBD2 has specific targets and its presence at these targets is indispensable for gene repression

The influence of a power law drift on the exit time of Brownian motion from a half-line

AbstractThe addition of a Bessel drift 1x to a Brownian motion affects the lifetime of the process in the interval (0,∞) in a well-understood way. We study the corresponding effect of a power −βxp(β≠0,p>0) of the Bessel drift. The most interesting case occurs when β>0. If p>1 then the effect of the drift is not too great in the sense that the exit time has the same critical value q0 for the existence of qth moments (q>0) as the exit time of Brownian motion. When p<1, the influence is much greater: the exit time has exponential moments

Comparing Hierarchical Data Structures and Hierarchical Data Analysis

Real world data is inherently noisy and data analysis can be especially complex when noise is compounded in hierarchical and multilevel data structures. Since such data structures can be described using multiple approaches, the way data is collapsed and grouped within these structures can influence its resulting interpretation and analyses. To avoid discrepancies in data collapsing and grouping, multiple statistical approaches have been developed specifically to analyze multilevel data structures. Examples of multilevel statistical models are the two-factor ANOVA and the general linear model with repeated-measures (GLM-RR) which is typically used in the context of looking at change over time. Unlike simple summary-statistics such as t-tests, multilevel models allow for precision in the effect of each level on the observed data. In this study, analyses will be done using both simple statistical models and multilevel models with a dataset from a behavioral decision-making assay that aims to see whether phototactic preference changes over 24 hours in larval zebrafish. The simple and multilevel analyses will be compared through the descriptive analyses and hypothesis testing. The descriptive analyses will provide insight into the practicality of collapsing levels of data in hierarchical data structures and the hypothesis testing will provide comparative insight into the use of both simple and multilevel statistical models

Brownian Motion with a Singular Drift

We study the effect of a power law drift on Brownian motion in the positive half-line, where the order of the drift at 0 and infinity is different.Comment: 29 page

A Role for Methyl-CpG Binding Domain Protein 2 in the Modulation of the Estrogen Response of pS2/TFF1 Gene

Background: In human Estrogen Receptor alpha (ER alpha)-positive breast cancers, 59 end dense methylation of the estrogen-regulated pS2/TFF1 gene correlates with its transcriptional inhibition. However, in some ER alpha-rich biopsies, pS2 expression is observed despite the methylation of its TATA-box region. Herein, we investigated the methylation-dependent mechanism of pS2 regulation. Methodology/Principal Findings: We observed interplay between Methyl-CpG Binding Domain protein 2 (MBD2) transcriptional repressor and ER alpha transactivator: (i) the pS2 gene is poised for transcription upon demethylation limited to the enhancer region containing the estrogen responsive element (ERE); (ii) MBD2-binding sites overlapped with the methylation status of the pS2 59 end; (iii) MBD2 depletion elevated pS2 expression and ectopic expression of ER alpha partially overcame the inhibitory effect of MBD2 when the ERE is unmethylated. Furthermore, serial chromatin immunoprecipitation assays indicated that MBD2 and ER alpha could simultaneously occupy the same pS2 DNA molecule; (iv) concomitant ectopic ER alpha expression and MBD2 depletion resulted in synergistic transcriptional stimulation, while the pS2 promoter remains methylated. Conclusions/Significance: MBD2 and ER alpha drive opposite effects on pS2 expression, which are associated with specific steady state levels of histone H3 acetylation and methylation marks. Thus, epigenetic silencing of pS2 could be dependent on balance of the relative intracellular concentrations of ER alpha and MBD2

Restaurant site selection

"Restaurant site selection is a complex decision often made without proper planning or sufficient information. It is generally held that the site selection process is more art than science and therefore difficult to quantify. The most important aspect of site selection is to assure that all factors that could possibly have any bearing on the decision are considered carefully."--First paragraph.Neil P. Quirk (Management Assistance Officer, Small Business Administration ; St. Louis), Robert F. Lukowski and Dante M. Laudadio (State Extension Specialists, Food Service and Lodging Management ; University of Missouri--Columbia)Includes bibliographical references

A Role for Methyl-CpG Binding Domain Protein 2 in the Modulation of the Estrogen Response of pS2/TFF1 Gene

In human Estrogen Receptor alpha (ERalpha)-positive breast cancers, 5' end dense methylation of the estrogen-regulated pS2/TFF1 gene correlates with its transcriptional inhibition. However, in some ERalpha-rich biopsies, pS2 expression is observed despite the methylation of its TATA-box region. Herein, we investigated the methylation-dependent mechanism of pS2 regulation.We observed interplay between Methyl-CpG Binding Domain protein 2 (MBD2) transcriptional repressor and ERalpha transactivator: (i) the pS2 gene is poised for transcription upon demethylation limited to the enhancer region containing the estrogen responsive element (ERE); (ii) MBD2-binding sites overlapped with the methylation status of the pS2 5' end; (iii) MBD2 depletion elevated pS2 expression and ectopic expression of ERalpha partially overcame the inhibitory effect of MBD2 when the ERE is unmethylated. Furthermore, serial chromatin immunoprecipitation assays indicated that MBD2 and ERalpha could simultaneously occupy the same pS2 DNA molecule; (iv) concomitant ectopic ERalpha expression and MBD2 depletion resulted in synergistic transcriptional stimulation, while the pS2 promoter remains methylated.MBD2 and ERalpha drive opposite effects on pS2 expression, which are associated with specific steady state levels of histone H3 acetylation and methylation marks. Thus, epigenetic silencing of pS2 could be dependent on balance of the relative intracellular concentrations of ERalpha and MBD2

Epidemiología de la tuberculosis en establecimientos de salud urbano marginales de Chaclacayo, Perú 2001-2010

Caracteriza la epidemiología de la tuberculosis, considerando los factores sociodemográficos, hábitos inadecuados de vida, antecedentes de internamiento y comorbilidades; historia de antecedentes personales y familiares de contactos asociados a la tuberculosis y caracteristicas sobre el diagnóstico de casos de tuberculosis. Los datos fueron recogidos de las historias clínicas y de los libros de registro de pacientes del Programa de Control de Tuberculosis, mediante una ficha ad hoc. La información fue procesada según criterios de estadística descriptiva y programa Statgraphics versión XIX. Fueron registrados en total 912 casos de tuberculosis, el número mayor fue del grupo etario de 18 a 29 años (37,4 %), seguido de 30 a 59 años (33,2 %), siendo el 57,3 % de género masculino. Respecto a los factores sociales el 52,6 % tenía nivel de instrucción secundaria y de ocupación estudiante 29 % (236/815); en relación a los hábitos de vida inadecuados, 50,7% consumía alcohol (204/402), tabaquismo 28,9 % (116/402) y 20,4 % reportó consumo de droga ilegal (82/402); en comorbilidades inmunosupresoras, se encontró diabetes mellitus en 53,7 % (36/67), infección con VIH 28,4 % (19/67) y asma bronquial 17,9 % (12/67); en antecedentes de internamiento institucional mayor a 15 dias, se reportó hospitalización en 60,9 % (56/92), prisión 21,4 % (20/92); en historia de antecedentes personales de tuberculosis 13,5 % (123/912) y antecedentes de contactos familiares 34,8 % (317/912) de tipo intradomiciliario 66,2 % (178/269). Sobre la forma de tuberculosis, la pulmonar representó 78,0 % con baciloscopía positiva (76,5%), mientras que 22 % fue extrapulmonar, de los cuales, tipo pleural (59,2%). Sobre otros exámenes, los rayos x tórax fueron compatibles en 71,5 %. La curación fue de 92,3 %. El grupo de edad mas afectado por TB estuvo conformado por la población económicamente activa de jovenes y adultos entre los 18 a 59 años, con predominio del género masculino y la forma pulmonar con baciloscopía positiva; así mismo presentan conductas de riesgo y comorbilidades inmunosupresoras como diabetes mellitus e infección por virus de la inmunodeficiencia humana y el tratamiento fue eficaz en más del 90

Specific association between the methyl-CpG-binding domain protein 2 and the hypermethylated region of the human telomerase reverse transcriptase promoter in cancer cells

Human telomerase reverse transcriptase (hTERT) is expressed in most cancer cells. Paradoxically, its promoter is embedded in a hypermethylated CpG island. A short region escapes to this alteration, allowing a basal level of transcription. However, the methylation of adjacent regions may play a role in the maintenance of low hTERT expression. It is now well established that methyl-CpG binding domain proteins mediate the transcriptional silencing of hypermethylated genes. The potential involvement of these proteins in the control of hTERT expression was firstly investigated in HeLa cells. Chromatin immunoprecipitation assays showed that only methyl-CpG-binding domain protein 2 (MBD2) associated the hypermethylated hTERT promoter. In MBD2 knockdown HeLa cells, constitutively depleted in MBD2, neither methyl CpG binding protein 2 (MeCP2) nor MBD1 acted as substitutes for MBD2. MBD2 depletion by transient or constitutive RNA interference led to an upregulation of hTERT transcription that can be downregulated by expressing mouse Mbd2 protein. Our results indicate that MBD2 is specifically and directly involved in the transcriptional repression of hTERT in HeLa cells. This specific transcriptional repression was also observed in breast, liver and neuroblastoma cancer cell lines. Thus, MBD2 seems to be a general repressor of hTERT in hTERT-methylated telomerase-positive cell