Transcriptional activation of the proapoptotic bik gene by E2F proteins in cancer cells

AbstractBH3-only proteins are required for execution of apoptotic cell death. We have found that one of these proteins, Bik, is strongly induced in cancer cells treated with chemotherapeutic agents. Furthermore, we showed that chemotherapy-induced expression of bik is independent of p53. Consistent with its pro-apoptotic activity, blockade of bik expression reduces the adriamycin-mediated apoptotic cell death. We also found that the bik gene is transcriptionally activated by E2F proteins. Consistently, adriamycin induces the E2F-bik pathway. In addition, E2Fs transactivate bik by a p53-independent mechanism. Thus, our data indicate that transcriptional regulation of bik contributes to the efficient apoptotic response to chemotherapeutic agents

Induction of Nod2 in Myelomonocytic and Intestinal Epithelial Cells via Nuclear Factor-kB Activation

Nod2, a member of the Apaf1/Nod protein family, confers responsiveness to bacterial products and activates NF-kB, a ranscription factor that plays a central role in innate immunity. Recently, genetic variation in Nod2 has been associated with susceptibility to Crohn’s disease. Here, we report that expression of Nod2 is induced upon differentiation of CD34+ hematopoietic progenitor cells into granulocyte or monocyte/macrophages. In peripheral blood cells, the highest levels of Nod2 were observed in CD14+ (monocytes), CD15+ (granulocytes), and CD40+/CD86+ (dendritic cells) cell populations. Notably, stimulation of myeloblastic and epithelial cells with bacterial lipopolysaccharide or TNF resulted in up-regulation of Nod2. A search for consensus sites within the Nod2 promoter revealed a NF-kB binding element that was required for transcriptional activity in response to TNF . Moreover, ectopic expression of p65 induced transactivation, whereas that of dominant-negative I B blocked the transcriptional activity of the Nod2 promoter. Upon stimulation with TNF or lipopolysaccharide, both p50 and p65 subunits of NF-kB were bound to the Nod2 promoter. Thus, Nod2 expression is enhanced by proinflammatory cytokines and bacterial components via NF-kB, a mechanism that may contribute to the amplification of the innate immune response and susceptibility to inflammatory disease

The Impact of Postnatal Systemic Steroids on the Growth of Preterm Infants: A Multicenter Cohort Study

Postnatal steroids, often used to prevent and treat bronchopulmonary dysplasia, may influence the growth of preterm infants, although data are scarce in the literature. This is a multicenter cohort study including surviving preterm infants <32 weeks at birth (n = 17,621) from the Spanish Neonatal Network SEN1500 database, without major congenital malformations. Linear regression models were adjusted for postnatal steroids, respiratory severity course (invasive mechanical ventilation at 28 days), progression to moderate-severe bronchopulmonary dysplasia (O2 at 36 weeks), length of stay, sex, gestational age and z-scores at birth. A subgroup analysis depending on the timing of administration, ventilation status at 28 days and moderate-severe BPD diagnosis was also performed. Overall, systemic postnatal steroids were not independently associated with poorer weight gain (0.1; 95% CI: -0.05 to 0.2 g/kg/day), linear growth (0; 95% CI: -0.03 to 0.01 cm/week) or head circumference growth (-0.01; 95% CI: -0.02 to 0 cm/week). Patients who received steroids after 28 days or who were not O2 dependent at 36 weeks after having received steroids gained more weight (0.22; 95% CI: 0.04 to 0.4 and 0.2; 95% CI: 0.004 to 0.5 g/kg/day, respectively). Globally, systemic postnatal steroids had no significant adjusted effect on postnatal growth

Aging of ECG characteristics over a five year period

The aim of this work was to find evidence of aging of ECG indicators in a population of young adults (52 subjects of age 19 ± 0.6 in 2002). For this purpose, an application which analyzes ECG signals was designed and implemented. The data consist in four different series for each subject of the studied population. Two ECG signals of 5 minute duration (one at rest and one after a mild effort) were taken in 2002 and the exact same procedure was repeated for each subject five years later in 2007. All these electrocardiographic signals were examined by computational techniques in order to extract the RR and QT intervals and the energy content of the T-wave. Next, we have compared all the data using first return maps and measured the data dispersion by evaluating the covariance ellipses. Relations between each of the four data series were studied. The analysis also included the gender and the categorical aspect “practicing sport”

Asymmetric Relatedness from Partial Correlation

Relatedness is a key concept in economic complexity, since the assessment of the similarity between industrial sectors enables policymakers to design optimal development strategies. However, among the different ways to quantify relatedness, a measure that takes explicitly into account the time correlation structure of exports is still lacking. In this paper, we introduce an asymmetric definition of relatedness by using statistically significant partial correlations between the exports of economic sectors and we apply it to a recently introduced database that integrates the export of physical goods with the export of services. Our asymmetric relatedness is obtained by generalising a recently introduced correlation-filtering algorithm, the partial correlation planar graph, in order to allow its application on multi-sample and multi-variate datasets, and in particular, bipartite temporal networks. The result is a network of economic activities whose links represent the respective influence in terms of temporal correlations; we also compute the statistical confidence of the edges in the network via an adapted bootstrapping procedure. We find that the underlying influence structure of the system leads to the formation of intuitively-related clusters of economic sectors in the network, and to a relatively strong assortative mixing of sectors according to their complexity. Moreover, hub nodes tend to form more robust connections than those in the periphery

Multiple regulation of S14 gene expression during brown fat differentiation

S14 is a gene known to be under thyroid hormone control. Its mRNA concentration is very high in lipogenic tissues, and although the precise function of the protein is still unknown, indirect data suggest its implication in triglyceride synthesis. S14 gene expression is up-regulated by thyroid hormone in liver, white adipose tissue, and lactating mammary gland. However, in brown fat, the level of this sequence is increased 3-fold in the hypothyroid animal. We have used primary cultures of brown preadipocytes differentiated to fully mature brown adipocytes to investigate the influence of cellular differentiation and hormonal stimulation on S14 gene expression. Steady state levels of S14 mRNA rose from nondetectable levels in preadipocytes to reach a maximum in fully mature adipocytes. Treatment of brown adipocytes cultures with T3 did induce S14 gene expression. This induction reflects in part a posttranscriptional stabilization of the messenger by T3. Insulin, insulin-like growth factor- I, and inositol phosphate-glycan also increase the level of S14 mRNA. Norepinephrine (NE) plays a major role in the regulation of S14 gene, and 24 h after its addition, NE elicited a 20-fold decrease in mRNA S14 concentrations. An elevated intracellular concentration of cAMP is a strong negative effector of S14 gene expression, and neither NE nor cAMP action is totally overcome by T3. As happens in vivo, glucose is a potent stimulator of S14 mRNA; however, there is a lag time of several hours before its effects can be detected. The increase in S14 gene expression with the maturation stage of the cell suggests an important role for S14 in adipocyte differentiation.This work was supported by grants frbm the Comunidad de Mahrid, the Fondo de Investigaciones Sanitarias de la Seguridad Social (FIS), and the DGICYT PM 88-0005.Peer Reviewe

Induction of Nod2 in Myelomonocytic and Intestinal Epithelial Cells via Nuclear Factor-kB Activation

Nod2, a member of the Apaf1/Nod protein family, confers responsiveness to bacterial products and activates NF-kB, a ranscription factor that plays a central role in innate immunity. Recently, genetic variation in Nod2 has been associated with susceptibility to Crohn’s disease. Here, we report that expression of Nod2 is induced upon differentiation of CD34+ hematopoietic progenitor cells into granulocyte or monocyte/macrophages. In peripheral blood cells, the highest levels of Nod2 were observed in CD14+ (monocytes), CD15+ (granulocytes), and CD40+/CD86+ (dendritic cells) cell populations. Notably, stimulation of myeloblastic and epithelial cells with bacterial lipopolysaccharide or TNF resulted in up-regulation of Nod2. A search for consensus sites within the Nod2 promoter revealed a NF-kB binding element that was required for transcriptional activity in response to TNF . Moreover, ectopic expression of p65 induced transactivation, whereas that of dominant-negative I B blocked the transcriptional activity of the Nod2 promoter. Upon stimulation with TNF or lipopolysaccharide, both p50 and p65 subunits of NF-kB were bound to the Nod2 promoter. Thus, Nod2 expression is enhanced by proinflammatory cytokines and bacterial components via NF-kB, a mechanism that may contribute to the amplification of the innate immune response and susceptibility to inflammatory disease