Up-regulation of 14-3-3sigma (Stratifin) is associated with high-grade CIN and high-risk human papillomavirus (HPV) at baseline but does not predict outcomes of HR-HPV infections or incident CIN in the LAMS study

To assess whether the potentially high-risk (HR) human papillomavirus (HPV)-related up-regulation of 14-3-3sigma (stratifin) has implications in the outcome of HPV infections or cervical intraepithelial neoplasia (CIN) lesions, cervical biopsy specimens from 225 women in the Latin American Screening Study were analyzed for 14-3-3sigma expression using immunohistochemical analysis. We assessed its associations with CIN grade and HR HPV at baseline and value in predicting outcomes of HR-HPV infections and the development of incident CIN 1+ and CIN 2+. Expression of 14-3-3sigma increased in parallel with the lesion grade. Up-regulation was also significantly related to HR-HPV detection (P = .004; odds ratio, 2.71; 95% confidence interval, 1.37-5.35) and showed a linear relationship to HR-HPV loads (P = .003). 14-3-3sigma expression was of no value in predicting the outcomes (incident, persistent, clearance) of HR-HPV infections or incident CIN 1+ and CIN 2+. 14-3-3sigma is not inactivated in cervical carcinoma and CIN but is up-regulated on transition from CIN 2 to CIN 3. Its normal functions in controlling G(1)/S and G(2)/M checkpoints are being bypassed by HR HPV.LAMS, Latin American Screening Study, funded by European Commission, INCO-DEV contract ICA4-CT-2001-10013

Up-regulation of microRNA-21 correlates with lower kidney cancer survival.

BackgroundMicroRNA-21 is up-regulated in a variety of cancers like, breast, colorectal, lung, head and neck etc. However, the regulation of miR-21 in renal cell carcinoma (RCC) has not yet been studied systematically.Methods and resultsWe measured miR-21 levels in 54 pairs of kidney cancers and their normal matched tissues by real-time PCR. The expression level of miR-21 was correlated with 5 year survival and the pathological stage. Functional studies were done after inhibiting miR-21 in RCC cell lines. We studied in vitro and in vivo effects of the chemo preventive agent genistein on miR-21 expression. In 48 cases (90%), miR-21 was increased. All patients with low miR-21 expression survived 5 years, while with high miR-21 expression, only 50% survived. Higher expression of miR-21 is associated with an increase in the stage of renal cancer. Functional studies after inhibiting miRNA-21 in RCC cell lines show cell cycle arrest, induction of apoptosis and reduced invasive and migratory capabilities. Western blot analysis showed an increase in the expression of p21 and p38 MAP kinase genes and a reduction in cyclin E2. Genistein inhibited the expression of miR-21 in A-498 cells and in the tumors formed after injecting genistein treated A-498 cells in nude mice besides inhibiting tumor formation.ConclusionsThe current study shows a clear correlation between miR-21 expression and clinical characteristics of renal cancer. Thus we believe that miR-21 can be used as a tumor marker and its inhibition may prove to be useful in controlling cancers with up-regulated miR-21

Environmental Sustainability and Regulation: To-Down Versus Bottom-Up Regulation

Environmental regulation can be broadly divided into those that follow the top-down and bottom-up approaches. The two approaches have similar objective with respect to environmental protection and sustainability. However, the success with which each approach achieves goals of environmental protection and sustainability may vary. Moreover, the costs and benefits of each approach differ. The present study will explore the implication of environmental regulation to sustainability, costs associated with regulations, and alternatives with respect to using mixes of market-based instruments. The study will review top-down and bottom-up environmental regulations with the objective of identifying weakness and strength of each approach. Furthermore, the study will make recommendations on possible strategies (e.g., mixes of regulatory instruments) that will contribute toward the attainment of sustainable environment, and by implication to sustainable development.Regulation; Top-down; Bottom-up; Market-based; Performance-based; Environmental

Gene up-regulation by DNA demethylation in 35S-gshI-transgenic poplars (Populus x canescens)

Gene expression levels of transgene 35S-gshI (γ-glutamylcysteine synthetase) cloned from E. coli, and the endogenous gene gsh1 of poplar (Populus x canescens) were upregulated by the DNA demethylating agent DHAC (5,6-dihydro-5'-azacytidine hydrochloride) (10-4 M for 7 days) in aseptic leaf discs cultures. Two 35S-gshI-transgenic (6lgl and 11ggs) and wild type (WT) poplar clones were used. The efficiency of gene upregulation was also analyzed under herbicide paraquat stress (4 x 10-7 M). Levels of gshI-mRNA and gsh1-mRNA were determined by RT-qPCR (reverse transcriptase quantitative PCR) after cDNA synthesis. For internal control, the constitutively expressed housekeeping poplar genes α-tubulin and actin were used, and the 2−HHCt method was applied for data analysis. In long term DHAC treatment (21 days), a morphogenetic response of de novo root development was observed on leaf discs in a wide concentration range of DHAC (10-8 to 10-6 M). Adventitious shoots (11ggs clone) also emerged from leaf discs after a combined treatment with DHAC (10-4 M) and paraquat (10-7 M). Shoots were dissected, rooted and transplanted in glass houses for further analyses for phytoremediation capacity. Since DNA methylation patterns are inherited (epigenetic memory), these poplar plants with increased gene expression levels of both transgene 35S-gshI and endogenous gene gsh1 provide novel plant sources for in situ application

Mind over chatter: plastic up-regulation of the fMRI alertness network by EEG neurofeedback

EEG neurofeedback (NFB) is a brain-computer interface (BCI) approach used to shape brain oscillations by means of real-time feedback from the electroencephalogram (EEG), which is known to reflect neural activity across cortical networks. Although NFB is being evaluated as a novel tool for treating brain disorders, evidence is scarce on the mechanism of its impact on brain function. In this study with 34 healthy participants, we examined whether, during the performance of an attentional auditory oddball task, the functional connectivity strength of distinct fMRI networks would be plastically altered after a 30-min NFB session of alpha-band reduction (n=17) versus a sham-feedback condition (n=17). Our results reveal that compared to sham, NFB induced a specific increase of functional connectivity within the alertness/salience network (dorsal anterior and mid cingulate), which was detectable 30 minutes after termination of training. Crucially, these effects were significantly correlated with reduced mind-wandering 'on-task' and were coupled to NFB-mediated resting state reductions in the alpha-band (8-12 Hz). No such relationships were evident for the sham condition. Although group default-mode network (DMN) connectivity was not significantly altered following NFB, we observed a positive association between modulations of resting alpha amplitude and precuneal connectivity, both correlating positively with frequency of mind-wandering. Our findings demonstrate a temporally direct, plastic impact of NFB on large-scale brain functional networks, and provide promising neurobehavioral evidence supporting its use as a noninvasive tool to modulate brain function in health and disease

CD45 up-regulation during lymphocyte maturation

CD4+CD8+ double-positive thymocytes differentiate into CD4+ and CD8+ single-positive T cells during thymic positive selection. This process requires the interaction between the TCR and self MHC molecules. In this context we have anaiyzed the expression of CD45, an abundant transmembrane protein tyrosine phosphatase, and describe here its differential surface expression during T cell maturation. Using four-color FACS analysis of thymocytes from normal as well as TCR-transgenic mice we demonstrate that CD45 is up-regulated only during positive selection concomitantly with the TCR-CD3 complex and the transient early activation marker CD69, but that this up-regulation precedes heat stable antigen down-regulation. The tight linkage of the upregulation of the TCR-CD3 complex and CD45 may be required because the CD45 tyrosine phosphatase plays a role in modulating signal transduction by the TCR-CD3 complex during positive selection. In addition, our findings argue for a regulation mechanism that adapts the CD45 levels to increasing antigen receptor levels on mature T cells and B cell

Synergistic up-regulation of CXCL10 by virus and IFN γ in human airway epithelial cells.

Airway epithelial cells are the first line of defense against viral infections and are instrumental in coordinating the inflammatory response. In this study, we demonstrate the synergistic stimulation of CXCL10 mRNA and protein, a key chemokine responsible for the early immune response to viral infection, following treatment of airway epithelial cells with IFN γ and influenza virus. The synergism also occurred when the cells were treated with IFN γ and a viral replication mimicker (dsRNA) both in vitro and in vivo. Despite the requirement of type I interferon (IFNAR) signaling in dsRNA-induced CXCL10, the synergism was independent of the IFNAR pathway since it wasn't affected by the addition of a neutralizing IFNAR antibody or the complete lack of IFNAR expression. Furthermore, the same synergistic effect was also observed when a CXCL10 promoter reporter was examined. Although the responsive promoter region contains both ISRE and NFκB sites, western blot analysis indicated that the combined treatment of IFN γ and dsRNA significantly augmented NFκB but not STAT1 activation as compared to the single treatment. Therefore, we conclude that IFN γ and dsRNA act in concert to potentiate CXCL10 expression in airway epithelial cells via an NFκB-dependent but IFNAR-STAT independent pathway and it is at least partly regulated at the transcriptional level

Lack of an HSP70 heat shock response in two Antarctic marine invertebrates

Members of the HSP70 gene family comprising the inducible (HSP70) genes and GRP78 (glucose-regulated protein 78 kDa) were identified in an Antarctic sea star (Odontaster validus) and an Antarctic gammarid (Paraceradocus gibber). These genes were surveyed for expression levels via Q-PCR after an acute 2-hour heat shock experiment in both animals and a time course assay in O. validus. No significant up-regulation was detected for any of the genes in either of the animals during the acute heat shock. The time course experiment in O. validus produced slightly different results with an initial down regulation in these genes at 2°C, but no significant up-regulation of the genes either at 2 or 6°C. Therefore, the classical heat shock response is absent in both species. The data is discussed in the context of the organisms’ thermal tolerance and the applicability of HSP70 to monitor thermal stress in Antarctic marine organisms