Global analysis of gene expression in NGF-deprived sympathetic neurons identifies molecular pathways associated with cell death

Developing sympathetic neurons depend on nerve growth factor (NGF) for survival and die by apoptosis after NGF withdrawal. This process requires de novo gene expression but only a small number of genes induced by NGF deprivation have been identified so far, either by a candidate gene approach or in mRNA differential display experiments. This is partly because it is difficult to obtain large numbers of sympathetic neurons for in vitro studies. Here, we describe for the first time, how advances in gene microarray technology have allowed us to investigate the expression of all known genes in sympathetic neurons cultured in the presence and absence of NGF

Thermostable Direct Hemolysin Downregulates Human Colon Carcinoma Cell Proliferation with the Involvement of E-Cadherin, and β-Catenin/Tcf-4 Signaling

BACKGROUND: Colon cancers are the frequent causes of cancer mortality worldwide. Recently bacterial toxins have received marked attention as promising approaches in the treatment of colon cancer. Thermostable direct hemolysin (TDH) secreted by Vibrio parahaemolyticus causes influx of extracellular calcium with the subsequent rise in intracellular calcium level in intestinal epithelial cells and it is known that calcium has antiproliferative activity against colon cancer. KEY RESULTS: In the present study it has been shown that TDH, a well-known traditional virulent factor inhibits proliferation of human colon carcinoma cells through the involvement of CaSR in its mechanism. TDH treatment does not induce DNA fragmentation, nor causes the release of lactate dehydrogenase. Therefore, apoptosis and cytotoxicity are not contributing to the TDH-mediated reduction of proliferation rate, and hence the reduction appears to be caused by decrease in cell proliferation. The elevation of E-cadherin, a cell adhesion molecule and suppression of β-catenin, a proto-oncogene have been observed in presence of CaSR agonists whereas reverse effect has been seen in presence of CaSR antagonist as well as si-RNA in TDH treated cells. TDH also triggers a significant reduction of Cyclin-D and cdk2, two important cell cycle regulatory proteins along with an up regulation of cell cycle inhibitory protein p27(Kip1) in presence of CaSR agonists. CONCLUSION: Therefore TDH can downregulate colonic carcinoma cell proliferation and involves CaSR in its mechanism of action. The downregulation occurs mainly through the involvement of E-cadherin-β-catenin mediated pathway and the inhibition of cell cycle regulators as well as upregulation of cell cycle inhibitors

MUC1-associated proliferation signature predicts outcomes in lung adenocarcinoma patients

Background: MUC1 protein is highly expressed in lung cancer. The cytoplasmic domain of MUC1 (MUC1-CD) induces tumorigenesis and resistance to DNA-damaging agents. We characterized MUC1-CD-induced transcriptional changes and examined their significance in lung cancer patients. Methods: Using DNA microarrays, we identified 254 genes that were differentially expressed in cell lines transformed by MUC1-CD compared to control cell lines. We then examined expression of these genes in 441 lung adenocarcinomas from a publicly available database. We employed statistical analyses independent of clinical outcomes, including hierarchical clustering, Student's t-tests and receiver operating characteristic (ROC) analysis, to select a seven-gene MUC1-associated proliferation signature (MAPS). We demonstrated the prognostic value of MAPS in this database using Kaplan-Meier survival analysis, log-rank tests and Cox models. The MAPS was further validated for prognostic significance in 84 lung adenocarcinoma patients from an independent database. Results: MAPS genes were found to be associated with proliferation and cell cycle regulation and included CCNB1, CDC2, CDC20, CDKN3, MAD2L1, PRC1 and RRM2. MAPS expressors (MAPS+) had inferior survival compared to non-expressors (MAPS-). In the initial data set, 5-year survival was 65% (MAPS-) vs. 45% (MAPS+, p < 0.0001). Similarly, in the validation data set, 5-year survival was 57% (MAPS-) vs. 28% (MAPS+, p = 0.005). Conclusions: The MAPS signature, comprised of MUC1-CD-dependent genes involved in the control of cell cycle and proliferation, is associated with poor outcomes in patients with adenocarcinoma of the lung. These data provide potential new prognostic biomarkers and treatment targets for lung adenocarcinoma

Early identification of first-year students at risk of dropping out of high-school entry medical school: the usefulness of teachers' ratings of class participation

Dropping out from undergraduate medical education is costly for students, medical schools, and society in general. Therefore, the early identification of potential dropout students is important. The contribution of personal features to dropout rates has merited exploration. However, there is a paucity of research on aspects of student experience that may lead to dropping out. In this study, underpinned by theoretical models of student commitment, involvement, and engagement, we explored the hypothesis of using inferior participation as an indicator of a higher probability of dropping out in year 1. Class participation was calculated as an aggregate score based on teachers' daily observations in class. The study used a longitudinal dataset of six cohorts of high-school entry students (N = 709, 67% females) in one medical school with an annual intake of 120 students. The findings confirmed the initial hypothesis and showed that lower scores of class participation in year 1 added predictive ability to pre-entry characteristics (Pseudo-R2 raised from 0.22 to 0.28). Even though the inclusion of course failure in year 1 resulted in higher explanatory power than participation in class (Pseudo-R2 raised from 0.28 to 0.63), ratings of class participation may be advantageous to anticipate dropout identification, as those can be collected prior to course failure. The implications for practice are that teachers' ratings of class participation can play a role in indicating medical students who may eventually drop out. We conclude that the scores of class participation can contribute to flagging systems for the early detection of student dropouts.(undefined)info:eu-repo/semantics/acceptedVersio

Casual Compressive Sensing for Gene Network Inference

We propose a novel framework for studying causal inference of gene interactions using a combination of compressive sensing and Granger causality techniques. The gist of the approach is to discover sparse linear dependencies between time series of gene expressions via a Granger-type elimination method. The method is tested on the Gardner dataset for the SOS network in E. coli, for which both known and unknown causal relationships are discovered

Anthropometry, carbohydrate and lipid metabolism in the East Flanders Prospective Twin Survey: heritabilities

AIMS/HYPOTHESIS: We determined the genetic contribution of 18 anthropometric and metabolic risk factors of type 2 diabetes using a young healthy twin population. METHODS: Traits were measured in 240 monozygotic (MZ) and 138 dizygotic (DZ) twin pairs aged 18 to 34 years. Twins were recruited from the Belgian population-based East Flanders Prospective Twin Survey, which is characterised by its accurate zygosity determination and extensive collection of perinatal and placental data, including information on chorionicity. Heritability was estimated using structural equation modelling implemented in the Mx software package. RESULTS: Intra-pair correlations of the anthropometric and metabolic characteristics did not differ between MZ monochorionic and MZ dichorionic pairs; consequently heritabilities were estimated using the classical twin approach. For body mass, BMI and fat mass, quantitative sex differences were observed; genetic variance explained 84, 85 and 81% of the total variation in men and 74, 75 and 70% in women, respectively. Heritability estimates of the waist-to-hip ratio, sum of four skinfold thicknesses and lean body mass were 70, 74 and 81%, respectively. The heritability estimates of fasting glucose, fasting insulin, homeostasis model assessment of insulin resistance and beta cell function, as well as insulin-like growth factor binding protein-1 levels were 67, 49, 48, 62 and 47%, in that order. Finally, for total cholesterol, LDL-cholesterol, HDL-cholesterol, total cholesterol:HDL-cholesterol ratio, triacylglycerol, NEFA and leptin levels, genetic factors explained 75, 78, 76, 79, 58, 37 and 53% of the total variation, respectively. CONCLUSIONS/INTERPRETATION: Genetic factors explain the greater part of the variation in traits related to obesity, glucose intolerance/insulin resistance and dyslipidaemia

RNA-Seq reveals large quantitative differences between the transcriptomes of outbreak and non-outbreak locusts

Outbreaks of locust populations repeatedly devastate economies and ecosystems in large parts of the world. The consequent behavioural shift from solitarious to gregarious and the concomitant changes in the locusts’ biology are of relevant scientific interest. Yet, research on the main locust species has not benefitted from recent advances in genomics. In this first RNA-Seq study on Schistocerca gregaria, we report two transcriptomes, including many novel genes, as well as differential gene expression results. In line with the large biological differences between solitarious and gregarious locusts, almost half of the transcripts are differentially expressed between their central nervous systems. Most of these transcripts are over-expressed in the gregarious locusts, suggesting positive correlations between the levels of activity at the population, individual, tissue and gene expression levels. We group these differentially expressed transcripts by gene function and highlight those that are most likely to be associated with locusts’ phase change either in a species-specific or general manner. Finally, we discuss our findings in the context of population-level and physiological events leading to gregariousness.M. Bakkali wishes to thank the Spanish Ministerio de Ciencia y Tecnología for the for the Ramón y Cajal fellowship and for the BFU2010-16438 grant that supported both this research and the FPI studentship to Rubén Martín Blázquez. We thank Mrs. Pernille Lavgesen for revision of the English language writing of this manuscript. We also thank the editor for the valuable comments on the manuscript

Development of the social brain from age three to twelve years

Human adults recruit distinct networks of brain regions to think about the bodies and minds of others. This study characterizes the development of these networks, and tests for relationships between neural development and behavioral changes in reasoning about others' minds ('theory of mind', ToM). A large sample of children (n = 122, 3-12 years), and adults (n = 33), watched a short movie while undergoing fMRI. The movie highlights the characters' bodily sensations (often pain) and mental states (beliefs, desires, emotions), and is a feasible experiment for young children. Here we report three main findings: (1) ToM and pain networks are functionally distinct by age 3 years, (2) functional specialization increases throughout childhood, and (3) functional maturity of each network is related to increasingly anti-correlated responses between the networks. Furthermore, the most studied milestone in ToM development, passing explicit false-belief tasks, does not correspond to discontinuities in the development of the social brain.National Science Foundation (U.S.) (Award 1122374)National Science Foundation (U.S.) (Award 095518)National Institutes of Health (U.S.) (Award R01-MH096914-05