The Herbicide Atrazine Activates Endocrine Gene Networks via Non-Steroidal NR5A Nuclear Receptors in Fish and Mammalian Cells

Atrazine (ATR) remains a widely used broadleaf herbicide in the United States despite the fact that this s-chlorotriazine has been linked to reproductive abnormalities in fish and amphibians. Here, using zebrafish we report that environmentally relevant ATR concentrations elevated zcyp19a1 expression encoding aromatase (2.2 µg/L), and increased the ratio of female to male fish (22 µg/L). ATR selectively increased zcyp19a1, a known gene target of the nuclear receptor SF-1 (NR5A1), whereas zcyp19a2, which is estrogen responsive, remained unchanged. Remarkably, in mammalian cells ATR functions in a cell-specific manner to upregulate SF-1 targets and other genes critical for steroid synthesis and reproduction, including Cyp19A1, StAR, Cyp11A1, hCG, FSTL3, LHß, INHα, αGSU, and 11ß-HSD2. Our data appear to eliminate the possibility that ATR directly affects SF-1 DNA- or ligand-binding. Instead, we suggest that the stimulatory effects of ATR on the NR5A receptor subfamily (SF-1, LRH-1, and zff1d) are likely mediated by receptor phosphorylation, amplification of cAMP and PI3K signaling, and possibly an increase in the cAMP-responsive cellular kinase SGK-1, which is known to be upregulated in infertile women. Taken together, we propose that this pervasive and persistent environmental chemical alters hormone networks via convergence of NR5A activity and cAMP signaling, to potentially disrupt normal endocrine development and function in lower and higher vertebrates

Internal tandem duplication, d835 mutation in acute myeloid and promielocitic leukemia

Introduction. Biological characteristics and prognostic values of FMS-like kinasi 3 (FLT3) gene dislocated on 13q12 were studied. This protein is employed in staminal and B cell differentiation. Mutations of FLT3 are present in 35- 40% of patients with acute myeloid leukaemia. These genetic alterations consist of “Internal tandem duplications” (ITDs) and substitution of aspartic acid (Asp) in the 835 positions. Aims of study The aim of this study was to individuate a diagnostic method for FLT3/ITDs and D835 mutation. Materials and methods. From January 2004, 34 consecutive cases with de novo Acute Myeloid Leukemia (AML) have been studied. Median age was 50 years (range 25 – 80). Twenty-three case were male and 11 female. Two PCR methods have been used for FLT3/ITDs and one for D835 mutations. Mixed lineage leukemia gene (MLL) study and t(9,22)p190, t(9,22)p210, t(8;21), t(4;11) translocations analyses have been performed. Study of sequence gene were made in Leukaemia Frankfurt Institute. Were utilised a set of new primers dislocated between 10/11 and 12/13 exons of FLT3 gene Results. In 11/34 (34,4%) cases, FLT3/ITDs transcripts were positives by RT-PCR. In only two cases, FLT3/ITDs positives was confirmed with sequence analysis. In 2/11 positive cases (18,1%) were revealed base substitutions butnot specific mutations in FLT3 gene. MLL studies and specific AML translocations were negative on all cases. D835 mutations by exon 17 were positives on 2 cases (5,8%). Conclusions The new primers set, for exon 11/12; 12/13 in FLT3/ITDs gene, had given results confirmed by sequence analysi

Replicating patterns of prospect theory for decision under risk

Prospect theory is among the most influential frameworks in behavioural science, specifically in research on decision-making under risk. Kahneman and Tversky’s 1979 study tested financial choices under risk, concluding that such judgements deviate significantly from the assumptions of expected utility theory, which had remarkable impacts on science, policy and industry. Though substantial evidence supports prospect theory, many presumed canonical theories have drawn scrutiny for recent replication failures. In response, we directly test the original methods in a multinational study (n = 4,098 participants, 19 countries, 13 languages), adjusting only for current and local currencies while requiring all participants to respond to all items. The results replicated for 94% of items, with some attenuation. Twelve of 13 theoretical contrasts replicated, with 100% replication in some countries. Heterogeneity between countries and intra-individual variation highlight meaningful avenues for future theorizing and applications. We conclude that the empirical foundations for prospect theory replicate beyond any reasonable thresholds