Regulation of insulin-like growth factor–dependent myoblast differentiation by Foxo forkhead transcription factors

Insulin-like growth factors promote myoblast differentiation through phosphoinositol 3-kinase and Akt signaling. Akt substrates required for myogenic differentiation are unknown. Forkhead transcription factors of the forkhead box gene, group O (Foxo) subfamily are phosphorylated in an insulin-responsive manner by phosphatidylinositol 3-kinase–dependent kinases. Phosphorylation leads to nuclear exclusion and inactivation. We show that a constitutively active Foxo1 mutant inhibits differentiation of C2C12 cells and prevents myotube differentiation induced by constitutively active Akt. In contrast, a transcriptionally inactive mutant Foxo1 partially rescues inhibition of C2C12 differentiation mediated by wortmannin, but not by rapamycin, and is able to induce aggregation-independent myogenic conversion of teratocarcinoma cells. Inhibition of Foxo expression by siRNA resulted in more efficient differentiation, associated with increased myosin expression. These observations indicate that Foxo proteins are key effectors of Akt-dependent myogenesis

Correlated Prompt Fission Data in Transport Simulations

Detailed information on the fission process can be inferred from the observation, modeling and theoretical understanding of prompt fission neutron and $\gamma$-ray~observables. Beyond simple average quantities, the study of distributions and correlations in prompt data, e.g., multiplicity-dependent neutron and \gray~spectra, angular distributions of the emitted particles, $n$-$n$, $n$-$\gamma$, and $\gamma$-$\gamma$~correlations, can place stringent constraints on fission models and parameters that would otherwise be free to be tuned separately to represent individual fission observables. The FREYA~and CGMF~codes have been developed to follow the sequential emissions of prompt neutrons and $\gamma$-rays~from the initial excited fission fragments produced right after scission. Both codes implement Monte Carlo techniques to sample initial fission fragment configurations in mass, charge and kinetic energy and sample probabilities of neutron and $\gamma$~emission at each stage of the decay. This approach naturally leads to using simple but powerful statistical techniques to infer distributions and correlations among many observables and model parameters. The comparison of model calculations with experimental data provides a rich arena for testing various nuclear physics models such as those related to the nuclear structure and level densities of neutron-rich nuclei, the $\gamma$-ray~strength functions of dipole and quadrupole transitions, the mechanism for dividing the excitation energy between the two nascent fragments near scission, and the mechanisms behind the production of angular momentum in the fragments, etc. Beyond the obvious interest from a fundamental physics point of view, such studies are also important for addressing data needs in various nuclear applications. (See text for full abstract.)Comment: 39 pages, 57 figure files, published in Eur. Phys. J. A, reference added this versio

Neutron Correlations in Special Nuclear Materials, Experiments and Simulations

Fissile materials emit neutrons with an unmistakable signature that can reveal characteristics of the material. We describe here measurements, simulations, and predicted signals expected and prospects for application of neutron correlation measurement methods to detection of special nuclear materials (SNM). The occurrence of fission chains in SNM can give rise to this distinctive, measurable time correlation signal. The neutron signals can be analyzed to detect the presence and to infer attributes of the SNM and surrounding materials. For instance, it is possible to infer attributes of an assembly containing a few kilograms of uranium, purely passively, using detectors of modest size in a reasonable time. Neutron signals of three radioactive sources are shown to illustrate the neutron correlation and analysis method. Measurements are compared with Monte Carlo calculations of the authenticated sources

Nonclassic lipoid congenital adrenal hyperplasia masquerading as familial glucocorticoid deficiency

Context: Familial glucocorticoid deficiency (FGD) is an autosomal recessive disorder resulting from resistance to the action of ACTH on the adrenal cortex. Affected individuals are deficient in cortisol and, if untreated, are likely to succumb to hypoglycemia and/or overwhelming infection. Mutations of the ACTH receptor (MC2R) and the melanocortin 2 receptor accessory protein (MRAP), FGD types 1 and 2 respectively, account for approximately 45% of cases. Objective: A locus on chromosome 8 has previously been linked to the disease in three families, but no underlying gene defect has to date been identified. Design: The study design comprised single-nucleotide polymorphism genotyping and mutation detection. Setting: The study was conducted at secondary and tertiary referral centers. Patients: Eighty probands from families referred for investigation of the genetic cause of FGD participated in the study. Interventions: There were no interventions. Results: Analysis by single-nucleotide polymorphism array of the genotype of one individual with FGD previously linked to chromosome 8 revealed a large region of homozygosity encompassing the steroidogenic acute regulatory protein gene, STAR. We identified homozygous STAR mutations in this patient and his affected siblings. Screening of our total FGD patient cohort revealed homozygous STAR mutations in a further nine individuals from four other families. Conclusions: Mutations in STAR usually cause lipoid congenital adrenal hyperplasia, a disorder characterized by both gonadal and adrenal steroid deficiency. Our results demonstrate that certain mutations in STAR (R192C and the previously reported R188C) can present with a phenotype indistinguishable from that seen in FGD

Epithelial cell turnover in relation to ongoing damage of the gastric mucosa in patients with early gastric cancer: increase of cell proliferation in paramalignant lesions

Gastric cancer is typically an end result of Helicobacter pylori -associated chronic gastritis. The pathogenesis is thought to involve effects on gastric mucosal epithelial cell turnover. In this study, we aimed to compare apoptosis and proliferation in the noncancer-containing mucosa of H. pylori -positive patients with early gastric cancer with these phenomena in H. pylori -positive controls.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41590/1/535_2004_Article_1549.pd

NKT Cell Stimulation with α-Galactosylceramide Results in a Block of Th17 Differentiation after Intranasal Immunization in Mice

In a previous study we demonstrated that intranasal (i.n.) vaccination promotes a Th17 biased immune response. Here, we show that co-administration of a pegylated derivative of α-galactosylceramide (αGCPEG) with an antigen, even in the presence of Th17-polarizing compounds, results in a strong blocking of Th17 differentiation. Additional studies demonstrated that this phenomenon is specifically dependent on soluble factors, like IL-4 and IFNγ, which are produced by NKT cells. Even NK1.1 negative NKT cells, which by themselves produce IL-17A, are able to block Th17 differentiation. It follows that the use of αGCPEG as adjuvant would enable to tailor Th17 responses, according to the specific clinical needs. This knowledge expands our understanding of the role played by NKT cells in overall control of the cytokine microenvironment, as well as in the overall shaping of adaptive immune responses

Molecular structure and biodegradation kinetics of Linear Alkylbenzene Sulphonates in sea water.

The present paper describes the results of the application of the biodegradation test proposed by the United States Environmental Protection Agency (USEPA) “Biodegradability in sea water” Office of Prevention, Pesticides, and Toxic Substances (OPPTS) 835.3160, to Linear Alkylbenzene Sulphonate (LAS), the synthetic surfactant with the highest consumption volume on a world-wide basis. High performance liquid chromatography (HPLC) has been employed for the separation and quantification of the different homologues and isomers of the surfactant. Water from the Bay of Cádiz (South–West of the Iberian peninsula) has been used as test medium. The results indicate how both lag and t50 time shows a significant linear relationship with the length of the alkyl chain of the homologue; the effect of this is that the homologues of longer chain length not only begin to degrade first but also degrade at a faster rate. Regarding the isomeric composition, it is observed that as the percentage of biodegradation increases, there is an increase in the proportion of internal isomers, in comparison with the isomeric relationships of the original test substanc