A bootstrap-based regression method for comprehensive discovery of differential gene expressions: An application to the osteoporosis study

A common purpose of microarray experiments is to study the variation in gene expression across the categories of an experimental factor such as tissue types and drug treatments. However, it is not uncommon that the studied experimental factor is a quantitative variable rather than categorical variable. Loss of information would occur by comparing gene-expression levels between groups that are factitiously defined according to the quantitative threshold values of an experimental factor. Additionally, lack of control for some sensitive clinical factors may bring serious false positive or negative findings.In the present study, we described a bootstrap-based regression method for analyzing gene-expression data from the non-categorical microarray experiments. To illustrate the utility of this method, we applied it to our recent gene-expression study of circulating monocytes in subjects with a wide range of variations in bone mineral density (BMD). This method allows a comprehensive discovery of gene expressions associated with osteoporosis-related traits while controlling other common confounding factors such as height, weight and age. Several genes identified in our study are involved in osteoblast and osteoclast functions and bone remodeling and/or menopause-associated estrogen-dependent pathways, which provide important clues to understand the etiology of osteoporosis. Availability: SAS code is available from the authors upon request. © 2011 Elsevier Masson SAS.postprin

Myocardial deletion of Smad4 using a novel alpha skeletal muscle actin Cre recombinase transgenic mouse causes misalignment of the cardiac outflow tract

S MAD4 acts as the converging point f or T GF β and BMP signaling in heart development. Here, we investigated the role of S MAD4 in heart development usi ng a novel α skeletal muscle actin Cre recombinase (MuCre) transgenic mouse strain. Lineage tracing using MuCre/ROSA26LacZ reporter mice indicated strong Cre-recombinase expression in developing and adult heart and skeletal muscles. In heart development, significant MuCre expression was noted at E11.5 in the atrial, ventricular, outflow tract and atrioventricular canal myocardium, but not in the endocardial cushions. MuCre-driven conditional deletion of Smad4 in mice caused double outlet right ventricle (DORV), ventricular septal defect (VSD), impaired trabeculation and thinning of ventricular myocardium, and mid-gestational embryonic lethality. In conclusion, MuCre mice effectively delete genes in both heart and skeletal muscles, thus enabling the discovery that myocardial Smad4 deletion causes misalignment of the outflow tract and DORV

Cytoplasmic p53 couples oncogene-driven glucose metabolism to apoptosis and is a therapeutic target in glioblastoma.

Cross-talk among oncogenic signaling and metabolic pathways may create opportunities for new therapeutic strategies in cancer. Here we show that although acute inhibition of EGFR-driven glucose metabolism induces only minimal cell death, it lowers the apoptotic threshold in a subset of patient-derived glioblastoma (GBM) cells. Mechanistic studies revealed that after attenuated glucose consumption, Bcl-xL blocks cytoplasmic p53 from triggering intrinsic apoptosis. Consequently, targeting of EGFR-driven glucose metabolism in combination with pharmacological stabilization of p53 with the brain-penetrant small molecule idasanutlin resulted in synthetic lethality in orthotopic glioblastoma xenograft models. Notably, neither the degree of EGFR-signaling inhibition nor genetic analysis of EGFR was sufficient to predict sensitivity to this therapeutic combination. However, detection of rapid inhibitory effects on [18F]fluorodeoxyglucose uptake, assessed through noninvasive positron emission tomography, was an effective predictive biomarker of response in vivo. Together, these studies identify a crucial link among oncogene signaling, glucose metabolism, and cytoplasmic p53, which may potentially be exploited for combination therapy in GBM and possibly other malignancies

Leaching as a pretreatment process to complement torrefaction in improving co-firing characteristics of Jatropha curcas seed cake

The presence of certain inorganic elements in biomass causes issues such as slagging, fouling and corrosion when co-firing with coal for power generation. In this work, the efficacy of leaching to remove these elements from Jatropha curcas seed cake was investigated. Leaching of both untorrefied and torrefied seed cakes was carried out in Milli-Q water at temperatures of 20, 35 and 50 °C. At 20 °C, the two critical elements, potassium and chlorine, decreased by as much as 85 and 97 %, respectively. Leaching at higher temperatures was only beneficial for the more intensely torrefied biomass, since they were more resistant to leaching. The electrical conductivity and ion content of the leachates were measured, as were the inorganic elemental content, dry ash content, volatile matter content and higher heating value (HHV) of the solid seed cake. A secondary benefit of the leaching was an increase in the HHV by up to 10 %

Measurement of the inclusive and dijet cross-sections of b-jets in pp collisions at sqrt(s) = 7 TeV with the ATLAS detector

The inclusive and dijet production cross-sections have been measured for jets containing b-hadrons (b-jets) in proton-proton collisions at a centre-of-mass energy of sqrt(s) = 7 TeV, using the ATLAS detector at the LHC. The measurements use data corresponding to an integrated luminosity of 34 pb^-1. The b-jets are identified using either a lifetime-based method, where secondary decay vertices of b-hadrons in jets are reconstructed using information from the tracking detectors, or a muon-based method where the presence of a muon is used to identify semileptonic decays of b-hadrons inside jets. The inclusive b-jet cross-section is measured as a function of transverse momentum in the range 20 < pT < 400 GeV and rapidity in the range |y| < 2.1. The bbbar-dijet cross-section is measured as a function of the dijet invariant mass in the range 110 < m_jj < 760 GeV, the azimuthal angle difference between the two jets and the angular variable chi in two dijet mass regions. The results are compared with next-to-leading-order QCD predictions. Good agreement is observed between the measured cross-sections and the predictions obtained using POWHEG + Pythia. MC@NLO + Herwig shows good agreement with the measured bbbar-dijet cross-section. However, it does not reproduce the measured inclusive cross-section well, particularly for central b-jets with large transverse momenta.Comment: 10 pages plus author list (21 pages total), 8 figures, 1 table, final version published in European Physical Journal

The muon system of the Daya Bay Reactor antineutrino experiment

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Search for a Light Sterile Neutrino at Daya Bay

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Methamphetamine withdrawal induces activation of CRF neurons in the brain stress system in parallel with an increased activity of cardiac sympathetic pathways.

Methamphetamine (METH) addiction is a major public health problem in some countries. There is evidence to suggest that METH use is associated with increased risk of developing cardiovascular problems. Here, we investigated the effects of chronic METH administration and withdrawal on the activation of the brain stress system and cardiac sympathetic pathways. Mice were treated with METH (2 mg/kg, i.p.) for 10 days and left to spontaneous withdraw for 7 days. The number of corticotrophin-releasing factor (CRF), c-Fos, and CRF/c-Fos neurons was measured by immunohistochemistry in the paraventricular nucleus of the hypothalamus (PVN) and the oval region of the bed nucleus of stria terminalis (ovBNST), two regions associated with cardiac sympathetic control. In parallel, levels of catechol-o-methyl-transferase (COMT), tyrosine hydroxylase (TH), and heat shock protein 27 (Hsp27) were measured in the heart. In the brain, chronic-METH treatment enhanced the number of c-Fos neurons and the CRF neurons with c-Fos signal (CRF+/c-Fos+) in PVN and ovBNST. METH withdrawal increased the number of CRF+neurons. In the heart, METH administration induced an increase in soluble (S)-COMT and membrane-bound (MB)-COMT without changes in phospho (p)-TH, Hsp27, or pHsp27. Similarly, METH withdrawal increased the expression of S- and MB-COMT. In contrast to chronic treatment, METH withdrawal enhanced levels of (p)TH and (p)Hsp27 in the heart. Overall, our results demonstrate that chronic METH administration and withdrawal activate the brain CRF systems associated with the heart sympathetic control and point towards a METH withdrawal induced activation of sympathetic pathways in the heart. Our findings provide further insight in the mechanism underlining the cardiovascular risk associated with METH use and proposes targets for its treatment

Independent measure of the neutrino mixing angle θ13 via neutron capture on hydrogen at Daya Bay

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