The impact of unloading stresses on post-caldera magma intrusions

Calderas represent morphological depressions several kilometers in diameter, and the unloaded crustal stresses they produce can form rapidly (e.g. Pinatubo, 1990) or slowly (e.g. Hawaii, 2018). Active calderas are known as sites of persistent magma intrusions, and yet the dynamics of their shallow plumbing system is not well constrained. We use scaled laboratory experiments to study how experimental intrusions are created beneath a caldera by injecting dyed water (magma analogue) into the base of an elastic gelatin solid (crust analogue) with a cylindrical cavity in its surface to mimic a caldera-like topography. The evolving dike geometry and stress field were qualitatively determined using polarized light, and digital image correlation allowed the incremental and total strain to be quantified by tracking passive-tracer particles in the gelatin that fluoresced in a thin 2D vertical laser sheet. Our results show that the unloaded stress field from a caldera can cause a divergence of vertical dikes, and leads to circumferential dikes and cone sheets. When the caldera was large the initially vertical dike became arrested, then grew laterally via circumferentially-propagating en echelon segments; these eventually joined to complete a cone sheet that was parallel to, but extended outside and beneath, the large caldera. When the caldera was small, a circumferential dike erupted, producing a short fissure which was outside, but parallel to, the caldera. We suggest that the distinct curved geometry, velocity, strain and stress characteristics of circumferential dikes and cone sheets can be used to interpret the origin and growth of post-caldera magmatism and the likelihood of eruption in caldera systems

Energy-Dependent Timing of Thermal Emission in Solar Flares

We report solar flare plasma to be multi-thermal in nature based on the theoretical model and study of the energy-dependent timing of thermal emission in ten M-class flares. We employ high-resolution X-ray spectra observed by the Si detector of the "Solar X-ray Spectrometer" (SOXS). The SOXS onboard the Indian GSAT-2 spacecraft was launched by the GSLV-D2 rocket on 8 May 2003. Firstly we model the spectral evolution of the X-ray line and continuum emission flux F(\epsilon) from the flare by integrating a series of isothermal plasma flux. We find that multi-temperature integrated flux F(\epsilon) is a power-law function of \epsilon with a spectral index (\gamma) \approx -4.65. Next, based on spectral-temporal evolution of the flares we find that the emission in the energy range E= 4 - 15 keV is dominated by temperatures of T= 12 - 50 MK, while the multi-thermal power-law DEM index (\gamma) varies in the range of -4.4 and -5.7. The temporal evolution of the X-ray flux F(\epsilon,t) assuming a multi-temperature plasma governed by thermal conduction cooling reveals that the temperature-dependent cooling time varies between 296 and 4640 s and the electron density (n_e) varies in the range of n_e= (1.77-29.3)*10^10 cm-3. Employing temporal evolution technique in the current study as an alternative method for separating thermal from non-thermal components in the energy spectra, we measure the break-energy point ranging between 14 and 21\pm1.0 keV.Comment: Solar Physics, in pres

Baseline characteristics and enrichment results from the SONAR trial

Aim: The SONAR trial uses an enrichment design based on the individual response to the selective endothelin receptor antagonist atrasentan on efficacy (the degree of the individual response in the urinary albumin‐to‐creatinine ratio [UACR]) and safety/tolerability (signs of sodium retention and acute increases in serum creatinine) to assess the effects of this agent on major renal outcomes. The patient population and enrichment results are described here. Methods: Patients with type 2 diabetes with an estimated glomerular filtration rate (eGFR) within 25 to 75 mL/min/1.73 m2 and UACR between 300 and 5000 mg/g were enrolled. After a run‐in period, eligible patients received 0.75 mg/d of atrasentan for 6 weeks. A total of 2648 responder patients in whom UACR decreased by ≥30% compared to baseline were enrolled, as were 1020 non‐responders with a UACR decrease of <30%. Patients who experienced a weight gain of >3 kg and in whom brain natriuretic peptide exceeded ≥300 pg/mL, or who experienced an increase in serum creatinine >20% (0.5 mg/dL), were not randomized. Results: Baseline characteristics were similar for atrasentan responders and non‐responders. Upon entry to the study, median UACR was 802 mg/g in responders and 920 mg/g in non‐responders. After 6 weeks of treatment with atrasentan, the UACR change in responders was −48.8% (95% CI, −49.8% to −47.9%) and in non‐responders was −1.2% (95% CI, −6.4% to 3.9%). Changes in other renal risk markers were similar between responders and non‐responders except for a marginally greater reduction in systolic blood pressure and eGFR in responders. Conclusions: The enrichment period has successfully identified a population with a profound UACR reduction without clinical signs of sodium retention in whom a large atrasentan effect on clinically important renal outcomes is possible. The SONAR trial aims to establish whether atrasentan confers renal protection

Iso-singlet Down Quark Mixing And CP Violation Experiments

We confront the new physics models with extra iso-singlet down quarks in the new CP violation experimental era with $\sin{(2\beta)}$ and $\epsilon'/\epsilon$ measurements, $K^+ \to \pi^+ \nu \bar{\nu}$ events, and $x_s$ limits. The closeness of the new experimental results to the standard model theory requires us to include full SM amplitudes in the analysis. In models allowing mixing to a new isosinglet down quark, as in E$_6$, flavor changing neutral currents are induced that allow a $Z^0$ mediated contribution to $B-\bar B$ mixing and which bring in new phases. In $(\rho,\eta)$, $(x_s,\sin{(\gamma)})$, and $(x_s, \sin{(2\phi_s)})$ plots we still find much larger regions in the four down quark model than in the SM, reaching down to $\eta \approx 0$, $0 \leq \sin{(\gamma)} \leq 1$, $-.75 \leq \sin{(2\alpha)} \leq 0.15$, and $\sin{(2\phi_s)}$ down to zero, all at 1$\sigma$. We elucidate the nature of the cancellation in an order $\lambda^5$ four down quark mixing matrix element which satisfies the experiments and reduces the number of independent angles and phases. We also evaluate tests of unitarity for the $3\times3$ CKM submatrix.Comment: 14 pages, 16 figures, REVTeX

Gemcitabine therapeutically disrupts essential SIRT1-mediated p53 repression in atypical teratoid/rhabdoid tumors

Atypical teratoid/rhabdoid tumors (ATRTs) are highly malignant embryonal tumors of the central nervous system with a dismal prognosis. Using a newly developed and validated patient-derived ATRT culture and xenograft model, alongside a panel of primary ATRT models, we found that ATRTs are selectively sensitive to the nucleoside analog gemcitabine. Gene expression and protein analyses indicate that gemcitabine treatment causes the degradation of sirtuin 1 (SIRT1), resulting in cell death through activation of nuclear factor κB (NF-κB) and p53. Furthermore, we discovered that gemcitabine-induced loss of SIRT1 results in a nucleus-to-cytoplasm translocation of the sonic hedgehog (SHH) signaling activator GLI2, explaining the observed additional gemcitabine sensitivity in SHH-subtype ATRT. Treatment of ATRT xenograft-bearing mice with gemcitabine resulted in a &gt;30% increase in median survival and yielded long-term survivors in two independent patient-derived xenograft models. These findings demonstrate that ATRTs are highly sensitive to gemcitabine treatment and may form part of a future multimodal treatment strategy for ATRTs.</p

Trimethylation of H3K27 during human cerebellar development in relation to medulloblastoma

Medulloblastoma (MB), the most common malignant childhood brain tumor, encompasses a collection of four clinically and molecularly distinct tumor subgroups, i.e. WNT, SHH, Group 3 and Group 4. These tumors are believed to originate from precursor cells during cerebellar development. Although the exact etiology of these brain tumors is not yet known, histone modifications are increasingly recognized as key events during cerebellum development and MB tumorigenesis. Recent studies show that key components involved in post-translational modifications of histone H3 lysine 27 (H3K27) are commonly deregulated in MB. In this descriptive study, we have investigated the trimethylation status of H3K27, as well as the expression of the H3K27 methylase EZH2 and demethylases KDM6A and KDM6B, during human cerebellum development in relation to MB. H3K27 Trimethylation status differed between the MB subgroups. Moreover, trimethylation of H3K27 and expression of its modifiers EZH2, KDM6A and KDM6B were detected in a spatio-temporal manner during development of the human cerebellum, with consistent high occurrence in the four proliferative zones, which are believed to harbor the precursor cells of the different MB subgroups. Our results suggest that H3K27 trimethylation in MB is deregulated by EZH2, KDM6A and KDM6B. Moreover, we provide evidence that during development of the human cerebellum H3K27me3 and its regulators are expressed in a spatio-temporal manner

FGF receptor genes and breast cancer susceptibility: results from the Breast Cancer Association Consortium

Background:Breast cancer is one of the most common malignancies in women. Genome-wide association studies have identified FGFR2 as a breast cancer susceptibility gene. Common variation in other fibroblast growth factor (FGF) receptors might also modify risk. We tested this hypothesis by studying genotyped single-nucleotide polymorphisms (SNPs) and imputed SNPs in FGFR1, FGFR3, FGFR4 and FGFRL1 in the Breast Cancer Association Consortium. Methods:Data were combined from 49 studies, including 53 835 cases and 50 156 controls, of which 89 050 (46 450 cases and 42 600 controls) were of European ancestry, 12 893 (6269 cases and 6624 controls) of Asian and 2048 (1116 cases and 932 controls) of African ancestry. Associations with risk of breast cancer, overall and by disease sub-type, were assessed using unconditional logistic regression. Results:Little evidence of association with breast cancer risk was observed for SNPs in the FGF receptor genes. The strongest evidence in European women was for rs743682 in FGFR3; the estimated per-allele odds ratio was 1.05 (95 confidence interval=1.02-1.09, P=0.0020), which is substantially lower than that observed for SNPs in FGFR2. Conclusion:Our results suggest that common variants in the other FGF receptors are not associated with risk of breast cancer to the degree observed for FGFR2. © 2014 Cancer Research UK

Characterization of the mechanism by which the RB/E2F pathway controls expression of the cancer genomic DNA deaminase APOBEC3B

APOBEC3B (A3B)-catalyzed DNA cytosine deamination contributes to the overall mutational landscape in breast cancer. Molecular mechanisms responsible for A3B upregulation in cancer are poorly understood. Here we show that a single E2F cis-element mediates repression in normal cells and that expression is activated by its mutational disruption in a reporter construct or the endogenous A3B gene. The same E2F site is required for A3B induction by polyomavirus T antigen indicating a shared molecular mechanism. Proteomic and biochemical experiments demonstrate the binding of wildtype but not mutant E2F promoters by repressive PRC1.6/E2F6 and DREAM/E2F4 complexes. Knockdown and overexpression studies confirm the involvement of these repressive complexes in regulating A3B expression. Altogether, these studies demonstrate that A3B expression is suppressed in normal cells by repressive E2F complexes and that viral or mutational disruption of this regulatory network triggers overexpression in breast cancer and provides fuel for tumor evolution

Measurement of νˉμ\bar{\nu}_{\mu} and νμ\nu_{\mu} charged current inclusive cross sections and their ratio with the T2K off-axis near detector

We report a measurement of cross section $\sigma(\nu_{\mu}+{\rm nucleus}\rightarrow\mu^{-}+X)$ and the first measurements of the cross section $\sigma(\bar{\nu}_{\mu}+{\rm nucleus}\rightarrow\mu^{+}+X)$ and their ratio $R(\frac{\sigma(\bar \nu)}{\sigma(\nu)})$ at (anti-)neutrino energies below 1.5 GeV. We determine the single momentum bin cross section measurements, averaged over the T2K $\bar{\nu}/\nu$-flux, for the detector target material (mainly Carbon, Oxygen, Hydrogen and Copper) with phase space restricted laboratory frame kinematics of $\theta_{\mu}$500 MeV/c. The results are $\sigma(\bar{\nu})=\left( 0.900\pm0.029{\rm (stat.)}\pm0.088{\rm (syst.)}\right)\times10^{-39}$ and $\sigma(\nu)=\left( 2.41\ \pm0.022{\rm{(stat.)}}\pm0.231{\rm (syst.)}\ \right)\times10^{-39}$in units of cm$^{2}$/nucleon and$R\left(\frac{\sigma(\bar{\nu})}{\sigma(\nu)}\right)= 0.373\pm0.012{\rm (stat.)}\pm0.015{\rm (syst.)}$.Comment: 18 pages, 8 figure