Molecular characterisation of childhood craniopharyngioma and identification and testing of novel drug targets

BACKGROUND: Adamantinomatous Craniopharyngiomas (ACPs) are clinically challenging sellar region tumours, known to be characterised by mutations in CTNNB1. ACPs are often histologically complex, with different morphological cell types and surrounded by a florid glial reaction. Murine models have been generated through activating β-catenin and support a critical role for nucleo-cytoplasmic accumulating β-catenin cell clusters (‘clusters’) in driving tumorigenesis. AIMS: To phenotype in detail the 3D growth patterns of human and murine ACP; To characterise the genomic and transcriptomic landscape of human and murine ACP, including of clusters; To characterise therapeutically targetable molecular pathways and perform pre-clinical therapeutic trials. METHODS: Human ACP samples underwent micro-focus-CT scanning, whole genome sequencing, targeted next generation sequencing and RNA sequencing, both with, and without, laser capture microdissection. The growth dynamics of murine ACP was characterised by serial MRI and a cohort of murine ACPs, at various stages, underwent RNA and exome sequencing. A pre-clinical murine trial using a Sonic Hedgehog (SHH) pathway inhibitor was performed. RESULTS: CTNNB1 mutationsin human ACP were confirmed as clonal within tumour epithelia. Gene expression signatures corresponding to tumour epithelia, reactive glia and immune infiltrate were derived and novel ACP genes were identified (e.g. BCL11B). A relationship between human and murine ACPs with the developing tooth was also established, in particular the similarity of clusters to the enamel knot. Further molecular dissection identified a complex interplay between tumour cell compartments demonstrating a role for paracrine signalling. Inhibition of the SHH pathway in the pre-clinical murine trial resulted in a decrease in median survival from 33 weeks to 11.9 weeks (p=0.048). A signature of inflammasome activation in ACP was also identified in solid and cystic components of ACP. CONCLUSIONS: ACPs have clonal mutations in CTNNB1 and exhibit complex signalling interplay between different cell compartments. Expression analysis reveals a new molecular paradigm for understanding ACP tumorigenesis as an aberrant copycat of natural tooth development, with inflammation driven by activation of inflammasomes. Caution is recommended in the use of SHH pathway inhibitors in patients with ACP

On the Metal Richness of M Dwarfs with Planets

Knowledge of the metallicities of M dwarfs rests predominantly on the photometric calibration of Bonfils and collaborators, which predicts that M dwarfs in the solar neighborhood, including those with known planets, are systematically metal poor compared to their higher-mass counterparts. We test this prediction using a volume-limited sample of low-mass stars, together with a subset of M dwarfs with high-metallicity, F, G, and K wide binary companions. We find that the Bonfils et al. photometric calibration systematically underestimates the metallicities of our high-metallicity M dwarfs by an average of 0.32 dex. We derive a new photometric metallicity calibration and show that M dwarfs with planets appear to be systematically metal rich, a result that is consistent with the metallicity distribution of FGK dwarfs with planets

Biosynthetic relationship between the major matrix proteins of adrenal chromaffin granules

AbstractThe matrix of the chromaffin granule contains a family of acidic proteins, collectively known as the chromogranins. It has been suggested that this family results protease action on the major component, chromogranin A. Evidence for this has now been obtained from in vitro translation of adrenal medullary messenger RNA and immunoprecipitation of translation products using an antiserum directed against chromogranin A, but which also recognises other chromogranins

Reactive transport simulations to study groundwater quality changes in response to CO2 leakage from deep geological storage

AbstractAs an effort to evaluate risks associated with geologic sequestration of CO2, this work assesses the potential effects of CO2 leakage on groundwater quality. Reactive transport simulations are performed to study the chemical evolution of aqueous Pb and As after the intrusion of CO2 from a storage reservoir into a shallow confined groundwater resource. The simulations use mineralogies representative of shallow potable aquifers in the USA; both 2D (depth-averaged) and 3D simulations are conducted. Sensitivity studies are also conducted for variation in hydrological and geochemical conditions, as well as several other critical parameters. Model results suggest that a significant increase of aqueous lead (Pb) and arsenic (As) may occur in response to CO2 intrusion, but in most sensitivity cases their concentrations remain below the EPA specified maximum contaminant levels (MCLs). Adsorption/desorption from mineral surfaces significantly impacts the mobilization of Pb and As. Results from the 3D model agree fairly well with the 2D model in cases where the rate of CO2 intrusion is relatively small (so that the majority of CO2 readily dissolves in the groundwater), whereas discrepancies between 2D and 3D models are observed when the CO2 intrusion rate is comparably large

The California Planet Survey II. A Saturn-Mass Planet Orbiting the M Dwarf Gl649

We report precise Doppler measurements of the nearby (d = 10.34 pc) M dwarf Gl649 that reveal the presence of a planet with a minimum mass Msini = 0.328 Mjup in an eccentric (e = 0.30), 598.3 day orbit. Our photometric monitoring reveals Gl649 to be a new variable star with brightness changes on both rotational and decadal timescales. However, neither of these timescales are consistent with the 600-day Doppler signal and so provide strong support for planetary reflex motion as the best interpretation of the observed radial velocity variations. Gl649b is only the seventh Doppler-detected giant planet around an M dwarf. The properties of the planet and host-star therefore contribute significant information to our knowledge of planet formation around low-mass stars. We revise and refine the occurrence rate of giant planets around M dwarfs based on the California Planet Survey sample of low-mass stars (M* < 0.6 Msun). We find that f = 3.4^{+2.2}_{-0.9}% of stars with M* < 0.6 Msun harbor planets with Msini > 0.3$ Mjup and a < 2.5 AU. When we restrict our analysis to metal-rich stars with [Fe/H] > +0.2 we find the occurrence rate is 10.7^{+5.9}_{-4.2}%.Comment: 8 pages, 4 figures, 3 tables, PASP accepte

M2K: I. A Jovian mass planet around the M3V star HIP79431

Doppler observations from Keck Observatory reveal the presence of a planet with Msini of 2.1 Mjup orbiting the M3V star HIP79431. This is the sixth giant planet to be detected in Doppler surveys of M dwarfs and it is one of the most massive planets discovered around an M dwarf star. The planet has an orbital period of 111.7 days and an orbital eccentricity of 0.29. The host star is metal rich, with an estimated [Fe/H] = +0.4. This is the first planet to emerge from our new survey of 1600 M-to-K dwarf stars.Comment: 5 figure

Numerical modeling of injection and mineral trapping of CO2 withH2S and SO2 in a Sandstone Formation

Carbon dioxide (CO{sub 2}) injection into deep geologic formations could decrease the atmospheric accumulation of this gas from anthropogenic sources. Furthermore, by co-injecting H{sub 2}S or SO{sub 2}, the products respectively of coal gasification or combustion, with captured CO{sub 2}, problems associated with surface disposal would be mitigated. We developed models that simulate the co-injection of H{sub 2}S or SO{sub 2} with CO{sub 2} into an arkose formation at a depth of about 2 km and 75 C. The hydrogeology and mineralogy of the injected formation are typical of those encountered in Gulf Coast aquifers of the United States. Six numerical simulations of a simplified 1-D radial region surrounding the injection well were performed. The injection of CO{sub 2} alone or co-injection with SO{sub 2} or H{sub 2}S results in a concentrically zoned distribution of secondary minerals surrounding a leached and acidified region adjacent to the injection well. Co-injection of SO{sub 2} with CO{sub 2} results in a larger and more strongly acidified zone, and alteration differs substantially from that caused by the co-injection of H{sub 2}S or injection of CO{sub 2} alone. Precipitation of carbonates occurs within a higher pH (pH &gt; 5) peripheral zone. Significant quantities of CO{sub 2} are sequestered by ankerite, dawsonite, and lesser siderite. The CO{sub 2} mineral-trapping capacity of the formation can attain 40-50 kg/m{sup 3} medium for the selected arkose. In contrast, secondary sulfates precipitate at lower pH (pH &lt; 5) within the acidified zone. Most of the injected SO{sub 2} is transformed and immobilized through alunite precipitation with lesser amounts of anhydrite and minor quantities of pyrite. The dissolved CO{sub 2} increases with time (enhanced solubility trapping). The mineral alteration induced by injection of CO{sub 2} with either SO{sub 2} or H{sub 2}S leads to corresponding changes in porosity. Significant increases in porosity occur in the acidified zones where mineral dissolution dominates. With co-injection of SO{sub 2}, the porosity increases from an initial 0.3 to 0.43 after 100 years. However, within the CO{sub 2} mineral-trapping zone, the porosity decreases to about 0.28 for both cases, because of the addition of CO{sub 2} mass as secondary carbonates to the rock matrix. Precipitation of sulfates at the acidification front causes porosity to decrease to 0.23. The limited information currently available on the mineralogy of naturally occurring high-pressure CO{sub 2} reservoirs is generally consistent with our simulations