Mutational Analysis of Hedgehog Signaling Pathway Genes in Human Malignant Mesothelioma

Background The Hedgehog (HH) signaling pathway is critical for embryonic development and adult homeostasis. Recent studies have identified regulatory roles for this pathway in certain cancers with mutations in the HH pathway genes. The extent to which mutations of the HH pathway genes are involved in the pathogenesis of malignant mesothelioma (MMe) is unknown. Methodology/Principal Findings Real-time PCR analysis of HH pathway genes PTCH1, GLI1 and GLI2 were performed on 7 human MMe cell lines. Exon sequencing of 13 HH pathway genes was also performed in cell lines and human MMe tumors. In silico programs were used to predict the likelihood that an amino-acid substitution would have a functional effect. GLI1, GLI2 and PTCH1 were highly expressed in MMe cells, indicative of active HH signaling. PTCH1, SMO and SUFU mutations were found in 2 of 11 MMe cell lines examined. A non-synonymous missense SUFU mutation (p.T411M) was identified in LO68 cells. In silico characterization of the SUFU mutant suggested that the p.T411M mutation might alter protein function. However, we were unable to demonstrate any functional effect of this mutation on Gli activity. Deletion of exons of the PTCH1 gene was found in JU77 cells, resulting in loss of one of two extracellular loops implicated in HH ligand binding and the intracellular C-terminal domain. A 3-bp insertion (69_70insCTG) in SMO, predicting an additional leucine residue in the signal peptide segment of SMO protein was also identified in LO68 cells and a MMe tumour. Conclusions/Significance We identified the first novel mutations in PTCH1, SUFU and SMO associated with MMe. Although HH pathway mutations are relatively rare in MMe, these data suggest a possible role for dysfunctional HH pathway in the pathogenesis of a subgroup of MMe and help rationalize the exploration of HH pathway inhibitors for MMe therapy

Development of a percutaneous coronary intervention patient level composite measure for a clinical quality registry

© 2020 The Author(s). Background: Composite measures combine data to provide a comprehensive view of patient outcomes. Despite composite measures being a valuable tool to assess post-intervention outcomes, the patient perspective is often missing. The purpose of this study was to develop a composite measure for an established cardiac outcome registry, by combining clinical outcomes following percutaneous coronary interventions (PCI) with a patient-reported outcome measure (PROM) developed specifically for this population (MC-PROM). Methods: Two studies were undertaken. Study 1: Patients who had undergone a PCI at one of the three participating registry hospital sites completed the 5-item MC-PROM. Clinical outcome data for the patients (e.g. death, myocardial infarction, repeat vascularisation, new bleeding event) were collected 30 days post-intervention as part of routine data collection for the cardiac registry. Exploratory factor analysis of clinical outcomes and MC-PROM data was conducted to determine the minimum number of constructs to be included in a composite measure. Study 2: Clinical experts participated in a Delphi technique, consisting of three rounds of online surveys, to determine the clinical outcomes to be included and the weighting of the clinical outcomes and MC-PROM score for the composite measure. Results: Study 1: Routine clinical outcomes and the MC-PROM data were collected from 266 patients 30 days post PCI. The MC-PROM score was not significantly correlated with any clinical outcomes. Study 2: There was a relatively consistent approach to the weighting of the clinical outcomes and MC-PROM items by the expert panel (n = 18) across the three surveys with the exception of the clinical outcome of 'deceased at 30 days'. The final composite measure included five clinical outcomes within 30 days weighted at 90% (new heart failure, new myocardial infarction, new stent thrombosis, major bleeding event, new stroke, unplanned cardiac rehospitalisation) and the MC-PROM score (comprising 10% of the total weighting). Conclusions: A single patient level composite score, which incorporates weighted clinical outcomes and a PROM was developed. This composite score provides a more comprehensive reported measure of individual patient wellbeing at 30 days post their PCI-procedure, and may assist clinicians to further assess and address patient level factors that potentially impact on clinical recovery

Bell-inequality violation with "thermal" radiation

The model of a quantum-optical device for a conditional preparation of entangled states from input mixed states is presented. It is demonstrated that even thermal or pseudo-thermal radiation can be entangled in such a way, that Bell-inequalities are violated

Geomorphological effectiveness of floods to rework gravel bars:insight from hyperscale topography and hydraulic modelling

Bars are key morphological units in river systems, fashioning the sediment regime and bedload transport processes within a reach. Reworking of these features underpins channel adjustment at larger scales, thereby acting as a key determinant of channel stability. Despite their importance to channel evolution, few investigations have acquired spatially continuous data on bar morphology and sediment‐size to investigate bar reworking. To this end, four bars along a 10 km reach of a wandering gravel‐bed river were surveyed with Terrestrial Laser Scanning (TLS), capturing downstream changes in slope, bed material size and channel planform. Detrended standard deviations (σz) were extracted from TLS point clouds and correlated to underlying physically measured median grain‐size (D50), across a greater range of σz values than have hitherto been reported. The resulting linear regression model was used to create a 1 m resolution median grain‐size map. A fusion of airborne LiDAR and optical‐empirical bathymetric mapping was used to develop reach‐scale Digital Elevation Models (DEMs) for rapid two‐dimensional hydraulic modelling using JFlow® software. The ratio of dimensionless shear stress over critical shear stress was calculated for each raster cell to calculate the effectiveness of a range of flood events (2.33‐100 year recurrence intervals) to entrain sediment and rework bar units. Results show that multiple bar forming discharges exist, whereby frequent flood flows rework tail and back‐channel areas, whilst much larger, less frequent floods are required to mobilise the coarser sediment fraction on bar heads. Valley confinement is shown to exert a primary influence on patterns of bar reworking. Historical aerial photography, hyperscale DEMs and hydraulic modelling are used to explain channel adjustment at the reach scale. The proportion of the bar comprised of more frequently entrained units (tail, back channel, supra‐platform) relative to more static units (bar head) exerts a direct influence upon geomorphic sensitivity

Estimating Wildfire Smoke Concentrations during the October 2017 California Fires through BME Space/Time Data Fusion of Observed, Modeled, and Satellite-Derived PM2.5

Exposure to wildfire smoke causes adverse health outcomes, suggesting the importance of accurately estimating smoke concentrations. Geostatistical methods can combine observed, modeled, and satellite-derived concentrations to produce accurate estimates. Here, we estimate daily average ground-level PM2.5 concentrations at a 1 km resolution during the October 2017 California wildfires, using the Constant Air Quality Model Performance (CAMP) and Bayesian Maximum Entropy (BME) methods to bias-correct and fuse three concentration datasets: permanent and temporary monitoring stations, a chemical transport model (CTM), and satellite-derived estimates. Four BME space/time kriging and data fusion methods were evaluated. All BME methods produce more accurate estimates than the standalone CTM and satellite products. Adding temporary station data increases the R2 by 36%. The data fusion of observations with the CAMP-corrected CTM and satellite-derived concentrations provides the best estimate (R2 = 0.713) in fire-impacted regions, emphasizing the importance of combining multiple datasets. We estimate that approximately 65,000 people were exposed to very unhealthy air (daily average PM2.5 ≥ 150.5 μg/m3)

Reduced relative volume in motor and attention regions in developmental coordination disorder: a voxel-based morphometry study.

Background and Objectives: Developmental coordination disorder (DCD) is a prevalent childhood movement disorder, impacting the ability to perform movement skills at an age appropriate level. Although differences in grey matter (GM) volumes have been found in related developmental disorders, no such evidence has been linked with DCD to date. This cross-sectional study assessed structural brain differences in children with and without DCD. Methods: High-resolution structural images were acquired from 44 children aged 7.8–12 years, including 22 children with DCD (≤16th percentile on MABC-2; no ADHD/ASD), and 22 typically developing controls (≥20th percentile on MABC-2). Structural voxel-based morphology analysis was performed to determine group differences in focal GM volumes. Results: Children with DCD were found to have significant, large, right lateralised reductions in grey matter volume in the medial and middle frontal, and superior frontal gyri compared to controls. The addition of motor proficiency as a covariate explained the between-group GM volume differences, suggesting that GM volumes in motor regions are reflective of the level of motor proficiency. A positive correlation between motor proficiency and relative GM volume was also identified in the left posterior cingulate and precuneus. Conclusions: GM volume reductions in premotor frontal regions may underlie the motor difficulties characteristic of DCD. It is possible that intervention approaches targeting motor planning, attention, and executive functioning processes associated with the regions of reduced GM volume may result in functional improvements in children with DCD

Mitochondrial dysfunction contributes to the senescent phenotype of IPF lung fibroblasts

Increasing evidence highlights that senescence plays an important role in idiopathic pulmonary fibrosis (IPF). This study delineates the specific contribution of mitochondria and the superoxide they form to the senescent phenotype of lung fibroblasts from IPF patients (IPF-LFs). Primary cultures of IPF-LFs exhibited an intensified DNA damage response (DDR) and were more senescent than age-matched fibroblasts from control donors (Ctrl-LFs). Furthermore, IPF-LFs exhibited mitochondrial dysfunction, exemplified by increases in mitochondrial superoxide, DNA, stress and activation of mTORC1. The DNA damaging agent etoposide elicited a DDR and augmented senescence in Ctrl-LFs, which were accompanied by disturbances in mitochondrial homoeostasis including heightened superoxide production. However, etoposide had no effect on IPF-LFs. Mitochondrial perturbation by rotenone involving sharp increases in superoxide production also evoked a DDR and senescence in Ctrl-LFs, but not IPF-LFs. Inhibition of mTORC1, antioxidant treatment and a mitochondrial targeting antioxidant decelerated IPF-LF senescence and/or attenuated pharmacologically induced Ctrl-LF senescence. In conclusion, increased superoxide production by dysfunctional mitochondria reinforces lung fibroblast senescence via prolongation of the DDR. As part of an auto-amplifying loop, mTORC1 is activated, altering mitochondrial homoeostasis and increasing superoxide production. Deeper understanding the mechanisms by which mitochondria contribute to fibroblast senescence in IPF has potentially important therapeutic implications

Estimating the parameters of the Sgr A* black hole

The measurement of relativistic effects around the galactic center may allow in the near future to strongly constrain the parameters of the supermassive black hole likely present at the galactic center (Sgr A*). As a by-product of these measurements it would be possible to severely constrain, in addition, also the parameters of the mass-density distributions of both the innermost star cluster and the dark matter clump around the galactic center.Comment: Accepted for publication on General Relativity and Gravitation, 2010. 11 Pages, 1 Figur

Isospin-Violating Meson-Nucleon Vertices as an Alternate Mechanism of Charge-Symmetry Breaking

We compute isospin-violating meson-nucleon coupling constants and their consequent charge-symmetry-breaking nucleon-nucleon potentials. The couplings result from evaluating matrix elements of quark currents between nucleon states in a nonrelativistic constituent quark model; the isospin violations arise from the difference in the up and down constituent quark masses. We find, in particular, that isospin violation in the omega-meson--nucleon vertex dominates the class IV CSB potential obtained from these considerations. We evaluate the resulting spin-singlet--triplet mixing angles, the quantities germane to the difference of neutron and proton analyzing powers measured in elastic $\vec{n}-\vec{p}$ scattering, and find them commensurate to those computed originally using the on-shell value of the $\rho$-$\omega$ mixing amplitude. The use of the on-shell $\rho$-$\omega$ mixing amplitude at $q^2=0$ has been called into question; rather, the amplitude is zero in a wide class of models. Our model possesses no contribution from $\rho$-$\omega$ mixing at $q^2=0$, and we find that omega-meson exchange suffices to explain the measured $n-p$ analyzing power difference~at~183 MeV.Comment: 20 pages, revtex, 3 uuencoded PostScript figure

Generation of atom-photon entangled states in atomic Bose-Einstein condensate via electromagnetically induced transparency

In this paper, we present a method to generate continuous-variable-type entangled states between photons and atoms in atomic Bose-Einstein condensate (BEC). The proposed method involves an atomic BEC with three internal states, a weak quantized probe laser and a strong classical coupling laser, which form a three-level Lambda-shaped BEC system. We consider a situation where the BEC is in electromagnetically induced transparency (EIT) with the coupling laser being much stronger than the probe laser. In this case, the upper and intermediate levels are unpopulated, so that their adiabatic elimination enables an effective two-mode model involving only the atomic field at the lowest internal level and the quantized probe laser field. Atom-photon quantum entanglement is created through laser-atom and inter-atomic interactions, and two-photon detuning. We show how to generate atom-photon entangled coherent states and entangled states between photon (atom) coherent states and atom-(photon-) macroscopic quantum superposition (MQS) states, and between photon-MQS and atom-MQS states.Comment: 9 pages, 1 figur