Background: Medulloblastoma (MB) is the most common solid malignant pediatric brain neoplasm. Group 3 (G3) MB, particularly MYC amplified G3 MB, is the most aggressive subgroup with the highest frequency of children presenting with metastatic disease, and is associated with a poor prognosis. To further our understanding of the role of MSI1 in MYC amplified G3 MB, we performed an unbiased integrative analysis of eCLIP binding sites, with changes observed at the transcriptome, the translatome, and the proteome after shMSI1 inhibition. Methods: Primary human pediatric MBs, SU_MB002 and HD-MB03 were kind gifts from Dr. Yoon-Jae Cho (Harvard, MS) and Dr. Till Milde (Heidelberg) and cultured for in vitro and in vivo experiments. eCLIP, RNA-seq, Polysome-seq, and TMT-MS were completed as previously described. Results: MSI1 is overexpressed in G3 MB. shRNA Msi1 interference resulted in a reduction in tumour burden conferring a survival advantage to mice injected with shMSI1 G3MB cells. Robust ranked multiomic analysis (RRA) identified an unconventional gene set directly perturbed by MSI1 in G3 MB. Conclusions: Our robust unbiased integrative analysis revealed a distinct role for MSI1 in the maintenance of the stem cell state in G3 MB through post-transcriptional modification of multiple pathways including identification of unconventional targets such as HIPK1.

Background: Spinal computer-assisted navigation (CAN) is proven to increase instrumentation accuracy. Adoption remains limited by workflow restrictions, learning curves and costs. Here, we assess spinal CAN usage among Ontario surgeons to identify gaps in application, and temporal trends of usage. Methods: A prospectively-collected database of provincial insurance billables and diagnostic codes was reviewed retrospectively, from 2002-2014. Patients undergoing instrumented spinal fusions or percutaneous vertebroplasty/kyphoplasty were identified. Fee and diagnostic codes were applied to distinguish surgical indication and approach. The use of intra-operative navigation was determined for each case. Results: We identified 4607 instrumented spinal fusions in our cohort. Most cases were performed by orthopedic surgeons (63.2%) and the remainder by neurosurgeons. Of 2239 cases with identifiable etiology, CAN was utilized in 8.8%, predominantly for trauma and degenerative pathologies rather than deformity. In univariate analyses, CAN was used more often by neurosurgeons (21.0% vs. 12.4%, p<0.001), in academic institutions (15.9% vs. 12.3%, p<0.001), and when performed in/after 2010 (18.9% vs. 8.9%, p<0.001). Differences by specialty and year remained significant in multiple logistic regression. Conclusions: Spinal CAN has proven benefit for instrumentation accuracy, but is used preferentially by academic neurosurgeons. Significant gains must be made in cost and usability to improve access across disciplines and institutions.

Simulation of turbulent flows with shocks employing subgrid-scale (SGS) filtering may encounter a loss of accuracy in the vicinity of a shock. This paper addresses the accuracy improvement of LES of turbulent flows in two ways: (a) from the SGS model standpoint and (b) from the numerical method improvement standpoint. In an internal report, Kotov et al. ( “High Order Numerical Methods for large eddy simulation (LES) of Turbulent Flows with Shocks”, CTR Tech Brief, Oct. 2014, Stanford University), we performed a preliminary comparative study of different approaches to reduce the loss of accuracy within the framework of the dynamic Germano SGS model. The high order low dissipative method of Yee & Sjögreen (2009) using local flow sensors to control the amount of numerical dissipation where needed is used for the LES simulation. The considered improved dynamics model approaches include applying the one-sided SGS test filter of Sagaut & Germano (2005) and/or disabling the SGS terms at the shock location. For Mach 1.5 and 3 canonical shock-turbulence interaction problems, both of these approaches show a similar accuracy improvement to that of the full use of the SGS terms. The present study focuses on a five levels of grid refinement study to obtain the reference direct numerical simulation (DNS) solution for additional LES SGS comparison and approaches. One of the numerical accuracy improvements included here applies Harten's subcell resolution procedure to locate and sharpen the shock, and uses a one-sided test filter at the grid points adjacent to the exact shock location.

Background: Global variation in the incidence of multiple sclerosis (MS) is generally ascribed to differences in genetic and environmental risk factors. Here we investigate temporal trends in the incidence of MS and related disorders in British Columbia, Canada, from 1986 to 2010, focusing particularly on the Asian ethnic subpopulation.Methods: A longitudinal database was screened to identify newly diagnosed cases of MS and related disorders, including neuromyelitis optica and clinically isolated syndromes. Age-standardized, sex-specific mean annual incidence was calculated for the Asian and non-Asian population of British Columbia for 5-year intervals from 1986 to 2010. Temporal changes and cohort differences in incidence rates and demographic characteristics were evaluated. Results: During this period, the incidence of MS and related disorders in the non-Asian population remained relatively unchanged, from 10.41 (95% confidence interval [CI]: 9.87-10.97) to 9.91 (95% CI: 9.46-10.39) per 100,000 (p=0.167). In contrast, incidence in the Asian population doubled during the same period. This increase was driven by a precipitous rise in the incidence of MS in females from 0.71 (95% CI: 0.01-1.50) to 2.08 (95% CI: 1.43-2.91) per 100,000 (p=0.004), including both Canadian-born and immigrant Asians. The incidence of neuromyelitis optica did not change significantly during this period. Conclusions: The incidence of MS may be increasing among females in the Asian ethnic population of British Columbia.

The variable high-order multiblock overlapping (overset) grids method of Sjögreen & Yee [CiCP, Vol. 5, 2009] for a perfect gas has been extended to nonequilibrium flows. This work makes use of the recently developed high-order well-balanced shock-capturing schemes and their filter counterparts [Wang et al., J. Comput. Phys., 2009, 2010] that exactly preserve certain non-trivial steady state solutions of the chemical nonequilibrium governing equations. Multiscale turbulence with strong shocks and flows containing both steady and unsteady components is best treated by mixing of numerical methods and switching on the appropriate scheme in the appropriate subdomains of the flow fields, even under the multiblock grid or adaptive grid refinement framework. While low dissipative sixth- or higher-order shock-capturing filter methods are appropriate for unsteady turbulence with shocklets, second- and third- order shock-capturing methods are more effective for strong steady or nearly steady shocks in terms of convergence. It is anticipated that our variable high-order overset grid framework capability with its highly modular design will allow for an optimum synthesis of these new algorithms in such a way that the most appropriate spatial discretizations can be tailored for each particular region of the flow. In this paper some of the latest developments in single block high-order filter schemes for chemical nonequilibrium flows are applied to overset grid geometries. The numerical approach is validated on a number of test cases characterized by hypersonic conditions with strong shocks, including the reentry flow surrounding a 3D Apollo-like NASA Crew Exploration Vehicle that might contain mixed steady and unsteady components, depending on the flow conditions.

Disruption of cell membranes triggers rapid metabolic energy exhaustion, then acute cellular necrosis. Cell membrane dysfunction due to loss of structure integrity is the pathology of tissue death in trauma, muscular dystrophies, reperfusion injuries and common diseases. It is now established that certain PEG-based biocompatible polymers, such as Poloxamer 188, Poloxamine 1107 and PEG, are effective in sealing of injured cell membranes, and thus can prevent acute necrosis if delivered within a few hours after injury. Despite these broad applications of PEG-based polymers for human health, the fundamental mechanisms of how PEG-based polymers interact with cell membranes are still under debate. Here, the effects of PEG-based biocompatible polymers on phospholipid membrane integrity under external stimuli (osmotic stress and oxidative stress) were explored using giant unilamellar vesicles (GUVs) as model cell membranes. Through fluorescence leakage assays and time-lapse fluorescence microscopy, we directly observed that the surface-adsorbed P188 can efficiently inhibits the loss of structural integrity of giant unilamellar vesicles (GUVs) under hypo-osmotic stress. We propose that the adsorption of polymers on the membrane surface is responsible for the cell membrane resealing process, while the insertion of the hydrophobic portion of the polymers increases membrane permeability. To elucidate the mechanism by which hydrophilic polymers help restore membrane integrity while their hydrophobic counterparts disrupt it, 1H Overhauser Dynamic Nuclear Polarization (ODNP)-NMR spectroscopy, a newly developed NMR technique that provides unprecedented resolution for differentiating weak surface adsorption versus translocation of polymers to membranes, was employed to sensitively detect polymer-lipid membrane interactions through the modulation of local hydration dynamics in lipid membranes. Our study shows that P188—the most hydrophilic poloxamer known as a membrane sealant—weakly adsorbs onto the membrane surface, yet effectively retards membrane hydration dynamics. Contrarily, P181—the most hydrophobic poloxamer known as a membrane permeabilizer—initially penetrates past lipid headgroups and enhances intrabilayer water diffusivity. Consequently, our results illustrate that the relative hydrophilic/hydrophobic ratio of the polymer dictates its functions. These findings gleaned from local hydration dynamics are well supported by our thermodynamics and fluorescence data.

We use deep nIR imaging of 15 galaxy clusters at z ≃ 1 to study the build-up of the red-sequence in rich clusters since the Universe was half its present age. We measured, for the first time, the luminous-to-faint ratio of red-sequence galaxies at z=1 from a large ensemble of clusters, and found an increase of 100% in the ratio of luminous-to-faint red-sequence galaxies from z=0.45 to 1.0. The measured change in this ratio as function of redshift is well-reproduced by a simple evolutionary model developed in this work, that consists in an early truncation of the star formation for bright cluster galaxies and a delayed truncation for faint cluster galaxies.

We investigate the dependence of galaxy populations on environment. Our samples are selected from the follow-up of Red-Sequence Cluster Survey (RCS) catalogs using wide-field BVRz' imaging for 60 intermediate redshift (0.3 < z < 0.6) clusters. Galaxy redshifts are estimated using an empirical photometric redshift technique with a training set of 3996 galaxies to z 1.4. To obtain photometric redshift probability density for each galaxy, we bootstrap the training set galaxies to estimate the fitting uncertainties and apply Monte-Carlo method to simulate galaxy magnitudes errors. In order to find galaxy groups using photometric redshift, we develop a modified friends-of-friends algorithm, ‘Probability Friends-of-Friends Algorithm (pFOF)’, where photometric redshift redshift probability densities of individual galaxies are used to determine member galaxies of a group. We calculate the red galaxy fraction to infer the evolutionary status of cluster galaxies and also for galaxies in groups selected in the same redshift space as the clusters.

A method is reported for predicting the shape of the phase boundary in two-phase isothermal constant-volume constant-mass rotating fluid systems. In contrast to previous methods that have employed the continuum concept of pressure, the proposed method uses the thermodynamic concept. The latter requires, in addition to the usual condition of a force balance existing at the boundary, that the equilibrium phase boundary shape be such that there is no net mass flux. The latter condition is imposed by requiring that the chemical potentials in the different phases be equal at the phase boundary. A non-dimensional parameter is defined that allows one to determine when the effects of a gravitational field acting at 90° to the axis of rotation may be neglected. Experiments have been performed under conditions where this restriction is satisfied. With known values of the experimentally controllable variables, the proposed method has been used to predict the length of the vapour phase. To within the experimental error, the predicted lengths are found to be in agreement with the measurements. If, however, a gravitational field of a sufficient magnitude is imposed the vapour phase has been found to become unstable and to break into two or more separate bubbles. Using the variable-gravity environment of an aircraft following a parabolic flight path, this instability has been investigated. By approximating the gravitational effects, the theoretical description has been extended and a method proposed to determine the conditions under which the phase boundary becomes unstable. If the angle of action of the net viscous shear force on the bubble were known, a prediction of the breakup could be made entirely in terms of experimentally controllable parameters. Using arguments for the value of this angle, bounds on the breakup condition are compared with experimental results.

The Red-Sequence Cluster Survey (RCS) is a 100 deg2 optical survey for high-redshift galaxy clusters. One of the goals of the survey is a measurement of Ωm and σ8 via the evolution of the mass spectrum of galaxy clusters. Herein we briefly describe how this will initially be done, and also demonstrate the eventual power of the RCS for this type of measurement by a qualitative analysis of the first 1/10th of the survey data.

A multi-object spectroscopy follow-up survey of galaxy clusters selected from the Red-sequence Cluster Survey (RCS) is being completed. About forty clusters were chosen with redshifts from 0.15 to 0.6, and in a wide range of richnesses. One of the main science drivers of this survey is a study of internal dynamics of clusters. We present some preliminary results for a subset of the clusters, including the correlation of optical richness with mass, and the mass-to-light ratio as a function of cluster mass.To search for other articles by the author(s) go to: http://adsabs.harvard.edu/abstract_service.html

Tea and coffee are rich in polyphenols with a variety of biological activities. Many of the demonstrated activities are consistent with favourable effects on the risk of chronic diseases. 4-O-methylgallic acid (4OMGA) and isoferulic acid are potential biomarkers of exposure to polyphenols derived from tea and coffee respectively. 4OMGA is derived from gallic acid in tea, and isoferulic acid is derived from chlorogenic acid in coffee. Our major objective was to explore the relationships of tea and coffee intake with 24 h urinary excretion of 4OMGA and isoferulic acid in human subjects. The relationships of long-term usual (111 participants) and contemporaneously recorded current (344 participants) tea and coffee intake with 24 h urinary excretion of 4OMGA and isoferulic acid were assessed in two populations. 4OMGA was related to usual (r 0·50, P<0·001) and current (r 0·57, P<0·001) tea intake, and isoferulic acid was related to usual (r 0·26, P=0·008) and current (r 0·18, P<0·001) coffee intake. Overall, our present results are consistent with the proposal that 4OMGA is a good biomarker for black tea-derived polyphenol exposure, but isoferulic acid may be of limited usefulness as a biomarker for coffee-derived polyphenol exposure.

We present the results of a study of the average mass profile around galaxies using weak gravitational lensing. We use 45.5 deg2 of RC band imaging data from the Red-Sequence Cluster Survey (RCS) and define a sample of ~ 1.2 × 105 lenses with 19.5 < RC < 21, and a sample of ~ 1.5 × 106 background galaxies with 21.5 < R < 24.

We constrain the power law scaling relations between the B-band luminosity and the mass and size of the halo, and find that the results are in excellent agreement with observed luminosity–line-width relations. Under the assumption that the luminosity does not evolve with redshift, the best fit NFW model yields a mass M200 = (8.8±0.7) × 1011h –1M ⊙ and a scale radius rs = I6.7+3.7 –3.0 h –1 kpc for a galaxy with a fiducial luminosity of Lb = 1010 h –2LB⊙. the latter result is in excellent agreement with predictions from numerical simulations for a halo of this mass. We also observe a signficant anisotropy of the lensing signal around the lenses, implying that the halos are flattened and aligned with the light distribution. We find an average (projected) halo ellipticity of 〈e halo〉 = 0.20+0.04 –0.05, in fair agreement with results from numerical simulations of CDM. Alternative theories of gravity (without dark matter) predict an isotropic lensing signal, which is excluded with 99.5% confidence. Hence, our results provide strong support for the existence of dark matter.

The application of porous low-k interlayer dielectrics is needed forreducing the parasitical capacitance, especially at 65-nm node and beyond.The understanding of process-induced modifications to material properties iscrucial for a successful integration of these low-k dielectrics. The dryetching processes of porous low-k materials are important modules in ULSIfabrication. In this study, the interaction between MSQ-based JSR LKD-5109films (shown by PALS to have interconnected 2.8 nm size pores) with CF4/O2 plasma has been investigated. Various ratios of O2 content were designed to characterize its effects on theetch rate, formation of polymerization layer, and properties of the LKD-5109film. Composition analysis was conducted by SIMS and FTIR. Moistureabsorption and fluorine diffusion into low-k films after etch process areobserved, along with carbon depletion near the surface region. The influenceof etching chemistries on the morphological characteristics of thin Tabarrier layers (8-nm in thickness) deposited on etched low-k films werefurther investigated by SEM, and it is found that oxygen concentration hassignificant influences on the morphological characteristics of thin Tabarriers.