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The extensive heterogeneity both between and within the medulloblastoma (MB) subgroups underscores a critical need for variant-specific biomarkers and therapeutic strategies. We previously identified a role for the CD271/p75 neurotrophin receptor (p75NTR) in regulating stem/progenitor cells in the SHH MB subgroup. Here, we demonstrate the utility of CD271 as a novel diagnostic and prognostic marker for SHH MB using immunohistochemical analysis as well as transcriptome data across 763 primary tumors. Characterization of CD271+ and CD271- cells by RNA sequencing revealed that these two subpopulations are molecularly distinct, co-existing cellular subsets both in vitro and in vivo. MAPK/ERK signaling is upregulated in the CD271+ population and inhibiting this pathway reduced CD271 levels, stem/progenitor cell proliferation and cell survival as well as cell migration in vitro. Importantly, the MEK inhibitor selumetinib extends survival and reduces CD271 levels in vivo. Our study demonstrates the clinical utility of CD271 as both a diagnostic and prognostic tool for SHH MB tumors and reveals a novel role for MEK inhibitors in targeting CD271+ SHH MB cells.
Molecular characterization of pediatric low-grade glioma (pLGG) over the last decade has identified recurrent alterations, most commonly involving BRAF, and less frequently other pathways including MYB and MYBL1. Many of these molecular markers have been exploited clinically to aid in diagnosis and treatment decisions. However, their frequency and prognostic significance remain unknown. Further, a significant portion of cases do not have any of these alterations and what underlies these cases remains unknown. To address this we compiled a cohort of 562 patients diagnosed at SickKids from 1990-2017. We identified molecular alterations in 454 cases (81% of the cohort). The most frequent events were those involving BRAF; either as fusions (most commonly with KIAA1549 (30%)) or V600E mutations (17%) and NF-1 (22%). Less frequently, we identified recurrent FGFR1 fusions and mutations (3%), MYB/MYBL alterations (2%), H3F3AK27M (2%) or IDH1R132H (0.5%) mutations, as well as other novel rare events. Survival analysis revealed significantly better progression-free survival (PFS) and overall survival (OS) of KIAA1549-BRAF fused patients compared to BRAFV600E with 10-year OS 97.7% (95%, CI 95.5-100) and 83.9% (95%, CI 72.5-95.6), respectively. In addition to survival, molecular alterations predicted differences in response to conventional therapeutics; BRAF fused patients showed a 46% response-rate, versus only 14% in V600E patients. pLGGs harboring H3F3AK27M progressed early with median PFS of 11 months. In patients with MYB/MYBL1, FGFR1/FGFR2 alterations, we observed only one death (FGFR1N546K case). The work here represents the largest cohort of pLGGs with molecular profiling and their impact on the clinical behaviour of the disease.
Phased Array Feed (PAF) technology is the next major advancement in radio astronomy in terms of combining high sensitivity and large field of view. The Focal L-band Array for the Green Bank Telescope (FLAG) is one of the most sensitive PAFs developed so far. It consists of 19 dual-polarization elements mounted on a prime focus dewar resulting in seven beams on the sky. Its unprecedented system temperature of ~17 K will lead to a 3 fold increase in pulsar survey speeds as compared to contemporary single pixel feeds. Early science observations were conducted in a recently concluded commissioning phase of the FLAG where we clearly demonstrated its science capabilities. We observed a selection of normal and millisecond pulsars and detected giant pulses from PSR B1937+21.
Canopy-forming fucoid algae have an important role as ecosystem engineers on rocky intertidal shores, where they increase the abundance of species otherwise limited by exposure during low tide. The facilitative relationship between Ascophyllum nodosum and associated organisms was explored using a frond breakage experiment (100%, 50%, 25%, 0% intact-frond treatments) in southern England, to assess the consequences of disturbance. Understorey substratum temperature was on average 3°C higher in 0% and 25% intact-frond treatments than in plots with 50% and 100% intact fronds. Light (as PAR during low tide) doubled in 0% intact-frond treatments in comparison to other treatments (which had similar light levels). Mobile invertebrate species richness declined by on average 1 species per m2 in the treatments with only 25% and 0% intact fronds, and the abundance of Littorina obtusata declined by 2.4–4.2 individuals per m2 in the treatments with 25 and 0% intact fronds. Sessile taxa, including Osmundea pinnatifida and encrusting coralline algae, declined by half on average in the 0% intact-frond treatment. These results suggest that the ability of Ascophyllum to mediate environmental conditions to the understorey is the mechanism responsible for species distributed in the understorey (autogenic ecosystem engineering). The results of this study imply that a pulse disturbance resulting in a 50% breakage of Ascophyllum fronds significantly increases temperature and decreases the abundance of mobile invertebrates usually associated with Ascophyllum. Sessile taxa associated with Ascophyllum can, however, withstand disturbances down to 25% intact Ascophyllum fronds.
The third symposium on Remote Sensing of Snow and Ice, organized by the International Glaciological Society, took place in Boulder, Colorado, 17–22 May 1992. As part of this meeting a total of 21 papers was presented on snow and ice applications of Advanced Very High Resolution Radiometer (AVHRR) satellite data in polar regions. Also during this meeting a NASA sponsored Workshop was held to review the status of polar surface measurements from AVHRR. In the following we have summarized the ideas and recommendations from the workshop, and the conclusions of relevant papers given during the regular symposium sessions. The seven topics discussed include cloud masking, ice surface temperature, narrow-band albedo, ice concentration, lead statistics, sea-ice motion and ice-sheet studies with specifics on applications, algorithms and accuracy, following recommendations for future improvements. In general, we can affirm the strong potential of AVHRR for studying sea ice and snow covered surfaces, and we highly recommend this satellite data set for long-term monitoring of polar process studies. However, progress is needed to reduce the uncertainty of the retrieved parameters for all of the above mentioned topics to make this data set useful for direct climate applications such as heat balance studies and others. Further, the acquisition and processing of polar AVHRR data must become better coordinated between receiving stations, data centers and funding agencies to guarantee a long-term commitment to the collection and distribution of high quality data.
This study examines the interplay between individual and social–developmental factors in the development of positive functioning, substance use problems, and mental health problems. This interplay is nested within positive and negative developmental cascades that span childhood, adolescence, the transition to adulthood, and adulthood. Data are drawn from the Seattle Social Development Project, a gender-balanced, ethnically diverse community sample of 808 participants interviewed 12 times from ages 10 to 33. Path modeling showed short- and long-term cascading effects of positive social environments, family history of depression, and substance-using social environments throughout development. Positive family social environments set a template for future partner social environment interaction and had positive influences on proximal individual functioning, both in the next developmental period and long term. Family history of depression adversely affected mental health functioning throughout adulthood. Family substance use began a cascade of substance-specific social environments across development, which was the pathway through which increasing severity of substance use problems flowed. The model also indicated that adolescent, but not adult, individual functioning influenced selection into positive social environments, and significant cross-domain effects were found in which substance-using social environments affected subsequent mental health.
The Center for Astrophysical Research in Antarctica conducts various educational outreach programs as part of its mission as a National Science Foundation Science and Technology Center. The method behind the outreach programs is one of forging partnerships between Center researchers and other educational organisations. The main program serves primary and secondary students in Chicago. The core of the program is called Space Explorers and is targeted at high school students. These students attend a summer residential institute at the University of Chicago’s Yerkes Observatory. The high school Space Explorers then extend the reach of the program during the academic year by teaching in primary schools using a portable planetarium. The Center also pursues many other outreach activities and is in the process of forming an Antarctic Education Alliance.
The dogwhelk Nucella lapillus experienced localized extinction in the 1980s and 1990s due to the use of tributyltin (TBT) antifoulants, causing imposex in females. The aim of this study was to establish the extent of the return of the species across the mainland coast of central southern England as TBT use has been progressively restricted, and to quantify the extent of imposex impact on the populations present. We surveyed from Poole to Selsey where isolated populations had become extinct, and the Isle of Wight where some populations had persisted. We found evidence that since TBT restrictions, recolonization and colonization by N. lapillus has been rapid. By 2007–2008, of the eleven surveyed mainland sites, seven were colonized, although indications of reduced imposex impacts were mixed. Distribution had also extended on the Isle of Wight and populations were larger with less imposex impact in sites with long term populations. The lack of continuous suitable habitat blocks and the hydrodynamic complexity of the region, leads us to hypothesize that recovery has been facilitated by man-made structures which may be acting as ‘stepping stones’. Populations that have become established on engineered structures such as sea walls, breakwaters and rock groynes demonstrate accelerated recovery in the region as TBT in the environment has generally declined. Sites with suitable substrates and food sources near to ports were either not recolonized or had small populations with imposex evident. For species with a short pelagic larval stage or with direct development, population connectivity between patches of harder substrata along hydrodynamically complex coastlines may be greater than previously thought.
An extremely simple and inexpensive apparatus for preparation of the C60 and C70 fullerenes is described. An efficient separatory technique is described which implements a phenylglycine based HFLC column for preparation of high purity (99.99%) C60 and C70 samples. Treatment of C60 with osmium tetroxide and pyridine gives the osmate ester (2:1 adduct) and establishes that oxygen functionality can be added to C60 without disrupting the carbon framework. Raman spectroscopy of high purity C60 indicates that several lines previously not assigned to C60 (D.S.Bethune, G.Meijer, W.C.Tang, and H.J.Rosen, Chem.Phys.Lett.174, 219(1990)) are attributable to C60.
A three-dimensional Monte Carlo computer program has been developed to study the heterogeneous nucleation and growth of oxide precipitates during the thermal treatment of crystalline silicon. In the simulations, oxygen atoms move on a lattice with randomly selected lattice points serving as nucleation sites. The change in free energy that the oxygen cluster would experience in gaining or losing one oxygen atom is used to govern growth or dissolution of the cluster. All the oxygen atoms undergo a jump or a growth decision during each time step of the anneal. The growth and decay kinetics of each nucleation site display interesting fluctuation phenomena. The time dependence of the cluster size generally differs from the expected 3/2 power law due to the fluctuations in oxygen arrival at and incorporation in a precipitate. Competition between growing sites and coarsening are observed.
Interstitial oxygen precipitates in silicon during thermal treatment. The amount precipitated increases in an S-shaped fashion as a function of increasing initial interstitial oxygen concentration. A likely hypothesis for this behavior is that the number of nucleation sites that develop into precipitates (successful sites) varies with the initial interstitial oxygen concentration as well as with the precipitation rate at each site. In this paper, a deterministic precipitate growth model is first used to show that a fit to the present data requires the precipitate density to increase by more than a factor of 10 when the oxygen concentration goes from 24 to 40 ppma.
Three-dimensional Monte Carlo calculations are then used to show how the nucleation site survival probability depends on the initial number of oxygen atoms at the site and the oxygen concentration. The program treats oxygen diffusion, growth at nucleation sites by the addition of oxygen atoms, and loss at nucleation sites by the escape of oxygen atoms.
This paper discusses four aspects of fabrication of an active address liquid crystal array from laser recrystallized polycrystalline silicon: recrystallization, processing, device performance and array fabrication. The recrystallization process produces material which is imperfect by silicon wafer standards, but which contains few incoherent defects. The material was used to fabricate discrete n-channel MOS devices which had consistent off currents of 10−11 amps (0.4pA/μm of channel width) and on currents of 10−4 amps. Device threshold is controlled to + 200 mV and channel mobility is 500 to 600 cm2 /V-sec. The crossovers between Al/1% Si source and degenerately doped polycrystalline silicon gate lines were fabricated by use of high temperature reflowed, phosphorus doped chemical vapor deposited SiO2. Completed arrays had very few defects (no crossover defects and 0.3% bad devices).
Aligned, coexisting liquid and solid regions are observed in cw laser annealing of polycrystalline Si films on quartz substrates. These stripe patterns are the precursors of surface topography that exists after cooling. It is proposed that a similar situation exists in the pulse annealing process. A calculation of the temperature evolution which assumes stripe symmetry and kinetic restraints of the crystallization process has been carried out. These calculations indicate a lattice temperature of between 1100 and 1300 K, 10 nsec after the sample has fully solidified.
In this paper we review the current understanding of laser-induced silicon thin film crystal growth on bulk amorphous substrates. We propose a model for oriented nucleation and show that the silicon reflectivity jump on melting coupled with radiant heating lead naturally to this autonucleation mechanism. We then survey various techniques for control of lateral epitaxial growth and conclude with the results of some recent electrical device characterization.
We demonstrate self-trapping of a two-dimensional beam at 1.3 microns wavelength in resonantly-enhanced InP. The self-trapped beam also induces a two-dimensional optical waveguide in bulk InP, which guides a second beam at 1.55 micron wavelength.
Uncertainties exist regarding the population risks of hospitalization due to pandemic influenza A(H1N1). Understanding these risks is important for patients, clinicians and policy makers. This study aimed to clarify these uncertainties. A national surveillance system was established for patients hospitalized with laboratory-confirmed pandemic influenza A(H1N1) in England. Information was captured on demographics, pre-existing conditions, treatment and outcomes. The relative risks of hospitalization associated with pre-existing conditions were estimated by combining the captured data with population prevalence estimates. A total of 2416 hospitalizations were reported up to 6 January 2010. Within the population, 4·7 people/100 000 were hospitalized with pandemic influenza A(H1N1). The estimated hospitalization rate of cases showed a U-shaped distribution with age. Chronic kidney disease, chronic neurological disease, chronic respiratory disease and immunosuppression were each associated with a 10- to 20-fold increased risk of hospitalization. Patients who received antiviral medication within 48 h of symptom onset were less likely to be admitted to critical care than those who received them after this time (adjusted odds ratio 0·64, 95% confidence interval 0·44–0·94, P=0·024). In England the risk of hospitalization with pandemic influenza A(H1N1) has been concentrated in the young and those with pre-existing conditions. By quantifying these risks, this study will prove useful in planning for the next winter in the northern and southern hemispheres, and for future pandemics.
The new Core-XAS (X-ray absorption spectroscopy) beamline (B18) at Diamond aims to provide a reliable spectrometer for a broad scientific community. With this in mind, B18 has been built as a general-purpose beamline and offers to users a variety of sample environments and detection methods. Here we will present the first commissioning results and some of the capabilities of this versatile instrument.