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OBJECTIVES/GOALS: Glioblastomas (GBMs) are heterogeneous, treatment-resistant tumors that are driven by populations of cancer stem cells (CSCs). In this study, we perform an epigenetic-focused functional genomics screen in GBM organoids and identify WDR5 as an essential epigenetic regulator in the SOX2-enriched, therapy resistant cancer stem cell niche. METHODS/STUDY POPULATION: Despite their importance for tumor growth, few molecular mechanisms critical for CSC population maintenance have been exploited for therapeutic development. We developed a spatially resolved loss-of-function screen in GBM patient-derived organoids to identify essential epigenetic regulators in the SOX2-enriched, therapy resistant niche. Our niche-specific screens identified WDR5, an H3K4 histone methyltransferase responsible for activating specific gene expression, as indispensable for GBM CSC growth and survival. RESULTS/ANTICIPATED RESULTS: In GBM CSC models, WDR5 inhibitors blocked WRAD complex assembly and reduced H3K4 trimethylation and expression of genes involved in CSC-relevant oncogenic pathways. H3K4me3 peaks lost with WDR5 inhibitor treatment occurred disproportionally on POU transcription factor motifs, required for stem cell maintenance and including the POU5F1(OCT4)::SOX2 motif. We incorporated a SOX2/OCT4 motif driven GFP reporter system into our CSC cell models and found that WDR5 inhibitor treatment resulted in dose-dependent silencing of stem cell reporter activity. Further, WDR5 inhibitor treatment altered the stem cell state, disrupting CSC in vitro growth and self-renewal as well as in vivo tumor growth. DISCUSSION/SIGNIFICANCE: Our results unveiled the role of WDR5 in maintaining the CSC state in GBM and provide a rationale for therapeutic development of WDR5 inhibitors for GBM and other advanced cancers. This conceptual and experimental framework can be applied to many cancers, and can unmask unique microenvironmental biology and rationally designed combination therapies.
The Bulge Asymmetries and Dynamical Evolution (BAaDE) survey aims to explore the complex structure of the inner Galaxy and Galactic Bulge, by using the 43 GHz receivers at the Karl G. Jansky Very Large Array (VLA) and the 86 GHz receivers at the Atacama Large Millimeter/submillimeter Array (ALMA) to observe SiO maser lines in red giant stars. The goal is to construct a sample of stellar point-mass probes that can be used to test models of the gravitational potential, and the final sample is expected to provide at least 20,000 line-of-sight velocities and positions. A possible bias between the VLA and the ALMA SiO maser lines is explored, and the 86 GHz SiO line-peak velocities agree using either of the four sampled lines. Additionally, the SiO maser velocities agree with the OH maser derived velocities.
The Bulge Asymmetries and Dynamical Evolution (BAaDE) survey aims to use circumstellar SiO maser line-of-sight velocities as probes for the Galactic gravitational potential and dynamical structure. The SiO masers are detected at a high rate in specific color-selected MSX infrared sources. Furthermore, the SiO maser properties and line ratios, in combination with infrared spectral energy distributions and location in the Galaxy, will statistically yield detailed information on population and evolution of low- to intermediate-mass evolved stars in the Galaxy.
Urinary tract infections (UTIs) are common among college-aged women and often recur. Some antibiotics recommended to treat UTIs trigger dysbiosis of intestinal and vaginal microbiomes – where uropathogens originate, though few studies have investigated associations between these therapies with recurrent infections. We retrospectively analysed the electronic medical records of 6651 college-aged women diagnosed with a UTI at a US university student health centre between 2006 and 2014. Women were followed for 6 months for incidence of a recurrent infection. In a secondary analysis, associations in women whose experienced UTI recurrence within 2 weeks were also considered for potential infection relapse. Logistic regression was used to assess associations between infection recurrence or relapse and antibiotics prescribed, in addition to baseline patient characteristics including age, race/ethnicity, region of origin, year of encounter, presence of symptomology, pyelonephritis, vaginal coinfection and birth control consultation. There were 1051 instances of infection recurrence among the 6620 patients, indicating a prevalence of 16%. In the analysis of patient characteristics, Asian women were statistically more likely to experience infection recurrence whereas African American were less likely. No significant associations were identified between the antibiotic administered at the initial infection and the risk of infection recurrence after multivariable adjustment. Treatment with trimethoprim-sulphamethoxazole and being born outside of the USA were significantly associated with increased odds of infection relapse in the multivariate analysis. The results of the analyses suggest that treatment with trimethoprim-sulphamethoxazole may lead to an increased risk of UTI relapse, warranting further study.
The role that vitamin D plays in pulmonary function remains uncertain. Epidemiological studies reported mixed findings for serum 25-hydroxyvitamin D (25(OH)D)–pulmonary function association. We conducted the largest cross-sectional meta-analysis of the 25(OH)D–pulmonary function association to date, based on nine European ancestry (EA) cohorts (n 22 838) and five African ancestry (AA) cohorts (n 4290) in the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. Data were analysed using linear models by cohort and ancestry. Effect modification by smoking status (current/former/never) was tested. Results were combined using fixed-effects meta-analysis. Mean serum 25(OH)D was 68 (sd 29) nmol/l for EA and 49 (sd 21) nmol/l for AA. For each 1 nmol/l higher 25(OH)D, forced expiratory volume in the 1st second (FEV1) was higher by 1·1 ml in EA (95 % CI 0·9, 1·3; P<0·0001) and 1·8 ml (95 % CI 1·1, 2·5; P<0·0001) in AA (Prace difference=0·06), and forced vital capacity (FVC) was higher by 1·3 ml in EA (95 % CI 1·0, 1·6; P<0·0001) and 1·5 ml (95 % CI 0·8, 2·3; P=0·0001) in AA (Prace difference=0·56). Among EA, the 25(OH)D–FVC association was stronger in smokers: per 1 nmol/l higher 25(OH)D, FVC was higher by 1·7 ml (95 % CI 1·1, 2·3) for current smokers and 1·7 ml (95 % CI 1·2, 2·1) for former smokers, compared with 0·8 ml (95 % CI 0·4, 1·2) for never smokers. In summary, the 25(OH)D associations with FEV1 and FVC were positive in both ancestries. In EA, a stronger association was observed for smokers compared with never smokers, which supports the importance of vitamin D in vulnerable populations.
We report on the Bulge Asymmetries and Dynamic Evolution (BAaDE) survey which has observed 19 000 MSX color selected red giant stars for SiO maser emission at 43 GHz with the VLA and is in the process of observing 9 000 of these stars with ALMA at 86 GHz in the Southern sky. Our setup covers the main maser transitions, as well as those of isotopologues and selected lines of carbon-bearing species. Observations of this set of lines allow a far-reaching catalog of line-of-sight velocities in the dust-obscured regions where optical surveys cannot reach. Our preliminary detection rate is close to 70%, predicting a wealth of new information on the distribution of metal rich stars, their kinematics as function of location in the Galaxy, as well as the occurrence of lines and line ratios between the different transitions in combination with the spectral energy distribution from about 1 to 100 μm. Similar to the OH/IR stars, a clear kinematic signature between disk and bulge stars can be seen. Furthermore, the SiO J = →10 (v=3) line plays a prominent role in the derived maser properties.
Circumstellar SiO masers can be observed in red giant evolved stars throughout the Galaxy. Since stellar masers are not affected by non-gravitational forces, they serve as point-mass probes of the gravitational potential and form an excellent sample for studies of the Galactic structure and dynamics. Compared to optical studies, the non-obscured masers are in particular valuable when observed close to the highly obscured Galactic Bulge and Plane. Their line-of-sight velocities can easily be obtained with high accuracy, proper motions can be measured and distances can be estimated. Furthermore, when different mass and metallicity effects can be accounted for, such a large sample will highlight asymmetries and evolutionary traces in the sample. In our Bulge Asymmetries and Dynamic Evolution (BAaDE) survey we have searched 20,000 infrared selected evolved stars for 43 GHz SiO masers with the VLA in the northern Bulge and Plane and are in the process of observing another 10,000 stars for 86 GHz SiO masers with ALMA in the southern Bulge. Our instantaneous detection rate in the Bulge is close to 70%, both at 43 and 86 GHz, with occasionally up to 7 simultaneous SiO transitions observed in a single star. Here we will outline the BAaDE survey, its first results and some of the peculiar maser features we have observed. Furthermore we will discuss the prospects for obtaining proper motions and parallaxes for individual maser stars to reconstruct individual stellar orbits.
A major avenue in the study of the Galaxy is the investigation of stellar populations and Galactic chemical evolution by stellar spectroscopy. Due to the dust obscuration, stars in the centre of the Galaxy can only be observed in the near-IR wavelength region. However, existing line lists in this wavelength region are demonstratively not of good enough quality for use in stellar spectroscopy. In response to this, we have developed an empirical astrophysical line list in the K-band based on modelling against the Sun and testing against Arcturus. Of ca. 700 identified interesting lines about 570 lines have been assigned empirically determined values.
Owing to their extreme crowding and high and variable extinction, stars in the Galactic Bulge, within ±2° of the Galactic plane, and especially those in the Nuclear Star Cluster, have only rarely been targeted for an analyses of their detailed abundances. There is also some disagreement about the high end of the abundance scale for these stars. It is now possible to obtain high dispersion, high S/N spectra in the infrared K band (~2.0 − 2.4 µm) for these giants; we report our progress at Keck and VLT in using these spectra to infer the composition of this stellar population.
Objectives: Confabulations occur in schizophrenia and certain severe neuropsychiatric conditions, and to a lesser degree in healthy individuals. The present study used a forced confabulation paradigm to assess differences in confabulation between schizophrenia patients and healthy controls. Methods: Schizophrenia patients (n=60) and healthy control participants (n=19) were shown a video with missing segments, asked to fill in the gaps with speculations, and tested on their memory for the story. Cognitive functions and severity of symptoms were also evaluated. Results: Schizophrenia patients generated significantly more confabulations than healthy control participants and had a greater tendency to generate confabulations that were related to each other. Schizophrenic confabulations were positively associated with temporal context confusions and formal thought disorder, and negatively with delusions. Conclusions: Our findings show that the schizophrenia patients generate more confabulations than healthy controls and schizophrenic confabulations are associated with positive symptoms. (JINS, 2016, 22, 911–919)
A radio survey of red giant SiO sources in the inner Galaxy and bulge is not hindered by extinction. Accurate stellar velocities (<1 km/s) are obtained with minimal observing time (<1 min) per source. Detecting over 20,000 SiO maser sources yields data comparable to optical surveys with the additional strength of a much more thorough coverage of the highly obscured inner Galaxy. Modeling of such a large sample would reveal dynamical structures and minority populations; the velocity structure can be compared to kinematic structures seen in molecular gas, complex orbit structure in the bar, or stellar streams resulting from recently infallen systems. Our Bulge Asymmetries and Dynamic Evolution (BAaDE) survey yields bright SiO masers suitable for follow-up Galactic orbit and parallax determination using VLBI.
Here we outline our early VLA observations at 43 GHz in the northern bulge and Galactic plane (0<l°<250), and ALMA observations at 86 GHz in the southern bulge (250<l°<360). We report a preliminary overall 70% detection rate in our color-selected MSX sources.
As part of the Z-PAndAS Keck II DEIMOS survey of resolved stars in our neighboring galaxy, Andromeda (M31), we have built up a unique data set of measured velocities and chemistries for thousands of stars in the Andromeda stellar halo, particularly probing its rich and complex substructure. In this contribution, we will discuss the structural, dynamical and chemical properties of Andromeda's dwarf spheroidal galaxies, and how there is no observational evidence for a difference in the evolutionary histories of those found on and off M31's vast plane of satellites. We will also discuss a possible extension to the most significant merger event in M31 - the Giant Southern Stream - and how we can use this feature to refine our understanding of M31's mass profile, and its complex evolution.
Observations of red giants in the Bulge globular cluster NGC 6273 with the Michigan/Magellan Fiber System (M2FS) mounted on the Nasmuth-East port of the Magellan-Clay 6.5-m telescope at the Las Campanas Observatory reveal a spread in metallicity. Members have been confirmed with radial velocity. NGC 6273 has at least two populations separated by 0.2-0.3 dex in [Fe/H]. The sodium and aluminum abundances are correlated while the magnesium and aluminum abundances are anti-correlated. The cluster also shows a rise in the abundance of the s-process element lanthanum with [Fe/H] similar to other massive clusters. The cluster contains a possible third population depleted in most elements by 0.3 dex.
We conducted infrared spectroscopic observations of bright stars in the direction of the molecular clouds W33 and GMC G23.3 − 0.3. We compared stellar spectro-photometric distances with parallactic distances to these regions, and we were able to assess the association of the detected massive stars with these molecular complexes. The spatial and temporal distributions of the detected stars enabled us to locate sources of ionizing radiation and to gather precise information on the star formation history of these clouds. The studied clouds present different distributions of massive stars.
We use the wide-field capabilities of the 2 degree field fibre positioner and the AAOmega spectrograph on the Anglo-Australian Telescope (AAT) to obtain redshifts of galaxies that hosted supernovae during the first 3 years of the Supernova Legacy Survey (SNLS). With exposure times ranging from 10 to 60 ks per galaxy, we were able to obtain redshifts for 400 host galaxies in two SNLS fields, thereby substantially increasing the total number of SNLS supernovae with host galaxy redshifts. The median redshift of the galaxies in our sample that hosted photometrically classified Type Ia supernovae (SNe Ia) is z ~ 0.77, which is 25% higher than the median redshift of spectroscopically confirmed SNe Ia in the 3-year sample of the SNLS. Our results demonstrate that one can use wide-field fibre-fed multi-object spectrographs on 4-m telescopes to efficiently obtain redshifts for large numbers of supernova host galaxies over the large areas of the sky that will be covered by future high-redshift supernova surveys, such as the Dark Energy Survey.
We use Schwarzschild's orbit-superposition technique to construct self-consistent models of the Galactic bar. Using χ2 minimisation, we find that the best-fit Galactic bar model has a pattern speed Ωp=60 km s−1 kpc−1, disk mass Md=1.0×1011M⊙ and bar angle θbar=20° for an adopted bar mass Mbar=2×1010M⊙. The model can reproduce not only the three-dimensional and projected density distributions but also velocity and velocity dispersion data from the BRAVA survey. We also predict the proper motions in the range l=[−12°,12°], b=[−10°,10°], which appear to be higher than observations in the longitudinal direction. The model is stable within a timescale of 0.5 Gyr, but appears to deviate from steady-state on longer timescales. Our model can be further tested by future observations such as those from GAIA.
We present an analysis of the properties of H i holes detected in 20 galaxies that are part of “The H i Nearby Galaxy Survey”. We detected more than 1000 holes in total in the sampled galaxies. The holes are found throughout the disks of the galaxies, out to the edge of the H i disk. We find that shear limits the age of holes in spirals. Shear is less important in dwarf galaxies which explains why H i holes in dwarfs are rounder, on average than in spirals. Shear is particularly strong in the inner part of spiral galaxies, limiting the lifespan of holes there and explaining why we find that holes outside R25 are larger and older. We proceed to derive the surface and volume porosity and find that this correlates with the type of the host galaxy: later Hubble types tend to be more porous. The size distribution of the holes in our sample follows a power law with a slope of aν ~ −2.9. Assuming that the holes are the result of massive star formation, we derive values for the supernova rate (SNR) and star formation rate (SFR) which scales with the SFR derived based on other tracers. If we extrapolate the observed number of holes to include those that fall below our resolution limit, down to holes created by a single supernova, we find that our results are compatible with the hypothesis that H i holes result from star formation.
The study of Globular Cluster (GC) stellar populations (SPs) addresses fundamental astrophysical questions ranging from stellar structure, evolution and dynamics, to Galaxy formation. Indeed, they represent: i) fossils from the remote and violent epoch of Galaxy formation, ii) test particles for studying Galaxy dynamics and stellar dynamical model, and iii) fiducial templates for studying integrated light from distant stellar systems. In particular, high resolution spectroscopy of GC SPs provides abundance patterns which are crucial for understanding the formation and chemical enrichment time–scale of the host galaxy. Here the major results on Galactic GCs based on high-resolution near-infrared (near–IR) spectroscopy are briefly reviewed. Optical and IR spectroscopy are complementary tools to investigate SPs in different environments, the latter being more suitable in the case of moderately–high extinction regions (AV≥2) and high metallicity.