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.

Many short gamma-ray bursts (GRBs) originate from binary neutron star mergers, and there are several theories that predict the production of coherent, prompt radio signals either prior, during, or shortly following the merger, as well as persistent pulsar-like emission from the spin-down of a magnetar remnant. Here we present a low frequency (170–200 MHz) search for coherent radio emission associated with nine short GRBs detected by the Swift and/or Fermi satellites using the Murchison Widefield Array (MWA) rapid-response observing mode. The MWA began observing these events within 30–60 s of their high-energy detection, enabling us to capture any dispersion delayed signals emitted by short GRBs for a typical range of redshifts. We conducted transient searches at the GRB positions on timescales of 5 s, 30 s, and 2 min, resulting in the most constraining flux density limits on any associated transient of 0.42, 0.29, and 0.084 Jy, respectively. We also searched for dispersed signals at a temporal and spectral resolution of 0.5 s and 1.28 MHz, but none were detected. However, the fluence limit of 80–100 Jy ms derived for GRB 190627A is the most stringent to date for a short GRB. Assuming the formation of a stable magnetar for this GRB, we compared the fluence and persistent emission limits to short GRB coherent emission models, placing constraints on key parameters including the radio emission efficiency of the nearly merged neutron stars ($\epsilon_r\lesssim10^{-4}$), the fraction of magnetic energy in the GRB jet ($\epsilon_B\lesssim2\times10^{-4}$), and the radio emission efficiency of the magnetar remnant ($\epsilon_r\lesssim10^{-3}$). Comparing the limits derived for our full GRB sample (along with those in the literature) to the same emission models, we demonstrate that our fluence limits only place weak constraints on the prompt emission predicted from the interaction between the relativistic GRB jet and the interstellar medium for a subset of magnetar parameters. However, the 30-min flux density limits were sensitive enough to theoretically detect the persistent radio emission from magnetar remnants up to a redshift of $z\sim0.6$. Our non-detection of this emission could imply that some GRBs in the sample were not genuinely short or did not result from a binary neutron star merger, the GRBs were at high redshifts, these mergers formed atypical magnetars, the radiation beams of the magnetar remnants were pointing away from Earth, or the majority did not form magnetars but rather collapse directly into black holes.

We present a broadband radio study of the transient jets ejected from the black hole candidate X-ray binary MAXI J1535–571, which underwent a prolonged outburst beginning on 2017 September 2. We monitored MAXI J1535–571 with the Murchison Widefield Array (MWA) at frequencies from 119 to 186 MHz over six epochs from 2017 September 20 to 2017 October 14. The source was quasi-simultaneously observed over the frequency range 0.84–19 GHz by UTMOST (the Upgraded Molonglo Observatory Synthesis Telescope) the Australian Square Kilometre Array Pathfinder (ASKAP), the Australia Telescope Compact Array (ATCA), and the Australian Long Baseline Array (LBA). Using the LBA observations from 2017 September 23, we measured the source size to be $34\pm1$ mas. During the brightest radio flare on 2017 September 21, the source was detected down to 119 MHz by the MWA, and the radio spectrum indicates a turnover between 250 and 500 MHz, which is most likely due to synchrotron self-absorption (SSA). By fitting the radio spectrum with a SSA model and using the LBA size measurement, we determined various physical parameters of the jet knot (identified in ATCA data), including the jet opening angle ($\phi_{\rm op} = 4.5\pm1.2^{\circ}$) and the magnetic field strength ($B_{\rm s} = 104^{+80}_{-78}$ mG). Our fitted magnetic field strength agrees reasonably well with that inferred from the standard equipartition approach, suggesting the jet knot to be close to equipartition. Our study highlights the capabilities of the Australian suite of radio telescopes to jointly probe radio jets in black hole X-ray binaries via simultaneous observations over a broad frequency range, and with differing angular resolutions. This suite allows us to determine the physical properties of X-ray binary jets. Finally, our study emphasises the potential contributions that can be made by the low-frequency part of the Square Kilometre Array (SKA-Low) in the study of black hole X-ray binaries.

Here we present stringent low-frequency (185 MHz) limits on coherent radio emission associated with a short-duration gamma-ray burst (SGRB). Our observations of the short gamma-ray burst (GRB) 180805A were taken with the upgraded Murchison Widefield Array (MWA) rapid-response system, which triggered within 20s of receiving the transient alert from the Swift Burst Alert Telescope, corresponding to 83.7 s post-burst. The SGRB was observed for a total of 30 min, resulting in a $3\sigma$ persistent flux density upper limit of 40.2 mJy beam–1. Transient searches were conducted at the Swift position of this GRB on 0.5 s, 5 s, 30 s and 2 min timescales, resulting in $3\sigma$ limits of 570–1 830, 270–630, 200–420, and 100–200 mJy beam–1, respectively. We also performed a dedispersion search for prompt signals at the position of the SGRB with a temporal and spectral resolution of 0.5 s and 1.28 MHz, respectively, resulting in a $6\sigma$ fluence upper-limit range from 570 Jy ms at DM $=3\,000$ pc cm–3 ($z\sim 2.5$) to 1 750 Jy ms at DM$=200$ pc cm–3 ($z\sim 0.1)$, corresponding to the known redshift range of SGRBs. We compare the fluence prompt emission limit and the persistent upper limit to SGRB coherent emission models assuming the merger resulted in a stable magnetar remnant. Our observations were not sensitive enough to detect prompt emission associated with the alignment of magnetic fields of a binary neutron star just prior to the merger, from the interaction between the relativistic jet and the interstellar medium (ISM) or persistent pulsar-like emission from the spin-down of the magnetar. However, in the case of a more powerful SGRB (a gamma-ray fluence an order of magnitude higher than GRB 180805A and/or a brighter X-ray counterpart), our MWA observations may be sensitive enough to detect coherent radio emission from the jet-ISM interaction and/or the magnetar remnant. Finally, we demonstrate that of all current low- frequency radio telescopes, only the MWA has the sensitivity and response times capable of probing prompt emission models associated with the initial SGRB merger event.

The Murchison Widefield Array (MWA) is an open access telescope dedicated to studying the low-frequency (80–300 MHz) southern sky. Since beginning operations in mid-2013, the MWA has opened a new observational window in the southern hemisphere enabling many science areas. The driving science objectives of the original design were to observe 21 cm radiation from the Epoch of Reionisation (EoR), explore the radio time domain, perform Galactic and extragalactic surveys, and monitor solar, heliospheric, and ionospheric phenomena. All together $60+$ programs recorded 20 000 h producing 146 papers to date. In 2016, the telescope underwent a major upgrade resulting in alternating compact and extended configurations. Other upgrades, including digital back-ends and a rapid-response triggering system, have been developed since the original array was commissioned. In this paper, we review the major results from the prior operation of the MWA and then discuss the new science paths enabled by the improved capabilities. We group these science opportunities by the four original science themes but also include ideas for directions outside these categories.

The Rio Grande Cone is a major fanlike depositional feature in the continental slope of the Pelotas Basin, Southern Brazil. Two representative sediment cores collected in the Cone area were retrieved using a piston core device. In this work, the organic matter (OM) in the sediments was characterized for a continental vs. marine origin using chemical proxies to help constrain the origin of gas in hydrates. The main contribution of OM was from marine organic carbon based on the stable carbon isotope (δ13C-org) and total organic carbon/total nitrogen ratio (TOC:TN) analyses. In addition, the 14C data showed important information about the origin of the OM and we suggest some factors that could modify the original organic matter and therefore mask the “real” 14C ages: (1) biological activity that could modify the carbon isotopic composition of bulk terrestrial organic matter values, (2) the existence of younger sediments from mass wasting deposits unconformably overlying older sediments, and (3) the deep-sediment-sourced methane contribution due to the input of “old” (>50 ka) organic compounds from migrating fluids.

A national need is to prepare for and respond to accidental or intentional disasters categorized as chemical, biological, radiological, nuclear, or explosive (CBRNE). These incidents require specific subject-matter expertise, yet have commonalities. We identify 7 core elements comprising CBRNE science that require integration for effective preparedness planning and public health and medical response and recovery. These core elements are (1) basic and clinical sciences, (2) modeling and systems management, (3) planning, (4) response and incident management, (5) recovery and resilience, (6) lessons learned, and (7) continuous improvement. A key feature is the ability of relevant subject matter experts to integrate information into response operations. We propose the CBRNE medical operations science support expert as a professional who (1) understands that CBRNE incidents require an integrated systems approach, (2) understands the key functions and contributions of CBRNE science practitioners, (3) helps direct strategic and tactical CBRNE planning and responses through first-hand experience, and (4) provides advice to senior decision-makers managing response activities. Recognition of both CBRNE science as a distinct competency and the establishment of the CBRNE medical operations science support expert informs the public of the enormous progress made, broadcasts opportunities for new talent, and enhances the sophistication and analytic expertise of senior managers planning for and responding to CBRNE incidents.

Introduction: Abdominal pain is one of the most frequent reasons for an emergency department (ED) visit. Most cases are functional and no therapy has proven effective. Our objective was to determine if hyoscine butylbromide (HBB) (BuscopanTM) is effective for children who present to the ED with functional abdominal pain. Methods: We conducted a randomized, blinded, superiority trial comparing HBB 10 mg plus acetaminophen placebo to oral acetaminophen 15 mg/kg (max 975 mg) plus HBB placebo using a double-dummy approach. We included children 8-17 years presenting to the ED at London Health Sciences Centre with colicky abdominal pain rated >40 mm on a 100 mm visual analog scale (VAS). The primary outcome was VAS pain score at 80 minutes post-administration. Secondary outcomes included adverse effects; caregiver satisfaction with pain management using a five-item Likert scale; recidivism and missed surgical diagnoses within 24-hours of discharge. Analysis was based on intention to treat. Results: We analyzed 225 participants (112 acetaminophen; 113 HBB). The mean (SD) age was 12.4 (3.0) years and 148/225 (65.8%) were females. Prior to enrollment, the median (IQR) duration of pain prior was 2 (4.5) hours and analgesia was provided to 101/225 (44.9%) of participants. The mean (SD) pre-intervention pain scores in the acetaminophen and HBB groups were 62.7 (15.9) mm and 60.3 (17.3) mm, respectively. At 80 minutes, the mean (SD) pain scores in the acetaminophen and HBB groups were 30.1 (28.8) mm and 29.4 (26.4) mm, respectively and there were no significant differences adjusting for pre-intervention scores (p = 0.96). The median (IQR) caregiver satisfaction was high in the acetaminophen [5 (2)] and HBB [5 (1)] groups (p = 0.79). The median (IQR) length of stay between acetaminophen [235 (101)] and HBB [234 (103)] was not significantly different (p = 0.53). The proportion of participants with a return visit for abdominal pain was 4/112 (3.5%) in the acetaminophen group and 6/113 (5.3%) in the HBB group. The most common adverse effect was nausea (9% in each group) and there were no significant differences in adverse effects between acetaminophen (26/112, 23.2%) and HBB (31/113, 27.4%) (p = 0.52). There were no missed surgical diagnoses. Conclusion: For children with presumed functional abdominal pain who present to the ED, both acetaminophen and HBB produce a clinically important (VAS < 30 mm) reduction in pain and should be routinely considered in this clinical setting.

Objectives: The present study constitutes the first randomized controlled trial to investigate the relation of lutein (L) and zeaxanthin (Z) to brain function using functional magnetic resonance imaging (fMRI). It was hypothesized that L and Z supplementation in older adults would enhance neural efficiency (i.e., reduce activation) and cognitive performance on a verbal learning task relative to placebo. Methods: A total of 44 community-dwelling older adults (mean age=72 years) were randomly assigned to receive either placebo or L+Z supplementation (12 mg/daily) for 1 year. Neurocognitive performance was assessed at baseline and post-intervention on an fMRI-adapted task involving learning and recalling word pairs. Imaging contrasts of blood-oxygen-level-dependent (BOLD) signal were created by subtracting active control trials from learning and recall trials. A flexible factorial model was employed to investigate the expected group (placebo vs. supplement) by time (baseline vs. post-intervention) interaction in pre-specified regions-of-interest. Results: L and Z appeared to buffer cognitive decline on the verbal learning task (Cohen’s d=.84). Significant interactions during learning were observed in left dorsolateral prefrontal cortex and anterior cingulate cortex (p < .05, family-wise-error corrected). However, these effects were in the direction of increased rather than decreased BOLD signal. Although the omnibus interaction was not significant during recall, within-group contrasts revealed significant increases in left prefrontal activation in the supplement group only. Conclusions: L and Z supplementation appears to benefit neurocognitive function by enhancing cerebral perfusion, even if consumed for a discrete period of time in late life. (JINS, 2018, 24, 77–90)

Using cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS), it was shown for four different types of carbon that electrode treatments at negative potentials enhance the kinetics of VIV-VV and inhibit the kinetics of VII-VIII while electrode treatments at positive potentials inhibit the kinetics of VIV-VV and enhance the kinetics of VII-VIII. These observations may explain conflicting reports in the literature. The potentials required for activation and deactivation of electrodes were examined in detail. The results suggest that interchanging the positive and negative electrodes in a vanadium flow battery (VFB) would reduce the overpotential at the negative electrode and so improve the performance. This is supported by flow-cell experiments. Thus, periodic catholyte-anolyte interchange, or equivalent alternatives such as battery overdischarge, show promise of improving the voltage efficiency of VFBs.

The Dark Energy Survey is undertaking an observational programme imaging 1/4 of the southern hemisphere sky with unprecedented photometric accuracy. In the process of observing millions of faint stars and galaxies to constrain the parameters of the dark energy equation of state, the Dark Energy Survey will obtain pre-discovery images of the regions surrounding an estimated 100 gamma-ray bursts over 5 yr. Once gamma-ray bursts are detected by, e.g., the Swift satellite, the DES data will be extremely useful for follow-up observations by the transient astronomy community. We describe a recently-commissioned suite of software that listens continuously for automated notices of gamma-ray burst activity, collates information from archival DES data, and disseminates relevant data products back to the community in near-real-time. Of particular importance are the opportunities that non-public DES data provide for relative photometry of the optical counterparts of gamma-ray bursts, as well as for identifying key characteristics (e.g., photometric redshifts) of potential gamma-ray burst host galaxies. We provide the functional details of the DESAlert software, and its data products, and we show sample results from the application of DESAlert to numerous previously detected gamma-ray bursts, including the possible identification of several heretofore unknown gamma-ray burst hosts.

This paper presents results from a joint Lockheed Martin/NASA Glenn effort to design and verify an ultra-compact, highly-survivable engine inlet subsonic duct based on the emerging technology of active inlet flow control (AIFC). In the AIFC concept, micro-scale actuation (∼mm in size) is used in an approach denoted ‘secondary flow control’ to intelligently alter a serpentine duct's inherent secondary flow characteristics with the goal of simultaneously improving the critical system-level performance metrics of total pressure recovery, spatial distortion, and RMS turbulence. In this approach, separation control is a secondary benefit, not a design requirement. The baseline concept for this study was a 4:1 aspect ratio ultra-compact (LID= 2·5) serpentine duct that fully obscured line-of-sight view of the engine face. At relevant flow conditions, this type of duct exhibits excessive pressure loss and distortion because of extreme wall curvature. Two sets of flow control effectors were designed with the intent of establishing high performance levels to the baseline duct. The first set used two arrays of 36 co-rotating microvane vortex generators (VGs); the second set used two arrays of 36 micro air-jet (microjet) VGs, which were designed to produce the same ‘vorticity signature’ as the microvanes. Optimisation of the microvane array was accomplished using a design of experiments (DOE) methodology to guide selection of parameters used in multiple Computational Fluid Dynamics (CFD) flow solutions. A verification test conducted in the NASA Glenn W1B test facility indicated low pressure recovery and high distortion for the baseline duct without flow control. With microvane flow control, at a throat Mach number of 0·60, pressure recovery was increased 5%, and both spatial distortion and turbulence were decreased approximately 50%. Microjet effectors also provided significantly improved performance over the baseline configuration.