OBJECTIVES/GOALS: Immunomodulatory drugs (IMiDs) are critical to multiple myeloma (MM) disease control. IMiDs act by inducing Cereblon-dependent degradation of IKZF1 and IKZF3, which leads to IRF4 and MYC downregulation (collectively termed the “Ikaros axis”). We therefore hypothesized that IMiD treatment fails to downregulate the Ikaros axis in IMiD resistant MM. METHODS/STUDY POPULATION: To measure IMiD-induced Ikaros axis downregulation, we designed an intracellular flow cytometry assay that measured relative protein levels of IKZF1, IKZF3, IRF4 and MYC in MM cells following ex vivo treatment with the IMiD Pomalidomide (Pom). We established this assay using Pom-sensitive parental and dose-escalated Pom-resistant MM cell lines before assessing Ikaros axis downregulation in CD38+CD138+ MM cells in patient samples (bone marrow aspirates). To assess the Ikaros axis in the context of MM intratumoral heterogeneity, we used a 35-marker mass cytometry panel to simultaneously characterize MM subpopulations in patient samples. Lastly, we determined ex vivo drug sensitivity in patient samples via flow cytometry. RESULTS/ANTICIPATED RESULTS: Our hypothesis was supported in MM cell lines, as resistant lines showed no IMiD-induced decrease in any Ikaros axis proteins. However, when assessed in patient samples, Pom treatment caused a significant decrease in IKZF1, IKZF3 and IRF4 regardless of IMiD sensitivity. Mass cytometry in patient samples revealed that individual Ikaros axis proteins were differentially expressed between subpopulations. When correlating this with ex vivo Pom sensitivity of MM subpopulations, we observed that low IKZF1 and IKZF3 corresponded to Pom resistance. Interestingly, most of these resistant populations still expressed MYC. We therefore assessed whether IMiD resistant MM was MYC dependent by treating with MYCi975. In 88% (7/8) of patient samples tested, IMiD resistant MM cells were sensitive to MYC inhibition. DISCUSSION/SIGNIFICANCE: While our findings did not support our initial hypothesis, our data suggest a mechanism where MYC expression becomes Ikaros axis independent to drive IMiD resistance, and resistant MM is still dependent on MYC. This suggests targeting MYC directly or indirectly via a mechanism to be determined may be an effective strategy to eradicate IMiD resistant MM.

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 discuss present and developing techniques for studying radiocarbon in marine organic carbon (C). Bulk DOC (dissolved organic C) Δ14C measurements reveal information about the cycling time and sources of DOC in the ocean, yet they are time consuming and need to be streamlined. To further elucidate the cycling of DOC, various fractions have been separated from bulk DOC, through solid phase extraction of DOC, and ultrafiltration of high and low molecular weight DOC. Research using 14C of DOC and particulate organic C separated into organic fractions revealed that the acid insoluble fraction is similar in 14C signature to that of the lipid fraction. Plans for utilizing this methodology are described. Studies using compound specific radiocarbon analyses to study the origin of biomarkers in the marine environment are reviewed and plans for the future are outlined. Development of ramped pyrolysis oxidation methods are discussed and scientific questions addressed. A modified elemental analysis (EA) combustion reactor is described that allows high particulate organic C sample throughput by direct coupling with the MIniCArbonDAtingSystem.

Metabolites produced by microbial fermentation in the human intestine, especially short-chain fatty acids (SCFAs), are known to play important roles in colonic and systemic health. Our aim here was to advance our understanding of how and why their concentrations and proportions vary between individuals. We have analysed faecal concentrations of microbial fermentation acids from 10 human volunteer studies, involving 163 subjects, conducted at the Rowett Institute, Aberdeen, UK over a 7-year period. In baseline samples, the % butyrate was significantly higher, whilst % iso-butyrate and % iso-valerate were significantly lower, with increasing total SCFA concentration. The decreasing proportions of iso-butyrate and iso-valerate, derived from amino acid fermentation, suggest that fibre intake was mainly responsible for increased SCFA concentrations. We propose that the increase in % butyrate among faecal SCFA is largely driven by a decrease in colonic pH resulting from higher SCFA concentrations. Consistent with this, both total SCFA and % butyrate increased significantly with decreasing pH across five studies for which faecal pH measurements were available. Colonic pH influences butyrate production through altering the stoichiometry of butyrate formation by butyrate-producing species, resulting in increased acetate uptake and butyrate formation, and facilitating increased relative abundance of butyrate-producing species (notably Roseburia and Eubacterium rectale).

This study aimed to explore effects of adjunctive minocycline treatment on inflammatory and neurogenesis markers in major depressive disorder (MDD). Serum samples were collected from a randomised, placebo-controlled 12-week clinical trial of minocycline (200 mg/day, added to treatment as usual) for adults (n = 71) experiencing MDD to determine changes in interleukin-6 (IL-6), lipopolysaccharide binding protein (LBP) and brain derived neurotrophic factor (BDNF). General Estimate Equation modelling explored moderation effects of baseline markers and exploratory analyses investigated associations between markers and clinical outcomes. There was no difference between adjunctive minocycline or placebo groups at baseline or week 12 in the levels of IL-6 (week 12; placebo 2.06 ± 1.35 pg/ml; minocycline 1.77 ± 0.79 pg/ml; p = 0.317), LBP (week 12; placebo 3.74 ± 0.95 µg/ml; minocycline 3.93 ± 1.33 µg/ml; p = 0.525) or BDNF (week 12; placebo 24.28 ± 6.69 ng/ml; minocycline 26.56 ± 5.45 ng/ml; p = 0.161). Higher IL-6 levels at baseline were a predictor of greater clinical improvement. Exploratory analyses suggested that the change in IL-6 levels were significantly associated with anxiety symptoms (HAMA; p = 0.021) and quality of life (Q-LES-Q-SF; p = 0.023) scale scores. No other clinical outcomes were shown to have this mediation effect, nor did the other markers (LBP or BDNF) moderate clinical outcomes. There were no overall changes in IL-6, LBP or BDNF following adjunctive minocycline treatment. Exploratory analyses suggest a potential role of IL-6 on mediating anxiety symptoms with MDD. Future trials may consider enrichment of recruitment by identifying several markers or a panel of factors to better represent an inflammatory phenotype in MDD with larger sample size.

Background: Objective markers of disease progression are needed for patients with multiple sclerosis (MS). Increased randomness in neural networks is hypothesized to be an important cause of morbidity that can be objectified using graph theory. Methods: We use voxel-based structural similarity determined from T1-weighted MRI scans of 23 patients with MS receiving autologous stem cell transplant (ASCT) to compute cortical covariance network parameters. We examine associations between measures of cortical integration or segregation and biochemical/clinical measures of cortical health or function using Spearman correlation coefficients. P<0.05 was considered significant. Results: Path length increase was associated with markers of greater inflammation (ρ=0.56,P<.046) at baseline and reduced Naa/Cr ratio (P<.041) at 12 months. Reduced lambda was associated with markers of greater grey matter atrophy (ρ=0.55,P<.019) after 12 months and lower cognition (ρ=0.56,P<.008) at 12 months. Reduced clustering was associated with higher neurofilament (ρ=-0.68,P<.010) at baseline, greater white matter atrophy (ρ=0.62,P<.006) after 12 months, lower 2-second PASAT performance (ρ=0.56,P<.011) at baseline, and reduced Naa/Cr ratio (P<.001) at 12 months. Conclusions: Reduced cortical integration and segregation (random network features) co-occur with unfavourable markers of cortical health and function in patients with MS receiving ASCT. Network features show promise as important longitudinal markers of patient status and progression.

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.

The GaLactic and Extragalactic All-sky Murchison Widefield Array (GLEAM) is a radio continuum survey at 76–227 MHz of the entire southern sky (Declination $<\!{+}30^{\circ}$ ) with an angular resolution of ${\approx}2$ arcmin. In this paper, we combine GLEAM data with optical spectroscopy from the 6dF Galaxy Survey to construct a sample of 1 590 local (median $z \approx 0.064$ ) radio sources with $S_{200\,\mathrm{MHz}} > 55$ mJy across an area of ${\approx}16\,700\,\mathrm{deg}^{2}$ . From the optical spectra, we identify the dominant physical process responsible for the radio emission from each galaxy: 73% are fuelled by an active galactic nucleus (AGN) and 27% by star formation. We present the local radio luminosity function for AGN and star-forming (SF) galaxies at 200 MHz and characterise the typical radio spectra of these two populations between 76 MHz and ${\sim}1$ GHz. For the AGN, the median spectral index between 200 MHz and ${\sim}1$ GHz, $\alpha_{\mathrm{high}}$ , is $-0.600 \pm 0.010$ (where $S \propto \nu^{\alpha}$ ) and the median spectral index within the GLEAM band, $\alpha_{\mathrm{low}}$ , is $-0.704 \pm 0.011$ . For the SF galaxies, the median value of $\alpha_{\mathrm{high}}$ is $-0.650 \pm 0.010$ and the median value of $\alpha_{\mathrm{low}}$ is $-0.596 \pm 0.015$ . Among the AGN population, flat-spectrum sources are more common at lower radio luminosity, suggesting the existence of a significant population of weak radio AGN that remain core-dominated even at low frequencies. However, around 4% of local radio AGN have ultra-steep radio spectra at low frequencies ( $\alpha_{\mathrm{low}} < -1.2$ ). These ultra-steep-spectrum sources span a wide range in radio luminosity, and further work is needed to clarify their nature.

The highland Wari (AD 600–1000) were an influential and expansive Andean civilisation, yet the nature and organisation of Wari power is debated. For example, it is suggested that coastal Nasca was governed by Wari, but doubts remain about its role in the region. Recent excavations at Huaca del Loro in Nasca have uncovered rectilinear compounds, a D-shaped temple, a large cemetery and a domestic area. The authors suggest that this evidence reflects Wari colonisation, undertaken during a period of primary expansion, on a site with long-established ties between Wari and Nasca. The use of multiple colonising strategies and local responses may reflect imperial situations in other world civilisations.

We developed a passive sampler for time-integrated collection and radiocarbon (14C) analysis of soil respiration, a major flux in the global C cycle. It consists of a permanent access well that controls the CO2 uptake rate and an exchangeable molecular sieve CO2 trap. We tested how access well dimensions and environmental conditions affect collected CO2, and optimized cleaning procedures to minimize 14CO2 memory. We also deployed two generations of the sampler in Arctic tundra for up to two years, collecting CO2 over periods of 3 days–2 months, while monitoring soil temperature, volumetric water content, and CO2 concentration. The sampler collects CO2 at a rate proportional to the length of a silicone tubing inlet (7–26 µg CO2-C day-1·m Si-1). With constant sampler dimensions in the field, CO2 recovery is best explained by soil temperature. We retrieved 0.1–5.3 mg C from the 1st and 0.6–13 mg C from the 2nd generation samplers, equivalent to uptake rates of 2–215 (n=17) and 10–247 µg CO2-C day-1 (n=20), respectively. The method blank is 8 ± 6 µg C (mean ± sd, n=8), with a radiocarbon content (fraction modern) ranging from 0.5875–0.6013 (n=2). The sampler enables more continuous investigations of soil C emission sources and is suitable for Arctic environments.

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.

We present the South Galactic Pole (SGP) data release from the GaLactic and Extragalactic All-sky Murchison Widefield Array (GLEAM) survey. These data combine both years of GLEAM observations at 72–231 MHz conducted with the Murchison Widefield Array (MWA) and cover an area of 5 113$\mathrm{deg}^{2}$ centred on the SGP at $20^{\mathrm{h}} 40^{\mathrm{m}} < \mathrm{RA} < 05^{\mathrm{h}} 04^{\mathrm{m}}$ and $-48^{\circ} < \mathrm{Dec} < -2^{\circ} $. At 216 MHz, the typical rms noise is ${\approx}5$ mJy beam–1 and the angular resolution ${\approx}2$ arcmin. The source catalogue contains a total of 108 851 components above $5\sigma$, of which 77% have measured spectral indices between 72 and 231 MHz. Improvements to the data reduction in this release include the use of the GLEAM Extragalactic catalogue as a sky model to calibrate the data, a more efficient and automated algorithm to deconvolve the snapshot images, and a more accurate primary beam model to correct the flux scale. This data release enables more sensitive large-scale studies of extragalactic source populations as well as spectral variability studies on a one-year timescale.

The Pi Sigma Alpha Undergraduate Journal of Politics (PSAJ), sponsored by the Pi Sigma Alpha National Honor Society, was founded in 2001 at Purdue University. After 20 years, much has changed in undergraduate research and publishing, but the benefits of producing a peer-reviewed journal remain the same. Undergraduate research has increased in prominence, and the journal has modernized to meet these transformations. This article describes the history, purpose, and operations of the PSAJ. Most important, a survey of former Editorial Board members, Pi Sigma Alpha Faculty Chapter Advisors, and published authors in the journal reveal attitudes toward operating an undergraduate journal, using undergraduate research in the college classroom, and publishing in a peer-reviewed journal, respectively. We conclude with calls to continue to encourage undergraduate research and to assign published undergraduate research in upper-level courses.

We study the pairwise interactions of drops in an applied uniform DC electric field within the framework of the leaky dielectric model. We develop three-dimensional numerical simulations using the boundary integral method and an analytical theory assuming small drop deformations. We apply the simulations and the theory to explore the electrohydrodynamic interactions between two identical drops with arbitrary orientation of their line of centres relative to the applied field direction. Our results show a complex dynamics depending on the conductivities and permittivities of the drops and suspending fluids, and the initial drop pair alignment with the applied electric field.

The remnant phase of a radio galaxy begins when the jets launched from an active galactic nucleus are switched off. To study the fraction of radio galaxies in a remnant phase, we take advantage of a $8.31$ deg$^2$ subregion of the GAMA 23 field which comprises of surveys covering the frequency range 0.1–9 GHz. We present a sample of 104 radio galaxies compiled from observations conducted by the Murchison Widefield Array (216 MHz), the Australia Square Kilometer Array Pathfinder (887 MHz), and the Australia Telescope Compact Array (5.5 GHz). We adopt an ‘absent radio core’ criterion to identify 10 radio galaxies showing no evidence for an active nucleus. We classify these as new candidate remnant radio galaxies. Seven of these objects still display compact emitting regions within the lobes at 5.5 GHz; at this frequency the emission is short-lived, implying a recent jet switch off. On the other hand, only three show evidence of aged lobe plasma by the presence of an ultra-steep-spectrum ($\alpha<-1.2$) and a diffuse, low surface brightness radio morphology. The predominant fraction of young remnants is consistent with a rapid fading during the remnant phase. Within our sample of radio galaxies, our observations constrain the remnant fraction to $4\%\lesssim f_{\mathrm{rem}} \lesssim 10\%$; the lower limit comes from the limiting case in which all remnant candidates with hotspots are simply active radio galaxies with faint, undetected radio cores. Finally, we model the synchrotron spectrum arising from a hotspot to show they can persist for 5–10 Myr at 5.5 GHz after the jets switch of—radio emission arising from such hotspots can therefore be expected in an appreciable fraction of genuine remnants.

Children's vocabulary ability at school entry is highly variable and predictive of later language and literacy outcomes. Sleep is potentially useful in understanding and explaining that variability, with sleep patterns being predictive of global trajectories of language acquisition. Here, we looked to replicate and extend these findings. Data from 354 children (without English as an additional language) in the Born in Bradford study were analysed, describing the mean intercepts and linear trends in parent-reported day-time and night-time sleep duration over five time points between 6 and 36 months-of-age. The mean difference between night-time and day-time sleep was predictive of receptive vocabulary at age five, with more night-time sleep relative to day-time sleep predicting better language. An exploratory analysis suggested that socioeconomic status was predictive of vocabulary outcomes, with sleep patterns partially mediating this relationship. We suggest that the consolidation of sleep patterns acts as a driver of early language development.