OBJECTIVES/GOALS: Triple-negative breast cancer (TNBC) is a subtype of breast cancer that lacks effective targeted treatment options. TNBC's greater degree of immunogenicity than other breast tumors makes immunotherapy a viable strategy. Strategies to improve the immunotherapy response includes targeting the cGAS-STING innate immune pathway with STING agonists. METHODS/STUDY POPULATION: We have previously shown in vitro that eribulin, a microtubule destabilizer currently used in the treatment of TNBC, functions as an indirect STING agonist because it promotes the release of mitochondrial DNA into the cytoplasm. Separately, eribulin also significantly enhances type I interferon expression induced by STING agonists measured by qRT-PCR through a second TBK1-dependent mechanism downstream of STING activation through detecting higher amounts of phosphorylated IRF-3 by western blot protein analysis. Mechanisms of eribulin-mediated interferon expression occur in immune and TNBC cells and are shared with other microtubule destabilizers but not with the microtubule stabilizing agent paclitaxel. RESULTS/ANTICIPATED RESULTS: We determine that the enhancement of type I interferon expression by eribulin is pharmacologically synergistic with multiple STING agonists. The significant enhancement by eribulin led us to evaluate the antitumor efficacy of eribulin in combination the STING agonist ADU-S100 in a challenging spontaneous mammary tumor model MMTV-PyVT. We show that the combination treatment significantly decreased tumor growth which allowed for longer survival compared to other groups. This is particularly interesting because of our previous studies showing that eribulin alone, but not paclitaxel, promotes the activation of CD4+ T-cells in the spleen and draining lymph nodes of BALB/c mice with 4T1 tumors through flow cytometric analysis. DISCUSSION/SIGNIFICANCE: These data contribute to accumulating evidence that there are important mechanistic differences between the microtubule targeted chemotherapeutics currently used in the treatment of TNBC and suggest that eribulin can act as an immune adjuvant in addition to its anti-mitotic effect.

In the present study, compressible low-Reynolds-number flow past a stationary isolated sphere was investigated by direct numerical simulations of the Navier–Stokes equations using a body-fitted grid with high-order schemes. The Reynolds number based on free-stream quantities and the diameter of the sphere was set to be between 250 and 1000, and the free-stream Mach number was set to be between 0.3 and 2.0. As a result, it was clarified that the wake of the sphere is significantly stabilized as the Mach number increases, particularly at the Mach number greater than or equal to 0.95, but turbulent kinetic energy at the higher Mach numbers conditions is higher than that at the lower Mach numbers conditions of similar flow regimes. A rapid extension of the length of the recirculation region was observed under the transitional condition between the steady and unsteady flows. The drag coefficient increases as the Mach number increases mainly in the transonic regime and its increment is almost due to the increment in the pressure component. In addition, the increment in the drag coefficient is approximately a function of the Mach number and independent of the Reynolds number in the continuum regime. Moreover, the effect of the Mach and Reynolds numbers on the flow properties such as the drag coefficient and flow regime can approximately be characterized by the position of the separation point.

Studies on community-acquired pneumonia (CAP) and pneumococcal pneumonia (PP) related to the 13-valent pneumococcal conjugate vaccine (PCV13) introduction in Asia are scarce. This study aimed to investigate the epidemiological and microbiological determinants of hospitalised CAP and PP after PCV13 was introduced in Japan. This observational hospital-based surveillance study included children aged ⩽15 years, admitted to hospitals in and around Chiba City, Japan. Participants had bacterial pneumonia based on a positive blood or sputum culture for bacterial pathogens. Serotype and antibiotic-susceptibility testing of Streptococcus pneumoniae and Haemophilus influenzae isolates from patients with bacterial pneumonia were assessed. The CAP hospitalisation rate per 1000 child-years was 17.7, 14.3 and 9.7 in children aged <5 years and 1.18, 2.64 and 0.69 in children aged 5–15 years in 2008, 2012 and 2018, respectively. There was a 45% and 41% reduction in CAP hospitalisation rates, between the pre-PCV7 and PCV13 periods, respectively. Significant reductions occurred in the proportion of CAP due to PP and PCV13 serotypes. Conversely, no change occurred in the proportion of CAP caused by H. influenzae. The incidence of hospitalised CAP in children aged ⩽15 years was significantly reduced after the introduction of PCV13 in Japan. Continuous surveillance is necessary to detect emerging PP serotypes.

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.

We studied a suitable procedure for preparing of water samples used in radiocarbon intercomparisons involving dissolved inorganic carbon (DIC). The water samples must have inter-batch consistency and stable 14C concentrations and no sterilizing agent (e.g., HgCl2) should be added, in order to avoid the production of hazardous material. Six water samples, containing widely different amounts and types of salts, DIC, and 14C concentrations (1–100 pMC), were prepared in order to assess the procedure. Sample consistency was investigated through δ13C and chemical compositions; their low variabilities indicate that our procedure can be applied to radiocarbon intercomparison. A specific sample preparation protocol was developed for this kind of applications.

We apply two methods to estimate the 21-cm bispectrum from data taken within the Epoch of Reionisation (EoR) project of the Murchison Widefield Array (MWA). Using data acquired with the Phase II compact array allows a direct bispectrum estimate to be undertaken on the multiple redundantly spaced triangles of antenna tiles, as well as an estimate based on data gridded to the uv-plane. The direct and gridded bispectrum estimators are applied to 21 h of high-band (167–197 MHz; z = 6.2–7.5) data from the 2016 and 2017 observing seasons. Analytic predictions for the bispectrum bias and variance for point-source foregrounds are derived. We compare the output of these approaches, the foreground contribution to the signal, and future prospects for measuring the bispectra with redundant and non-redundant arrays. We find that some triangle configurations yield bispectrum estimates that are consistent with the expected noise level after 10 h, while equilateral configurations are strongly foreground-dominated. Careful choice of triangle configurations may be made to reduce foreground bias that hinders power spectrum estimators, and the 21-cm bispectrum may be accessible in less time than the 21-cm power spectrum for some wave modes, with detections in hundreds of hours.

In this study, direct numerical simulation of the flow around a rotating sphere at high Mach and low Reynolds numbers is conducted to investigate the effects of rotation rate and Mach number upon aerodynamic force coefficients and wake structures. The simulation is carried out by solving the three-dimensional compressible Navier–Stokes equations. A free-stream Reynolds number (based on the free-stream velocity, density and viscosity coefficient and the diameter of the sphere) is set to be between 100 and 300, the free-stream Mach number is set to be between 0.2 and 2.0, and the dimensionless rotation rate defined by the ratio of the free-stream and surface velocities above the equator is set between 0.0 and 1.0. Thus, we have clarified the following points: (1) as free-stream Mach number increased, the increment of the lift coefficient due to rotation was reduced; (2) under subsonic conditions, the drag coefficient increased with increase of the rotation rate, whereas under supersonic conditions, the increment of the drag coefficient was reduced with increasing Mach number; and (3) the mode of the wake structure becomes low-Reynolds-number-like as the Mach number is increased.

For livestock production systems to play a positive role in global food security, the balance between their benefits and disbenefits to society must be appropriately managed. Based on the evidence provided by field-scale randomised controlled trials around the world, this debate has traditionally centred on the concept of economic-environmental trade-offs, of which existence is theoretically assured when resource allocation is perfect on the farm. Recent research conducted on commercial farms indicates, however, that the economic-environmental nexus is not nearly as straightforward in the real world, with environmental performances of enterprises often positively correlated with their economic profitability. Using high-resolution primary data from the North Wyke Farm Platform, an intensively instrumented farm-scale ruminant research facility located in southwest United Kingdom, this paper proposes a novel, information-driven approach to carry out comprehensive assessments of economic-environmental trade-offs inherent within pasture-based cattle and sheep production systems. The results of a data-mining exercise suggest that a potentially systematic interaction exists between ‘soil health’, ecological surroundings and livestock grazing, whereby a higher level of soil organic carbon (SOC) stock is associated with a better animal performance and less nutrient losses into watercourses, and a higher stocking density with greater botanical diversity and elevated SOC. We contend that a combination of farming system-wide trials and environmental instrumentation provides an ideal setting for enrolling scientifically sound and biologically informative metrics for agricultural sustainability, through which agricultural producers could obtain guidance to manage soils, water, pasture and livestock in an economically and environmentally acceptable manner. Priority areas for future farm-scale research to ensure long-term sustainability are also discussed.

The Japanese Antarctic Research Expedition (JARE) has set up automatic weather stations at six sites on a 1000 km long traverse route between Syowa station (21 ma.s.l..) and Dome Fuji station (3810 ma.s.l.) since 1993. Large temperature rises in winter were observed several times in this area. There were two patterns of time delay of the temperature rises. One was that the temperature rise at Mizuho station preceded that at other stations, and the other was that the temperature rise at Dome Fuji station preceded the others. The former occurred when a disturbance came from the coast between east Enderby Land and the Amery Ice Shelf and strong winds destroyed the stable inversion layer. The latter occurred when the low-pressure center was near the coast of west Wilkes Land. in this case, temperature rise was caused by adveclion of warm air. The atmospheric pressure at Dome Fuji station and Relay Point oscillated with a period of 0.5 year and amplitude of about 15hPa. The pressure was higher in July and December, and was accompanied by a temperature rise. Fluctuations of hourly air temperature at Dome Fuji station were approximately twice as large as fluctuations at the other sites. The lapse rale of the annual mean temperature increased with elevation, while the monthly lapse rate was largest in April.

A good correlation was found between the ablation of snow and degree day index (cumulative values of positive daily mean air temperature) during the summer of 1978 on the Yukikabe snow patch in the Daisetsu mountains, central Hokkaido. The volume change of the snow patch in the ablation season of any year can hence be estimated from air temperature using this relationship. Each of the heat-balance terms controlling the ablation is evaluated separately by using empirical equations and assumed values for meteorological parameters at the snow patch. Triangular diagrams are constructed in order to illustrate the relative contributions of sensible heat, latent heat, and net radiation, the main three heat sources. A higher contribution from sensible and latent heat is found for the snow patches of Japan than for many glaciers and ice caps elsewhere. This may be due to higher mid-summer air temperatures than in other glaciated parts of the world.