The Integrated Science Investigation of the Sun (ISIS) is a complete science investigation on the Solar Probe Plus (SPP) mission, which flies to within nine solar radii of the Sun’s surface. ISIS ...comprises a two-instrument suite to measure energetic particles over a very broad energy range, as well as coordinated management, science operations, data processing, and scientific analysis. Together, ISIS observations allow us to explore the mechanisms of energetic particles dynamics, including their: (1) Origins—defining the seed populations and physical conditions necessary for energetic particle acceleration; (2) Acceleration—determining the roles of shocks, reconnection, waves, and turbulence in accelerating energetic particles; and (3) Transport—revealing how energetic particles propagate from the corona out into the heliosphere. The two ISIS Energetic Particle Instruments measure lower (EPI-Lo) and higher (EPI-Hi) energy particles. EPI-Lo measures ions and ion composition from ∼20 keV/nucleon–15 MeV total energy and electrons from ∼25–1000 keV. EPI-Hi measures ions from ∼1–200 MeV/nucleon and electrons from ∼0.5–6 MeV. EPI-Lo comprises 80 tiny apertures with fields-of-view (FOVs) that sample over nearly a complete hemisphere, while EPI-Hi combines three telescopes that together provide five large-FOV apertures. ISIS observes continuously inside of 0.25 AU with a high data collection rate and burst data (EPI-Lo) coordinated with the rest of the SPP payload; outside of 0.25 AU, ISIS runs in low-rate science mode whenever feasible to capture as complete a record as possible of the solar energetic particle environment and provide calibration and continuity for measurements closer in to the Sun. The ISIS Science Operations Center plans and executes commanding, receives and analyzes all ISIS data, and coordinates science observations and analyses with the rest of the SPP science investigations. Together, ISIS’ unique observations on SPP will enable the discovery, untangling, and understanding of the important physical processes that govern energetic particles in the innermost regions of our heliosphere, for the first time. This paper summarizes the ISIS investigation at the time of the SPP mission Preliminary Design Review in January 2014.
Dasatinib, a potent inhibitor of BCR-ABL in vitro, is effective for patients with chronic myelogenous leukemia (CML) resistant or intolerant to imatinib. To provide a more definitive assessment of ...dasatinib in chronic-phase (CP)-CML, we report extended follow-up of a phase II trial, presenting data for the entire patient cohort (N=387). Dasatinib (70 mg) twice daily was administered to patients with imatinib-resistant or -intolerant CP-CML. With median follow-up of 15.2 months (treatment duration, <1-18.4 months), a complete hematologic response was attained or maintained in 91% of patients. A major cytogenetic response (MCyR) was attained or maintained by 59% (52% imatinib resistant and 80% imatinib intolerant); this was complete in 49% of patients (40% imatinib resistant and 75% imatinib intolerant). Of 230 patients achieving an MCyR, 7 experienced disease progression. Fifteen-month progression-free survival was 90% while overall survival was 96%. Grade 3/4 thrombocytopenia and neutropenia were reported in 48 and 49% of patients, respectively. Non-hematologic toxicity (any grade) consisted primarily of diarrhea (37%), headache (32%), fatigue (31%), dyspnea (30%) and pleural effusion (27%). Pleural effusions were classified as grade 3 in 6% of reported events, with no incidence of grade 4. Dasatinib is associated with high response rates in patients with imatinib-resistant or -intolerant CP-CML.
This phase 1b trial investigated several doses and schedules of midostaurin in combination with daunorubicin and cytarabine induction and high-dose cytarabine post-remission therapy in newly ...diagnosed patients with acute myeloid leukemia (AML). The discontinuation rate on the 50-mg twice-daily dose schedule was lower than 100 mg twice daily, and no grade 3/4 nausea or vomiting was seen. The complete remission rate for the midostaurin 50-mg twice-daily dose schedule was 80% (FMS-like tyrosine kinase 3 receptor (FLT3)-wild-type: 20 of 27 (74%), FLT3-mutant: 12 of 13 (92%)). Overall survival (OS) probabilities of patients with FLT3-mutant AML at 1 and 2 years (0.85 and 0.62, respectively) were similar to the FLT3-wild-type population (0.78 and 0.52, respectively). Midostaurin in combination with standard chemotherapy demonstrated high complete response and OS rates in newly diagnosed younger adults with AML, and was generally well tolerated at 50 mg twice daily for 14 days. A phase III prospective trial is ongoing (CALGB 10603, NCT00651261).
The non-linear evolution of the Kelvin-Helmholtz instability is a popular test for code verification. To date, most Kelvin-Helmholtz problems discussed in the literature are ill-posed: they do not ...converge to any single solution with increasing resolution. This precludes comparisons among different codes and severely limits the utility of the Kelvin-Helmholtz instability as a test problem. The lack of a reference solution has led various authors to assert the accuracy of their simulations based on ad hoc proxies, e.g. the existence of small-scale structures. This paper proposes well-posed two-dimensional Kelvin-Helmholtz problems with smooth initial conditions and explicit diffusion. We show that in many cases numerical errors/noise can seed spurious small-scale structure in Kelvin-Helmholtz problems. We demonstrate convergence to a reference solution using both athena, a Godunov code, and dedalus, a pseudo-spectral code. Problems with constant initial density throughout the domain are relatively straightforward for both codes. However, problems with an initial density jump (which are the norm in astrophysical systems) exhibit rich behaviour and are more computationally challenging. In the latter case, athena simulations are prone to an instability of the inner rolled-up vortex; this instability is seeded by grid-scale errors introduced by the algorithm, and disappears as resolution increases. Both athena and dedalus exhibit late-time chaos. Inviscid simulations are riddled with extremely vigorous secondary instabilities which induce more mixing than simulations with explicit diffusion. Our results highlight the importance of running well-posed test problems with demonstrated convergence to a reference solution. To facilitate future comparisons, we include as supplementary material the resolved, converged solutions to the Kelvin-Helmholtz problems in this paper in machine-readable form.
The objective of this study was to use automated activity, lying, and rumination monitors to characterize prepartum behavior and predict calving in dairy cattle. Data were collected from 20 ...primiparous and 33 multiparous Holstein dairy cattle from September 2011 to May 2013 at the University of Kentucky Coldstream Dairy. The HR Tag (SCR Engineers Ltd., Netanya, Israel) automatically collected neck activity and rumination data in 2-h increments. The IceQube (IceRobotics Ltd., South Queensferry, United Kingdom) automatically collected number of steps, lying time, standing time, number of transitions from standing to lying (lying bouts), and total motion, summed in 15-min increments. IceQube data were summed in 2-h increments to match HR Tag data. All behavioral data were collected for 14 d before the predicted calving date. Retrospective data analysis was performed using mixed linear models to examine behavioral changes by day in the 14 d before calving. Bihourly behavioral differences from baseline values over the 14 d before calving were also evaluated using mixed linear models. Changes in daily rumination time, total motion, lying time, and lying bouts occurred in the 14 d before calving. In the bihourly analysis, extreme values for all behaviors occurred in the final 24 h, indicating that the monitored behaviors may be useful in calving prediction. To determine whether technologies were useful at predicting calving, random forest, linear discriminant analysis, and neural network machine-learning techniques were constructed and implemented using R version 3.1.0 (R Foundation for Statistical Computing, Vienna, Austria). These methods were used on variables from each technology and all combined variables from both technologies. A neural network analysis that combined variables from both technologies at the daily level yielded 100.0% sensitivity and 86.8% specificity. A neural network analysis that combined variables from both technologies in bihourly increments was used to identify 2-h periods in the 8 h before calving with 82.8% sensitivity and 80.4% specificity. Changes in behavior and machine-learning alerts indicate that commercially marketed behavioral monitors may have calving prediction potential.
Currently available combination chemotherapy for acute myeloid leukemia (AML) often fails to result in long-term remissions, emphasizing the need for novel therapeutic strategies. We reasoned that ...targeted inhibition of a prominent nuclear exporter, XPO1/CRM1, could eradicate self-renewing leukemia-initiating cells (LICs) whose survival depends on timely XPO1-mediated transport of specific protein and RNA cargoes. Using an immunosuppressed mouse model bearing primary patient-derived AML cells, we demonstrate that selinexor (KPT-330), an oral antagonist of XPO1 that is currently in clinical trials, has strong activity against primary AML cells while sparing normal stem and progenitor cells. Importantly, limiting dilution transplantation assays showed that this cytotoxic activity is not limited to the rapidly proliferating bulk population of leukemic cells but extends to the LICs, whose inherent drug resistance and unrestricted self-renewal capacity has been implicated in the difficulty of curing AML patients with conventional chemotherapy alone.
Increases in extreme precipitation greater than in the mean under increased greenhouse gases have been reported in many climate models both on global and regional scales. It has been proposed in a ...previous study that whereas global-mean precipitation change is primarily constrained by the global energy budget, the heaviest events can be expected when effectively all the moisture in a volume of air is precipitated out, suggesting the intensity of these events increases with availability of moisture, and significantly faster than the global mean. Thus under conditions of constant relative humidity one might expect the Clausius-Clapeyron relation to give a constraint on changes in the uppermost quantiles of precipitation distributions. This study examines if the phenomenon manifests on regional and seasonal scales also. Zonal analysis of daily precipitation in the HadCM3 model under a transient CO₂ forcing scenario shows increased extreme precipitation in the tropics accompanied by increased drying at lower percentiles. At mid- to high-latitudes there is increased precipitation over all percentiles. The greatest agreement with Clausius-Clapeyron predicted change occurs at mid-latitudes. This pattern is consistent with other climate model projections, and suggests that regions in which the nature of the ambient flows change little give the greatest agreement with Clausius-Clapeyron prediction. This is borne out by repeating the analyses at gridbox level and over season. Furthermore, it is found that Clausius-Clapeyron predicted change in extreme precipitation is a better predictor than directly using the change in mean precipitation, particularly between 60°N and 60°S. This could explain why extreme precipitation changes may be more detectable then mean changes.
Upgraded electronics, improved water system dynamics, better calibration and analysis techniques allowed Super-Kamiokande-IV to clearly observe very low-energy B8 solar neutrino interactions, with ...recoil electron kinetic energies as low as ∼3.5 MeV. Super-Kamiokande-IV data-taking began in September of 2008; this paper includes data until February 2014, a total livetime of 1664 days. The measured solar neutrino flux is (2.308±0.020(stat)−0.040+0.039(syst))×106/(cm2 sec) assuming no oscillations. The observed recoil electron energy spectrum is consistent with no distortions due to neutrino oscillations. An extended maximum likelihood fit to the amplitude of the expected solar zenith angle variation of the neutrino-electron elastic scattering rate in SK-IV results in a day/night asymmetry of (−3.6±1.6(stat)±0.6(syst))%. The SK-IV solar neutrino data determine the solar mixing angle as sin2θ12=0.327−0.031+0.026, all SK solar data (SK-I, SK-II, SK III and SK-IV) measures this angle to be sin2θ12=0.334−0.023+0.027, the determined mass-squared splitting is Δm212=4.8−0.8+1.5×10−5 eV2.
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