DC hybrid power systems are of interest for future low emission, fuel-efficient vessels. In spite of the advantages they offer onboard a ship, they result in a complex, interconnected system, which ...requires effective analysis tools to enable a full realization of the advantages. Modeling and simulation are essential tools to facilitate design, analysis, and optimization of the system. This paper reviews modeling of hybrid electric ship components including mechanical and electrical elements. Power electronic converters are modeled by nonlinear averaging methods to suit system-level studies. A unified model for bidirectional converters is proposed to avoid transitions between two separate models. A simulation platform using the derived models is developed for the system-level analysis of hybrid electric ships. Simulation results of power sharing among two diesel generators, a fuel cell module, and an energy storage system are presented for three modes of operation.
Chemo-immunotherapy has improved survival in B-cell lymphoma patients, but refractory/relapsed diseases still represent a major challenge, urging for development of new therapeutics. Karonudib ...(TH1579) was developed to inhibit MTH1, an enzyme preventing oxidized dNTP-incorporation in DNA. MTH1 is highly upregulated in tumor biopsies from patients with diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma, hence confirming a rationale for targeting MTH1. Here, we tested the efficacy of karonudib in vitro and in preclinical B-cell lymphoma models. Using a range of B-cell lymphoma cell lines, karonudib strongly reduced viability at concentrations well tolerated by activated normal B cells. In B-cell lymphoma cells, karonudib increased incorporation of 8-oxo-dGTP into DNA, and prominently induced prometaphase arrest and apoptosis due to failure in spindle assembly. MTH1 knockout cell lines were less sensitive to karonudib-induced apoptosis, but were displaying cell cycle arrest phenotype similar to the wild type cells, indicating a dual inhibitory role of the drug. Karonudib was highly potent as single agent in two different lymphoma xenograft models, including an ABC DLBCL patient derived xenograft, leading to prolonged survival and fully controlled tumor growth. Together, our preclinical findings provide a rationale for further clinical testing of karonudib in B-cell lymphoma.
IntroductionPostoperative delirium is common in older cardiac surgery patients and associated with negative short-term and long-term outcomes. The alpha-2-adrenergic receptor agonist dexmedetomidine ...shows promise as prophylaxis and treatment for delirium in intensive care units (ICU) and postoperative settings. Clonidine has similar pharmacological properties and can be administered both parenterally and orally. We aim to study whether repurposing of clonidine can represent a novel treatment option for delirium, and the possible effects of dexmedetomidine and clonidine on long-term cognitive trajectories, motor activity patterns and biomarkers of neuronal injury, and whether these effects are associated with frailty status.Methods and analysisThis five-centre, double-blind randomised controlled trial will include 900 cardiac surgery patients aged 70+ years. Participants will be randomised 1:1:1 to dexmedetomidine or clonidine or placebo. The study drug will be given as a continuous intravenous infusion from the start of cardiopulmonary bypass, at a rate of 0.4 µg/kg/hour. The infusion rate will be decreased to 0.2 µg/kg/hour postoperatively and be continued until discharge from the ICU or 24 hours postoperatively, whichever happens first.Primary end point is the 7-day cumulative incidence of postoperative delirium (Diagnostic and Statistical Manual of Mental Disorders, fifth edition). Secondary end points include the composite end point of coma, delirium or death, in addition to delirium severity and motor activity patterns, levels of circulating biomarkers of neuronal injury, cognitive function and frailty status 1 and 6 months after surgery.Ethics and disseminationThis trial is approved by the Regional Committee for Ethics in Medical Research in Norway (South-East Norway) and by the Norwegian Medicines Agency. Dissemination plans include publication in peer-reviewed medical journals and presentation at scientific meetings.Trial registration numberNCT05029050.
Although chemo-immunotherapy has improved survival in B-cell lymphoma patients, refractory and relapsed disease still represents a major challenge, urging for development of new therapeutics. A new ...approach is to target nucleotide metabolism. Karonudib (TH1579), was developed to inhibit MutT-homologue-1/Nudix hydrolase 1 (MTH1/NUDT1), an enzyme that prevents oxidized nucleotides to be incorporated into DNA. Under normal conditions with low reactive oxygen species (ROS) burden, MTH1 is not essential for cell survival. This contrasts cancer cells which frequently upregulate MTH1 to compensate for increased ROS with corresponding higher oxidized nucleotide levels, and therefore become more susceptible for MTH1 inhibition. Here, our aim was to perform preclinical testing of karonudib in B-cell lymphoma.
Using two different gene expression datasets, we demonstrate that NUDT1, the gene encoding MTH1, was highly upregulated in tumor biopsies from patients with diffuse large B-cell lymphoma (DLBCL) and Burkitt’s lymphoma as compared to follicular lymphoma and peripheral blood B cells from healthy donors, hence demonstrating a rationale for targeting MTH1 in aggressive B-cell lymphoma. We tested the efficacy of karonudib (0.06-1 µM) in vitro in a range of B-cell lymphoma cell lines using CellTiterGlo and by flow cytometry detection of active caspase-3 and TUNEL to identify apoptotic cells. Karonudib strongly reduced viability in all B-cell lymphoma cell lines tested (n = 12) and induced apoptosis at concentrations well tolerated by peripheral blood B cells from healthy donors. Cell cycle analysis and microscopy revealed that most cells arrested in prometaphase in the presence of karonudib. Failed spindle assembly led to mitotic arrest and subsequent apoptosis. Prometaphase arrest was seen in TP53 mutant as well as in TP53 wild type cell lines, confirming that karonudib induced apoptosis independent of TP53 mutational status. To test the efficacy of karonudib in vivo, we utilized two different lymphoma xenograft models, including an ABC DLBCL patient-derived model. Mice were treated with karonudib (90 mg/kg) or vehicle b.i.d, three times a week and tumor growth was monitored by in vivo imaging system or MR. In both models, karonudib as single agent completely controlled tumor growth, and significantly prolonged survival (p<0.0001, as compared to control mice).
The specificity of MTH1 inhibitors has been debated and TH588, the first generation MTH1 inhibitor, was recently shown to bind b-tubulin and induce mitotic arrest in MTH1 knock out cell lines (Patterson et al, Cell Syst 2019). To elucidate the mechanism of karonudib in B-cell lymphoma, we generated MTH1 knock out cells using CRISPR/Cas9, and compared the functional effects of karonudib in these clones with the original lymphoma cells. We demonstrated on-target effect of the inhibitor as the MTH1 knock out clones were less sensitive towards karonudib. However, MTH1 knock out clones exhibited a similar cell cycle arrest as the wild type cells after karonudib treatment. This clearly indicates that karonudib can induce cell cycle arrest independent of MTH1, and hence has a dual mechanism of action.
Our preclinical data suggest that karonudib is a promising drug with potential therapeutic use in B-cell lymphoma, and may be particular effective in aggressive lymphoma types.
Warpman Berglund:Oxcia AB: Other: shareholders; non profit Thomas Helleday Foundation for Medical Research: Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties. Gad:Oxcia: Other: shareholder; non profit Thomas Helleday Foundation for Medical Research: Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties. Pham:Oxcia AB: Other: Shareholder. Sanjiv:Oxcia AB: Other: Shareholder; non profit Thomas Helleday Foundation for Medical Research: Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties. Helleday:Oxcia AB: Other: Shareholder; non profit Thomas Helleday Foundation for Medical Research: Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties.
Short Range Correlations (SRCs) have been identiffed as being responsible for the high momentum tail of the nucleon momentum distribution, n(k). Hard, short-range interactions of nucleon pairs ...generate the high momentum tail and imprint a universal character on n(k) for all nuclei at large momentum. Triple coincidence experiments have shown a strong dominance of np pairs, but these measurements involve large final state interactions. This paper presents the results from Jefferson Lab experiment E08014 which measured inclusive electron scattering cross-section from Ca isotopes. Here, by comparing the inclusive cross section from 48Ca to 40Ca in a kinematic region dominated by SRCs we provide a new way to study the isospin structure of SRCs.
Hybrid power systems with dc distribution are being considered for commercial marine vessels to comply with new stringent environmental regulations, and to achieve higher fuel economy. In this paper, ...detailed efficiency analysis of a shipboard dc hybrid power system is carried out. An optimization algorithm is proposed to minimize fuel consumption under various loading conditions. The studied system includes diesel engines, synchronous generator–rectifier units, a full-bridge bidirectional converter, and a Li-Ion battery bank as energy storage. In order to evaluate potential fuel saving provided by such a system, an online optimization strategy for fuel consumption is implemented. An Offshore Support Vessel (OSV) is simulated over different operating modes using the online control strategy. The resulted consumed fuel in the simulation is compared to that of a conventional ac power system, and also a dc power system without energy storage. The results show that while the dc system without energy storage provides noticeable fuel saving compared to the conventional ac system, optimal utilization of the energy storage in the dc system results in twice as much fuel saving.
•Detailed efficiency analysis of a shipboard dc hybrid power system is carried out.•An optimization algorithm is proposed to minimize fuel consumption under various loading conditions.•An online optimization strategy for fuel saving is implemented in MATLAB/Simulink.•An offshore support vessel (OSV) is simulated over different modes under online optimization control.•The method achieves around 15% fuel saving with optimally utilized energy storage in the studied dc system.
Cross-section values for Compton scattering on the proton were measured at 25 kinematic settings over the range s=5-11 and -t=2-7 GeV2 with a statistical accuracy of a few percent. The scaling power ...for the s dependence of the cross section at fixed center-of-mass angle was found to be 8.0+/-0.2, strongly inconsistent with the prediction of perturbative QCD. The observed cross-section values are in fair agreement with the calculations using the handbag mechanism, in which the external photons couple to a single quark.
Measurements of elastic electron scattering data within the past decade have highlighted two-photon exchange contributions as a necessary ingredient in theoretical calculations to precisely evaluate ...hydrogen elastic scattering cross sections. This correction can modify the cross section at the few percent level. In contrast, dispersive effects can cause significantly larger changes from the Born approximation. The purpose of this experiment is to extract the carbon-12 elastic cross section around the first diffraction minimum, where the Born term contributions to the cross section are small to maximize the sensitivity to dispersive effects. The analysis uses the LEDEX data from the high resolution Jefferson Lab Hall A spectrometers to extract the cross sections near the first diffraction minimum of
12
C at beam energies of 362 MeV and 685 MeV. The results are in very good agreement with previous world data, although with less precision. The average deviation from a static nuclear charge distribution expected from linear and quadratic fits indicate a 30.6% contribution of dispersive effects to the cross section at 1 GeV. The magnitude of the dispersive effects near the first diffraction minimum of
12
C has been confirmed to be large with a strong energy dependence and could account for a large fraction of the magnitude for the observed quenching of the longitudinal nuclear response. These effects could also be important for nuclei radii extracted from parity-violating asymmetries measured near a diffraction minimum.
We report on a precise measurement of double-polarization asymmetries in electron-induced breakup of He3 proceeding to pd and ppn final states, performed in quasi-elastic kinematics at ...Q2=0.25(GeV/c)2 for missing momenta up to 250MeV/c. These observables represent highly sensitive tools to investigate the electromagnetic and spin structure of He3 and the relative importance of two- and three-body effects involved in the breakup reaction dynamics. The measured asymmetries cannot be satisfactorily reproduced by state-of-the-art calculations of He3 unless their three-body segment is adjusted, indicating that the spin-dependent part of the nuclear interaction governing the three-body breakup process is much smaller than previously thought.
PDF
