| 1. |
- Berglund, U. W., et al.
(författare)
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Validation and development of MTH1 inhibitors for treatment of cancer
- 2016
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Ingår i: Annals of Oncology. - : Elsevier BV. - 0923-7534 .- 1569-8041. ; 27:12, s. 2275-2283
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Tidskriftsartikel (refereegranskat)abstract
- Background: Previously, we showed cancer cells rely on the MTH1 protein to prevent incorporation of otherwise deadly oxidised nucleotides into DNA and we developed MTH1 inhibitors which selectively kill cancer cells. Recently, several new and potent inhibitors of MTH1 were demonstrated to be non-toxic to cancer cells, challenging the utility of MTH1 inhibition as a target for cancer treatment. Material and methods: Human cancer cell lines were exposed in vitro to MTH1 inhibitors or depleted of MTH1 by siRNA or shRNA. 8-oxodG was measured by immunostaining and modified comet assay. Thermal Proteome profiling, proteomics, cellular thermal shift assays, kinase and CEREP panel were used for target engagement, mode of action and selectivity investigations of MTH1 inhibitors. Effect of MTH1 inhibition on tumour growth was explored in BRAF V600E-mutated malignant melanoma patient derived xenograft and human colon cancer SW480 and HCT116 xenograft models. Results: Here, we demonstrate that recently described MTH1 inhibitors, which fail to kill cancer cells, also fail to introduce the toxic oxidized nucleotides into DNA. We also describe a new MTH1 inhibitor TH1579, (Karonudib), an analogue of TH588, which is a potent, selective MTH1 inhibitor with good oral availability and demonstrates excellent pharmacokinetic and anti-cancer properties in vivo. Conclusion: We demonstrate that in order to kill cancer cells MTH1 inhibitors must also introduce oxidized nucleotides into DNA. Furthermore, we describe TH1579 as a best-in-class MTH1 inhibitor, which we expect to be useful in order to further validate the MTH1 inhibitor concept.
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| 2. |
- Breuillard, H., et al.
(författare)
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The Properties of Lion Roars and Electron Dynamics in Mirror Mode Waves Observed by the Magnetospheric MultiScale Mission
- 2018
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Ingår i: Journal of Geophysical Research - Space Physics. - : American Geophysical Union (AGU). - 2169-9380 .- 2169-9402. ; 123:1, s. 93-103
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Tidskriftsartikel (refereegranskat)abstract
- Mirror mode waves are ubiquitous in the Earth's magnetosheath, in particular behind the quasi-perpendicular shock. Embedded in these nonlinear structures, intense lion roars are often observed. Lion roars are characterized by whistler wave packets at a frequency similar to 100Hz, which are thought to be generated in the magnetic field minima. In this study, we make use of the high time resolution instruments on board the Magnetospheric MultiScale mission to investigate these waves and the associated electron dynamics in the quasi-perpendicular magnetosheath on 22 January 2016. We show that despite a core electron parallel anisotropy, lion roars can be generated locally in the range 0.05-0.2f(ce) by the perpendicular anisotropy of electrons in a particular energy range. We also show that intense lion roars can be observed up to higher frequencies due to the sharp nonlinear peaks of the signal, which appear as sharp spikes in the dynamic spectra. As a result, a high sampling rate is needed to estimate correctly their amplitude, and the latter might have been underestimated in previous studies using lower time resolution instruments. We also present for the first-time 3-D high time resolution electron velocity distribution functions in mirror modes. We demonstrate that the dynamics of electrons trapped in the mirror mode structures are consistent with the Kivelson and Southwood (1996) model. However, these electrons can also interact with the embedded lion roars: first signatures of electron quasi-linear pitch angle diffusion and possible signatures of nonlinear interaction with high-amplitude wave packets are presented. These processes can lead to electron untrapping from mirror modes.
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| 3. |
- Burch, J. L., et al.
(författare)
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Electron-scale measurements of magnetic reconnection in space
- 2016
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Ingår i: Science. - : AMER ASSOC ADVANCEMENT SCIENCE. - 0036-8075 .- 1095-9203. ; 352:6290, s. 1189-
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Forskningsöversikt (refereegranskat)abstract
- Magnetic reconnection is a fundamental physical process in plasmas whereby stored magnetic energy is converted into heat and kinetic energy of charged particles. Reconnection occurs in many astrophysical plasma environments and in laboratory plasmas. Using measurements with very high time resolution, NASA's Magnetospheric Multiscale (MMS) mission has found direct evidence for electron demagnetization and acceleration at sites along the sunward boundary of Earth's magnetosphere where the interplanetary magnetic field reconnects with the terrestrial magnetic field. We have (i) observed the conversion of magnetic energy to particle energy; (ii) measured the electric field and current, which together cause the dissipation of magnetic energy; and (iii) identified the electron population that carries the current as a result of demagnetization and acceleration within the reconnection diffusion/dissipation region.
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| 4. |
- Le Contel, O., et al.
(författare)
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Lower Hybrid Drift Waves and Electromagnetic Electron Space-Phase Holes Associated With Dipolarization Fronts and Field-Aligned Currents Observed by the Magnetospheric Multiscale Mission During a Substorm
- 2017
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Ingår i: Journal of Geophysical Research - Space Physics. - : AMER GEOPHYSICAL UNION. - 2169-9380 .- 2169-9402. ; 122:12, s. 12236-12257
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Tidskriftsartikel (refereegranskat)abstract
- We analyze two ion scale dipolarization fronts associated with field-aligned currents detected by the Magnetospheric Multiscale mission during a large substorm on 10 August 2016. The first event corresponds to a fast dawnward flow with an antiparallel current and could be generated by the wake of a previous fast earthward flow. It is associated with intense lower hybrid drift waves detected at the front and propagating dawnward with a perpendicular phase speed close to the electric drift and the ion thermal velocity. The second event corresponds to a flow reversal: from southwward/dawnward to northward/duskward associated with a parallel current consistent with a brief expansion of the plasma sheet before the front crossing and with a smaller lower hybrid drift wave activity. Electromagnetic electron phase-space holes are detected near these low-frequency drift waves during both events. The drift waves could accelerate electrons parallel to the magnetic field and produce the parallel electron drift needed to generate the electron holes. Yet we cannot rule out the possibility that the drift waves are produced by the antiparallel current associated with the fast flows, leaving the source for the electron holes unexplained.
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| 5. |
- Nakamura, R., et al.
(författare)
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Transient, small-scale field-aligned currents in the plasma sheet boundary layer during storm time substorms
- 2016
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Ingår i: Geophysical Research Letters. - 0094-8276 .- 1944-8007. ; 43:10, s. 4841-4849
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Tidskriftsartikel (refereegranskat)abstract
- We report on field-aligned current observations by the four Magnetospheric Multiscale (MMS) spacecraft near the plasma sheet boundary layer (PSBL) during two major substorms on 23 June 2015. Small-scale field-aligned currents were found embedded in fluctuating PSBL flux tubes near the separatrix region. We resolve, for the first time, short-lived earthward (downward) intense field-aligned current sheets with thicknesses of a few tens of kilometers, which are well below the ion scale, on flux tubes moving equatorward/earthward during outward plasma sheet expansion. They coincide with upward field-aligned electron beams with energies of a few hundred eV. These electrons are most likely due to acceleration associated with a reconnection jet or high-energy ion beam-produced disturbances. The observations highlight coupling of multiscale processes in PSBL as a consequence of magnetotail reconnection.
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| 6. |
- Andre, M., Behlke, R., Wahlund, J.E., Vaivads, A., Eriksson, A., Tjulin, A., Carozzi, T. D., Cully, C., Gustafsson, G., Sundkvist, D., Khotyaintsev, Y., Cornilleau-Wehrlin, N., Rezeau, L., Maksimovic, M., Lucek, E., Balogh, A., Dunlop, M., Lindqvist, P.A.
(författare)
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Multi-spacecraft observations of broadband waves near the lower hybrid frequency at the Earthward edge of the magnetopause.
- 2001
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Ingår i: Annales Geophysicae. ; 19:6, s. 1471-1481
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Tidskriftsartikel (refereegranskat)abstract
- Broadband waves around the lower hybrid frequency (around 10 Hz) near the magnetopause are studied, using the four Cluster satellites. These waves are common at the Earthward edge of the boundary layer, consistent with earlier observations, and can have a
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| 7. |
- Breuillard, H., et al.
(författare)
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Multispacecraft analysis of dipolarization fronts and associated whistler wave emissions using MMS data
- 2016
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Ingår i: Geophysical Research Letters. - : Blackwell Publishing. - 0094-8276 .- 1944-8007. ; 43:14, s. 7279-7286
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Tidskriftsartikel (refereegranskat)abstract
- Dipolarization fronts (DFs), embedded in bursty bulk flows, play a crucial role in Earth's plasma sheet dynamics because the energy input from the solar wind is partly dissipated in their vicinity. This dissipation is in the form of strong low-frequency waves that can heat and accelerate energetic electrons up to the high-latitude plasma sheet. However, the dynamics of DF propagation and associated low-frequency waves in the magnetotail are still under debate due to instrumental limitations and spacecraft separation distances. In May 2015 the Magnetospheric Multiscale (MMS) mission was in a string-of-pearls configuration with an average intersatellite distance of 160km, which allows us to study in detail the microphysics of DFs. Thus, in this letter we employ MMS data to investigate the properties of dipolarization fronts propagating earthward and associated whistler mode wave emissions. We show that the spatial dynamics of DFs are below the ion gyroradius scale in this region (approximate to 500km), which can modify the dynamics of ions in the vicinity of the DF (e.g., making their motion nonadiabatic). We also show that whistler wave dynamics have a temporal scale of the order of the ion gyroperiod (a few seconds), indicating that the perpendicular temperature anisotropy can vary on such time scales.
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| 8. |
- Ergun, R. E., et al.
(författare)
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Drift waves, intense parallel electric fields, and turbulence associated with asymmetric magnetic reconnection at the magnetopause
- 2017
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Ingår i: Geophysical Research Letters. - : American Geophysical Union (AGU). - 0094-8276 .- 1944-8007. ; 44:7, s. 2978-2986
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Tidskriftsartikel (refereegranskat)abstract
- Observations of magnetic reconnection at Earth's magnetopause often display asymmetric structures that are accompanied by strong magnetic field (B) fluctuations and large-amplitude parallel electric fields (E-||). The B turbulence is most intense at frequencies above the ion cyclotron frequency and below the lower hybrid frequency. The B fluctuations are consistent with a thin, oscillating current sheet that is corrugated along the electron flow direction (along the X line), which is a type of electromagnetic drift wave. Near the X line, electron flow is primarily due to a Hall electric field, which diverts ion flow in asymmetric reconnection and accompanies the instability. Importantly, the drift waves appear to drive strong parallel currents which, in turn, generate large-amplitude (similar to 100mV/m) E-|| in the form of nonlinear waves and structures. These observations suggest that turbulence may be common in asymmetric reconnection, penetrate into the electron diffusion region, and possibly influence the magnetic reconnection process.
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| 9. |
- Pedersen, A., et al.
(författare)
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Electron density estimations derived from spacecraft potential measurements on Cluster in tenuous plasma regions
- 2008
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Ingår i: Journal of Geophysical Research. - 0148-0227 .- 2156-2202. ; 113:A7, s. A07S33-
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Tidskriftsartikel (refereegranskat)abstract
- Spacecraft potential measurements by the EFW electric field experiment on the Cluster satellites can be used to obtain plasma density estimates in regions barely accessible to other type of plasma experiments. Direct calibrations of the plasma density as a function of the measured potential difference between the spacecraft and the probes can be carried out in the solar wind, the magnetosheath, and the plasmashere by the use of CIS ion density and WHISPER electron density measurements. The spacecraft photoelectron characteristic ( photoelectrons escaping to the plasma in current balance with collected ambient electrons) can be calculated from knowledge of the electron current to the spacecraft based on plasma density and electron temperature data from the above mentioned experiments and can be extended to more positive spacecraft potentials by CIS ion and the PEACE electron experiments in the plasma sheet. This characteristic enables determination of the electron density as a function of spacecraft potential over the polar caps and in the lobes of the magnetosphere, regions where other experiments on Cluster have intrinsic limitations. Data from 2001 to 2006 reveal that the photoelectron characteristics of the Cluster spacecraft as well as the electric field probes vary with the solar cycle and solar activity. The consequences for plasma density measurements are addressed. Typical examples are presented to demonstrate the use of this technique in a polar cap/lobe plasma.
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| 10. |
- Torbert, R. B., et al.
(författare)
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Electron-scale dynamics of the diffusion region during symmetric magnetic reconnection in space
- 2018
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Ingår i: Science. - : AMER ASSOC ADVANCEMENT SCIENCE. - 0036-8075 .- 1095-9203. ; 362:6421, s. 1391-1395
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Tidskriftsartikel (refereegranskat)abstract
- Magnetic reconnection is an energy conversion process that occurs in many astrophysical contexts including Earth's magnetosphere, where the process can be investigated in situ by spacecraft. On 11 July 2017, the four Magnetospheric Multiscale spacecraft encountered a reconnection site in Earth's magnetotail, where reconnection involves symmetric inflow conditions. The electron-scale plasma measurements revealed (i) super-Alfvenic electron jets reaching 15,000 kilometers per second; (ii) electron meandering motion and acceleration by the electric field, producing multiple crescent-shaped structures in the velocity distributions; and (iii) the spatial dimensions of the electron diffusion region with an aspect ratio of 0.1 to 0.2, consistent with fast reconnection. The well-structured multiple layers of electron populations indicate that the dominant electron dynamics are mostly laminar, despite the presence of turbulence near the reconnection site.
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