| 1. |
- Bonagas, Nadilly, et al.
(författare)
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Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress
- 2022
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Ingår i: NATURE CANCER. - : Springer Science and Business Media LLC. - 2662-1347. ; 3:2, s. 156-
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Tidskriftsartikel (refereegranskat)abstract
- The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells. Mechanistically, MTHFD2 inhibitors prevented thymidine production leading to misincorporation of uracil into DNA and replication stress. Overall, these results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors. Helleday and colleagues describe a nanomolar MTHFD2 inhibitor that causes replication stress and DNA damage accumulation in cancer cells via thymidine depletion, demonstrating a potential therapeutic strategy in AML tumors in vivo.
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| 2. |
- Gan, H., et al.
(författare)
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Statistical analysis of the causes of excess variance in the 21 cm signal power spectra obtained with the Low-Frequency Array
- 2022
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 663
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Tidskriftsartikel (refereegranskat)abstract
- Context. The detection of the 21 cm signal of neutral hydrogen from the Epoch of Reionization (EoR) is challenging due to bright foreground sources, radio frequency interference (RFI), and the ionosphere as well as instrumental effects. Even after correcting for these effects in the calibration step and applying foreground removal techniques, the remaining residuals in the observed 21 cm power spectra are still above the thermal noise, which is referred to as the “excess variance.”Aims. We study a number of potential causes of this excess variance based on 13 nights of data obtained with the Low-Frequency Array (LOFAR).Methods. We focused on the impact of gain errors, the sky model, and ionospheric effects on the excess variance by correlating the relevant parameters such as the gain variance over time or frequency, local sidereal time (LST), diffractive scale, and phase structure–function slope with the level of excess variance.Results. Our analysis shows that the excess variance, at the current level, is neither strongly correlated with gain variance nor the ionospheric parameters. Rather, excess variance has an LST dependence, which is related to the power from the sky. Furthermore, the simulated Stokes I power spectra from bright sources and the excess variance show a similar progression over LST with the minimum power appearing at LST bin 6h to 9h. This LST dependence is also present in sky images of the residual Stokes I of the observations. In very-wide sky images based on one night of observation after direction-dependent calibration, we demonstrate that the extra power comes exactly from the direction of bright and distant sources Cassiopeia A and Cygnus A with the array beam patterns.Conclusions. These results suggest that the level of excess variance in the 21 cm signal power spectra is related to sky effects and, hence, it depends on LST. In particular, very bright and distant sources such as Cassiopeia A and Cygnus A can dominate the effect. This is in line with earlier studies and offers a path forward toward a solution, since the correlation between the sky-related effects and the excess variance is non-negligible.
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| 3. |
- Ghara, Raghunath, et al.
(författare)
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Constraining the intergalactic medium at z approximate to 9.1 using LOFAR Epoch of Reionization observations
- 2020
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Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 493:4, s. 4728-4747
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Tidskriftsartikel (refereegranskat)abstract
- We derive constraints on the thermal and ionization states of the intergalactic medium (IGM) at redshift approximate to 9.1 using new upper limits on the 21-cm power spectrum measured by the LOFAR radio telescope and a prior on the ionized fraction at that redshift estimated from recent cosmic microwave background (CMB) observations. We have used results from the reionization simulation code GRIZZLY and a Bayesian inference framework to constrain the parameters which describe the physical state of the IGM. We find that, if the gas heating remains negligible, an IGM with ionized fraction greater than or similar to 0.13 and a distribution of the ionized regions with a characteristic size greater than or similar to 8 h(-1) comoving megaparsec (Mpc) and a full width at half-maximum (FWHM) greater than or similar to 16 h(-1) Mpc is ruled out. For an IGM with a uniform spin temperature T-S greater than or similar to 3 K, no constraints on the ionized component can be computed. If the large-scale fluctuations of the signal are driven by spin temperature fluctuations, an IGM with a volume fraction less than or similar to 0.34 of heated regions with a temperature larger than CMB, average gas temperature 7-160 K, and a distribution of the heated regions with characteristic size 3.5-70 h(-1) Mpc and FWHM of less than or similar to 110 h(-1) Mpc is ruled out. These constraints are within the 95 per cent credible intervals. With more stringent future upper limits from LOFAR at multiple redshifts, the constraints will become tighter and will exclude an increasingly large region of the parameter space.
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| 4. |
- Kamran, Mohammed, et al.
(författare)
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Redshifted 21-cm bispectrum : impact of the source models on the signal and the IGM physics from the Cosmic Dawn
- 2022
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Ingår i: Journal of Cosmology and Astroparticle Physics. - : IOP Publishing. - 1475-7516. ; 2022:11
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Tidskriftsartikel (refereegranskat)abstract
- The emissions from the first luminous sources drive the fluctuations in the 21-cm signal at Cosmic Dawn (CD) via two main astrophysical processes, namely Lyα coupling and X-ray heating, yielding a highly non-Gaussian signal. The impact of these processes on the 21-cm signal and its non-Gaussianity depends on the properties of these first sources of light. In this work, we consider different CD scenarios by varying two major source parameters i.e. the minimum halo mass Mh,min and X-ray photon production efficiency fX using the 1D radiative transfer code GRIZZLY. We study the impact of variation in these source parameters on the large scale (K1 = 0.16 Mpc-1) 21-cm bispectrum for all possible unique triangles in the Fourier domain. Our detailed and comparative analysis of the power spectrum and bispectrum shows that the shape, sign and magnitude of the bispectrum jointly provide a better measure of the signal fluctuations and its non-Gaussianity than the power spectrum alone. We also conclude that it is important to study the sequence of sign changes along with the variations in the shape and magnitude of the bispectrum throughout the CD history to arrive at a robust conclusion about the dominant processes in the intergalactic medium at different cosmic times. We further observe that among all the possible unique k-triangles, the large-scale non-Gaussianity of the signal is best probed by the small k-triangles in the squeezed limit and by triangle shapes in its vicinity. This opens up the possibility of constraining the source parameters during the CD using the 21-cm bispectrum.
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| 5. |
- Mertens, F. G., et al.
(författare)
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Improved upper limits on the 21 cm signal power spectrum of neutral hydrogen at z approximate to 9.1 from LOFAR
- 2020
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Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 493:2, s. 1662-1685
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Tidskriftsartikel (refereegranskat)abstract
- A new upper limit on the 21 cm signal power spectrum at a redshift of z approximate to 9.1 is presented, based on 141 h of data obtained with the Low-Frequency Array (LOFAR). The analysis includes significant improvements in spectrally smooth gain-calibration, Gaussian Process Regression (GPR) foreground mitigation and optimally weighted power spectrum inference. Previously seen 'excess power' due to spectral structure in the gain solutions has markedly reduced but some excess power still remains with a spectral correlation distinct from thermal noise. This excess has a spectral coherence scale of 0.25-0.45 MHz and is partially correlated between nights, especially in the foreground wedge region. The correlation is stronger between nights covering similar local sidereal times. A best 2-sigma upper limit of Delta(2)(21) < (73)(2) mK(2) at k = 0.075 h cMpc(-1) is found, an improvement by a factor approximate to 8 in power compared to the previously reported upper limit. The remaining excess power could be due to residual foreground emission from sources or diffuse emission far away from the phase centre, polarization leakage, chromatic calibration errors, ionosphere, or low-level radiofrequency interference. We discuss future improvements to the signal processing chain that can further reduce or even eliminate these causes of excess power.
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| 6. |
- Mevius, M., et al.
(författare)
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A numerical study of 21-cm signal suppression and noise increase in direction-dependent calibration of LOFAR data
- 2021
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Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 509:3, s. 3693-3702
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Tidskriftsartikel (refereegranskat)abstract
- We investigate systematic effects in direction-dependent gain calibration in the context of the Low-Frequency Array (LOFAR) 21-cm Epoch of Reionization (EoR) experiment. The LOFAR EoR Key Science Project aims to detect the 21-cm signal of neutral hydrogen on interferometric baselines of 50–250 λ. We show that suppression of faint signals can effectively be avoided by calibrating these short baselines using only the longer baselines. However, this approach causes an excess variance on the short baselines due to small gain errors induced by overfitting during calibration. We apply a regularized expectation–maximization algorithm with consensus optimization (SAGECAL-CO) to real data with simulated signals to show that overfitting can be largely mitigated by penalising spectrally non-smooth gain solutions during calibration. This reduces the excess power with about a factor of 4 in the simulations. Our results agree with earlier theoretical analysis of this bias-variance trade off and support the gain-calibration approach to the LOFAR 21-cm signal data.
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| 7. |
- Mondal, Rajesh, et al.
(författare)
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Tight constraints on the excess radio background at z=9.1 from LOFAR
- 2020
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Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 498:3, s. 4178-4191
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Tidskriftsartikel (refereegranskat)abstract
- The ARCADE2 and LWA1 experiments have claimed an excess over the cosmic microwave background (CMB) at low radio frequencies. If the cosmological high-redshift contribution to this radio background is between 0.1 per cent and 22 per cent of the CMB at 1.42 GHz, it could explain the tentative EDGES low-band detection of the anomalously deep absorption in the 21-cm signal of neutral hydrogen. We use the upper limit on the 21-cm signal from the Epoch of Reionization (z = 9.1) based on 141 h of observations with LOFAR to evaluate the contribution of the high-redshift Universe to the detected radio background. Marginalizing over astrophysical properties of star-forming haloes, we find (at 95 per cent CL) that the cosmological radio background can be at most 9.6 per cent of the CMB at 1.42 GHz. This limit rules out strong contribution of the high-redshift Universe to the ARCADE2 and LWA1 measurements. Even though LOFAR places limit on the extra radio background, excess of 0.1-9.6 per cent over the CMB (at 1.42 GHz) is still allowed and could explain the EDGES low-band detection. We also constrain the thermal and ionization state of the gas at z = 9.1, and put limits on the properties of the first star-forming objects. We find that, in agreement with the limits from EDGES high-band data, LOFAR data constrain scenarios with inefficient X-ray sources, and cases where the Universe was ionized by stars in massive haloes only.
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