| 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. |
- Jones, Benedict C, et al.
(författare)
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To which world regions does the valence-dominance model of social perception apply?
- 2021
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Ingår i: Nature Human Behaviour. - : Springer Science and Business Media LLC. - 2397-3374. ; 5:1, s. 159-169
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Tidskriftsartikel (refereegranskat)abstract
- Over the past 10 years, Oosterhof and Todorov's valence-dominance model has emerged as the most prominent account of how people evaluate faces on social dimensions. In this model, two dimensions (valence and dominance) underpin social judgements of faces. Because this model has primarily been developed and tested in Western regions, it is unclear whether these findings apply to other regions. We addressed this question by replicating Oosterhof and Todorov's methodology across 11 world regions, 41 countries and 11,570 participants. When we used Oosterhof and Todorov's original analysis strategy, the valence-dominance model generalized across regions. When we used an alternative methodology to allow for correlated dimensions, we observed much less generalization. Collectively, these results suggest that, while the valence-dominance model generalizes very well across regions when dimensions are forced to be orthogonal, regional differences are revealed when we use different extraction methods and correlate and rotate the dimension reduction solution. PROTOCOL REGISTRATION: The stage 1 protocol for this Registered Report was accepted in principle on 5 November 2018. The protocol, as accepted by the journal, can be found at https://doi.org/10.6084/m9.figshare.7611443.v1 .
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| 3. |
- Adam, R., et al.
(författare)
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Planck 2015 results IX. Diffuse component separation : CMB maps
- 2016
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 594
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Tidskriftsartikel (refereegranskat)abstract
- We present foreground-reduced cosmic microwave background (CMB) maps derived from the full Planck data set in both temperature and polarization. Compared to the corresponding Planck 2013 temperature sky maps, the total data volume is larger by a factor of 3.2 for frequencies between 30 and 70 GHz, and by 1.9 for frequencies between 100 and 857 GHz. In addition, systematic errors in the forms of temperature-topolarization leakage, analogue-to-digital conversion uncertainties, and very long time constant errors have been dramatically reduced, to the extent that the cosmological polarization signal may now be robustly recovered on angular scales l greater than or similar to 40. On the very largest scales, instrumental systematic residuals are still non-negligible compared to the expected cosmological signal, and modes with l < 20 are accordingly suppressed in the current polarization maps by high-pass filtering. As in 2013, four different CMB component separation algorithms are applied to these observations, providing a measure of stability with respect to algorithmic and modelling choices. The resulting polarization maps have rms instrumental noise ranging between 0.21 and 0.27 mu K averaged over 55' pixels, and between 4.5 and 6.1 mu K averaged over 3.'4 pixels. The cosmological parameters derived from the analysis of temperature power spectra are in agreement at the 1 sigma level with the Planck 2015 likelihood. Unresolved mismatches between the noise properties of the data and simulations prevent a satisfactory description of the higher-order statistical properties of the polarization maps. Thus, the primary applications of these polarization maps are those that do not require massive simulations for accurate estimation of uncertainties, for instance estimation of cross-spectra and cross-correlations, or stacking analyses. However, the amplitude of primordial non-Gaussianity is consistent with zero within 2 sigma for all local, equilateral, and orthogonal configurations of the bispectrum, including for polarization E-modes. Moreover, excellent agreement is found regarding the lensing B-mode power spectrum, both internally among the various component separation codes and with the best-fit Planck 2015 Lambda cold dark matter model.
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| 4. |
- Adam, R., et al.
(författare)
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Planck 2015 results X. Diffuse component separation : Foreground maps
- 2016
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 594
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Tidskriftsartikel (refereegranskat)abstract
- Planck has mapped the microwave sky in temperature over nine frequency bands between 30 and 857 GHz and in polarization over seven frequency bands between 30 and 353 GHz in polarization. In this paper we consider the problem of diffuse astrophysical component separation, and process these maps within a Bayesian framework to derive an internally consistent set of full-sky astrophysical component maps. Component separation dedicated to cosmic microwave background (CMB) reconstruction is described in a companion paper. For the temperature analysis, we combine the Planck observations with the 9-yr Wilkinson Microwave Anisotropy Probe (WMAP) sky maps and the Haslam et al. 408 MHz map, to derive a joint model of CMB, synchrotron, free-free, spinning dust, CO, line emission in the 94 and 100 GHz channels, and thermal dust emission. Full-sky maps are provided for each component, with an angular resolution varying between 7: 5 and 1 degrees. Global parameters (monopoles, dipoles, relative calibration, and bandpass errors) are fitted jointly with the sky model, and best-fit values are tabulated. For polarization, the model includes CMB, synchrotron, and thermal dust emission. These models provide excellent fits to the observed data, with rms temperature residuals smaller than 4pK over 93% of the sky for all Planck frequencies up to 353 GHz, and fractional errors smaller than 1% in the remaining 7% of the sky. The main limitations of the temperature model at the lower frequencies are internal degeneracies among the spinning dust, free-free, and synchrotron components; additional observations from external low-frequency experiments will be essential to break these degeneracies. The main limitations of the temperature model at the higher frequencies are uncertainties in the 545 and 857 GHz calibration and zero-points. For polarization, the main outstanding issues are instrumental systematics in the 100-353 GHz bands on large angular scales in the form of temperature-to-polarization leakage, uncertainties in the analogue-to-digital conversion, and corrections for the very long time constant of the bolometer detectors, all of which are expected to improve in the near future.
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| 5. |
- Adam, R., et al.
(författare)
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Planck intermediate results XLII. Large-scale Galactic magnetic fields
- 2016
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 596
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Tidskriftsartikel (refereegranskat)abstract
- Recent models for the large-scale Galactic magnetic fields in the literature have been largely constrained by synchrotron emission and Faraday rotation measures. We use three different but representative models to compare their predicted polarized synchrotron and dust emission with that measured by the Planck satellite. We first update these models to match the Planck synchrotron products using a common model for the cosmic-ray leptons. We discuss the impact on this analysis of the ongoing problems of component separation in the Planck microwave bands and of the uncertain cosmic-ray spectrum. In particular, the inferred degree of ordering in the magnetic fields is sensitive to these systematic uncertainties, and we further show the importance of considering the expected variations in the observables in addition to their mean morphology. We then compare the resulting simulated emission to the observed dust polarization and find that the dust predictions do not match the morphology in the Planck data but underpredict the dust polarization away from the plane. We modify one of the models to roughly match both observables at high latitudes by increasing the field ordering in the thin disc near the observer. Though this specific analysis is dependent on the component separation issues, we present the improved model as a proof of concept for how these studies can be advanced in future using complementary information from ongoing and planned observational projects.
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| 6. |
- Adam, R., et al.
(författare)
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Planck intermediate results XLIII. Spectral energy distribution of dust in clusters of galaxies
- 2016
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 596
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Tidskriftsartikel (refereegranskat)abstract
- Although infrared (IR) overall dust emission from clusters of galaxies has been statistically detected using data from the Infrared Astronomical Satellite (IRAS), it has not been possible to sample the spectral energy distribution (SED) of this emission over its peak, and thus to break the degeneracy between dust temperature and mass. By complementing the IRAS spectral coverage with Planck satellite data from 100 to 857 GHz, we provide new constraints on the IR spectrum of thermal dust emission in clusters of galaxies. We achieve this by using a stacking approach for a sample of several hundred objects from the Planck cluster sample. This procedure averages out fluctuations from the IR sky, allowing us to reach a significant detection of the faint cluster contribution. We also use the large frequency range probed by Planck, together with component-separation techniques, to remove the contamination from both cosmic microwave background anisotropies and the thermal Sunyaev-Zeldovich effect (tSZ) signal, which dominate at v <= 353 GHz. By excluding dominant spurious signals or systematic effects, averaged detections are reported at frequencies 353 GHz <= v <= 5000 GHz. We confirm the presence of dust in clusters of galaxies at low and intermediate redshifts, yielding an SED with a shape similar to that of the Milky Way. Planck's resolution does not allow us to investigate the detailed spatial distribution of this emission (e.g. whether it comes from intergalactic dust or simply the dust content of the cluster galaxies), but the radial distribution of the emission appears to follow that of the stacked SZ signal, and thus the extent of the clusters. The recovered SED allows us to constrain the dust mass responsible for the signal and its temperature.
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| 7. |
- Adam, R., et al.
(författare)
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Planck intermediate results XLVII. Planck constraints on reionization history
- 2016
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 596
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Tidskriftsartikel (refereegranskat)abstract
- We investigate constraints on cosmic reionization extracted from the Planck cosmic microwave background (CMB) data. We combine the Planck CMB anisotropy data in temperature with the low-multipole polarization data to fit Lambda CDM models with various parameterizations of the reionization history. We obtain a Thomson optical depth tau = 0.058 +/- 0.012 for the commonly adopted instantaneous reionization model. This confirms, with data solely from CMB anisotropies, the low value suggested by combining Planck 2015 results with other data sets, and also reduces the uncertainties. We reconstruct the history of the ionization fraction using either a symmetric or an asymmetric model for the transition between the neutral and ionized phases. To determine better constraints on the duration of the reionization process, we also make use of measurements of the amplitude of the kinetic Sunyaev-Zeldovich (kSZ) effect using additional information from the high-resolution Atacama Cosmology Telescope and South Pole Telescope experiments. The average redshift at which reionization occurs is found to lie between z = 7.8 and 8.8, depending on the model of reionization adopted. Using kSZ constraints and a redshift-symmetric reionization model, we find an upper limit to the width of the reionization period of Delta z < 2.8. In all cases, we find that the Universe is ionized at less than the 10% level at redshifts above z similar or equal to 10. This suggests that an early onset of reionization is strongly disfavoured by the Planck data. We show that this result also reduces the tension between CMB-based analyses and constraints from other astrophysical sources.
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| 8. |
- Ade, P. A. R., et al.
(författare)
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Planck 2015 results XIV. Dark energy and modified gravity
- 2016
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 594
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Tidskriftsartikel (refereegranskat)abstract
- We study the implications of Planck data for models of dark energy (DE) and modified gravity (MG) beyond the standard cosmological constant scenario. We start with cases where the DE only directly affects the background evolution, considering Taylor expansions of the equation of state w(a), as well as principal component analysis and parameterizations related to the potential of a minimally coupled DE scalar field. When estimating the density of DE at early times, we significantly improve present constraints and find that it has to be below similar to 2% (at 95% confidence) of the critical density, even when forced to play a role for z < 50 only. We then move to general parameterizations of the DE or MG perturbations that encompass both effective field theories and the phenomenology of gravitational potentials in MG models. Lastly, we test a range of specific models, such as k-essence, f(R) theories, and coupled DE. In addition to the latest Planck data, for our main analyses, we use background constraints from baryonic acoustic oscillations, type-Ia supernovae, and local measurements of the Hubble constant. We further show the impact of measurements of the cosmological perturbations, such as redshift-space distortions and weak gravitational lensing. These additional probes are important tools for testing MG models and for breaking degeneracies that are still present in the combination of Planck and background data sets. All results that include only background parameterizations (expansion of the equation of state, early DE, general potentials in minimally-coupled scalar fields or principal component analysis) are in agreement with ACDM. When testing models that also change perturbations (even when the background is fixed to ACDM), some tensions appear in a few scenarios: the maximum one found is similar to 2 sigma for Planck TT + lowP when parameterizing observables related to the gravitational potentials with a chosen time dependence; the tension increases to, at most, 3 sigma when external data sets are included. It however disappears when including CMB lensing.
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| 9. |
- Ade, P. A. R., et al.
(författare)
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Planck 2015 results XIX. Constraints on primordial magnetic fields
- 2016
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 594
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Tidskriftsartikel (refereegranskat)abstract
- We compute and investigate four types of imprint of a stochastic background of primordial magnetic fields (PMFs) on the cosmic microwave background (CMB) anisotropies: the impact of PMFs on the CMB temperature and polarization spectra, which is related to their contribution to cosmological perturbations; the effect on CMB polarization induced by Faraday rotation; the impact of PMFs on the ionization history; magnetically-induced non-Gaussianities and related non-zero bispectra; and the magnetically-induced breaking of statistical isotropy. We present constraints on the amplitude of PMFs that are derived from different Planck data products, depending on the specific effect that is being analysed. Overall, Planck data constrain the amplitude of PMFs to less than a few nanoGauss, with different bounds that depend on the considered model. In particular, individual limits coming from the analysis of the CMB angular power spectra, using the Planck likelihood, are B-1 (Mpc) < 4.4 nG (where B1 Mpc is the comoving field amplitude at a scale of 1 Mpc) at 95% confidence level, assuming zero helicity. By considering the Planck likelihood, based only on parity-even angular power spectra, we obtain B-1 (Mpc) < 5.6 nG for a maximally helical field. For nearly scale-invariant PMFs we obtain B-1 (Mpc) < 2.0 nG and B-1 (Mpc) < 0.9 nG if the impact of PMFs on the ionization history of the Universe is included in the analysis. From the analysis of magnetically-induced non-Gaussianity, we obtain three different values, corresponding to three applied methods, all below 5 nG. The constraint from the magnetically-induced passive-tensor bispectrum is B-1 (Mpc) < 2.8 nG. A search for preferred directions in the magnetically-induced passive bispectrum yields B-1 (Mpc) < 4.5 nG, whereas the compensated-scalar bispectrum gives B-1 (Mpc) < 3 nG. The analysis of the Faraday rotation of CMB polarization by PMFs uses the Planck power spectra in EE and BB at 70 GHz and gives B-1 (Mpc) < 1380 nG. In our final analysis, we consider the harmonic-space correlations produced by Alfven waves, finding no significant evidence for the presence of these waves. Together, these results comprise a comprehensive set of constraints on possible PMFs with Planck data.
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| 10. |
- Ade, P. A. R., et al.
(författare)
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Planck 2015 results XV. Gravitational lensing
- 2016
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 594
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Tidskriftsartikel (refereegranskat)abstract
- We present the most significant measurement of the cosmic microwave background (CMB) lensing potential to date (at a level of 40 sigma), using temperature and polarization data from the Planck 2015 full-mission release. Using a polarization-only estimator, we detect lensing at a significance of 5 sigma. We cross-check the accuracy of our measurement using the wide frequency coverage and complementarity of the temperature and polarization measurements. Public products based on this measurement include an estimate of the lensing potential over approximately 70% of the sky, an estimate of the lensing potential power spectrum in bandpowers for the multipole range 40 <= L <= 400, and an associated likelihood for cosmological parameter constraints. We find good agreement between our measurement of the lensing potential power spectrum and that found in the Lambda CDM model that best fits the Planck temperature and polarization power spectra. Using the lensing likelihood alone we obtain a percent-level measurement of the parameter combination sigma(8) Omega(0.25)(m) = 0.591 +/- 0.021. We combine our determination of the lensing potential with the E-mode polarization, also measured by Planck, to generate an estimate of the lensing B-mode. We show that this lensing B-mode estimate is correlated with the B-modes observed directly by Planck at the expected level and with a statistical significance of 10 sigma, confirming Planck's sensitivity to this known sky signal. We also correlate our lensing potential estimate with the large-scale temperature anisotropies, detecting a cross-correlation at the 3 sigma level, as expected because of dark energy in the concordance Lambda CDM model.
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