| 1. |
- Chapuis, Julien, et al.
(författare)
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Genome-wide, high-content siRNA screening identifies the Alzheimer’s genetic risk factor FERMT2 as a major modulator of APP metabolism
- 2017
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Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 133:6, s. 955-966
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWASs) have identified 19 susceptibility loci for Alzheimer’s disease (AD). However, understanding how these genes are involved in the pathophysiology of AD is one of the main challenges of the “post-GWAS” era. At least 123 genes are located within the 19 susceptibility loci; hence, a conventional approach (studying the genes one by one) would not be time- and cost-effective. We therefore developed a genome-wide, high-content siRNA screening approach and used it to assess the functional impact of gene under-expression on APP metabolism. We found that 832 genes modulated APP metabolism. Eight of these genes were located within AD susceptibility loci. Only FERMT2 (a β3-integrin co-activator) was also significantly associated with a variation in cerebrospinal fluid Aβ peptide levels in 2886 AD cases. Lastly, we showed that the under-expression of FERMT2 increases Aβ peptide production by raising levels of mature APP at the cell surface and facilitating its recycling. Taken as a whole, our data suggest that FERMT2 modulates the AD risk by regulating APP metabolism and Aβ peptide production.
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| 2. |
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| 3. |
- Gratz, Lukas, et al.
(författare)
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Pathway selectivity in Frizzleds is achieved by conserved micro-switches defining pathway-determining, active conformations
- 2023
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- The class Frizzled of G protein-coupled receptors (GPCRs), consisting of ten Frizzled (FZD(1-10)) paralogs and Smoothened, remains one of the most enigmatic GPCR families. This class mediates signaling predominantly through Disheveled (DVL) or heterotrimeric G proteins. However, the mechanisms underlying pathway selection are elusive. Here we employ a structure-driven mutagenesis approach in combination with an extensive panel of functional signaling readouts to investigate the importance of conserved state-stabilizing residues in FZD(5) for signal specification. Similar data were obtained for FZD(4) and FZD(10) suggesting that our findings can be extrapolated to other members of the FZD family. Comparative molecular dynamics simulations of wild type and selected FZD(5) mutants further support the concept that distinct conformational changes in FZDs specify the signal outcome. In conclusion, we find that FZD(5) and FZDs in general prefer coupling to DVL rather than heterotrimeric G proteins and that distinct active state micro-switches in the receptor are essential for pathway selection arguing for conformational changes in the receptor protein defining transducer selectivity. Signaling pathway selectivity downstream of GPCRs is not fully understood. Here, authors perform functional analysis of Frizzled mutants to uncover state-stabilizing residues or 'micro-switches' mediating selectivity towards Disheveled over G proteins.
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| 4. |
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| 5. |
- Lambert, Julien, et al.
(författare)
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A new nonlocal thermodynamical equilibrium radiative transfer method for cool stars Method and numerical implementation
- 2015
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Ingår i: Astronomy & Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 580
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Tidskriftsartikel (refereegranskat)abstract
- Context. The solution of the nonlocal thermodynamical equilibrium (non-LTE) radiative transfer equation usually relies on stationary iterative methods, which may falsely converge in some cases. Furthermore, these methods are often unable to handle large-scale systems, such as molecular spectra emerging from, for example, cool stellar atmospheres. Aims. Our objective is to develop a new method, which aims to circumvent these problems, using nonstationary numerical techniques and taking advantage of parallel computers. Methods. The technique we develop may be seen as a generalization of the coupled escape probability method. It solves the statistical equilibrium equations in all layers of a discretized model simultaneously. The numerical scheme adopted is based on the generalized minimum residual method. Results. The code has already been applied to the special case of the water spectrum in a red supergiant stellar atmosphere. This demonstrates the fast convergence of this method, and opens the way to a wide variety of astrophysical problems.
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| 6. |
- Lambert, Julien, et al.
(författare)
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Numerical radiative transfer with state-of-the-art iterative methods made easy
- 2016
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Ingår i: European Journal of Physics. - : IOP Publishing. - 1361-6404 .- 0143-0807. ; 37:1
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Tidskriftsartikel (refereegranskat)abstract
- This article presents an on-line tool and its accompanying software resources for the numerical solution of basic radiation transfer out of local thermodynamic equilibrium (LTE). State-of-the-art stationary iterative methods such as Accelerated Lambda-iteration and Gauss-Seidel schemes, using a short characteristics-based formal solver are used. We also comment on typical numerical experiments associated to the basic non-LTE radiation problem. These resources are intended for the largest use and benefit, in support to more classical radiation transfer lectures usually given at the Master level.
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| 7. |
- Menkveld, Albert J., et al.
(författare)
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Nonstandard Errors
- 2024
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Ingår i: JOURNAL OF FINANCE. - : Wiley-Blackwell. - 0022-1082 .- 1540-6261. ; 79:3, s. 2339-2390
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Tidskriftsartikel (refereegranskat)abstract
- In statistics, samples are drawn from a population in a data-generating process (DGP). Standard errors measure the uncertainty in estimates of population parameters. In science, evidence is generated to test hypotheses in an evidence-generating process (EGP). We claim that EGP variation across researchers adds uncertainty-nonstandard errors (NSEs). We study NSEs by letting 164 teams test the same hypotheses on the same data. NSEs turn out to be sizable, but smaller for more reproducible or higher rated research. Adding peer-review stages reduces NSEs. We further find that this type of uncertainty is underestimated by participants.
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| 8. |
- Ryde, Nils, et al.
(författare)
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Systematic trend of water vapour absorption in red giant atmospheres revealed by high resolution TEXES 12 mu m spectra
- 2015
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 573
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Tidskriftsartikel (refereegranskat)abstract
- Context. The structures of the outer atmospheres of red giants are very complex. Recent interpretations of a range of different observations have led to contradictory views of these regions. It is clear, however, that classical model photospheres are inadequate to describe the nature of the outer atmospheres. The notion of large optically thick molecular spheres around the stars (MOLspheres) has been invoked in order to explain spectro-interferometric observations and low-and high-resolution spectra. On the other hand high-resolution spectra in the mid-IR do not easily fit into this picture because they rule out any large sphere of water vapour in LTE surrounding red giants. Aims. In order to approach a unified scenario for these outer regions of red giants, more empirical evidence from different diagnostics are needed. Our aim here is to investigate high-resolution, mid-IR spectra for a range of red giants, spanning spectral types from early K to mid M. We want to study how the pure rotational lines of water vapour change with effective temperature, and whether we can find common properties that can put new constraints on the modelling of these regions, so that we can gain new insights. Methods. We have recorded mid-IR spectra at 12.2-12.4 mu m at high spectral resolution of ten well-studied bright red giants, with TEXES mounted on the IRTF on Mauna Kea. These stars span effective temperatures from 3450 K to 4850 K. Results. We find that all red giants in our study cooler than 4300 K, spanning a wide range of effective temperatures (down to 3450 K), show water absorption lines stronger than expected and none are detected in emission, in line with what has been previously observed for a few stars. The strengths of the lines vary smoothly with spectral type. We identify several spectral features in the wavelength region that are undoubtedly formed in the photosphere. From a study of water-line ratios of the stars, we find that the excitation temperatures, in the line-forming regions, are several hundred Kelvin lower than expected from a classical photospheric model. Conclusions. All stars in our sample show several photospheric features in their 12 mu m spectra, which can be modelled with a classical model photosphere. However, in all stars showing water-vapour lines (stars cooler than similar to 4300 K), the water lines are found to be much deeper than expected. The line ratios of these pure-rotational lines reveal low excitation temperatures. This could either be due to lower temperatures than expected in the outer regions of the photospheres caused by for example extra cooling, or due to non-LTE level populations, affecting the source function and line opacities, but this needs further investigation. We have demonstrated that these diagnostically interesting water lines are a general feature of red giants across spectral types, and we argue for a general explanation of their formation rather than explanations requiring specific properties, such as dust. Since the water lines are neither weak (filled in by emission) nor do they appear in emission, as predicted by LTE MOLsphere models in their simplest forms, the evidence of the existence of such large optically-thick, molecular spheres enshrouding the stars is weakened. It is still a challenge to find a unifying picture of the outer regions of the atmospheres of red giants, but we have presented new empirical evidence that needs to be taken into account and explained in any model of these regions.
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| 9. |
- Vodungbo, Boris, et al.
(författare)
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Indirect excitation of ultrafast demagnetization.
- 2016
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Does the excitation of ultrafast magnetization require direct interaction between the photons of the optical pump pulse and the magnetic layer? Here, we demonstrate unambiguously that this is not the case. For this we have studied the magnetization dynamics of a ferromagnetic cobalt/palladium multilayer capped by an IR-opaque aluminum layer. Upon excitation with an intense femtosecond-short IR laser pulse, the film exhibits the classical ultrafast demagnetization phenomenon although only a negligible number of IR photons penetrate the aluminum layer. In comparison with an uncapped cobalt/palladium reference film, the initial demagnetization of the capped film occurs with a delayed onset and at a slower rate. Both observations are qualitatively in line with energy transport from the aluminum layer into the underlying magnetic film by the excited, hot electrons of the aluminum film. Our data thus confirm recent theoretical predictions.
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| 11. |
- Weisshaar, E, et al.
(författare)
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European S2k Guideline on Chronic Pruritus.
- 2019
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Ingår i: Acta Dermato-Venereologica. - : Medical Journals Sweden AB. - 1651-2057 .- 0001-5555. ; 99:5, s. 469-506
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Tidskriftsartikel (refereegranskat)
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