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| 2. |
- Hamdi, Yosr, et al.
(författare)
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Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression : identification of a modifier of breast cancer risk at locus 11q22.3
- 2017
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Ingår i: Breast Cancer Research and Treatment. - : Springer Science and Business Media LLC. - 0167-6806 .- 1573-7217. ; 161:1, s. 117-134
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Cis-acting regulatory SNPs resulting in differential allelic expression (DAE) may, in part, explain the underlying phenotypic variation associated with many complex diseases. To investigate whether common variants associated with DAE were involved in breast cancer susceptibility among BRCA1 and BRCA2 mutation carriers, a list of 175 genes was developed based of their involvement in cancer-related pathways. Methods: Using data from a genome-wide map of SNPs associated with allelic expression, we assessed the association of ~320 SNPs located in the vicinity of these genes with breast and ovarian cancer risks in 15,252 BRCA1 and 8211 BRCA2 mutation carriers ascertained from 54 studies participating in the Consortium of Investigators of Modifiers of BRCA1/2. Results: We identified a region on 11q22.3 that is significantly associated with breast cancer risk in BRCA1 mutation carriers (most significant SNP rs228595 p = 7 × 10−6). This association was absent in BRCA2 carriers (p = 0.57). The 11q22.3 region notably encompasses genes such as ACAT1, NPAT, and ATM. Expression quantitative trait loci associations were observed in both normal breast and tumors across this region, namely for ACAT1, ATM, and other genes. In silico analysis revealed some overlap between top risk-associated SNPs and relevant biological features in mammary cell data, which suggests potential functional significance. Conclusion: We identified 11q22.3 as a new modifier locus in BRCA1 carriers. Replication in larger studies using estrogen receptor (ER)-negative or triple-negative (i.e., ER-, progesterone receptor-, and HER2-negative) cases could therefore be helpful to confirm the association of this locus with breast cancer risk.
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| 3. |
- Zeng, Chenjie, et al.
(författare)
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Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus
- 2016
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Ingår i: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 18
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Tidskriftsartikel (refereegranskat)abstract
- Background: Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk. Method: We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation. Results: Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06-1.12; P = 3 x 10(-9)), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 x 10(-5)), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 x 10(-4)) identified in the general populations, and rs113824616 (P = 7 x 10(-5)) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P < 0.05. Conclusion: This study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk.
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| 4. |
- Baum, Matthew L, et al.
(författare)
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CSMD1 regulates brain complement activity and circuit development
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Ingår i: Brain, Behavior, and Immunity. - 1090-2139.
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Tidskriftsartikel (refereegranskat)abstract
- Complement proteins facilitate synaptic elimination during neurodevelopmental pruning, but neural complement regulation is not well understood. CUB and Sushi Multiple Domains 1 (CSMD1) can regulate complement activity in vitro, is expressed in the brain, and is associated with increased schizophrenia risk. Beyond this, little is known about CSMD1 including whether it regulates complement activity in the brain or otherwise plays a role in neurodevelopment. We used biochemical, immunohistochemical, and proteomic techniques to examine the regional, cellular, and subcellular distribution as well as protein interactions of CSMD1 in the brain. To evaluate whether CSMD1 is involved in complement-mediated synapse elimination, we examined Csmd1-knockout mice and CSMD1-knockout human stem cell-derived neurons. We interrogated synapse and circuit development of the mouse visual thalamus, a process that involves complement pathway activity. We also quantified complement deposition on synapses in mouse visual thalamus and on cultured human neurons. Finally, we assessed uptake of synaptosomes by cultured microglia. We found that CSMD1 is present at synapses and interacts with complement proteins in the brain. Mice lacking Csmd1 displayed increased levels of complement component C3, an increased colocalization of C3 with presynaptic terminals, fewer retinogeniculate synapses, and aberrant segregation of eye-specific retinal inputs to the visual thalamus during the critical period of complement-dependent refinement of this circuit. Loss of CSMD1 in vivo enhanced synaptosome engulfment by microglia in vitro, and this effect was dependent on activity of the microglial complement receptor, CR3. Finally, human stem cell-derived neurons lacking CSMD1 were more vulnerable to complement deposition. These data suggest that CSMD1 can function as a regulator of complement-mediated synapse elimination in the CNS during development.
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| 5. |
- Benseguane, Selma, et al.
(författare)
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Evolution of pits at the surface of 67P/Churyumov-Gerasimenko
- 2022
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 668
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Tidskriftsartikel (refereegranskat)abstract
- Context. The observation of pits at the surface of comets offers the opportunity to take a glimpse into the properties and the mechanisms that shape a nucleus through cometary activity. If the origin of these pits is still a matter of debate, multiple studies have recently suggested that known phase transitions (such as volatile sublimation or amorphous water ice crystallization) alone could not have carved these morphological features on the surface of 67P/Churyumov-Gerasimenko (hereafter 67P).Aims. We want to understand how the progressive modification of 67P' s surface due to cometary activity might have affected the characteristics of pits and alcoves. In particular, we aim to understand whether signatures of the formation mechanism of these surface morphological features can still be identified.Methods. To quantify the amount of erosion sustained at the surface of 67P since it arrived on its currently observed orbit, we selected 380 facets of a medium-resolution shape model of the nucleus, sampling 30 pits and alcoves across the surface. We computed the surface energy balance with a high temporal resolution, including shadowing and self-heating contributions. We then applied a thermal evolution model to assess the amount of erosion sustained after ten orbital revolutions under current illumination conditions.Results. We find that the maximum erosion sustained after ten orbital revolutions is on the order of 80 m, for facets located in the southern hemisphere. We thus confirm that progressive erosion cannot form pits and alcoves, as local erosion is much lower than their observed depth and diameter. We find that plateaus tend to erode more than bottoms, especially for the deepest depressions, and that some differential erosion can affect their morphology. As a general rule, our results suggest that sharp morphological features tend to be erased by progressive erosion.Conclusions. This study supports the assumption that deep circular pits, such as Seth_01, are the least processed morphological features at the surface of 67P, or the best preserved since their formation.
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| 6. |
- Bergman, Sofia, 1991-, et al.
(författare)
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Flow directions of low-energy ions in and around the diamagnetic cavity of comet 67P
- 2021
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Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press. - 0035-8711 .- 1365-2966. ; 507:4, s. 4900-4913
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Tidskriftsartikel (refereegranskat)abstract
- The flow direction of low-energy ions around comet 67P/Churyumov–Gerasimenko has previously been difficult to constrain due to the influence of the spacecraft potential. The Ion Composition Analyzer of the Rosetta Plasma Consortium (RPC-ICA) on Rosetta measured the distribution function of positive ions with energies down to just a few eV/q throughout the escort phase ofthe mission. Unfortunately, the substantial negative spacecraft potential distorted the directional information of the low-energy data. In this work, we present the flow directions of low-energy ions around comet 67P, corrected for the spacecraft potential using Particle-In-Cell simulation results. We focus on the region in and around the diamagnetic cavity, where low-energy ions are especially important for the dynamics. We separate between slightly accelerated ‘burst’ features and a more constant ‘band’ of low-energy ions visible in the data. The ‘bursts’ are flowing radially outwards from the nucleus with an antisunward component while the ‘band’ is predominantly streaming back towards the comet. This provides evidence of counter-streaming ions, which has implications for the overall expansion velocity of the ions. The backstreaming ions are present also at times when the diamagnetic cavity was not detected, indicating that the process accelerating the ions back towards the comet is not connected to the cavity boundary.
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| 7. |
- Beth, Arnaud, et al.
(författare)
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First investigation of the diamagnetic cavity boundary layer with a 1D3V PIC simulation
- 2022
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 667
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Tidskriftsartikel (refereegranskat)abstract
- Context: Amongst the different features and boundaries encountered around comets, one remains of particular interest to the plasma community: the diamagnetic cavity. Crossed for the first time at 1P/Halley during the Giotto flyby in 1986 and later met more than 700 times by the ESA Rosetta spacecraft around Comet 67P/Churyumov-Gerasimenko, this region, almost free of any magnetic field, surrounds nuclei of active comets. However, previous observations and modelling of this part of the coma have not yet provided a definitive answer as to the origin of such a cavity and on its border, the diamagnetic cavity boundary layer.Aims: We investigate which forces and equilibrium might be at play and balance the magnetic pressure at this boundary down to the spatial and temporal scales of the electrons in the 1D collisionless case. In addition, we scrutinise assumptions made in magneto-hydrodynamic and hybrid simulations of this environment and check for their validity.Methods: We simulated this region at the electron scale by means of 1D3V particle-in-cell simulations and SMILEI code.Results: Across this layer, depending on the magnetic field strength, the electric field is governed by different equilibria, with a thin double-layer forming ahead. In addition, we show that the electron distribution function departs from Maxwellian and/or gyrotropic distributions and that electrons do not behave adiabatically. We demonstrate the need to investigate this region at the electron scale in depth with fully kinetic simulations.
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| 8. |
- Beth, Arnaud, et al.
(författare)
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ROSINA ion zoo at Comet 67P
- 2020
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 642
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Tidskriftsartikel (refereegranskat)abstract
- Context: The Rosetta spacecraft escorted Comet 67P/Churyumov-Gerasimenko for 2 yr along its journey through the Solar System between 3.8 and 1.24 au. Thanks to the high resolution mass spectrometer on board Rosetta, the detailed ion composition within a coma has been accurately assessed in situ for the very first time.Aims: Previous cometary missions, such as Giotto, did not have the instrumental capabilities to identify the exact nature of the plasma in a coma because the mass resolution of the spectrometers onboard was too low to separate ion species with similar masses. In contrast, the Double Focusing Mass Spectrometer (DFMS), part of the Rosetta Orbiter Spectrometer for Ion and Neutral Analysis on board Rosetta (ROSINA), with its high mass resolution mode, outperformed all of them, revealing the diversity of cometary ions.Methods: We calibrated and analysed the set of spectra acquired by DFMS in ion mode from October 2014 to April 2016. In particular, we focused on the range from 13–39 u q−1. The high mass resolution of DFMS allows for accurate identifications of ions with quasi-similar masses, separating 13C+ from CH+, for instance.Results: We confirm the presence in situ of predicted cations at comets, such as CHm+ (m = 1−4), HnO+ (n = 1−3), O+, Na+, and several ionised and protonated molecules. Prior to Rosetta, only a fraction of them had been confirmed from Earth-based observations. In addition, we report for the first time the unambiguous presence of a molecular dication in the gas envelope of a Solar System body, namely CO2++.
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| 9. |
- Deca, Jan, et al.
(författare)
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Building a Weakly Outgassing Comet from a Generalized Ohm's Law
- 2019
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Ingår i: Physical Review Letters. - : AMER PHYSICAL SOC. - 0031-9007 .- 1079-7114. ; 123:5
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Tidskriftsartikel (refereegranskat)abstract
- When a weakly outgassing comet is sufficiently close to the Sun, the formation of an ionized coma results in solar wind mass loading and magnetic field draping around its nucleus. Using a 3D fully kinetic approach, we distill the components of a generalized Ohm's law and the effective electron equation of state directly from the self-consistently simulated electron dynamics and identify the driving physics in the various regions of the cometary plasma environment. Using the example of space plasmas, in particular multispecies cometary plasmas, we show how the description for the complex kinetic electron dynamics can be simplified through a simple effective closure, and identify where an isotropic single-electron fluid Ohm's law approximation can be used, and where it fails.
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| 10. |
- Goetz, Charlotte, et al.
(författare)
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The plasma environment of comet 67P/Churyumov-Gerasimenko
- 2022
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Ingår i: Space Science Reviews. - : Springer. - 0038-6308 .- 1572-9672. ; 218:8
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Forskningsöversikt (refereegranskat)abstract
- The environment of a comet is a fascinating and unique laboratory to study plasma processes and the formation of structures such as shocks and discontinuities from electron scales to ion scales and above. The European Space Agency's Rosetta mission collected data for more than two years, from the rendezvous with comet 67P/Churyumov-Gerasimenko in August 2014 until the final touch-down of the spacecraft end of September 2016. This escort phase spanned a large arc of the comet's orbit around the Sun, including its perihelion and corresponding to heliocentric distances between 3.8 AU and 1.24 AU. The length of the active mission together with this span in heliocentric and cometocentric distances make the Rosetta data set unique and much richer than sets obtained with previous cometary probes. Here, we review the results from the Rosetta mission that pertain to the plasma environment. We detail all known sources and losses of the plasma and typical processes within it. The findings from in-situ plasma measurements are complemented by remote observations of emissions from the plasma. Overviews of the methods and instruments used in the study are given as well as a short review of the Rosetta mission. The long duration of the Rosetta mission provides the opportunity to better understand how the importance of these processes changes depending on parameters like the outgassing rate and the solar wind conditions. We discuss how the shape and existence of large scale structures depend on these parameters and how the plasma within different regions of the plasma environment can be characterised. We end with a non-exhaustive list of still open questions, as well as suggestions on how to answer them in the future.
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