| 1. |
- Vergallo, A., et al.
(författare)
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Association of plasma YKL-40 with brain amyloid-β levels, memory performance, and sex in subjective memory complainers
- 2020
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Ingår i: Neurobiology of Aging. - : Elsevier BV. - 0197-4580. ; 96, s. 22-32
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Tidskriftsartikel (refereegranskat)abstract
- Neuroinflammation, a key early pathomechanistic alteration of Alzheimer's disease, may represent either a detrimental or a compensatory mechanism or both (according to the disease stage). YKL-40, a glycoprotein highly expressed in differentiated glial cells, is a candidate biomarker for in vivo tracking neuroinflammation in humans. We performed a longitudinal study in a monocentric cohort of cognitively healthy individuals at risk for Alzheimer's disease exploring whether age, sex, and the apolipoprotein E ε4 allele affect plasma YKL-40 concentrations. We investigated whether YKL-40 is associated with brain amyloid-β (Aβ) deposition, neuronal activity, and neurodegeneration as assessed via neuroimaging biomarkers. Finally, we investigated whether YKL-40 may predict cognitive performance. We found an age-associated increase of YKL-40 and observed that men display higher concentrations than women, indicating a potential sexual dimorphism. Moreover, YKL-40 was positively associated with memory performance and negatively associated with brain Aβ deposition (but not with metabolic signal). Consistent with translational studies, our results suggest a potentially protective effect of glia on incipient brain Aβ accumulation and neuronal homeostasis. © 2020 Elsevier Inc.
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| 2. |
- Bonavita, M., et al.
(författare)
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New binaries from the SHINE survey
- 2022
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 663
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Tidskriftsartikel (refereegranskat)abstract
- We present the multiple stellar systems observed within the SpHere INfrared survey for Exoplanet (SHINE). SHINE searched for sub-stellar companions to young stars using high contrast imaging. Although stars with known stellar companions within the SPHERE field of view (< 5.5 arcsec) were removed from the original target list, we detected additional stellar companions to 78 of the 463 SHINE targets observed so far. Twenty-seven per cent of the systems have three or more components. Given the heterogeneity of the sample in terms of observing conditions and strategy, tailored routines were used for data reduction and analysis, some of which were specifically designed for these datasets. We then combined SPHERE data with literature and archival data, TESS light curves, and Gaia parallaxes and proper motions for an accurate characterisation of the systems. Combining all data, we were able to constrain the orbits of 25 systems. We carefully assessed the completeness of our sample for separations between 50–500 mas (corresponding to periods of a few years to a few decades), taking into account the initial selection biases and recovering part of the systems excluded from the original list due to their multiplicity. This allowed us to compare the binary frequency for our sample with previous studies and highlight interesting trends in the mass ratio and period distribution. We also found that, when such an estimate was possible, the values of the masses derived from dynamical arguments were in good agreement with the model predictions. Stellar and orbital spins appear fairly well aligned for the 12 stars that have enough data, which favours a disk fragmentation origin. Our results highlight the importance of combining different techniques when tackling complex problems such as the formation of binaries and show how large samples can be useful for more than one purpose.
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| 3. |
- Gratton, R., et al.
(författare)
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Investigating three Sirius-like systems with SPHERE
- 2021
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 646
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Tidskriftsartikel (refereegranskat)abstract
- Context. Sirius-like systems are relatively wide binaries with a separation from a few to hundreds of au; they are composed of a white dwarf (WD) and a companion of a spectral type earlier than M0. Here we consider main sequence (MS) companions, where the WD progenitor evolves in isolation, but its wind during the former asymptotic giant branch (AGB) phase pollutes the companion surface and transfers some angular momentum. They are rich laboratories to constrain stellar models and binary evolution.Aims. Within the SpHere INfrared survey for Exoplanet survey that uses the Spectro-Polarimetric High-contrast Exoplanet REsearch (SPHERE) instrument at the Very Large Telescope, our goal is to acquire high contrast multi-epoch observations of three Sirius-like systems, HD 2133, HD 114174, and CD-56 7708 and to combine this data with archive high resolution spectra of the primaries, TESS archive, and literature data.Methods. These WDs are easy targets for SPHERE and were used as spectrophotometric standards. We performed very accurate abundance analyses for the MS stars using methods considered for solar analogs. Whenever possible, WD parameters and orbits were obtained using Monte Carlo Markov chain methods.Results. We found brighter J and K magnitudes for HD 114174B than obtained previously and extended the photometry down to 0.95 μm. Our new data indicate a higher temperature and then shorter cooling age (5.57 ± 0.02 Gyr) and larger mass (0.75 ± 0.03 M⊙) for this WD than previously assumed. Together with the oldest age for the MS star connected to the use of the Gaia DR2 distance, this solved the discrepancy previously found with the age of the MS star. The two other WDs are less massive, indicating progenitors of ∼1.3 M⊙ and 1.5 − 1.8 M⊙ for HD 2133B and CD-56 7708B, respectively. In spite of the rather long periods, we were able to derive useful constraints on the orbit for HD 114174 and CD-56 7708. They are both seen close to edge-on, which is in agreement with the inclination of the MS stars that are obtained coupling the rotational periods, stellar radii, and the projected rotational velocity from spectroscopy. The composition of the MS stars agrees fairly well with expectations from pollution by the AGB progenitors of the WDs: HD 2133A has a small enrichment of n-capture elements, which is as expected for pollution by an AGB star with an initial mass < 1.5 M⊙; CD-56 7708A is a previously unrecognized mild Ba-star, which is also expected due to pollution by an AGB star with an initial mass in the range of 1.5 − 3.0 M⊙; and HD 114174 has a very moderate excess of n-capture elements, which is in agreement with the expectation for a massive AGB star to have an initial mass > 3.0 M⊙.Conclusions. On the other hand, none of these stars show the excesses of C that are expected to go along with those of n-capture elements. This might be related to the fact that these stars are at the edges of the mass range where we expect nucleosynthesis related to thermal pulses. More work, both theoretical and observational, is required to better understand this issue.
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| 4. |
- Vergallo, A., et al.
(författare)
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Plasma amyloid beta 40/42 ratio predicts cerebral amyloidosis in cognitively normal individuals at risk for Alzheimer's disease
- 2019
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Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 15:6, s. 764-775
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Blood-based biomarkers of pathophysiological brain amyloid beta (A beta) accumulation, particularly for preclinical target and large-scale interventions, are warranted to effectively enrich Alzheimer's disease clinical trials and management. Methods: We investigated whether plasma concentrations of the A beta(1-40)/A beta(1-42) ratio, assessed using the single-molecule array (Simoa) immunoassay, may predict brain A beta positron emission tomography status in a large-scale longitudinal monocentric cohort (N = 276) of older individuals with subjective memory complaints. We performed a hypothesis-driven investigation followed by a no-apriori hypothesis study using machine learning. Results: The receiver operating characteristic curve and machine learning showed a balanced accuracy of 76.5% and 81%, respectively, for the plasma A beta(1-40)/A beta(1-42) ratio. The accuracy is not affected by the apolipoprotein E (APOE) epsilon 4 allele, sex, or age. Discussion: Our results encourage an independent validation cohort study to confirm the indication that the plasma A beta(1-40)/A beta(1-42) ratio, assessed via Simoa, may improve future standard of care and clinical trial design. (C) 2019 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.
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| 5. |
- Desgrange, C., et al.
(författare)
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In-depth direct imaging and spectroscopic characterization of the young Solar System analog HD 95086
- 2022
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 664
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Tidskriftsartikel (refereegranskat)abstract
- Context. HD 95086 is a young nearby Solar System analog hosting a giant exoplanet orbiting at 57 au from the star between an inner and outer debris belt. The existence of additional planets has been suggested as the mechanism that maintains the broad cavity between the two belts.Aims. We present a dedicated monitoring of HD 95086 with the VLT/SPHERE instrument to refine the orbital and atmospheric properties of HD 95086 b, and to search for additional planets in this system.Methods. SPHERE observations, spread over ten epochs from 2015 to 2019 and including five new datasets, were used. Combined with archival observations, from VLT/NaCo (2012-2013) and Gemini/GPI (2013-2016), the extended set of astrometric measurements allowed us to refine the orbital properties of HD 95086 b. We also investigated the spectral properties and the presence of a circumplanetary disk around HD 95086 b by using the special fitting tool exploring the diversity of several atmospheric models. In addition, we improved our detection limits in order to search for a putative planet c via the K-Stacker algorithm.Results. We extracted for the first time the JH low-resolution spectrum of HD 95086 b by stacking the six best epochs, and confirm its very red spectral energy distribution. Combined with additional datasets from GPI and NaCo, our analysis indicates that this very red color can be explained by the presence of a circumplanetary disk around planet b, with a range of high-temperature solutions (1400–1600 K) and significant extinction (Av ≳ 10 mag), or by a super-solar metallicity atmosphere with lower temperatures (800–300 K), and small to medium amount of extinction (Av ≲ 10 mag). We do not find any robust candidates for planet c, but give updated constraints on its potential mass and location.
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| 6. |
- Gratton, R., et al.
(författare)
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Searching for the near-infrared counterpart of Proxima c using multi-epoch high-contrast SPHERE data at VLT
- 2020
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 638
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Tidskriftsartikel (refereegranskat)abstract
- Context. Proxima Centauri is the closest star to the Sun and it is known to host an Earth-like planet in its habitable zone; very recently a second candidate planet was proposed based on radial velocities. At quadrature, the expected projected separation of this new candidate is larger than 1 arcsec, making it a potentially interesting target for direct imaging.Aims. While identification of the optical counterpart of this planet is expected to be very difficult, successful identification would allow for a detailed characterization of the closest planetary system.Methods. We searched for a counterpart in SPHERE images acquired over four years through the SHINE survey. In order to account for the expected large orbital motion of the planet, we used a method that assumes the circular orbit obtained from radial velocities and exploits the sequence of observations acquired close to quadrature in the orbit. We checked this with a more general approach that considers Keplerian motion, called K-stacker.Results. We did not obtain a clear detection. The best candidate has signal-to-noise ratio (S/N) = 6.1 in the combined image. A statistical test suggests that the probability that this detection is due to random fluctuation of noise is <1%, but this result depends on the assumption that the distribution of noise is uniform over the image, a fact that is likely not true. The position of this candidate and the orientation of its orbital plane fit well with observations in the ALMA 12 m array image. However, the astrometric signal expected from the orbit of the candidate we detected is 3 away from the astrometric motion of Proxima as measured from early Gaia data. This, together with the unexpectedly high flux associated with our direct imaging detection, means we cannot confirm that our candidate is indeed Proxima c.Conclusions. On the other hand, if confirmed, this would be the first observation in imaging of a planet discovered from radial velocities and the second planet (after Fomalhaut b) of reflecting circumplanetary material. Further confirmation observations should be done as soon as possible.
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| 7. |
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| 8. |
- Hanbouch, L., et al.
(författare)
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Specific Mutations in the Cholesterol-Binding Site of APP Alter Its Processing and Favor the Production of Shorter, Less Toxic A beta Peptides
- 2022
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Ingår i: Molecular Neurobiology. - : Springer Science and Business Media LLC. - 0893-7648 .- 1559-1182. ; 59, s. 7056-7073
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Tidskriftsartikel (refereegranskat)abstract
- Excess brain cholesterol is strongly implicated in the pathogenesis of Alzheimer's disease (AD). Here we evaluated how the presence of a cholesterol-binding site (CBS) in the transmembrane and juxtamembrane regions of the amyloid precursor protein (APP) regulates its processing. We generated nine point mutations in the APP gene, changing the charge and/or hydrophobicity of the amino-acids which were previously shown as part of the CBS. Most mutations triggered a reduction of amyloid-beta peptides A beta 40 and A beta 42 secretion from transiently transfected HEK293T cells. Only the mutations at position 28 of A beta in the APP sequence resulted in a concomitant significant increase in the production of shorter A beta peptides. Mass spectrometry (MS) confirmed the predominance of A beta x-33 and A beta x-34 with the APP(K28A) mutant. The enzymatic activity of alpha-, beta-, and gamma-secretases remained unchanged in cells expressing all mutants. Similarly, subcellular localization of the mutants in early endosomes did not differ from the APP(WT) protein. A transient increase of plasma membrane cholesterol enhanced the production of A beta 40 and A beta 42 by APP(WT), an effect absent in APP(K28A) mutant. Finally, WT but not CBS mutant A beta derived peptides bound to cholesterol-rich exosomes. Collectively, the present data revealed a major role of juxtamembrane amino acids of the APP CBS in modulating the production of toxic A beta species. More generally, they underpin the role of cholesterol in the pathophysiology of AD.
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| 9. |
- Lemercier, P., et al.
(författare)
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Association of plasma A beta 40/A beta 42 ratio and brain A beta accumulation: testing a whole-brain PLS-VIP approach in individuals at risk of Alzheimer's disease
- 2021
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Ingår i: Neurobiology of Aging. - : Elsevier BV. - 0197-4580. ; 107, s. 57-69
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Tidskriftsartikel (refereegranskat)abstract
- Molecular and brain regional/network-wise pathophysiological changes at preclinical stages of Alzheimer's disease (AD) have primarily been found through knowledge-based studies conducted in late-stage mild cognitive impairment/dementia populations. However, such an approach may compromise the objective of identifying the earliest spatial-temporal pathophysiological processes. We investigated 261 individuals with subjective memory complaints, a condition at increased risk of AD, to test a whole-brain, non-a-priori method based on partial least squares in unraveling the association between plasma A beta 42/A beta 40 ratio and an extensive set of brain regions characterized through molecular imaging of A beta accumulation and cortical metabolism. Significant associations were mapped onto large-scale networks, identified through an atlas and by knowledge, to elaborate on the reliability of the results. Plasma A beta 42/beta 40 ratio was associated with A beta-PET uptake (but not FDG-PET) in regions generally investigated in preclinical AD such as those belonging to the default mode network, but also in regions/networks normally not accounted including the central executive and salience networks which likely have a selective vulnerability to incipient A beta accumulation. The present whole-brain approach is promising to investigate early pathophysiological changes of AD to fully capture the complexity of the disease, which is essential to develop timely screening, detection, diagnostic, and therapeutic interventions. (C) 2021 Elsevier Inc. All rights reserved.
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| 10. |
- Gagnon, Keith T., et al.
(författare)
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Allele-Selective Inhibition of Mutant Huntingtin Expression with Antisense Oligonucleotides Targeting the Expanded CAG Repeat
- 2010
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Ingår i: Biochemistry. - : American Chemical Society (ACS). - 0006-2960 .- 1520-4995. ; 49:47, s. 10166-10178
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Tidskriftsartikel (refereegranskat)abstract
- Huntington's disease (HD) is a currently incurable neurodegenerative disease caused by the expansion of a CAG trinucleotide repeat within the huntingtin (HTT) gene. Therapeutic approaches include selectively inhibiting the expression of the mutated HTT allele while conserving function of the normal allele. We have evaluated a series of antisense oligonucleotides (ASOs) targeted to the expanded CAG repeat within HTT mRNA for their ability to selectively inhibit expression of mutant HTT protein. Several ASOs incorporating a variety of modifications, including bridged nucleic acids and phosphorothioate internucleotide linkages, exhibited allele-selective silencing in patient-derived fibroblasts. Allele-selective ASOs did not affect the expression of other CAG repeat-containing genes and selectivity was observed in cell lines containing minimal CAG repeat lengths representative of most HD patients. Allele-selective ASOs left HTT mRNA intact and did not support ribonuclease H activity in vitro. We observed cooperative binding of multiple ASO molecules to CAG repeat-containing HTT mRNA transcripts in vitro. These results are consistent with a mechanism involving inhibition at the level of translation. ASOs targeted to the CAG repeat of HTT provide a starting point for the development of oligonucleotide-based therapeutics that can inhibit gene expression with allelic discrimination in patients with HD.
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