| 1. |
- Aad, G, et al.
(author)
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- 2015
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swepub:Mat__t
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| 2. |
- Chelban, V., et al.
(author)
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PDXK mutations cause polyneuropathy responsive to pyridoxal 5′-phosphate supplementation
- 2019
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In: Annals of Neurology. - : Wiley. - 0364-5134 .- 1531-8249. ; 86:2, s. 225-240
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Journal article (peer-reviewed)abstract
- Objective: To identify disease-causing variants in autosomal recessive axonal polyneuropathy with optic atrophy and provide targeted replacement therapy. Methods: We performed genome-wide sequencing, homozygosity mapping, and segregation analysis for novel disease-causing gene discovery. We used circular dichroism to show secondary structure changes and isothermal titration calorimetry to investigate the impact of variants on adenosine triphosphate (ATP) binding. Pathogenicity was further supported by enzymatic assays and mass spectroscopy on recombinant protein, patient-derived fibroblasts, plasma, and erythrocytes. Response to supplementation was measured with clinical validated rating scales, electrophysiology, and biochemical quantification. Results: We identified biallelic mutations in PDXK in 5 individuals from 2 unrelated families with primary axonal polyneuropathy and optic atrophy. The natural history of this disorder suggests that untreated, affected individuals become wheelchair-bound and blind. We identified conformational rearrangement in the mutant enzyme around the ATP-binding pocket. Low PDXK ATP binding resulted in decreased erythrocyte PDXK activity and low pyridoxal 5′-phosphate (PLP) concentrations. We rescued the clinical and biochemical profile with PLP supplementation in 1 family, improvement in power, pain, and fatigue contributing to patients regaining their ability to walk independently during the first year of PLP normalization. Interpretation: We show that mutations in PDXK cause autosomal recessive axonal peripheral polyneuropathy leading to disease via reduced PDXK enzymatic activity and low PLP. We show that the biochemical profile can be rescued with PLP supplementation associated with clinical improvement. As B6 is a cofactor in diverse essential biological pathways, our findings may have direct implications for neuropathies of unknown etiology characterized by reduced PLP levels. ANN NEUROL 2019;86:225–240. © 2019 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.
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| 3. |
- Zouganelis, I., et al.
(author)
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The Solar Orbiter Science Activity Plan : Translating solar and heliospheric physics questions into action
- 2020
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In: Astronomy and Astrophysics. - : EDP SCIENCES S A. - 0004-6361 .- 1432-0746. ; 642
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Journal article (peer-reviewed)abstract
- Solar Orbiter is the first space mission observing the solar plasma both in situ and remotely, from a close distance, in and out of the ecliptic. The ultimate goal is to understand how the Sun produces and controls the heliosphere, filling the Solar System and driving the planetary environments. With six remote-sensing and four in-situ instrument suites, the coordination and planning of the operations are essential to address the following four top-level science questions: (1) What drives the solar wind and where does the coronal magnetic field originate?; (2) How do solar transients drive heliospheric variability?; (3) How do solar eruptions produce energetic particle radiation that fills the heliosphere?; (4) How does the solar dynamo work and drive connections between the Sun and the heliosphere? Maximising the mission's science return requires considering the characteristics of each orbit, including the relative position of the spacecraft to Earth (affecting downlink rates), trajectory events (such as gravitational assist manoeuvres), and the phase of the solar activity cycle. Furthermore, since each orbit's science telemetry will be downloaded over the course of the following orbit, science operations must be planned at mission level, rather than at the level of individual orbits. It is important to explore the way in which those science questions are translated into an actual plan of observations that fits into the mission, thus ensuring that no opportunities are missed. First, the overarching goals are broken down into specific, answerable questions along with the required observations and the so-called Science Activity Plan (SAP) is developed to achieve this. The SAP groups objectives that require similar observations into Solar Orbiter Observing Plans, resulting in a strategic, top-level view of the optimal opportunities for science observations during the mission lifetime. This allows for all four mission goals to be addressed. In this paper, we introduce Solar Orbiter's SAP through a series of examples and the strategy being followed.
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| 4. |
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| 5. |
- Bercic, L., et al.
(author)
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Whistler instability driven by the sunward electron deficit in the solar wind High-cadence Solar Orbiter observations
- 2021
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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 656
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Journal article (peer-reviewed)abstract
- Context. Solar wind electrons play an important role in the energy balance of the solar wind acceleration by carrying energy into interplanetary space in the form of electron heat flux. The heat flux is stored in the complex electron velocity distribution functions (VDFs) shaped by expansion, Coulomb collisions, and field-particle interactions. Aims. We investigate how the suprathermal electron deficit in the anti-strahl direction, which was recently discovered in the near-Sun solar wind, drives a kinetic instability and creates whistler waves with wave vectors that are quasi-parallel to the direction of the background magnetic field.Methods. We combined high-cadence measurements of electron pitch-angle distribution functions and electromagnetic waves provided by Solar Orbiter during its first orbit. Our case study is based on a burst-mode data interval from the Electrostatic Analyser System (SWA-EAS) at a distance of 112 R-S (0.52 au) from the Sun, during which several whistler wave packets were detected by Solar Orbiter's Radio and Plasma Waves (RPW) instrument.Results. The sunward deficit creates kinetic conditions under which the quasi-parallel whistler wave becomes unstable. We directly test our predictions for the existence of these waves through solar wind observations. We find whistler waves that are quasi-parallel and almost circularly polarised, propagating away from the Sun, coinciding with a pronounced sunward deficit in the electron VDF. The cyclotron-resonance condition is fulfilled for electrons moving in the direction opposite to the direction of wave propagation, with energies corresponding to those associated with the sunward deficit.Conclusions. We conclude that the sunward deficit acts as a source of quasi-parallel whistler waves in the solar wind. The quasilinear diffusion of the resonant electrons tends to fill the deficit, leading to a reduction in the total electron heat flux.
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| 6. |
- Brown, C, et al.
(author)
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A systematic review of miRNAs as biomarkers for chemotherapy-induced cardiotoxicity in breast cancer patients reveals potentially clinically informative panels as well as key challenges in miRNA research
- 2022
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In: Cardio-oncology (London, England). - : Springer Science and Business Media LLC. - 2057-3804. ; 8:1, s. 16-
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Journal article (peer-reviewed)abstract
- Breast cancer patients are at a particularly high risk of cardiotoxicity from chemotherapy having a detrimental effect on quality-of-life parameters and increasing the risk of mortality. Prognostic biomarkers would allow the management of therapies to mitigate the risks of cardiotoxicity in vulnerable patients and a key potential candidate for such biomarkers are microRNAs (miRNA). miRNAs are post-transcriptional regulators of gene expression which can also be released into the circulatory system and have been associated with the progression of many chronic diseases including many types of cancer. In this review, the evidence for the potential application of miRNAs as biomarkers for chemotherapy-induced cardiotoxicity (CIC) in breast cancer patientsis evaluated and a simple meta-analysis is performed to confirm the replication status of each reported miRNA. Further selection of miRNAs is performed by reviewing the reported associations of each miRNA with other cardiovascular conditions. Based on this research, the most representative panels targeting specific chemotherapy agents and treatment regimens are suggested, that contain several informative miRNAs, including both general markers of cardiac damage as well as those for the specific cancer treatments.
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| 7. |
- Burisch, J, et al.
(author)
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Natural disease course of Crohn's disease during the first 5 years after diagnosis in a European population-based inception cohort: an Epi-IBD study
- 2019
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In: Gut. - : BMJ. - 1468-3288 .- 0017-5749. ; 68:3, s. 423-433
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Journal article (peer-reviewed)abstract
- The Epi-IBD cohort is a prospective population-based inception cohort of unselected patients with inflammatory bowel disease from 29 European centres covering a background population of almost 10 million people. The aim of this study was to assess the 5-year outcome and disease course of patients with Crohn’s disease (CD).DesignPatients were followed up prospectively from the time of diagnosis, including collection of their clinical data, demographics, disease activity, medical therapy, surgery, cancers and deaths. Associations between outcomes and multiple covariates were analysed by Cox regression analysis.ResultsIn total, 488 patients were included in the study. During follow-up, 107 (22%) patients received surgery, while 176 (36%) patients were hospitalised because of CD. A total of 49 (14%) patients diagnosed with non-stricturing, non-penetrating disease progressed to either stricturing and/or penetrating disease. These rates did not differ between patients from Western and Eastern Europe. However, significant geographic differences were noted regarding treatment: more patients in Western Europe received biological therapy (33%) and immunomodulators (66%) than did those in Eastern Europe (14% and 54%, respectively, P<0.01), while more Eastern European patients received 5-aminosalicylates (90% vs 56%, P<0.05). Treatment with immunomodulators reduced the risk of surgery (HR: 0.4, 95% CI 0.2 to 0.6) and hospitalisation (HR: 0.3, 95% CI 0.2 to 0.5).ConclusionDespite patients being treated early and frequently with immunomodulators and biological therapy in Western Europe, 5-year outcomes including surgery and phenotype progression in this cohort were comparable across Western and Eastern Europe. Differences in treatment strategies between Western and Eastern European centres did not affect the disease course. Treatment with immunomodulators reduced the risk of surgery and hospitalisation.
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| 8. |
- Behar, Etienne, et al.
(author)
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The root of a comet tail : Rosetta ion observations at comet 67P/Churyumov–Gerasimenko
- 2018
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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 616
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Journal article (peer-reviewed)abstract
- Context.The first 1000 km of the ion tail of comet 67P/Churyumov–Gerasimenko were explored by the EuropeanRosettaspacecraft,2.7 au away from the Sun.Aims.We characterised the dynamics of both the solar wind and the cometary ions on the night-side of the comet’s atmosphere.Methods.We analysed in situ ion and magnetic field measurements and compared the data to a semi-analytical model.Results.The cometary ions are observed flowing close to radially away from the nucleus during the entire excursion. The solar windis deflected by its interaction with the new-born cometary ions. Two concentric regions appear, an inner region dominated by theexpanding cometary ions and an outer region dominated by the solar wind particles.Conclusions.The single night-side excursion operated byRosettarevealed that the near radial flow of the cometary ions can beexplained by the combined action of three different electric field components, resulting from the ion motion, the electron pressuregradients, and the magnetic field draping. The observed solar wind deflection is governed mostly by the motional electric field−uion×B.
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| 9. |
- Berecic, Laura, et al.
(author)
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Cometary ion dynamics observed in the close vicinity of comet 67P/Churyumov-Gerasimenko during the intermediate activity period
- 2018
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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 613, s. 1-8
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Journal article (peer-reviewed)abstract
- Aims.Cometary ions are constantly produced in the coma, and once produced they are accelerated and eventually escape the coma.We describe and interpret the dynamics of the cometary ion flow, of an intermediate active comet, very close to the nucleus and in theterminator plane.Methods.We analysed in situ ion and magnetic field measurements, and characterise the velocity distribution functions (mostly usingplasma moments). We propose a statistical approach over a period of one month.Results.On average, two populations were observed, separated in phase space. The motion of the first is governed by its interactionwith the solar wind farther upstream, while the second one is accelerated in the inner coma and displays characteristics compatiblewith an ambipolar electric field. Both populations display a consistent anti-sunward velocity component.Conclusions.Cometary ions born in different regions of the coma are seen close to the nucleus of comet 67P/Churyumov–Gerasimenko with distinct motions governed in one case by the solar wind electric field and in the other case by the position relative tothe nucleus. A consistent anti-sunward component is observed for all cometary ions. An asymmetry is found in the average cometaryion density in a solar wind electric field reference frame, with higher density in the negative (south) electric field hemisphere. Thereis no corresponding signature in the average magnetic field strengt
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| 10. |
- Majounie, Elisa, et al.
(author)
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Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study
- 2012
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In: Lancet Neurology. - 1474-4465. ; 11:4, s. 323-330
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Journal article (peer-reviewed)abstract
- Background We aimed to accurately estimate the frequency of a hexanucleotide repeat expansion in C9orf72 that has been associated with a large proportion of cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Methods We screened 4448 patients diagnosed with ALS (El Escorial criteria) and 1425 patients with FTD (Lund-Manchester criteria) from 17 regions worldwide for the GGGGCC hexanucleotide expansion using a repeat-primed PCR assay. We assessed familial disease status on the basis of self-reported family history of similar neurodegenerative diseases at the time of sample collection. We compared haplotype data for 262 patients carrying the expansion with the known Finnish founder risk haplotype across the chromosomal locus. We calculated age-related penetrance using the Kaplan-Meier method with data for 603 individuals with the expansion. Findings In patients with sporadic ALS, we identified the repeat expansion in 236 (7.0%) of 3377 white individuals from the USA, Europe, and Australia, two (4.1%) of 49 black individuals from the USA, and six (8.3%) of 72 Hispanic individuals from the USA. The mutation was present in 217 (39.3%) of 552 white individuals with familial MS from Europe and the USA. 59 (6.0%) of 981 white Europeans with sporadic FTD had the mutation, as did 99 (24.8%) of 400 white Europeans with familial FTD. Data for other ethnic groups were sparse, but we identified one Asian patient with familial ALS (from 20 assessed) and two with familial FTD (from three assessed) who carried the mutation. The mutation was not carried by the three Native Americans or 360 patients from Asia or the Pacific Islands with sporadic MS who were tested, or by 41 Asian patients with sporadic FTD. All patients with the repeat expansion had (partly or fully) the founder haplotype, suggesting a one-off expansion occurring about 1500 years ago. The pathogenic expansion was non-penetrant in individuals younger than 35 years, 50% penetrant by 58 years, and almost fully penetrant by 80 years. Interpretation A common Mendelian genetic lesion in C9472 is implicated in many cases of sporadic and familial ALS and FTD. Testing for this pathogenic expansion should be considered in the management and genetic counselling of patients with these fatal neurodegenerative diseases.
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