| 1. |
- Mullins, N., et al.
(författare)
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Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology
- 2021
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 53, s. 817-829
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Tidskriftsartikel (refereegranskat)abstract
- Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies. Genome-wide association analyses of 41,917 bipolar disorder cases and 371,549 controls of European ancestry provide new insights into the etiology of this disorder and identify novel therapeutic leads and potential opportunities for drug repurposing.
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| 2. |
- Nicolas, Aude, et al.
(författare)
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Genome-wide Analyses Identify KIF5A as a Novel ALS Gene
- 2018
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Ingår i: Neuron. - : Cell Press. - 0896-6273 .- 1097-4199. ; 97:6, s. 1268-1283.e6
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Tidskriftsartikel (refereegranskat)abstract
- To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.
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| 3. |
- Lewis, Cathryn M, et al.
(författare)
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Genome scan meta-analysis of schizophrenia and bipolar disorder, part II : Schizophrenia
- 2003
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Ingår i: American Journal of Human Genetics. - 0002-9297 .- 1537-6605. ; 73:1, s. 34-48
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Tidskriftsartikel (refereegranskat)abstract
- Schizophrenia is a common disorder with high heritability and a 10-fold increase in risk to siblings of probands. Replication has been inconsistent for reports of significant genetic linkage. To assess evidence for linkage across studies, rank-based genome scan meta-analysis (GSMA) was applied to data from 20 schizophrenia genome scans. Each marker for each scan was assigned to 1 of 120 30-cM bins, with the bins ranked by linkage scores (1 = most significant) and the ranks averaged across studies (R(avg)) and then weighted for sample size (N(sqrt)[affected casess]). A permutation test was used to compute the probability of observing, by chance, each bin's average rank (P(AvgRnk)) or of observing it for a bin with the same place (first, second, etc.) in the order of average ranks in each permutation (P(ord)). The GSMA produced significant genomewide evidence for linkage on chromosome 2q (PAvgRnk<.000417). Two aggregate criteria for linkage were also met (clusters of nominally significant P values that did not occur in 1,000 replicates of the entire data set with no linkage present): 12 consecutive bins with both P(AvgRnk) and P(ord)<.05, including regions of chromosomes 5q, 3p, 11q, 6p, 1q, 22q, 8p, 20q, and 14p, and 19 consecutive bins with P(ord)<.05, additionally including regions of chromosomes 16q, 18q, 10p, 15q, 6q, and 17q. There is greater consistency of linkage results across studies than has been previously recognized. The results suggest that some or all of these regions contain loci that increase susceptibility to schizophrenia in diverse populations.
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| 4. |
- Andersson, L., et al.
(författare)
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Dust observations at orbital altitudes surrounding Mars
- 2015
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 350:6261
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Tidskriftsartikel (refereegranskat)abstract
- Dust is common close to the martian surface, but no known process can lift appreciable concentrations of particles to altitudes above similar to 150 kilometers. We present observations of dust at altitudes ranging from 150 to above 1000 kilometers by the Langmuir Probe and Wave instrument on the Mars Atmosphere and Volatile Evolution spacecraft. Based on its distribution, we interpret this dust to be interplanetary in origin. A comparison with laboratory measurements indicates that the dust grain size ranges from 1 to 12 micrometers, assuming a typical grain velocity of similar to 18 kilometers per second. These direct observations of dust entering the martian atmosphere improve our understanding of the sources, sinks, and transport of interplanetary dust throughout the inner solar system and the associated impacts on Mars's atmosphere.
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| 5. |
- Bridel, Claire, et al.
(författare)
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Diagnostic Value of Cerebrospinal Fluid Neurofilament Light Protein in Neurology : A Systematic Review and Meta-analysis
- 2019
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Ingår i: JAMA Neurology. - : American Medical Association (AMA). - 2168-6149 .- 2168-6157. ; 76:9, s. 1035-1048
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Forskningsöversikt (refereegranskat)abstract
- Importance Neurofilament light protein (NfL) is elevated in cerebrospinal fluid (CSF) of a number of neurological conditions compared with healthy controls (HC) and is a candidate biomarker for neuroaxonal damage. The influence of age and sex is largely unknown, and levels across neurological disorders have not been compared systematically to date.Objectives To assess the associations of age, sex, and diagnosis with NfL in CSF (cNfL) and to evaluate its potential in discriminating clinically similar conditions.Data Sources PubMed was searched for studies published between January 1, 2006, and January 1, 2016, reporting cNfL levels (using the search terms neurofilament light and cerebrospinal fluid) in neurological or psychiatric conditions and/or in HC.Study Selection Studies reporting NfL levels measured in lumbar CSF using a commercially available immunoassay, as well as age and sex.Data Extraction and Synthesis Individual-level data were requested from study authors. Generalized linear mixed-effects models were used to estimate the fixed effects of age, sex, and diagnosis on log-transformed NfL levels, with cohort of origin modeled as a random intercept.Main Outcome and Measure The cNfL levels adjusted for age and sex across diagnoses.Results Data were collected for 10 059 individuals (mean [SD] age, 59.7 [18.8] years; 54.1% female). Thirty-five diagnoses were identified, including inflammatory diseases of the central nervous system (n = 2795), dementias and predementia stages (n = 4284), parkinsonian disorders (n = 984), and HC (n = 1332). The cNfL was elevated compared with HC in a majority of neurological conditions studied. Highest levels were observed in cognitively impaired HIV-positive individuals (iHIV), amyotrophic lateral sclerosis, frontotemporal dementia (FTD), and Huntington disease. In 33.3% of diagnoses, including HC, multiple sclerosis, Alzheimer disease (AD), and Parkinson disease (PD), cNfL was higher in men than women. The cNfL increased with age in HC and a majority of neurological conditions, although the association was strongest in HC. The cNfL overlapped in most clinically similar diagnoses except for FTD and iHIV, which segregated from other dementias, and PD, which segregated from atypical parkinsonian syndromes.Conclusions and Relevance These data support the use of cNfL as a biomarker of neuroaxonal damage and indicate that age-specific and sex-specific (and in some cases disease-specific) reference values may be needed. The cNfL has potential to assist the differentiation of FTD from AD and PD from atypical parkinsonian syndromes.
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| 6. |
- Palmroth, Minna, et al.
(författare)
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Lower-thermosphere-ionosphere (LTI) quantities : current status of measuring techniques and models
- 2021
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Ingår i: Annales Geophysicae. - : Copernicus Publications. - 0992-7689 .- 1432-0576. ; 39:1, s. 189-237
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Tidskriftsartikel (refereegranskat)abstract
- The lower-thermosphere-ionosphere (LTI) system consists of the upper atmosphere and the lower part of the ionosphere and as such comprises a complex system coupled to both the atmosphere below and space above. The atmospheric part of the LTI is dominated by laws of continuum fluid dynamics and chemistry, while the ionosphere is a plasma system controlled by electromagnetic forces driven by the magnetosphere, the solar wind, as well as the wind dynamo. The LTI is hence a domain controlled by many different physical processes. However, systematic in situ measurements within this region are severely lacking, although the LTI is located only 80 to 200 km above the surface of our planet. This paper reviews the current state of the art in measuring the LTI, either in situ or by several different remote-sensing methods. We begin by outlining the open questions within the LTI requiring high-quality in situ measurements, before reviewing directly observable parameters and their most important derivatives. The motivation for this review has arisen from the recent retention of the Daedalus mission as one among three competing mission candidates within the European Space Agency (ESA) Earth Explorer 10 Programme. However, this paper intends to cover the LTI parameters such that it can be used as a background scientific reference for any mission targeting in situ observations of the LTI.
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| 7. |
- Sarris, Theodoros, et al.
(författare)
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Plasma-neutral interactions in the lower thermosphere-ionosphere : The need for in situ measurements to address focused questions
- 2023
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Ingår i: Frontiers in Astronomy and Space Sciences. - : Frontiers Media SA. - 2296-987X. ; 9
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Forskningsöversikt (refereegranskat)abstract
- The lower thermosphere-ionosphere (LTI) is a key transition region between Earth's atmosphere and space. Interactions between ions and neutrals maximize within the LTI and in particular at altitudes from 100 to 200 km, which is the least visited region of the near-Earth environment. The lack of in situ co-temporal and co-spatial measurements of all relevant parameters and their elusiveness to most remote-sensing methods means that the complex interactions between its neutral and charged constituents remain poorly characterized to this date. This lack of measurements, together with the ambiguity in the quantification of key processes in the 100-200 km altitude range affect current modeling efforts to expand atmospheric models upward to include the LTI and limit current space weather prediction capabilities. We present focused questions in the LTI that are related to the complex interactions between its neutral and charged constituents. These questions concern core physical processes that govern the energetics, dynamics, and chemistry of the LTI and need to be addressed as fundamental and long-standing questions in this critically unexplored boundary region. We also outline the range of in situ measurements that are needed to unambiguously quantify key LTI processes within this region, and present elements of an in situ concept based on past proposed mission concepts.
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| 8. |
- Akbari, H., et al.
(författare)
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In Situ Electron Density From Active Sounding : The Influence of the Spacecraft Wake
- 2019
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Ingår i: Geophysical Research Letters. - : AMER GEOPHYSICAL UNION. - 0094-8276 .- 1944-8007. ; 46:17-18, s. 10250-10256
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Tidskriftsartikel (refereegranskat)abstract
- Results obtained in the Martian ionosphere by the Langmuir Probe and Waves instrument aboard the Mars Atmosphere and Volatile EvolutioN Mission spacecraft are presented. The results include ionospheric electron densities determined from the frequency of Langmuir waves. Since the amplitude of thermal Langmuir waves is often below the instrument's detection level, Langmuir Probe and Waves excites these waves by injecting into the plasma a 3.3-V white noise signal. Electric field spectral measurements obtained shortly after the excitation show a resonance line at frequencies slightly below the local plasma frequency. The observed resonance line is interpreted to originate from plasma waves excited in the wake behind the spacecraft. These results reveal an important phenomenon in electron density estimation from stimulated Langmuir waves. The observed phenomenon, not previously reported by earlier missions, may be a common process in active sounding that can affect in situ electron density measurements.
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| 9. |
- Goodrich, Katherine A., et al.
(författare)
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MMS Multipoint electric field observations of small-scale magnetic holes
- 2016
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Ingår i: Geophysical Research Letters. - : Blackwell Publishing. - 0094-8276 .- 1944-8007. ; 43:12, s. 5953-5959
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Tidskriftsartikel (refereegranskat)abstract
- Small-scale magnetic holes (MHs), local depletions in magnetic field strength, have been observed multiple times in the Earth's magnetosphere in the bursty bulk flow (BBF) braking region. This particular subset of MHs has observed scale sizes perpendicular to the background magnetic field (B) less than the ambient ion Larmor radius (rho(i)). Previous observations by Time History of Events and Macroscale Interactions during Substorms (THEMIS) indicate that this subset of MHs can be supported by a current driven by the E x B drift of electrons. Ions do not participate in the E x B drift due to the small-scale size of the electric field. While in the BBF braking region, during its commissioning phase, the Magnetospheric Multiscale (MMS) spacecraft observed a small-scale MH. The electric field observations taken during this event suggest the presence of electron currents perpendicular to the magnetic field. These observations also suggest that these currents can evolve to smaller spatial scales.
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| 10. |
- Malaspina, David M., et al.
(författare)
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Evidence that Interaction with the Spacecraft Plasma Wake Generates Plasma Waves Close to the Electron Cyclotron Frequency in the Near-Sun Solar Wind
- 2022
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Ingår i: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8205 .- 2041-8213. ; 936:2
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Tidskriftsartikel (refereegranskat)abstract
- Prior observations of the near-Sun solar wind (sunward of 0.25 au) identified frequent, intense plasma waves near the local electron cyclotron frequency (f (ce)), and its harmonics. In this Letter, it is shown that near-f (ce) wave properties are consistent with generation via interaction between the observing spacecraft's ion wake and the ambient plasma and magnetic fields. This result implies that many observed near-f (ce) waves are not intrinsic to the unobstructed solar wind flow, and therefore are unlikely to play a significant role in the dynamic evolution of particle distributions in the solar wind.
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