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| 2. |
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| 3. |
- Aartsen, M. G., et al.
(författare)
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Multiwavelength follow-up of a rare IceCube neutrino multiplet
- 2017
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Ingår i: Astronomy and Astrophysics. - : EDP SCIENCES S A. - 0004-6361 .- 1432-0746. ; 607
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Tidskriftsartikel (refereegranskat)abstract
- On February 17, 2016, the IceCube real-time neutrino search identified, for the first time, three muon neutrino candidates arriving within 100 s of one another, consistent with coming from the same point in the sky. Such a triplet is expected once every 13.7 years as a random coincidence of background events. However, considering the lifetime of the follow-up program the probability of detecting at least one triplet from atmospheric background is 32%. Follow-up observatories were notified in order to search for an electromagnetic counterpart. Observations were obtained by Swift's X-ray telescope, by ASAS-SN, LCO and MASTER at optical wavelengths, and by VERITAS in the very-high-energy gamma-ray regime. Moreover, the Swift BAT serendipitously observed the location 100 s after the first neutrino was detected, and data from the Fermi LAT and HAWC observatory were analyzed. We present details of the neutrino triplet and the follow-up observations. No likely electromagnetic counterpart was detected, and we discuss the implications of these constraints on candidate neutrino sources such as gamma-ray bursts, core-collapse supernovae and active galactic nucleus flares. This study illustrates the potential of and challenges for future follow-up campaigns.
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| 4. |
- Abeysekara, A. U., et al.
(författare)
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VERITAS and Fermi-LAT Observations of TeV Gamma-Ray Sources Discovered by HAWC in the 2HWC Catalog
- 2018
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Ingår i: Astrophysical Journal. - : Institute of Physics Publishing. - 0004-637X .- 1538-4357. ; 866:1
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Tidskriftsartikel (refereegranskat)abstract
- The High Altitude Water Cherenkov (HAWC) collaboration recently published their 2HWC catalog, listing 39 very high energy (VHE; >100 GeV) gamma-ray sources based on 507 days of observation. Among these, 19 sources are not associated with previously known teraelectronvolt (TeV) gamma-ray sources. We have studied 14 of these sources without known counterparts with VERITAS and Fermi-LAT. VERITAS detected weak gamma-ray emission in the 1 TeV-30 TeV band in the region of DA 495, a pulsar wind nebula coinciding with 2HWC J1953+294, confirming the discovery of the source by HAWC. We did not find any counterpart for the selected 14 new HAWC sources from our analysis of Fermi-LAT data for energies higher than 10 GeV. During the search, we detected gigaelectronvolt (GeV) gamma-ray emission coincident with a known TeV pulsar wind nebula, SNR G54.1+0.3 (VER J1930+188), and a 2HWC source, 2HWC J1930+188. The fluxes for isolated, steady sources in the 2HWC catalog are generally in good agreement with those measured by imaging atmospheric Cherenkov telescopes. However, the VERITAS fluxes for SNR G54.1+0.3, DA 495, and TeV J2032+4130 are lower than those measured by HAWC, and several new HAWC sources are not detected by VERITAS. This is likely due to a change in spectral shape, source extension, or the influence of diffuse emission in the source region.
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| 5. |
- de Rojas, I., et al.
(författare)
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Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores
- 2021
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease. © 2021, The Author(s).
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| 8. |
- 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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| 9. |
- 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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| 10. |
- Zaborowski, AM, et al.
(författare)
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Microsatellite instability in young patients with rectal cancer: molecular findings and treatment response
- 2022
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Ingår i: The British journal of surgery. - : Oxford University Press (OUP). - 1365-2168 .- 0007-1323. ; 109:3, s. 251-255
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Tidskriftsartikel (refereegranskat)abstract
- In this study of 400 patients with early-onset rectal cancer, 12.5 per cent demonstrated microsatellite instability (MSI). MSI was associated with a reduced likelihood of nodal positivity, an increased rate of pathological complete response, and improved disease-specific survival.
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| 11. |
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| 13. |
- Bellenguez, C, et al.
(författare)
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New insights into the genetic etiology of Alzheimer's disease and related dementias
- 2022
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 54:4, s. 412-436
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Tidskriftsartikel (refereegranskat)abstract
- Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.
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| 15. |
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| 16. |
- Loth, Daan W, et al.
(författare)
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Genome-wide association analysis identifies six new loci associated with forced vital capacity
- 2014
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 46, s. 669-677
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Tidskriftsartikel (refereegranskat)abstract
- Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10(-8)) with FVC in or near EFEMP1, BMP6, MIR129-2-HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease.
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| 19. |
- Aprile, E., et al.
(författare)
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Physics reach of the XENON1T dark matter experiment
- 2016
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Ingår i: Journal of Cosmology and Astroparticle Physics. - : IOP Publishing. - 1475-7516. ; :4
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Tidskriftsartikel (refereegranskat)abstract
- The XENON1T experiment is currently in the commissioning phase at the Laboratori Nazionali del Gran Sasso, Italy. In this article we study the experiment's expected sensitivity to the spin-independent WIMP-nucleon interaction cross section, based on Monte Carlo predictions of the electronic and nuclear recoil backgrounds. The total electronic recoil background in 1 tonne fiducial volume and (1, 12) keV electronic recoil equivalent energy region, before applying any selection to discriminate between electronic and nuclear recoils, is (1.80+/-0.15) . 10(-4) (kg.day.keV)(-1), mainly due to the decay of Rn-222 daughters inside the xenon target. The nuclear recoil background in the corresponding nuclear recoil equivalent energy region (4, 50) keV, is composed of (0.6 +/- 0.1) (t.y)(-1) from radiogenic neutrons, (1.8+/-0.3) . 10(-2) (t.y)(-1) from coherent scattering of neutrinos, and less than 0.01 (t.y)(-1) from muon-induced neutrons. The sensitivity of XENON1T is calculated with the Pro file Likelihood Ratio method, after converting the deposited energy of electronic and nuclear recoils into the scintillation and ionization signals seen in the detector. We take into account the systematic uncertainties on the photon and electron emission model, and on the estimation of the backgrounds, treated as nuisance parameters. The main contribution comes from the relative scintillation efficiency L-eff, which affects both the signal from WIMPs and the nuclear recoil backgrounds. After a 2 y measurement in 1 tonne fiducial volume, the sensitivity reaches a minimum cross section of 1.6 . 10(-47) cm(2) at m(chi) = 50 GeV/c(2).
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| 20. |
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| 21. |
- Gauthier, S, et al.
(författare)
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Mild cognitive impairment
- 2006
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Ingår i: Lancet (London, England). - 1474-547X. ; 367:9518, s. 1262-1270
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Tidskriftsartikel (refereegranskat)
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| 22. |
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| 23. |
- Beelen, Rob, et al.
(författare)
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Natural-Cause Mortality and Long-Term Exposure to Particle Components : An Analysis of 19 European Cohorts within the Multi-Center ESCAPE Project
- 2015
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Ingår i: Journal of Environmental Health Perspectives. - : Environmental Health Perspectives. - 0091-6765 .- 1552-9924. ; 123:6, s. 525-533
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Forskningsöversikt (refereegranskat)abstract
- Background: Studies have shown associations between mortality and long-term exposure to particulate matter air pollution. Few cohort studies have estimated the effects of the elemental composition of particulate matter on mortality. Objectives: Our aim was to study the association between natural-cause mortality and long-term exposure to elemental components of particulate matter. Methods: Mortality and confounder data from 19 European cohort studies were used. Residential exposure to eight a priori-selected components of particulate matter ( PM) was characterized following a strictly standardized protocol. Annual average concentrations of copper, iron, potassium, nickel, sulfur, silicon, vanadium, and zinc within PM size fractions <= 2.5 mu m (PM2.5) and <= 10 mu m (PM10) were estimated using land-use regression models. Cohort-specific statistical analyses of the associations between mortality and air pollution were conducted using Cox proportional hazards models using a common protocol followed by meta-analysis. Results: The total study population consisted of 291,816 participants, of whom 25,466 died from a natural cause during follow-up (average time of follow-up, 14.3 years). Hazard ratios were positive for almost all elements and statistically significant for PM2.5 sulfur (1.14; 95% CI: 1.06, 1.23 per 200ng/m(3)). In a two-pollutant model, the association with PM2.5 sulfur was robust to adjustment for PM2.5 mass, whereas the association with PM2.5 mass was reduced. Conclusions: Long-term exposure to PM2.5 sulfur was associated with natural-cause mortality. This association was robust to adjustment for other pollutants and PM2.5.
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| 24. |
- Cavedo, E, et al.
(författare)
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The Road Ahead to Cure Alzheimer's Disease: Development of Biological Markers and Neuroimaging Methods for Prevention Trials Across all Stages and Target Populations
- 2014
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Ingår i: The journal of prevention of Alzheimer's disease. - : SERDI. - 2274-5807. ; 1:3, s. 181-202
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD) is a slowly progressing non-linear dynamic brain disease in which pathophysiological abnormalities, detectable in vivo by biological markers, precede overt clinical symptoms by many years to decades. Use of these biomarkers for the detection of early and preclinical AD has become of central importance following publication of two international expert working group's revised criteria for the diagnosis of AD dementia, mild cognitive impairment (MCI) due to AD, prodromal AD and preclinical AD. As a consequence of matured research evidence six AD biomarkers are sufficiently validated and partly qualified to be incorporated into operationalized clinical diagnostic criteria and use in primary and secondary prevention trials. These biomarkers fall into two molecular categories: biomarkers of amyloid-beta (Aβ) deposition and plaque formation as well as of tau-protein related hyperphosphorylation and neurodegeneration. Three of the six gold-standard ("core feasible) biomarkers are neuroimaging measures and three are cerebrospinal fluid (CSF) analytes. CSF Aβ 1-42 (Aβ1-42), also expressed as Aβ1-42 : Aβ1- 40 ratio, T-tau, and P-tau Thr181 & Thr231 proteins have proven diagnostic accuracy and risk enhancement in prodromal MCI and AD dementia. Conversely, having all three biomarkers in the normal range rules out AD. Intermediate conditions require further patient follow-up. Magnetic resonance imaging (MRI) at increasing field strength and resolution allows detecting the evolution of distinct types of structural and functional abnormality pattern throughout early to late AD stages. Anatomical or volumetric MRI is the most widely used technique and provides local and global measures of atrophy. The revised diagnostic criteria for “prodromal AD” and "mild cognitive impairment due to AD" include hippocampal atrophy (as the fourth validated biomarker), which is considered an indicator of regional neuronal injury. Advanced image analysis techniques generate automatic and reproducible measures both in regions of interest, such as the hippocampus and in an exploratory fashion, observer and hypothesis-indedendent, throughout the entire brain. Evolving modalities such as diffusion-tensor imaging (DTI) and advanced tractography as well as resting-state functional MRI provide useful additionally useful measures indicating the degree of fiber tract and neural network disintegration (structural, effective and functional connectivity) that may substantially contribute to early detection and the mapping of progression. These modalities require further standardization and validation. The use of molecular in vivo amyloid imaging agents (the fifth validated biomarker), such as the Pittsburgh Compound-B and markers of neurodegeneration, such as fluoro-2-deoxy-D-glucose (FDG) (as the sixth validated biomarker) support the detection of early AD pathological processes and associated neurodegeneration. How to use, interpret, and disclose biomarker results drives the need for optimized standardization. Multimodal AD biomarkers do not evolve in an identical manner but rather in a sequential but temporally overlapping fashion. Models of the temporal evolution of AD biomarkers can take the form of plots of biomarker severity (degree of abnormality) versus time. AD biomarkers can be combined to increase accuracy or risk. A list of genetic risk factors is increasingly included in secondary prevention trials to stratify and select individuals at genetic risk of AD. Although most of these biomarker candidates are not yet qualified and approved by regulatory authorities for their intended use in drug trials, they are nonetheless applied in ongoing clinical studies for the following functions: (i) inclusion/exclusion criteria, (ii) patient stratification, (iii) evaluation of treatment effect, (iv) drug target engagement, and (v) safety. Moreover, novel promising hypothesis-driven, as well as exploratory biochemical, genetic, electrophysiological, and neuroimaging markers for use in clinical trials are being developed. The current state-of-the-art and future perspectives on both biological and neuroimaging derived biomarker discovery and development as well as the intended application in prevention trials is outlined in the present publication.
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