1. |
- Kattge, Jens, et al.
(author)
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TRY plant trait database - enhanced coverage and open access
- 2020
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In: Global Change Biology. - : Wiley-Blackwell. - 1354-1013 .- 1365-2486. ; 26:1, s. 119-188
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Journal article (peer-reviewed)abstract
- Plant traits-the morphological, anatomical, physiological, biochemical and phenological characteristics of plants-determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait-based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits-almost complete coverage for 'plant growth form'. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait-environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives.
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2. |
- Jansen, Willemijn J, et al.
(author)
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Association of Cerebral Amyloid-β Aggregation With Cognitive Functioning in Persons Without Dementia.
- 2018
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In: JAMA psychiatry. - : American Medical Association (AMA). - 2168-6238 .- 2168-622X. ; 75:1, s. 84-95
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Journal article (peer-reviewed)abstract
- Cerebral amyloid-β aggregation is an early event in Alzheimer disease (AD). Understanding the association between amyloid aggregation and cognitive manifestation in persons without dementia is important for a better understanding of the course of AD and for the design of prevention trials.To investigate whether amyloid-β aggregation is associated with cognitive functioning in persons without dementia.This cross-sectional study included 2908 participants with normal cognition and 4133 with mild cognitive impairment (MCI) from 53 studies in the multicenter Amyloid Biomarker Study. Normal cognition was defined as having no cognitive concerns for which medical help was sought and scores within the normal range on cognitive tests. Mild cognitive impairment was diagnosed according to published criteria. Study inclusion began in 2013 and is ongoing. Data analysis was performed in January 2017.Global cognitive performance as assessed by the Mini-Mental State Examination (MMSE) and episodic memory performance as assessed by a verbal word learning test. Amyloid aggregation was measured with positron emission tomography or cerebrospinal fluid biomarkers and dichotomized as negative (normal) or positive (abnormal) according to study-specific cutoffs. Generalized estimating equations were used to examine the association between amyloid aggregation and low cognitive scores (MMSE score ≤27 or memory z score≤-1.28) and to assess whether this association was moderated by age, sex, educational level, or apolipoprotein E genotype.Among 2908 persons with normal cognition (mean [SD] age, 67.4 [12.8] years), amyloid positivity was associated with low memory scores after age 70 years (mean difference in amyloid positive vs negative, 4% [95% CI, 0%-7%] at 72 years and 21% [95% CI, 10%-33%] at 90 years) but was not associated with low MMSE scores (mean difference, 3% [95% CI, -1% to 6%], P=.16). Among 4133 patients with MCI (mean [SD] age, 70.2 [8.5] years), amyloid positivity was associated with low memory (mean difference, 16% [95% CI, 12%-20%], P<.001) and low MMSE (mean difference, 14% [95% CI, 12%-17%], P<.001) scores, and this association decreased with age. Low cognitive scores had limited utility for screening of amyloid positivity in persons with normal cognition and those with MCI. In persons with normal cognition, the age-related increase in low memory score paralleled the age-related increase in amyloid positivity with an intervening period of 10 to 15 years.Although low memory scores are an early marker of amyloid positivity, their value as a screening measure for early AD among persons without dementia is limited.
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3. |
- Jansen, Willemijn J, et al.
(author)
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Prevalence Estimates of Amyloid Abnormality Across the Alzheimer Disease Clinical Spectrum.
- 2022
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In: JAMA neurology. - : American Medical Association (AMA). - 2168-6157 .- 2168-6149. ; 79:3, s. 228-243
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Journal article (peer-reviewed)abstract
- One characteristic histopathological event in Alzheimer disease (AD) is cerebral amyloid aggregation, which can be detected by biomarkers in cerebrospinal fluid (CSF) and on positron emission tomography (PET) scans. Prevalence estimates of amyloid pathology are important for health care planning and clinical trial design.To estimate the prevalence of amyloid abnormality in persons with normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia and to examine the potential implications of cutoff methods, biomarker modality (CSF or PET), age, sex, APOE genotype, educational level, geographical region, and dementia severity for these estimates.This cross-sectional, individual-participant pooled study included participants from 85 Amyloid Biomarker Study cohorts. Data collection was performed from January 1, 2013, to December 31, 2020. Participants had normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia. Normal cognition and subjective cognitive decline were defined by normal scores on cognitive tests, with the presence of cognitive complaints defining subjective cognitive decline. Mild cognitive impairment and clinical AD dementia were diagnosed according to published criteria.Alzheimer disease biomarkers detected on PET or in CSF.Amyloid measurements were dichotomized as normal or abnormal using cohort-provided cutoffs for CSF or PET or by visual reading for PET. Adjusted data-driven cutoffs for abnormal amyloid were calculated using gaussian mixture modeling. Prevalence of amyloid abnormality was estimated according to age, sex, cognitive status, biomarker modality, APOE carrier status, educational level, geographical location, and dementia severity using generalized estimating equations.Among the 19097 participants (mean [SD] age, 69.1 [9.8] years; 10148 women [53.1%]) included, 10139 (53.1%) underwent an amyloid PET scan and 8958 (46.9%) had an amyloid CSF measurement. Using cohort-provided cutoffs, amyloid abnormality prevalences were similar to 2015 estimates for individuals without dementia and were similar across PET- and CSF-based estimates (24%; 95% CI, 21%-28%) in participants with normal cognition, 27% (95% CI, 21%-33%) in participants with subjective cognitive decline, and 51% (95% CI, 46%-56%) in participants with mild cognitive impairment, whereas for clinical AD dementia the estimates were higher for PET than CSF (87% vs 79%; mean difference, 8%; 95% CI, 0%-16%; P=.04). Gaussian mixture modeling-based cutoffs for amyloid measures on PET scans were similar to cohort-provided cutoffs and were not adjusted. Adjusted CSF cutoffs resulted in a 10% higher amyloid abnormality prevalence than PET-based estimates in persons with normal cognition (mean difference, 9%; 95% CI, 3%-15%; P=.004), subjective cognitive decline (9%; 95% CI, 3%-15%; P=.005), and mild cognitive impairment (10%; 95% CI, 3%-17%; P=.004), whereas the estimates were comparable in persons with clinical AD dementia (mean difference, 4%; 95% CI, -2% to 9%; P=.18).This study found that CSF-based estimates using adjusted data-driven cutoffs were up to 10% higher than PET-based estimates in people without dementia, whereas the results were similar among people with dementia. This finding suggests that preclinical and prodromal AD may be more prevalent than previously estimated, which has important implications for clinical trial recruitment strategies and health care planning policies.
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4. |
- Jansen, Willemijn J, et al.
(author)
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Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis.
- 2015
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In: JAMA. - : American Medical Association (AMA). - 1538-3598 .- 0098-7484. ; 313:19, s. 1924-38
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Journal article (peer-reviewed)abstract
- Cerebral amyloid-β aggregation is an early pathological event in Alzheimer disease (AD), starting decades before dementia onset. Estimates of the prevalence of amyloid pathology in persons without dementia are needed to understand the development of AD and to design prevention studies.
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5. |
- van Maurik, Ingrid S., et al.
(author)
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Biomarker-based prognosis for people with mild cognitive impairment (ABIDE) : a modelling study
- 2019
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In: Lancet Neurology. - : The Lancet Publishing Group. - 1474-4422 .- 1474-4465. ; 18:11, s. 1034-1044
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Journal article (peer-reviewed)abstract
- BACKGROUND: Biomarker-based risk predictions of dementia in people with mild cognitive impairment are highly relevant for care planning and to select patients for treatment when disease-modifying drugs become available. We aimed to establish robust prediction models of disease progression in people at risk of dementia.METHODS: In this modelling study, we included people with mild cognitive impairment (MCI) from single-centre and multicentre cohorts in Europe and North America: the European Medical Information Framework for Alzheimer's Disease (EMIF-AD; n=883), Alzheimer's Disease Neuroimaging Initiative (ADNI; n=829), Amsterdam Dementia Cohort (ADC; n=666), and the Swedish BioFINDER study (n=233). Inclusion criteria were a baseline diagnosis of MCI, at least 6 months of follow-up, and availability of a baseline Mini-Mental State Examination (MMSE) and MRI or CSF biomarker assessment. The primary endpoint was clinical progression to any type of dementia. We evaluated performance of previously developed risk prediction models-a demographics model, a hippocampal volume model, and a CSF biomarkers model-by evaluating them across cohorts, incorporating different biomarker measurement methods, and determining prognostic performance with Harrell's C statistic. We then updated the models by re-estimating parameters with and without centre-specific effects and evaluated model calibration by comparing observed and expected survival. Finally, we constructed a model combining markers for amyloid deposition, tauopathy, and neurodegeneration (ATN), in accordance with the National Institute on Aging and Alzheimer's Association research framework.FINDINGS: We included all 2611 individuals with MCI in the four cohorts, 1007 (39%) of whom progressed to dementia. The validated demographics model (Harrell's C 0·62, 95% CI 0·59-0·65), validated hippocampal volume model (0·67, 0·62-0·72), and updated CSF biomarkers model (0·72, 0·68-0·74) had adequate prognostic performance across cohorts and were well calibrated. The newly constructed ATN model had the highest performance (0·74, 0·71-0·76).INTERPRETATION: We generated risk models that are robust across cohorts, which adds to their potential clinical applicability. The models could aid clinicians in the interpretation of CSF biomarker and hippocampal volume results in individuals with MCI, and help research and clinical settings to prepare for a future of precision medicine in Alzheimer's disease. Future research should focus on the clinical utility of the models, particularly if their use affects participants' understanding, emotional wellbeing, and behaviour.
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6. |
- Abbasi, Rasha, et al.
(author)
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IceCube search for neutrinos from GRB 221009A
- 2023
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In: Proceedings of 38th International Cosmic Ray Conference (ICRC 2023). - : Sissa Medialab Srl.
-
Conference paper (peer-reviewed)abstract
- GRB 221009A is the brightest Gamma Ray Burst (GRB) ever observed. The observed extremelyhigh flux of high and very-high-energy photons provide a unique opportunity to probe the predictedneutrino counterpart to the electromagnetic emission. We have used a variety of methods to searchfor neutrinos in coincidence with the GRB over several time windows during the precursor, promptand afterglow phases of the GRB. MeV scale neutrinos are studied using photo-multiplier ratescalers which are normally used to search for galactic core-collapse supernovae neutrinos. GeVneutrinos are searched starting with DeepCore triggers. These events don’t have directionallocalization, but instead can indicate an excess in the rate of events. 10 GeV - 1 TeV and >TeVneutrinos are searched using traditional neutrino point source methods which take into accountthe direction and time of events with DeepCore and the entire IceCube detector respectively. The>TeV results include both a fast-response analysis conducted by IceCube in real-time with timewindows of T0 − 1 to T0 + 2 hours and T0 ± 1 day around the time of GRB 221009A, as well asan offline analysis with 3 new time windows up to a time window of T0 − 1 to T0 + 14 days, thelongest time period we consider. The combination of observations by IceCube covers 9 ordersof magnitude in neutrino energy, from MeV to PeV, placing upper limits across the range forpredicted neutrino emission.
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7. |
- Allard, Bert, 1945-, et al.
(author)
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Mining waste management in the Baltic Sea Region : Min-Novation project
- 2013
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Book (peer-reviewed)abstract
- Mining waste and what to do about it is a common challenge facing companies, local authorities, environmental organizations, policymakers and increasingly other stakeholders in several countries of the Baltic Sea Region. From 2011 to 2013, a network of scientific and regional expertise brought together in the Min-Novation project has put this topic in the spotlight. The importance of the management of waste from extractive industries is due to the substantial share this waste has in the overall stream of waste generated in the EU. In 2010, 672 Mt or 28.3% of the total waste generated in the EU was attributable to the mining and quarrying industry, second only to construction (34.4%) and ahead of manufacturing (11.0%) and households (8.7%)1. Apart from this, mining waste is the raw material for one of the more visible man-made landmarks that surround us, with waste heaps of various shapes and sizes dotting the landscape up and down the Baltic Sea Region. Despite this dual prominence, mining waste is most often seen only as an environmental problem and in no way a resource. To move away from a one-sided view of mining waste, a life-cycle approach, which recognises that value can be recovered from waste and re-introduced into the product cycle is of the essence. It cannot be stressed enough that mining waste is a source of secondary raw materials, the use of which helps to protect the natural mineral deposits for future generations. Equally important is an appreciation of how the waste can be re-cycled in the excavation process (preventionand recovery) and adapted to create value for local communities (reclamation and revitalisation). However, for there to be effective mining waste management, both in the prevention stage, as well as in the recovery stage, and finally during land reclamation many conditions must be fulfilled. Of these the most important are access to appropriate technologies and methods and common sense legislation. Another condition not without importance is social acceptance for the recovery of waste located in old landfills. The Min-Novation Network over a span of 3 years has worked to understand and appreciate mining waste both as a corporate, community, regulatory and strategic issue. Set against the background of mining activity and waste management in the partner countries: Estonia, Finland, Germany, Norway, Poland and Sweden, both good practices and problem areas, which need to be addressed have been presented in this monograph. The purpose of this monograph is to show a cross-section of topics that affect how mining waste management works today, and which will play a decisive role in whether management of mining waste remains – an issue of primarily local relevance or whether it becomes a growth opportunity of national and EU-wide importance. The monograph focuses primarily on issues related to the management of waste from extractive industries in the countries whose representatives were involved in the Min-Novation project. Examples from outside the Baltic Sea Region of the use of waste heaps as an industrial heritage of the mining regions and also as attractions for local communities are presented as well. Indeed, every experience is valuable for the environment and socio-economic development of the Baltic Sea Region.
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8. |
- Bloß, Dana, et al.
(author)
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X-ray radiation damage cycle of solvated inorganic ions
- 2024
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In: Nature Communications. - : Springer Nature. - 2041-1723. ; 15:1
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Journal article (peer-reviewed)abstract
- X-ray-induced damage is one of the key topics in radiation chemistry. Substantial damage is attributed to low-energy electrons and radicals emerging from direct inner-shell photoionization or produced by subsequent processes. We apply multi-electron coincidence spectroscopy to X-ray-irradiated aqueous solutions of inorganic ions to investigate the production of low-energy electrons (LEEs) in a predicted cascade of intermolecular charge- and energy-transfer processes, namely electron-transfer-mediated decay (ETMD) and interatomic/intermolecular Coulombic decay (ICD). An advanced coincidence technique allows us to identify several LEE-producing steps during the decay of 1s vacancies in solvated Mg2+ ions, which escaped observation in previous non-coincident experiments. We provide strong evidence for the predicted recovering of the ion’s initial state. In natural environments the recovering of the ion’s initial state is expected to cause inorganic ions to be radiation-damage hot spots, repeatedly producing destructive particles under continuous irradiation.
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9. |
- Bos, Isabelle, et al.
(author)
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The frequency and influence of dementia risk factors in prodromal Alzheimer's disease
- 2017
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In: Neurobiology of Aging. - : Elsevier. - 0197-4580 .- 1558-1497. ; 56, s. 33-40
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Journal article (peer-reviewed)abstract
- We investigated whether dementia risk factors were associated with prodromal Alzheimer's disease (AD) according to the International Working Group-2 and National Institute of Aging-Alzheimer's Association criteria, and with cognitive decline. A total of 1394 subjects with mild cognitive impairment from 14 different studies were classified according to these research criteria, based on cognitive performance and biomarkers. We compared the frequency of 10 risk factors between the subgroups, and used Cox-regression to examine the effect of risk factors on cognitive decline. Depression, obesity, and hypercholesterolemia occurred more often in individuals with low-AD-likelihood, compared with those with a high-AD-likelihood. Only alcohol use increased the risk of cognitive decline, regardless of AD pathology. These results suggest that traditional risk factors for AD are not associated with prodromal AD or with progression to dementia, among subjects with mild cognitive impairment. Future studies should validate these findings and determine whether risk factors might be of influence at an earlier stage (i.e., preclinical) of AD.
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10. |
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11. |
- Campos-Pereira, Hugo, et al.
(author)
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Effect of pH, surface charge and soil properties on the solid-solution partitioning of perfluoroalkyl substances (PFASs) in a wide range of temperate soils
- 2023
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In: Chemosphere. - : PERGAMON-ELSEVIER SCIENCE LTD. - 0045-6535 .- 1879-1298. ; 321
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Journal article (peer-reviewed)abstract
- The pH-dependent soil-water partitioning of six perfluoroalkyl substances (PFASs) of environmental concern (PFOA, PFDA, PFUnDA, PFHxS, PFOS and FOSA), was investigated for 11 temperate mineral soils and related to soil properties such as organic carbon content (0.2-3%), concentrations of Fe and Al (hydr)oxides, and texture. PFAS sorption was positively related to the perfluorocarbon chain length of the molecule, and inversely related to solution pH for all substances. The negative slope between log Kd and pH became steeper with increasing perfluorocarbon chain length of the PFAS (r2 = 0.75, p <= 0.05). Organic carbon (OC) alone was a poor predictor of the partitioning for all PFASs, except for FOSA (r2 = 0.71), and the OC-normalized PFAS partitioning, as derived from organic soil materials, underestimated PFAS sorption to the soils. Multiple linear regression suggested sorption contributions (p <= 0.05) from OC for perfluorooctane sulfonate (PFOS) and FOSA, and Fe/Al (hydr) oxides for PFOS, FOSA, and perfluorodecanoate (PFDA). FOSA was the only substance under study for which there was a statistically significant correlation between its binding and soil texture (silt + clay). To predict PFAS sorption, the surface net charge of the soil organic matter fraction of all soils was calculated using the Stockholm Humic Model. When calibrated against charge-dependent PFAS sorption to a peat (Oe) material, the derived model significantly underestimated the measured Kd values for 10 out of 11 soils. To conclude, additional
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12. |
- de Jong, Roelof S., et al.
(author)
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4MOST-4-metre Multi-Object Spectroscopic Telescope
- 2014
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In: Ground-based and Airborne Instrumentation for Astronomy V. - : SPIE. - 0277-786X .- 1996-756X. ; 9147
-
Conference paper (peer-reviewed)abstract
- 4MOST is a wide-field, high-multiplex spectroscopic survey facility under development for the VISTA telescope of the European Southern Observatory (ESO). Its main science drivers are in the fields of galactic archeology, high-energy physics, galaxy evolution and cosmology. 4MOST will in particular provide the spectroscopic complements to the large area surveys coming from space missions like Gaia, eROSITA, Euclid, and PLATO and from ground-based facilities like VISTA, VST, DES, LSST and SKA. The 4MOST baseline concept features a 2.5 degree diameter field-of-view with similar to 2400 fibres in the focal surface that are configured by a fibre positioner based on the tilting spine principle. The fibres feed two types of spectrographs; similar to 1600 fibres go to two spectrographs with resolution R> 5000 (lambda similar to 390-930 nm) and similar to 800 fibres to a spectrograph with R> 18,000 (lambda similar to 392-437 nm & 515-572 nm & 605-675 nm). Both types of spectrographs are fixed-configuration, three-channel spectrographs. 4MOST will have an unique operations concept in which 5 year public surveys from both the consortium and the ESO community will be combined and observed in parallel during each exposure, resulting in more than 25 million spectra of targets spread over a large fraction of the southern sky. The 4MOST Facility Simulator (4FS) was developed to demonstrate the feasibility of this observing concept. 4MOST has been accepted for implementation by ESO with operations expected to start by the end of 2020. This paper provides a top-level overview of the 4MOST facility, while other papers in these proceedings provide more detailed descriptions of the instrument concept[1], the instrument requirements development[2], the systems engineering implementation[3], the instrument model[4], the fibre positioner concepts[5], the fibre feed[6], and the spectrographs[7].
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13. |
- Gattringer, Johannes P., et al.
(author)
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Flooding tolerance of four floodplain meadow species depends on age
- 2017
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In: PLOS ONE. - : PUBLIC LIBRARY SCIENCE. - 1932-6203. ; 12:5
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Journal article (peer-reviewed)abstract
- Numerous restoration campaigns focused on re-establishing species-rich floodplain meadows of Central Europe, whose species composition is essentially controlled by regular flooding. Climate change predictions expect strong alterations on the discharge regime of Europe's large rivers with little-known consequences on floodplain meadow plants. In this study, we aim to determine the effects of flooding on seedlings of different ages of four typical flood meadow species. To this end, we flooded seedlings of two familial pairs of flood meadow species of wetter and dryer microhabitats for 2 weeks each, starting 2, 4, 6, and 8 weeks after seedling germination, respectively. We show that a 2-week-flooding treatment had a negative effect on performance of seedlings younger than 6 weeks. Summer floods with high floodwater temperatures may have especially detrimental effects on seedlings, which is corroborated by previous findings. As expected, the plants from wet floodplain meadow microhabitats coped better with the flooding treatment than those from dryer microhabitats. In conclusion, our results suggest that restoration measures may perform more successfully if seedlings of restored species are older than the critical age of about 6 weeks before a spring flooding begins. Seasonal flow patterns may influence vegetation dynamics of floodplain meadows and should, therefore, be taken into account when timing future restoration campaigns.
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14. |
- Godoy, Patricio, et al.
(author)
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Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME
- 2013
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In: Archives of Toxicology. - : Springer Science and Business Media LLC. - 0340-5761 .- 1432-0738. ; 87:8, s. 1315-1530
-
Research review (peer-reviewed)abstract
- This review encompasses the most important advances in liver functions and hepatotoxicity and analyzes which mechanisms can be studied in vitro. In a complex architecture of nested, zonated lobules, the liver consists of approximately 80 % hepatocytes and 20 % non-parenchymal cells, the latter being involved in a secondary phase that may dramatically aggravate the initial damage. Hepatotoxicity, as well as hepatic metabolism, is controlled by a set of nuclear receptors (including PXR, CAR, HNF-4 alpha, FXR, LXR, SHP, VDR and PPAR) and signaling pathways. When isolating liver cells, some pathways are activated, e.g., the RAS/MEK/ERK pathway, whereas others are silenced (e.g. HNF-4 alpha), resulting in up- and downregulation of hundreds of genes. An understanding of these changes is crucial for a correct interpretation of in vitro data. The possibilities and limitations of the most useful liver in vitro systems are summarized, including three-dimensional culture techniques, co-cultures with non-parenchymal cells, hepatospheres, precision cut liver slices and the isolated perfused liver. Also discussed is how closely hepatoma, stem cell and iPS cell-derived hepatocyte-like-cells resemble real hepatocytes. Finally, a summary is given of the state of the art of liver in vitro and mathematical modeling systems that are currently used in the pharmaceutical industry with an emphasis on drug metabolism, prediction of clearance, drug interaction, transporter studies and hepatotoxicity. One key message is that despite our enthusiasm for in vitro systems, we must never lose sight of the in vivo situation. Although hepatocytes have been isolated for decades, the hunt for relevant alternative systems has only just begun.
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15. |
- Hampel, Harald, et al.
(author)
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Lithium trial in Alzheimer's disease : a randomized, single-blind, placebo-controlled, multicenter 10-week study
- 2009
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In: Journal of Clinical Psychiatry. - 0160-6689 .- 1555-2101. ; 70:6, s. 922-931
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Journal article (peer-reviewed)abstract
- OBJECTIVE: Lithium, a first-line drug for the treatment of bipolar depression, has recently been shown to regulate glycogen synthase kinase-3 (GSK-3), a kinase that is involved in the phosphorylation of the tau protein. Since hyperphosphorylation of tau is a core pathological feature in Alzheimer's disease, lithium-induced inhibition of GSK-3 activity may have therapeutic effects in Alzheimer's disease. In the current study, we tested the effect of short-term lithium treatment in patients with Alzheimer's disease. METHOD: A total of 71 patients with mild Alzheimer's disease (Mini-Mental State Examination score > or = 21 and < or = 26) were successfully randomly assigned to placebo (N = 38) or lithium treatment (N = 33) at 6 academic expert memory clinics. The 10-week treatment included a 6-week titration phase to reach the target serum level of lithium (0.5-0.8 mmol/L). The primary outcome measures were cerebrospinal fluid (CSF) levels of phosphorylated tau (p-tau) and GSK-3 activity in lymphocytes. Secondary outcome measures were CSF concentration of total tau and beta-amyloid(1-42) (Abeta(1-42)), plasma levels of Abeta(1-42), Alzheimer's Disease Assessment Scale (ADAS)-Cognitive summary scores, MMSE, and Neuropsychiatric Inventory (NPI). Patients were enrolled in the study from November 2004 to July 2005. RESULTS: No treatment effect on GSK-3 activity or CSF-based biomarker concentrations (P > .05) was observed. Lithium treatment did not lead to change in global cognitive performance as measured by the ADAS-Cog subscale (P = .11) or in depressive symptoms. CONCLUSIONS: The current results do not support the notion that lithium treatment may lead to reduced hyperphosphorylation of tau protein after a short 10-week treatment in the Alzheimer's disease target population.
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16. |
- Hess, Timo, et al.
(author)
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Dissecting the genetic heterogeneity of gastric cancer
- 2023
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In: EBioMedicine. - : Elsevier. - 2352-3964. ; 92
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Journal article (peer-reviewed)abstract
- Background: Gastric cancer (GC) is clinically heterogenous according to location (cardia/non-cardia) and histopathology (diffuse/intestinal). We aimed to characterize the genetic risk architecture of GC according to its subtypes. Another aim was to examine whether cardia GC and oesophageal adenocarcinoma (OAC) and its precursor lesion Barrett's oesophagus (BO), which are all located at the gastro-oesophageal junction (GOJ), share polygenic risk architecture.Methods: We did a meta-analysis of ten European genome-wide association studies (GWAS) of GC and its subtypes. All patients had a histopathologically confirmed diagnosis of gastric adenocarcinoma. For the identification of risk genes among GWAS loci we did a transcriptome-wide association study (TWAS) and expression quantitative trait locus (eQTL) study from gastric corpus and antrum mucosa. To test whether cardia GC and OAC/BO share genetic aetiology we also used a European GWAS sample with OAC/BO.Findings: Our GWAS consisting of 5816 patients and 10,999 controls highlights the genetic heterogeneity of GC according to its subtypes. We newly identified two and replicated five GC risk loci, all of them with subtype-specific association. The gastric transcriptome data consisting of 361 corpus and 342 antrum mucosa samples revealed that an upregulated expression of MUC1, ANKRD50, PTGER4, and PSCA are plausible GC-pathomechanisms at four GWAS loci. At another risk locus, we found that the blood-group 0 exerts protective effects for non-cardia and diffuse GC, while blood-group A increases risk for both GC subtypes. Furthermore, our GWAS on cardia GC and OAC/BO (10,279 patients, 16,527 controls) showed that both cancer entities share genetic aetiology at the polygenic level and identified two new risk loci on the single-marker level.Interpretation: Our findings show that the pathophysiology of GC is genetically heterogenous according to location and histopathology. Moreover, our findings point to common molecular mechanisms underlying cardia GC and OAC/BO.
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17. |
- Jackson, Guy, et al.
(author)
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Gods, Spirits and Natural Hazards : Ontologies and Epistemologies of Natural Hazards and Climate Change in Kiribati and Papua New Guinea
- 2021
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In: Beyond Belief : Opportunities for Faith-Engaged Approaches to Climate-Change Adaptation in the Pacific Islands - Opportunities for Faith-Engaged Approaches to Climate-Change Adaptation in the Pacific Islands. - 9783030676018 - 9783030676049 - 9783030676025 ; , s. 81-98
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Book chapter (peer-reviewed)abstract
- Pacific Island countries are already experiencing severe impacts from climate change and these will likely increase in the future. In response, a plethora of climate change adaptation projects have been implemented across the region with the aim of assisting those most affected. Yet these projects have largely failed to reduce vulnerability to climate change in a meaningful way. This chapter addresses a commonly overlooked, but argued here to be crucial, reason for failure: how religion shapes local perspectives of climate change, and the lack of acknowledgement with these by external actors. We address this gap through exploring the changing ontological and epistemological understandings of climate change and hazards among two distinct cultural groups from the Pacific Islands—the Bedamuni of Western Province, Papua New Guinea and the I-Kiribati. To structure our diachronic investigation, we explore the drivers of socio-cultural change across three periods: pre-contact, colonial and missionary, and contemporary. A complex story of interaction with exogenous ideas and syncretism is portrayed within both societies. Yet today we find the Bedamuni continuing to draw heavily from traditional belief systems, especially the presence and influence of spirits, to explain hazards while simultaneously being devout Christians. Despite noting changes in weather and seasonality, Bedamuni people have had little exposure to global climate change discourses. Conversely, the I-Kiribati, as the occupants of one of the countries most exposed to climate change, have had relatively high exposure to scientific climate change discourses. Notwithstanding this, I-Kiribati mostly draw from Christian beliefs to explain natural phenomena while maintaining traditional beliefs in gods, spirits and magic. Like others in the Pacific, these cultures have unique histories, ontologies and epistemologies so, for climate change adaptation to be successful in the region, governments, agencies, and NGOs must acknowledge that no two places are alike and that understanding recipients’ ontological worldviews and accommodating these into adaptation strategies is an essential starting point for the development of effective future strategies.
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18. |
- Jansen, Iris E, et al.
(author)
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Genome-wide meta-analysis for Alzheimer's disease cerebrospinal fluid biomarkers.
- 2022
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In: Acta neuropathologica. - : Springer Science and Business Media LLC. - 1432-0533 .- 0001-6322. ; 144:5, s. 821-842
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Journal article (peer-reviewed)abstract
- Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer's disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n=8074; replication n=5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aβ42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple Aβ42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume.
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19. |
- Jones, Benedict C, et al.
(author)
-
To which world regions does the valence-dominance model of social perception apply?
- 2021
-
In: Nature Human Behaviour. - : Springer Science and Business Media LLC. - 2397-3374. ; 5:1, s. 159-169
-
Journal article (peer-reviewed)abstract
- Over the past 10 years, Oosterhof and Todorov's valence-dominance model has emerged as the most prominent account of how people evaluate faces on social dimensions. In this model, two dimensions (valence and dominance) underpin social judgements of faces. Because this model has primarily been developed and tested in Western regions, it is unclear whether these findings apply to other regions. We addressed this question by replicating Oosterhof and Todorov's methodology across 11 world regions, 41 countries and 11,570 participants. When we used Oosterhof and Todorov's original analysis strategy, the valence-dominance model generalized across regions. When we used an alternative methodology to allow for correlated dimensions, we observed much less generalization. Collectively, these results suggest that, while the valence-dominance model generalizes very well across regions when dimensions are forced to be orthogonal, regional differences are revealed when we use different extraction methods and correlate and rotate the dimension reduction solution. PROTOCOL REGISTRATION: The stage 1 protocol for this Registered Report was accepted in principle on 5 November 2018. The protocol, as accepted by the journal, can be found at https://doi.org/10.6084/m9.figshare.7611443.v1 .
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20. |
- Kikuchi, Johannes, et al.
(author)
-
Analysis of per- and polyfluoroalkyl substances (PFASs) in soil from Swedish background sites
- 2018
-
Reports (other academic/artistic)abstract
- Syftet med denna studie var att undersöka miljökoncentrationer, sammansättning och potentiella geografiska trender av 28 PFAS-ämnen i mark från svenska bakgrundsområden. Totalt analyserades 31 jordprover tagna på olika skogsmarksområden i Sverige. Vi detekterade 15 PFAS-ämnen och den totala koncentrationen var i genomsnitt 2,4 ng Σ28PFAS per gram torrsubstans (TS). De dominerande PFAS-ämnena var perfluoroktansulfonsyra (PFOS, 20 %), fluoroktansulfonamidättiksyra (FOSAA, 15 %), 6:2 fluortelomersulfonsyra (6:2 FTSA, 14 %) och perfluorbutansulfonsyra (PFBS, 13 %). PFOS hade också den högsta detektionsfrekvensen (77 %) och en mediankoncentration på 0,30 ng g-1 TS (n = 31). Dess halt översteg dock inte riktvärdet för känslig markanvändning (3 ng g-1 TS; Statens geotekniska institut) i något av fallen. Om man antar samma toxicitet för samtliga PFAS-ämnen, så översteg Σ28PFAS riktvärdet för PFOS i 9 fall av 31 (29 %). PFOS och perfluorundekankarboxylsyra (PFUnDA) uppvisade ökande koncentrationer från norr till söder (signifikant negativ korrelation med latitud; p < 0,05), medan FOSAA uppvisade det motsatta (p <0,05). Andelen PFOS (%) uppvisade på samma sätt en ökande trend från norr till söder (signifikant negativ korrelation med latitud; p < 0,05) och motsatt trend för FOSAA (p < 0,05). Koncentrationen av PFBS uppvisade ökande koncentrationer från väst till öst (signifikant negativ korrelation med longitud; p < 0,05). Några PFAS-ämnen uppvisade signifikant positiv korrelation med markens halt av totalt organiskt kol (TOC, mg g-1 TS), t.ex. FOSAA, PFBS och perfluortridekankarboxylsyra (PFTriDA) som var signifikant positivt korrelerade med TOC (p < 0,05). En signifikant positiv korrelation påvisades också mellan halten FOSAA och PFTriDA samt PFBS (p < 0,05). Vår studie har visat att PFAS-ämnen kan detekteras i skogsmark i hela landet och att det finns signifikanta geografiska trender, både i riktningarna nord-syd och väst-öst. Ytterligare studier behövs för att kunna förklara dessa samband, klargöra mekanismerna för spridningen och för att finna eventuella områden med högre halter (s.k. hot-spots).
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21. |
- Kikuchi, Johannes, et al.
(author)
-
Analysis of per- and polyfluoroalkyl substances (PFASs) in soil from Swedish background sites
- 2018
-
Reports (other academic/artistic)abstract
- Per- and polyfluoroalkyl substances (PFASs) are persistent organic pollutants with bioaccumulative and toxic potential. This study investigated the levels, composition profiles and geographical distribution of 28 PFASs in 31 soil samples from Swedish background areas. In total, 15 of the 28 analysed PFASs were detected, with an average concentration of 2.4 ng g-1 dw (median of 1.9 ng g-1 dw, n = 31). The dominant PFASs in the soil samples were perfluorooctane sulfonic acid (PFOS) (20 % of the ∑28PFASs), perfluorooctane sulfonamidoacetic acid (FOSAA, 15 %), 6:2 fluorotelomer sulfonic acid (6:2 FTSA, 14 %) and perfluorobutane sulfonic acid (PFBS, 13 %). Perfluorooctane sulfonic acid (PFOS) had also the highest detection frequency of the studied PFASs (77 %) in the soil samples with a median concentration of 0.30 ng g-1 dw. However, the guideline value for PFOS in soil for sensitive land use from the Swedish Geotechnical Institute (SGI) (3 ng g-1 dw) was not exceeded in any sample. However, assuming the same toxicity for all PFASs, the ∑28PFAS concentrations exceeded the guideline value (3 ng g-1 dw) in 9 out of 31 samples (29 %). PFOS and perfluoroundecanoic acid (PFUnDA) concentrations showed higher concentrations towards the south (significant negative correlation with latitude; p < 0.05), while FOSAA showed an opposite trend (p < 0.05). Furthermore, PFBS showed higher concentrations towards the west (significant negative correlation with longitude; p < 0.05). The proportion of PFOS (%) decreased significantly with latitude (i.e. towards the south), while the proportion of FOSAA (%) increased with latitude (p < 0.05). Furthermore, the concentrations of FOSAA, PFBS and perfluorotridecanoic acid (PFTriDA) showed a significant positive correlation with total organic carbon (TOC) (p < 0.05). The concentrations of FOSAA correlated significantly positive with both PFTriDA and PFBS (p < 0.05). Overall, PFASs were ubiquitously detected in Swedish background soil samples and showed distinguish geographical distribution. However, more data are needed regarding the pathways and sources of PFASs in soil and identifying potential hot spots.
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22. |
- Kim, Min, et al.
(author)
-
Primary fatty amides in plasma associated with brain amyloid burden, hippocampal volume, and memory in the European Medical Information Framework for Alzheimer's Disease biomarker discovery cohort
- 2019
-
In: Alzheimer's & Dementia. - : Elsevier. - 1552-5260 .- 1552-5279. ; 15:6, s. 817-827
-
Journal article (peer-reviewed)abstract
- INTRODUCTION: A critical and as-yet unmet need in Alzheimer's disease (AD) is the discovery of peripheral small molecule biomarkers. Given that brain pathology precedes clinical symptom onset, we set out to test whether metabolites in blood associated with pathology as indexed by cerebrospinal fluid (CSF) AD biomarkers.METHODS: This study analyzed 593 plasma samples selected from the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery study, of individuals who were cognitively healthy (n = 242), had mild cognitive impairment (n = 236), or had AD-type dementia (n = 115). Logistic regressions were carried out between plasma metabolites (n = 883) and CSF markers, magnetic resonance imaging, cognition, and clinical diagnosis.RESULTS: Eight metabolites were associated with amyloid β and one with t-tau in CSF, these were primary fatty acid amides (PFAMs), lipokines, and amino acids. From these, PFAMs, glutamate, and aspartate also associated with hippocampal volume and memory.DISCUSSION: PFAMs have been found increased and associated with amyloid β burden in CSF and clinical measures.
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23. |
- Küçükali, Fahri, et al.
(author)
-
Whole-exome rare-variant analysis of Alzheimer's disease and related biomarker traits
- 2023
-
In: Alzheimer's & Dementia. - : John Wiley & Sons. - 1552-5260 .- 1552-5279. ; 19:6, s. 2317-2331
-
Journal article (peer-reviewed)abstract
- INTRODUCTION: Despite increasing evidence of a role of rare genetic variation in the risk of Alzheimer's disease (AD), limited attention has been paid to its contribution to AD-related biomarker traits indicative of AD-relevant pathophysiological processes.METHODS: We performed whole-exome gene-based rare-variant association studies (RVASs) of 17 AD-related traits on whole-exome sequencing (WES) data generated in the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) study (n = 450) and whole-genome sequencing (WGS) data from ADNI (n = 808).RESULTS: Mutation screening revealed a novel probably pathogenic mutation (PSEN1 p.Leu232Phe). Gene-based RVAS revealed the exome-wide significant contribution of rare coding variation in RBKS and OR7A10 to cognitive performance and protection against left hippocampal atrophy, respectively.DISCUSSION: The identification of these novel gene-trait associations offers new perspectives into the role of rare coding variation in the distinct pathophysiological processes culminating in AD, which may lead to identification of novel therapeutic and diagnostic targets.
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24. |
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25. |
- Liebi, Marianne, 1984, et al.
(author)
-
3D nanoscale analysis of bone healing around degrading Mg implants evaluated by X-ray scattering tensor tomography
- 2021
-
In: Acta Biomaterialia. - : Elsevier BV. - 1878-7568 .- 1742-7061. ; 134, s. 804-817
-
Journal article (peer-reviewed)abstract
- The nanostructural adaptation of bone is crucial for its biocompatibility with orthopedic implants. The bone nanostructure also determines its mechanical properties and performance. However, the bone's temporal and spatial nanoadaptation around degrading implants remains largely unknown. Here, we present insights into this important bone adaptation by applying scanning electron microscopy, elemental analysis, and small-angle X-ray scattering tensor tomography (SASTT). We extend the novel SASTT reconstruction method and provide a 3D scattering reciprocal space map per voxel of the sample's volume. From this reconstruction, parameters such as the thickness of the bone mineral particles are quantified, which provide additional information on nanostructural adaptation of bone during healing. We selected a rat femoral bone and a degrading ZX10 magnesium implant as model system, and investigated it over the course of 18 months, using a sham as control. We observe that the bone's nanostructural adaptation starts with an initially fast interfacial bone growth close to the implant, which spreads by a re-orientation of the nanostructure in the bone volume around the implant, and is consolidated in the later degradation stages. These observations reveal the complex bulk bone-implant interactions and enable future research on the related biomechanical bone responses. Statement of significance: Traumatic bone injuries are among the most frequent causes of surgical treatment, and often require the placement of an implant. The ideal implant supports and induces bone formation, while being mechanically and chemically adapted to the bone structure, ensuring a gradual load transfer. While magnesium implants fulfill these requirements, the nanostructural changes during bone healing and implant degradation remain not completely elucidated. Here, we unveil these processes in rat femoral bones with ZX10 magnesium implants and show different stages of bone healing in such a model system.
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26. |
- Lind, Lovisa, et al.
(author)
-
Effects of initial leaching for estimates of mass loss and microbial decomposition-Call for an increased nuance
- 2022
-
In: Ecology and Evolution. - : John Wiley & Sons. - 2045-7758. ; 12:8, s. 1-10
-
Journal article (peer-reviewed)abstract
- Decomposition is essential to carbon, nutrient, and energy cycling among and within ecosystems. Several methods have been proposed for studying litter decomposition by using a standardized and commercially available substrate. One of these methods is the Tea Bag Index (TBI) which uses tea bags (green and rooibos tea) incubated for similar to 90 days. The TBI is now applied all over the globe, but despite its usefulness and wide application, the TBI (as well as other methods) does not explicitly account for the differences in potential loss of litter mass due to initial leaching in habitats with large differences in moisture. We, therefore, studied the short-term mass losses (3-4 h) due to initial leaching under field and laboratory conditions for green and rooibos tea using the TBI and contextualized our findings using existing long-term mass loss (90 days) in the field for both aquatic and terrestrial environments. For both tea litter types, we found a fast initial leaching rate, which could be mistaken for decomposition through microbial activity. This initial leaching was higher than the hydrolyzable fraction given in the description of the TBI. We also found that leaching increased with increasing temperature and that leaching in terrestrial environments with high soil moisture (> 90%) is almost as large as in aquatic environments. When comparing our findings to long-term studies, we found that up to 30-50% of the mass loss of green tea reported as decomposition could be lost through leaching alone in high moisture environments (> 90% soil moisture and submerged). Not accounting for such differences in initial leaching across habitats may lead to a systematic overestimation of the microbial decomposition in wet habitats. Future studies of microbial decomposition should adjust their methods depending on the habitat, and clearly specify the type of decomposition that the study focuses on.
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27. |
- López-Ballesteros, Ana, et al.
(author)
-
Towards a feasible and representative pan-African research infrastructure network for GHG observations
- 2018
-
In: Environmental Research Letters. - : IOP Publishing. - 1748-9326. ; 13:8
-
Journal article (peer-reviewed)abstract
- There is currently a lack of representative, systematic and harmonised greenhouse gas (GHG) observations covering the variety of natural and human-altered biomes that occur in Africa. This impedes the long-term assessment of the drivers of climate change, in addition to their impacts and feedback loops at the continental scale, but also limits our understanding of the contribution of the African continent to the global carbon (C) cycle. Given the current and projected transformation of socio-economic conditions in Africa (i.e. the increasing trend of urbanisation and population growth) and the adverse impacts of climate change, the development of a GHG research infrastructure (RI) is needed to support the design of suitable mitigation and adaptation strategies required to assure food, fuel, nutrition and economic security for the African population. This paper presents the initial results of the EU-African SEACRIFOG project, which aims to design a GHG observation RI for Africa. The first stages of this project included the identification and engagement of key stakeholders, the definition of the conceptual monitoring framework and an assessment of existing infrastructural capacity. Feedback from stakeholder sectors was obtained through three Stakeholder Consultation Workshops held in Kenya, Ghana and Zambia. Main concerns identified were data quality and accessibility, the need for capacity building and networking among the scientific community, and adaptation to climate change, which was confirmed to be a priority for Africa. This feedback in addition to input from experts in the atmospheric, terrestrial and oceanic thematic areas, facilitated the selection of a set of 'essential variables' that need to be measured in the future environmental RI. An inventory of 47 existing and planned networks across the continent allowed for an assessment of the current RIs needs and gaps in Africa. Overall, the development of a harmonised and standardised pan-African RI will serve to address the continent's primary societal and scientific challenges through a potential cross-domain synergy among existing and planned networks at regional, continental and global scales.
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28. |
- Merbold, Lutz, et al.
(author)
-
Opportunities for an African greenhouse gas observation system
- 2021
-
In: Regional Environmental Change. - : Springer Science and Business Media LLC. - 1436-3798 .- 1436-378X. ; 21:4
-
Journal article (peer-reviewed)abstract
- Global population projections foresee the biggest increase to occur in Africa with most of the available uncultivated land to ensure food security remaining on the continent. Simultaneously, greenhouse gas emissions are expected to rise due to ongoing land use change, industrialisation, and transport amongst other reasons with Africa becoming a major emitter of greenhouse gases globally. However, distinct knowledge on greenhouse gas emissions sources and sinks as well as their variability remains largely unknown caused by its vast size and diversity and an according lack of observations across the continent. Thus, an environmental research infrastructure—as being setup in other regions—is more needed than ever. Here, we present the results of a design study that developed a blueprint for establishing such an environmental research infrastructure in Africa. The blueprint comprises an inventory of already existing observations, the spatial disaggregation of locations that will enable to reduce the uncertainty in climate forcing’s in Africa and globally as well as an overall estimated cost for such an endeavour of about 550 M€ over the next 30 years. We further highlight the importance of the development of an e-infrastructure, the necessity for capacity development and the inclusion of all stakeholders to ensure African ownership.
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29. |
- Müller, Petra, et al.
(author)
-
Inter-laboratory study on standardized MPS libraries : evaluation of performance, concordance, and sensitivity using mixtures and degraded DNA
- 2020
-
In: International Journal of Legal Medicine. - : Springer Science and Business Media LLC. - 0937-9827 .- 1437-1596. ; 134:1, s. 185-198
-
Journal article (peer-reviewed)abstract
- We present results from an inter-laboratory massively parallel sequencing (MPS) study in the framework of the SeqForSTRs project to evaluate forensically relevant parameters, such as performance, concordance, and sensitivity, using a standardized sequencing library including reference material, mixtures, and ancient DNA samples. The standardized library was prepared using the ForenSeq DNA Signature Prep Kit (primer mix A). The library was shared between eight European laboratories located in Austria, France, Germany, The Netherlands, and Sweden to perform MPS on their particular MiSeq FGx sequencers. Despite variation in performance between sequencing runs, all laboratories obtained quality metrics that fell within the manufacturer’s recommended ranges. Furthermore, differences in locus coverage did not inevitably adversely affect heterozygous balance. Inter-laboratory concordance showed 100% concordant genotypes for the included autosomal and Y-STRs, and still, X-STR concordance exceeded 83%. The exclusive reasons for X-STR discordances were drop-outs at DXS10103. Sensitivity experiments demonstrated that correct allele calling varied between sequencing instruments in particular for lower DNA amounts (≤ 125 pg). The analysis of compromised DNA samples showed the drop-out of one sample (FA10013B01A) while for the remaining three degraded DNA samples MPS was able to successfully type ≥ 87% of all aSTRs, ≥ 78% of all Y-STRs, ≥ 68% of all X-STRs, and ≥ 92% of all iSNPs demonstrating that MPS is a promising tool for human identity testing, which in return, has to undergo rigorous in-house validation before it can be implemented into forensic routine casework.
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30. |
- Patel, Riyaz S., et al.
(author)
-
Association of Chromosome 9p21 With Subsequent Coronary Heart Disease Events : A GENIUS-CHD Study of Individual Participant Data
- 2019
-
In: Circulation. - 2574-8300. ; 12:4
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Genetic variation at chromosome 9p21 is a recognized risk factor for coronary heart disease (CHD). However, its effect on disease progression and subsequent events is unclear, raising questions about its value for stratification of residual risk.METHODS: A variant at chromosome 9p21 (rs1333049) was tested for association with subsequent events during follow-up in 103 357 Europeans with established CHD at baseline from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) Consortium (73.1% male, mean age 62.9 years). The primary outcome, subsequent CHD death or myocardial infarction (CHD death/myocardial infarction), occurred in 13 040 of the 93 115 participants with available outcome data. Effect estimates were compared with case/control risk obtained from the CARDIoGRAMplusC4D consortium (Coronary Artery Disease Genome-wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) including 47 222 CHD cases and 122 264 controls free of CHD.RESULTS: Meta-analyses revealed no significant association between chromosome 9p21 and the primary outcome of CHD death/myocardial infarction among those with established CHD at baseline (GENIUSCHD odds ratio, 1.02; 95% CI, 0.99-1.05). This contrasted with a strong association in CARDIoGRAMPlusC4D odds ratio 1.20; 95% CI, 1.18-1.22; P for interaction < 0.001 compared with the GENIUS-CHD estimate. Similarly, no clear associations were identified for additional subsequent outcomes, including all-cause death, although we found a modest positive association between chromosome 9p21 and subsequent revascularization (odds ratio, 1.07; 95% CI, 1.04-1.09).CONCLUSIONS: In contrast to studies comparing individuals with CHD to disease-free controls, we found no clear association between genetic variation at chromosome 9p21 and risk of subsequent acute CHD events when all individuals had CHD at baseline. However, the association with subsequent revascularization may support the postulated mechanism of chromosome 9p21 for promoting atheroma development.
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31. |
- Patel, Riyaz S., et al.
(author)
-
Subsequent Event Risk in Individuals With Established Coronary Heart Disease : Design and Rationale of the GENIUS-CHD Consortium
- 2019
-
In: Circulation. - 2574-8300. ; 12:4
-
Journal article (peer-reviewed)abstract
- BACKGROUND: The Genetics of Subsequent Coronary Heart Disease (GENIUS-CHD) consortium was established to facilitate discovery and validation of genetic variants and biomarkers for risk of subsequent CHD events, in individuals with established CHD.METHODS: The consortium currently includes 57 studies from 18 countries, recruiting 185 614 participants with either acute coronary syndrome, stable CHD, or a mixture of both at baseline. All studies collected biological samples and followed-up study participants prospectively for subsequent events.RESULTS: Enrollment into the individual studies took place between 1985 to present day with a duration of follow-up ranging from 9 months to 15 years. Within each study, participants with CHD are predominantly of self-reported European descent (38%-100%), mostly male (44%-91%) with mean ages at recruitment ranging from 40 to 75 years. Initial feasibility analyses, using a federated analysis approach, yielded expected associations between age (hazard ratio, 1.15; 95% CI, 1.14-1.16) per 5-year increase, male sex (hazard ratio, 1.17; 95% CI, 1.13-1.21) and smoking (hazard ratio, 1.43; 95% CI, 1.35-1.51) with risk of subsequent CHD death or myocardial infarction and differing associations with other individual and composite cardiovascular endpoints.CONCLUSIONS: GENIUS-CHD is a global collaboration seeking to elucidate genetic and nongenetic determinants of subsequent event risk in individuals with established CHD, to improve residual risk prediction and identify novel drug targets for secondary prevention. Initial analyses demonstrate the feasibility and reliability of a federated analysis approach. The consortium now plans to initiate and test novel hypotheses as well as supporting replication and validation analyses for other investigators.
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32. |
- Petrescu, Ana Maria Roxana, et al.
(author)
-
The uncertain climate footprint of wetlands under human pressure
- 2015
-
In: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 112:15, s. 4594-4599
-
Journal article (peer-reviewed)abstract
- Significant climate risks are associated with a positive carbon-temperature feedback in northern latitude carbon-rich ecosystems, making an accurate analysis of human impacts on the net greenhouse gas balance of wetlands a priority. Here, we provide a coherent assessment of the climate footprint of a network of wetland sites based on simultaneous and quasi-continuous ecosystem observations of CO2 and CH4 fluxes. Experimental areas are located both in natural and in managed wetlands and cover a wide range of climatic regions, ecosystem types, and management practices. Based on direct observations we predict that sustained CH4 emissions in natural ecosystems are in the long term (i.e., several centuries) typically offset by CO2 uptake, although with large spatiotemporal variability. Using a space-for-time analogy across ecological and climatic gradients, we represent the chronosequence from natural to managed conditions to quantify the "cost" of CH4 emissions for the benefit of net carbon sequestration. With a sustained pulse-response radiative forcing model, we found a significant increase in atmospheric forcing due to land management, in particular for wetland converted to cropland. Our results quantify the role of human activities on the climate footprint of northern wetlands and call for development of active mitigation strategies for managed wetlands and new guidelines of the Intergovernmental Panel on Climate Change (IPCC) accounting for both sustained CH4 emissions and cumulative CO2 exchange.
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33. |
- Pohl, Johannes, et al.
(author)
-
Embryotoxicity of ozonated diclofenac, carbamazepine, and oxazepam in zebrafish (Danio rerio)
- 2019
-
In: Chemosphere. - : Elsevier BV. - 0045-6535 .- 1879-1298. ; 225, s. 191-199
-
Journal article (peer-reviewed)abstract
- Pharmaceutical residues are polluting the surface water environments worldwide. Sewage and wastewater treatment, therefore, needs to be improved in order to remove pharmaceutical residues from the effluent. One such treatment improvement is effluent ozonation. Even though ozonation has proven to be very efficient in reducing pharmaceutical parent compound concentrations in wastewater effluents, much remains unclear regarding potentially toxic ozonation by-product (OBP) formation. In this study, we sought to elucidate the aquatic toxicity of ozonated pharmaceuticals in zebrafish (Danio rerio) embryos in a static 144 h post fertilization (hpf) fish embryotoxicity (ZFET) assay. Three pharmaceuticals commonly detected in wastewater effluents, i.e. carbamazepine, diclofenac, and oxazepam, were selected for testing. Toxicity was assessed before and after 1 min ozonation (0.053 mg L-1 peak O-3 concentration) and 10 min ozonation (0.147 mg L-1 peak O-3 concentration). Chemical analysis showed that carbamazepine and diclofenac were largely removed by ozone (90 +/- 11% and 97 +/- 3.8%), whereas oxazepam was removed to a lesser extent (19 +/- 5.7%). The ZFET assay revealed diverging toxicities. Diclofenac embryotoxicity decreased with increasing ozonation. Oxazepam did not cause embryotoxicity in the ZFET assay either pre- or post ozonation, but larvae swimming activity was affected at 144 hpf. Carbamazepine embryotoxicity, on the other hand, increased with increasing ozonation. Chemical analysis showed the formation of two OBPs (carbamazepine-10,11-epoxide and 10,11-dihydrocarbamazepine), possibly explaining the increased embryotoxicity. The results of this study highlight the importance of new chemical and toxicological knowledge regarding the formation of OBPs in post-ozonated effluents. (C) 2019 The Authors. Published by Elsevier Ltd.
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34. |
- Richards, Stephen, et al.
(author)
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The genome of the model beetle and pest Tribolium castaneum.
- 2008
-
In: Nature. - 1476-4687. ; 452:7190, s. 949-55
-
Journal article (peer-reviewed)abstract
- Tribolium castaneum is a representative of earth’s most numerous eukaryotic order, a powerful model organism for the study of generalized insect development, and also an important pest of stored agricultural products. We describe its genome sequence here. This omnivorous beetle has evolved an ability to interact with a diverse chemical environment as evidenced by large expansions in odorant and gustatory receptors, as well as p450 and other detoxification enzymes. Developmental patterns in Tribolium are more representative of other arthropods than those found in Drosophila, a fact represented in gene content and function. For one, Tribolium has retained more ancestral genes involved in cell-cell communication than Drosophila, and some are expressed in the growth zone crucial for axial elongation in short germ development. Systemic RNAi in T. castaneum appears to use mechanisms distinct from those found in C. elegans, but nevertheless offers similar power for the elucidation of gene function and identification of targets for selective insect control.
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35. |
- Selezska, Katherina, et al.
(author)
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Pseudomonas aeruginosa population structure revisited under environmental focus: impact of water quality and phage pressure.
- 2012
-
In: Environmental Microbiology. - : Wiley. - 1462-2920 .- 1462-2912. ; 14:8, s. 1952-1967
-
Journal article (peer-reviewed)abstract
- Pseudomonas aeruginosa attracts research attention as a common opportunistic nosocomial pathogen causing severe health problems in humans. Nevertheless, its primary habitat is the natural environment. Here, we relate the genetic diversity of 381 environmental isolates from rivers in northern Germany to ecological factors such as river system, season of sampling and different levels of water quality. From representatives of 99 environmental clones, also in comparison with 91 clinical isolates, we determined motility phenotypes, virulence factors, biofilm formation, serotype and the resistance to seven environmental P. aeruginosa phages. The integration of genetic, ecological and phenotypic data showed (i) the presence of several extended clonal complexes (ecc) which are non-uniformly distributed across different water qualities, and (ii) a correlation of the hosts' serotype composition with susceptibility towards distinct groups of environmental phages. For at least one ecc (eccB), we assumed the ecophysiological differences on environmental water adaptation and phage resistance to be so distinct as to reinforce an environmentally driven cladogenic split from the remainder of P. aeruginosa. In summary, we conclude that the majority of the microevolutionary population dynamics of P. aeruginosa were shaped by the natural environment and not by the clinical habitat.
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36. |
- Shevela, Dmitriy, et al.
(author)
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Biogenesis of water splitting by photosystem II during de-etiolation of barley (Hordeum vulgare L.)
- 2016
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In: Plant, Cell and Environment. - : John Wiley & Sons. - 0140-7791 .- 1365-3040. ; 39:7, s. 1524-1536
-
Journal article (peer-reviewed)abstract
- Etioplasts lack thylakoid membranes and photosystem complexes. Light triggers differentiation of etioplasts into mature chloroplasts, and photosystem complexes assemble in parallel with thylakoid membrane development. Plastids isolated at various time points of de-etiolation are ideal to study the kinetic biogenesis of photosystem complexes during chloroplast development. Here, we investigated the chronology of photosystem II (PSII) biogenesis by monitoring assembly status of chlorophyll-binding protein complexes and development of water splitting via O2 production in plastids (etiochloroplasts) isolated during de-etiolation of barley (Hordeum vulgare L.). Assembly of PSII monomers, dimers and complexes binding outer light-harvesting antenna [PSII-light-harvesting complex II (LHCII) supercomplexes] was identified after 1, 2 and 4 h of de-etiolation, respectively. Water splitting was detected in parallel with assembly of PSII monomers, and its development correlated with an increase of bound Mn in the samples. After 4 h of de-etiolation, etiochloroplasts revealed the same water-splitting efficiency as mature chloroplasts. We conclude that the capability of PSII to split water during de-etiolation precedes assembly of the PSII-LHCII supercomplexes. Taken together, data show a rapid establishment of water-splitting activity during etioplast-to-chloroplast transition and emphasize that assembly of the functional water-splitting site of PSII is not the rate-limiting step in the formation of photoactive thylakoid membranes.
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37. |
- Shevela, Dmitriy, 1979-, et al.
(author)
-
'Birth defects' of photosystem II make it highly susceptible to photodamage during chloroplast biogenesis
- 2019
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In: Physiologia Plantarum. - : Wiley-Blackwell. - 0031-9317 .- 1399-3054. ; 166:1, s. 165-180
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Journal article (peer-reviewed)abstract
- High solar flux is known to diminish photosynthetic growth rates, reducing biomass productivity and lowering disease tolerance. Photosystem II (PSII) of plants is susceptible to photodamage (also known as photoinactivation) in strong light, resulting in severe loss of water oxidation capacity and destruction of the water‐oxidizing complex (WOC). The repair of damaged PSIIs comes at a high energy cost and requires de novo biosynthesis of damaged PSII subunits, reassembly of the WOC inorganic cofactors and membrane remodeling. Employing membrane‐inlet mass spectrometry and O2‐polarography under flashing light conditions, we demonstrate that newly synthesized PSII complexes are far more susceptible to photodamage than are mature PSII complexes. We examined these ‘PSII birth defects’ in barley seedlings and plastids (etiochloroplasts and chloroplasts) isolated at various times during de‐etiolation as chloroplast development begins and matures in synchronization with thylakoid membrane biogenesis and grana membrane formation. We show that the degree of PSII photodamage decreases simultaneously with biogenesis of the PSII turnover efficiency measured by O2‐polarography, and with grana membrane stacking, as determined by electron microscopy. Our data from fluorescence, QB‐inhibitor binding, and thermoluminescence studies indicate that the decline of the high‐light susceptibility of PSII to photodamage is coincident with appearance of electron transfer capability QA− → QB during de‐etiolation. This rate depends in turn on the downstream clearing of electrons upon buildup of the complete linear electron transfer chain and the formation of stacked grana membranes capable of longer‐range energy transfer.
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38. |
- Shi, Liu, et al.
(author)
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Dickkopf-1 Overexpression in vitro Nominates Candidate Blood Biomarkers Relating to Alzheimer's Disease Pathology.
- 2020
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In: Journal of Alzheimer's disease : JAD. - : IOS Press. - 1875-8908 .- 1387-2877. ; 77:3, s. 1353-1368
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Journal article (peer-reviewed)abstract
- Previous studies suggest that Dickkopf-1 (DKK1), an inhibitor of Wnt signaling, plays a role in amyloid-induced toxicity and hence Alzheimer's disease (AD). However, the effect of DKK1 expression on protein expression, and whether such proteins are altered in disease, is unknown.We aim to test whether DKK1 induced protein signature obtained in vitro were associated with markers of AD pathology as used in the amyloid/tau/neurodegeneration (ATN) framework as well as with clinical outcomes.We first overexpressed DKK1 in HEK293A cells and quantified 1,128 proteins in cell lysates using aptamer capture arrays (SomaScan) to obtain a protein signature induced by DKK1. We then used the same assay to measure the DKK1-signature proteins in human plasma in two large cohorts, EMIF (n = 785) and ANM (n = 677).We identified a 100-protein signature induced by DKK1 in vitro. Subsets of proteins, along with age and apolipoprotein E ɛ4 genotype distinguished amyloid pathology (A + T-N-, A+T+N-, A+T-N+, and A+T+N+) from no AD pathology (A-T-N-) with an area under the curve of 0.72, 0.81, 0.88, and 0.85, respectively. Furthermore, we found that some signature proteins (e.g., Complement C3 and albumin) were associated with cognitive score and AD diagnosis in both cohorts.Our results add further evidence for a role of DKK regulation of Wnt signaling in AD and suggest that DKK1 induced signature proteins obtained in vitro could reflect theATNframework as well as predict disease severity and progression in vivo.
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39. |
- Shi, Liu, et al.
(author)
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Discovery and validation of plasma proteomic biomarkers relating to brain amyloid burden by SOMAscan assay.
- 2019
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In: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279 .- 1552-5260. ; 15:11, s. 1478-1488
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Journal article (peer-reviewed)abstract
- Plasma proteins have been widely studied as candidate biomarkers to predict brain amyloid deposition to increase recruitment efficiency in secondary prevention clinical trials for Alzheimer's disease. Most such biomarker studies are targeted to specific proteins or are biased toward high abundant proteins.4001 plasma proteins were measured in two groups of participants (discovery group=516, replication group=365) selected from the European Medical Information Framework for Alzheimer's disease Multimodal Biomarker Discovery study, all of whom had measures of amyloid.A panel of proteins (n=44), along with age and apolipoprotein E (APOE) ε4, predicted brain amyloid deposition with good performance in both the discovery group (area under the curve=0.78) and the replication group (area under the curve=0.68). Furthermore, a causal relationship between amyloid and tau was confirmed by Mendelian randomization.The results suggest that high-dimensional plasma protein testing could be a useful and reproducible approach for measuring brain amyloid deposition.
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40. |
- Shi, Liu, et al.
(author)
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Replication study of plasma proteins relating to Alzheimer's pathology.
- 2021
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In: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279 .- 1552-5260. ; 17:9, s. 1452-1464
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Journal article (peer-reviewed)abstract
- This study sought to discover and replicate plasma proteomic biomarkers relating to Alzheimer's disease (AD) including both the "ATN" (amyloid/tau/neurodegeneration) diagnostic framework and clinical diagnosis.Plasma proteins from 972 subjects (372 controls, 409 mild cognitive impairment [MCI], and 191 AD) were measured using both SOMAscan and targeted assays, including 4001 and 25 proteins, respectively.Protein co-expression network analysis of SOMAscan data revealed the relation between proteins and "N" varied across different neurodegeneration markers, indicating that the ATN variants are not interchangeable. Using hub proteins, age, and apolipoprotein E ε4 genotype discriminated AD from controls with an area under the curve (AUC) of 0.81 and MCI convertors from non-convertors with an AUC of 0.74. Targeted assays replicated the relation of four proteins with the ATN framework and clinical diagnosis.Our study suggests that blood proteins can predict the presence of AD pathology as measured in the ATN framework as well as clinical diagnosis.
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41. |
- Stamate, Daniel, et al.
(author)
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A metabolite-based machine learning approach to diagnose Alzheimer-type dementia in blood : Results from the European Medical Information Framework for Alzheimer disease biomarker discovery cohort
- 2019
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In: Alzheimer’s & Dementia. - : John Wiley & Sons. - 2352-8737. ; 5:C, s. 933-938
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Journal article (peer-reviewed)abstract
- IntroductionMachine learning (ML) may harbor the potential to capture the metabolic complexity in Alzheimer Disease (AD). Here we set out to test the performance of metabolites in blood to categorize AD when compared to CSF biomarkers.MethodsThis study analyzed samples from 242 cognitively normal (CN) people and 115 with AD‐type dementia utilizing plasma metabolites (n = 883). Deep Learning (DL), Extreme Gradient Boosting (XGBoost) and Random Forest (RF) were used to differentiate AD from CN. These models were internally validated using Nested Cross Validation (NCV).ResultsOn the test data, DL produced the AUC of 0.85 (0.80–0.89), XGBoost produced 0.88 (0.86–0.89) and RF produced 0.85 (0.83–0.87). By comparison, CSF measures of amyloid, p‐tau and t‐tau (together with age and gender) produced with XGBoost the AUC values of 0.78, 0.83 and 0.87, respectively.DiscussionThis study showed that plasma metabolites have the potential to match the AUC of well‐established AD CSF biomarkers in a relatively small cohort. Further studies in independent cohorts are needed to validate whether this specific panel of blood metabolites can separate AD from controls, and how specific it is for AD as compared with other neurodegenerative disorders.
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42. |
- Sörengård, Mattias, et al.
(author)
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Spatial distribution and load of per- and polyfluoroalkyl substances (PFAS) in background soils in Sweden
- 2022
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In: Chemosphere. - : Elsevier BV. - 0045-6535 .- 1879-1298. ; 295
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Journal article (peer-reviewed)abstract
- Per- and polyfluoroalkyl substances (PFAS) are known to be persistent, bioaccumulative, and have adverse health effects, but very little is known about PFAS in the terrestrial environment and factors influencing their distribution. This paper presents one of the first comprehensive studies investigating PFAS (n = 28) in background forest soils (n = 27) on national scale across Sweden. The results showed that 16 of 28 target PFAS were present and all sites contained at least three PFAS compounds, with total concentrations ranging between 0.40 ng/g dry weight (dw) and 6.6 ng/g dw. Perfluorooctanesulfonic acid (PFOS) showed the highest detection frequency of 89% and a median concentration of 0.39 ng/g dw. The PFOS loads (ng/m(3)) showed a distinct spatial distribution, with a significant exponential increase from north to south (R-2 = 0.55; p < 0.001) and west to east (R-2 = 0.35; p < 0.01). In some parts of Sweden, the compound 6:2 fluorotelomer sulfonate (6:2 FTSA) had a higher median concentration (1.4 ng/g dw), but was in comparison to PFOS more impacted by local sources. Partial least squares discriminant analysis (PLS-DA) showed regional clustering of PFAS compositional profiles, indicating that PFAS soil background concentrations are functions of spatial variations at local, regional, and countrywide scale. Such spatial trends have not been observed previously and it could not be deduced whether they are indicative of trends on a global scale, or country-specific and better explained by proximity to densely populated urban areas. An interpolation and extrapolation raster map created from the results was used to calculate the average total PFAS load on Swedish soils. Estimated total load in the top 10-cm soil layer was 2.7 +/- 2.4 tons for PFOS and 16 +/- 14 tons for n-ary sumation PFAS, indicating that soil carries a considerable legacy of past PFAS release.
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43. |
- Visser, Pieter Jelle, et al.
(author)
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Cerebrospinal fluid total tau levels indicate aberrant neuronal plasticity in Alzheimer's disease.
- 2020
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In: medRxiv : the preprint server for health sciences. - : Cold Spring Harbor Laboratory.
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Journal article (other academic/artistic)abstract
- Alzheimer's disease (AD) is characterised by abnormal amyloid beta and tau processing. Previous studies reported that cerebrospinal fluid (CSF) total tau (t-tau) levels vary between patients. Here we show that CSF t-tau variability is associated with distinct impairments in neuronal plasticity mediated by gene repression factors SUZ12 and REST. AD individuals with abnormal t-tau levels have increased CSF concentrations of plasticity proteins regulated by SUZ12 and REST. AD individuals with normal t-tau, on the contrary, have decreased concentrations of these plasticity proteins and increased concentrations in proteins associated with blood-brain and blood CSF-barrier dysfunction. Genomic analyses suggested that t-tau levels in part depend on genes involved in gene expression. The distinct plasticity abnormalities in AD as signaled by t-tau urge the need for personalised treatment.
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44. |
- Vos, Stephanie J. B., et al.
(author)
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Prevalence and prognosis of Alzheimer's disease at the mild cognitive impairment stage
- 2015
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In: Brain. - : Oxford University Press. - 0006-8950 .- 1460-2156. ; 138:5, s. 1327-1338
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Journal article (peer-reviewed)abstract
- Three sets of research criteria are available for diagnosis of Alzheimer's disease in subjects with mild cognitive impairment: the International Working Group-1, International Working Group-2, and National Institute of Aging-Alzheimer Association criteria. We compared the prevalence and prognosis of Alzheimer's disease at the mild cognitive impairment stage according to these criteria. Subjects with mild cognitive impairment (n = 1607), 766 of whom had both amyloid and neuronal injury markers, were recruited from 13 cohorts. We used cognitive test performance and available biomarkers to classify subjects as prodromal Alzheimer's disease according to International Working Group-1 and International Working Group-2 criteria and in the high Alzheimer's disease likelihood group, conflicting biomarker groups (isolated amyloid pathology or suspected non-Alzheimer pathophysiology), and low Alzheimer's disease likelihood group according to the National Institute of Ageing-Alzheimer Association criteria. Outcome measures were the proportion of subjects with Alzheimer's disease at the mild cognitive impairment stage and progression to Alzheimer's disease-type dementia. We performed survival analyses using Cox proportional hazards models. According to the International Working Group-1 criteria, 850 (53%) subjects had prodromal Alzheimer's disease. Their 3-year progression rate to Alzheimer's disease-type dementia was 50% compared to 21% for subjects without prodromal Alzheimer's disease. According to the International Working Group-2 criteria, 308 (40%) subjects had prodromal Alzheimer's disease. Their 3-year progression rate to Alzheimer's disease-type dementia was 61% compared to 22% for subjects without prodromal Alzheimer's disease. According to the National Institute of Ageing-Alzheimer Association criteria, 353 (46%) subjects were in the high Alzheimer's disease likelihood group, 49 (6%) in the isolated amyloid pathology group, 220 (29%) in the suspected non-Alzheimer pathophysiology group, and 144 (19%) in the low Alzheimer's disease likelihood group. The 3-year progression rate to Alzheimer's disease-type dementia was 59% in the high Alzheimer's disease likelihood group, 22% in the isolated amyloid pathology group, 24% in the suspected non-Alzheimer pathophysiology group, and 5% in the low Alzheimer's disease likelihood group. Our findings support the use of the proposed research criteria to identify Alzheimer's disease at the mild cognitive impairment stage. In clinical settings, the use of both amyloid and neuronal injury markers as proposed by the National Institute of Ageing-Alzheimer Association criteria offers the most accurate prognosis. For clinical trials, selection of subjects in the National Institute of Ageing-Alzheimer Association high Alzheimer's disease likelihood group or the International Working Group-2 prodromal Alzheimer's disease group could be considered.
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45. |
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46. |
- Westwood, Sarah, et al.
(author)
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Validation of Plasma Proteomic Biomarkers Relating to Brain Amyloid Burden in the EMIF-Alzheimer's Disease Multimodal Biomarker Discovery Cohort
- 2020
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In: Journal of Alzheimer's Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 74:1, s. 213-225
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Journal article (peer-reviewed)abstract
- We have previously investigated, discovered, and replicated plasma protein biomarkers for use to triage potential trials participants for PET or cerebrospinal fluid measures of Alzheimer's disease (AD) pathology. This study sought to undertake validation of these candidate plasma biomarkers in a large, multi-center sample collection. Targeted plasma analyses of 34 proteins with prior evidence for prediction of in vivo pathology were conducted in up to 1,000 samples from cognitively healthy elderly individuals, people with mild cognitive impairment, and in patients with AD-type dementia, selected from the EMIF-AD catalogue. Proteins were measured using Luminex xMAP, ELISA, and Meso Scale Discovery assays. Seven proteins replicated in their ability to predict in vivo amyloid pathology. These proteins form a biomarker panel that, along with age, could significantly discriminate between individuals with high and low amyloid pathology with an area under the curve of 0.74. The performance of this biomarker panel remained consistent when tested in apolipoprotein E ɛ4 non-carrier individuals only. This blood-based panel is biologically relevant, measurable using practical immunocapture arrays, and could significantly reduce the cost incurred to clinical trials through screen failure.
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47. |
- Xu, Jin, et al.
(author)
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Sex-Specific Metabolic Pathways Were Associated with Alzheimer's Disease (AD) Endophenotypes in the European Medical Information Framework for AD Multimodal Biomarker Discovery Cohort
- 2021
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In: Biomedicines. - : MDPI. - 2227-9059. ; 9:11
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Journal article (peer-reviewed)abstract
- BACKGROUND: physiological differences between males and females could contribute to the development of Alzheimer's Disease (AD). Here, we examined metabolic pathways that may lead to precision medicine initiatives.METHODS: We explored whether sex modifies the association of 540 plasma metabolites with AD endophenotypes including diagnosis, cerebrospinal fluid (CSF) biomarkers, brain imaging, and cognition using regression analyses for 695 participants (377 females), followed by sex-specific pathway overrepresentation analyses, APOE ε4 stratification and assessment of metabolites' discriminatory performance in AD.RESULTS: In females with AD, vanillylmandelate (tyrosine pathway) was increased and tryptophan betaine (tryptophan pathway) was decreased. The inclusion of these two metabolites (area under curve (AUC) = 0.83, standard error (SE) = 0.029) to a baseline model (covariates + CSF biomarkers, AUC = 0.92, SE = 0.019) resulted in a significantly higher AUC of 0.96 (SE = 0.012). Kynurenate was decreased in males with AD (AUC = 0.679, SE = 0.046).CONCLUSIONS: metabolic sex-specific differences were reported, covering neurotransmission and inflammation pathways with AD endophenotypes. Two metabolites, in pathways related to dopamine and serotonin, were associated to females, paving the way to personalised treatment.
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48. |
- Zabl, Johannes, et al.
(author)
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MusE GAs FLOw and Wind (MEGAFLOW) II. A study of gas accretion around z approximate to 1 star-forming galaxies with background quasars
- 2019
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In: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 485:2, s. 1961-1980
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Journal article (peer-reviewed)abstract
- We use the MusE GAs FLOw and Wind (MEGAFLOW) survey to study the kinematics of extended disc-like structures of cold gas around z approximate to 1 star-forming galaxies. The combination of VLT/MUSE and VLT/UVES observations allows us to connect the kinematics of the gas measured through MgII quasar absorption spectroscopy to the kinematics and orientation of the associated galaxies constrained through integral field spectroscopy. Confirming previous results, we find that the galaxy-absorber pairs of the MEGAFLOW survey follow a strong bimodal distribution, consistent with a picture of MgII absorption being predominantly present in outflow cones and extended disc-like structures. This allows us to select a bona-fide sample of galaxy-absorber pairs probing these discs for impact paramometers of 10-70 kpc. We test the hypothesis that the disc-like gas is co-rotating with the galaxy discs, and find that for seven out of nine pairs the absorption velocity shares the sign of the disc velocity, disfavouring random orbits. We further show that the data are roughly consistent with inflow velocities and angular momenta predicted by simulations, and that the corresponding mass accretion rates are sufficient to balance the star formation rates.
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49. |
- Zamora, Juan Carlos, et al.
(author)
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Considerations and consequences of allowing DNA sequence data as types of fungal taxa
- 2018
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In: IMA Fungus. - : INT MYCOLOGICAL ASSOC. - 2210-6340 .- 2210-6359. ; 9:1, s. 167-185
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Journal article (peer-reviewed)abstract
- Nomenclatural type definitions are one of the most important concepts in biological nomenclature. Being physical objects that can be re-studied by other researchers, types permanently link taxonomy (an artificial agreement to classify biological diversity) with nomenclature (an artificial agreement to name biological diversity). Two proposals to amend the International Code of Nomenclature for algae, fungi, and plants (ICN), allowing DNA sequences alone (of any region and extent) to serve as types of taxon names for voucherless fungi (mainly putative taxa from environmental DNA sequences), have been submitted to be voted on at the 11th International Mycological Congress (Puerto Rico, July 2018). We consider various genetic processes affecting the distribution of alleles among taxa and find that alleles may not consistently and uniquely represent the species within which they are contained. Should the proposals be accepted, the meaning of nomenclatural types would change in a fundamental way from physical objects as sources of data to the data themselves. Such changes are conducive to irreproducible science, the potential typification on artefactual data, and massive creation of names with low information content, ultimately causing nomenclatural instability and unnecessary work for future researchers that would stall future explorations of fungal diversity. We conclude that the acceptance of DNA sequences alone as types of names of taxa, under the terms used in the current proposals, is unnecessary and would not solve the problem of naming putative taxa known only from DNA sequences in a scientifically defensible way. As an alternative, we highlight the use of formulas for naming putative taxa (candidate taxa) that do not require any modification of the ICN.
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