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1.
  • Fenstermacher, M.E., et al. (författare)
  • DIII-D research advancing the physics basis for optimizing the tokamak approach to fusion energy
  • 2022
  • Ingår i: Nuclear Fusion. - : IOP Publishing. - 0029-5515 .- 1741-4326. ; 62:4
  • Tidskriftsartikel (refereegranskat)abstract
    • DIII-D physics research addresses critical challenges for the operation of ITER and the next generation of fusion energy devices. This is done through a focus on innovations to provide solutions for high performance long pulse operation, coupled with fundamental plasma physics understanding and model validation, to drive scenario development by integrating high performance core and boundary plasmas. Substantial increases in off-axis current drive efficiency from an innovative top launch system for EC power, and in pressure broadening for Alfven eigenmode control from a co-/counter-I p steerable off-axis neutral beam, all improve the prospects for optimization of future long pulse/steady state high performance tokamak operation. Fundamental studies into the modes that drive the evolution of the pedestal pressure profile and electron vs ion heat flux validate predictive models of pedestal recovery after ELMs. Understanding the physics mechanisms of ELM control and density pumpout by 3D magnetic perturbation fields leads to confident predictions for ITER and future devices. Validated modeling of high-Z shattered pellet injection for disruption mitigation, runaway electron dissipation, and techniques for disruption prediction and avoidance including machine learning, give confidence in handling disruptivity for future devices. For the non-nuclear phase of ITER, two actuators are identified to lower the L-H threshold power in hydrogen plasmas. With this physics understanding and suite of capabilities, a high poloidal beta optimized-core scenario with an internal transport barrier that projects nearly to Q = 10 in ITER at ∼8 MA was coupled to a detached divertor, and a near super H-mode optimized-pedestal scenario with co-I p beam injection was coupled to a radiative divertor. The hybrid core scenario was achieved directly, without the need for anomalous current diffusion, using off-axis current drive actuators. Also, a controller to assess proximity to stability limits and regulate β N in the ITER baseline scenario, based on plasma response to probing 3D fields, was demonstrated. Finally, innovative tokamak operation using a negative triangularity shape showed many attractive features for future pilot plant operation.
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  • 2021
  • swepub:Mat__t
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3.
  • Bravo, L, et al. (författare)
  • 2021
  • swepub:Mat__t
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4.
  • Tabiri, S, et al. (författare)
  • 2021
  • swepub:Mat__t
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5.
  • Tran, K. B., et al. (författare)
  • The global burden of cancer attributable to risk factors, 2010-19: a systematic analysis for the Global Burden of Disease Study 2019
  • 2022
  • Ingår i: Lancet. - 0140-6736. ; 400:10352, s. 563-591
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Understanding the magnitude of cancer burden attributable to potentially modifiable risk factors is crucial for development of effective prevention and mitigation strategies. We analysed results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 to inform cancer control planning efforts globally. Methods The GBD 2019 comparative risk assessment framework was used to estimate cancer burden attributable to behavioural, environmental and occupational, and metabolic risk factors. A total of 82 risk-outcome pairs were included on the basis of the World Cancer Research Fund criteria. Estimated cancer deaths and disability-adjusted life-years (DALYs) in 2019 and change in these measures between 2010 and 2019 are presented. Findings Globally, in 2019, the risk factors included in this analysis accounted for 4.45 million (95% uncertainty interval 4.01-4.94) deaths and 105 million (95.0-116) DALYs for both sexes combined, representing 44.4% (41.3-48.4) of all cancer deaths and 42.0% (39.1-45.6) of all DALYs. There were 2.88 million (2.60-3.18) risk-attributable cancer deaths in males (50.6% [47.8-54.1] of all male cancer deaths) and 1.58 million (1.36-1.84) risk-attributable cancer deaths in females (36.3% [32.5-41.3] of all female cancer deaths). The leading risk factors at the most detailed level globally for risk-attributable cancer deaths and DALYs in 2019 for both sexes combined were smoking, followed by alcohol use and high BMI. Risk-attributable cancer burden varied by world region and Socio-demographic Index (SDI), with smoking, unsafe sex, and alcohol use being the three leading risk factors for risk-attributable cancer DALYs in low SDI locations in 2019, whereas DALYs in high SDI locations mirrored the top three global risk factor rankings. From 2010 to 2019, global risk-attributable cancer deaths increased by 20.4% (12.6-28.4) and DALYs by 16.8% (8.8-25.0), with the greatest percentage increase in metabolic risks (34.7% [27.9-42.8] and 33.3% [25.8-42.0]). Interpretation The leading risk factors contributing to global cancer burden in 2019 were behavioural, whereas metabolic risk factors saw the largest increases between 2010 and 2019. Reducing exposure to these modifiable risk factors would decrease cancer mortality and DALY rates worldwide, and policies should be tailored appropriately to local cancer risk factor burden. Copyright (C) 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.
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6.
  • 2021
  • swepub:Mat__t
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  • Glasbey, JC, et al. (författare)
  • 2021
  • swepub:Mat__t
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9.
  • Campbell, PJ, et al. (författare)
  • Pan-cancer analysis of whole genomes
  • 2020
  • Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 578:7793, s. 82-
  • Tidskriftsartikel (refereegranskat)abstract
    • Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale1–3. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter4; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation5,6; analyses timings and patterns of tumour evolution7; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity8,9; and evaluates a range of more-specialized features of cancer genomes8,10–18.
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10.
  • Bryazka, D., et al. (författare)
  • Population-level risks of alcohol consumption by amount, geography, age, sex, and year: a systematic analysis for the Global Burden of Disease Study 2020
  • 2022
  • Ingår i: Lancet. - 0140-6736. ; 400:10347, s. 185-235
  • Tidskriftsartikel (refereegranskat)abstract
    • Background The health risks associated with moderate alcohol consumption continue to be debated. Small amounts of alcohol might lower the risk of some health outcomes but increase the risk of others, suggesting that the overall risk depends, in part, on background disease rates, which vary by region, age, sex, and year. Methods For this analysis, we constructed burden-weighted dose-response relative risk curves across 22 health outcomes to estimate the theoretical minimum risk exposure level (TMREL) and non-drinker equivalence (NDE), the consumption level at which the health risk is equivalent to that of a non-drinker, using disease rates from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2020 for 21 regions, including 204 countries and territories, by 5-year age group, sex, and year for individuals aged 15-95 years and older from 1990 to 2020. Based on the NDE, we quantified the population consuming harmful amounts of alcohol. Findings The burden-weighted relative risk curves for alcohol use varied by region and age. Among individuals aged 15-39 years in 2020, the TMREL varied between 0 (95% uncertainty interval 0-0) and 0.603 (0.400-1.00) standard drinks per day, and the NDE varied between 0.002 (0-0) and 1.75 (0.698-4.30) standard drinks per day. Among individuals aged 40 years and older, the burden-weighted relative risk curve was J-shaped for all regions, with a 2020 TMREL that ranged from 0.114 (0-0.403) to 1.87 (0.500-3.30) standard drinks per day and an NDE that ranged between 0.193 (0-0.900) and 6.94 (3.40-8.30) standard drinks per day. Among individuals consuming harmful amounts of alcohol in 2020, 59.1% (54.3-65.4) were aged 15-39 years and 76.9% (7.0-81.3) were male. Interpretation There is strong evidence to support recommendations on alcohol consumption varying by age and location. Stronger interventions, particularly those tailored towards younger individuals, are needed to reduce the substantial global health loss attributable to alcohol. Copyright (C) 2022 The Author(s). Published by Elsevier Ltd.
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16.
  • Bousquet, J, et al. (författare)
  • Nrf2-interacting nutrients and COVID-19: time for research to develop adaptation strategies
  • 2020
  • Ingår i: Clinical and translational allergy. - : Wiley. - 2045-7022. ; 10:1, s. 58-
  • Tidskriftsartikel (refereegranskat)abstract
    • There are large between- and within-country variations in COVID-19 death rates. Some very low death rate settings such as Eastern Asia, Central Europe, the Balkans and Africa have a common feature of eating large quantities of fermented foods whose intake is associated with the activation of the Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) anti-oxidant transcription factor. There are many Nrf2-interacting nutrients (berberine, curcumin, epigallocatechin gallate, genistein, quercetin, resveratrol, sulforaphane) that all act similarly to reduce insulin resistance, endothelial damage, lung injury and cytokine storm. They also act on the same mechanisms (mTOR: Mammalian target of rapamycin, PPARγ:Peroxisome proliferator-activated receptor, NFκB: Nuclear factor kappa B, ERK: Extracellular signal-regulated kinases and eIF2α:Elongation initiation factor 2α). They may as a result be important in mitigating the severity of COVID-19, acting through the endoplasmic reticulum stress or ACE-Angiotensin-II-AT1R axis (AT1R) pathway. Many Nrf2-interacting nutrients are also interacting with TRPA1 and/or TRPV1. Interestingly, geographical areas with very low COVID-19 mortality are those with the lowest prevalence of obesity (Sub-Saharan Africa and Asia). It is tempting to propose that Nrf2-interacting foods and nutrients can re-balance insulin resistance and have a significant effect on COVID-19 severity. It is therefore possible that the intake of these foods may restore an optimal natural balance for the Nrf2 pathway and may be of interest in the mitigation of COVID-19 severity.
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17.
  • Munk, P., et al. (författare)
  • Genomic analysis of sewage from 101 countries reveals global landscape of antimicrobial resistance
  • 2022
  • Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Antimicrobial resistance (AMR) is a major threat to global health. Understanding the emergence, evolution, and transmission of individual antibiotic resistance genes (ARGs) is essential to develop sustainable strategies combatting this threat. Here, we use metagenomic sequencing to analyse ARGs in 757 sewage samples from 243 cities in 101 countries, collected from 2016 to 2019. We find regional patterns in resistomes, and these differ between subsets corresponding to drug classes and are partly driven by taxonomic variation. The genetic environments of 49 common ARGs are highly diverse, with most common ARGs carried by multiple distinct genomic contexts globally and sometimes on plasmids. Analysis of flanking sequence revealed ARG-specific patterns of dispersal limitation and global transmission. Our data furthermore suggest certain geographies are more prone to transmission events and should receive additional attention.
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18.
  • Abbafati, Cristiana, et al. (författare)
  • 2020
  • Tidskriftsartikel (refereegranskat)
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19.
  • Abdalla, H., et al. (författare)
  • HESS detection of very high-energy gamma-ray emission from the quasar PKS 0736+017
  • 2020
  • Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 633, s. 1-11
  • Tidskriftsartikel (refereegranskat)abstract
    • Context. Flat-spectrum radio-quasars (FSRQs) are rarely detected at very high energies (E& x2004;>=& x2004;100 GeV) due to their low-frequency-peaked spectral energy distributions. At present, only six FSRQs are known to emit very high-energy (VHE) photons, representing only 7% of the VHE extragalactic catalog, which is largely dominated by high-frequency-peaked BL Lacertae objects. Aims. Following the detection of MeV-GeV gamma-ray flaring activity from the FSRQ PKS 0736+017 (z& x2004;=& x2004;0.189) with Fermi-LAT, the H.E.S.S. array of Cherenkov telescopes triggered target-of-opportunity (ToO) observations on February 18, 2015, with the goal of studying the gamma-ray emission in the VHE band. Methods. H.E.S.S. ToO observations were carried out during the nights of February 18, 19, 21, and 24, 2015. Together with Fermi-LAT, the multi-wavelength coverage of the flare includes Swift observations in soft X-ray and optical-UV bands, and optical monitoring (photometry and spectro-polarimetry) by the Steward Observatory, and the ATOM, the KAIT, and the ASAS-SN telescopes. Results. VHE emission from PKS 0736+017 was detected with H.E.S.S. only during the night of February 19, 2015. Fermi-LAT data indicate the presence of a gamma-ray flare, peaking at the time of the H.E.S.S. detection, with a flux doubling timescale of around six hours. The gamma-ray flare was accompanied by at least a 1 mag brightening of the non-thermal optical continuum. No simultaneous observations at longer wavelengths are available for the night of the H.E.S.S. detection. The gamma-ray observations with H.E.S.S. and Fermi-LAT are used to put constraints on the location of the gamma-ray emitting region during the flare: it is constrained to be just outside the radius of the broad-line region r(BLR) with a bulk Lorentz factor Gamma& x2004;similar or equal to& x2004;20, or at the level of the radius of the dusty torus r(torus) with Gamma& x2004;similar or equal to& x2004;60. Conclusions. PKS 0736+017 is the seventh FSRQ known to emit VHE photons, and at z& x2004;=& x2004;0.189 is the nearest so far. The location of the gamma-ray emitting region during the flare can be tightly constrained thanks to opacity, variability, and collimation arguments.
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20.
  • Abdalla, H., et al. (författare)
  • Resolving acceleration to very high energies along the jet of Centaurus A
  • 2020
  • Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 582:7812, s. 356-359
  • Tidskriftsartikel (refereegranskat)abstract
    • The nearby radio galaxy Centaurus A belongs to a class of active galaxies that are luminous at radio wavelengths. Most show collimated relativistic outflows known as jets, which extend over hundreds of thousands of parsecs for the most powerful sources. Accretion of matter onto the central supermassive black hole is believed to fuel these jets and power their emission(1). Synchrotron radiation from relativistic electrons causes the radio emission, and it has been suggested that the X-ray emission from Centaurus A also originates in electron synchrotron processes(2-4). Another possible explanation is inverse Compton scattering with cosmic microwave background (CMB) soft photons(5-7). Synchrotron radiation needs ultrarelativistic electrons (about 50 teraelectronvolts) and, given their short cooling times, requires some continuous re-acceleration mechanism(8). Inverse Compton scattering, on the other hand, does not require very energetic electrons, but the jets must stay highly relativistic on large scales (exceeding 1 megaparsec). Some recent evidence disfavours inverse Compton-CMB models(9-12), although other work seems to be compatible with them(13,14). In principle, the detection of extended gamma-ray emission, which directly probes the presence of ultrarelativistic electrons, could distinguish between these options. At gigaelectronvolt energies there is also an unusual spectral hardening(15,16)in Centaurus A that has not yet been explained. Here we report observations of Centaurus A at teraelectronvolt energies that resolve its large-scale jet. We interpret the data as evidence for the acceleration of ultrarelativistic electrons in the jet, and favour the synchrotron explanation for the X-rays. Given that this jet is not exceptional in terms of power, length or speed, it is possible that ultrarelativistic electrons are commonplace in the large-scale jets of radio-loud active galaxies. Observations of the radio galaxy Centaurus A at teraelectronvolt energies resolve its large-scale jet and favour electron synchrotron processes as the source of its X-ray emission.
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21.
  • Abdalla, H., et al. (författare)
  • Resolving the Crab pulsar wind nebula at teraelectronvolt energies
  • 2020
  • Ingår i: Nature Astronomy. - : Nature Publishing Group. - 2397-3366. ; 4:2, s. 167-173
  • Tidskriftsartikel (refereegranskat)abstract
    • An angular extension at gamma-ray energies of 52 arcseconds is detected for the Crab nebula, revealing the emission region of the highest-energy gamma rays; simulations of the electromagnetic emission provide a non-trivial test of our understanding of particle acceleration in the Crab nebula. The Crab nebula is one of the most-studied cosmic particle accelerators, shining brightly across the entire electromagnetic spectrum up to very-high-energy gamma rays(1,2). It is known from observations in the radio to gamma-ray part of the spectrum that the nebula is powered by a pulsar, which converts most of its rotational energy losses into a highly relativistic outflow. This outflow powers a pulsar wind nebula, a region of up to ten light-years across, filled with relativistic electrons and positrons. These particles emit synchrotron photons in the ambient magnetic field and produce very-high-energy gamma rays by Compton up-scattering of ambient low-energy photons. Although the synchrotron morphology of the nebula is well established, it has not been known from which region the very-high-energy gamma rays are emitted(3-8). Here we report that the Crab nebula has an angular extension at gamma-ray energies of 52 arcseconds (assuming a Gaussian source width), much larger than at X-ray energies. This result closes a gap in the multi-wavelength coverage of the nebula, revealing the emission region of the highest-energy gamma rays. These gamma rays enable us to probe a previously inaccessible electron and positron energy range. We find that simulations of the electromagnetic emission reproduce our measurement, providing a non-trivial test of our understanding of particle acceleration in the Crab nebula.
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24.
  • Chen, Zhishan, et al. (författare)
  • Fine-mapping analysis including over 254 000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes
  • 2024
  • Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 15:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development.
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25.
  • Librado, P., et al. (författare)
  • The origins and spread of domestic horses from the Western Eurasian steppes
  • 2021
  • Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 598, s. 634-640
  • Tidskriftsartikel (refereegranskat)abstract
    • Analysis of 273 ancient horse genomes reveals that modern domestic horses originated in the Western Eurasian steppes, especially the lower Volga-Don region. Domestication of horses fundamentally transformed long-range mobility and warfare(1). However, modern domesticated breeds do not descend from the earliest domestic horse lineage associated with archaeological evidence of bridling, milking and corralling(2-4) at Botai, Central Asia around 3500 bc(3). Other longstanding candidate regions for horse domestication, such as Iberia(5) and Anatolia(6), have also recently been challenged. Thus, the genetic, geographic and temporal origins of modern domestic horses have remained unknown. Here we pinpoint the Western Eurasian steppes, especially the lower Volga-Don region, as the homeland of modern domestic horses. Furthermore, we map the population changes accompanying domestication from 273 ancient horse genomes. This reveals that modern domestic horses ultimately replaced almost all other local populations as they expanded rapidly across Eurasia from about 2000 bc, synchronously with equestrian material culture, including Sintashta spoke-wheeled chariots. We find that equestrianism involved strong selection for critical locomotor and behavioural adaptations at the GSDMC and ZFPM1 genes. Our results reject the commonly held association(7) between horseback riding and the massive expansion of Yamnaya steppe pastoralists into Europe around 3000 bc(8,9) driving the spread of Indo-European languages(10). This contrasts with the scenario in Asia where Indo-Iranian languages, chariots and horses spread together, following the early second millennium bc Sintashta culture(11,12).
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27.
  • Hellings, P. W., et al. (författare)
  • EUFOREA summit in Brussels 2023 : inspiring the future of allergy & respiratory care
  • 2023
  • Ingår i: Frontiers in Allergy. - 2673-6101. ; 4
  • Tidskriftsartikel (refereegranskat)abstract
    • In March 2023, the European Forum for Research and Education in Allergy and Airways diseases (EUFOREA) organized its bi-annual Summit in Brussels with expert panel members of EUFOREA, representatives of the EUFOREA patient advisory board, and the EUFOREA board and management teams. Its aim was to define the research, educational and advocacy initiatives to be developed by EUFOREA over the next 2 years until the 10th anniversary in 2025. EUFOREA is an international non-for-profit organization forming an alliance of all stakeholders dedicated to reducing the prevalence and burden of chronic allergic and respiratory diseases via research, education, and advocacy. Based on its medical scientific core competency, EUFOREA offers an evidence-supported platform to introduce innovation and education in healthcare leading to optimal patient care, bridging the gap between latest scientific evidence and daily practice. Aligned with the mission of improving health care, the expert panels of asthma, allergic rhinitis (AR), chronic rhinosinusitis (CRS) & European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS), allergen immunotherapy (AIT) and paediatrics have proposed and elaborated a variety of activities that correspond to major unmet needs in the allergy and respiratory field. The current report provides a concise overview of the achievements, ambitions, and action plan of EUFOREA for the future, allowing all stakeholders in the allergy and respiratory field to be up-dated and inspired to join forces in Europe and beyond.
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28.
  • Kanis, J. A., et al. (författare)
  • Use of age-dependent FRAX-based intervention thresholds for Singapore
  • 2020
  • Ingår i: Archives of Osteoporosis. - : Springer Science and Business Media LLC. - 1862-3522 .- 1862-3514. ; 15:1
  • Tidskriftsartikel (refereegranskat)abstract
    • The Summary Assessment and treatment pathways based on age-specific intervention thresholds in Singapore using FRAX paths can be used to identify patients at high risk of fracture and avoid unnecessary treatment in those at low risk. Purpose Intervention thresholds for the treatment of osteoporosis have been based historically on the measurement of bone mineral density. The development of FRAX (R) has permitted a more accurate assessment of fracture risk. The aim of the present study was to explore treatment paths and characteristics of women selected for treatment in Singapore based on FRAX. Methods The approach to the setting of intervention and assessment thresholds used the methodology adopted by the National Osteoporosis Guideline Group for FRAX-based guidelines in the UK but based on the epidemiology of fracture and death in Singapore. The methodology was applied to women age 50 years or more drawn from the population-based Singapore Chinese Health Study (SCHS) cohort. Missing data for the calculation of FRAX was simulated using data from Chinese cohorts from Hong Kong. Results Intervention thresholds expressed as a 10-year probability of a major osteoporotic fracture ranged from 2.9% at the age of 50 years increasing to 32% at the age of 90 years. A total of 1927 of 29,323 women (7%) had a prior fragility fracture and would be eligible for treatment for this reason. An additional 3019 women (10.3%) would be eligible for treatment on the basis of age-dependent thresholds. The mean BMD T-score of women so selected was -2.94. Conclusion Probability-based assessment of fracture risk using age-specific intervention thresholds was developed for Singapore to help guide decisions about treatment.
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29.
  • Lau, Angus, et al. (författare)
  • alpha-Synuclein strains target distinct brain regions and cell types
  • 2020
  • Ingår i: Nature Neuroscience. - : NATURE PUBLISHING GROUP. - 1097-6256 .- 1546-1726. ; 23, s. 21-31
  • Tidskriftsartikel (refereegranskat)abstract
    • The clinical and pathological differences between synucleinopathies such as Parkinson's disease and multiple system atrophy have been postulated to stem from unique strains of alpha-synuclein aggregates, akin to what occurs in prion diseases. Here we demonstrate that inoculation of transgenic mice with different strains of recombinant or brain-derived alpha-synuclein aggregates produces clinically and pathologically distinct diseases. Strain-specific differences were observed in the signs of neurological illness, time to disease onset, morphology of cerebral alpha-synuclein deposits and the conformational properties of the induced aggregates. Moreover, different strains targeted distinct cellular populations and cell types within the brain, recapitulating the selective targeting observed among human synucleinopathies. Strain-specific clinical, pathological and biochemical differences were faithfully maintained after serial passaging, which implies that alpha-synuclein propagates via prion-like conformational templating. Thus, pathogenic alpha-synuclein exhibits key hallmarks of prion strains, which provides evidence that disease heterogeneity among the synucleinopathies is caused by distinct alpha-synuclein strains.
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30.
  • Leung, Y., et al. (författare)
  • Cognition, function, and prevalent dementia in centenarians and near-centenarians: An individual participant data (IPD) meta-analysis of 18 studies
  • 2023
  • Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 19:6, s. 2265-2275
  • Tidskriftsartikel (refereegranskat)abstract
    • IntroductionThere are limited data on prevalence of dementia in centenarians and near-centenarians (C/NC), its determinants, and whether the risk of dementia continues to rise beyond 100. MethodsParticipant-level data were obtained from 18 community-based studies (N = 4427) in 11 countries that included individuals >= 95 years. A harmonization protocol was applied to cognitive and functional impairments, and a meta-analysis was performed. ResultsThe mean age was 98.3 years (SD = 2.67); 79% were women. After adjusting for age, sex, and education, dementia prevalence was 53.2% in women and 45.5% in men, with risk continuing to increase with age. Education (OR 0.95;0.92-0.98) was protective, as was hypertension (odds ratio [OR] 0.51;0.35-0.74) in five studies. Dementia was not associated with diabetes, vision and hearing impairments, smoking, and body mass index (BMI). DiscussionAmong the exceptional old, dementia prevalence remains higher in the older participants. Education was protective against dementia, but other factors for dementia-free survival in C/NC remain to be understood.
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34.
  • Vickman, R. E., et al. (författare)
  • Deconstructing tumor heterogeneity : The stromal perspective
  • 2020
  • Ingår i: Oncotarget. - : Impact Journals LLC. - 1949-2553. ; 11:40, s. 3621-3632
  • Tidskriftsartikel (refereegranskat)abstract
    • Significant advances have been made towards understanding the role of immune cell-tumor interplay in either suppressing or promoting tumor growth, progression, and recurrence, however, the roles of additional stromal elements, cell types and/or cell states remain ill-defined. The overarching goal of this NCI-sponsored workshop was to highlight and integrate the critical functions of non-immune stromal components in regulating tumor heterogeneity and its impact on tumor initiation, progression, and resistance to therapy. The workshop explored the opposing roles of tumor supportive versus suppressive stroma and how cellular composition and function may be altered during disease progression. It also highlighted microenvironment-centered mechanisms dictating indolence or aggressiveness of early lesions and how spatial geography impacts stromal attributes and function. The prognostic and therapeutic implications as well as potential vulnerabilities within the heterogeneous tumor microenvironment were also discussed. These broad topics were included in this workshop as an effort to identify current challenges and knowledge gaps in the field. Copyright:
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35.
  • Zuberbier, T., et al. (författare)
  • Proposal of 0.5 mg of protein/100 g of processed food as threshold for voluntary declaration of food allergen traces in processed food-A first step in an initiative to better inform patients and avoid fatal allergic reactions: A GA(2)LEN position paper
  • 2022
  • Ingår i: Allergy. - : Wiley. - 0105-4538 .- 1398-9995. ; 77:6, s. 1736-1750
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Food anaphylaxis is commonly elicited by unintentional ingestion of foods containing the allergen above the tolerance threshold level of the individual. While labeling the 14 main allergens used as ingredients in food products is mandatory in the EU, there is no legal definition of declaring potential contaminants. Precautionary allergen labeling such as "may contain traces of" is often used. However, this is unsatisfactory for consumers as they get no information if the contamination is below their personal threshold. In discussions with the food industry and technologists, it was suggested to use a voluntary declaration indicating that all declared contaminants are below a threshold of 0.5 mg protein per 100 g of food. This concentration is known to be below the threshold of most patients, and it can be technically guaranteed in most food production. However, it was also important to assess that in case of accidental ingestion of contaminants below this threshold by highly allergic patients, no fatal anaphylactic reaction could occur. Therefore, we performed a systematic review to assess whether a fatal reaction to 5mg of protein or less has been reported, assuming that a maximum portion size of 1kg of a processed food exceeds any meal and thus gives a sufficient safety margin. Methods MEDLINE and EMBASE were searched until 24 January 2021 for provocation studies and case reports in which one of the 14 major food allergens was reported to elicit fatal or life-threatening anaphylactic reactions and assessed if these occurred below the ingestion of 5mg of protein. A Delphi process was performed to obtain an expert consensus on the results. Results In the 210 studies included, in our search, no reports of fatal anaphylactic reactions reported below 5 mg protein ingested were identified. However, in provocation studies and case reports, severe reactions below 5 mg were reported for the following allergens: eggs, fish, lupin, milk, nuts, peanuts, soy, and sesame seeds. Conclusion Based on the literature studied for this review, it can be stated that cross-contamination of the 14 major food allergens below 0.5 mg/100 g is likely not to endanger most food allergic patients when a standard portion of food is consumed. We propose to use the statement "this product contains the named allergens in the list of ingredients, it may contain traces of other contaminations (to be named, e.g. nut) at concentrations less than 0.5 mg per 100 g of this product" for a voluntary declaration on processed food packages. This level of avoidance of cross-contaminations can be achieved technically for most processed foods, and the statement would be a clear and helpful message to the consumers. However, it is clearly acknowledged that a voluntary declaration is only a first step to a legally binding solution. For this, further research on threshold levels is encouraged.
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36.
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37.
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38.
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39.
  • Boateng, Irene, et al. (författare)
  • Using microbiological data to improve the use of antibiotics for respiratory tract infections: A protocol for an individual patient data meta-analysis
  • 2023
  • Ingår i: PLOS ONE. - : PUBLIC LIBRARY SCIENCE. - 1932-6203. ; 18:11
  • Tidskriftsartikel (refereegranskat)abstract
    • BackgroundResistance to antibiotics is rising and threatens future antibiotic effectiveness. 'Antibiotic targeting' ensures patients who may benefit from antibiotics receive them, while being safely withheld from those who may not. Point-of-care tests may assist with antibiotic targeting by allowing primary care clinicians to establish if symptomatic patients have a viral, bacterial, combined, or no infection. However, because organisms can be harmlessly carried, it is important to know if the presence of the virus/bacteria is related to the illness for which the patient is being assessed. One way to do this is to look for associations with more severe/prolonged symptoms and test results. Previous research to answer this question for acute respiratory tract infections has given conflicting results with studies has not having enough participants to provide statistical confidence.AimTo undertake a synthesis of IPD from both randomised controlled trials (RCTs) and observational cohort studies of respiratory tract infections (RTI) in order to investigate the prognostic value of microbiological data in addition to, or instead of, clinical symptoms and signs.MethodsA systematic search of Cochrane Central Register of Controlled Trials, Ovid Medline and Ovid Embase will be carried out for studies of acute respiratory infection in primary care settings. The outcomes of interest are duration of disease, severity of disease, repeated consultation with new/worsening illness and complications requiring hospitalisation. Authors of eligible studies will be contacted to provide anonymised individual participant data. The data will be harmonised and aggregated. Multilevel regression analysis will be conducted to determine key outcome measures for different potential pathogens and whether these offer any additional information on prognosis beyond clinical symptoms and signs.Trial registrationPROSPERO Registration number: CRD42023376769.
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40.
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41.
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42.
  • Conti, Diego M., et al. (författare)
  • A EUFOREA comment on a lost comorbidity of asthma
  • 2023
  • Ingår i: Allergy, Asthma and Clinical Immunology. - 1710-1484. ; 19:1
  • Tidskriftsartikel (refereegranskat)abstract
    • “Epidemiology of comorbidities and their association with asthma control” (Tomisa, G., Horváth, A., Sánta, B. et al. Epidemiology of comorbidities and their association with asthma control. Allergy Asthma Clin Immunol 17, 95 (2021). https://doi.org/10.1186/s13223-021-00598-3) is an interesting paper reflecting data collection from more than 12,000 asthmatic patients in Hungary regarding their condition and associated comorbidities. We found it valuable that the paper provides an overview of asthma comorbidities not usually considered in similar reports. Nevertheless, we believe that chronic rhinosinusitis (CRS) with or without nasal polyps (CRSwNP or CRSsNP) should have been listed due to its high incidence and prevalence, its association with asthma which is also endorsed in both GINA and EPOS, as well as in several peer-reviewed scientific papers, and to reflect the role of this comorbidity in poor control and a most severe presentation of asthma for the patient. Consequently, several targeted therapies (especially monoclonal antibodies) used for several years in severe forms of asthma are now indicated also for the effective treatment of nasal polyps.
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43.
  • Couto, Rafael Carvalho, et al. (författare)
  • Breaking inversion symmetry by protonation : Experimental and theoretical NEXAFS study of the diazynium ion, N2H
  • 2021
  • Ingår i: Physical Chemistry, Chemical Physics - PCCP. - : Royal Society of Chemistry (RSC). - 1463-9076 .- 1463-9084. ; 23:32, s. 17166-17176
  • Tidskriftsartikel (refereegranskat)abstract
    • As an example of symmetry breaking in NEXAFS spectra of protonated species we present a high resolution NEXAFS spectrum of protonated dinitrogen, the diazynium ion N2H+. By ab initio calculations we show that the spectrum consists of a superposition of two nitrogen 1s absorption spectra, each including a π∗ band, and a nitrogen 1s to H+ charge transfer band followed by a weak irregular progression of high energy excitations. Calculations also show that, as an effect of symmetry breaking by protonation, the π∗ transitions are separated by 0.23 eV, only slightly exceeding the difference in the corresponding dark (symmetry forbidden) and bright (symmetry allowed) core excitations of neutral N2. By DFT and calculations and vibrational analysis, the complex π∗ excitation band of N2H+ is understood as due to the superposition of the significantly different vibrational progressions of excitations from terminal and central nitrogen atoms, both leading to bent final state geometries. We also show computationally that the electronic structure of the charge transfer excitation smoothly depends on the nitrogen-proton distance and that there is a clear extension of the spectra going from infinity to close nitrogen-proton distance where fine structures show some, although not fully detailed, similarities. An interesting feature of partial localization of the nitrogen core orbitals, with a strong, non-monotonous, variation with nitrogen-proton distance could be highlighted. Specific effects could be unraveled when comparing molecular cation NEXAFS spectra, as represented by recently recorded spectra of N2+ and CO+, and spectra of protonated molecules as represented here by the N2H+ ion. Both types containing rich physical effects not represented in NEXAFS of neutral molecules because of the positive charge, whereas protonation also breaks the symmetry. The effect of the protonation on dinitrogen can be separated in charge, which extends the high-energy part of the spectrum, and symmetry-breaking, which is most clearly seen in the low-energy π∗ transition.
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44.
  • Dahlin, Anna M., 1979-, et al. (författare)
  • A genome-wide association study on medulloblastoma
  • 2020
  • Ingår i: Journal of Neuro-Oncology. - : Springer. - 0167-594X .- 1573-7373. ; 147:2, s. 309-315
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: Medulloblastoma is a malignant embryonal tumor of the cerebellum that occurs predominantly in children. To find germline genetic variants associated with medulloblastoma risk, we conducted a genome-wide association study (GWAS) including 244 medulloblastoma cases and 247 control subjects from Sweden and Denmark.Methods: Genotyping was performed using Illumina BeadChips, and untyped variants were imputed using IMPUTE2.Results: Fifty-nine variants in 11 loci were associated with increased medulloblastoma risk (p < 1 × 10–5), but none were statistically significant after adjusting for multiple testing (p < 5 × 10–8). Thirteen of these variants were genotyped, whereas 46 were imputed. Genotyped variants were further investigated in a validation study comprising 249 medulloblastoma cases and 629 control subjects. In the validation study, rs78021424 (18p11.23, PTPRM) was associated with medulloblastoma risk with OR in the same direction as in the discovery cohort (ORT = 1.59, pvalidation = 0.02). We also selected seven medulloblastoma predisposition genes for investigation using a candidate gene approach: APC, BRCA2, PALB2, PTCH1, SUFU, TP53, and GPR161. The strongest evidence for association was found for rs201458864 (PALB2, ORT = 3.76, p = 3.2 × 10–4) and rs79036813 (PTCH1, ORA = 0.42, p = 2.6 × 10–3).Conclusion: The results of this study, including a novel potential medulloblastoma risk loci at 18p11.23, are suggestive but need further validation in independent cohorts.
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45.
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46.
  • Heinonen, Ilkka, 1982-, et al. (författare)
  • Cellular, mitochondrial and molecular alterations associate with early left ventricular diastolic dysfunction in a porcine model of diabetic metabolic derangement
  • 2020
  • Ingår i: Scientific Reports. - London : Nature Publishing Group. - 2045-2322. ; 10:1
  • Tidskriftsartikel (refereegranskat)abstract
    • The prevalence of diabetic metabolic derangement (DMetD) has increased dramatically over the last decades. Although there is increasing evidence that DMetD is associated with cardiac dysfunction, the early DMetD-induced myocardial alterations remain incompletely understood. Here, we studied early DMetD-related cardiac changes in a clinically relevant large animal model. DMetD was established in adult male Göttingen miniswine by streptozotocin injections and a high-fat, high-sugar diet, while control animals remained on normal pig chow. Five months later left ventricular (LV) function was assessed by echocardiography and hemodynamic measurements, followed by comprehensive biochemical, molecular and histological analyses. Robust DMetD developed, evidenced by hyperglycemia, hypercholesterolemia and hypertriglyceridemia. DMetD resulted in altered LV nitrosoredox balance, increased superoxide production—principally due to endothelial nitric oxide synthase (eNOS) uncoupling—reduced nitric oxide (NO) production, alterations in myocardial gene-expression— particularly genes related to glucose and fatty acid metabolism—and mitochondrial dysfunction. These abnormalities were accompanied by increased passive force of isolated cardiomyocytes, and impaired LV diastolic function, evidenced by reduced LV peak untwist velocity and increased E/e′. However, LV weight, volume, collagen content, and cardiomyocyte cross-sectional area were unchanged at this stage of DMetD. In conclusion, DMetD, in a clinically relevant large-animal model results in myocardial oxidative stress, eNOS uncoupling and reduced NO production, together with an altered metabolic gene expression profle and mitochondrial dysfunction. These molecular alterations are associated with stifening of the cardiomyocytes and early diastolic dysfunction before any structural cardiac remodeling occurs. Therapies should be directed to ameliorate these early DMetDinduced myocardial changes to prevent the development of overt cardiac failure. © 2020, The Author(s).
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47.
  • Ivanics, Tommy, et al. (författare)
  • The Toronto Postliver Transplantation Hepatocellular Carcinoma Recurrence Calculator : A Machine Learning Approach
  • 2022
  • Ingår i: Liver transplantation. - : John Wiley & Sons. - 1527-6465 .- 1527-6473. ; 28:4, s. 593-602
  • Tidskriftsartikel (refereegranskat)abstract
    • Liver transplantation (LT) listing criteria for hepatocellular carcinoma (HCC) remain controversial. To optimize the utility of limited donor organs, this study aims to leverage machine learning to develop an accurate posttransplantation HCC recurrence prediction calculator. Patients with HCC listed for LT from 2000 to 2016 were identified, with 739 patients who underwent LT used for modeling. Data included serial imaging, alpha-fetoprotein (AFP), locoregional therapies, treatment response, and posttransplantation outcomes. We compared the CoxNet (regularized Cox regression), survival random forest, survival support vector machine, and DeepSurv machine learning algorithms via the mean cross-validated concordance index. We validated the selected CoxNet model by comparing it with other currently available recurrence risk algorithms on a held-out test set (AFP, Model of Recurrence After Liver Transplant [MORAL], and Hazard Associated with liver Transplantation for Hepatocellular Carcinoma [HALT-HCC score]). The developed CoxNet-based recurrence prediction model showed a satisfying overall concordance score of 0.75 (95% confidence interval [CI], 0.64-0.84). In comparison, the recalibrated risk algorithms' concordance scores were as follows: AFP score 0.64 (outperformed by the CoxNet model, 1-sided 95% CI, >0.01; P = 0.04) and MORAL score 0.64 (outperformed by the CoxNet model 1-sided 95% CI, >0.02; P = 0.03). The recalibrated HALT-HCC score performed well with a concordance of 0.72 (95% CI, 0.63-0.81) and was not significantly outperformed (1-sided 95% CI, >= 0.05; P = 0.29). Developing a comprehensive posttransplantation HCC recurrence risk calculator using machine learning is feasible and can yield higher accuracy than other available risk scores. Further research is needed to confirm the utility of machine learning in this setting.
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48.
  • Jencson, Jacob E., et al. (författare)
  • AT 2019qyl in NGC 300 : Internal Collisions in the Early Outflow from a Very Fast Nova in a Symbiotic Binary
  • 2021
  • Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 920:2
  • Tidskriftsartikel (refereegranskat)abstract
    • Nova eruptions, thermonuclear explosions on the surfaces of white dwarfs (WDs), are now recognized to be among the most common shock-powered astrophysical transients. We present the early discovery and rapid ultraviolet (UV), optical, and infrared (IR) temporal development of AT 2019qyl, a recent nova in the nearby Sculptor Group galaxy NGC 300. The light curve shows a rapid rise lasting ≲1 day, reaching a peak absolute magnitude of MV = −9.2 mag and a very fast decline, fading by 2 mag over 3.5 days. A steep dropoff in the light curves after 71 days and the rapid decline timescale suggest a low-mass ejection from a massive WD with MWD ≳ 1.2 M⊙. We present an unprecedented view of the early spectroscopic evolution of such an event. Three spectra prior to the peak reveal a complex, multicomponent outflow giving rise to internal collisions and shocks in the ejecta of an He/N-class nova. We identify a coincident IR-variable counterpart in the extensive preeruption coverage of the transient location and infer the presence of a symbiotic progenitor system with an O-rich asymptotic-giant-branch donor star, as well as evidence for an earlier UV-bright outburst in 2014. We suggest that AT 2019qyl is analogous to the subset of Galactic recurrent novae with red-giant companions such as RS Oph and other embedded nova systems like V407 Cyg. Our observations provide new evidence that internal shocks between multiple, distinct outflow components likely contribute to the generation of the shock-powered emission from such systems.
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49.
  • Lau, Heather H. C., et al. (författare)
  • The G51D SNCA mutation generates a slowly progressive alpha-synuclein strain in early-onset Parkinson's disease
  • 2023
  • Ingår i: Acta neuropathologica communications. - : BioMed Central (BMC). - 2051-5960. ; 11:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Unique strains of a-synuclein aggregates have been postulated to underlie the spectrum of clinical and pathological presentations seen across the synucleinopathies. Whereas multiple system atrophy (MSA) is associated with a predominance of oligodendroglial a-synuclein inclusions, a-synuclein aggregates in Parkinson's disease (PD) preferentially accumulate in neurons. The G51D mutation in the SNCA gene encoding a-synuclein causes an aggressive, early-onset form of PD that exhibits clinical and neuropathological traits reminiscent of both PD and MSA. To assess the strain characteristics of G51D PD a-synuclein aggregates, we performed propagation studies in M83 transgenic mice by intracerebrally inoculating patient brain extracts. The properties of the induced a-synuclein aggregates in the brains of injected mice were examined using immunohistochemistry, a conformational stability assay, and by performing a-synuclein seed amplification assays. Unlike MSA-injected mice, which developed a progressive motor phenotype, G51D PD-inoculated animals remained free of overt neurological illness for up to 18 months post-inoculation. However, a subclinical synucleinopathy was present in G51D PD-inoculated mice, characterized by the accumulation of a-synuclein aggregates in restricted regions of the brain. The induced a-synuclein aggregates in G51D PD-injected mice exhibited distinct properties in a seed amplification assay and were much more stable than those present in mice injected with MSA extract, which mirrored the differences observed between human MSA and G51D PD brain samples. These results suggest that the G51D SNCA mutation specifies the formation of a slowly propagating a-synuclein strain that more closely resembles a-synuclein aggregates associated with PD than MSA.
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50.
  • Leung, Edison, et al. (författare)
  • Alterations in brain synaptic proteins and mRNAs in mood disorders : a systematic review and meta-analysis of postmortem brain studies
  • 2022
  • Ingår i: Molecular Psychiatry. - : Springer Nature. - 1359-4184 .- 1476-5578. ; 27:3, s. 1362-1372
  • Forskningsöversikt (refereegranskat)abstract
    • The pathophysiological mechanisms underlying bipolar (BD) and major depressive disorders (MDD) are multifactorial but likely involve synaptic dysfunction and dysregulation. There are multiple synaptic proteins but three synaptic proteins, namely SNAP-25, PSD-95, and synaptophysin, have been widely studied for their role in synaptic function in human brain postmortem studies in BD and MDD. These studies have yielded contradictory results, possibly due to the small sample size and sourcing material from different cortical regions of the brain. We performed a systematic review and meta-analysis to understand the role of these three synaptic proteins and other synaptic proteins, messenger RNA (mRNA) and their regional localizations in BD and MDD. A systematic literature search was conducted and the review is reported in accordance with the MOOSE Guidelines. Meta-analysis was performed to compare synaptic marker levels between BD/MDD groups and controls separately. 1811 papers were identified in the literature search and screened against the preset inclusion and exclusion criteria. A total of 72 studies were screened in the full text, of which 47 were identified as eligible to be included in the systematic review. 24 of these 47 papers were included in the meta-analysis. The meta-analysis indicated that SNAP-25 protein levels were significantly lower in BD. On average, PSD-95 mRNA levels were lower in BD, and protein levels of SNAP-25, PSD-95, and syntaxin were lower in MDD. Localization analysis showed decreased levels of PSD-95 protein in the frontal cortex. We found specific alterations in synaptic proteins and RNAs in both BD and MDD. The review was prospectively registered online in PROSPERO international prospective register of systematic reviews, registration no. CRD42020196932.
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