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1.
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2.
  • De Angelis, A., et al. (författare)
  • Science with e-ASTROGAM A space mission for MeV-GeV gamma-ray astrophysics
  • 2018
  • Ingår i: Journal of High Energy Astrophysics. - : Elsevier. - 2214-4048 .- 2214-4056. ; 19, s. 1-106
  • Tidskriftsartikel (refereegranskat)abstract
    • e-ASTROGAM ('enhanced ASTROGAM') is a breakthrough Observatory space mission, with a detector composed by a Silicon tracker, a calorimeter, and an anticoincidence system, dedicated to the study of the non-thermal Universe in the photon energy range from 0.3 MeV to 3 GeV - the lower energy limit can be pushed to energies as low as 150 keV for the tracker, and to 30 keV for calorimetric detection. The mission is based on an advanced space-proven detector technology, with unprecedented sensitivity, angular and energy resolution, combined with polarimetric capability. Thanks to its performance in the MeV-GeV domain, substantially improving its predecessors, e-ASTROGAM will open a new window on the non-thermal Universe, making pioneering observations of the most powerful Galactic and extragalactic sources, elucidating the nature of their relativistic outflows and their effects on the surroundings. With a line sensitivity in the MeV energy range one to two orders of magnitude better than previous generation instruments, e-ASTROGAM will determine the origin of key isotopes fundamental for the understanding of supernova explosion and the chemical evolution of our Galaxy. The mission will provide unique data of significant interest to a broad astronomical community, complementary to powerful observatories such as LIGO-Virgo-GEO600-KAGRA, SKA, ALMA, E-ELT, TMT, LSST, JWST, Athena, CTA, IceCube, KM3NeT, and LISA.
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3.
  • Ackermann, M., et al. (författare)
  • Unresolved Gamma-Ray Sky through its Angular Power Spectrum
  • 2018
  • Ingår i: Physical Review Letters. - : American Physical Society. - 0031-9007 .- 1079-7114. ; 121:24
  • Tidskriftsartikel (refereegranskat)abstract
    • The gamma-ray sky has been observed with unprecedented accuracy in the last decade by the Fermi-large area telescope (LAT), allowing us to resolve and understand the high-energy Universe. The nature of the remaining unresolved emission [unresolved gamma-ray background (UGRB)] below the LAT source detection threshold can be uncovered by characterizing the amplitude and angular scale of the UGRB fluctuation field. This Letter presents a measurement of the UGRB autocorrelation angular power spectrum based on eight years of Fermi-LAT Pass 8 data products. The analysis is designed to be robust against contamination from resolved sources and noise systematics. The sensitivity to subthreshold sources is greatly enhanced with respect to previous measurements. We find evidence (with similar to 3.7 sigma significance) that the scenario in which two classes of sources contribute to the UGRB signal is favored over a single class. A double power law with exponential cutoff can explain the anisotropy energy spectrum well, with photon indices of the two populations being 2.55 +/- 0.23 and 1.86 +/- 0.15.
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4.
  • Jentschel, M., et al. (författare)
  • EXILL - a high-efficiency, high-resolution setup for gamma-spectroscopy at an intense cold neutron beam facility
  • 2017
  • Ingår i: Journal of Instrumentation. - : IOP PUBLISHING LTD. - 1748-0221. ; 12
  • Tidskriftsartikel (refereegranskat)abstract
    • In the EXILL campaign a highly efficient array of high purity germanium (HPGe) detectors was operated at the cold neutron beam facility PF1B of the Institut Laue-Langevin (ILL) to carry out nuclear structure studies, via measurements of gamma-rays following neutron-induced capture and fission reactions. The setup consisted of a collimation system producing a pencil beam with a thermal capture equivalent flux of about 10(8) ns(-1)cm(2) at the target position and negligible neutron halo. The targetwas surrounded by an array of eight to ten anti-Compton shielded EXOGAMClover detectors, four to six anti-Compton shielded large coaxial GASP detectors and two standard Clover detectors. For a part of the campaign the array was combined with 16 LaBr3:(Ce) detectors from the FATIMA collaboration. The detectorswere arranged in an array of rhombicuboctahedron geometry, providing the possibility to carry out very precise angular correlation and directional-polarization correlation measurements. The triggerless acquisition system allowed a signal collection rate of up to 6 x 10(5) Hz. The data allowed to set multi-fold coincidences to obtain decay schemes and in combination with the FATIMA array of LaBr3:(Ce) detectors to analyze half-lives of excited levels in the pico-to microsecond range. Precise energy and efficiency calibrations of EXILL were performed using standard calibration sources of Ba-133, Co-60 and Eu-152 as well as data from the reactions Al-27(n, gamma)Al-28 and Cl-35(n,gamma)Cl-36 in the energy range from 30 keV up to 10MeV.
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5.
  • Chishti, M.M.R., et al. (författare)
  • Response of the FAst TIMing Array (FATIMA) for DESPEC at FAIR Phase-0
  • 2023
  • Ingår i: Nuclear Instruments & Methods in Physics Research. Section A: Accelerators, Spectrometers, Detectors, and Associated Equipment. - : Elsevier B.V.. - 0168-9002 .- 1872-9576. ; 1056
  • Tidskriftsartikel (refereegranskat)abstract
    • The Monte-Carlo simulated response for γ-ray detection of the FAst TIMing Array (FATIMA) for exploitation within the DEcay SPECtroscopy (DESPEC) experimental system at the FAIR Phase-0 facility at Darmstadt, Germany is presented. In this configuration, FATIMA consisted of 36 LaBr3(Ce) detectors surrounding the AIDA, position-sensitive charged-particle active stopper. The decay of the Iπ=8+ isomer-fed decay cascade in 96Pd, measured in the first DESPEC experiment at the FAIR-0 facility was used to validate the simulations. The experimental data yielded in-situ full-energy peak efficiency values for FATIMA of 11.2(11)%, 6.8(7)%, 3.8(4)% and 2.1(4)% at 106, 325, 684 and 1415 keV respectively, consistent with the values derived from the simulated response.
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6.
  • Pasqualato, G., et al. (författare)
  • Shape evolution in even-mass 98-104Zr isotopes via lifetime measurements using the γ γ-coincidence technique
  • 2023
  • Ingår i: European Physical Journal A. - : Springer. - 1434-6001 .- 1434-601X. ; 59:11
  • Tidskriftsartikel (refereegranskat)abstract
    • The Zirconium (Z = 40) isotopic chain has attracted interest for more than four decades. The abrupt lowering of the energy of the first 2(+) state and the increase in the transition strength B(E2; 2(1)(+) -> 0(1)(+) ) going from Zr-98 to Zr-100 has been the first example of "quantum phase transition" in nuclear shapes, which has few equivalents in the nuclear chart. Although a multitude of experiments have been performed to measure nuclear properties related to nuclear shapes and collectivity in the region, none of the measured lifetimes were obtained using the Recoil Distance Doppler Shift method in the gamma gamma-coincidence mode where a gate on the direct feeding transition of the state of interest allows a strict control of systematical errors. This work reports the results of lifetime measurements for the first yrast excited states in Zr98-104 carried out to extract reduced transition probabilities. The new lifetime values in gamma gamma-coincidence and gamma-single mode are compared with the results of former experiments. Recent predictions of the Interacting Boson Model with Configuration Mixing, the Symmetry Conserving Configuration Mixing model based on the Hartree-Fock- Bogoliubov approach and the Monte Carlo Shell Model are presented and compared with the experimental data.
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7.
  • Heald, G., et al. (författare)
  • Magnetism science with the square kilometre array
  • 2020
  • Ingår i: Galaxies. - : MDPI AG. - 2075-4434. ; 8:8
  • Tidskriftsartikel (refereegranskat)abstract
    • The Square Kilometre Array (SKA) will answer fundamental questions about the origin, evolution, properties, and influence of magnetic fields throughout the Universe. Magnetic fields can illuminate and influence phenomena as diverse as star formation, galactic dynamics, fast radio bursts, active galactic nuclei, large-scale structure, and dark matter annihilation. Preparations for the SKA are swiftly continuing worldwide, and the community is making tremendous observational progress in the field of cosmic magnetism using data from a powerful international suite of SKA pathfinder and precursor telescopes. In this contribution, we revisit community plans for magnetism research using the SKA, in light of these recent rapid developments. We focus in particular on the impact that new radio telescope instrumentation is generating, thus advancing our understanding of key SKA magnetism science areas, as well as the new techniques that are required for processing and interpreting the data. We discuss these recent developments in the context of the ultimate scientific goals for the SKA era.
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8.
  • Menkveld, Albert J., et al. (författare)
  • Nonstandard Errors
  • 2024
  • Ingår i: JOURNAL OF FINANCE. - : Wiley-Blackwell. - 0022-1082 .- 1540-6261. ; 79:3, s. 2339-2390
  • Tidskriftsartikel (refereegranskat)abstract
    • In statistics, samples are drawn from a population in a data-generating process (DGP). Standard errors measure the uncertainty in estimates of population parameters. In science, evidence is generated to test hypotheses in an evidence-generating process (EGP). We claim that EGP variation across researchers adds uncertainty-nonstandard errors (NSEs). We study NSEs by letting 164 teams test the same hypotheses on the same data. NSEs turn out to be sizable, but smaller for more reproducible or higher rated research. Adding peer-review stages reduces NSEs. We further find that this type of uncertainty is underestimated by participants.
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9.
  • Weltman, A., et al. (författare)
  • Fundamental physics with the Square Kilometre Array
  • 2020
  • Ingår i: Publications Astronomical Society of Australia. - : CAMBRIDGE UNIV PRESS. - 1323-3580 .- 1448-6083. ; 37
  • Forskningsöversikt (refereegranskat)abstract
    • The Square Kilometre Array (SKA) is a planned large radio interferometer designed to operate over a wide range of frequencies, and with an order of magnitude greater sensitivity and survey speed than any current radio telescope. The SKA will address many important topics in astronomy, ranging from planet formation to distant galaxies. However, in this work, we consider the perspective of the SKA as a facility for studying physics. We review four areas in which the SKA is expected to make major contributions to our understanding of fundamental physics: cosmic dawn and reionisation; gravity and gravitational radiation; cosmology and dark energy; and dark matter and astroparticle physics. These discussions demonstrate that the SKA will be a spectacular physics machine, which will provide many new breakthroughs and novel insights on matter, energy, and spacetime.
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10.
  • Werner, V., et al. (författare)
  • Evolution of collectivity near mid-shell from excited-state lifetime measurements in rare earth nuclei
  • 2016
  • Ingår i: Physical Review C. - 2469-9985 .- 2469-9993. ; 93:3
  • Tidskriftsartikel (refereegranskat)abstract
    • The B(E2) excitation strength of the first excited 2(+) state in even-even nuclei should directly correlate with the size of the valence space and maximize at mid-shell. A previously found saturation of B(E2) strengths in well-deformed rotors at mid-shell is tested through high-precision measurements of the lifetimes of the lowest-lying 2(+) states of the Hf-168 and W-174 rare earth isotopes. Measurements were performed using fast LaBr3 scintillation detectors. Combined with the recently remeasured B(E2; 2(1)(+) -> 0(1)(+)) values for Hf and W isotopes the new data remove discrepancies observed in the differentials of B(E2) values for these isotopes.
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11.
  • Zamora, Juan Carlos, et al. (författare)
  • Considerations and consequences of allowing DNA sequence data as types of fungal taxa
  • 2018
  • Ingår i: IMA Fungus. - : INT MYCOLOGICAL ASSOC. - 2210-6340 .- 2210-6359. ; 9:1, s. 167-185
  • Tidskriftsartikel (refereegranskat)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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12.
  • Andreoni, Igor, et al. (författare)
  • Target-of-opportunity Observations of Gravitational-wave Events with Vera C. Rubin Observatory
  • 2022
  • Ingår i: Astrophysical Journal Supplement Series. - : American Astronomical Society. - 0067-0049 .- 1538-4365. ; 260:1
  • Tidskriftsartikel (refereegranskat)abstract
    • The discovery of the electromagnetic counterpart to the binary neutron star (NS) merger GW170817 has opened the era of gravitational-wave multimessenger astronomy. Rapid identification of the optical/infrared kilonova enabled a precise localization of the source, which paved the way to deep multiwavelength follow-up and its myriad of related science results. Fully exploiting this new territory of exploration requires the acquisition of electromagnetic data from samples of NS mergers and other gravitational-wave sources. After GW170817, the frontier is now to map the diversity of kilonova properties and provide more stringent constraints on the Hubble constant, and enable new tests of fundamental physics. The Vera C. Rubin Observatory's Legacy Survey of Space and Time can play a key role in this field in the 2020s, when an improved network of gravitational-wave detectors is expected to reach a sensitivity that will enable the discovery of a high rate of merger events involving NSs (∼tens per year) out to distances of several hundred megaparsecs. We design comprehensive target-of-opportunity observing strategies for follow-up of gravitational-wave triggers that will make the Rubin Observatory the premier instrument for discovery and early characterization of NS and other compact-object mergers, and yet unknown classes of gravitational-wave events.
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13.
  • Arridge, Christopher S., et al. (författare)
  • Uranus Pathfinder : exploring the origins and evolution of Ice Giant planets
  • 2012
  • Ingår i: Experimental astronomy. - : Springer Science and Business Media LLC. - 0922-6435 .- 1572-9508. ; 33:2-3, s. 753-791
  • Tidskriftsartikel (refereegranskat)abstract
    • The "Ice Giants" Uranus and Neptune are a different class of planet compared to Jupiter and Saturn. Studying these objects is important for furthering our understanding of the formation and evolution of the planets, and unravelling the fundamental physical and chemical processes in the Solar System. The importance of filling these gaps in our knowledge of the Solar System is particularly acute when trying to apply our understanding to the numerous planetary systems that have been discovered around other stars. The Uranus Pathfinder (UP) mission thus represents the quintessential aspects of the objectives of the European planetary community as expressed in ESA's Cosmic Vision 2015-2025. UP was proposed to the European Space Agency's M3 call for medium-class missions in 2010 and proposed to be the first orbiter of an Ice Giant planet. As the most accessible Ice Giant within the M-class mission envelope Uranus was identified as the mission target. Although not selected for this call the UP mission concept provides a baseline framework for the exploration of Uranus with existing low-cost platforms and underlines the need to develop power sources suitable for the outer Solar System. The UP science case is based around exploring the origins, evolution, and processes at work in Ice Giant planetary systems. Three broad themes were identified: (1) Uranus as an Ice Giant, (2) An Ice Giant planetary system, and (3) An asymmetric magnetosphere. Due to the long interplanetary transfer from Earth to Uranus a significant cruise-phase science theme was also developed. The UP mission concept calls for the use of a Mars Express/Rosetta-type platform to launch on a Soyuz-Fregat in 2021 and entering into an eccentric polar orbit around Uranus in the 2036-2037 timeframe. The science payload has a strong heritage in Europe and beyond and requires no significant technology developments.
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14.
  • Beeh, Kai M, et al. (författare)
  • How Do Dual Long-acting Bronchodilators Prevent Exacerbations of Chronic Obstructive Pulmonary Disease?
  • 2017
  • Ingår i: American Journal of Respiratory and Critical Care Medicine. - 1073-449X .- 1535-4970. ; 196:2, s. 139-149
  • Forskningsöversikt (refereegranskat)abstract
    • Decreasing the frequency and severity of exacerbations is one of the main goals of treatment for patients with chronic obstructive pulmonary disease (COPD). Several studies have documented that long-acting bronchodilators (LABDs) can reduce exacerbation rate and/or severity, and others have shown that combinations of long-acting β2-adrenergic agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) provide greater reductions in exacerbation frequency than either their monocomponents or LABA/inhaled corticosteroids (LABA/ICS) combinations in patients at low and high risk for these events. In this review, small groups of experts critically evaluated mechanisms potentially responsible for the increased benefit of LABA/LAMA combinations over single LABDs or LABA/ICS in decreasing exacerbation. These included effects on lung hyperinflation and mechanical stress, inflammation, excessive mucus production with impaired mucociliary clearance, and symptom severity. The data assembled and analyzed by each group were reviewed by all authors and combined into this manuscript. Available clinical results support the possibility that effects of LABA/LAMA combinations on hyperinflation, mucociliary clearance, and symptom severity may all contribute to decreasing exacerbations. While preclinical studies suggest LABAs and LAMAs have anti-inflammatory effects, such effects have not been demonstrated yet in patients with COPD.
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15.
  • Brown, Solomon, et al. (författare)
  • CO(2)QUEST : Techno-economic assessment of CO2 quality effect on its storage and transport
  • 2014
  • Ingår i: 12TH INTERNATIONAL CONFERENCE ON GREENHOUSE GAS CONTROL TECHNOLOGIES, GHGT-12. - : Elsevier BV. ; , s. 2622-2629
  • Konferensbidrag (refereegranskat)abstract
    • Presented is an overview of the CO(2)QUEST project that addresses fundamentally important issues regarding the impact of typical impurities in the gas or dense phase CO2 stream captured from fossil fuel power plants on its safe and economic transportation and storage. Previous studies have mainly investigated the impact of CO2 stream impurities on each part of the carbon capture and storage (CCS) chain in isolation. This is a significant drawback given the different sensitivities of pipeline, wellbore materials and storage sites to the various impurities. The project brings together leading researchers and stakeholders, to address the impact of the typical impurities upon safe and economic CO2 transportation and storage. State-of-the-art mathematical models, backed by laboratory and industrial-scale experimentation, are implemented to perform a comprehensive techno-economic assessment of the impact of impurities upon the thermo-physical phenomena governing pipeline and storage-site integrities.
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16.
  • Gilbert, Penney M., et al. (författare)
  • A single cell bioengineering approach to elucidate mechanisms of adult stem cell self-renewal
  • 2012
  • Ingår i: Integrative Biology. - : Oxford University Press (OUP). - 1757-9694 .- 1757-9708. ; 4:4, s. 360-367
  • Tidskriftsartikel (refereegranskat)abstract
    • The goal of regenerative medicine is to restore form and function to damaged and aging tissues. Adult stem cells, present in tissues such as skeletal muscle, comprise a reservoir of cells with a remarkable capacity to proliferate and repair tissue damage. Muscle stem cells, known as satellite cells, reside in a quiescent state in an anatomically distinct compartment, or niche, ensheathed between the membrane of the myofiber and the basal lamina. Recently, procedures for isolating satellite cells were developed and experiments testing their function upon transplantation into muscles revealed an extraordinary potential to contribute to muscle fibers and access and replenish the satellite cell compartment. However, these properties are rapidly lost once satellite cells are plated in culture. Accordingly, elucidating the role of extrinsic factors in controlling muscle stem cell fate, in particular self-renewal, is critical. Through careful design of bioengineered culture platforms, analysis of specific proteins presented to stem cells is possible. Critical to the success of the approach is single cell analysis, as more rapidly proliferating progenitors may mask the behavior of stem cells that proliferate slowly. Bioengineering approaches provide a potent means of gaining insight into the role of extrinsic factors in the stem cell microenvironment on stem cell function and the mechanisms that control their diverse fates. Ultimately, the multidisciplinary approach presented here will lead to novel therapeutic strategies for degenerative diseases.
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17.
  • Neumann, Alexander, et al. (författare)
  • Multivariate GWAS of Alzheimer's disease CSF biomarker profiles implies GRIN2D in synaptic functioning.
  • 2023
  • Ingår i: Genome medicine. - 1756-994X. ; 15:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Genome-wide association studies (GWAS) of Alzheimer's disease (AD) have identified several risk loci, but many remain unknown. Cerebrospinal fluid (CSF) biomarkers may aid in gene discovery and we previously demonstrated that six CSF biomarkers (β-amyloid, total/phosphorylated tau, NfL, YKL-40, and neurogranin) cluster into five principal components (PC), each representing statistically independent biological processes. Here, we aimed to (1) identify common genetic variants associated with these CSF profiles, (2) assess the role of associated variants in AD pathophysiology, and (3) explore potential sex differences.We performed GWAS for each of the five biomarker PCs in two multi-center studies (EMIF-AD and ADNI). In total, 973 participants (n=205 controls, n=546 mild cognitive impairment, n=222 AD) were analyzed for 7,433,949 common SNPs and 19,511 protein-coding genes. Structural equation models tested whether biomarker PCs mediate genetic risk effects on AD, and stratified and interaction models probed for sex-specific effects.Five loci showed genome-wide significant association with CSF profiles, two were novel (rs145791381 [inflammation] and GRIN2D [synaptic functioning]) and three were previously described (APOE, TMEM106B, and CHI3L1). Follow-up analysesof the two novel signals in independent datasets only supported the GRIN2D locus, which contains several functionally interesting candidate genes. Mediation tests indicated that variants in APOE are associated with AD status via processes related to amyloid and tau pathology, while markers in TMEM106B and CHI3L1 are associated with AD only via neuronal injury/inflammation. Additionally, seven loci showed sex-specific associations with AD biomarkers.These results suggest that pathway and sex-specific analyses can improve our understanding of AD genetics and may contribute to precision medicine.
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18.
  • Porter, Richard T. J., et al. (författare)
  • Techno-economic assessment of CO2 quality effect on its storage and transport : CO(2)QUEST An overview of aims, objectives and main findings
  • 2016
  • Ingår i: International Journal of Greenhouse Gas Control. - : Elsevier BV. - 1750-5836 .- 1878-0148. ; 54, s. 662-681
  • Tidskriftsartikel (refereegranskat)abstract
    • This paper provides an overview of the aims, objectives and the main findings of the CO(2)QUEST FP7 collaborative project, funded by the European Commission and designed to address the fundamentally important and urgent issues regarding the impact of the typical impurities in CO2 streams captured from fossil fuel power plants and other CO2 intensive industries on their safe and economic pipeline transportation and storage. The main features and results recorded from some of the unique test facilities constructed as part of the project are presented. These include an extensively instrumented realistic-scale test pipeline for conducting pipeline rupture and dispersion tests in China, an injection test facility in France to study the mobility of trace metallic elements contained in a CO2 stream following injection near a shallow-water qualifier and fluid/rock interactions and well integrity experiments conducted using a fully instrumented deep-well CO2/impurities injection test facility in Israel. The above, along with the various unique mathematical models developed, provide the fundamentally important tools needed to define impurity tolerance levels, mixing protocols and control measures for pipeline networks and storage infrastructure, thus contributing to the development of relevant standards for the safe design and economic operation of CCS.
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19.
  • Shi, Liu, et al. (författare)
  • Dickkopf-1 Overexpression in vitro Nominates Candidate Blood Biomarkers Relating to Alzheimer's Disease Pathology.
  • 2020
  • Ingår i: Journal of Alzheimer's disease : JAD. - : IOS Press. - 1875-8908 .- 1387-2877. ; 77:3, s. 1353-1368
  • Tidskriftsartikel (refereegranskat)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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20.
  • Shi, Liu, et al. (författare)
  • Replication study of plasma proteins relating to Alzheimer's pathology.
  • 2021
  • Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279 .- 1552-5260. ; 17:9, s. 1452-1464
  • Tidskriftsartikel (refereegranskat)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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21.
  • Sytiuk, Anna, et al. (författare)
  • Predicting the structure and functions of peatland microbial communities from Sphagnum phylogeny, anatomical and morphological traits and metabolites
  • 2022
  • Ingår i: Journal of Ecology. - : John Wiley & Sons. - 0022-0477 .- 1365-2745. ; 110:1, s. 80-96
  • Tidskriftsartikel (refereegranskat)abstract
    • Sphagnum mosses are keystone species in northern peatlands. Notably, they play an important role in peatland carbon (C) cycling by regulating the composition and activity of microbial communities. However, it remains unclear whether information on Sphagnum phylogeny and/or traits-based composition (i.e. anatomical and morphological traits and metabolites) can be used to predict the structure of microbial communities and their functioning. Here we evaluated whether Sphagnum phylogeny and traits predict additional variation in peatland microbial community composition and functioning beyond what would be predicted from environmental characteristics (i.e. climatic and edaphic conditions).We collected Sphagnum and microbial data from five European peatlands distributed along a latitudinal gradient from northern Sweden to southern France. These data allowed us to assess Sphagnum anatomical and morphological traits and metabolites at different sites along changing environmental conditions. Using structural equation modelling (SEM) and phylogenetic distance analyses, we investigated the role of Sphagnum traits in shaping microbial community composition and functioning along with environmental conditions.We show that microbial community composition and traits varied independently from both Sphagnum phylogeny and the latitudinal gradient. Specifically, the addition of Sphagnum traits to climatic and edaphic variables to the SEM allowed it to explain a larger proportion of the explained variance (R2). This observation was most apparent for the biomass of decomposers (+42%) and phototrophs (+19%), as well as for growth yield microbial traits (+10%). As such, that Sphagnum metabolites were important drivers for microbial community structure and traits, while Sphagnum anatomical and morphological traits were poor predictors.Synthesis. Our results highlight that Sphagnum metabolites are more likely to influence peatland microbial food web structure and functioning than Sphagnum anatomical and morphological traits. We provide further evidence that measurements of the plant metabolome, when combined with classical functional traits, improve our understanding of how the plants interact with their associated microbiomes.
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22.
  • van Bodegraven, Eduard A., et al. (författare)
  • Minimally invasive robot-assisted and laparoscopic distal pancreatectomy in a pan-European registry a retrospective cohort study
  • 2024
  • Ingår i: International Journal of Surgery. - : LIPPINCOTT WILLIAMS & WILKINS. - 1743-9191 .- 1743-9159. ; 110:6, s. 3554-3561
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: International guidelines recommend monitoring the use and outcome of minimally invasive pancreatic surgery (MIPS). However, data from prospective international audits on minimally invasive distal pancreatectomy (MIDP) are lacking. This study examined the use and outcome of robot-assisted (RDP) and laparoscopic (LDP) distal pancreatectomy in the E-MIPS registry. Patients and methods: Post-hoc analysis in a prospective audit on MIPS, including consecutive patients undergoing MIDP in 83 centers from 19 European countries (01-01-2019/31-12-2021). Primary outcomes included intraoperative events (grade 1: excessive blood loss, grade 2: conversion/change in operation, grade 3: intraoperative death), major morbidity, and in-hospital/30-day mortality. Multivariable logistic regression analyses identified high-risk groups for intraoperative events. RDP and LDP were compared in the total cohort and high-risk groups. Results: Overall, 1672 patients undergoing MIDP were included; 606 (36.2%) RDP and 1066 (63.8%) LDP. The annual use of RDP increased from 30.5% to 42.6% (P<0.001). RDP was associated with fewer grade 2 intraoperative events compared with LDP (9.6% vs. 16.8%, P<0.001), with longer operating time (238 vs. 201 min, P<0.001). No significant differences were observed between RDP and LDP regarding major morbidity (23.4% vs. 25.9%, P=0.264) and in-hospital/30-day mortality (0.3% vs. 0.8%, P=0.344). Three high-risk groups were identified; BMI greater than 25 kg/m(2), previous abdominal surgery, and vascular involvement. In each group, RDP was associated with fewer conversions and longer operative times. Conclusion: This European registry-based study demonstrated favorable outcomes for MIDP, with mortality rates below 1%. LDP remains the predominant approach, whereas the use of RDP is increasing. RDP was associated with fewer conversions and longer operative time, including in high-risk subgroups. Future randomized trials should confirm these findings and assess cost differences.
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23.
  • Zeichner, Sarah S., et al. (författare)
  • Polycyclic aromatic hydrocarbons in samples of Ryugu formed in the interstellar medium
  • 2023
  • Ingår i: Science. - : AMER ASSOC ADVANCEMENT SCIENCE. - 0036-8075 .- 1095-9203. ; 382:6677, s. 1411-1415
  • Tidskriftsartikel (refereegranskat)abstract
    • Polycyclic aromatic hydrocarbons (PAHs) contain less than or similar to 20% of the carbon in the interstellar medium. They are potentially produced in circumstellar environments (at temperatures greater than or similar to 1000 kelvin), by (similar to 10 kelvin) interstellar clouds, or by processing of carbon-rich dust grains. We report isotopic properties of PAHs extracted from samples of the asteroid Ryugu and the meteorite Murchison. The doubly-C-13 substituted compositions (Delta 2x(13)C values) of the PAHs naphthalene, fluoranthene, and pyrene are 9 to 51 parts per thousand higher than values expected for a stochastic distribution of isotopes. The Delta 2x(13)C values are higher than expected if the PAHs formed in a circumstellar environment, but consistent with formation in the interstellar medium. By contrast, the PAHs phenanthrene and anthracene in Ryugu samples have Delta 2x(13)C values consistent with formation by higher-temperature reactions.
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24.
  • Boudier, Anne, et al. (författare)
  • Data-driven adult asthma phenotypes based on clinical characteristics are associated with asthma outcomes twenty years later
  • 2019
  • Ingår i: Allergy. European Journal of Allergy and Clinical Immunology. - : John Wiley & Sons. - 0105-4538 .- 1398-9995. ; 74:5, s. 953-963
  • Tidskriftsartikel (refereegranskat)abstract
    • BackgroundResearch based on cluster analyses led to the identification of particular phenotypes confirming phenotypic heterogeneity of asthma. The long-term clinical course of asthma phenotypes defined by clustering analysis remains unknown, although it is a key aspect to underpin their clinical relevance. We aimed to estimate risk of poor asthma events between asthma clusters identified 20years earlier. MethodsThe study relied on two cohorts of adults with asthma with 20-year follow-up, ECRHS (European Community Respiratory Health Survey) and EGEA (Epidemiological study on Genetics and Environment of Asthma). Regression models were used to compare asthma characteristics (current asthma, asthma exacerbations, asthma control, quality of life, and FEV1) at follow-up and the course of FEV(1)between sevencluster-based asthma phenotypes identified20years earlier. ResultsThe analysis included 1325 adults with ever asthma. For each asthma characteristic assessed at follow-up, the risk for adverse outcomes differed significantly between the seven asthma clusters identified at baseline. As compared with the mildest asthma phenotype, ORs (95% CI) for asthma exacerbations varied from 0.9 (0.4 to 2.0) to 4.0 (2.0 to 7.8) and the regression estimates (95% CI) for FEV1% predicted varied from 0.6 (-3.5 to 4.6) to -9.9 (-14.2 to -5.5) between clusters. Change in FEV1 over time did not differ significantly across clusters. ConclusionOur findings show that the long-term risk for poor asthma outcomes differed between comprehensive adult asthma phenotypes identified 20years earlier, and suggest a strong tracking of asthma activity and impaired lung function over time.
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25.
  • Cerullo, Gabriella, et al. (författare)
  • Directed evolution of the type C feruloyl esterase from Fusarium oxysporum FoFaeC and molecular docking analysis of its improved variants
  • 2019
  • Ingår i: New Biotechnology. - : Elsevier. - 1871-6784 .- 1876-4347. ; 51, s. 14-20
  • Tidskriftsartikel (refereegranskat)abstract
    • The need to develop competitive and eco-friendly processes in the cosmetic industry leads to the search for new enzymes with improved properties for industrial bioconversions in this sector. In the present study, a complete methodology to generate, express and screen diversity for the type C feruloyl esterase from Fusarium oxysporium FoFaeC was set up in a high-throughput fashion. A library of around 30,000 random mutants of FoFaeC was generated by error prone PCR of fofaec cDNA and expressed in Yarrowia lipolytica. Screening for enzymatic activity towards the substrates 5-bromo-4-chloroindol-3-yl and 4-nitrocatechol-1-yl ferulates allowed the selection of 96 enzyme variants endowed with improved enzymatic activity that were then characterized for thermo- and solvent- tolerance. The five best mutants in terms of higher activity, thermo- and solvent- tolerance were selected for analysis of substrate specificity. Variant L432I was shown to be able to hydrolyze all the tested substrates, except methyl sinapate, with higher activity than wild type FoFaeC towards methyl p-coumarate, methyl ferulate and methyl caffeate. Moreover, the E455D variant was found to maintain completely its hydrolytic activity after two hour incubation at 55 °C, whereas the L284Q/V405I variant showed both higher thermo- and solvent- tolerance than wild type FoFaeC. Small molecule docking simulations were applied to the five novel selected variants in order to examine the binding pattern of substrates used for enzyme characterization of wild type FoFaeC and the evolved variants.
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26.
  • Devos, David, et al. (författare)
  • Trial of Deferiprone in Parkinson’s Disease
  • 2022
  • Ingår i: New England Journal of Medicine. - : Massachusetts Medical Society. - 0028-4793 .- 1533-4406. ; 387:22, s. 2045-2055
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUNDIron content is increased in the substantia nigra of persons with Parkinson's disease and may contribute to the pathophysiology of the disorder. Early research suggests that the iron chelator deferiprone can reduce nigrostriatal iron content in persons with Parkinson's disease, but its effects on disease progression are unclear.METHODSWe conducted a multicenter, phase 2, randomized, double-blind trial involving participants with newly diagnosed Parkinson's disease who had never received levodopa. Participants were assigned (in a 1:1 ratio) to receive oral deferiprone at a dose of 15 mg per kilogram of body weight twice daily or matched placebo for 36 weeks. Dopaminergic therapy was withheld unless deemed necessary for symptom control. The primary outcome was the change in the total score on the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS; range, 0 to 260, with higher scores indicating more severe impairment) at 36 weeks. Secondary and exploratory clinical outcomes at up to 40 weeks included measures of motor and nonmotor disability. Brain iron content measured with the use of magnetic resonance imaging was also an exploratory outcome.RESULTSA total of 372 participants were enrolled; 186 were assigned to receive deferiprone and 186 to receive placebo. Progression of symptoms led to the initiation of dopaminergic therapy in 22.0% of the participants in the deferiprone group and 2.7% of those in the placebo group. The mean MDS-UPDRS total score at baseline was 34.3 in the deferiprone group and 33.2 in the placebo group and increased (worsened) by 15.6 points and 6.3 points, respectively (difference, 9.3 points; 95% confidence interval, 6.3 to 12.2; P<0.001). Nigrostriatal iron content decreased more in the deferiprone group than in the placebo group. The main serious adverse events with deferiprone were agranulocytosis in 2 participants and neutropenia in 3 participants.CONCLUSIONSIn participants with early Parkinson's disease who had never received levodopa and in whom treatment with dopaminergic medications was not planned, deferiprone was associated with worse scores in measures of parkinsonism than those with placebo over a period of 36 weeks.
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27.
  • Fitzal, Florian, et al. (författare)
  • Retrospective, Multicenter Analysis Comparing Conventional with Oncoplastic Breast Conserving Surgery : Oncological and Surgical Outcomes in Women with High-Risk Breast Cancer from the OPBC-01/iTOP2 Study
  • 2022
  • Ingår i: Annals of Surgical Oncology. - : Springer Nature. - 1068-9265 .- 1534-4681. ; 29:2, s. 1061-1070
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction Recent data suggest that margins >= 2 mm after breast-conserving surgery may improve local control in invasive breast cancer (BC). By allowing large resection volumes, oncoplastic breast-conserving surgery (OBCII; Clough level II/Tubingen 5-6) may achieve better local control than conventional breast conserving surgery (BCS; Tubingen 1-2) or oncoplastic breast conservation with low resection volumes (OBCI; Clough level I/Tubingen 3-4). Methods Data from consecutive high-risk BC patients treated in 15 centers from the Oncoplastic Breast Consortium (OPBC) network, between January 2010 and December 2013, were retrospectively reviewed. Results A total of 3,177 women were included, 30% of whom were treated with OBC (OBCI n = 663; OBCII n = 297). The BCS/OBCI group had significantly smaller tumors and smaller resection margins compared with OBCII (pT1: 50% vs. 37%, p = 0.002; proportion with margin <1 mm: 17% vs. 6%, p < 0.001). There were significantly more re-excisions due to R1 ("ink on tumor") in the BCS/OBCI compared with the OBCII group (11% vs. 7%, p = 0.049). Univariate and multivariable regression analysis adjusted for tumor biology, tumor size, radiotherapy, and systemic treatment demonstrated no differences in local, regional, or distant recurrence-free or overall survival between the two groups. Conclusions Large resection volumes in oncoplastic surgery increases the distance from cancer cells to the margin of the specimen and reduces reexcision rates significantly. With OBCII larger tumors are resected with similar local, regional and distant recurrence-free as well as overall survival rates as BCS/OBCI.
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28.
  • Hitimana, Regis, et al. (författare)
  • Health-related quality of life determinants among Rwandan women after delivery: does antenatal care utilization matter? A cross-sectional study
  • 2018
  • Ingår i: Journal of Health Population and Nutrition. - : Springer Science and Business Media LLC. - 1606-0997 .- 2072-1315. ; 37
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Despite the widespread use of antenatal care (ANC), its effectiveness in low-resource settings remains unclear. In this study, self-reported health-related quality of life (HRQoL) was used as an alternative to other maternal health measures previously used to measure the effectiveness of antenatal care. The main objective of this study was to determine whether adequate antenatal care utilization is positively associated with women's HRQoL. Furthermore, the associations between the HRQoL during the first year (113 months) after delivery and socio-economic and demographic factors were explored in Rwanda. Methods: In 2014, we performed a cross-sectional population-based survey involving 922 women who gave birth 1-13 months prior to the data collection. The study population was randomly selected from two provinces in Rwanda, and a structured questionnaire was used. HRQoL was measured using the EQ-5D-3L and a visual analogue scale (VAS). The average HRQoL scores were computed by demographic and socio-economic characteristics. The effect of adequate antenatal care utilization on HRQoL was tested by performing two multivariable linear regression models with the EQ-5D and EQ-VAS scores as the outcomes and ANC utilization and socio-economic and demographic variables as the predictors. Results: Adequate ANC utilization affected women's HRQoL when the outcome was measured using the EQ-VAS. Social support and living in a wealthy household were associated with a better HRQoL using both the EQ-VAS and EQ-5D. Cohabitating, and single/unmarried women exhibited significantly lower HRQoL scores than did married women in the EQ-VAS model, and women living in urban areas exhibited lower HRQoL scores than women living in rural areas in the ED-5D model. The effect of education on HRQoL was statistically significant using the EQ-VAS but was inconsistent across the educational categories. The women's age and the age of their last child were not associated with their HRQoL. Conclusions: ANC attendance of at least four visits should be further promoted and used in low-income settings. Strategies to improve families' socio-economic conditions and promote social networks among women, particularly women at the reproductive age, are needed.
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29.
  • Hitimana, Regis, et al. (författare)
  • Health related quality of life determinants for Rwandan women after delivery
  • 2017
  • Ingår i: European Journal of Public Health. - : OXFORD UNIV PRESS. - 1101-1262 .- 1464-360X. ; 27:Suppl_3, s. 436-
  • Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
    • Health related quality of life determinants for Rwandan women after delivery. Does Antenatal care utilization matter? Maternal health conditions are still a major problem in most low-income countries. The postpartum health status and the effect of antenatal care utilization on health are relatively under researched. This study aims at (1) assessing whether receipt of antenatal care according to Rwandan guidelines is associated with mother’s health-related quality of life (HRQoL) and (2) exploring determinants associated with mother’s HRQoL in the first year (1-13 months) after delivery in Rwanda. In 2014 a cross-sectional survey was conducted on 922 women from Kigali City and Northern province of Rwanda, who gave birth in the period of 1–13 months prior to survey. The study population was randomly selected and interviewed using a questionnaire. HRQoL was measured using EQ-5D-3L. Average values of HRQoL were computed by demographic and socio-economic characteristics. The effect of adequate antenatal care on HRQoL was tested in two multivariable linear regression models - with EQ-5D weights and the Visual Analogue Scale score as outcomes respectively - with ANC adequacy and socio-demographic and psychosocial variables as predictors. Mean HRQoL was 0.92 using EQ-5D and 69.58 using EQ-VAS. Fifteen per cent reported moderate pain/discomfort and 1% reported extreme pain/discomfort, 16% reported being moderately anxious/depressed and 3% reported being extremely anxious/depressed. Having more than one child and being cohabitant or single/not married was associated with significantly lower HRQoL, while having good social support and belonging to the highest wealth quintile was associated with higher HRQoL. Antenatal care utilization was not associated with HRQoL among postpartum mothers. Policy makers should address the social determinants of health, and promote social networks among women. There is a need to assess the quality of Antenatal care in Rwanda.Key messages:Health related quality of life among postpartum mothers is high. Pain or discomfort and anxiety of depression are most prevalent problems.Antenatal care utilization was not associated with HRQoL among postpartum mothers. Rather social determinants of health are important in determining mother's HRQoL
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30.
  • Hitimana, Regis, et al. (författare)
  • Incremental cost and health gains of the 2016 WHO antenatal care recommendations for Rwanda: results from expert elicitation
  • 2019
  • Ingår i: Health Research Policy and Systems. - : Springer Science and Business Media LLC. - 1478-4505. ; 17
  • Tidskriftsartikel (refereegranskat)abstract
    • Objectives: High-quality evidence of effectiveness and cost-effectiveness is rarely available and relevant for health policy decisions in low-resource settings. In such situations, innovative approaches are needed to generate locally relevant evidence. This study aims to inform decision-making on antenatal care (ANC) recommendations in Rwanda by estimating the incremental cost-effectiveness of the recent (2016) WHO antenatal care recommendations compared to current practice in Rwanda. Methods: Two health outcome scenarios (optimistic, pessimistic) in terms of expected maternal and perinatal mortality reduction were constructed using expert elicitation with gynaecologists/obstetricians currently practicing in Rwanda. Three costing scenarios were constructed from the societal perspective over a 1-year period. The two main inputs to the cost analyses were a Monte Carlo simulation of the distribution of ANC attendance for a hypothetical cohort of 373,679 women and unit cost estimation of the new recommendations using data from a recent primary costing study of current ANC practice in Rwanda. Results were reported in 2015 USD and compared with the 2015 Rwandan per-capita gross domestic product (US$ 697). Results: Incremental health gains were estimated as 162,509 life-years saved (LYS) in the optimistic scenario and 65,366 LYS in the pessimistic scenario. Incremental cost ranged between $5.8 and $11 million (an increase of 42% and 79%, respectively, compared to current practice) across the costing scenarios. In the optimistic outcome scenario, incremental cost per LYS ranged between $36 (for low ANC attendance) and $67 (high ANC attendance), while in the pessimistic outcome scenario, it ranged between $90 (low ANC attendance) and $168 (high ANC attendance) per LYS. Incremental cost effectiveness was below the GDP-based thresholds in all six scenarios. Discussion: Implementing the new WHO ANC recommendations in Rwanda would likely be very cost-effective; however, the additional resource requirements are substantial. This study demonstrates how expert elicitation combined with other data can provide an affordable source of locally relevant evidence for health policy decisions in low-resource settings.
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31.
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32.
  • Homann, Jan, et al. (författare)
  • Genome-Wide Association Study of Alzheimer's Disease Brain Imaging Biomarkers and Neuropsychological Phenotypes in the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery Dataset.
  • 2022
  • Ingår i: Frontiers in aging neuroscience. - : Frontiers Media SA. - 1663-4365. ; 14
  • Tidskriftsartikel (refereegranskat)abstract
    • Alzheimer's disease (AD) is the most frequent neurodegenerative disease with an increasing prevalence in industrialized, aging populations. AD susceptibility has an established genetic basis which has been the focus of a large number of genome-wide association studies (GWAS) published over the last decade. Most of these GWAS used dichotomized clinical diagnostic status, i.e., case vs. control classification, as outcome phenotypes, without the use of biomarkers. An alternative and potentially more powerful study design is afforded by using quantitative AD-related phenotypes as GWAS outcome traits, an analysis paradigm that we followed in this work. Specifically, we utilized genotype and phenotype data from n = 931 individuals collected under the auspices of the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) study to perform a total of 19 separate GWAS analyses. As outcomes we used five magnetic resonance imaging (MRI) traits and seven cognitive performance traits. For the latter, longitudinal data from at least two timepoints were available in addition to cross-sectional assessments at baseline. Our GWAS analyses revealed several genome-wide significant associations for the neuropsychological performance measures, in particular those assayed longitudinally. Among the most noteworthy signals were associations in or near EHBP1 (EH domain binding protein 1; on chromosome 2p15) and CEP112 (centrosomal protein 112; 17q24.1) with delayed recall as well as SMOC2 (SPARC related modular calcium binding 2; 6p27) with immediate recall in a memory performance test. On the X chromosome, which is often excluded in other GWAS, we identified a genome-wide significant signal near IL1RAPL1 (interleukin 1 receptor accessory protein like 1; Xp21.3). While polygenic score (PGS) analyses showed the expected strong associations with SNPs highlighted in relevant previous GWAS on hippocampal volume and cognitive function, they did not show noteworthy associations with recent AD risk GWAS findings. In summary, our study highlights the power of using quantitative endophenotypes as outcome traits in AD-related GWAS analyses and nominates several new loci not previously implicated in cognitive decline.
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33.
  • Hong, Shengjun, et al. (författare)
  • Genome-wide association study of Alzheimer's disease CSF biomarkers in the EMIF-AD Multimodal Biomarker Discovery dataset.
  • 2020
  • Ingår i: Translational psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 10:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder and the most common form of dementia in the elderly. Susceptibility to AD is considerably determined by genetic factors which hitherto were primarily identified using case-control designs. Elucidating the genetic architecture of additional AD-related phenotypic traits, ideally those linked to the underlying disease process, holds great promise in gaining deeper insights into the genetic basis of AD and in developing better clinical prediction models. To this end, we generated genome-wide single-nucleotide polymorphism (SNP) genotyping data in 931 participants of the European Medical Information Framework Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) sample to search for novel genetic determinants of AD biomarker variability. Specifically, we performed genome-wide association study (GWAS) analyses on 16 traits, including 14 measures derived from quantifications of five separate amyloid-beta (Aβ) and tau-protein species in the cerebrospinal fluid (CSF). In addition to confirming the well-established effects of apolipoprotein E (APOE) on diagnostic outcome and phenotypes related to Aβ42, we detected novel potential signals in the zinc finger homeobox 3 (ZFHX3) for CSF-Aβ38 and CSF-Aβ40 levels, and confirmed the previously described sex-specific association between SNPs in geminin coiled-coil domain containing (GMNC) and CSF-tau. Utilizing the results from independent case-control AD GWAS to construct polygenic risk scores (PRS) revealed that AD risk variants only explain a small fraction of CSF biomarker variability. In conclusion, our study represents a detailed first account of GWAS analyses on CSF-Aβ and -tau-related traits in the EMIF-AD MBD dataset. In subsequent work, we will utilize the genomics data generated here in GWAS of other AD-relevant clinical outcomes ascertained in this unique dataset.
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34.
  • Jiguet, Frédéric, et al. (författare)
  • An update of the European breeding population sizes and trends of the Ortolan Bunting (Emberiza hortulana)
  • 2016
  • Ingår i: Ornis Fennica. - : University of Helsinki. - 0030-5685. ; 93:3, s. 186-196
  • Forskningsöversikt (refereegranskat)abstract
    • Following recent updates proposed by BirdLife International and further updates across Europe gathered in the context of a continent-wide study of the migration strategy of the species, we propose here an update of national population sizes and associated recent trends of the Ortolan Bunting (Emberiza hortulana). Previous estimates for the period 1999-2002 reported 5,200,000 to 16,000,000 breeding pairs, for an area extending east to European Russia, and south to the Caucasus and Turkey. The countries holding the largest populations were Turkey (3-10 million pairs) and Russia (1.5-5.0 million pairs). The updated results give approximately 3,319,000 to 7,057,000 pairs in Europe (for the period 2012-2014), representing a c. 50% decrease in numbers over the last decade. This decrease is partly due to overestimates proposed in previous reports for the key country, Turkey, which is now considered to support only 500,000 to 1,000,000 pairs. Russia still holds 2.0-4.3 million pairs, although with an estimated decline of c.15-30% since 2000. Overall, within the 39 European countries assessed here, recent decadal trends (on average 2000-2012) in population size are reported as unknown in 15 countries, increasing in 2 countries (Germany and Serbia), stable or fluctuating in 6 countries, and decreasing in 16 countries including recent extinctions in Belgium, Hungary, Slovakia and the Netherlands. Overall, declining populations are mostly located in northern Europe, and fourteen of the 15 northern European countries with a known national trend have declining breeding populations, suggesting that northern breeders are of particular conservation concern.
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35.
  • Lof, Sanne, et al. (författare)
  • Learning Curves of Minimally Invasive Distal Pancreatectomy in Experienced Pancreatic Centers
  • 2023
  • Ingår i: JAMA Surgery. - : AMER MEDICAL ASSOC. - 2168-6254 .- 2168-6262. ; 158:9, s. 927-933
  • Tidskriftsartikel (refereegranskat)abstract
    • IMPORTANCE Understanding the learning curve of a new complex surgical technique helps to reduce potential patient harm. Current series on the learning curve of minimally invasive distal pancreatectomy (MIDP) are mostly small, single-center series, thus providing limited data. OBJECTIVE To evaluate the length of pooled learning curves of MIDP in experienced centers. DESIGN, SETTING, AND PARTICIPANTS This international, multicenter, retrospective cohort study included MIDP procedures performed from January 1, 2006, through June 30, 2019, in 26 European centers from 8 countries that each performed more than 15 distal pancreatectomies annually, with an overall experience exceeding 50 MIDP procedures. Consecutive patients who underwent elective laparoscopic or robotic distal pancreatectomy for all indications were included. Data were analyzed between September 1, 2021, and May 1, 2022. EXPOSURES The learning curve for MIDP was estimated by pooling data from all centers. MAIN OUTCOMES AND MEASURES The learning curvewas assessed for the primary textbook outcome (TBO), which is a composite measure that reflects optimal outcome, and for surgical mastery. Generalized additive models and a 2-piece linear model with a break point were used to estimate the learning curve length of MIDP. Case mix-expected probabilities were plotted and compared with observed outcomes to assess the association of changing case mix with outcomes. The learning curve also was assessed for the secondary outcomes of operation time, intraoperative blood loss, conversion to open rate, and postoperative pancreatic fistula grade B/C. RESULTS From a total of 2610 MIDP procedures, the learning curve analysis was conducted on 2041 procedures (mean [SD] patient age, 58 [15.3] years; among 2040 with reported sex, 1249 were female [61.2%] and 791 male [38.8%]). The 2-piece model showed an increase and eventually a break point for TBO at 85 procedures (95% CI, 13-157 procedures), with a plateau TBO rate at 70%. The learning-associated loss of TBO rate was estimated at 3.3%. For conversion, a break point was estimated at 40 procedures (95% CI, 11-68 procedures); for operation time, at 56 procedures (95% CI, 35-77 procedures); and for intraoperative blood loss, at 71 procedures (95% CI, 28-114 procedures). For postoperative pancreatic fistula, no break point could be estimated. CONCLUSION AND RELEVANCE In experienced international centers, the learning curve length of MIDP for TBO was considerable with 85 procedures. These findings suggest that although learning curves for conversion, operation time, and intraoperative blood loss are completed earlier, extensive experience may be needed to master the learning curve of MIDP.
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36.
  • Ludvigsson, Johnny, et al. (författare)
  • GAD65 antigen therapy in recently diagnosed type 1 diabetes mellitus
  • 2012
  • Ingår i: New England Journal of Medicine. - : Massachusetts Medical Society. - 0028-4793 .- 1533-4406. ; 366:5, s. 433-442
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: The 65-kD isoform of glutamic acid decarboxylase (GAD65) is a major autoantigen in type 1 diabetes. We hypothesized that alum-formulated GAD65 (GAD-alum) can preserve beta-cell function in patients with recent-onset type 1 diabetes.METHODS: We studied 334 patients, 10 to 20 years of age, with type 1 diabetes, fasting C-peptide levels of more than 0.3 ng per milliliter (0.1 nmol per liter), and detectable serum GAD65 autoantibodies. Within 3 months after diagnosis, patients were randomly assigned to receive one of three study treatments: four doses of GAD-alum, two doses of GAD-alum followed by two doses of placebo, or four doses of placebo. The primary outcome was the change in the stimulated serum C-peptide level (after a mixed-meal tolerance test) between the baseline visit and the 15-month visit. Secondary outcomes included the glycated hemoglobin level, mean daily insulin dose, rate of hypoglycemia, and fasting and maximum stimulated C-peptide levels.RESULTS: The stimulated C-peptide level declined to a similar degree in all study groups, and the primary outcome at 15 months did not differ significantly between the combined active-drug groups and the placebo group (P=0.10). The use of GAD-alum as compared with placebo did not affect the insulin dose, glycated hemoglobin level, or hypoglycemia rate. Adverse events were infrequent and mild in the three groups, with no significant differences.CONCLUSIONS: Treatment with GAD-alum did not significantly reduce the loss of stimulated C peptide or improve clinical outcomes over a 15-month period.
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37.
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38.
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40.
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41.
  • Morin, Lucas, et al. (författare)
  • Estimating the need for palliative care at the population level : A cross-national study in 12 countries
  • 2017
  • Ingår i: Palliative Medicine. - : SAGE Publications. - 0269-2163 .- 1477-030X. ; 31:6, s. 526-536
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: To implement the appropriate services and develop adequate interventions, detailed estimates of the needs for palliative care in the population are needed.Aim: To estimate the proportion of decedents potentially in need of palliative care across 12 European and non-European countries.Design: This is a cross-sectional study using death certificate data.Setting/participants: All adults (18years) who died in 2008 in Belgium, Czech Republic, France, Hungary, Italy, Spain (Andalusia, 2010), Sweden, Canada, the United States (2007), Korea, Mexico, and New Zealand (N=4,908,114). Underlying causes of death were used to apply three estimation methods developed by Rosenwax et al., the French National Observatory on End-of-Life Care, and Murtagh et al., respectively.Results: The proportion of individuals who died from diseases that indicate palliative care needs at the end of life ranged from 38% to 74%. We found important cross-country variation: the population potentially in need of palliative care was lower in Mexico (24%-58%) than in the United States (41%-76%) and varied from 31%-83% in Hungary to 42%-79% in Spain. Irrespective of the estimation methods, female sex and higher age were independently associated with the likelihood of being in need of palliative care near the end of life. Home and nursing home were the two places of deaths with the highest prevalence of palliative care needs.Conclusion: These estimations of the size of the population potentially in need of palliative care provide robust indications of the challenge countries are facing if they want to seriously address palliative care needs at the population level.
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42.
  • Nuttin, Bart, et al. (författare)
  • Consensus on guidelines for stereotactic neurosurgery for psychiatric disorders
  • 2014
  • Ingår i: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ Publishing Group. - 0022-3050 .- 1468-330X. ; 85:9, s. 1003-1008
  • Tidskriftsartikel (refereegranskat)abstract
    • Background For patients with psychiatric illnesses remaining refractory to 'tandard' therapies, neurosurgical procedures may be considered. Guidelines for safe and ethical conduct of such procedures have previously and independently been proposed by various local and regional expert groups. Methods To expand on these earlier documents, representative members of continental and international psychiatric and neurosurgical societies, joined efforts to further elaborate and adopt a pragmatic worldwide set of guidelines. These are intended to address a broad range of neuropsychiatric disorders, brain targets and neurosurgical techniques, taking into account cultural and social heterogeneities of healthcare environments. Findings The proposed consensus document highlights that, while stereotactic ablative procedures such as cingulotomy and capsulotomy for depression and obsessive-compulsive disorder are considered 'stablished' in some countries, they still lack level I evidence. Further, it is noted that deep brain stimulation in any brain target hitherto tried, and for any psychiatric or behavioural disorder, still remains at an investigational stage. Researchers are encouraged to design randomised controlled trials, based on scientific and data-driven rationales for disease and brain target selection. Experienced multidisciplinary teams are a mandatory requirement for the safe and ethical conduct of any psychiatric neurosurgery, ensuring documented refractoriness of patients, proper consent procedures that respect patient's capacity and autonomy, multifaceted preoperative as well as postoperative long-term follow-p evaluation, and reporting of effects and side effects for all patients. Interpretation This consensus document on ethical and scientific conduct of psychiatric surgery worldwide is designed to enhance patient safety.
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43.
  • Piens, Kathleen, et al. (författare)
  • Glycosynthase activity of hybrid aspen xyloglucan endo-transglycosylase PttXET16-34 nucleophile mutants
  • 2007
  • Ingår i: Organic and Biomolecular Chemistry. - : Royal Society of Chemistry (RSC). - 1477-0520 .- 1477-0539. ; 5:24
  • Tidskriftsartikel (refereegranskat)abstract
    • Glycosynthases are active-site mutants of glycoside hydrolases that catalyse glycosyl transfer using suitable activated donor substrates without competing product hydrolysis ( S. M. Hancock, M. D. Vaughan and S. G. Withers, Curr. Opin. Chem. Biol., 2006, 10, 509-519). Site-directed mutagenesis of the catalytic nucleophile, Glu-85, of a Populus tremula x tremuloides xyloglucan endo-transglycosylase (PttXET16-34, EC 2.4.1.207) into alanine, glycine, and serine yielded enzymes with glycosynthase activity. Product analysis indicated that PttXET16-34 E85A in particular was able to catalyse regio- and stereospecific homo- and hetero- condensations of alpha-xylogluco-oligosaccharyl fluoride donors XXXG alpha F andXLLG alpha F to produce xyloglucans with regular sidechain substitution patterns. This substrate promiscuity contrasts that of the Humicola insolens Ce17B E197A glycosynthase, which was not able to polymerise the di-galactosylated substrate XLLG alpha F. The production of the PttXET16-34 E85A xyloglucosynthase thus expands the repertoire of glycosynthases to include those capable of synthesising structurally homogenenous xyloglucans
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44.
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45.
  • Sytiuk, Anna, et al. (författare)
  • Biochemical traits enhance the trait concept in Sphagnum ecology
  • 2022
  • Ingår i: Oikos. - : John Wiley & Sons. - 0030-1299 .- 1600-0706. ; :4
  • Tidskriftsartikel (refereegranskat)abstract
    • Sphagnum mosses are key to northern peatland carbon sequestration. They have a range of morphological and anatomical characteristics that allow them to cope with environmental stress. Sphagnum also produces a plethora of biochemicals that may prevent stress-induced cell-damage. However, the linkages between Sphagnum anatomical, morphological and biochemical traits (i.e. metabolites, pigments and antioxidant enzyme activities) are poorly known, neither are their joint responses to environmental change. Here, we quantify and link an array of Sphagnum anatomical, morphological and biochemical traits in five Sphagnum-dominated peatlands distributed along a latitudinal gradient in Europe, covering a range of regional and local environmental conditions. Sphagnum morphological and anatomical traits were intrinsically linked to Sphagnum metabolites and enzyme activities, and these relationships were driven by shared responses to local and regional environmental factors. More particularly, we found that Sphagnum traits can be grouped into four clusters related to growth, biomass, defense and water stress tolerance. We used regional and local environmental conditions data to further show that biochemicals and their specific linkages with some morphological traits describe dimensions of physiology not captured by anatomical and morphological traits alone. These results suggest that Sphagnum morphology and function is rooted in the metabolome, and that incorporating biochemicals into the functional trait space concept can enhance our mechanistic understanding and predictive power in Sphagnum ecology.
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46.
  • van Ramshorst, Tess M. E., et al. (författare)
  • Benchmarking of robotic and laparoscopic spleen-preserving distal pancreatectomy by using two different methods
  • 2023
  • Ingår i: British Journal of Surgery. - : Oxford University Press. - 0007-1323 .- 1365-2168. ; 110:1, s. 76-83
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Benchmarking is an important tool for quality comparison and improvement. However, no benchmark values are available for minimally invasive spleen-preserving distal pancreatectomy, either laparoscopically or robotically assisted. The aim of this study was to establish benchmarks for these techniques using two different methods. Methods Data from patients undergoing laparoscopically or robotically assisted spleen-preserving distal pancreatectomy were extracted from a multicentre database (2006-2019). Benchmarks for 10 outcomes were calculated using the Achievable Benchmark of Care (ABC) and best-patient-in-best-centre methods. Results Overall, 951 laparoscopically assisted (77.3 per cent) and 279 robotically assisted (22.7 per cent) procedures were included. Using the ABC method, the benchmarks for laparoscopically assisted and robotically assisted spleen-preserving distal pancreatectomy respectively were: 150 and 207 min for duration of operation, 55 and 100 ml for blood loss, 3.5 and 1.7 per cent for conversion, 0 and 1.7 per cent for failure to preserve the spleen, 27.3 and 34.0 per cent for overall morbidity, 5.1 and 3.3 per cent for major morbidity, 3.6 and 7.1 per cent for pancreatic fistula grade B/C, 5 and 6 days for duration of hospital stay, 2.9 and 5.4 per cent for readmissions, and 0 and 0 per cent for 90-day mortality. Best-patient-in-best-centre methodology revealed milder benchmark cut-offs for laparoscopically and robotically assisted procedures, with operating times of 254 and 262.5 min, blood loss of 150 and 195 ml, conversion rates of 5.8 and 8.2 per cent, rates of failure to salvage spleen of 29.9 and 27.3 per cent, overall morbidity rates of 62.7 and 55.7 per cent, major morbidity rates of 20.4 and 14 per cent, POPF B/C rates of 23.8 and 24.2 per cent, duration of hospital stay of 8 and 8 days, readmission rates of 20 and 15.1 per cent, and 90-day mortality rates of 0 and 0 per cent respectively. Conclusion Two benchmark methods for minimally invasive distal pancreatectomy produced different values, and should be interpreted and applied differently. This study established benchmark values for laparoscopically and robotically assisted spleen-preserving distal pancreatectomy in both unselected and low-risk patients using two validated methodologies. The benchmark values require different interpretation and application based on the purpose of benchmarking and the patient cohort, and can be used for in-hospital and interhospital comparison and improvement purposes.
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47.
  • Varriale, Simona, et al. (författare)
  • Evolution of the feruloyl esterase MtFae1a from Myceliophthora thermophila towards improved catalysts for antioxidants synthesis
  • 2018
  • Ingår i: Applied Microbiology and Biotechnology. - : Springer. - 0175-7598 .- 1432-0614. ; 102:12, s. 5185-5196
  • Tidskriftsartikel (refereegranskat)abstract
    • The chemical syntheses currently employed for industrial purposes, including in the manufacture of cosmetics, present limitations such as unwanted side reactions and the need for harsh chemical reaction conditions. In order to overcome these drawbacks, novel enzymes are developed to catalyze the targeted bioconversions. In the present study, a methodology for the construction and the automated screening of evolved variants library of a Type B feruloyl esterase from Myceliophthora thermophila (MtFae1a) was developed and applied to generation of 30,000 mutants and their screening for selecting the variants with higher activity than the wild-type enzyme. The library was generated by error-prone PCR of mtfae1a cDNA and expressed in Saccharomyces cerevisiae. Screening for extracellular enzymatic activity towards 4-nitrocatechol-1-yl ferulate, a new substrate developed ad hoc for high-throughput assays of feruloyl esterases, led to the selection of 30 improved enzyme variants. The best four variants and the wild-type MtFae1a were investigated in docking experiments with hydroxycinnamic acid esters using a model of 3D structure of MtFae1a. These variants were also used as biocatalysts in transesterification reactions leading to different target products in detergentless microemulsions and showed enhanced synthetic activities, although the screening strategy had been based on improved hydrolytic activity.
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48.
  • Venkatakrishnan, Vignesh, 1987, et al. (författare)
  • Glycan analysis of human neutrophil granules implicates a maturation-dependent glycosylation machinery
  • 2020
  • Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 295:36, s. 12648-12660
  • Tidskriftsartikel (refereegranskat)abstract
    • Protein glycosylation is essential to trafficking and immune functions of human neutrophils. During granulopoiesis in the bone marrow, distinct neutrophil granules are successively formed. Distinct receptors and effector proteins, many of which are glycosylated, are targeted to each type of granule according to their time of expression, a process called "targeting by timing." Therefore, these granules are time capsules reflecting different times of maturation that can be used to understand the glycosylation process during granulopoiesis. Herein, neutrophil subcellular granules were fractionated by Percoll density gradient centrifugation, andN- andO-glycans present in each compartment were analyzed by LC-MS. We found abundant paucimannosidicN-glycans and lack ofO-glycans in the early-formed azurophil granules, whereas the later-formed specific and gelatinase granules and secretory vesicles contained complexN-andO-glycans with remarkably elongatedN-acetyllactosamine repeats with Lewis epitopes. Immunoblotting and histochemical analysis confirmed the expression of Lewis X and sialyl-Lewis X in the intracellular granules and on the cell surface, respectively. Many glycans identified are unique to neutrophils, and their complexity increased progressively from azurophil granules to specific granules and then to gelatinase granules, suggesting temporal changes in the glycosylation machinery indicative of "glycosylation by timing" during granulopoiesis. In summary, this comprehensive neutrophil granule glycome map, the first of its kind, highlights novel granule-specific glycosylation features and is a crucial first step toward a better understanding of the mechanisms regulating protein glycosylation during neutrophil granulopoiesis and a more detailed understanding of neutrophil biology and function.
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49.
  • Zakhozhay, Olga, et al. (författare)
  • Radial Velocity Survey for Planets around Young stars (RVSPY) Target characterisation and high-cadence survey
  • 2022
  • Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 667
  • Tidskriftsartikel (refereegranskat)abstract
    • Context. The occurrence rate and period distribution of (giant) planets around young stars is still not as well constrained as for older main-sequence stars. This is mostly due to the intrinsic activity-related complications and the avoidance of young stars in many large planet search programmes. Yet, dynamical restructuring processes in planetary systems may last significantly longer than the actual planet formation phase and may well extend long into the debris disc phase, such that the planet populations around young stars may differ from those observed around main-sequence stars.Aims. We introduce our Radial Velocity Survey for Planets around Young stars (RVSPY), which is closely related to the NaCo-ISPY direct imaging survey, characterise our target stars, and search for substellar companions at orbital separations smaller than a few au from the host star.Methods. We used the FEROS spectrograph, mounted to the MPG/ESO 2.2 m telescope in Chile, to obtain high signal-to-noise spectra and time series of precise radial velocities (RVs) of 111 stars, most of which are surrounded by debris discs. Our target stars have spectral types between early F and late K, a median age of 400 Myr, and a median distance of 45 pc. During the initial reconnaissance phase of our survey, we determined stellar parameters and used high-cadence observations to characterise the intrinsic stellar activity, searched for hot companions with orbital periods of up to 10 days, and derived the detection thresholds for longer-period companions. In our analysis we, have included archival spectroscopic data, spectral energy distribution, and data for photometric time series from the TESS mission.Results. For all target stars we determined their basic stellar parameters and present the results of the high-cadence RV survey and activity characterisation. We have achieved a median single-measurement RV precision of 6 m s−1 and derived the short-term intrinsic RV scatter of our targets (median 23 m s−1), which is mostly caused by stellar activity and decays with an age from >100 m s−1 at <20 Myr to <20 m s−1 at >500 Myr. We analysed time series periodograms of the high-cadence RV data and the shape of the individual cross-correlation functions. We discovered six previously unknown close companions with orbital periods between 10 and 100 days, three of which are low-mass stars, and three are in the brown dwarf mass regime. We detected no hot companion with an orbital period <10 days down to a median mass limit of ~1 MJup for stars younger than 500 Myr, which is still compatible with the established occurrence rate of such companions around main-sequence stars. We found significant RV periodicities between 1.3 and 4.5 days for 14 stars, which are, however, all caused by rotational modulation due to starspots. We also analysed the data for TESS photometric time series and found significant periodicities for most of the stars. For 11 stars, the photometric periods are also clearly detected in the RV data. We also derived stellar rotation periods ranging from 1 to 10 days for 91 stars, mostly from the TESS data. From the intrinsic activity-related short-term RV jitter, we derived the expected mass-detection thresholds for longer-period companions, and selected 84 targets for the longer-term RV monitoring.
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