| 1. |
- Aamodt, K., et al.
(författare)
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The ALICE experiment at the CERN LHC
- 2008
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Ingår i: Journal of Instrumentation. - 1748-0221. ; 3:S08002
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Forskningsöversikt (refereegranskat)abstract
- ALICE (A Large Ion Collider Experiment) is a general-purpose, heavy-ion detector at the CERN LHC which focuses on QCD, the strong-interaction sector of the Standard Model. It is designed to address the physics of strongly interacting matter and the quark-gluon plasma at extreme values of energy density and temperature in nucleus-nucleus collisions. Besides running with Pb ions, the physics programme includes collisions with lighter ions, lower energy running and dedicated proton-nucleus runs. ALICE will also take data with proton beams at the top LHC energy to collect reference data for the heavy-ion programme and to address several QCD topics for which ALICE is complementary to the other LHC detectors. The ALICE detector has been built by a collaboration including currently over 1000 physicists and engineers from 105 Institutes in 30 countries, Its overall dimensions are 16 x 16 x 26 m(3) with a total weight of approximately 10 000 t. The experiment consists of 18 different detector systems each with its own specific technology choice and design constraints, driven both by the physics requirements and the experimental conditions expected at LHC. The most stringent design constraint is to cope with the extreme particle multiplicity anticipated in central Pb-Pb collisions. The different subsystems were optimized to provide high-momentum resolution as well as excellent Particle Identification (PID) over a broad range in momentum, up to the highest multiplicities predicted for LHC. This will allow for comprehensive studies of hadrons, electrons, muons, and photons produced in the collision of heavy nuclei. Most detector systems are scheduled to be installed and ready for data taking by mid-2008 when the LHC is scheduled to start operation, with the exception of parts of the Photon Spectrometer (PHOS), Transition Radiation Detector (TRD) and Electro Magnetic Calorimeter (EMCal). These detectors will be completed for the high-luminosity ion run expected in 2010. This paper describes in detail the detector components as installed for the first data taking in the summer of 2008.
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| 2. |
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| 3. |
- Blach, S., et al.
(författare)
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Global change in hepatitis C virus prevalence and cascade of care between 2015 and 2020: a modelling study
- 2022
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Ingår i: Lancet Gastroenterology & Hepatology. - : Elsevier BV. - 2468-1253. ; 7:5, s. 396-415
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Tidskriftsartikel (refereegranskat)abstract
- Background Since the release of the first global hepatitis elimination targets in 2016, and until the COVID-19 pandemic started in early 2020, many countries and territories were making progress toward hepatitis C virus (HCV) elimination. This study aims to evaluate HCV burden in 2020, and forecast HCV burden by 2030 given current trends. Methods This analysis includes a literature review, Delphi process, and mathematical modelling to estimate HCV prevalence (viraemic infection, defined as HCV RNA-positive cases) and the cascade of care among people of all ages (age =0 years from birth) for the period between Jan 1, 2015, and Dec 31, 2030. Epidemiological data were collected from published sources and grey literature (including government reports and personal communications) and were validated among country and territory experts. A Markov model was used to forecast disease burden and cascade of care from 1950 to 2050 for countries and territories with data. Model outcomes were extracted from 2015 to 2030 to calculate population-weighted regional averages, which were used for countries or territories without data. Regional and global estimates of HCV prevalence, cascade of care, and disease burden were calculated based on 235 countries and territories. Findings Models were built for 110 countries or territories: 83 were approved by local experts and 27 were based on published data alone. Using data from these models, plus population-weighted regional averages for countries and territories without models (n=125), we estimated a global prevalence of viraemic HCV infection of 0.7% (95% UI 0.7-0.9), corresponding to 56.8 million (95% UI 55.2-67.8) infections, on Jan 1, 2020. This number represents a decrease of 6.8 million viraemic infections from a 2015 (beginning of year) prevalence estimate of 63.6 million (61.8-75.8) infections (0.9% [0.8-1.0] prevalence). By the end of 2020, an estimated 12.9 million (12.5-15.4) people were living with a diagnosed viraemic infection. In 2020, an estimated 641 000 (623 000-765 000) patients initiated treatment. Interpretation At the beginning of 2020, there were an estimated 56.8 million viraemic HCV infections globally. Although this number represents a decrease from 2015, our forecasts suggest we are not currently on track to achieve global elimination targets by 2030. As countries recover from COVID-19, these findings can help refocus efforts aimed at HCV elimination. Copyright (C) 2022 Elsevier Ltd. All rights reserved.
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| 4. |
- Botvinik-Nezer, Rotem, et al.
(författare)
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Variability in the analysis of a single neuroimaging dataset by many teams
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 582, s. 84-88
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Tidskriftsartikel (refereegranskat)abstract
- Data analysis workflows in many scientific domains have become increasingly complex and flexible. Here we assess the effect of this flexibility on the results of functional magnetic resonance imaging by asking 70 independent teams to analyse the same dataset, testing the same 9 ex-ante hypotheses(1). The flexibility of analytical approaches is exemplified by the fact that no two teams chose identical workflows to analyse the data. This flexibility resulted in sizeable variation in the results of hypothesis tests, even for teams whose statistical maps were highly correlated at intermediate stages of the analysis pipeline. Variation in reported results was related to several aspects of analysis methodology. Notably, a meta-analytical approach that aggregated information across teams yielded a significant consensus in activated regions. Furthermore, prediction markets of researchers in the field revealed an overestimation of the likelihood of significant findings, even by researchers with direct knowledge of the dataset(2-5). Our findings show that analytical flexibility can have substantial effects on scientific conclusions, and identify factors that may be related to variability in the analysis of functional magnetic resonance imaging. The results emphasize the importance of validating and sharing complex analysis workflows, and demonstrate the need for performing and reporting multiple analyses of the same data. Potential approaches that could be used to mitigate issues related to analytical variability are discussed. The results obtained by seventy different teams analysing the same functional magnetic resonance imaging dataset show substantial variation, highlighting the influence of analytical choices and the importance of sharing workflows publicly and performing multiple analyses.
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| 5. |
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| 6. |
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| 7. |
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| 8. |
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| 9. |
- Bruggmann, P., et al.
(författare)
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Historical epidemiology of hepatitis C virus (HCV) in selected countries
- 2014
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Ingår i: Journal of Viral Hepatitis. - Hoboken : Wiley-Blackwell. - 1352-0504 .- 1365-2893. ; 21, s. 5-33
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Tidskriftsartikel (refereegranskat)abstract
- Chronic infection with hepatitis C virus (HCV) is a leading indicator for liver disease. New treatment options are becoming available, and there is a need to characterize the epidemiology and disease burden of HCV. Data for prevalence, viremia, genotype, diagnosis and treatment were obtained through literature searches and expert consensus for 16 countries. For some countries, data from centralized registries were used to estimate diagnosis and treatment rates. Data for the number of liver transplants and the proportion attributable to HCV were obtained from centralized databases. Viremic prevalence estimates varied widely between countries, ranging from 0.3% in Austria, England and Germany to 8.5% in Egypt. The largest viremic populations were in Egypt, with 6358000 cases in 2008 and Brazil with 2106000 cases in 2007. The age distribution of cases differed between countries. In most countries, prevalence rates were higher among males, reflecting higher rates of injection drug use. Diagnosis, treatment and transplant levels also differed considerably between countries. Reliable estimates characterizing HCV-infected populations are critical for addressing HCV-related morbidity and mortality. There is a need to quantify the burden of chronic HCV infection at the national level.
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| 10. |
- Razavi, H., et al.
(författare)
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Hepatitis C virus prevalence and level of intervention required to achieve the WHO targets for elimination in the European Union by 2030: a modelling study
- 2017
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Ingår i: Lancet Gastroenterology & Hepatology. - : Elsevier BV. - 2468-1253. ; 2:5, s. 325-336
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Tidskriftsartikel (refereegranskat)abstract
- Background Hepatitis C virus (HCV) is a leading cause of liver-related morbidity and mortality worldwide. In the European Union (EU), treatment and cure of HCV with direct-acting antiviral therapies began in 2014. WHO targets are to achieve a 65% reduction in liver-related deaths, a 90% reduction of new viral hepatitis infections, and 90% of patients with viral hepatitis infections being diagnosed by 2030. This study assessed the prevalence of HCV in the EU and the level of intervention required to achieve WHO targets for HCV elimination. Methods We populated country Markov models for the 28 EU countries through a literature search of PubMed and Embase between Jan 1, 2000, and March 31, 2016, and a Delphi process to gain expert consensus and validate inputs. We aggregated country models to create a regional EU model. We used the EU model to forecast HCV disease progression (considering the effect of immigration) and developed a strategy to acehive WHO targets. We used weighted average sustained viral response rates and fibrosis restrictions to model the effect of current therapeutic guidelines. We used the EU model to forecast HCV disease progression (considering the effect of immigration) under current screening and therapeutic guidelines. Additionally, we back-calculated the total number of patients needing to be screened and treated to achieve WHO targets. Findings We estimated the number of viraemic HCV infections in 2015 to be 3 238 000 (95% uncertainty interval [UI] 2 106 000-3 795 000) of a total population of 509 868 000 in the EU, equating to a prevalence of viraemic HCV of 0.64% (95% UI 0.41-0.74). We estimated that 1 180 000 (95% UI 1 003 000-1 357 000) people were diagnosed with viraemia (36.4%), 150 000 (12 000-180 000) were treated (4.6% of the total infected population or 12.7% of the diagnosed population), 133 000 (106 000-160 000) were cured (4.1%), and 57 900 (43 900-67 300) were newly infected (1.8%) in 2015. Additionally, 30 400 (26 600-42 500) HCV-positive immigrants entered the EU. To achieve WHO targets, unrestricted treatment needs to increase from 150 000 patients in 2015 to 187 000 patients in 2025 and diagnosis needs to increase from 88 800 new cases annually in 2015 to 180 000 in 2025. Interpretation Given its advanced health-care infrastructure, the EU is uniquely poised to eliminate HCV; however, expansion of screening programmes is essential to increase treatment to achieve the WHO targets. A united effort, grounded in sound epidemiological evidence, will also be necessary.
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| 11. |
- Razavi, H., et al.
(författare)
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The present and future disease burden of hepatitis C virus (HCV) infection with today's treatment paradigm
- 2014
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Ingår i: Journal of Viral Hepatitis. - Hoboken : Wiley-Blackwell. - 1352-0504 .- 1365-2893. ; 21:Suppl. 1, s. 34-59
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Tidskriftsartikel (refereegranskat)abstract
- The disease burden of hepatitis C virus (HCV) is expected to increase as the infected population ages. A modelling approach was used to estimate the total number of viremic infections, diagnosed, treated and new infections in 2013. In addition, the model was used to estimate the change in the total number of HCV infections, the disease progression and mortality in 2013-2030. Finally, expert panel consensus was used to capture current treatment practices in each country. Using today's treatment paradigm, the total number of HCV infections is projected to decline or remain flat in all countries studied. However, in the same time period, the number of individuals with late-stage liver disease is projected to increase. This study concluded that the current treatment rate and efficacy are not sufficient to manage the disease burden of HCV. Thus, alternative strategies are required to keep the number of HCV individuals with advanced liver disease and liver-related deaths from increasing.
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| 12. |
- Wedemeyer, H., et al.
(författare)
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Strategies to manage hepatitis C virus (HCV) disease burden
- 2014
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Ingår i: Journal of Viral Hepatitis. - Hoboken : Wiley-Blackwell. - 1352-0504 .- 1365-2893. ; 21, s. 60-89
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Tidskriftsartikel (refereegranskat)abstract
- The number of hepatitis C virus (HCV) infections is projected to decline while those with advanced liver disease will increase. A modeling approach was used to forecast two treatment scenarios: (i) the impact of increased treatment efficacy while keeping the number of treated patients constant and (ii) increasing efficacy and treatment rate. This analysis suggests that successful diagnosis and treatment of a small proportion of patients can contribute significantly to the reduction of disease burden in the countries studied. The largest reduction in HCV-related morbidity and mortality occurs when increased treatment is combined with higher efficacy therapies, generally in combination with increased diagnosis. With a treatment rate of approximately 10%, this analysis suggests it is possible to achieve elimination of HCV (defined as a >90% decline in total infections by 2030). However, for most countries presented, this will require a 3-5 fold increase in diagnosis and/or treatment. Thus, building the public health and clinical provider capacity for improved diagnosis and treatment will be critical.
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| 13. |
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| 14. |
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| 15. |
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| 16. |
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| 17. |
- Crandall, H, et al.
(författare)
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Bb2Bb3 regulation of murine Lyme arthritis is distinct from Ncf1 and independent of the phagocyte nicotinamide adenine dinucleotide phosphate oxidase
- 2005
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Ingår i: American Journal of Pathology. - 1525-2191. ; 167:3, s. 775-785
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Tidskriftsartikel (refereegranskat)abstract
- Several quantitative trait loci regulating murine Lyme arthritis severity have been mapped, including a highly significant linkage found on chromosome 5, termed Bb2Bb3. Within this region, the Ncf1 gene of the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase has recently been identified as a major regulator of arthritis severity in rodent models of rheumatoid arthritis, an effect attributed to protective properties of reactive oxygen species. To assess the role of Ncf1 in Lyme arthritis, we introgressed Bb2Bb3 from severely arthritic C3H/He mice onto mildly arthritic C57BL/6 mice. This increased Lyme arthritis severity, whereas the reciprocal transfer conferred protection from disease. A single nucleotide polymorphism was identified in the Ncf1 gene that did not influence the protein sequence or expression of Ncf1. Although polymorphonuclear leukocytes from C57BL/6 mice generated a greater oxidative burst than polymorphonuclear leukocytes from C3H/He mice, studies with the Bb2Bb3 congenic mice demonstrated this difference was not linked to Ncf1 alleles. Furthermore, Lyme arthritis severity was not altered in mice lacking either the Ncf1 or Gp91phox subunits of the NADPH oxidase complex. Together, these results argue that Ncf1 is not a candidate gene for regulation of Lyme arthritis and reveal Lyme arthritis to be independent of NADPH oxidase activity, distinguishing it from other models of rheumatoid arthritis.
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| 18. |
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| 19. |
- Peters, S., et al.
(författare)
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Reconditioning the Neurogenic Niche of Adult Non-human Primates by Antisense Oligonucleotide-Mediated Attenuation of TGFβ Signaling
- 2021
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Ingår i: Neurotherapeutics. - : Springer Nature. - 1933-7213 .- 1878-7479. ; 18:3, s. 1963-1979
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Tidskriftsartikel (refereegranskat)abstract
- Adult neurogenesis is a target for brain rejuvenation as well as regeneration in aging and disease. Numerous approaches showed efficacy to elevate neurogenesis in rodents, yet translation into therapies has not been achieved. Here, we introduce a novel human TGFβ-RII (Transforming Growth Factor—Receptor Type II) specific LNA-antisense oligonucleotide (“locked nucleotide acid”—“NVP-13”), which reduces TGFβ-RII expression and downstream receptor signaling in human neuronal precursor cells (ReNcell CX® cells) in vitro. After we injected cynomolgus non-human primates repeatedly i.th. with NVP-13 in a preclinical regulatory 13-week GLP-toxicity program, we could specifically downregulate TGFβ-RII mRNA and protein in vivo. Subsequently, we observed a dose-dependent upregulation of the neurogenic niche activity within the hippocampus and subventricular zone: human neural progenitor cells showed significantly (up to threefold over control) enhanced differentiation and cell numbers. NVP-13 treatment modulated canonical and non-canonical TGFβ pathways, such as MAPK and PI3K, as well as key transcription factors and epigenetic factors involved in stem cell maintenance, such as MEF2A and pFoxO3. The latter are also dysregulated in clinical neurodegeneration, such as amyotrophic lateral sclerosis. Here, we provide for the first time in vitro and in vivo evidence for a novel translatable approach to treat neurodegenerative disorders by modulating neurogenesis.
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| 20. |
- Smith, Nathan, et al.
(författare)
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Kinematics and Ultraviolet to Infrared Morphology of the Inner Homunculus of η Carinae
- 2004
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 605:1, s. 405-424
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Tidskriftsartikel (refereegranskat)abstract
- We present the first ultraviolet and optical images of η Car and itscircumstellar Homunculus nebula, obtained with the Advanced Camera forSurveys/High Resolution Camera (ACS/HRC) on board the Hubble SpaceTelescope (HST). Compared to those at visual wavelengths, UV imagesreveal excess emission 0.1"-0.6" from the central source along the minoraxis that may emanate from the outer parts of η Car's nonsphericalstellar wind, which dominates the UV flux from η Car. The UVemission fills the cavity inside a dust torus measured from infrared(IR) data; within 0.2" of the star the UV emission projects a morphologyreminiscent of the IR torus, but it is a factor of 10 smaller. This``little torus'' seen in the UV may be related to the ``LittleHomunculus'' discovered recently, signifying recurrent mass ejectionswith the same geometry. Finally, we reexamine the kinematics of nebularcondensations near the star (Weigelt objects C and D) in HST images andspectra obtained over the past decade. We measure heliocentricvelocities slower than previous estimates, and from proper motions wederive an ejection date of 1908+/-12 yr, assuming linear motion.However, because of radiative acceleration, these objects may have beenejected earlier-perhaps during the 1890 outburst of η Car.Based on observations made with the NASA/ESA Hubble Space Telescope,obtained at the Space Telescope Science Institute, operated by theAssociation of Universities for Research in Astronomy, Inc., under NASAcontract NAS 5-26555.
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| 21. |
- Aquila, A., et al.
(författare)
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The linac coherent light source single particle imaging road map
- 2015
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Ingår i: Structural Dynamics. - : AIP Publishing. - 2329-7778. ; 2:4
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Tidskriftsartikel (refereegranskat)abstract
- Intense femtosecond x-ray pulses from free-electron laser sources allow the imag-ing of individual particles in a single shot. Early experiments at the Linac CoherentLight Source (LCLS) have led to rapid progress in the field and, so far, coherentdiffractive images have been recorded from biological specimens, aerosols, andquantum systems with a few-tens-of-nanometers resolution. In March 2014, LCLSheld a workshop to discuss the scientific and technical challenges for reaching theultimate goal of atomic resolution with single-shot coherent diffractive imaging. This paper summarizes the workshop findings and presents the roadmap towardreaching atomic resolution, 3D imaging at free-electron laser sources.
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| 22. |
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| 23. |
- Kovacs, Gabor G., et al.
(författare)
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Aging-related tau astrogliopathy (ARTAG) : harmonized evaluation strategy
- 2016
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Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 131:1, s. 87-102
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Tidskriftsartikel (refereegranskat)abstract
- Pathological accumulation of abnormally phosphorylated tau protein in astrocytes is a frequent, but poorly characterized feature of the aging brain. Its etiology is uncertain, but its presence is sufficiently ubiquitous to merit further characterization and classification, which may stimulate clinicopathological studies and research into its pathobiology. This paper aims to harmonize evaluation and nomenclature of aging-related tau astrogliopathy (ARTAG), a term that refers to a morphological spectrum of astroglial pathology detected by tau immunohistochemistry, especially with phosphorylation-dependent and 4R isoform-specific antibodies. ARTAG occurs mainly, but not exclusively, in individuals over 60 years of age. Tau-immunoreactive astrocytes in ARTAG include thorn-shaped astrocytes at the glia limitans and in white matter, as well as solitary or clustered astrocytes with perinuclear cytoplasmic tau immunoreactivity that extends into the astroglial processes as fine fibrillar or granular immunopositivity, typically in gray matter. Various forms of ARTAG may coexist in the same brain and might reflect different pathogenic processes. Based on morphology and anatomical distribution, ARTAG can be distinguished from primary tauopathies, but may be concurrent with primary tauopathies or other disorders. We recommend four steps for evaluation of ARTAG: (1) identification of five types based on the location of either morphologies of tau astrogliopathy: subpial, subependymal, perivascular, white matter, gray matter; (2) documentation of the regional involvement: medial temporal lobe, lobar (frontal, parietal, occipital, lateral temporal), subcortical, brainstem; (3) documentation of the severity of tau astrogliopathy; and (4) description of subregional involvement. Some types of ARTAG may underlie neurological symptoms; however, the clinical significance of ARTAG is currently uncertain and awaits further studies. The goal of this proposal is to raise awareness of astroglial tau pathology in the aged brain, facilitating communication among neuropathologists and researchers, and informing interpretation of clinical biomarkers and imaging studies that focus on tau-related indicators.
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| 24. |
- Kovacs, Gabor G., et al.
(författare)
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Multisite Assessment of Aging-Related Tau Astrogliopathy (ARTAG)
- 2017
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Ingår i: Journal of Neuropathology and Experimental Neurology. - : Oxford University Press (OUP). - 0022-3069 .- 1554-6578. ; 76:7, s. 605-619
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Tidskriftsartikel (refereegranskat)abstract
- Aging-related tau astrogliopathy (ARTAG) is a recently introduced terminology. To facilitate the consistent identification of ARTAG and to distinguish it from astroglial tau pathologies observed in the primary frontotemporal lobar degeneration tauopathies we evaluated how consistently neuropathologists recognize (1) different astroglial tau immunoreactivities, including those of ARTAG and those associated with primary tauopathies (Study 1); (2) ARTAG types (Study 2A); and (3) ARTAG severity (Study 2B). Microphotographs and scanned sections immunostained for phosphorylated tau (AT8) were made available for download and preview. Percentage of agreement and kappa values with 95% confidence interval (CI) were calculated for each evaluation. The overall agreement for Study 1 was > 60% with a kappa value of 0.55 (95% CI 0.433-0.645). Moderate agreement (> 90%, kappa 0.48, 95% CI 0.457-0.900) was reached in Study 2A for the identification of ARTAG pathology for each ARTAG subtype (kappa 0.37-0.72), whereas fair agreement (kappa 0.40, 95% CI 0.341-0.445) was reached for the evaluation of ARTAG severity. The overall assessment of ARTAG showed moderate agreement (kappa 0.60, 95% CI 0.534-0.653) among raters. Our study supports the application of the current harmonized evaluation strategy for ARTAG with a slight modification of the evaluation of its severity.
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| 25. |
- Maccarana, Marco, et al.
(författare)
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Asporin-deficient mice have tougher skin and altered skin glycosaminoglycan content and structure
- 2017
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 12:8
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Tidskriftsartikel (refereegranskat)abstract
- The main structural component of connective tissues is fibrillar, cross-linked collagen whose fibrillogenesis can be modulated by Small Leucine-Rich Proteins/Proteoglycans (SLRPs). Not all SLRPs’ effects on collagen and extracellular matrix in vivo have been elucidated; one of the less investigated SLRPs is asporin. Here we describe the successful generation of an Aspn-/- mouse model and the investigation of the Aspn-/- skin phenotype. Functionally, Aspn-/- mice had an increased skin mechanical toughness, although there were no structural changes present on histology or immunohistochemistry. Electron microscopy analyses showed 7% thinner collagen fibrils in Aspn-/- mice (not statistically significant). Several matrix genes were upregulated, including collagens (Col1a1, Col1a2, Col3a1), matrix metalloproteinases (Mmp2, Mmp3) and lysyl oxidases (Lox, Loxl2), while lysyl hydroxylase (Plod2) was downregulated. Intriguingly no differences were observed in collagen protein content or in collagen cross-linking-related lysine oxidation or hydroxylation. The glycosaminoglycan content and structure in Aspn-/- skin was profoundly altered: chondroitin/dermatan sulfate was more than doubled and had an altered composition, while heparan sulfate was halved and had a decreased sulfation. Also, decorin and biglycan were doubled in Aspn-/- skin. Overall, asporin deficiency changes skin glycosaminoglycan composition, and decorin and biglycan content, which may explain the changes in skin mechanical properties.
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| 26. |
- Oldfors Hedberg, Carola, 1969, et al.
(författare)
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Loss of supervillin causes myopathy with myofibrillar disorganization and autophagic vacuoles
- 2020
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 143:8, s. 2406-2420
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Tidskriftsartikel (refereegranskat)abstract
- The muscle specific isoform of the supervillin protein (SV2), encoded by the SVIL gene, is a large sarcolemmal myosin II- and F-actin-binding protein. Supervillin (SV2) binds and co-localizes with costameric dystrophin and binds nebulin, potentially attaching the sarcolemma to myofibrillar Z-lines. Despite its important role in muscle cell physiology suggested by various in vitro studies, there are so far no reports of any human disease caused by SVIL mutations. We here report four patients from two unrelated, consanguineous families with a childhood/adolescence onset of a myopathy associated with homozygous loss-of-function mutations in SVIL. Wide neck, anteverted shoulders and prominent trapezius muscles together with variable contractures were characteristic features. All patients showed increased levels of serum creatine kinase but no or minor muscle weakness. Mild cardiac manifestations were observed. Muscle biopsies showed complete loss of large supervillin isoforms in muscle fibres by western blot and immunohistochemical analyses. Light and electron microscopic investigations revealed a structural myopathy with numerous lobulated muscle fibres and considerable myofibrillar alterations with a coarse and irregular intermyofibrillar network. Autophagic vacuoles, as well as frequent and extensive deposits of lipoproteins, including immature lipofuscin, were observed. Several sarcolemma-associated proteins, including dystrophin and sarcoglycans, were partially mis-localized. The results demonstrate the importance of the supervillin (SV2) protein for the structural integrity of muscle fibres in humans and show that recessive loss-of-function mutations in SVIL cause a distinctive and novel myopathy
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| 27. |
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| 28. |
- Troll, Valentin R., et al.
(författare)
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Fault-Controlled Magma Ascent Recorded in the Central Series of the Rum Layered Intrusion, NW Scotland
- 2020
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Ingår i: Journal of Petrology. - : Oxford University Press (OUP). - 0022-3530 .- 1460-2415. ; 61:10
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Tidskriftsartikel (refereegranskat)abstract
- The Palaeogene layered ultrabasic intrusion of the Isle of Rum forms the hearth of the Rum Igneous Centre in NW-Scotland. The regional Long Loch Fault, which is widely held to represent the feeder system to the layered magma reservoir, dissects the intrusion and is marked by extensive ultrabasic breccias of various types. Here we explore the connection between the layered ultrabasic cumulate rocks and breccias of central Rum that characterize the fault zone (the ‘Central Series’) and evaluate their relationship with the Long Loch Fault system. We show that fault splays in the Central Series define a transtensional graben above the Long Loch Fault into which portions of the layered units subsided and collapsed to form the extensive breccias of central Rum. The destabilization of the cumulate pile was aided by intrusion of Ca-rich ultrabasic magmas along the faults, fractures and existing bedding planes, creating a widespread network of veins and dykelets that provided a further means of disintegration and block detachment. Enrichment in LREE and compositional zoning in intra cumulate interstices suggest that the collapsed cumulates were infiltrated by relatively evolved plagioclase-rich melt, which led to extensive re-crystallization of interstices. Clinopyroxene compositions in Ca-rich gabbro and feldspathic peridotite veins suggest that the intruding magma was also relatively water-rich, and that pyroxene crystallized dominantly below the current level of exposure. We propose that the Long Loch Fault opened and closed repeatedly to furnish the Rum volcano with a pulsing magma conduit. When the conduit was shut, pressure built up in the underlying plumbing system, but was released during renewed fault movements to permit dense and often crystal-rich ultrabasic magmas to ascend rapidly from depth. These spread laterally on arrival in the shallow Rum magma reservoir, supplying repetitive recharges of crystal-rich magma to assemble the rhythmic layering of the Rum layered intrusion.
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| 29. |
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| 30. |
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| 31. |
- De Zuani, Stefano, et al.
(författare)
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Large-Area Two-Dimensional Plasmonic Meta-Glasses and Meta-Crystals: a Comparative Study
- 2017
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Ingår i: Plasmonics. - : Springer Science and Business Media LLC. - 1557-1963 .- 1557-1955. ; 12:5, s. 1381-1390
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Tidskriftsartikel (refereegranskat)abstract
- The geometrical arrangement of metallic nanoparticles plays a crucial role on the optical response of nanoplasmonic samples due to particle-particle interactions. In this work, large-area, two-dimensional meta-glasses (random arrangements) and meta-crystals (periodic arrangements) made of identical metallic nanoparticles are investigated for three different particle densities of 5, 10, and 15 discs/mu m(2). A direct comparison between random and periodically ordered arrays is presented. The comparison clearly shows that the particle density has the largest influence on the extinction spectra for both periodic and random samples, and that for equal densities, the optical response away from diffraction effects is strikingly similar in both cases. The role of the radial density function and minimum particle distance is also determined. This study elucidates the role of the particle-particle interactions on the response of plasmonic nanoparticles and indicates how to control position and shape of the plasmonic resonance.
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| 32. |
- Eriksson, Jonas, et al.
(författare)
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Synthesis and preclinical evaluation of the CRTH2 antagonist [11C]MK-7246 as a novel PET tracer and potential surrogate marker for pancreatic beta-cell mass
- 2019
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Ingår i: Nuclear Medicine and Biology. - : Elsevier BV. - 0969-8051 .- 1872-9614. ; 71, s. 1-10
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: MK-7246 is a potent and selective antagonist for chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2). Within the pancreas CRTH2 is selectively expressed in pancreatic β-cells where it is believed to play a role in insulin release. Reduction in β-cell mass and insufficient insulin secretion in response to elevated blood glucose levels is a hallmark for type 1 and type 2 diabetes. Reported here is the synthesis of [11C]MK-7246 and initial preclinical evaluation towards CRTH2 imaging. The aim is to develop a method to quantify β-cell mass with PET and facilitate non-invasive studies of disease progression in individuals with type 2 diabetes.Methods: The precursor N-desmethyl-O-methyl MK-7246 was synthesized in seven steps and subjected to methylation with [11C]methyl iodide followed by hydrolysis to obtain [11C]MK-7246 labelled in the N-methyl position. Preclinical evaluation included in vitro radiography and immune-staining performed in human pancreatic biopsies. Biodistribution studies were performed in rat by PET-MRI and in pig by PET-CT imaging. The specific tracer uptake was examined in pig by scanning before and after administration of MK-7246 (1 mg/kg). Predicted dosimetry of [11C]MK-7246 in human males was estimated based on the biodistribution in rat.Results: [11C]MK-7246 was obtained with activities sufficient for the current investigations (270±120 MBq) and a radiochemical purity of 93±2%. The tracer displayed focal binding in areas with insulin positive islet of Langerhans in human pancreas sections. Baseline uptake in pig was significantly reduced in CRTH2-rich areas after administration of MK-7246; pancreas (66% reduction) and spleen (88% reduction). [11C]MK-7246 exhibited a safe human predicted dosimetry profile as extrapolated from the rat biodistribution data.Conclusions: Initial preclinical in vitro and in vivo evaluation of [11C]MK-7246 show binding and biodistribution properties suitable for PET imaging of CRTH2. Further studies are warranted to assess its potential in β-cell mass imaging and CRTH2 drug development.
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| 33. |
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| 34. |
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| 35. |
- Geahlen, J. H., et al.
(författare)
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Evolution of the human gastrokine locus and confounding factors regarding the pseudogenicity of GKN3
- 2013
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Ingår i: Physiological Genomics. - : American Physiological Society. - 1094-8341 .- 1531-2267. ; 45:15, s. 667-683
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Tidskriftsartikel (refereegranskat)abstract
- In a screen for genes expressed specifically in gastric mucous neck cells, we identified GKN3, the recently discovered third member of the gastrokine family. We present confirmatory mouse data and novel porcine data showing that mouse GKN3 expression is confined to mucous cells of the corpus neck and antrum base and is prominently expressed in metaplastic lesions. GKN3 was proposed originally to be expressed in some human populations and a pseudogene in others. To investigate that hypothesis, we studied human GKN3 evolution in the context of its paralogous genomic neighbors, GKN1 and GKN2. Haplotype analysis revealed that GKN3 mimics GKN2 in patterns of exonic SNP allocation, whereas GKN1 appeared to be more stringently selected. GKN3 showed signatures of both directional selection and population based selective sweeps in humans. One such selective sweep includes SNP rs10187256, originally identified as an ancestral tryptophan to premature STOP codon mutation. The derived (nonancestral) allele went to fixation in Asia. We show that another SNP, rs75578132, identified 5 bp downstream of rs10187256, exhibits a second selective sweep in almost all Europeans, some Latinos, and some Africans, possibly resulting from a reintroduction of European genes during African colonization. Finally, we identify a mutation that would destroy the splice donor site in the putative exon3-intron3 boundary, which occurs in all human genomes examined to date. Our results highlight a stomach-specific human genetic locus, which has undergone various selective sweeps across European, Asian, and African populations and thus reflects geographic and ethnic patterns in genome evolution.
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| 36. |
- Grasse, P., et al.
(författare)
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GEOTRACES Intercalibration of the Stable Silicon Isotope Composition of Dissolved Silicic Acid in Seawater
- 2017
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Ingår i: Journal of Analytical Atomic Spectrometry. - London. - 0267-9477. ; 32, s. 562-578
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Tidskriftsartikel (refereegranskat)abstract
- The first inter-calibration study of the stable silicon isotope composition of dissolved silicic acid in seawater, d30Si(OH)4, is presented as a contribution to the international GEOTRACES program. Eleven laboratories from seven countries analyzed two seawater samples from the North Pacific subtropical gyre (Station ALOHA) collected at 300 m and at 1000 m water depth. Sampling depths were chosen to obtain samples with a relatively low (9 mmol L-1, 300 m) and a relatively high (113 mmol L-1, 1000 m) silicic acid concentration as sample preparation differs for low- and high concentration samples. Data for the 1000 m water sample were not normally distributed so the median is used to represent the central tendency for the two samples. Median d30Si(OH)4 values of +1.66‰ for the low-concentration sample and +1.25‰ for the high-concentration sample were obtained. Agreement among laboratories is overall considered very good; however, small but statistically significant differences among the mean isotope values obtained by different laboratories were detected, likely reflecting inter-laboratory differences in chemical preparation including preconcentration and purification methods together with different volumes of seawater analyzed, andthe use of different mass spectrometers including the Neptune MC-ICP-MS (Thermo Fisher™, Germany), the Nu Plasma MC-ICP-MS (Nu Instruments™, Wrexham, UK), and the Finnigan™ (now Thermo Fisher™, Germany) MAT 252 IRMS. Future studies analyzing d30Si(OH)4 in seawater should also analyze and report values for these same two reference waters in order to facilitate comparison of data generated among and within laboratories over time.
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| 37. |
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| 38. |
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| 39. |
- Görke, U, et al.
(författare)
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Visualization of anisotropic pulsations in extraembryonic compartments of incubated quail eggs by NMR microimaging.
- 1996
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Ingår i: Magnetic Resonance Imaging. - 0730-725X .- 1873-5894. ; 14:9, s. 1079-84
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Tidskriftsartikel (refereegranskat)abstract
- Multi-plane tagging time-of-flight and bipolar gradient phase-encoding and amplitude-weighting NMR microimaging techniques have been employed to study transport in extraembryonic compartments of fertilized quail eggs during the first seven days of incubation. After the fourth day coherent and incoherent motions became visible in certain regions, in particular in the upper part of the albumen. Coherent motions as visualized by deformations of multiplane tagging grids were specified by local velocities less than 1 mm/s at most. On the other hand, incoherent motions led to much more pronounced phenomena. The multiplane tagging grid completely faded in a region comprising the upper third of the albumen after 4.5 incubation days. Images weighted by signal attenuation owing to incoherent displacements indicate motions in the same region. The fact that a reproducible localization of the motions is only possible when signals from different transients are averaged indicates that the incoherence at least partly is temporal in nature. The signal intensity of a volume selected in the incoherent-motion region consequently fluctuates with time. The Fourier analysis of these fluctuations revealed a distinct pulsation with a frequency of 0.4 Hz.
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| 40. |
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| 41. |
- Jonsson, Erik, et al.
(författare)
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Magmatic origin of giant 'Kiruna-type' apatite-iron-oxide ores in Central Sweden
- 2013
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 3, s. 1644-
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Tidskriftsartikel (refereegranskat)abstract
- Iron is the most important metal for modern industry and Sweden is by far the largest iron-producer in Europe, yet the genesis of Sweden's main iron-source, the 'Kiruna-type' apatite-iron-oxide ores, remains enigmatic. We show that magnetites from the largest central Swedish 'Kiruna-type' deposit at Grangesberg have delta O-18 values between -0.4 and +3.7%, while the 1.90-1.88 Ga meta-volcanic host rocks have d18O values between +4.9 and +9%. Over 90% of the magnetite data are consistent with direct precipitation from intermediate to felsic magmas or magmatic fluids at high-temperature (delta O-18(mgt). > +0.9 parts per thousand, i.e. ortho-magmatic). A smaller group of magnetites (delta O-18(mgt) <= +0.9 parts per thousand), in turn, equilibrated with high-delta O-18, likely meteoric, hydrothermal fluids at low temperatures. The central Swedish 'Kiruna-type' ores thus formed dominantly through magmatic iron-oxide precipitation within a larger volcanic superstructure, while local hydrothermal activity resulted from low-temperature fluid circulation in the shallower parts of this system.
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| 42. |
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| 43. |
- Kalamajski, Sebastian, et al.
(författare)
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Increased C-Telopeptide Cross-linking of Tendon Type I Collagen in Fibromodulin-deficient Mice.
- 2014
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Ingår i: Journal of Biological Chemistry. - 1083-351X .- 0021-9258. ; 289:27, s. 18873-18879
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Tidskriftsartikel (refereegranskat)abstract
- The controlled assembly of collagen monomers into fibrils, with accompanying intermolecular cross-linking by lysyl oxidase-mediated bonds, is vital to the structural and mechanical integrity of connective tissues. This process is influenced by collagen-associated proteins, including Small Leucine-Rich Proteins (SLRPs), but the regulatory mechanisms are not well understood. Deficiency in fibromodulin, an SLRP, causes abnormal collagen fibril ultrastructure and decreased mechanical strength in mouse tendons. In this study, fibromodulin deficiency rendered tendon collagen more resistant to non-proteolytic extraction. The collagen had an increased and altered cross-linking pattern at an early stage of fibril formation. Collagen extracts contained a higher proportion of stably cross-linked α1(I) chains as a result of their C-telopeptide lysines being more completely oxidized to aldehydes. The findings suggest that fibromodulin selectively affects the extent and pattern of lysyl oxidase-mediated collagen cross-linking by sterically hindering access of the enzyme to telopeptides, presumably through binding to the collagen. Such activity implies a broader role for SLRP family members in regulating collagen cross-linking placement and quantity.
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| 44. |
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| 45. |
- Majidi, Seyed Afshin, et al.
(författare)
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Employing geochemistry and geochronology to unravel genesis and tectonic setting of iron oxide-apatite deposits of the Bafq-Saghand metallogenic belt, Central Iran
- 2021
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Ingår i: International journal of earth sciences. - : Springer. - 1437-3254 .- 1437-3262. ; 110, s. 127-164
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Tidskriftsartikel (refereegranskat)abstract
- The Bafq-Saghand metallogenic belt is located in the central part of the Kerman-Kashmar tectonic zone and contains 39 individual occurrences of iron oxide-apatite +/- REE mineralizations. These mineral concentrations, e.g., Chadormalu, Choghart, Sechahun, and Esfordi, comprise a total of similar to 1500 million tons of iron ore with an average grade of similar to 55% Fe. In terms of origin, time, and geodynamic setting, several modes of formation have been suggested for these ore deposits, including magmatic, hydrothermal, and banded iron formation scenarios. In the present study, the tectonic setting and metallogeny of iron oxide-apatites of the Bafq-Saghand belt are investigated utilizing trace element geochemistry, age dating, and oxygen isotope analyses. The geochemical characteristics of apatite and magnetite and the delta O-18 values of magnetite (from - 0.1 to + 2.2 parts per thousand) indicate a dominantly magmatic-hydrothermal (delta O-18 > + 0.9 parts per thousand) formation process, although primary magmatic mineralizations were locally leached and hydrothermally redeposited (e.g., samples with delta O-18 < + 0.9 parts per thousand). The Cambrian volcano-sedimentary host rocks to the mineralization is intruded by calc-alkaline tonalite, trondhjemite, granodioritic, dioritic, and granitic rocks that formed in association with subduction of the Proto-Tethys Ocean under the Gondwana supercontinent in the Neoproterozoic to Early Cambrian (525-547 Ma). Additionally, a later geodynamic episode produced intrusions of alkaline syenite and monzosyenite bodies during a continental rifting event. We provide new geochronological constraints for these younger alkaline igneous rocks that document a temporal range from 421 to 447 Ma for their intrusion. In combination with the previously reported overlapping ages of the older calc-alkaline magma bodies (525-547 Ma) with the volcano-sedimentary host rock (528 Ma) and the iron oxide mineralization (510-539 Ma), we can now exclude continental rifting as a geodynamic processes that is linked to ore formation in the region. Our results corroborate that the Bafq iron ore mineralization formed during subduction of the Proto-Tethys Ocean under the Gondwana supercontinent in a near surface continental margin setting.
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| 46. |
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| 47. |
- Müller, H P, et al.
(författare)
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Six-dimensional spin density/velocity NMR microscopy of percolation clusters.
- 1996
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Ingår i: Magnetic Resonance Imaging. - 0730-725X .- 1873-5894. ; 14:7-8, s. 955-8
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Tidskriftsartikel (refereegranskat)abstract
- Using computer-simulated random-site percolation networks as templates, three-dimensional percolation cluster objects were fabricated. The pore space was filled with water and experimentally investigated with the aid of NMR microimaging. A pulse sequence for six-dimensional spin density/velocity NMR imaging was employed for the combined record of the three-dimensional spin-density distribution and the three-dimensional velocity vector field of water percolating through the pore space. An evaluation procedure for the NMR image data was established that reliably renders the characteristic parameters (fractal dimensionality, fractal dimensionality of the backbone, correlation length).
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| 48. |
- Peters, Stefan T. M., et al.
(författare)
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Amphibole megacrysts as a probe into the deep plumbing system of Merapi volcano, Central Java, Indonesia
- 2017
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Ingår i: Contributions to Mineralogy and Petrology. - : SPRINGER. - 0010-7999 .- 1432-0967. ; 172:4
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Tidskriftsartikel (refereegranskat)abstract
- Amphibole has been discussed to potentially represent an important phase during early chemical evolution of arc magmas, but is not commonly observed in eruptive arc rocks. Here, we present an in-depth study of metastable calcic amphibole megacrysts in basaltic andesites of Merapi volcano, Indonesia. Radiogenic Sr and Nd isotope compositions of the amphibole megacrysts overlap with the host rock range, indicating that they represent antecrysts to the host magmas rather than xenocrysts. Amphibolebased barometry suggests that the megacrysts crystallised at pressures of >500 MPa, i.e., in the mid-to lower crust beneath Merapi. Rare-earth element concentrations, in turn, require the absence of magmatic garnet in the Merapi feeding system and, therefore, place an uppermost limit for the pressure of amphibole crystallisation at ca. 800 MPa. The host magmas of the megacrysts seem to have fractionated significant amounts of amphibole and/or clinopyroxene, because of their low Dy/Yb ratios relative to the estimated compositions of the parent magmas to the megacrysts. The megacrysts' parent magmas at depth may thus have evolved by amphibole fractionation, in line with apparently coupled variations of trace element ratios in the megacrysts, such as e.g., decreasing Zr/Hf with Dy/Yb. Moreover, the Th/U ratios of the amphibole megacrysts decrease with increasing Dy/Yb and are lower than Th/U ratios in the basaltic andesite host rocks. Uranium in the megacrysts' parent magmas, therefore, may have occurred predominantly in the tetravalent state, suggesting that magmatic fO(2) in the Merapi plumbing system increased from below the FMQ buffer in the mid-to-lower crust to 0.6-2.2 log units above it in the near surface environment. In addition, some of the amphibole megacrysts experienced dehydrogenation (H-2 loss) and/or dehydration (H2O loss), as recorded by their variable H2O contents and D/H and Fe3+/Fe2+ ratios, and the release of these volatile species into the shallow plumbing system may facilitate Merapi's often erratic eruptive behaviour.
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| 49. |
- Sahlström, Fredrik, et al.
(författare)
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Interaction between high-temperature magmatic fluids and limestone explains 'Bastnäs-type' REE deposits in central Sweden
- 2019
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- The presently increasing demand for rare earth elements (REE), particularly in high-tech and "green energy" applications, has led to global interest in the distribution, origins and formation conditions of REE deposits. The World's first hard-rock REE sources, the polymetallic deposits of Bastnasfaltet in Bergslagen, central Sweden, were also the place of the original discovery of several REE and many of their host minerals. Similar deposits with high concentrations of REE occur along a >100 km corridor in the region and they share a number of geological and mineralogical features; all comprising Palaeoproterozoic, skarn-hosted magnetite-REE mineralisation of ambiguous origin. Here we report oxygen isotope data for magnetite and quartz, and oxygen and carbon isotope data for carbonates from ten of these classic deposits, to model and assess their mode of origin. Combined with existing geological observations, the isotope results support an origin in a c. 1.9 Ga shallow-marine back-arc, sub-seafloor setting, where felsic magmatic-sourced, high-temperature fluids reacted with pre-existing limestone interlayers, leading to localised skarn formation and magnetite-REE-mineral precipitation. These findings help us to better understand the geological processes that have produced economic REE mineralisation and may assist future exploration for these critical commodities.
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| 50. |
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