| 1. |
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| 2. |
- Rajewsky, N., et al.
(författare)
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LifeTime and improving European healthcare through cell-based interceptive medicine
- 2020
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Ingår i: Nature. - : Springer Nature. - 0028-0836 .- 1476-4687. ; 587:7834, s. 377-386
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Tidskriftsartikel (refereegranskat)abstract
- LifeTime aims to track, understand and target human cells during the onset and progression of complex diseases and their response to therapy at single-cell resolution. This mission will be implemented through the development and integration of single-cell multi-omics and imaging, artificial intelligence and patient-derived experimental disease models during progression from health to disease. Analysis of such large molecular and clinical datasets will discover molecular mechanisms, create predictive computational models of disease progression, and reveal new drug targets and therapies. Timely detection and interception of disease embedded in an ethical and patient-centered vision will be achieved through interactions across academia, hospitals, patient-associations, health data management systems and industry. Applying this strategy to key medical challenges in cancer, neurological, infectious, chronic inflammatory and cardiovascular diseases at the single-cell level will usher in cell-based interceptive medicine in Europe over the next decade.
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| 3. |
- van Bragt, JJMH, et al.
(författare)
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Characteristics and treatment regimens across ERS SHARP severe asthma registries
- 2020
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Ingår i: The European respiratory journal. - : European Respiratory Society (ERS). - 1399-3003 .- 0903-1936. ; 55:1
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Tidskriftsartikel (refereegranskat)abstract
- Little is known about the characteristics and treatments of patients with severe asthma across Europe, but both are likely to vary. This is the first study in the European Respiratory Society Severe Heterogeneous Asthma Research collaboration, Patient-centred (SHARP) Clinical Research Collaboration and it is designed to explore these variations. Therefore, we aimed to compare characteristics of patients in European severe asthma registries and treatments before starting biologicals.This was a cross-sectional retrospective analysis of aggregated data from 11 national severe asthma registries that joined SHARP with established patient databases.Analysis of data from 3236 patients showed many differences in characteristics and lifestyle factors. Current smokers ranged from 0% (Poland and Sweden) to 9.5% (Belgium), mean body mass index ranged from 26.2 (Italy) to 30.6 kg·m−2 (the UK) and the largest difference in mean pre-bronchodilator forced expiratory volume in 1 s % predicted was 20.9% (the Netherlands versus Hungary). Before starting biologicals patients were treated differently between countries: mean inhaled corticosteroid dose ranged from 700 to 1335 µg·day−1 between those from Slovenia versus Poland when starting anti-interleukin (IL)-5 antibody and from 772 to 1344 µg·day−1 in those starting anti-IgE (Slovenia versus Spain). Maintenance oral corticosteroid use ranged from 21.0% (Belgium) to 63.0% (Sweden) and from 9.1% (Denmark) to 56.1% (the UK) in patients starting anti-IL-5 and anti-IgE, respectively.The severe asthmatic population in Europe is heterogeneous and differs in both clinical characteristics and treatment, often appearing not to comply with the current European Respiratory Society/American Thoracic Society guidelines definition of severe asthma. Treatment regimens before starting biologicals were different from inclusion criteria in clinical trials and varied between countries.
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| 4. |
- Beal, Jacob, et al.
(författare)
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Robust estimation of bacterial cell count from optical density
- 2020
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Ingår i: Communications Biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 3:1
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Tidskriftsartikel (refereegranskat)abstract
- Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data.
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| 5. |
- Willemse, Jorke, et al.
(författare)
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Hydrogels derived from decellularized liver tissue support the growth and differentiation of cholangiocyte organoids
- 2022
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Ingår i: Biomaterials. - : Elsevier BV. - 0142-9612. ; 284
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Tidskriftsartikel (refereegranskat)abstract
- Human cholangiocyte organoids are promising for regenerative medicine applications, such as repair of damaged bile ducts. However, organoids are typically cultured in mouse tumor-derived basement membrane extracts (BME), which is poorly defined, highly variable and limits the direct clinical applications of organoids in patients. Extracellular matrix (ECM)-derived hydrogels prepared from decellularized human or porcine livers are attractive alternative culture substrates. Here, the culture and expansion of human cholangiocyte organoids in liver ECM(LECM)-derived hydrogels is described. These hydrogels support proliferation of cholangiocyte organoids and maintain the cholangiocyte-like phenotype. The use of LECM hydrogels does not significantly alter the expression of selected genes or proteins, such as the cholangiocyte marker cytokeratin-7, and no species-specific effect is found between human or porcine LECM hydrogels. Proliferation rates of organoids cultured in LECM hydrogels are lower, but the differentiation capacity of the cholangiocyte organoids towards hepatocyte-like cells is not altered by the presence of tissue-specific ECM components. Moreover, human LECM extracts support the expansion of ICO in a dynamic culture set up without the need for laborious static culture of organoids in hydrogel domes. Liver ECM hydrogels can successfully replace tumor-derived BME and can potentially unlock the full clinical potential of human cholangiocyte organoids.
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| 6. |
- Garcia-Benito, R., et al.
(författare)
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CALIFA, the Calar Alto Legacy Integral Field Area survey III. Second public data release
- 2015
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 576:A135
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Tidskriftsartikel (refereegranskat)abstract
- This paper describes the Second Public Data Release (DR2) of the Calar Alto Legacy Integral Field Area (CALIFA) survey. The data for 200 objects are made public, including the 100 galaxies of the First Public Data Release (DR1). Data were obtained with the integral-field spectrograph PMAS /PPak mounted on the 3.5 m telescope at the Calar Alto observatory. Two different spectral setups are available for each galaxy, (i) a low-resolution V500 setup covering the wavelength range 3745-7500 angstrom with a spectral resolution of 6.0 angstrom (FWHM); and (ii) a medium-resolution V1200 setup covering the wavelength range 3650-4840 angstrom with a spectral resolution of 2.3 angstrom (FWHM). The sample covers a redshift range between 0.005 and 0.03, with a wide range of properties in the color-magnitude diagram, stellar mass, ionization conditions, and morphological types. All the cubes in the data release were reduced with the latest pipeline, which includes improved spectrophotometric calibration, spatial registration, and spatial resolution. The spectrophotometric calibration is better than 6% and the median spatial resolution is 2 4. In total, the second data release contains over 1.5 million spectra.
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| 7. |
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| 8. |
- Ferwerda, Bart, et al.
(författare)
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Functional and genetic evidence that the Mal/TIRAP allele variant 180L has been selected by providing protection against septic shock.
- 2009
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 106:25, s. 10272-10277
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Tidskriftsartikel (refereegranskat)abstract
- Adequate responses by our innate immune system toward invading pathogens were of vital importance for surviving infections, especially before the antibiotic era. Recently, a polymorphism in Mal (Ser180Leu, TIRAP rs8177374), an important adaptor protein downstream of the Toll-like receptor (TLR) 2 and 4 pathways, has been described to provide protection against a broad range of infectious pathogens. We assessed the functional effects of this polymorphism in human experimental endotoxemia, and we demonstrate that individuals bearing the TIRAP 180L allele display an increased, innate immune response to TLR4 and TLR2 ligands, but not to TLR9 stimulation. This phenotype has been related to an increased resistance to infection. However, an overshoot in the release of proinflammatory cytokines by TIRAP 180L homozygous individuals suggests a scenario of balanced evolution. We have also investigated the worldwide distribution of the Ser180Leu polymorphism in 14 populations around the globe to correlate the genetic makeup of TIRAP with the local infectious pressures. Based on the immunological, clinical, and genetic data, we propose that this mutation might have been selected in West Eurasia during the early settlement of this region after the out-of-Africa migration of modern Homo sapiens. This combination of functional and genetic data provides unique insights to our understanding of the pathogenesis of sepsis.
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| 9. |
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| 10. |
- van Krieken, J. H., et al.
(författare)
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Guideline on the requirements of external quality assessment programs in molecular pathology
- 2013
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Ingår i: Virchows Archiv. - : Springer Science and Business Media LLC. - 0945-6317 .- 1432-2307. ; 462:1, s. 27-37
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Tidskriftsartikel (refereegranskat)abstract
- Molecular pathology is an integral part of daily diagnostic pathology and used for classification of tumors, for prediction of prognosis and response to therapy, and to support treatment decisions. For these reasons, analyses in molecular pathology must be highly reliable and hence external quality assessment (EQA) programs are called for. Several EQA programs exist to which laboratories can subscribe, but they vary in scope, number of subscribers, and execution. The guideline presented in this paper has been developed with the purpose to harmonize EQA in molecular pathology. It presents recommendations on how an EQA program should be organized, provides criteria for a reference laboratory, proposes requirements for EQA test samples, and defines the number of samples needed for an EQA program. Furthermore, a system for scoring of the results is proposed as well as measures to be taken for poorly performing laboratories. Proposals are made regarding the content requirements of an EQA report and how its results should be communicated. Finally, the need for an EQA database and a participant manual are elaborated. It is the intention of this guideline to improve EQA for molecular pathology in order to provide more reliable molecular analyses as well as optimal information regarding patient selection for treatment.
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| 11. |
- Zeng, Chenjie, et al.
(författare)
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Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus
- 2016
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Ingår i: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 18
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Tidskriftsartikel (refereegranskat)abstract
- Background: Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk. Method: We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation. Results: Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06-1.12; P = 3 x 10(-9)), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 x 10(-5)), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 x 10(-4)) identified in the general populations, and rs113824616 (P = 7 x 10(-5)) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P < 0.05. Conclusion: This study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk.
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| 12. |
- de Fouw, Jimmy, et al.
(författare)
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A facultative mutualism facilitates European seagrass meadows
- 2023
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Ingår i: Ecography. - 0906-7590 .- 1600-0587. ; 2023:5
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Tidskriftsartikel (refereegranskat)abstract
- Coastal ecosystem functioning often hinges on habitat-forming foundation species that engage in positive interactions (e.g. facilitation and mutualism) to reduce environmental stress. Seagrasses are important foundation species in coastal zones but are rapidly declining with losses typically linked to intensifying global change-related environmental stress. There is growing evidence that loss or disruption of positive interactions can amplify coastal ecosystem degradation as it compromises its stress mitigating capacity. Multiple recent studies highlight that seagrass can engage in a facultative mutualistic relationship with lucinid bivalves that alleviate sulphide toxicity. So far, however, the generality of this mutualism, and how its strength and relative importance depend on environmental conditions, remains to be investigated. Here we study the importance of the seagrass-lucinid mutualistic interaction on a continental-scale using a field survey across Europe. We found that the lucinid bivalve Loripes orbiculatus is associated with the seagrasses Zostera noltii and Zostera marina across a large latitudinal range. At locations where the average minimum temperature was above 1 °C, L. orbiculatus was present in 79% of the Zostera meadows; whereas, it was absent below this temperature. At locations above this minimum temperature threshold, mud content was the second most important determinant explaining the presence or absence of L. orbiculatus. Further analyses suggest that the presence of the lucinids have a positive effect on seagrass biomass by mitigating sulphide stress. Finally, results of a structural equation model (SEM) support the existence of a mutualistic feedback between L. orbiculatus and Z. noltii. We argue that this seagrass-lucinid mutualism should be more solidly integrated into management practices to improve seagrass ecosystem resilience to global change as well as the success of restoration efforts.
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| 13. |
- Eekers, Danielle B. P., et al.
(författare)
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The EPTN consensus-based atlas for CT- and MR-based contouring in neuro-oncology
- 2018
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Ingår i: Radiotherapy and Oncology. - : ELSEVIER IRELAND LTD. - 0167-8140 .- 1879-0887. ; 128:1, s. 37-43
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To create a digital, online atlas for organs at risk (OAR) delineation in neuro-oncology based on high-quality computed tomography (Cr) and magnetic resonance (MR) imaging. Methods: CT and 3 Tesla (3T) MR images (slice thickness 1 mm with intravenous contrast agent) were obtained from the same patient and subsequently fused. In addition, a 7T MR without intravenous contrast agent was obtained from a healthy volunteer. Based on discussion between experienced radiation oncologists, the clinically relevant organs at risk (OARs) to be included in the atlas for neuro-oncology were determined, excluding typical head and neck OARs previously published. The draft atlas was delineated by a senior radiation oncologist, 2 residents in radiation oncology, and a senior neuro-radiologist incorporating relevant available literature. The proposed atlas was then critically reviewed and discussed by European radiation oncologists until consensus was reached. Results: The online atlas includes one CT-scan at two different window settings and one MR scan (3T) showing the OARs in axial, coronal and sagittal view. This manuscript presents the three-dimensional descriptions of the fifteen consensus OARs for neuro-oncology. Among these is a new OAR relevant for neuro-cognition, the posterior cerebellum (illustrated on 7T MR images). Conclusion: In order to decrease inter- and intra-observer variability in delineating OARs relevant for neuro-oncology and thus derive consistent dosimetric data, we propose this atlas to be used in photon and particle therapy. The atlas is available online at w.cancerdata.c and will be updated whenever required.
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| 14. |
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| 15. |
- Peletier, R. F., et al.
(författare)
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Stars and gas in the inner parts of galaxies seen in SAURON integral field observations
- 2007
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Ingår i: New Astronomy Reviews. - : Elsevier BV. - 1387-6473. ; 51:1-2, s. 29-33
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Tidskriftsartikel (refereegranskat)abstract
- We give two examples of spiral galaxies that show non-circular gas motions in the inner kiloparsecs, from SAURON integral field spectroscopy. We use harmonic decomposition of the velocity field of the ionized gas to study the underlying mass distribution, employing linear theory. The higher order harmonic terms and the main kinematic features of the observed data are consistent with an analytically constructed simple bar model. We also present maps of a number of strong absorption lines in M 100, derive simple stellar populations and correlate them with features in the gas kinematics.
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| 16. |
- Alfaro-Cuello, M., et al.
(författare)
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A Deep View into the Nucleus of the Sagittarius Dwarf Spheroidal Galaxy with MUSE. II. Kinematic Characterization of the Stellar Populations
- 2020
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 892:1
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Tidskriftsartikel (refereegranskat)abstract
- The Sagittarius dwarf spheroidal galaxy is in an advanced stage of disruption but still hosts its nuclear star cluster (NSC), M54, at its center. In this paper, we present a detailed kinematic characterization of the three stellar populations present in M54: Young metal-rich (YMR); intermediate-age metal-rich (IMR); and old metal-poor (OMP), based on the spectra of 6500 individual M54 member stars extracted from a large Multi-Unit Spectroscopic Explorer (MUSE)/Very Large Telescope data set. We find that the OMP population is slightly flattened with a low amount of rotation (0.8 km s-1) and with a velocity dispersion that follows a Plummer profile. The YMR population displays a high amount of rotation (5 km s-1) and a high degree of flattening, with a lower and flat velocity dispersion profile. The IMR population shows a high but flat velocity dispersion profile, with some degree of rotation (2 km s-1). We complement our MUSE data with information from Gaia DR2 and confirm that the stars from the OMP and YMR populations are comoving in 3D space, suggesting that they are dynamically bound. While dynamical evolutionary effects (e.g., energy equipartition) are able to explain the differences in velocity dispersion between the stellar populations, the strong differences in rotation indicate different formation paths for the populations, as supported by an N-body simulation tailored to emulate the YMR-OMP system. This study provides additional evidence for the M54 formation scenario proposed in our previous work, where this NSC formed via GC accretion (OMP) and in situ formation from gas accretion in a rotationally supported disk (YMR).
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| 17. |
- Bordes, Romain, 1981, et al.
(författare)
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Nanocellulose: What used to be cellulose micelles
- 2017
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Ingår i: Current Opinion in Colloid and Interface Science. - : Elsevier BV. - 1359-0294 .- 1879-0399. ; 29, s. A1-A2
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 18. |
- Pinol-Ferrer, Nuria, et al.
(författare)
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Physical condition of the molecular gas at the centre of NGC 1097
- 2011
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Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 414:1, s. 529-537
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Tidskriftsartikel (refereegranskat)abstract
- We have used the X(CO) conversion factor, local thermodynamic equilibrium and large velocity gradient approximation to parametrize the cold and warm phases of the interstellar medium from five different low transitions of the CO molecule in the central 21 arcsec (kpc) region of NGC 1097. We have applied a one-component model and derived a typical kinetic temperature of about 33 K, a molecular hydrogen density of 4.9 x 10(3) M(circle dot) pc(-3) and a CO column density of 1.2 x 10(-2) M(circle dot) pc(-2). A two-component model results in 85 per cent cold-to-total gas fraction in the presence of a 90 K warm counterpart. Furthermore, we 'resolve' the spatially unresolved single-dish observations by selecting velocity channels that in an interferometric velocity map correspond to specific regions. We have selected five such regions and found that the physical properties in these regions are comparable to those derived from the full line profile. This implies that the central kpc of NGC 1097 is rather homogeneous in nature and, although the regions are not uniquely located within the ring, the star formation along the ring is homogeneously distributed (in agreement with recent Herschel observations). We have further revised the mass-inflow rate on to the supermassive black hole in this prototype low-ionization nuclear emission-line region/Seyfert 1 galaxy and found that accounting for the total interstellar medium and applying a careful contribution of the disc thickness and corresponding stability criterion increases the previous estimations by a factor of 10. Finally, we have calculated the X(CO) conversion factor for the centre of NGC 1097 using an independent estimation of the surface density to the CO emission and obtained X(CO) = (2.8 +/- 0.5) x 10(20) cm(-2) (K km s(-1))(-1) at a radius 10.5 arcsec and X(CO) = (5.0 +/- 0.5) x 10(20) cm(-2) (K km s(-1))(-1) at a radius 7.5 arcsec. With the approach and analysis described in this paper, we have demonstrated that important physical properties can be derived to a resolution beyond the single-dish resolution element; however, caution is necessary while interpreting the results.
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| 19. |
- Strazisar, M, et al.
(författare)
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MIR137 variants identified in psychiatric patients affect synaptogenesis and neuronal transmission gene sets
- 2015
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Ingår i: Molecular Psychiatry. - : Nature Publishing Group. - 1359-4184 .- 1476-5578. ; 20:4, s. 472-481
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Tidskriftsartikel (refereegranskat)abstract
- Sequence analysis of 13 microRNA (miRNA) genes expressed in the human brain and located in genomic regions associated with schizophrenia and/or bipolar disorder, in a northern Swedish patient/control population, resulted in the discovery of two functional variants in the MIR137 gene. On the basis of their location and the allele frequency differences between patients and controls, we explored the hypothesis that the discovered variants impact the expression of the mature miRNA and consequently influence global mRNA expression affecting normal brain functioning. Using neuronal-like SH-SY5Y cells, we demonstrated significantly reduced mature miR-137 levels in the cells expressing the variant miRNA gene. Subsequent transcriptome analysis showed that the reduction in miR-137 expression led to the deregulation of gene sets involved in synaptogenesis and neuronal transmission, all implicated in psychiatric disorders. Our functional findings add to the growing data, which implicate that miR-137 has an important role in the etiology of psychiatric disorders and emphasizes its involvement in nervous system development and proper synaptic function.
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| 20. |
- van de Ven, Johannes P. H., et al.
(författare)
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A functional variant in the CFI gene confers a high risk of age-related macular degeneration
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 45:7, s. 813-813
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Tidskriftsartikel (refereegranskat)abstract
- Up to half of the heritability of age-related macular degeneration (AMD) is explained by common variants(1-5). Here, we report the identification of a rare, highly penetrant missense mutation in CFI encoding a p.Gly119Arg substitution that confers high risk of AMD (P = 3.79 x 10(-6); odds ratio (OR) = 22.20, 95% confidence interval (CI) = 2.98-164.49). Plasma and sera from cases carrying the p.Gly119Arg substitution mediated the degradation of C3b, both in the fluid phase and on the cell surface, to a lesser extent than those from controls. Recombinant protein studies showed that the Gly119Arg mutant protein is both expressed and secreted at lower levels than wild-type protein. Consistent with these findings, human CFI mRNA encoding Arg119 had reduced activity compared to wild-type mRNA encoding Gly119 in regulating vessel thickness and branching in the zebrafish retina. Taken together, these findings demonstrate that rare, highly penetrant mutations contribute to the genetic burden of AMD.
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