| 1. |
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| 2. |
- Bell, Taylor, et al.
(författare)
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Nightside clouds and disequilibrium chemistry on the hot Jupiter WASP-43b
- 2024
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Ingår i: Nature Astronomy. - 2397-3366. ; 8:7, s. 879-898
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Tidskriftsartikel (refereegranskat)abstract
- Hot Jupiters are among the best-studied exoplanets, but it is still poorly understood how their chemical composition and cloud properties vary with longitude. Theoretical models predict that clouds may condense on the nightside and that molecular abundances can be driven out of equilibrium by zonal winds. Here we report a phase-resolved emission spectrum of the hot Jupiter WASP-43b measured from 5 μm to 12 μm with the JWST’s Mid-Infrared Instrument. The spectra reveal a large day–night temperature contrast (with average brightness temperatures of 1,524 ± 35 K and 863 ± 23 K, respectively) and evidence for water absorption at all orbital phases. Comparisons with three-dimensional atmospheric models show that both the phase-curve shape and emission spectra strongly suggest the presence of nightside clouds that become optically thick to thermal emission at pressures greater than ~100 mbar. The dayside is consistent with a cloudless atmosphere above the mid-infrared photosphere. Contrary to expectations from equilibrium chemistry but consistent with disequilibrium kinetics models, methane is not detected on the nightside (2σ upper limit of 1–6 ppm, depending on model assumptions). Our results provide strong evidence that the atmosphere of WASP-43b is shaped by disequilibrium processes and provide new insights into the properties of the planet’s nightside clouds. However, the remaining discrepancies between our observations and our predictive atmospheric models emphasize the importance of further exploring the effects of clouds and disequilibrium chemistry in numerical models.
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| 3. |
- Carter, Aarynn L., et al.
(författare)
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A benchmark JWST near-infrared spectrum for the exoplanet WASP-39 b
- 2024
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Ingår i: Nature Astronomy. - 2397-3366. ; 8:8, s. 1008-1019
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Tidskriftsartikel (refereegranskat)abstract
- A combined analysis of datasets across four JWST instrument modes provides a benchmark transmission spectrum for the Saturn-mass WASP-39 b. The broad wavelength range and high resolution constrain orbital and stellar parameters to below 1%.
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| 4. |
- Klionsky, Daniel J., et al.
(författare)
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Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes
- 2008
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Ingår i: Autophagy. - : Landes Bioscience. - 1554-8627 .- 1554-8635. ; 4:2, s. 151-175
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Forskningsöversikt (refereegranskat)abstract
- Research in autophagy continues to accelerate,1 and as a result many new scientists are entering the field. Accordingly, it is important to establish a standard set of criteria for monitoring macroautophagy in different organisms. Recent reviews have described the range of assays that have been used for this purpose.2,3 There are many useful and convenient methods that can be used to monitor macroautophagy in yeast, but relatively few in other model systems, and there is much confusion regarding acceptable methods to measure macroautophagy in higher eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers of autophagosomes versus those that measure flux through the autophagy pathway; thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from fully functional autophagy that includes delivery to, and degradation within, lysosomes (in most higher eukaryotes) or the vacuole (in plants and fungi). Here, we present a set of guidelines for the selection and interpretation of the methods that can be used by investigators who are attempting to examine macroautophagy and related processes, as well as by reviewers who need to provide realistic and reasonable critiques of papers that investigate these processes. This set of guidelines is not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to verify an autophagic response.
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| 5. |
- Novak, R., et al.
(författare)
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Robotic fluidic coupling and interrogation of multiple vascularized organ chips
- 2020
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Ingår i: Nature Biomedical Engineering. - : Nature Research. - 2157-846X.
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Tidskriftsartikel (refereegranskat)abstract
- Organ chips can recapitulate organ-level (patho)physiology, yet pharmacokinetic and pharmacodynamic analyses require multi-organ systems linked by vascular perfusion. Here, we describe an ‘interrogator’ that employs liquid-handling robotics, custom software and an integrated mobile microscope for the automated culture, perfusion, medium addition, fluidic linking, sample collection and in situ microscopy imaging of up to ten organ chips inside a standard tissue-culture incubator. The robotic interrogator maintained the viability and organ-specific functions of eight vascularized, two-channel organ chips (intestine, liver, kidney, heart, lung, skin, blood–brain barrier and brain) for 3 weeks in culture when intermittently fluidically coupled via a common blood substitute through their reservoirs of medium and endothelium-lined vascular channels. We used the robotic interrogator and a physiological multicompartmental reduced-order model of the experimental system to quantitatively predict the distribution of an inulin tracer perfused through the multi-organ human-body-on-chips. The automated culture system enables the imaging of cells in the organ chips and the repeated sampling of both the vascular and interstitial compartments without compromising fluidic coupling.
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| 6. |
- Carleo, Ilaria, et al.
(författare)
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The Multiplanet System TOI-421*
- 2020
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Ingår i: Astronomical Journal. - : American Astronomical Society. - 1538-3881 .- 0004-6256. ; 160:3
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Tidskriftsartikel (refereegranskat)abstract
- We report the discovery of a warm Neptune and a hot sub-Neptune transiting TOI-421 (BD-14 1137, TIC 94986319), a bright (V = 9.9) G9 dwarf star in a visual binary system observed by the Transiting Exoplanet Survey Satellite (TESS) space mission in Sectors 5 and 6. We performed ground-based follow-up observations-comprised of Las Cumbres Observatory Global Telescope transit photometry, NIRC2 adaptive optics imaging, and FIbre-fed Echelle Spectrograph, CORALIE, High Accuracy Radial velocity Planet Searcher, High Resolution echelle Spectrometer, and Planet Finder Spectrograph high-precision Doppler measurements-and confirmed the planetary nature of the 16 day transiting candidate announced by the TESS team. We discovered an additional radial velocity signal with a period of five days induced by the presence of a second planet in the system, which we also found to transit its host star. We found that the inner mini-Neptune, TOI-421 b, has an orbital period of P-b = 5.19672 +/- 0.00049 days, a mass of M-b = 7.17 +/- 0.66 M-circle plus, and a radius of R-b = R-circle plus, whereas the outer warm Neptune, TOI-421 c, has a period of P-c = 16.06819 +/- 0.00035 days, a mass of M-c = 16.42(-1.04)(+1.06)M(circle plus), a radius of R-c = 5.09(-0.15)(+0.16)R(circle plus), and a density of rho(c) = 0.685(-0.072)(+0.080) cm(-3). With its characteristics, the outer planet (rho(c) = 0.685(-0.0072)(+0.080) cm(-3)) is placed in the intriguing class of the super-puffy mini-Neptunes. TOI-421 b and TOI-421 c are found to be well-suited for atmospheric characterization. Our atmospheric simulations predict significant Ly alpha transit absorption, due to strong hydrogen escape in both planets, as well as the presence of detectable CH4 in the atmosphere of TOI-421 c if equilibrium chemistry is assumed.
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| 7. |
- Grewling, L., et al.
(författare)
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Outdoor airborne allergens: Characterization, behavior and monitoring in Europe
- 2023
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Ingår i: SCIENCE OF THE TOTAL ENVIRONMENT. - 0048-9697. ; 905
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Tidskriftsartikel (refereegranskat)abstract
- Aeroallergens or inhalant allergens, are proteins dispersed through the air and have the potential to induce allergic conditions such as rhinitis, conjunctivitis, and asthma. Outdoor aeroallergens are found predominantly in pollen grains and fungal spores, which are allergen carriers. Aeroallergens from pollen and fungi have seasonal emission patterns that correlate with plant pollination and fungal sporulation and are strongly associated with atmospheric weather conditions. They are released when allergen carriers come in contact with the respiratory system, e.g. the nasal mucosa. In addition, due to the rupture of allergen carriers, airborne allergen molecules may be released directly into the air in the form of micronic and submicronic particles (cytoplasmic debris, cell wall fragments, droplets etc.) or adhered onto other airborne particulate matter. Therefore, aeroallergen detection strategies must consider, in addition to the allergen carriers, the allergen molecules themselves. This review article aims to present the current knowledge on inhalant allergens in the outdoor environment, their structure, localization, and factors affecting their production, transformation, release or degradation. In addition, methods for collecting and quantifying aeroallergens are listed and thoroughly discussed. Finally, the knowledge gaps, challenges and implications associated with aeroallergen analysis are described.
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| 8. |
- Kuzuhara, Masayuki, et al.
(författare)
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Gliese 12 b: A Temperate Earth-sized Planet at 12 pc Ideal for Atmospheric Transmission Spectroscopy
- 2024
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Ingår i: Astrophysical Journal Letters. - 2041-8213 .- 2041-8205. ; 969:1
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Tidskriftsartikel (refereegranskat)abstract
- Recent discoveries of Earth-sized planets transiting nearby M dwarfs have made it possible to characterize the atmospheres of terrestrial planets via follow-up spectroscopic observations. However, the number of such planets receiving low insolation is still small, limiting our ability to understand the diversity of the atmospheric composition and climates of temperate terrestrial planets. We report the discovery of an Earth-sized planet transiting the nearby (12 pc) inactive M3.0 dwarf Gliese 12 (TOI-6251) with an orbital period (P(or)b) of 12.76 days. The planet, Gliese 12 b, was initially identified as a candidate with an ambiguous P-orb from TESS data. We confirmed the transit signal and P-orb using ground-based photometry with MuSCAT2 and MuSCAT3, and validated the planetary nature of the signal using high-resolution images from Gemini/NIRI and Keck/NIRC2 as well as radial velocity (RV) measurements from the InfraRed Doppler instrument on the Subaru 8.2 m telescope and from CARMENES on the CAHA 3.5 m telescope. X-ray observations with XMM-Newton showed the host star is inactive, with an X-ray-to-bolometric luminosity ratio of log L-X/L-bol approximate to - 5.7. Joint analysis of the light curves and RV measurements revealed that Gliese 12 b has a radius of 0.96 +/- 0.05 R-circle plus, a 3 sigma mass upper limit of 3.9M(circle plus), and an equilibrium temperature of 315 +/- 6 K assuming zero albedo. The transmission spectroscopy metric (TSM) value of Gliese 12 b is close to the TSM values of the TRAPPIST-1 planets, adding Gliese 12 b to the small list of potentially terrestrial, temperate planets amenable to atmospheric characterization with JWST.
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| 9. |
- Smith, Bradley N., et al.
(författare)
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The C9ORF72 expansion mutation is a common cause of ALS+/-FTD in Europe and has a single founder
- 2013
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Ingår i: European Journal of Human Genetics. - London : Nature Publishing Group. - 1018-4813 .- 1476-5438. ; 21:1, s. 102-108
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Tidskriftsartikel (refereegranskat)abstract
- A massive hexanucleotide repeat expansion mutation (HREM) in C9ORF72 has recently been linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we describe the frequency, origin and stability of this mutation in ALS+/-FTD from five European cohorts (total n = 1347). Single-nucleotide polymorphisms defining the risk haplotype in linked kindreds were genotyped in cases (n = 434) and controls (n = 856). Haplotypes were analysed using PLINK and aged using DMLE+. In a London clinic cohort, the HREM was the most common mutation in familial ALS+/-FTD: C9ORF72 29/112 (26%), SOD1 27/112 (24%), TARDBP 1/112 (1%) and FUS 4/112 (4%) and detected in 13/216 (6%) of unselected sporadic ALS cases but was rare in controls (3/856, 0.3%). HREM prevalence was high for familial ALS+/-FTD throughout Europe: Belgium 19/22 (86%), Sweden 30/41 (73%), the Netherlands 10/27 (37%) and Italy 4/20 (20%). The HREM did not affect the age at onset or survival of ALS patients. Haplotype analysis identified a common founder in all 137 HREM carriers that arose around 6300 years ago. The haplotype from which the HREM arose is intrinsically unstable with an increased number of repeats (average 8, compared with 2 for controls, P<10(-8)). We conclude that the HREM has a single founder and is the most common mutation in familial and sporadic ALS in Europe.
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| 10. |
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| 11. |
- Bro-Jørgensen, Maiken Hemme, et al.
(författare)
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Ancient DNA analysis of Scandinavian medieval drinking horns and the horn of the last aurochs bull
- 2018
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Ingår i: Journal of Archaeological Science. - : Elsevier BV. - 0305-4403 .- 1095-9238. ; 99, s. 47-54
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Tidskriftsartikel (refereegranskat)abstract
- The aurochs (Bos primigenius) was once widespread in Europe, Asia and North Africa. The aurochs was both the ancestor of domestic cattle, and co-existed alongside them for millennia post domestication, before going extinct in 1627. Several studies have suggested that admixture occurred between wild aurochs populations and domestic cattle. To contribute towards our understanding of this process, we generated near complete mitochondrial genomes (between 15063 and 16338 nucleotides) from material derived from the horn of the last aurochs bull (died in 1620) as well as five medieval period Scandinavian drinking horns that have been attributed to aurochs based on their size. Phylogenetic analysis on the data shows that three drinking horns carry European aurochs haplotype P, while two of the drinking horns and the horn of the last aurochs bull carry modern domestic taurine cattle T haplotypes. Our results therefore demonstrate that drinking horns may represent a unique source of material with which to study aurochs genetics, and that the last European aurochs likely underwent a degree of admixture with domestic cattle. We anticipate that future analysis of the nuclear DNA content of such horns will be able to shed further light into the specifics of these admixture events.
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| 12. |
- Calderón-Contreras, Rafael, et al.
(författare)
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A regional PECS node built from place-based social-ecological sustainability research in Latin America and the Caribbean
- 2022
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Ingår i: Ecosystems and People. - : Informa UK Limited. - 2639-5908 .- 2639-5916. ; 18:1, s. 1-14
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Tidskriftsartikel (refereegranskat)abstract
- Sustainability requires a combination of meaningful co-production of locally relevant solutions, synthesis of insights gained across regions, and increased cooperation between science, policy and practice. The Programme for Ecosystem Change and Society (PECS) has been coordinating Place-Based Social-Ecological Sustainability Research (PBSESR) across the globe and emphasizes the need for regional scientific nodes from diverse biocultural regions to inform sustainability science and action. In this paper, we assess the strengths of the PBSESR communities in Latin America and the Caribbean (LAC). We provide an overview of PBSESR literature associated with this region and highlight the achievements of two prominent regional networks: The Social-Ecological Systems and Sustainability Research Network from Mexico (SocioEcoS) and the South American Institute for Resilience and Sustainability Studies from Uruguay (SARAS Institute). Finally, we identify the potential in these nodes to constitute a regional PECS node in Latin America and discuss the capacity needed to ensure such function. The results of the literature review show that while still loosely interconnected across the region, networks play key roles in connecting otherwise cloistered teams and we illustrate how the SocioEcoS network (focusing on transdisciplinary co-production of knowledge towards sustainability) and the SARAS Institute (focusing on innovative approaches for looking at complex social-ecological problems, rooted in slow science and arts) operate as key connectors in the region. We conclude that these organizations combined can embody a Latin American node for PECS, and would thereby not only contribute to regional but also global capacities to advance the sustainability agenda.
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| 13. |
- Davies, Stuart J., et al.
(författare)
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ForestGEO: Understanding forest diversity and dynamics through a global observatory network
- 2021
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Ingår i: Biological Conservation. - : Elsevier BV. - 0006-3207. ; 253
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Tidskriftsartikel (refereegranskat)abstract
- ForestGEO is a network of scientists and long-term forest dynamics plots (FDPs) spanning the Earth's major forest types. ForestGEO's mission is to advance understanding of the diversity and dynamics of forests and to strengthen global capacity for forest science research. ForestGEO is unique among forest plot networks in its large-scale plot dimensions, censusing of all stems ≥1 cm in diameter, inclusion of tropical, temperate and boreal forests, and investigation of additional biotic (e.g., arthropods) and abiotic (e.g., soils) drivers, which together provide a holistic view of forest functioning. The 71 FDPs in 27 countries include approximately 7.33 million living trees and about 12,000 species, representing 20% of the world's known tree diversity. With >1300 published papers, ForestGEO researchers have made significant contributions in two fundamental areas: species coexistence and diversity, and ecosystem functioning. Specifically, defining the major biotic and abiotic controls on the distribution and coexistence of species and functional types and on variation in species' demography has led to improved understanding of how the multiple dimensions of forest diversity are structured across space and time and how this diversity relates to the processes controlling the role of forests in the Earth system. Nevertheless, knowledge gaps remain that impede our ability to predict how forest diversity and function will respond to climate change and other stressors. Meeting these global research challenges requires major advances in standardizing taxonomy of tropical species, resolving the main drivers of forest dynamics, and integrating plot-based ground and remote sensing observations to scale up estimates of forest diversity and function, coupled with improved predictive models. However, they cannot be met without greater financial commitment to sustain the long-term research of ForestGEO and other forest plot networks, greatly expanded scientific capacity across the world's forested nations, and increased collaboration and integration among research networks and disciplines addressing forest science.
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| 14. |
- De Groot, Natasja M.S., et al.
(författare)
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Critical appraisal of technologies to assess electrical activity during atrial fibrillation : a position paper from the European Heart Rhythm Association and European Society of Cardiology Working Group on eCardiology in collaboration with the Heart Rhythm Society, Asia Pacific Heart Rhythm Society, Latin American Heart Rhythm Society and Computing in Cardiology
- 2022
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Ingår i: Europace. - : Oxford University Press (OUP). - 1099-5129. ; 24:2, s. 313-330
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Forskningsöversikt (refereegranskat)abstract
- We aim to provide a critical appraisal of basic concepts underlying signal recording and processing technologies applied for (i) atrial fibrillation (AF) mapping to unravel AF mechanisms and/or identifying target sites for AF therapy and (ii) AF detection, to optimize usage of technologies, stimulate research aimed at closing knowledge gaps, and developing ideal AF recording and processing technologies. Recording and processing techniques for assessment of electrical activity during AF essential for diagnosis and guiding ablative therapy including body surface electrocardiograms (ECG) and endo- or epicardial electrograms (EGM) are evaluated. Discussion of (i) differences in uni-, bi-, and multi-polar (omnipolar/Laplacian) recording modes, (ii) impact of recording technologies on EGM morphology, (iii) global or local mapping using various types of EGM involving signal processing techniques including isochronal-, voltage- fractionation-, dipole density-, and rotor mapping, enabling derivation of parameters like atrial rate, entropy, conduction velocity/direction, (iv) value of epicardial and optical mapping, (v) AF detection by cardiac implantable electronic devices containing various detection algorithms applicable to stored EGMs, (vi) contribution of machine learning (ML) to further improvement of signals processing technologies. Recording and processing of EGM (or ECG) are the cornerstones of (body surface) mapping of AF. Currently available AF recording and processing technologies are mainly restricted to specific applications or have technological limitations. Improvements in AF mapping by obtaining highest fidelity source signals (e.g. catheter-electrode combinations) for signal processing (e.g. filtering, digitization, and noise elimination) is of utmost importance. Novel acquisition instruments (multi-polar catheters combined with improved physical modelling and ML techniques) will enable enhanced and automated interpretation of EGM recordings in the near future.
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| 15. |
- Hobson, Melissa J., et al.
(författare)
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TOI-199 b : A Well-characterized 100 day Transiting Warm Giant Planet with TTVs Seen from Antarctica
- 2023
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Ingår i: Astronomical Journal. - 0004-6256. ; 166:5
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Tidskriftsartikel (refereegranskat)abstract
- We present the spectroscopic confirmation and precise mass measurement of the warm giant planet TOI-199 b. This planet was first identified in TESS photometry and confirmed using ground-based photometry from ASTEP in Antarctica including a full 6.5 hr long transit, PEST, Hazelwood, and LCO; space photometry from NEOSSat; and radial velocities (RVs) from FEROS, HARPS, CORALIE, and CHIRON. Orbiting a late G-type star, TOI-199 b has a 104.854 − 0.002 + 0.001 day period, a mass of 0.17 ± 0.02 M J, and a radius of 0.810 ± 0.005 R J. It is the first warm exo-Saturn with a precisely determined mass and radius. The TESS and ASTEP transits show strong transit timing variations (TTVs), pointing to the existence of a second planet in the system. The joint analysis of the RVs and TTVs provides a unique solution for the nontransiting companion TOI-199 c, which has a period of 273.69 − 0.22 + 0.26 days and an estimated mass of 0.28 − 0.01 + 0.02 M J . This period places it within the conservative habitable zone.
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| 16. |
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| 17. |
- Orell-Miquel, J., et al.
(författare)
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HD 191939 revisited: New and refined planet mass determinations, and a new planet in the habitable zone
- 2023
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 669
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Tidskriftsartikel (refereegranskat)abstract
- HD 191939 (TOI-1339) is a nearby (d = 54 pc), bright (V = 9 mag), and inactive Sun-like star (G9 V) known to host a multi-planet transiting system. Ground-based spectroscopic observations confirmed the planetary nature of the three transiting sub-Neptunes (HD 191939 b, c, and d) originally detected by TESS and were used to measure the masses for planets b and c with 3Ï precision. These previous observations also reported the discovery of an additional Saturn-mass planet (HD 191939 e) and evidence for a further, very long-period companion (HD 191939 f). Here, we report the discovery of a new non-transiting planet in the system and a refined mass determination of HD 191939 d. The new planet, HD 191939 g, has a minimum mass of 13.5±2.0 M- and a period of about 280 days. This period places the planet within the conservative habitable zone of the host star, and near a 1:3 resonance with HD 191939 e. The compilation of 362 radial velocity measurements with a baseline of 677 days from four different high-resolution spectrographs also allowed us to refine the properties of the previously known planets, including a 4.6Ï mass determination for planet d, for which only a 2Ï upper limit had been set until now. We confirm the previously suspected low density of HD 191939 d, which makes it an attractive target for attempting atmospheric characterisation. Overall, the planetary system consists of three sub-Neptunes interior to a Saturn-mass and a Uranus-mass planet plus a high-mass long-period companion. This particular configuration has no counterpart in the literature and makes HD 191939 an exceptional multi-planet transiting system with an unusual planet demographic worthy of future observation.
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| 18. |
- Pablos, Isabel, et al.
(författare)
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Mechanistic insights into COVID-19 by global analysis of the SARS-CoV-2 3CL(pro) substrate degradome
- 2021
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Ingår i: Cell Reports. - : Cell Press. - 2211-1247. ; 37:4
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Tidskriftsartikel (refereegranskat)abstract
- The main viral protease (3CL(pro)) is indispensable for SARS-CoV-2 replication. We delineate the human protein substrate landscape of 3CL(pro) by TAILS substrate-targeted N-terminomics. We identify more than 100 substrates in human lung and kidney cells supported by analyses of SARS-CoV-2-infected cells. Enzyme kinetics and molecular docking simulations of 3CL(pro) engaging substrates reveal how noncanonical cleavage sites, which diverge from SARS-CoV, guide substrate specificity. Cleaving the interactors of essential effector proteins, effectively stranding them from their binding partners, amplifies the consequences of proteolysis. We show that 3CL(pro) targets the Hippo pathway, including inactivation of MAP4K5, and key effectors of transcription, mRNA processing, and translation. We demonstrate that Spike glycoprotein directly binds galectin-8, with galectin-8 cleavage disengaging CALCOCO2/NDP52 to decouple antiviral-autophagy. Indeed, in post-mortem COVID-19 lung samples, NDP52 rarely colocalizes with galectin-8, unlike in healthy lungs. The 3CL(pro) substrate degradome establishes a foundational substrate atlas to accelerate exploration of SARSCoV-2 pathology and drug design.
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| 19. |
- Reddington, James P, et al.
(författare)
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Redistribution of H3K27me3 upon DNA hypomethylation results in de-repression of Polycomb target genes
- 2013
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Ingår i: Genome Biology. - : Springer Science and Business Media LLC. - 1465-6906 .- 1474-760X. ; 14:3, s. R25-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: DNA methylation and the Polycomb repression system are epigenetic mechanisms that play important roles in maintaining transcriptional repression. Recent evidence suggests that DNA methylation can attenuate the binding of Polycomb protein components to chromatin and thus plays a role in determining their genomic targeting. However, whether this role of DNA methylation is important in the context of transcriptional regulation is unclear.RESULTS: By genome-wide mapping of the Polycomb Repressive Complex 2-signature histone mark, H3K27me3, in severely DNA hypomethylated mouse somatic cells, we show that hypomethylation leads to widespread H3K27me3 redistribution, in a manner that reflects the local DNA methylation status in wild-type cells. Unexpectedly, we observe striking loss of H3K27me3 and Polycomb Repressive Complex 2 from Polycomb target gene promoters in DNA hypomethylated cells, including Hox gene clusters. Importantly, we show that many of these genes become ectopically expressed in DNA hypomethylated cells, consistent with loss of Polycomb-mediated repression.CONCLUSIONS: An intact DNA methylome is required for appropriate Polycomb-mediated gene repression by constraining Polycomb Repressive Complex 2 targeting. These observations identify a previously unappreciated role for DNA methylation in gene regulation and therefore influence our understanding of how this epigenetic mechanism contributes to normal development and disease.
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| 20. |
- Arandia-Gorostidi, Nestor, et al.
(författare)
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Efficient carbon and nitrogen transfer from marine diatom aggregates to colonizing bacterial groups
- 2022
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Bacterial degradation of sinking diatom aggregates is key for the availability of organic matter in the deep-ocean. Yet, little is known about the impact of aggregate colonization by different bacterial taxa on organic carbon and nutrient cycling within aggregates. Here, we tracked the carbon (C) and nitrogen (N) transfer from the diatom Leptocylindrus danicus to different environmental bacterial groups using a combination of C-13 and N-15 isotope incubation (incubated for 72 h), CARD-FISH and nanoSIMS single-cell analysis. Pseudoalteromonas bacterial group was the first colonizing diatom-aggregates, succeeded by the Alteromonas group. Within aggregates, diatom-attached bacteria were considerably more enriched in C-13 and N-15 than non-attached bacteria. Isotopic mass balance budget indicates that both groups showed comparable levels of diatom C in their biomass, accounting for 19 +/- 7% and 15 +/- 11%, respectively. In contrast to C, bacteria of the Alteromonas groups showed significantly higher levels of N derived from diatoms (77 +/- 28%) than Pseudoalteromonas (47 +/- 17%), suggesting a competitive advantage for Alteromonas in the N-limiting environments of the deep-sea. Our results imply that bacterial succession within diatom aggregates may largely impact taxa-specific C and N uptake, which may have important consequences for the quantity and quality of organic matter exported to the deep ocean.
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| 21. |
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| 22. |
- Bruhn, Sören, et al.
(författare)
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A Generally Applicable Translational Strategy Identifies S100A4 as a Candidate Gene in Allergy
- 2014
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 6:218
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Tidskriftsartikel (refereegranskat)abstract
- The identification of diagnostic markers and therapeutic candidate genes in common diseases is complicated by the involvement of thousands of genes. We hypothesized that genes co-regulated with a key gene in allergy, IL13, would form a module that could help to identify candidate genes. We identified a T helper 2 (T(H)2) cell module by small interfering RNA-mediated knockdown of 25 putative IL13-regulating transcription factors followed by expression profiling. The module contained candidate genes whose diagnostic potential was supported by clinical studies. Functional studies of human TH2 cells as well as mouse models of allergy showed that deletion of one of the genes, S100A4, resulted in decreased signs of allergy including TH2 cell activation, humoral immunity, and infiltration of effector cells. Specifically, dendritic cells required S100A4 for activating T cells. Treatment with an anti-S100A4 antibody resulted in decreased signs of allergy in the mouse model as well as in allergen-challenged T cells from allergic patients. This strategy, which may be generally applicable to complex diseases, identified and validated an important diagnostic and therapeutic candidate gene in allergy.
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| 23. |
- Buhr, Katarina, et al.
(författare)
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End users’ challenges, needs and requirements for assessing resilience
- 2018
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- This report summarizes the results from the work in Task 1.3 of the SmartResilience project. Within the Work Package “Establishing the project baseline and the common framework”, Task 1.3 contributes to a better understanding of the indicators for resilience assessment by examining the actual needs from the ones responsible for such an assessment.This deliverable establishes, at an early stage in the project, a baseline for understanding end users’ current and projected challenges, needs and requirements for assessing resilience of critical infrastructures and using resilience indicators (RIs) for doing so. This is a necessary step to ensure that the resilience assessment methodology and smart RIs will be designed in ways that are useful and therefore adopted, thus delivering increased resilience for critical infrastructures, beyond the project.The identification of end users’ challenges, needs and requirements in assessing resilience within Task 1.3 has been guided by an actor analysis approach and is predominantly based on qualitative methods, consisting of semi-structured individual or group interviews with key end users connected to critical infrastructures, desktop studies and literature reviews. The task has covered eight critical infrastructures in the SmartResilience case studies (ALPHA-HOTEL) as well as an additional case study covering interconnected critical infrastructures (DSB). Furthermore, in order to take into account end users beyond these nine case studies, a literature review has been carried out as well as a survey among the Members of the Community of Users of Safe, Secure and Resilient Societies (CoU).The key findings from Task 1.3 are summarized below:Designing useful indicators requires extensive end user involvement in order to be able to integrate the indicators into existing organizational processes. There is a need to define the “work” that the indicators are supposed to do and make sure they meet the challenges of interconnected infrastructures.End users in the case studies confirmed and provided further insight into the following key challenges, which are illustrated by examples: the concept of resilience; external threats (climate change, cyber-attacks, terrorist attacks, flooding); the complexity of critical infrastructures; and data management.End users in the case studies expressed specific needs and requirements, which has been analyzed in terms of five dimensions of resilience and illustrated by examples: system/physical; information/data; organizational/business: societal/political and cognitive/decision-making.The survey to the CoU indicated that some actors do not see a need to develop RIs because they think current practices are sufficient. Although the low response rate calls for caution in interpreting the results, the responses suggests a number of challenges for the SmartResilience project. First, the need for the project to create assessments and RIs that are clearly regarded as providing added value in relation to end users’ current and projected needs. Second, the challenge to design assessments and RIs that can be widely disseminated, while at the same time taking different contexts into account.Three implications for indicator development are suggested. Firstly, indicators should be developed with an appropriate end user in mind. This means posing questions such as: What organization, and what function or user group, will use it? What is their interest in using indicators? What is their legitimacy to spread the indicator in the critical infrastructure? Secondly, indicators should be developed in dialogue with end users, in order to increase the likelihood that they cover areas that are relevant and currently not sufficiently covered; are relevant, understandable and legitimate; and are designed according to end users’ own motives for assessing resilience and perceptions of usefulness. Thirdly, indicators should be developed in alignment with end users’ organizational processes. This suggests that the project should develop indicators which are easy to understand in order to decrease the dependency of individual expertise and misunderstandings across different organizations; meet the level of capacity of resources that the organization(s) are willing to spend on assessments of resilience; and allow end users to collect, process and share (big) data, taking data security into account.
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| 24. |
- Carmichael, Theron W., et al.
(författare)
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Two Intermediate-mass Transiting Brown Dwarfs from the TESS Mission
- 2020
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Ingår i: Astronomical Journal. - : American Astronomical Society. - 1538-3881 .- 0004-6256. ; 160:1
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Tidskriftsartikel (refereegranskat)abstract
- We report the discovery of two intermediate-mass transiting brown dwarfs (BDs), TOI-569b and TOI-1406b, from NASA's Transiting Exoplanet Survey Satellite mission. TOI-569b has an orbital period of P=.55604±0.00016 days, a mass of Mb = 64.1±1.9 MJ, and a radius of Rb = 0.75±0.02 RJ. Its host star, TOI-569, has a mass of Må = 1.21±0.05 M, a radius of Rå = 1.47±0.03 R, [Fe H 0.29 0.09] = + dex, and an effective temperature of Teff = 5768±10K. TOI-1406b has an orbital period of P=10.57415±0.00063 days, a mass of Mb = 46.0± 2.7 MJ, and a radius of Rb = 0.86±0.03 RJ. The host star for this BD has a mass of Må = 1.18±0.09 M, a radius of Rå = 1.35±0.03 R, [Fe/H] =-0.08± 0.09 dex, and an effective temperature of Teff = 6290±100 K. Both BDs are in circular orbits around their host stars and are older than 3 Gyr based on stellar isochrone models of the stars. TOI-569 is one of two slightly evolved stars known to host a transiting BD (the other being KOI-415). TOI-1406b is one of three known transiting BDs to occupy the mass range of 40-50 MJ and one of two to have a circular orbit at a period near 10 days (with the first being KOI-205b). Both BDs have reliable ages from stellar isochrones, in addition to their well-constrained masses and radii, making them particularly valuable as tests for substellar isochrones in the BD mass-radius diagram.
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| 25. |
- Corcoran, Martin M., et al.
(författare)
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Production of individualized V gene databases reveals high levels of immunoglobulin genetic diversity
- 2016
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Ingår i: nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Comprehensive knowledge of immunoglobulin genetics is required to advance our understanding of B cell biology. Validated immunoglobulin variable (V) gene databases are close to completion only for human and mouse. We present a novel computational approach, IgDiscover, that identifies germline V genes from expressed repertoires to a specificity of 100%. IgDiscover uses a cluster identification process to produce candidate sequences that, once filtered, results in individualized germline V gene databases. IgDiscover was tested in multiple species, validated by genomic cloning and cross library comparisons and produces comprehensive gene databases even where limited genomic sequence is available. IgDiscover analysis of the allelic content of the Indian and Chinese-origin rhesus macaques reveals high levels of immunoglobulin gene diversity in this species. Further, we describe a novel human IGHV3-21 allele and confirm significant gene differences between Balb/c and C57BL6 mouse strains, demonstrating the power of IgDiscover as a germline V gene discovery tool.
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| 26. |
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| 27. |
- Garcia, Cesar, et al.
(författare)
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Predicting the impact of adding metakaolin on the splitting strength of concrete using ensemble ML classification and symbolic regression techniques –a comparative study
- 2024
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Ingår i: Frontiers in Built Environment. - : Frontiers. - 2297-3362. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- The mechanical characteristics of concrete are crucial factors in structural design standards especially in concrete technology. Employing reliable prediction models for concrete’s mechanical properties can reduce the number of necessary laboratory trials, checks and experiments to obtain valuable representative design data, thus saving both time and resources. Metakaolin (MK) is commonly utilized as a supplementary replacement for Portland cement in sustainable concrete production due to its technical and environmental benefits towards net-zero goals of the United Nations Sustainable Development Goals (UNSDGs). In this research work, 204 data entries from concrete mixes produced with the addition of metakaolin (MK) were collected and analyzed using eight (8) ensemble machine learning tools and one (1) symbolic regression technique. The application of multiple machine learning protocols such as the ensemble group and the symbolic regression techniques have not been presented in any previous research work on the modeling of splitting tensile strength of MK mixed concrete. The data was partitioned and applied according to standard conditions. Lastly, some selected performance evaluation indices were used to test the models’ accuracy in predicting the splitting strength (Fsp) of the studied MK-mixed concrete. At the end, results show that the k-nearest neighbor (KNN) outperformed the other techniques in the ensemble group with the following indices; SSE of 4% and 1%, MAE of 0.1 and 0.2 MPa, MSE of 0, RMSE of 0.1 and 0.2 MPa, Error of 0.04% and 0.04%, Accuracy of 0.96 and 0.96 and R2 of 0.98 and 0.98 for the training and validation models, respectively. This is followed closely by the support vector machine (SVM) with the following indices; SSE of 7% and 3%, MAE of 0.2 and 0.2 MPa, MSE of 0.0 and 0.1 MPa, RMSE of 0.2 and 0.3 MPa, Error of 0.05% and 0.06%, Accuracy of 0.95 and 0.94, and R2 of 0.96 and 0.95, for the training and validation models, respectively. The third model in the superiority rank is the CN2 with the following performance indices; SSE of 15% and 4%, MAE of 0.2 and 0.2 MPa, MSE of 0.1 and 0.1 MPa, RMSE of 0.3 and 0.3 MPa, Error of 0.08% and 0.07%, Accuracy of 0.92 and 0.93 and R2 of 0.92 and 0.93, for the training and validation models, respectively. These models outperformed the models utilized on the MK-mixed concrete found in the literature, therefore are the better decisive modes for the prediction of the splitting strength (Fsp) of the studied MK-mixed concrete with 204 mix data entries. Conversely, the NB and SGD produced unacceptable model performances, however, this is true for the modeled database collected for the MK-mixed Fsp. The RSM model also produced superior performance with an accuracy of over 95% and adequate precision of more than 27. Overall, the KNN, SVM, CN2 and RSM have shown to possess the potential to predict the MK-mixed Fsp for structural concrete designs and production.
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| 28. |
- Groopman, Emily E., et al.
(författare)
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Diagnostic Utility of Exome Sequencing for Kidney Disease
- 2019
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Ingår i: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 380:2, s. 142-151
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND Exome sequencing is emerging as a first-line diagnostic method in some clinical disciplines, but its usefulness has yet to be examined for most constitutional disorders in adults, including chronic kidney disease, which affects more than 1 in 10 persons globally.METHODS We conducted exome sequencing and diagnostic analysis in two cohorts totaling 3315 patients with chronic kidney disease. We assessed the diagnostic yield and, among the patients for whom detailed clinical data were available, the clinical implications of diagnostic and other medically relevant findings.RESULTS In all, 3037 patients (91.6%) were over 21 years of age, and 1179 (35.6%) were of self-identified non-European ancestry. We detected diagnostic variants in 307 of the 3315 patients (9.3%), encompassing 66 different monogenic disorders. Of the disorders detected, 39 (59%) were found in only a single patient. Diagnostic variants were detected across all clinically defined categories, including congenital or cystic renal disease (127 of 531 patients [23.9%]) and nephropathy of unknown origin (48 of 281 patients [17.1%]). Of the 2187 patients assessed, 34 (1.6%) had genetic findings for medically actionable disorders that, although unrelated to their nephropathy, would also lead to subspecialty referral and inform renal management.CONCLUSIONS Exome sequencing in a combined cohort of more than 3000 patients with chronic kidney disease yielded a genetic diagnosis in just under 10% of cases.
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| 29. |
- Hackett, Jamie A., et al.
(författare)
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Promoter DNA methylation couples genome-defence mechanisms to epigenetic reprogramming in the mouse germline
- 2012
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Ingår i: Development. - : The Company of Biologists. - 0950-1991 .- 1477-9129. ; 139:19, s. 3623-3632
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Tidskriftsartikel (refereegranskat)abstract
- Mouse primordial germ cells (PGCs) erase global DNA methylation (5mC) as part of the comprehensive epigenetic reprogramming that occurs during PGC development. 5mC plays an important role in maintaining stable gene silencing and repression of transposable elements (TE) but it is not clear how the extensive loss of DNA methylation impacts on gene expression and TE repression in developing PGCs. Using a novel epigenetic disruption and recovery screen and genetic analyses, we identified a core set of germline-specific genes that are dependent exclusively on promoter DNA methylation for initiation and maintenance of developmental silencing. These gene promoters appear to possess a specialised chromatin environment that does not acquire any of the repressive H3K27me3, H3K9me2, H3K9me3 or H4K20me3 histone modifications when silenced by DNA methylation. Intriguingly, this methylation-dependent subset is highly enriched in genes with roles in suppressing TE activity in germ cells. We show that the mechanism for developmental regulation of the germline genome-defence genes involves DNMT3B-dependent de novo DNA methylation. These genes are then activated by lineage-specific promoter demethylation during distinct global epigenetic reprogramming events in migratory (~E8.5) and post-migratory (E10.5-11.5) PGCs. We propose that genes involved in genome defence are developmentally regulated primarily by promoter DNA methylation as a sensory mechanism that is coupled to the potential for TE activation during global 5mC erasure, thereby acting as a failsafe to ensure TE suppression and maintain genomic integrity in the germline.
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| 30. |
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| 31. |
- Ingelshed, Katrine, et al.
(författare)
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MDM2/MDMX inhibition by Sulanemadlin synergizes with anti-Programmed Death 1 immunotherapy in wild-type p53 tumors
- 2024
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Ingår i: iScience. - : Elsevier. - 2589-0042. ; 27:6
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Tidskriftsartikel (refereegranskat)abstract
- Immunotherapy has revolutionized cancer treatment but its efficacy depends on a robust immune response in the tumor. Silencing of the tumor suppressor p53 is common in tumors and can affect the recruitment and activation of different immune cells, leading to immune evasion and poor therapy response. We found that the p53 activating stapled peptide MDM2/MDMX inhibitor Sulanemadlin (ALRN-6924) inhibited p53 wild-type cancer cell growth in vitro and in vivo. In mice carrying p53 wild-type CT26.WT tumors, monotherapy with the PD-1 inhibitor DX400 or Sulanemadlin delayed tumor doubling time by 50% and 37%, respectively, while combination therapy decreased tumor doubling time by 93% leading to an increased median survival time. Sulanemadlin treatment led to increased immunogenicity and combination treatment with PD-1 inhibition resulted in an increased tumor infiltration of lymphocytes. This combination treatment strategy could potentially turn partial responders into responders of immunotherapy, expanding the patient target group for PD-1-targeting immunotherapy.
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| 32. |
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| 33. |
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| 34. |
- Johansson, Patrik, et al.
(författare)
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A Patient-Derived Cell Atlas Informs Precision Targeting of Glioblastoma
- 2020
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 32:2
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Tidskriftsartikel (refereegranskat)abstract
- Glioblastoma (GBM) is a malignant brain tumor with few therapeutic options. The disease presents with a complex spectrum of genomic aberrations, but the pharmacological consequences of these aberrations are partly unknown. Here, we report an integrated pharmacogenomic analysis of 100 patient-derived GBM cell cultures from the human glioma cell culture (HGCC) cohort. Exploring 1,544 drugs, we find that GBM has two main pharmacological subgroups, marked by differential response to proteasome inhibitors and mutually exclusive aberrations in TP53 and CDKN2A/B. We confirm this trend in cell and in xenotransplantation models, and identify both Bcl-2 family inhibitors and p53 activators as potentiators of proteasome inhibitors in GBM cells, We can further predict the responses of individual cell cultures to several existing drug classes, presenting opportunities for drug repurposing and design of stratified trials. Our functionally profiled biobank provides a valuable resource for the discovery of new treatments for GBM.
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| 35. |
- Kissling, W. Daniel, et al.
(författare)
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Building essential biodiversity variables (EBVs) of species distribution and abundance at a global scale
- 2018
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Ingår i: Biological Reviews. - : Wiley. - 1464-7931 .- 1469-185X. ; 93:1, s. 600-625
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Tidskriftsartikel (refereegranskat)abstract
- © 2017 Cambridge Philosophical Society. Much biodiversity data is collected worldwide, but it remains challenging to assemble the scattered knowledge for assessing biodiversity status and trends. The concept of Essential Biodiversity Variables (EBVs) was introduced to structure biodiversity monitoring globally, and to harmonize and standardize biodiversity data from disparate sources to capture a minimum set of critical variables required to study, report and manage biodiversity change. Here, we assess the challenges of a 'Big Data' approach to building global EBV data products across taxa and spatiotemporal scales, focusing on species distribution and abundance. The majority of currently available data on species distributions derives from incidentally reported observations or from surveys where presence-only or presence-absence data are sampled repeatedly with standardized protocols. Most abundance data come from opportunistic population counts or from population time series using standardized protocols (e.g. repeated surveys of the same population from single or multiple sites). Enormous complexity exists in integrating these heterogeneous, multi-source data sets across space, time, taxa and different sampling methods. Integration of such data into global EBV data products requires correcting biases introduced by imperfect detection and varying sampling effort, dealing with different spatial resolution and extents, harmonizing measurement units from different data sources or sampling methods, applying statistical tools and models for spatial inter- or extrapolation, and quantifying sources of uncertainty and errors in data and models. To support the development of EBVs by the Group on Earth Observations Biodiversity Observation Network (GEO BON), we identify 11 key workflow steps that will operationalize the process of building EBV data products within and across research infrastructures worldwide. These workflow steps take multiple sequential activities into account, including identification and aggregation of various raw data sources, data quality control, taxonomic name matching and statistical modelling of integrated data. We illustrate these steps with concrete examples from existing citizen science and professional monitoring projects, including eBird, the Tropical Ecology Assessment and Monitoring network, the Living Planet Index and the Baltic Sea zooplankton monitoring. The identified workflow steps are applicable to both terrestrial and aquatic systems and a broad range of spatial, temporal and taxonomic scales. They depend on clear, findable and accessible metadata, and we provide an overview of current data and metadata standards. Several challenges remain to be solved for building global EBV data products: (i) developing tools and models for combining heterogeneous, multi-source data sets and filling data gaps in geographic, temporal and taxonomic coverage, (ii) integrating emerging methods and technologies for data collection such as citizen science, sensor networks, DNA-based techniques and satellite remote sensing, (iii) solving major technical issues related to data product structure, data storage, execution of workflows and the production process/cycle as well as approaching technical interoperability among research infrastructures, (iv) allowing semantic interoperability by developing and adopting standards and tools for capturing consistent data and metadata, and (v) ensuring legal interoperability by endorsing open data or data that are free from restrictions on use, modification and sharing. Addressing these challenges is critical for biodiversity research and for assessing progress towards conservation policy targets and sustainable development goals.
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| 36. |
- Kolbeck, Roland, et al.
(författare)
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MEDI-563, a humanized anti-IL-5 receptor alpha mAb with enhanced antibody-dependent cell-mediated cytotoxicity function
- 2010
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Ingår i: Journal of Allergy and Clinical Immunology. - : Elsevier BV. - 1097-6825 .- 0091-6749. ; 125:6, s. 1344-1353
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Tidskriftsartikel (refereegranskat)abstract
- Background: Peripheral blood eosinophilia and lung mucosal eosinophil infiltration are hallmarks of bronchial asthma. IL-5 is a critical cytokine for eosinophil maturation, survival, and mobilization. Attempts to target eosinophils for the treatment of asthma by means of IL-5 neutralization have only resulted in partial removal of airway eosinophils, and this warrants the development of more effective interventions to further explore the role of eosinophils in the clinical expression of asthma. Objective: We sought to develop a novel humanized anti IL-5 receptor alpha (IL-5R alpha) mAb with enhanced effector function (MEDI-563) that potently depletes circulating and tissue. resident eosinophils and basophils for the treatment of asthma. Methods: We used surface plasmon resonance to determine the binding affinity of MEDI-563 to Fc gamma RIII alpha. Primary human eosinophils and basophils were used to demonstrate antibody-dependent cell-mediated cytotoxicity. The binding epitope of MEDI-563 on IL-5R alpha was determined by using site-directed mutagenesis. The consequences of MEDI-563 administration on peripheral blood and bone marrow eosinophil depletion was investigated in nonhuman primates. Results: MEDI-563 binds to an epitope on IL-5R alpha that is in close proximity to the IL-5 binding site, and it inhibits IL-5 mediated cell proliferation. MEDI-563 potently induces antibody-dependent cell-mediated cytotoxicity of both eosinophils (half-maximal effective concentration = 0.9 pmol/L) and basophils (half-maximal effective concentration = 0.5 pmol/L) in vitro. In nonhuman primates MEDI-563 depletes blood eosinophils and eosinophil precursors in the bone marrow. Conclusions: MEDI-563 might provide a novel approach for the treatment of asthma through active antibody-dependent cell-mediated depletion of eosinophils and basophils rather than through passive removal of IL-5. (J Allergy Clin Immunol 2010;125:1344-53.)
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| 37. |
- Kosten, Sarian, et al.
(författare)
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Warmer climates boost cyanobacterial dominance in shallow lakes
- 2012
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Ingår i: Global Change Biology. - : Wiley. - 1354-1013. ; 18:1, s. 118-126
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Tidskriftsartikel (refereegranskat)abstract
- Dominance by cyanobacteria hampers human use of lakes and reservoirs worldwide. Previous studies indicate that excessive nutrient loading and warmer conditions promote dominance by cyanobacteria, but evidence from global scale field data has so far been scarce. Our analysis, based on a study of 143 lakes along a latitudinal transect ranging from subarctic Europe to southern South America, shows that although warmer climates do not result in higher overall phytoplankton biomass, the percentage of the total phytoplankton biovolume attributable to cyanobacteria increases steeply with temperature. Our results also reveal that the percent cyanobacteria is greater in lakes with high rates of light absorption. This points to a positive feedback because restriction of light availability is often a consequence of high phytoplankton biovolume, which in turn may be driven by nutrient loading. Our results indicate a synergistic effect of nutrients and climate. The implications are that in a future warmer climate, nutrient concentrations may have to be reduced substantially from present values in many lakes if cyanobacterial dominance is to be controlled.
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| 38. |
- Magnusson, Rasmus, 1992-, et al.
(författare)
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LASSIM-A network inference toolbox for genome-wide mechanistic modeling
- 2017
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Ingår i: PLoS Computational Biology. - : Public Library of Science (PLoS). - 1553-734X .- 1553-7358. ; 13:6, s. Article no. e1005608 -
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Tidskriftsartikel (refereegranskat)abstract
- Recent technological advancements have made time-resolved, quantitative, multi-omics data available for many model systems, which could be integrated for systems pharmacokinetic use. Here, we present large-scale simulation modeling (LASSIM), which is a novel mathematical tool for performing large-scale inference using mechanistically defined ordinary differential equations (ODE) for gene regulatory networks (GRNs). LASSIM integrates structural knowledge about regulatory interactions and non-linear equations with multiple steady state and dynamic response expression datasets. The rationale behind LASSIM is that biological GRNs can be simplified using a limited subset of core genes that are assumed to regulate all other gene transcription events in the network. The LASSIM method is implemented as a general-purpose toolbox using the PyGMO Python package to make the most of multicore computers and high performance clusters, and is available at https://gitlab.com/Gustafsson-lab/lassim. As a method, LASSIM works in two steps, where it first infers a non-linear ODE system of the pre-specified core gene expression. Second, LASSIM in parallel optimizes the parameters that model the regulation of peripheral genes by core system genes. We showed the usefulness of this method by applying LASSIM to infer a large-scale non-linear model of naive Th2 cell differentiation, made possible by integrating Th2 specific bindings, time-series together with six public and six novel siRNA-mediated knock-down experiments. ChIP-seq showed significant overlap for all tested transcription factors. Next, we performed novel time-series measurements of total T-cells during differentiation towards Th2 and verified that our LASSIM model could monitor those data significantly better than comparable models that used the same Th2 bindings. In summary, the LASSIM toolbox opens the door to a new type of model-based data analysis that combines the strengths of reliable mechanistic models with truly systems-level data. We demonstrate the power of this approach by inferring a mechanistically motivated, genome-wide model of the Th2 transcription regulatory system, which plays an important role in several immune related diseases.
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| 39. |
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| 40. |
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| 41. |
- Mortensen, Anja, et al.
(författare)
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Selection, characterization and in vivo evaluation of novel CD44v6-targeting antibodies for targeted molecular radiotherapy
- 2023
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Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Molecular radiotherapy combines the advantages of systemic administration of highly specific antibodies or peptides and the localized potency of ionizing radiation. A potential target for molecular radiotherapy is the cell surface antigen CD44v6, which is overexpressed in numerous cancers, with limited expression in normal tissues. The aim of the present study was to generate and characterize a panel of human anti-CD44v6 antibodies and identify a suitable candidate for future use in molecular radiotherapy of CD44v6-expressing cancers. Binders were first isolated from large synthetic phage display libraries containing human scFv and Fab antibody fragments. The antibodies were extensively analyzed through in vitro investigations of binding kinetics, affinity, off-target binding, and cell binding. Lead candidates were further subjected to in vivo biodistribution studies in mice bearing anaplastic thyroid cancer xenografts that express high levels of CD44v6. Additionally, antigen-dependent tumor uptake of the lead candidate was verified in additional xenograft models with varying levels of target expression. Interestingly, although only small differences were observed among the top antibody candidates in vitro, significant differences in tumor uptake and retention were uncovered in in vivo experiments. A high-affinity anti-CD44v6 lead drug candidate was identified, mAb UU-40, which exhibited favorable target binding properties and in vivo distribution. In conclusion, a panel of human anti-CD44v6 antibodies was successfully generated and characterized in this study. Through comprehensive evaluation, mAb UU-40 was identified as a promising lead candidate for future molecular radiotherapy of CD44v6-expressing cancers due to its high affinity, excellent target binding properties, and desirable in vivo distribution characteristics.
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| 42. |
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| 43. |
- Nestor, Colm, et al.
(författare)
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5-Hydroxymethylcytosine Remodeling Precedes Lineage Specification during Differentiation of Human CD4(+) T Cells
- 2016
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Ingår i: Cell Reports. - : CELL PRESS. - 2211-1247. ; 16:2, s. 559-570
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Tidskriftsartikel (refereegranskat)abstract
- 5-methylcytosine (5mC) is converted to 5-hydroxymethylcytosine (5hmC) by the TET family of enzymes as part of a recently discovered active DNA de-methylation pathway. 5hmC plays important roles in regulation of gene expression and differentiation and has been implicated in T cell malignancies and autoimmunity. Here, we report early and widespread 5mC/5hmC remodeling during human CD4(+) T cell differentiation ex vivo at genes and cell-specific enhancers with known T cell function. We observe similar DNA de-methylation in CD4(+) memory T cells in vivo, indicating that early remodeling events persist long term in differentiated cells. Underscoring their important function, 5hmC loci were highly enriched for genetic variants associated with T cell diseases and T-cell-specific chromosomal interactions. Extensive functional validation of 22 risk variants revealed potentially pathogenic mechanisms in diabetes and multiple sclerosis. Our results support 5hmC-mediated DNA de-methylation as a key component of CD4(+) T cell biology in humans, with important implications for gene regulation and lineage commitment.
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| 44. |
- Nestor, Colm, et al.
(författare)
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DNA Methylation Changes Separate Allergic Patients from Healthy Controls and May Reflect Altered CD4⁺ T-Cell Population Structure
- 2014
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Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Altered DNA methylation patterns in CD4+ T-cells indicate the importance of epigenetic mechanisms in inflammatory diseases. However, the identification of these alterations is complicated by the heterogeneity of most inflammatory diseases. Seasonal allergic rhinitis (SAR) is an optimal disease model for the study of DNA methylation because of its well-defined phenotype and etiology. We generated genome-wide DNA methylation (Npatients = 8, Ncontrols = 8) and gene expression (Npatients = 9, Ncontrols = 10) profiles of CD4+ T-cells from SAR patients and healthy controls using Illumina's HumanMethylation450 and HT-12 microarrays, respectively. DNA methylation profiles clearly and robustly distinguished SAR patients from controls, during and outside the pollen season. In agreement with previously published studies, gene expression profiles of the same samples failed to separate patients and controls. Separation by methylation (Npatients = 12, Ncontrols = 12), but not by gene expression (Npatients = 21, Ncontrols = 21) was also observed in an in vitro model system in which purified PBMCs from patients and healthy controls were challenged with allergen. We observed changes in the proportions of memory T-cell populations between patients (Npatients = 35) and controls (Ncontrols = 12), which could explain the observed difference in DNA methylation. Our data highlight the potential of epigenomics in the stratification of immune disease and represents the first successful molecular classification of SAR using CD4+ T cells.
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| 45. |
- Nestor, Colm E, et al.
(författare)
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Rapid reprogramming of epigenetic and transcriptional profiles in mammalian culture systems.
- 2015
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Ingår i: Genome Biology. - : BioMed Central. - 1465-6906 .- 1474-760X. ; 16, s. 11-
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundThe DNA methylation profile of mammalian cell lines differs from the primary tissue from which they were derived, exhibiting increasing divergence from the in vivo methylation profile with extended time in culture. Few studies have directly examined the initial epigenetic and transcriptional consequences of adaptation of primary mammalian cells to culture, and the potential mechanisms through which this epigenetic dysregulation occurs is unknown.ResultsWe demonstrate that adaptation of mouse embryonic fibroblast, MEFS, to cell culture results in a rapid reprogramming of epigenetic and transcriptional states. We observed global 5-hydroxymethylcytosine (5hmC) erasure within three days of culture initiation. Loss of genic 5hmC was independent of global 5-methylcytosine (5mC) levels and could be partially rescued by addition of Vitamin C. Significantly, 5hmC loss was not linked to concomitant changes in transcription. Discrete promoter-specific gains of 5mC were also observed within seven days of culture initiation. Against this background of global 5hmC loss we identified a handful of developmentally important genes that maintained their 5hmC profile in culture, including the imprinted loci Gnas and H19. Similar outcomes were identified in the adaption of CD4+ T-cells to culture.ConclusionsWe report a dramatic and novel consequence of adaptation of mammalian cells to culture in which global loss of 5hmC occurs; suggesting rapid concomitant loss of methylcytosine dioxygenase activity. The observed epigenetic and transcriptional re-programming occurs much earlier than previously assumed, and has significant implications for the use of cell lines as faithful mimics of in vivo epigenetic and physiological processes.
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| 46. |
- Nestor, David, 1992-, et al.
(författare)
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Evaluation of the FilmArray (TM) Meningitis/Encephalitis panel with focus on bacteria and Cryptococcus spp
- 2019
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Ingår i: Journal of Microbiological Methods. - : Elsevier BV. - 0167-7012 .- 1872-8359. ; 157, s. 113-116
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Molecular methods provide fast and accurate detection of both bacteria and viruses in the cerebrospinal fluid (CSF) causing infection in the central nervous system (CNS). In the present study we evaluated the bacterial detection performance of the fully automated FilmArray (TM) Meningitis/Encephalitis (ME) panel (bioMerieux) by comparing it with culture and multiplexed in-house PCR. Methods: Three sample types were analysed; Contrived samples with known bacterial/fungal concentration (n = 29), clinical samples from patients with verified cause of CNS infection (n = 17) and external quality assessment (EQA) samples (n = 11). Another six samples were purposely prepared with multiple targets to evaluate multiplex capacity. Results: The FilmArray (TM) had a slightly higher limit of detection for Streptococcus pneumoniae, Neisseria meningitidis, Listeria monocytogenes and Streptococcus agalactiae compared to in-house PCR methods but performed equal or better when compared to culture. The FilmArray (TM) ME panel detected the expected pathogen in 17 of 17 clinical samples and yielded detection of three additional viruses of which one was confirmed with comparator techniques. All but one of the EQA samples were correctly detected. Conclusions: The results of this study are promising and the FilmArray (TM) ME panel could add to the diagnostic algorithm in CNS-infections. However, the limit of detection for the important pathogens N. meningitidis and S. pneumoniae could be improved.
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| 47. |
- Nestor, Gustav, et al.
(författare)
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A detailed picture of a protein-carbohydrate hydrogen-bonding network revealed by NMR and MD simulations
- 2021
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Ingår i: Glycobiology. - : Oxford University Press (OUP). - 0959-6658 .- 1460-2423. ; 31:4, s. 508-518
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Tidskriftsartikel (refereegranskat)abstract
- Cyanovirin-N (CV-N) is a cyanobacterial lectin with antiviral activity towards HIV and several other viruses. Here, we identify mannoside hydroxyl protons that are hydrogen bonded to the protein backbone of the CV-N domain B binding site, using NMR spectroscopy. For the two carbohydrate ligands Manα(1→2)ManαOMe and Manα(1→2) Manα(1→6)ManαOMe five hydroxyl protons are involved in hydrogen-bonding networks. Comparison with previous crystallographic results revealed that four of these hydroxyl protons donate hydrogen bonds to protein backbone carbonyl oxygens in solution and in the crystal. Hydrogen bonds were not detected between the side chains of Glu41 and Arg76 with sugar hydroxyls, as previously proposed for CV-N binding of mannosides. Molecular dynamics simulations of the CV-N/Manα(1→2)Manα(1→6)ManαOMe complex confirmed the NMR-determined hydrogen-bonding network. Detailed characterization of CV-N/mannoside complexes provides a better understanding of lectin-carbohydrate interactions and opens up to the use of CV-N and similar lectins as antiviral agents.
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| 48. |
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| 49. |
- Nowak, Grzegorz, et al.
(författare)
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K2-280 b - a low density warm sub-Saturn around a mildly evolved star
- 2020
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Ingår i: Monthly Notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 497:4, s. 4423-4435
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Tidskriftsartikel (refereegranskat)abstract
- We present an independent discovery and detailed characterization of K2-280 b, a transiting low density warm sub-Saturn in a 19.9-d moderately eccentric orbit (e = 0.35(-0.04)(+0.05)) from K2 campaign 7. A joint analysis of high precision HARPS, HARPS-N, and FIES radial velocity measurements and K2 photometric data indicates that K2-280 b has a radius of R-b = 7.50 +/- 0.44 R-circle plus and a mass of M-b = 37.1 +/- 5.6 M-circle plus, yielding a mean density of rho(b) = 0.48(-0.10)(+0.13) g cm(-3). The host star is a mildly evolved G7 star with an effective temperature of T-eff = 5500 +/- 100 K, a surface gravity of log g(star) = 4.21 +/- 0.05 (cgs), and an iron abundance of [Fe/H] = 0.33 +/- 0.08 dex, and with an inferred mass of M-star = 1.03 +/- 0.03 M-circle dot and a radius of R-star = 1.28 +/- 0.07 R-circle dot. We discuss the importance of K2-280 b for testing formation scenarios of sub-Saturn planets and the current sample of this intriguing group of planets that are absent in the Solar system.
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| 50. |
- Riman, Tomas, et al.
(författare)
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Hormone replacement therapy and the risk of invasive epithelial ovarian cancer in Swedish women
- 2002
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 94:7, s. 497-504
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Estrogen replacement therapy (ERT), which is mainly used to relieve climacteric symptoms, increases a woman's risk for uterine endometrial cancer and epithelial ovarian cancer (EOC). Estrogens are often combined with progestins in hormone replacement therapy (HRT) to reduce the risk of uterine endometrial cancer. Data on the association between HRT including progestins and EOC risk are limited. This nationwide case-control study examined EOC risk in relation to HRT regimens with sequentially added progestins (HRTsp) and continuously added progestins (HRTcp). METHODS: Between 1993 and 1995, we enrolled 655 histologically verified incident case patients with EOC and 3899 randomly selected population controls, all 50-74 years of age. Data on HRT use were collected through mailed questionnaires. Multivariate-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by the use of unconditional logistic regression. RESULTS: Risks of EOC were elevated among ever users as compared with never users of both ERT (OR = 1.43, 95% CI = 1.02 to 2.00) and HRTsp (OR = 1.54, 95% CI = 1.15 to 2.05); risks were elevated for serous, mucinous, and endometrioid subtypes. For all EOC types combined, the greatest risk increases were seen with hormone use exceeding 10 years. Ever use of HRTcp was not associated with increased EOC risk relative to HRTcp never use (OR = 1.02, 95% CI = 0.73 to 1.43). The risk of EOC was elevated among HRTsp ever users as compared with HRTcp ever users (OR = 1.78, 95% CI = 1.05 to 3.01). ORs for EOC after ever use of low-potency estrogens were 1.18 (95% CI = 0.89 to 1.55) for oral and 1.33 (95% CI = 1.03 to 1.72) for vaginal applications, but no relationship was seen between EOC risk and duration of use. CONCLUSION: Ever users of ERT and HRTsp but not HRTcp may be at increased risk of EOC.
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