| 2061. |
- O'Seaghdha, Conall M., et al.
(författare)
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Meta-Analysis of Genome-Wide Association Studies Identifies Six New Loci for Serum Calcium Concentrations
- 2013
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Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 9:9, s. e1003796-
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Tidskriftsartikel (refereegranskat)abstract
- Calcium is vital to the normal functioning of multiple organ systems and its serum concentration is tightly regulated. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17 population-based cohorts and investigated the 14 most strongly associated loci in <= 21,679 additional individuals. Seven loci (six new regions) in association with serum calcium were identified and replicated. Rs1570669 near CYP24A1 (P = 9.1E-12), rs10491003 upstream of GATA3 (P = 4.8E-09) and rs7481584 in CARS (P = 1.2E-10) implicate regions involved in Mendelian calcemic disorders: Rs1550532 in DGKD (P = 8.2E-11), also associated with bone density, and rs7336933 near DGKH/KIAA0564 (P = 9.1E-10) are near genes that encode distinct isoforms of diacylglycerol kinase. Rs780094 is in GCKR. We characterized the expression of these genes in gut, kidney, and bone, and demonstrate modulation of gene expression in bone in response to dietary calcium in mice. Our results shed new light on the genetics of calcium homeostasis.
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| 2062. |
- Ostergaard, Henrik, et al.
(författare)
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Prolonged half-life and preserved enzymatic properties of factor IX selectively PEGylated on native N-glycans in the activation peptide
- 2011
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 118:8, s. 2333-2341
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Tidskriftsartikel (refereegranskat)abstract
- Current management of hemophilia B entails multiple weekly infusions of factor IX (FIX) to prevent bleeding episodes. In an attempt to make a longer acting recombinant FIX (rFIX), we have explored a new releasable protraction concept using the native N-glycans in the activation peptide as sites for attachment of polyethylene glycol (PEG). Release of the activation peptide by physiologic activators converted glycoPEGylated rFIX (N9-GP) to native rFIXa and proceeded with normal kinetics for FXIa, while the Km for activation by FVIIa-tissue factor (TF) was increased by 2-fold. Consistent with minimal perturbation of rFIX by the attached PEG, N9-GP retained 73%-100% specific activity in plasma and whole-blood-based assays and showed efficacy comparable with rFIX in stopping acute bleeds in hemophilia B mice. In animal models N9-GP exhibited up to 2-fold increased in vivo recovery and a markedly prolonged half-life in mini-pig (76 hours) and hemophilia B dog (113 hours) compared with rFIX (16 hours). The extended circulation time of N9-GP was reflected in prolonged correction of coagulation parameters in hemophilia B dog and duration of effect in hemophilia B mice. Collectively, these results suggest that N9-GP has the potential to offer efficacious prophylactic and acute treatment of hemophilia B patients at a reduced dosing frequency. (Blood. 2011; 118(8): 2333-2341)
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| 2063. |
- Ottmann, Christian, et al.
(författare)
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Phosphorylation-independent interaction between 14-3-3 and exoenzyme S : from structure to pathogenesis.
- 2007
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Ingår i: EMBO Journal. - : Wiley. - 0261-4189 .- 1460-2075. ; 26:3, s. 902-913
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Tidskriftsartikel (refereegranskat)abstract
- 14-3-3 proteins are phosphoserine/phosphothreonine-recognizing adapter proteins that regulate the activity of a vast array of targets. There are also examples of 14-3-3 proteins binding their targets via unphosphorylated motifs. Here we present a structural and biological investigation of the phosphorylation-independent interaction between 14-3-3 and exoenzyme S (ExoS), an ADP-ribosyltransferase toxin of Pseudomonas aeruginosa. ExoS binds to 14-3-3 in a novel binding mode mostly relying on hydrophobic contacts. The 1.5 A crystal structure is supported by cytotoxicity analysis, which reveals that substitution of the corresponding hydrophobic residues significantly weakens the ability of ExoS to modify the endogenous targets RAS/RAP1 and to induce cell death. Furthermore, mutation of key residues within the ExoS binding site for 14-3-3 impairs virulence in a mouse pneumonia model. In conclusion, we show that ExoS binds 14-3-3 in a novel reversed orientation that is primarily dependent on hydrophobic residues. This interaction is phosphorylation independent and is required for the function of ExoS.
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| 2064. |
- Otto-Bliesner, Bette L., et al.
(författare)
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Large-scale features of Last Interglacial climate : results from evaluating the lig127k simulations for the Coupled Model Intercomparison Project (CMIP6)–Paleoclimate Modeling Intercomparison Project (PMIP4)
- 2021
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Ingår i: Climate of the Past. - : Copernicus GmbH. - 1814-9324 .- 1814-9332. ; 17:1, s. 63-94
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Tidskriftsartikel (refereegranskat)abstract
- The modeling of paleoclimate, using physically based tools, is increasingly seen as a strong out-of-sample test of the models that are used for the projection of future climate changes. New to the Coupled Model Intercomparison Project (CMIP6) is the Tier 1 Last Interglacial experiment for 127 000 years ago (lig127k), designed to address the climate responses to stronger orbital forcing than the midHolocene experiment, using the same state-of-the-art models as for the future and following a common experimental protocol. Here we present a first analysis of a multi-model ensemble of 17 climate models, all of which have completed the CMIP6 DECK (Diagnostic, Evaluation and Characterization of Klima) experiments. The equilibrium climate sensitivity (ECS) of these models varies from 1.8 to 5.6 ∘C. The seasonal character of the insolation anomalies results in strong summer warming over the Northern Hemisphere continents in the lig127k ensemble as compared to the CMIP6 piControl and much-reduced minimum sea ice in the Arctic. The multi-model results indicate enhanced summer monsoonal precipitation in the Northern Hemisphere and reductions in the Southern Hemisphere. These responses are greater in the lig127k than the CMIP6 midHolocene simulations as expected from the larger insolation anomalies at 127 than 6 ka.New synthesis for surface temperature and precipitation, targeted for 127 ka, have been developed for comparison to the multi-model ensemble. The lig127k model ensemble and data reconstructions are in good agreement for summer temperature anomalies over Canada, Scandinavia, and the North Atlantic and for precipitation over the Northern Hemisphere continents. The model–data comparisons and mismatches point to further study of the sensitivity of the simulations to uncertainties in the boundary conditions and of the uncertainties and sparse coverage in current proxy reconstructions.The CMIP6–Paleoclimate Modeling Intercomparison Project (PMIP4) lig127k simulations, in combination with the proxy record, improve our confidence in future projections of monsoons, surface temperature, and Arctic sea ice, thus providing a key target for model evaluation and optimization.
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| 2065. |
- Ottosson, Ulf, et al.
(författare)
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Garden Warbler Sylvia borin migration in sub-Saharan West Africa: phenology and body mass changes
- 2005
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Ingår i: Ibis. - 0019-1019. ; 147:4, s. 750-757
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Tidskriftsartikel (refereegranskat)abstract
- The Garden Warbler is a classic subject for the study of Palaearctic-African bird migration strategies. Most studies have considered the situation close to the breeding areas, while the African and especially the sub-Saharan part of the species' migration have received comparatively little attention. Here we use autumn and spring ringing data from Nigeria and The Gambia to study the movements and energetics of the species in West Africa during the non-breeding season. The first Garden Warblers arrive south of the desert around the beginning of September, roughly at the same time as the median date for their passage through the Baltic Sea region and c. 3 weeks before their median passage date through southern Italy. In the Nigerian Sahel savannahs, where, owing to the rainy season and its associated increase in food availability, many more Garden Warblers stop over in autumn than in the dry spring, the median date of passage is 1 October. The body mass on arrival south of the desert is normally only a few grams more than the lean body mass (LBM; 15 g) - with a mean of 16.6 g (sd = +/- 1.8 g) in The Gambia and 17.4 g (sd = +/- 1.8 g) in the Nigerian Sahel. After resting and refuelling in the Sahel, Sudan and Guinea-type savannahs the Garden Warblers depart during November-December for wintering areas further south. Before leaving, they again increase their body mass, with an average fuel load of c. 20%, and often more than 50% relative to LBM. Some of the birds passing through Nigeria probably spend midwinter around the Congo Basin. During spring they return northwards to the Guinea savannah zone in April and fuel-up there for the trans-Sahara passage. At this time they normally increase their body reserves to around 50% of the LBM, but c. 10% of the birds gain 100%, thus doubling their mass. The passage there peaks around 20 April and continues well into May. That the main take-off northwards is directly from the Guinea savannahs is indicated by the very low numbers trapped in the Sahel during spring.
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| 2066. |
- Over, Bjorn, et al.
(författare)
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Structural and conformational determinants of macrocycle cell permeability
- 2016
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Ingår i: Nature Chemical Biology. - New York : Nature Publishing Group. - 1552-4450 .- 1552-4469. ; 12:12, s. 1065-1074
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Tidskriftsartikel (refereegranskat)abstract
- Macrocycles are of increasing interest as chemical probes and drugs for intractable targets like protein-protein interactions, but the determinants of their cell permeability and oral absorption are poorly understood. To enable rational design of cell-permeable macrocycles, we generated an extensive data set under consistent experimental conditions for more than 200 nonpeptidic, de novo-designed macrocycles from the Broad Institute's diversity-oriented screening collection. This revealed how specific functional groups, substituents and molecular properties impact cell permeability. Analysis of energy-minimized structures for stereo- and regioisomeric sets provided fundamental insight into how dynamic, intramolecular interactions in the 3D conformations of macrocycles may be linked to physicochemical properties and permeability. Combined use of quantitative structure-permeability modeling and the procedure for conformational analysis now, for the first time, provides chemists with a rational approach to design cell-permeable non-peptidic macrocycles with potential for oral absorption.
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| 2067. |
- Paalvast, M., et al.
(författare)
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Properties and redshift evolution of star-forming galaxies with high [0 III]/[O II] ratios with MUSE at 0.28 < z < 0.85
- 2018
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 618
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Tidskriftsartikel (refereegranskat)abstract
- We present a study of the [O III]/[O II] ratios of star-forming galaxies drawn from Multi-Unit Spectroscopic Explorer (MUSE) data spanning a redshift range 0.28 < z < 0.85. Recently discovered Lyman continuum (LyC) emitters have extremely high oxygen line ratios: [O III]lambda 5007/[O II]lambda lambda 3726, 3729 > 4. Here we aim to understand the properties and the occurrences of galaxies with such high line ratios. Combining data from several MUSE Guaranteed Time Observing (GTO) programmes, we select a population of star-forming galaxies with bright emission lines, from which we draw 406 galaxies for our analysis based on their position in the z-dependent star formation rate (SFR) stellar mass (M*) plane. Out of this sample 15 are identified as extreme oxygen emitters based on their [O III]/[O II] ratios (3.7%) and 104 galaxies have [O III]/[O II] > 1 (26%). Our analysis shows no significant correlation between M*, SFR, and the distance from the SFR M, relation with [O III]/[O II]. We find a decrease in the fraction of galaxies with [O III]/[O II] > 1 with increasing M*, however, this is most likely a result of the relationship between [O III]/[O II] and metallicity, rather than between [O III]/[O II] and M. We draw a comparison sample of local analogues with < z > 0.03 from the Sloan Digital Sky Survey, and find similar incidence rates for this sample. In order to investigate the evolution in the fraction of high [O III]/[O II] emitters with redshift, we bin the sample into three redshift subsamples of equal number, but find no evidence for a dependence on redshift. Furthermore, we compare the observed line ratios with those predicted by nebular models with no LyC escape and find that most of the extreme oxygen emitters can be reproduced by low metallicity models. The remaining galaxies are likely LyC emitter candidates.
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| 2068. |
- Paasonen, Pauli, et al.
(författare)
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Warming-induced increase in aerosol number concentration likely to moderate climate change
- 2013
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Ingår i: Nature Geoscience. - 1752-0908. ; 6:6, s. 438-442
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Tidskriftsartikel (refereegranskat)abstract
- Atmospheric aerosol particles influence the climate system directly by scattering and absorbing solar radiation, and indirectly by acting as cloud condensation nuclei(1-4). Apart from black carbon aerosol, aerosols cause a negative radiative forcing at the top of the atmosphere and substantially mitigate the warming caused by greenhouse gases(1). In the future, tightening of controls on anthropogenic aerosol and precursor vapour emissions to achieve higher air quality may weaken this beneficial effect(5-)7. Natural aerosols, too, might affect future warming(2,3,8,9). Here we analyse long-term observations of concentrations and compositions of aerosol particles and their biogenic precursor vapours in continental mid-and high-latitude environments. We use measurements of particle number size distribution together with boundary layer heights derived from reanalysis data to show that the boundary layer burden of cloud condensation nuclei increases exponentially with temperature. Our results confirm a negative feedback mechanism between the continental biosphere, aerosols and climate: aerosol cooling effects are strengthened by rising biogenic organic vapour emissions in response to warming, which in turn enhance condensation on particles and their growth to the size of cloud condensation nuclei. This natural growth mechanism produces roughly 50% of particles at the size of cloud condensation nuclei across Europe. We conclude that biosphere-atmosphere interactions are crucial for aerosol climate effects and can significantly influence the effects of anthropogenic aerosol emission controls, both on climate and air quality.
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| 2069. |
- Pallas, Frank, et al.
(författare)
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Privacy Engineering From Principles to Practice : A Roadmap
- 2024
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Ingår i: IEEE Security and Privacy. - : Institute of Electrical and Electronics Engineers (IEEE). - 1540-7993 .- 1558-4046. ; 22:2, s. 86-92
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Tidskriftsartikel (refereegranskat)abstract
- Privacy engineering is gaining momentum in industry and academia alike. So far, manifold low-level primitives and higher-level methods and strategies have successfully been established. Still, fostering adoption in real-world information systems calls for additional aspects to be consciously considered in research and practice.
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| 2070. |
- Pansch, Christian, et al.
(författare)
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A new flow-through bioassay for testing low-emission antifouling coatings
- 2017
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Ingår i: Biofouling. - : Informa UK Limited. - 0892-7014 .- 1029-2454. ; 33:8, s. 613-623
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Tidskriftsartikel (refereegranskat)abstract
- Current antifouling (AF) technologies are based on the continuous release of biocides into the water, and consequently discharge into the environment. Major efforts to develop more environmentally friendly coatings require efficient testing in laboratory assays, followed by field studies. Barnacles are important fouling organisms worldwide, increasing hydrodynamic drag on ships and damaging coatings on underwater surfaces, and thus are extensively used as models in AF research, mostly in static, laboratory-based systems. Reliable flow-through test assays for the screening of biocidecontaining AF paints, however, are rare. Herein, a flow-through bioassay was developed to screen for diverse low-release biocide paints, and to evaluate their effects on pre- andpost-settlement traits in barnacles. The assay distinguishes between the effects from direct surface contact and bulk-water effects, which are crucial when developing low-emission AF coatings. This flow-through bioassay adds a new tool for rapid laboratory-based first-stage screening of candidate compounds and novel AF formulations.
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