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3.
  • 2019
  • Journal article (peer-reviewed)
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4.
  • Klionsky, Daniel J., et al. (author)
  • Guidelines for the use and interpretation of assays for monitoring autophagy
  • 2012
  • In: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
  • Research review (peer-reviewed)abstract
    • In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are 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 monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
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5.
  • Loza, M. J., et al. (author)
  • Validated and longitudinally stable asthma phenotypes based on cluster analysis of the ADEPT study
  • 2016
  • In: Respiratory Research. - : Springer Nature. - 1465-9921 .- 1465-993X. ; 17:1
  • Journal article (peer-reviewed)abstract
    • Background: Asthma is a disease of varying severity and differing disease mechanisms. To date, studies aimed at stratifying asthma into clinically useful phenotypes have produced a number of phenotypes that have yet to be assessed for stability and to be validated in independent cohorts. The aim of this study was to define and validate, for the first time ever, clinically driven asthma phenotypes using two independent, severe asthma cohorts: ADEPT and U-BIOPRED. Methods: Fuzzy partition-around-medoid clustering was performed on pre-specified data from the ADEPT participants (n = 156) and independently on data from a subset of U-BIOPRED asthma participants (n = 82) for whom the same variables were available. Models for cluster classification probabilities were derived and applied to the 12-month longitudinal ADEPT data and to a larger subset of the U-BIOPRED asthma dataset (n = 397). High and low type-2 inflammation phenotypes were defined as high or low Th2 activity, indicated by endobronchial biopsies gene expression changes downstream of IL-4 or IL-13. Results: Four phenotypes were identified in the ADEPT (training) cohort, with distinct clinical and biomarker profiles. Phenotype 1 was "mild, good lung function, early onset", with a low-inflammatory, predominantly Type-2, phenotype. Phenotype 2 had a "moderate, hyper-responsive, eosinophilic" phenotype, with moderate asthma control, mild airflow obstruction and predominant Type-2 inflammation. Phenotype 3 had a "mixed severity, predominantly fixed obstructive, non-eosinophilic and neutrophilic" phenotype, with moderate asthma control and low Type-2 inflammation. Phenotype 4 had a "severe uncontrolled, severe reversible obstruction, mixed granulocytic" phenotype, with moderate Type-2 inflammation. These phenotypes had good longitudinal stability in the ADEPT cohort. They were reproduced and demonstrated high classification probability in two subsets of the U-BIOPRED asthma cohort. Conclusions: Focusing on the biology of the four clinical independently-validated easy-to-assess ADEPT asthma phenotypes will help understanding the unmet need and will aid in developing tailored therapies. Trial registration:NCT01274507(ADEPT), registered October 28, 2010 and NCT01982162(U-BIOPRED), registered October 30, 2013.
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6.
  • Tinetti, G., et al. (author)
  • A chemical survey of exoplanets with ARIEL
  • 2018
  • In: Experimental Astronomy. - : Springer Science and Business Media LLC. - 0922-6435 .- 1572-9508. ; 46:1, s. 135-209
  • Journal article (peer-reviewed)abstract
    • Thousands of exoplanets have now been discovered with a huge range of masses, sizes and orbits: from rocky Earth-like planets to large gas giants grazing the surface of their host star. However, the essential nature of these exoplanets remains largely mysterious: there is no known, discernible pattern linking the presence, size, or orbital parameters of a planet to the nature of its parent star. We have little idea whether the chemistry of a planet is linked to its formation environment, or whether the type of host star drives the physics and chemistry of the planet’s birth, and evolution. ARIEL was conceived to observe a large number (~1000) of transiting planets for statistical understanding, including gas giants, Neptunes, super-Earths and Earth-size planets around a range of host star types using transit spectroscopy in the 1.25–7.8 μm spectral range and multiple narrow-band photometry in the optical. ARIEL will focus on warm and hot planets to take advantage of their well-mixed atmospheres which should show minimal condensation and sequestration of high-Z materials compared to their colder Solar System siblings. Said warm and hot atmospheres are expected to be more representative of the planetary bulk composition. Observations of these warm/hot exoplanets, and in particular of their elemental composition (especially C, O, N, S, Si), will allow the understanding of the early stages of planetary and atmospheric formation during the nebular phase and the following few million years. ARIEL will thus provide a representative picture of the chemical nature of the exoplanets and relate this directly to the type and chemical environment of the host star. ARIEL is designed as a dedicated survey mission for combined-light spectroscopy, capable of observing a large and well-defined planet sample within its 4-year mission lifetime. Transit, eclipse and phase-curve spectroscopy methods, whereby the signal from the star and planet are differentiated using knowledge of the planetary ephemerides, allow us to measure atmospheric signals from the planet at levels of 10–100 part per million (ppm) relative to the star and, given the bright nature of targets, also allows more sophisticated techniques, such as eclipse mapping, to give a deeper insight into the nature of the atmosphere. These types of observations require a stable payload and satellite platform with broad, instantaneous wavelength coverage to detect many molecular species, probe the thermal structure, identify clouds and monitor the stellar activity. The wavelength range proposed covers all the expected major atmospheric gases from e.g. H2O, CO2, CH4 NH3, HCN, H2S through to the more exotic metallic compounds, such as TiO, VO, and condensed species. Simulations of ARIEL performance in conducting exoplanet surveys have been performed – using conservative estimates of mission performance and a full model of all significant noise sources in the measurement – using a list of potential ARIEL targets that incorporates the latest available exoplanet statistics. The conclusion at the end of the Phase A study, is that ARIEL – in line with the stated mission objectives – will be able to observe about 1000 exoplanets depending on the details of the adopted survey strategy, thus confirming the feasibility of the main science objectives.
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7.
  • Östling, Jörgen, et al. (author)
  • IL-17-high asthma with features of a psoriasis immunophenotype
  • 2019
  • In: Journal of Allergy and Clinical Immunology. - : Elsevier. - 0091-6749 .- 1097-6825. ; 144:5, s. 1198-1213
  • Journal article (peer-reviewed)abstract
    • Background: The role of IL-17 immunity is well established in patients with inflammatory diseases, such as psoriasis and inflammatory bowel disease, but not in asthmatic patients, in whom further study is required.Objective: We sought to undertake a deep phenotyping study of asthmatic patients with upregulated IL-17 immunity.Methods: Whole-genome transcriptomic analysis was performed by using epithelial brushings, bronchial biopsy specimens (91 asthmatic patients and 46 healthy control subjects), and whole blood samples (n = 498) from the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) cohort. Gene signatures induced in vitro by IL-17 and IL-13 in bronchial epithelial cells were used to identify patients with IL-17–high and IL-13–high asthma phenotypes.Results: Twenty-two of 91 patients were identified with IL-17, and 9 patients were identified with IL-13 gene signatures. The patients with IL-17–high asthma were characterized by risk of frequent exacerbations, airway (sputum and mucosal) neutrophilia, decreased lung microbiota diversity, and urinary biomarker evidence of activation of the thromboxane B2 pathway. In pathway analysis the differentially expressed genes in patients with IL-17-high asthma were shared with those reported as altered in psoriasis lesions and included genes regulating epithelial barrier function and defense mechanisms, such as IL1B, IL6, IL8, and β-defensin.Conclusion: The IL-17–high asthma phenotype, characterized by bronchial epithelial dysfunction and upregulated antimicrobial and inflammatory response, resembles the immunophenotype of psoriasis, including activation of the thromboxane B2 pathway, which should be considered a biomarker for this phenotype in further studies, including clinical trials targeting IL-17.
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8.
  • Wright, Gillian, et al. (author)
  • The Mid-infrared Instrument for JWST and Its In-flight Performance
  • 2023
  • In: Publications of the Astronomical Society of the Pacific. - 0004-6280 .- 1538-3873. ; 135:1046
  • Journal article (peer-reviewed)abstract
    • The Mid-Infrared Instrument (MIRI) extends the reach of the James Webb Space Telescope (JWST) to 28.5 μm. It provides subarcsecond-resolution imaging, high sensitivity coronagraphy, and spectroscopy at resolutions of λ/Δλ ∼ 100-3500, with the high-resolution mode employing an integral field unit to provide spatial data cubes. The resulting broad suite of capabilities will enable huge advances in studies over this wavelength range. This overview describes the history of acquiring this capability for JWST. It discusses the basic attributes of the instrument optics, the detector arrays, and the cryocooler that keeps everything at approximately 7 K. It gives a short description of the data pipeline and of the instrument performance demonstrated during JWST commissioning. The bottom line is that the telescope and MIRI are both operating to the standards set by pre-launch predictions, and all of the MIRI capabilities are operating at, or even a bit better than, the level that had been expected. The paper is also designed to act as a roadmap to more detailed papers on different aspects of MIRI.
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9.
  • Akiyama, Kazunori, et al. (author)
  • First Sagittarius A* Event Horizon Telescope Results. II. EHT and Multiwavelength Observations, Data Processing, and Calibration
  • 2022
  • In: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8213 .- 2041-8205. ; 930:2
  • Journal article (peer-reviewed)abstract
    • We present Event Horizon Telescope (EHT) 1.3 mm measurements of the radio source located at the position of the supermassive black hole Sagittarius A* (Sgr A*), collected during the 2017 April 5-11 campaign. The observations were carried out with eight facilities at six locations across the globe. Novel calibration methods are employed to account for Sgr A*'s flux variability. The majority of the 1.3 mm emission arises from horizon scales, where intrinsic structural source variability is detected on timescales of minutes to hours. The effects of interstellar scattering on the image and its variability are found to be subdominant to intrinsic source structure. The calibrated visibility amplitudes, particularly the locations of the visibility minima, are broadly consistent with a blurred ring with a diameter of similar to 50 mu as, as determined in later works in this series. Contemporaneous multiwavelength monitoring of Sgr A* was performed at 22, 43, and 86 GHz and at near-infrared and X-ray wavelengths. Several X-ray flares from Sgr A* are detected by Chandra, one at low significance jointly with Swift on 2017 April 7 and the other at higher significance jointly with NuSTAR on 2017 April 11. The brighter April 11 flare is not observed simultaneously by the EHT but is followed by a significant increase in millimeter flux variability immediately after the X-ray outburst, indicating a likely connection in the emission physics near the event horizon. We compare Sgr A*'s broadband flux during the EHT campaign to its historical spectral energy distribution and find that both the quiescent emission and flare emission are consistent with its long-term behavior.
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10.
  • Akiyama, Kazunori, et al. (author)
  • First Sagittarius A* Event Horizon Telescope Results. III. Imaging of the Galactic Center Supermassive Black Hole
  • 2022
  • In: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8213 .- 2041-8205. ; 930:2
  • Journal article (peer-reviewed)abstract
    • We present the first event-horizon-scale images and spatiotemporal analysis of Sgr A* taken with the Event Horizon Telescope in 2017 April at a wavelength of 1.3 mm. Imaging of Sgr A* has been conducted through surveys over a wide range of imaging assumptions using the classical CLEAN algorithm, regularized maximum likelihood methods, and a Bayesian posterior sampling method. Different prescriptions have been used to account for scattering effects by the interstellar medium toward the Galactic center. Mitigation of the rapid intraday variability that characterizes Sgr A* has been carried out through the addition of a "variability noise budget" in the observed visibilities, facilitating the reconstruction of static full-track images. Our static reconstructions of Sgr A* can be clustered into four representative morphologies that correspond to ring images with three different azimuthal brightness distributions and a small cluster that contains diverse nonring morphologies. Based on our extensive analysis of the effects of sparse (u, v)-coverage, source variability, and interstellar scattering, as well as studies of simulated visibility data, we conclude that the Event Horizon Telescope Sgr A* data show compelling evidence for an image that is dominated by a bright ring of emission with a ring diameter of similar to 50 mu as, consistent with the expected "shadow" of a 4 x 10(6) M (circle dot) black hole in the Galactic center located at a distance of 8 kpc.
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11.
  • Akiyama, Kazunori, et al. (author)
  • First Sagittarius A* Event Horizon Telescope Results. IV. Variability, Morphology, and Black Hole Mass
  • 2022
  • In: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8213 .- 2041-8205. ; 930:2
  • Journal article (peer-reviewed)abstract
    • In this paper we quantify the temporal variability and image morphology of the horizon-scale emission from Sgr A*, as observed by the EHT in 2017 April at a wavelength of 1.3 mm. We find that the Sgr A* data exhibit variability that exceeds what can be explained by the uncertainties in the data or by the effects of interstellar scattering. The magnitude of this variability can be a substantial fraction of the correlated flux density, reaching similar to 100% on some baselines. Through an exploration of simple geometric source models, we demonstrate that ring-like morphologies provide better fits to the Sgr A* data than do other morphologies with comparable complexity. We develop two strategies for fitting static geometric ring models to the time-variable Sgr A* data; one strategy fits models to short segments of data over which the source is static and averages these independent fits, while the other fits models to the full data set using a parametric model for the structural variability power spectrum around the average source structure. Both geometric modeling and image-domain feature extraction techniques determine the ring diameter to be 51.8 +/- 2.3 mu as (68% credible intervals), with the ring thickness constrained to have an FWHM between similar to 30% and 50% of the ring diameter. To bring the diameter measurements to a common physical scale, we calibrate them using synthetic data generated from GRMHD simulations. This calibration constrains the angular size of the gravitational radius to be 4.8(-0.7)(+1.4) mu as, which we combine with an independent distance measurement from maser parallaxes to determine the mass of Sgr A* to be 4.0(-0.6)(+1.1) x 10(6) M-circle dot.
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12.
  • Akiyama, Kazunori, et al. (author)
  • First Sagittarius A* Event Horizon Telescope Results. V. Testing Astrophysical Models of the Galactic Center Black Hole
  • 2022
  • In: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8213 .- 2041-8205. ; 930:2
  • Journal article (peer-reviewed)abstract
    • In this paper we provide a first physical interpretation for the Event Horizon Telescope's (EHT) 2017 observations of Sgr A*. Our main approach is to compare resolved EHT data at 230 GHz and unresolved non-EHT observations from radio to X-ray wavelengths to predictions from a library of models based on time-dependent general relativistic magnetohydrodynamics simulations, including aligned, tilted, and stellar-wind-fed simulations; radiative transfer is performed assuming both thermal and nonthermal electron distribution functions. We test the models against 11 constraints drawn from EHT 230 GHz data and observations at 86 GHz, 2.2 mu m, and in the X-ray. All models fail at least one constraint. Light-curve variability provides a particularly severe constraint, failing nearly all strongly magnetized (magnetically arrested disk (MAD)) models and a large fraction of weakly magnetized models. A number of models fail only the variability constraints. We identify a promising cluster of these models, which are MAD and have inclination i <= 30 degrees. They have accretion rate (5.2-9.5) x 10(-9) M (circle dot) yr(-1), bolometric luminosity (6.8-9.2) x 10(35) erg s(-1), and outflow power (1.3-4.8) x 10(38) erg s(-1). We also find that all models with i >= 70 degrees fail at least two constraints, as do all models with equal ion and electron temperature; exploratory, nonthermal model sets tend to have higher 2.2 mu m flux density; and the population of cold electrons is limited by X-ray constraints due to the risk of bremsstrahlung overproduction. Finally, we discuss physical and numerical limitations of the models, highlighting the possible importance of kinetic effects and duration of the simulations.
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13.
  • Akiyama, Kazunori, et al. (author)
  • First Sagittarius A* Event Horizon Telescope Results. VI. Testing the Black Hole Metric
  • 2022
  • In: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8213 .- 2041-8205. ; 930:2
  • Journal article (peer-reviewed)abstract
    • Astrophysical black holes are expected to be described by the Kerr metric. This is the only stationary, vacuum, axisymmetric metric, without electromagnetic charge, that satisfies Einstein's equations and does not have pathologies outside of the event horizon. We present new constraints on potential deviations from the Kerr prediction based on 2017 EHT observations of Sagittarius A* (Sgr A*). We calibrate the relationship between the geometrically defined black hole shadow and the observed size of the ring-like images using a library that includes both Kerr and non-Kerr simulations. We use the exquisite prior constraints on the mass-to-distance ratio for Sgr A* to show that the observed image size is within similar to 10% of the Kerr predictions. We use these bounds to constrain metrics that are parametrically different from Kerr, as well as the charges of several known spacetimes. To consider alternatives to the presence of an event horizon, we explore the possibility that Sgr A* is a compact object with a surface that either absorbs and thermally reemits incident radiation or partially reflects it. Using the observed image size and the broadband spectrum of Sgr A*, we conclude that a thermal surface can be ruled out and a fully reflective one is unlikely. We compare our results to the broader landscape of gravitational tests. Together with the bounds found for stellar-mass black holes and the M87 black hole, our observations provide further support that the external spacetimes of all black holes are described by the Kerr metric, independent of their mass.
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14.
  • Broderick, Avery E., et al. (author)
  • Characterizing and Mitigating Intraday Variability: Reconstructing Source Structure in Accreting Black Holes with mm-VLBI
  • 2022
  • In: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8213 .- 2041-8205. ; 930:2
  • Journal article (peer-reviewed)abstract
    • The extraordinary physical resolution afforded by the Event Horizon Telescope has opened a window onto the astrophysical phenomena unfolding on horizon scales in two known black holes, M87* and Sgr A*. However, with this leap in resolution has come a new set of practical complications. Sgr A* exhibits intraday variability that violates the assumptions underlying Earth aperture synthesis, limiting traditional image reconstruction methods to short timescales and data sets with very sparse (u, v) coverage. We present a new set of tools to detect and mitigate this variability. We develop a data-driven, model-agnostic procedure to detect and characterize the spatial structure of intraday variability. This method is calibrated against a large set of mock data sets, producing an empirical estimator of the spatial power spectrum of the brightness fluctuations. We present a novel Bayesian noise modeling algorithm that simultaneously reconstructs an average image and statistical measure of the fluctuations about it using a parameterized form for the excess variance in the complex visibilities not otherwise explained by the statistical errors. These methods are validated using a variety of simulated data, including general relativistic magnetohydrodynamic simulations appropriate for Sgr A* and M87*. We find that the reconstructed source structure and variability are robust to changes in the underlying image model. We apply these methods to the 2017 EHT observations of M87*, finding evidence for variability across the EHT observing campaign. The variability mitigation strategies presented are widely applicable to very long baseline interferometry observations of variable sources generally, for which they provide a data-informed averaging procedure and natural characterization of inter-epoch image consistency.
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15.
  • Issaoun, Sara, et al. (author)
  • Resolving the Inner Parsec of the Blazar J1924-2914 with the Event Horizon Telescope
  • 2022
  • In: Astrophysical Journal. - : American Astronomical Society. - 1538-4357 .- 0004-637X. ; 934:2
  • Journal article (peer-reviewed)abstract
    • The blazar J1924-2914 is a primary Event Horizon Telescope (EHT) calibrator for the Galactic center's black hole Sagittarius A*. Here we present the first total and linearly polarized intensity images of this source obtained with the unprecedented 20 mu as resolution of the EHT. J1924-2914 is a very compact flat-spectrum radio source with strong optical variability and polarization. In April 2017 the source was observed quasi-simultaneously with the EHT (April 5-11), the Global Millimeter VLBI Array (April 3), and the Very Long Baseline Array (April 28), giving a novel view of the source at four observing frequencies, 230, 86, 8.7, and 2.3 GHz. These observations probe jet properties from the subparsec to 100 pc scales. We combine the multifrequency images of J1924-2914 to study the source morphology. We find that the jet exhibits a characteristic bending, with a gradual clockwise rotation of the jet projected position angle of about 90 degrees between 2.3 and 230 GHz. Linearly polarized intensity images of J1924-2914 with the extremely fine resolution of the EHT provide evidence for ordered toroidal magnetic fields in the blazar compact core.
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16.
  • Kattge, Jens, et al. (author)
  • TRY plant trait database - enhanced coverage and open access
  • 2020
  • In: Global Change Biology. - : Wiley-Blackwell. - 1354-1013 .- 1365-2486. ; 26:1, s. 119-188
  • Journal article (peer-reviewed)abstract
    • Plant traits-the morphological, anatomical, physiological, biochemical and phenological characteristics of plants-determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait-based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits-almost complete coverage for 'plant growth form'. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait-environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives.
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17.
  • Teslovich, Tanya M., et al. (author)
  • Biological, clinical and population relevance of 95 loci for blood lipids
  • 2010
  • In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 466:7307, s. 707-713
  • Journal article (peer-reviewed)abstract
    • Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P<5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.
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18.
  • Torne, Pablo, et al. (author)
  • A Search for Pulsars around Sgr A* in the First Event Horizon Telescope Data Set
  • 2023
  • In: Astrophysical Journal. - 1538-4357 .- 0004-637X. ; 959:1
  • Journal article (peer-reviewed)abstract
    • In 2017 the Event Horizon Telescope (EHT) observed the supermassive black hole at the center of the Milky Way, Sagittarius A* (Sgr A*), at a frequency of 228.1 GHz (lambda = 1.3 mm). The fundamental physics tests that even a single pulsar orbiting Sgr A* would enable motivate searching for pulsars in EHT data sets. The high observing frequency means that pulsars-which typically exhibit steep emission spectra-are expected to be very faint. However, it also negates pulse scattering, an effect that could hinder pulsar detections in the Galactic center. Additionally, magnetars or a secondary inverse Compton emission could be stronger at millimeter wavelengths than at lower frequencies. We present a search for pulsars close to Sgr A* using the data from the three most sensitive stations in the EHT 2017 campaign: the Atacama Large Millimeter/submillimeter Array, the Large Millimeter Telescope, and the IRAM 30 m Telescope. We apply three detection methods based on Fourier-domain analysis, the fast folding algorithm, and single-pulse searches targeting both pulsars and burst-like transient emission. We use the simultaneity of the observations to confirm potential candidates. No new pulsars or significant bursts were found. Being the first pulsar search ever carried out at such high radio frequencies, we detail our analysis methods and give a detailed estimation of the sensitivity of the search. We conclude that the EHT 2017 observations are only sensitive to a small fraction (less than or similar to 2.2%) of the pulsars that may exist close to Sgr A*, motivating further searches for fainter pulsars in the region.
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19.
  • Wielgus, Maciek, et al. (author)
  • Millimeter Light Curves of Sagittarius A* Observed during the 2017 Event Horizon Telescope Campaign
  • 2022
  • In: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8213 .- 2041-8205. ; 930:2
  • Journal article (peer-reviewed)abstract
    • The Event Horizon Telescope (EHT) observed the compact radio source, Sagittarius A* (Sgr A*), in the Galactic Center on 2017 April 5-11 in the 1.3 mm wavelength band. At the same time, interferometric array data from the Atacama Large Millimeter/submillimeter Array and the Submillimeter Array were collected, providing Sgr A* light curves simultaneous with the EHT observations. These data sets, complementing the EHT very long baseline interferometry, are characterized by a cadence and signal-to-noise ratio previously unattainable for Sgr A* at millimeter wavelengths, and they allow for the investigation of source variability on timescales as short as a minute. While most of the light curves correspond to a low variability state of Sgr A*, the April 11 observations follow an X-ray flare and exhibit strongly enhanced variability. All of the light curves are consistent with a red-noise process, with a power spectral density (PSD) slope measured to be between -2 and -3 on timescales between 1 minute and several hours. Our results indicate a steepening of the PSD slope for timescales shorter than 0.3 hr. The spectral energy distribution is flat at 220 GHz, and there are no time lags between the 213 and 229 GHz frequency bands, suggesting low optical depth for the event horizon scale source. We characterize Sgr A*'s variability, highlighting the different behavior observed just after the X-ray flare, and use Gaussian process modeling to extract a decorrelation timescale and a PSD slope. We also investigate the systematic calibration uncertainties by analyzing data from independent data reduction pipelines.
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20.
  • Beal, Jacob, et al. (author)
  • Robust estimation of bacterial cell count from optical density
  • 2020
  • In: Communications Biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 3:1
  • Journal article (peer-reviewed)abstract
    • Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data.
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21.
  • Farmakis, Dimitrios, et al. (author)
  • Impact of left ventricular ejection fraction phenotypes on healthcare resource utilization in hospitalized heart failure: a secondary analysis of REPORT-HF
  • 2023
  • In: European Journal of Heart Failure. - : WILEY. - 1388-9842 .- 1879-0844. ; 25:6, s. 818-828
  • Journal article (peer-reviewed)abstract
    • Aim Evidence on healthcare resource utilization (HCRU) for hospitalized patients with heart failure (HF) and reduced (HFrEF), mildly reduced (HFmrEF) and preserved (HFpEF) ejection fraction is limited.Methods and results We analysed HCRU in relation to left ventricular ejection fraction (LVEF) phenotypes, clinical features and in-hospital and 12-month outcomes in 16 943 patients hospitalized for HF in a worldwide registry. HFrEF was more prevalent (53%) than HFmrEF (17%) or HFpEF (30%). Patients with HFmrEF and HFpEF were older, more often women, with milder symptoms and more comorbidities, but differences were not pronounced. HCRU was high in all three groups; two or more in- and out-of-hospital services were required by 51%, 49% and 52% of patients with HFrEF, HFmrEF and HFpEF, respectively, and intensive care unit by 41%, 41% and 37%, respectively. Hospitalization length was similar (median, 8 days). Discharge prescription of neurohormonal inhibitors was <80% for each agent in HFrEF and only slightly lower in HFmrEF and HFpEF (74% and 67%, respectively, for beta-blockers). Compared to HFrEF, 12-month all-cause and cardiovascular mortality were lower for HFmrEF (adjusted hazard ratios 0.78 [95% confidence interval 0.59-0.71] and 0.80 [0.70-0.92]) and HFpEF (0.64 [0.59-0.87] and 0.63 [0.56-0.71]); 12-month HF hospitalization was also lower for HFpEF and HFmrEF (21% and 20% vs. 25% for HFrEF). In-hospital mortality, 12-month non-cardiovascular mortality and 12-month all-cause hospitalization were similar among groups.Conclusions In patients hospitalized for HF, overall HCRU was similarly high across LVEF spectrum, reflecting the subtle clinical differences among LVEF phenotypes during hospitalization. Discharge prescription of neurohormonal inhibitors was suboptimal in HFrEF and lower but significant in patients with HFpEF and HFmrEF, who had better long-term cardiovascular outcomes than HFrEF, but similar risk for non-cardiovascular events.
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22.
  • Zewinger, Stephen, et al. (author)
  • Relations between lipoprotein(a) concentrations, LPA genetic variants, and the risk of mortality in patients with established coronary heart disease : a molecular and genetic association study
  • 2017
  • In: The Lancet Diabetes and Endocrinology. - : ELSEVIER SCIENCE INC. - 2213-8587 .- 2213-8595. ; 5:7, s. 534-543
  • Journal article (peer-reviewed)abstract
    • Background: Lipoprotein(a) concentrations in plasma are associated with cardiovascular risk in the general population. Whether lipoprotein(a) concentrations or LPA genetic variants predict long-term mortality in patients with established coronary heart disease remains less clear.Methods: We obtained data from 3313 patients with established coronary heart disease in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. We tested associations of tertiles of lipoprotein(a) concentration in plasma and two LPA single-nucleotide polymorphisms ([SNPs] rs10455872 and rs3798220) with all-cause mortality and cardiovascular mortality by Cox regression analysis and with severity of disease by generalised linear modelling, with and without adjustment for age, sex, diabetes diagnosis, systolic blood pressure, BMI, smoking status, estimated glomerular filtration rate, LDL-cholesterol concentration, and use of lipid-lowering therapy. Results for plasma lipoprotein(a) concentrations were validated in five independent studies involving 10 195 patients with established coronary heart disease. Results for genetic associations were replicated through large-scale collaborative analysis in the GENIUS-CHD consortium, comprising 106 353 patients with established coronary heart disease and 19 332 deaths in 22 studies or cohorts.Findings: The median follow-up was 9.9 years. Increased severity of coronary heart disease was associated with lipoprotein(a) concentrations in plasma in the highest tertile (adjusted hazard radio [HR] 1.44, 95% CI 1.14-1.83) and the presence of either LPA SNP (1.88, 1.40-2.53). No associations were found in LURIC with all-cause mortality (highest tertile of lipoprotein(a) concentration in plasma 0.95, 0.81-1.11 and either LPA SNP 1.10, 0.92-1.31) or cardiovascular mortality (0.99, 0.81-1.2 and 1.13, 0.90-1.40, respectively) or in the validation studies.Interpretation: In patients with prevalent coronary heart disease, lipoprotein(a) concentrations and genetic variants showed no associations with mortality. We conclude that these variables are not useful risk factors to measure to predict progression to death after coronary heart disease is established.
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23.
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24.
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25.
  • Andreoli, L., et al. (author)
  • COVID-19 VACCINE SAFETY DURING PREGNANCY AND BREASTFEEDING IN WOMEN WITH AUTOIMMUNE DISEASES : RESULTS FROM THE COVAD STUDY
  • 2023
  • In: Annals of the Rheumatic Diseases. - : HighWire Press. - 0003-4967 .- 1468-2060. ; 82:Suppl. 1, s. 56-57
  • Journal article (other academic/artistic)abstract
    • Background: COVID-19 vaccine hesitancy among pregnant and breastfeeding women with autoimmune diseases (AID) is often attributed to the fear of adverse events (AE) and disease flares (DF). No data are available regarding COVID-19 vaccine safety in this population.Objectives: We aimed at describing delayed-onset (>7 days) vaccine-related AE (minor and major), DF, and related AID treatment modifications from the COVID-19 Vaccination in Autoimmune Diseases (COVAD) study.Methods: Among complete responses from 9201 participants as of June 21, 2022, 6787 (73.8%) were women. Six subgroups were identified upon diagnosis of AID vs healthy controls (HC) and their pregnancy/breastfeeding status at the time of any dose of vaccine (Figure 1).Results: Forty pregnant and 52 breastfeeding AID patients were identified and their vaccination rates (at least one dose) was 100% and 96.2%, respectively (Table 1). Overall AE, minor AE, and major AE were reported significantly more frequently by pregnant than non-pregnant patients (45% vs. 26%, p=0.01; 40% vs. 25.9%, p=0.03; 17.5% vs. 4.6%, p<0.01), but no difference was found in comparison with pregnant HC. No difference was observed between breastfeeding patients and HC. Post-vaccination DF were reported by 17.5% of pregnant and 20% of breastfeeding patients, and by 18% of age- and disease-matched control patients (n=2315). All DF in pregnant/breastfeeding patients were managed with glucocorticoids and a fifth of them required initiation or change in immunosuppressive treatment.Conclusion: This study provides the first insights into the safety of COVID-19 vaccination during the antenatal period in women with AID. While AEs were more commonly reported by pregnant patients with AID, these were no higher than among pregnant healthy controls without AID. These observations are reassuring, likely to strengthen physician-patient communication and overcome hesitancy as the benefits for the mother and fetus by passive immunization are likely to overweigh the potential risks of AE and DF.Reference: [1]Fazal ZZ, et al; COVAD Study Group. COVAD survey 2 long-term outcomes: unmet need and protocol. Rheumatol Int 2022; 42:2151-2158.
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26.
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27.
  • Dyrek, Achrène, et al. (author)
  • SO2, silicate clouds, but no CH4 detected in a warm Neptune
  • 2024
  • In: Nature. - 0028-0836 .- 1476-4687. ; 625, s. 51-54
  • Journal article (peer-reviewed)abstract
    • WASP-107b is a warm (approximately 740 K) transiting planet with a Neptune-like mass of roughly 30.5 M⊕ and Jupiter-like radius of about 0.94 RJ (refs. 1,2), whose extended atmosphere is eroding3. Previous observations showed evidence for water vapour and a thick, high-altitude condensate layer in the atmosphere of WASP-107b (refs. 4,5). Recently, photochemically produced sulfur dioxide (SO2) was detected in the atmosphere of a hot (about 1,200 K) Saturn-mass planet from transmission spectroscopy near 4.05 μm (refs. 6,7), but for temperatures below about 1,000 K, sulfur is predicted to preferably form sulfur allotropes instead of SO2 (refs. 8,9,10). Here we report the 9σ detection of two fundamental vibration bands of SO2, at 7.35 μm and 8.69 μm, in the transmission spectrum of WASP-107b using the Mid-Infrared Instrument (MIRI) of JWST. This discovery establishes WASP-107b as the second irradiated exoplanet with confirmed photochemistry, extending the temperature range of exoplanets exhibiting detected photochemistry from about 1,200 K down to about 740 K. Furthermore, our spectral analysis reveals the presence of silicate clouds, which are strongly favoured (around 7σ) over simpler cloud set-ups. Furthermore, water is detected (around 12σ) but methane is not. These findings provide evidence of disequilibrium chemistry and indicate a dynamically active atmosphere with a super-solar metallicity.
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28.
  • Fountoulakis, Konstantinos N., et al. (author)
  • Gender, age at onset, and duration of being ill as predictors for the long-term course and outcome of schizophrenia : an international multicenter study
  • 2022
  • In: CNS Spectrums. - : CAMBRIDGE UNIV PRESS. - 1092-8529 .- 2165-6509. ; 27:6, s. 716-723
  • Journal article (peer-reviewed)abstract
    • Background The aim of the current study was to explore the effect of gender, age at onset, and duration on the long-term course of schizophrenia. Methods Twenty-nine centers from 25 countries representing all continents participated in the study that included 2358 patients aged 37.21 +/- 11.87 years with a DSM-IV or DSM-5 diagnosis of schizophrenia; the Positive and Negative Syndrome Scale as well as relevant clinicodemographic data were gathered. Analysis of variance and analysis of covariance were used, and the methodology corrected for the presence of potentially confounding effects. Results There was a 3-year later age at onset for females (P < .001) and lower rates of negative symptoms (P < .01) and higher depression/anxiety measures (P < .05) at some stages. The age at onset manifested a distribution with a single peak for both genders with a tendency of patients with younger onset having slower advancement through illness stages (P = .001). No significant effects were found concerning duration of illness. Discussion Our results confirmed a later onset and a possibly more benign course and outcome in females. Age at onset manifested a single peak in both genders, and surprisingly, earlier onset was related to a slower progression of the illness. No effect of duration has been detected. These results are partially in accord with the literature, but they also differ as a consequence of the different starting point of our methodology (a novel staging model), which in our opinion precluded the impact of confounding effects. Future research should focus on the therapeutic policy and implications of these results in more representative samples.
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29.
  • Grant, Sierra L., et al. (author)
  • MINDS. The Detection of 13 CO 2 with JWST-MIRI Indicates Abundant CO 2 in a Protoplanetary Disk
  • 2023
  • In: Astrophysical Journal Letters. - 2041-8213 .- 2041-8205. ; 947:1
  • Journal article (peer-reviewed)abstract
    • We present JWST-MIRI Medium Resolution Spectrometer (MRS) spectra of the protoplanetary disk around the low-mass T Tauri star GW Lup from the MIRI mid-INfrared Disk Survey Guaranteed Time Observations program. Emission from 12CO213CO2, H2O, HCN, C2H2, and OH is identified with 13CO2 being detected for the first time in a protoplanetary disk. We characterize the chemical and physical conditions in the inner few astronomical units of the GW Lup disk using these molecules as probes. The spectral resolution of JWST-MIRI MRS paired with high signal-to-noise data is essential to identify these species and determine their column densities and temperatures. The Q branches of these molecules, including those of hot bands, are particularly sensitive to temperature and column density. We find that the 12CO2 emission in the GW Lup disk is coming from optically thick emission at a temperature of ∼400 K. 13CO2 is optically thinner and based on a lower temperature of ∼325 K, and thus may be tracing deeper into the disk and/or a larger emitting radius than 12CO2. The derived N CO 2 / N H 2 O ratio is orders of magnitude higher than previously derived for GW Lup and other targets based on Spitzer-InfraRed-Spectrograph data. This high column density ratio may be due to an inner cavity with a radius in between the H2O and CO2 snowlines and/or an overall lower disk temperature. This paper demonstrates the unique ability of JWST to probe inner disk structures and chemistry through weak, previously unseen molecular features.
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30.
  • Holloway, A., et al. (author)
  • EVALUATING GLOBAL PATTERNS IN TREATMENT AND PREVALENCE OF COMORBIDITIES IN SYSTEMIC LUPUS ERYTHEMATOSUS
  • 2023
  • In: Annals of the Rheumatic Diseases. - : HighWire Press. - 0003-4967 .- 1468-2060. ; 82:Suppl. 1, s. 1456-1458
  • Journal article (other academic/artistic)abstract
    • Background: Regional disparities in the management of systemic lupus erythematosus (SLE) are frequently described. Governance, funding, logistic barriers, and physician choice may be important determinants though scarce data from underrepresented regions limits our understanding.Objectives: To evaluate global patterns in treatment of SLE and identify the prevalence of comorbidities.Methods: We identified SLE patients from the COVAD 2 database, consisting of over 20,000 respondents worldwide. Healthy controls (HC) were included to assess population comorbidity levels. Demographics, treatment i.e., corticosteroids (CS), antimalarials, immunosuppressants (IS), cyclophosphamide and biologics plus comorbidity data was recorded. Country Human Development Index (HDI) classification, a composite index formulated by the United Nations to rank countries into tiers of development, was utilised.Results: 3323 HCs and 1167 SLE patients were included in analysis. Patients from low/medium HDI (lmHDI) countries were younger than those from high/very high HDI (hvhHDI) countries (median age 32, IQR 27-41 vs 41, IQR 32-52 years, p<0.0001). Disease duration was shorter in lmHDI countries (median 5, IQR 3-10 vs 10, IQR 5-19 years, p<0.0001).A higher proportion of SLE patients from lmHDI countries were on CS (73% vs 59%, p=0.0002), antimalarials (81% vs 68%, p=0.0002) and IS (66% vs 53%, p=0.0009) compared with patients from hvhHDI countries. Choice of IS varied with azathioprine prescribed more frequently in lmHDI countries (p=0.049). Biologics use was more common in hvhHDI countries (7% vs 2%, p=0.0055). Comorbidity prevalence was similar between groups, however when adjusted for age, patients with chronic kidney disease were significantly younger in lmHDI countries (36.67 vs 44.64 years, p=0.015), as were patients with coronary artery disease (35.7 vs. 44.6 years, p=0.015) and hypertension (41.5 vs 49.8 years, p=0.003). Results are detailed in Table 1.Conclusion: To our knowledge, this is the largest study evaluating treatment and comorbidity incidence in SLE populations based on country HDI. We identified striking differences in pharmacological management globally. Cardiovascular comorbidities were seen in younger patients and earlier in the disease course in lmHDI countries, suggestive of premature organ damage. This could be due to limited global access to high-cost medication and increasing access may improve outcomes. Our results call for review of cardiovascular risk guidelines and regional approaches to preventive action as well as pharmacological and non-pharmacological management of patients with established cardiovascular comorbidity.
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31.
  • Karampotsis, Evangelos, et al. (author)
  • Computational intelligence techniques for modelling the critical flashover voltage of insulators : From accuracy to comprehensibility
  • 2017
  • In: Advances in Artificial Intelligence: From Theory to Practice. - Cham : Springer. - 9783319600413 - 9783319600420 ; , s. 295-301
  • Conference paper (peer-reviewed)abstract
    • This paper copes with the problem of flashover voltage on polluted insulators, being one of the most important components of electric power systems. Α number of appropriately selected computational intelligence techniques are developed and applied for the modelling of the problem. Some of the applied techniques work as black-box models, but they are capable of achieving highly accurate results (artificial neural networks and gravitational search algorithms). Other techniques, on the contrary, obtain results somewhat less accurate, but highly comprehensible (genetic programming and inductive decision trees). However, all the applied techniques outperform standard data analysis approaches, such as regression models. The variables used in the analyses are the insulator’s maximum diameter, height, creepage distance, insulator’s manufacturing constant, and also the insulator’s pollution. In this research work the critical flashover voltage on a polluted insulator is expressed as a function of the aforementioned variables. The used database consists of 168 different cases of polluted insulators, created through both actual and simulated values. Results are encouraging, with room for further study, aiming towards the development of models for the proper inspection and maintenance of insulators.
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32.
  • Labiano, A., et al. (author)
  • Wavelength calibration and resolving power of the JWST MIRI Medium Resolution Spectrometer
  • 2021
  • In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 656
  • Journal article (peer-reviewed)abstract
    • Context. The Mid-Infrared Instrument (MIRI) onboard the James Webb Space Telescope (JWST) will provide imaging, coronagraphy, low-resolution spectroscopy, and medium-resolution spectroscopy at unprecedented sensitivity levels in the mid-infrared wavelength range. The Medium Resolution Spectrometer (MRS) of MIRI is an integral field spectrograph that provides diffraction-limited spectroscopy between 4.9 and 28.3 μm, within a field of view (FOV) varying from ∼13 to ∼56 arcsec square. The design for MIRI MRS conforms with the goals of the JWST mission to observe high redshift galaxies and to study cosmology as well as observations of galactic objects, and stellar and planetary systems. Aims. From ground testing, we calculate the physical parameters essential for general observers and calibrating the wavelength solution and resolving power of the MRS which is critical for maximizing the scientific performance of the instrument. Methods. We have used ground-based observations of discrete spectral features in combination with Fabry-Perot etalon spectra to characterize the wavelength solution and spectral resolving power of the MRS. We present the methodology used to derive the MRS spectral characterization, which includes the precise wavelength coverage of each MRS sub-band, computation of the resolving power as a function of wavelength, and measuring slice-dependent spectral distortions. Results. The ground calibration of the MRS shows that it will cover the wavelength ranges from 4.9 to 28.3 μm, divided in 12 overlapping spectral sub-bands. The resolving power is R 3500 in channel 1, R 3000 in channel 2, R 2500 in channel 3, and R 1500 in channel 4. The MRS spectral resolution optimizes the sensitivity for detection of spectral features with a velocity width of ∼100 km s-1 which is characteristic of most astronomical phenomena JWST aims to study in the mid-infrared. Based on the ground test data, the wavelength calibration accuracy is estimated to be below one-tenth of a pixel (0.1 nm at 5 μm and 0.4 at 28 μm), with small systematic shifts due to the target position within a slice for unresolved sources that have a maximum amplitude of about 0.25 spectral resolution elements. The absolute wavelength calibration is presently uncertain at the level of 0.35 nm at 5 μm and 46 nm at 28 μm, and it will be refined using in-flight commissioning observations. Conclusions. Based on ground test data, the MRS complies with the spectral requirements for both the R and wavelength accuracy for which it was designed. We also present the commissioning strategies and targets that will be followed to update the spectral characterization of the MRS.
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33.
  • Langeveld, H., et al. (author)
  • Assessing Environmental Impacts of Short Rotation Coppice (SRC) Expansion: Model Definition and Preliminary Results
  • 2012
  • In: Bioenergy Research. - : Springer Science and Business Media LLC. - 1939-1234 .- 1939-1242. ; 5:3, s. 621-635
  • Journal article (peer-reviewed)abstract
    • Short rotation coppice (SRC) systems can play a role as feedstock for bioenergy supply contributing to EU energy and climate policy targets. A scenario depicting intensive arable crop cultivation in a homogeneous landscape (lacking habitat structures) was compared to a scenario including SRC cultivation on 20 % of arable land. A range of indicators was selected to assess the consequences of SRC on soil, water and biodiversity, using data from the Rating-SRC project (Sweden and Germany). The results of the assessment were presented using spider diagrams. Establishment and use of SRC for bioenergy has both positive and negative effects. The former include increased carbon sequestration and reduced GHG emissions as well as reduced soil erosion, groundwater nitrate and surface runoff. SRC can be used in phytoremediation and improves plant and breeding bird biodiversity (exceptions: grassland and arable land species) but should not be applied in dry areas or on soils high in toxic trace elements (exception: cadmium). The scenario-based analysis was found useful for studying the consequences of SRC cultivation at larger scales. Limitations of the approach are related to data requirements and compatibility and its restricted ability to cover spatial diversity and dynamic processes. The findings should not be generalised beyond the representativeness of the data used.
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34.
  • Lee, S. Y., et al. (author)
  • IDENTIFYING DETERMINANTS OF FAVOURABLE AND POOR PHYSICAL FUNCTION IN SYSTEMIC LUPUS ERYTHEMATOSUS : RESULTS FROM AN INTERNATIONAL COLLABORATIVE STUDY
  • 2023
  • In: Annals of the Rheumatic Diseases. - : HighWire Press. - 0003-4967 .- 1468-2060. ; 82:Suppl. 1, s. 1110-1112
  • Journal article (other academic/artistic)abstract
    • Background: Systemic lupus erythematosus (SLE) can result in impaired daily physical function through various mechanisms including active disease, chronic damage, and mental health symptoms that are common in the disease. However, the key drivers of reduced physical function are poorly understood, and no large-scale global studies investigating this have been conducted to date.Objectives: To investigate key factors that contribute to impaired physical function in SLE globally.Methods: SLE patients were identified from the COVAD 2 database, a global register of more than 20,000 respondents. Healthy controls (HC) were included to compare differences in physical function using the Patient Reported Outcome Measurement Information System (PROMIS) questionnaire. Demographics, medication, comorbidities, disease activity, Global Physical Health (GPH) and Global Mental Health (GMH) were collected. Multivariable regression analysis was used to identify contributing factors to favourable or poor physical function (measured by PROMIS Physical Function shortform PF-10a score).Results: 979 SLE patients and 3358 HCs were included in analysis. Patients with SLE had significantly lower PF-10a score as compared to HCs (median 42, IQR 36-47 vs median 49, IQR 45-50, p<0.0001). Determinants of physical function status in patients with SLE are summarised in Table 1. Briefly, factors associated with poor physical function included increasing age (-0.042, 95% CI -0.069 to -0.015, p=0.002) and methotrexate use (-0.928, 95% CI -1.844 to -0.012, p=0.047). Diabetes (-1.862, 95% CI -3.481 to -0.243, p=0.024) and interstitial lung disease (ILD) (-2.441, 95% CI -4.366 to -0.517, p=0.013), but not asthma or COPD, also contributed to lower PF-10a score. From a mental health perspective, anxiety (-0.970, 95% CI -1.853 to -0.087, p=0.031) but not depression contributed to a lower physical function score. Higher Pain Visual Analogue Scales (VAS) (-2.889, 95% CI -3.107 to -2.671, p<0.001) and Fatigue VAS (-1.459, 95% CI -1.974 to -0.945, p<0.001) also contributed to lower PF-10 scores. Hydroxychloroquine use (0.844, 95% CI 0.190 to 1.498, p=0.012) and higher GPH score (2.287, 95% CI 2.079 to 2.494, p<0.001) were associated with favourable physical function.Conclusion: Patients with SLE show significantly reduced physical function compared with HCs. Key contributors to poor physical function include intercurrent diabetes and ILD. Screening for, and aggressive early treatment of these conditions may confer improved long-term function. As expected, higher levels of pain and fatigue were associated with poor physical function. Methotrexate use was also identified as a contributing factor to reduced function, which could represent its use in articular manifestations that limit physical function. Importantly, use of hydroxychloroquine was associated with favourable physical function, adding to the well-recognised benefits of this drug in SLE.
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35.
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36.
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37.
  • Papalampros, Alexandros, et al. (author)
  • Unique Spatial Immune Profiling in Pancreatic Ductal Adenocarcinoma with Enrichment of Exhausted and Senescent T Cells and Diffused CD47-SIRP proportional to Expression
  • 2020
  • In: Cancers. - : MDPI AG. - 2072-6694. ; 12:7
  • Journal article (peer-reviewed)abstract
    • Background: Pancreatic ductal adenocarcinoma (PDAC) is resistant to single-agent immunotherapies. To understand the mechanisms leading to the poor response to this treatment, a better understanding of the PDAC immune landscape is required. The present work aims to study the immune profile in PDAC in relationship to spatial heterogeneity of the tissue microenvironment (TME) in intact tissues. Methods: Serial section and multiplex in situ analysis were performed in 42 PDAC samples to assess gene and protein expression at single-cell resolution in the: (a) tumor center (TC), (b) invasive front (IF), (c) normal parenchyma adjacent to the tumor, and (d) tumor positive and negative draining lymph nodes (LNs). Results: We observed: (a) enrichment of T cell subpopulations with exhausted and senescent phenotype in the TC, IF and tumor positive LNs; (b) a dominant type 2 immune response in the TME, which is more pronounced in the TC; (c) an emerging role of CD47-SIRP a axis; and (d) a similar immune cell topography independently of the neoadjuvant chemotherapy. Conclusion: This study reveals the existence of dysfunctional T lymphocytes with specific spatial distribution, thus opening a new dimension both conceptually and mechanistically in tumor-stroma interaction in PDAC with potential impact on the efficacy of immune-regulatory therapeutic modalities.
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38.
  • Pappis, Ioannis, et al. (author)
  • Implications to the electricity system of Paraguay of different demand scenarios and export prices to Brazil
  • 2021
  • In: Energy Systems, Springer Verlag. - : Springer Science and Business Media Deutschland GmbH. - 1868-3967 .- 1868-3975.
  • Journal article (peer-reviewed)abstract
    • Paraguay's power system is based entirely on hydropower. It serves as the largest net electricity exporter in Latin America. Nonetheless, the country´s electricity consumption per capita is one of the lowest in the world and the transmission and distribution network has one of the highest losses in Latin America. This paper presents an electricity expansion investment outlook (2018–2040) for Paraguay using OSeMOSYS, analyzing three electricity demand scenarios under different electricity export prices to Brazil. The study identifies the least-cost power generation mix, future investments and the financial requirements to meet the needs of different demand scenarios. We find that Paraguay will need to invest in hydropower plants, by mainly expanding the capacity of Yacyreta to cover its electricity needs and sustain national electricity exports levels. In the High demand scenario, where the electricity demand could approximately double by 2040, the country's overall electricity exports decrease by 50% compared to the Reference scenario. Based on the different scenarios examined, the government spends approximately 18.3–31.2 billion USD on power plant investments for the period 2018–2040 to cover future electricity demand. The findings could be useful in supporting decision-making concerning socio-economic development pathways in the country.
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39.
  • Pateras, Ioannis S., et al. (author)
  • Diagnostic challenges during inflammation and cancer : current biomarkers and future perspectives in navigating through the minefield of reactive versus dysplastic and cancerous lesions in the digestive system
  • 2024
  • In: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 25:2
  • Research review (peer-reviewed)abstract
    • In the setting of pronounced inflammation, changes in the epithelium may overlap with neoplasia, often rendering it impossible to establish a diagnosis with certainty in daily clinical practice. Here, we discuss the underlying molecular mechanisms driving tissue response during persistent inflammatory signaling along with the potential association with cancer in the gastrointestinal tract, pancreas, extrahepatic bile ducts, and liver. We highlight the histopathological challenges encountered in the diagnosis of chronic inflammation in routine practice and pinpoint tissue-based biomarkers that could complement morphology to differentiate reactive from dysplastic or cancerous lesions. We refer to the advantages and limitations of existing biomarkers employing immunohistochemistry and point to promising new markers, including the generation of novel antibodies targeting mutant proteins, miRNAs, and array assays. Advancements in experimental models, including mouse and 3D models, have improved our understanding of tissue response. The integration of digital pathology along with artificial intelligence may also complement routine visual inspections. Navigating through tissue responses in various chronic inflammatory contexts will help us develop novel and reliable biomarkers that will improve diagnostic decisions and ultimately patient treatment.
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40.
  • Pateras, Ioannis S., et al. (author)
  • Short term starvation potentiates the efficacy of chemotherapy in triple negative breast cancer via metabolic reprogramming
  • 2023
  • In: Journal of Translational Medicine. - : BioMed Central (BMC). - 1479-5876. ; 21:1
  • Journal article (peer-reviewed)abstract
    • Background: Chemotherapy (CT) is central to the treatment of triple negative breast cancer (TNBC), but drug toxicity and resistance place strong restrictions on treatment regimes. Fasting sensitizes cancer cells to a range of chemotherapeutic agents and also ameliorates CT-associated adverse effects. However, the molecular mechanism(s) by which fasting, or short-term starvation (STS), improves the efficacy of CT is poorly characterized.Methods: The differential responses of breast cancer or near normal cell lines to combined STS and CT were assessed by cellular viability and integrity assays (Hoechst and PI staining, MTT or H2DCFDA staining, immunofluorescence), metabolic profiling (Seahorse analysis, metabolomics), gene expression (quantitative real-time PCR) and iRNA-mediated silencing. The clinical significance of the in vitro data was evaluated by bioinformatical integration of transcriptomic data from patient data bases: The Cancer Genome Atlas (TCGA), European Genome-phenome Archive (EGA), Gene Expression Omnibus (GEO) and a TNBC cohort. We further examined the translatability of our findings in vivo by establishing a murine syngeneic orthotopic mammary tumor-bearing model.Results: We provide mechanistic insights into how preconditioning with STS enhances the susceptibility of breast cancer cells to CT. We showed that combined STS and CT enhanced cell death and increased reactive oxygen species (ROS) levels, in association with higher levels of DNA damage and decreased mRNA levels for the NRF2 targets genes NQO1 and TXNRD1 in TNBC cells compared to near normal cells. ROS enhancement was associated with compromised mitochondrial respiration and changes in the metabolic profile, which have a significant clinical prognostic and predictive value. Furthermore, we validate the safety and efficacy of combined periodic hypocaloric diet and CT in a TNBC mouse model.Conclusions: Our in vitro, in vivo and clinical findings provide a robust rationale for clinical trials on the therapeutic benefit of short-term caloric restriction as an adjuvant to CT in triple breast cancer treatment.
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41.
  • Terenius, Olle, et al. (author)
  • RNA interference in Lepidoptera : An overview of successful and unsuccessful studies and implications for experimental design
  • 2011
  • In: Journal of insect physiology. - : Elsevier BV. - 0022-1910 .- 1879-1611. ; 57:2, s. 231-245
  • Journal article (peer-reviewed)abstract
    • Gene silencing through RNA interference (RNAi) has revolutionized the study of gene function, particularly in non-model insects. However, in Lepidoptera (moths and butterflies) RNAi has many times proven to be difficult to achieve. Most of the negative results have been anecdotal and the positive experiments have not been collected in such a way that they are possible to analyze. In this review, we have collected detailed data from more than 150 experiments including all to date published and many unpublished experiments. Despite a large variation in the data, trends that are found are that RNAi is particularly successful in the family Saturniidae and in genes involved in immunity. On the contrary, gene expression in epidermal tissues seems to be most difficult to silence. In addition, gene silencing by feeding dsRNA requires high concentrations for success. Possible causes for the variability of success in RNAi experiments in Lepidoptera are discussed. The review also points to a need to further investigate the mechanism of RNAi in lepidopteran insects and its possible connection to the innate immune response. Our general understanding of RNAi in Lepidoptera will be further aided in the future as our public database at http://insectacentral.org/RNAi will continue to gather information on RNAi experiments.
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42.
  • Albshesh, Ahmad, et al. (author)
  • Effectiveness of Third-Class Biologic Treatment in Crohn's Disease : A Multi-Center Retrospective Cohort Study
  • 2021
  • In: Journal of Clinical Medicine. - : MDPI. - 2077-0383. ; 10:13
  • Journal article (peer-reviewed)abstract
    • Background: Multiple studies have described the effectiveness of ustekinumab (UST) and vedolizumab (VDZ) in patients with Crohn's disease (CD) failing anti- Tumor necrosis factors (TNFs); however, the effectiveness of VDZ or UST as a third-class biologic has not yet been described.Aims and Methods: In this retrospective multicenter cohort study, we aimed to investigate the effectiveness of VDZ and UST as a third-class biologic in patients with CD.Results: Two-hundred and four patients were included; 156/204 (76%) patients received VDZ as a second- and UST as a third-class therapy (group A); the remaining 48/204 (24%) patients received UST as a second- and VDZ as a third-class therapy (group B). At week 16-22, 87/156 (55.5%) patients and 27/48 (56.2%) in groups A and B, respectively, responded to treatment (p = 0.9); 41/156 (26.2%) and 15/48 (31.2%) were in clinical remission (p = 0.5). At week 52; 89/103 (86%) patients and 25/29 (86.2%) of the patients with available data had responded to third-class treatment in groups A and B, respectively (p = 0.9); 31/103 (30%) and 47/29 (24.1%) were in clinical remission (p = 0.5).Conclusion: Third-class biological therapy was effective in more than half of the patients with CD. No differences in effectiveness were detected between the use of VDZ and UST as a third-class agent.
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43.
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44.
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45.
  • Altenhoff, Adrian M., et al. (author)
  • Standardized benchmarking in the quest for orthologs
  • 2016
  • In: Nature Methods. - 1548-7091 .- 1548-7105. ; 13:5, s. 425-
  • Journal article (peer-reviewed)abstract
    • Achieving high accuracy in orthology inference is essential for many comparative, evolutionary and functional genomic analyses, yet the true evolutionary history of genes is generally unknown and orthologs are used for very different applications across phyla, requiring different precision-recall trade-offs. As a result, it is difficult to assess the performance of orthology inference methods. Here, we present a community effort to establish standards and an automated web-based service to facilitate orthology benchmarking. Using this service, we characterize 15 well-established inference methods and resources on a battery of 20 different benchmarks. Standardized benchmarking provides a way for users to identify the most effective methods for the problem at hand, sets a minimum requirement for new tools and resources, and guides the development of more accurate orthology inference methods.
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46.
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47.
  • Antonino-Daviu, José Alfonso, et al. (author)
  • Multi-harmonic tracking for diagnosis of rotor asymmetries in wound rotor induction motors
  • 2013
  • In: IECON Proceedings (Industrial Electronics Conference). - Piscataway, NJ : Institute of Electrical and Electronics Engineers (IEEE). - 9781479902248 ; , s. 5555-5560
  • Conference paper (peer-reviewed)abstract
    • Most of the research work hitherto carried out in the induction motors fault diagnosis area has been focused on squirrel-cage motors in spite of the fact that wound-rotor motors are typically less robust, having a more delicate maintenance. Over recent years, wound-rotor machines have drawn an increasing attention in the fault diagnosis community due to the advent of wind power technologies for electricity generation and the widely spread use of its generator variant, the Doubly-Fed Induction Generators (DFIGs) in that specific context. Nonetheless, there is still a lack of reliable techniques suited and properly validated in wound-rotor industrial induction motors. This paper proposes an integral methodology to diagnose rotor asymmetries in wound-rotor motors with high reliability. It is based on a twofold approach; the Empirical Mode Decomposition (EMD) method is employed to track the low-frequency fault-related components, while the Wigner-Ville Distribution (WVD) is used for detecting the high-frequency failure harmonics during a startup. Experimental results with real wound-rotor motors demonstrate that the combination of both perspectives enables to correctly diagnose the failure with higher reliability than alternative techniques relying on a unique informational source
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48.
  • Aoude, M., et al. (author)
  • TREATMENT PATTERNS OF IDIOPATHIC INFLAMMATORY MYOPATHIES : RESULTS FROM AN INTERNATIONAL COHORT OF OVER 1,400 PATIENTS
  • 2022
  • In: Annals of the Rheumatic Diseases. - : HighWire Press. - 0003-4967 .- 1468-2060. ; 81:Suppl. 1, s. 105-106
  • Journal article (other academic/artistic)abstract
    • Idiopathic inflammatory myopathies (IIM) are a group of heterogeneous autoimmune disorders with limited standardization of treatment protocols.ObjectivesTo evaluate frequency and patterns of various treatments used for IIM based on disease subtype, world region, and organ involvement.MethodsCross-sectional data from the international CoVAD self-report e-survey1 was extracted on Sep 14th, 2021. Patient details included demographics, IIM subtypes (dermatomyositis (DM), polymyositis (PM), inclusion body myositis (IBM), antisynthetase syndrome (ASSD), necrotizing myositis (NM) and overlap myositis (OM)), clinical symptoms, disease duration and activity, and current treatments. Treatments were categorized in corticosteroids (CS), antimalarials, immunosuppressants (IS), intravenous immunoglobulins (IVIG), biologics, and others. Typical clinical symptoms (dyspnea, dysphagia) were used as surrogate for organ involvement. Factors associated with IS were analyzed using multivariable logistic regression, adjusting for IIM subtype, demographics, world region, disease activity, and prevalent clinical symptoms (>10%).ResultsIn 1418 patients with IIM, median age was 61 years [IQR 49-70], 62.5% were females, median disease duration was 6 years [IQR 3-11], most common subset was DM (32.4%).The most used treatments were IS (49.4%, including Methotrexate 19.6%, Mycophenolate Mofetil 18.2%, Azathioprine 8.8%, Cyclosporine 2.7%, Tacrolimus 2%, Leflunomide 1.6%, Sulfasalazine 1%, and Cyclophosphamide 0.6%), followed by CS (40.8%), antimalarials (13.8%) and IVIG (9.4%). Biologics were used in 4.3% of patients.Treatment patterns differed significantly by IIM subtypes with a higher frequency of IS (77.7%) and CS (63.4%) use in ASSD; antimalarials (28.6%) and biologics (9.8%) use in OM and IVIG use in NM (24.6%) (Table 1). Also, treatment patterns were different in regions of the world (Figure 1), with a higher frequency of CS use in Europe (60.5%) and IS use in South America (77.2%). Antimalarials were most used in Asia (19.4%), while IVIG use was most common in Oceania (16.9%). Dyspnea was associated with higher use of IS (69.9%) and CS (65.8%) (p<0.001), whereas dysphagia was negatively associated with IS (39.7%) and CS (32.7%) likely due to a higher proportion in IBM patients reporting dysphagia.Table 1.Current Treatments for IIM, Stratified by Disease SubtypesDermatomyositisPolymyositisInclusion Body MyositisAnti-synthetase syndromeNecrotizing myositisOverlap syndromeAll IIMp-valueNumber of patients459182348148572241418Immunosuppressants*269 (58.6)107 (58.8)39 (11.2)115 (77.7)40 (70.2)130 (58.0)700 (49.4)<0.001Corticosteroids208 (48.0)81 (46.8)32 (9.7)90 (63.4)32 (59.3)103 (50.0)546 (40.8)<0.001Antimalarials99 (21.6)7 (3.8)0 (0.0)25 (16.9)1 (1.8)64 (28.6)196 (13.8)<0.001Intravenous Immunoglobulins54 (11.8)16 (8.8)19 (5.5)10 (6.8)14 (24.6)20 (8.9)133 (9.4)<0.001Biologics**17 (3.7)7 (3.8)0 (0.0)13 (8.8)2 (3.5)22 (9.8)61 (4.3)<0.001Others***6 (1.3)0 (0.0)0 (0.0)1 (0.7)0 (0.0)5 (2,2)12 (0.8)0.098*Methotrexate (278), Mycophenolate Mofetil (258), Azathioprine (125), Cyclosporine (38), Tacrolimus (28), Leflunomide (23), Sulfasalazine (14), Cyclophosphamide (9). **Rituximab (44), Abatacept (5), TNF inhibitors (4), Tocilizumab (3), Belimumab (3), Secukinumab (1). ***JAK(10) and PDE4 inhibitors (2)Multivariable logistic regression analysis showed an association of IS with the IIM subtype (least used in IBM (OR 0.07 [95%CI 0.04-0.13] compared to DM), world region (most used in South America (OR 2.35 [1.12-4.91] compared to North America), active and worsening disease activity (OR 3.49 [1.76-6.91] compared to remission), and some clinical features (dyspnea, fatigue, and muscle weakness).ConclusionIIM treatment patterns differ significantly by disease subtypes, world regions and organ involvement, highlighting the need for unified international consensus-driven guidelines.References[1]Parikshit S. et al. Rheumatol Int. 2022 Jan;42(1):23–9.Disclosure of InterestsNone declared
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49.
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50.
  • Bountouris, Ioannis, et al. (author)
  • Serum leptin levels in patients undergoing carotid endarterectomy: a pilot study.
  • 2009
  • In: Angiology. - : SAGE Publications. - 1940-1574 .- 0003-3197. ; 60:6, s. 698-704
  • Journal article (peer-reviewed)abstract
    • INTRODUCTION: Elevated serum leptin levels are associated with cardiovascular events. We investigated the role of serum leptin in patients undergoing carotid endarterectomy (CEA). METHODS: A total of 74 patients (55 men; 38 symptomatic and 36 asymptomatic; mean age 66.9 +/- 8.2 years) undergoing CEA for >70% carotid artery stenosis were enrolled. RESULTS: Serum leptin levels were lower in symptomatic compared with asymptomatic patients (7.1 +/- 1.3 vs 14.4 +/- 4.7 ng/dL; P < .001). Interleukin-6 (IL-6) levels were higher in symptomatic compared with asymptomatic patients (4.3 +/- 1.7 vs 3.3 +/- 1.1 pg/dL; P = .017). Symptomatic patients had more intense macrophage accumulation (0.7% +/- 0.1% vs 0.3% +/- 0.1%; P < .001). Serum leptin and serum IL-6 levels were independently associated with the presence of symptoms in multivariate analysis. CONCLUSION: Serum leptin levels were decreased in symptomatic carotid artery disease. This finding requires further investigation in larger studies.
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