| 1. |
- Aad, G, et al.
(författare)
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- 2015
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swepub:Mat__t
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| 2. |
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| 3. |
- Ried, Janina S., et al.
(författare)
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A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.
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| 4. |
- Kattge, Jens, et al.
(författare)
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TRY plant trait database - enhanced coverage and open access
- 2020
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Ingår i: Global Change Biology. - : Wiley-Blackwell. - 1354-1013 .- 1365-2486. ; 26:1, s. 119-188
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Tidskriftsartikel (refereegranskat)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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| 5. |
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| 6. |
- Liu, Z. G., et al.
(författare)
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Hemizygous variants in protein phosphatase 1 regulatory subunit 3F (PPP1R3F) are associated with a neurodevelopmental disorder characterized by developmental delay, intellectual disability and autistic features
- 2023
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Ingår i: Human Molecular Genetics. - 0964-6906 .- 1460-2083. ; 32:20, s. 2981-2995
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Tidskriftsartikel (refereegranskat)abstract
- Protein phosphatase 1 regulatory subunit 3F (PPP1R3F) is a member of the glycogen targeting subunits (GTSs), which belong to the large group of regulatory subunits of protein phosphatase 1 (PP1), a major eukaryotic serine/threonine protein phosphatase that regulates diverse cellular processes. Here, we describe the identification of hemizygous variants in PPP1R3F associated with a novel X-linked recessive neurodevelopmental disorder in 13 unrelated individuals. This disorder is characterized by developmental delay, mild intellectual disability, neurobehavioral issues such as autism spectrum disorder, seizures and other neurological findings including tone, gait and cerebellar abnormalities. PPP1R3F variants segregated with disease in affected hemizygous males that inherited the variants from their heterozygous carrier mothers. We show that PPP1R3F is predominantly expressed in brain astrocytes and localizes to the endoplasmic reticulum in cells. Glycogen content in PPP1R3F knockout astrocytoma cells appears to be more sensitive to fluxes in extracellular glucose levels than in wild-type cells, suggesting that PPP1R3F functions in maintaining steady brain glycogen levels under changing glucose conditions. We performed functional studies on nine of the identified variants and observed defects in PP1 binding, protein stability, subcellular localization and regulation of glycogen metabolism in most of them. Collectively, the genetic and molecular data indicate that deleterious variants in PPP1R3F are associated with a new X-linked disorder of glycogen metabolism, highlighting the critical role of GTSs in neurological development. This research expands our understanding of neurodevelopmental disorders and the role of PP1 in brain development and proper function.
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| 7. |
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| 8. |
- Curtis, Bruce A., et al.
(författare)
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Algal genomes reveal evolutionary mosaicism and the fate of nucleomorphs
- 2012
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 492:7427, s. 59-65
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Tidskriftsartikel (refereegranskat)abstract
- Cryptophyte and chlorarachniophyte algae are transitional forms in the widespread secondary endosymbiotic acquisition of photosynthesis by engulfment of eukaryotic algae. Unlike most secondary plastid-bearing algae, miniaturized versions of the endosymbiont nuclei (nucleomorphs) persist in cryptophytes and chlorarachniophytes. To determine why, and to address other fundamental questions about eukaryote-eukaryote endosymbiosis, we sequenced the nuclear genomes of the cryptophyte Guillardia theta and the chlorarachniophyte Bigelowiella natans. Both genomes have >21,000 protein genes and are intron rich, and B. natans exhibits unprecedented alternative splicing for a single-celled organism. Phylogenomic analyses and subcellular targeting predictions reveal extensive genetic and biochemical mosaicism, with both host-and endosymbiont-derived genes servicing the mitochondrion, the host cell cytosol, the plastid and the remnant endosymbiont cytosol of both algae. Mitochondrion-to-nucleus gene transfer still occurs in both organisms but plastid-to-nucleus and nucleomorph-to-nucleus transfers do not, which explains why a small residue of essential genes remains locked in each nucleomorph.
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| 9. |
- Kulka, U., et al.
(författare)
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Realising the European network of biodosimetry : RENEB-status quo
- 2015
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Ingår i: Radiation Protection Dosimetry. - : Oxford University Press (OUP). - 0144-8420 .- 1742-3406. ; 164:1-2, s. 42-45
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Tidskriftsartikel (refereegranskat)abstract
- Creating a sustainable network in biological and retrospective dosimetry that involves a large number of experienced laboratories throughout the European Union (EU) will significantly improve the accident and emergency response capabilities in case of a large-scale radiological emergency. A well-organised cooperative action involving EU laboratories will offer the best chance for fast and trustworthy dose assessments that are urgently needed in an emergency situation. To this end, the EC supports the establishment of a European network in biological dosimetry (RENEB). The RENEB project started in January 2012 involving cooperation of 23 organisations from 16 European countries. The purpose of RENEB is to increase the biodosimetry capacities in case of large-scale radiological emergency scenarios. The progress of the project since its inception is presented, comprising the consolidation process of the network with its operational platform, intercomparison exercises, training activities, proceedings in quality assurance and horizon scanning for new methods and partners. Additionally, the benefit of the network for the radiation research community as a whole is addressed.
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| 10. |
- Casewell, Nicholas R, et al.
(författare)
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Solenodon genome reveals convergent evolution of venom in eulipotyphlan mammals.
- 2019
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 116:51, s. 25745-25755
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Tidskriftsartikel (refereegranskat)abstract
- Venom systems are key adaptations that have evolved throughout the tree of life and typically facilitate predation or defense. Despite venoms being model systems for studying a variety of evolutionary and physiological processes, many taxonomic groups remain understudied, including venomous mammals. Within the order Eulipotyphla, multiple shrew species and solenodons have oral venom systems. Despite morphological variation of their delivery systems, it remains unclear whether venom represents the ancestral state in this group or is the result of multiple independent origins. We investigated the origin and evolution of venom in eulipotyphlans by characterizing the venom system of the endangered Hispaniolan solenodon (Solenodon paradoxus). We constructed a genome to underpin proteomic identifications of solenodon venom toxins, before undertaking evolutionary analyses of those constituents, and functional assessments of the secreted venom. Our findings show that solenodon venom consists of multiple paralogous kallikrein 1 (KLK1) serine proteases, which cause hypotensive effects in vivo, and seem likely to have evolved to facilitate vertebrate prey capture. Comparative analyses provide convincing evidence that the oral venom systems of solenodons and shrews have evolved convergently, with the 4 independent origins of venom in eulipotyphlans outnumbering all other venom origins in mammals. We find that KLK1s have been independently coopted into the venom of shrews and solenodons following their divergence during the late Cretaceous, suggesting that evolutionary constraints may be acting on these genes. Consequently, our findings represent a striking example of convergent molecular evolution and demonstrate that distinct structural backgrounds can yield equivalent functions.
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| 11. |
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| 12. |
- Engel, Philipp, et al.
(författare)
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The Bee Microbiome: Impact on Bee Health and Model for Evolution and Ecology of Host-Microbe Interactions
- 2016
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Ingår i: mBio. - : American Society for Microbiology. - 2161-2129 .- 2150-7511. ; 7:2
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Forskningsöversikt (refereegranskat)abstract
- As pollinators, bees are cornerstones for terrestrial ecosystem stability and key components in agricultural productivity. All animals, including bees, are associated with a diverse community of microbes, commonly referred to as the micro biome. The bee micro biome is likely to be a crucial factor affecting host health. However, with the exception of a few pathogens, the impacts of most members of the bee microbiome on host health are poorly understood. Further, the evolutionary and ecological forces that shape and change the microbiome are unclear. Here, we discuss recent progress in our understanding of the bee microbiome, and we present challenges associated with its investigation. We conclude that global coordination of research efforts is needed to fully understand the complex and highly dynamic nature of the interplay between the bee micro biome, its host, and the environment. High-throughput sequencing technologies are ideal for exploring complex biological systems, including host-microbe interactions. To maximize their value and to improve assessment of the factors affecting bee health, sequence data should be archived, curated, and analyzed in ways that promote the synthesis of different studies. To this end, the BeeBiome consortium aims to develop an online database which would provide reference sequences, archive metadata, and host analytical resources. The goal would be to support applied and fundamental research on bees and their associated microbes and to provide a collaborative framework for sharing primary data from different research programs, thus furthering our understanding of the bee microbiome and its impact on pollinator health.
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| 13. |
- Facchetti, D., et al.
(författare)
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Heparin enriched-wpi coating on ti6al4v increases hydrophilicity and improves proliferation and differentiation of human bone marrow stromal cells
- 2022
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- Titanium alloy (Ti6Al4V) is one of the most prominent biomaterials for bone contact because of its ability to bear mechanical loading and resist corrosion. The success of Ti6Al4V implants depends on bone formation on the implant surface. Hence, implant coatings which promote adhesion, proliferation and differentiation of bone-forming cells are desirable. One coating strategy is by adsorption of biomacromolecules. In this study, Ti6Al4V substrates produced by additive manufacturing (AM) were coated with whey protein isolate (WPI) fibrils, obtained at pH 2, and heparin or tinzaparin (a low molecular weight heparin LMWH) in order to improve the proliferation and differentiation of bone-forming cells. WPI fibrils proved to be an excellent support for the growth of human bone marrow stromal cells (hBMSC). Indeed, WPI fibrils were resistant to sterilization and were stable during storage. This WPI-heparin-enriched coating, especially the LMWH, enhanced the differentiation of hBMSC by increasing tissue non-specific alkaline phosphatase (TNAP) activity. Finally, the coating increased the hydrophilicity of the material. The results confirmed that WPI fibrils are an excellent biomaterial which can be used for biomedical coatings, as they are easily modifiable and resistant to heat treatments. Indeed, the already known positive effect on osteogenic integration of WPI-only coated substrates has been further enhanced by a simple adsorption procedure.
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| 14. |
- Flärdh, Klas, et al.
(författare)
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Regulation of apical growth and hyphal branching in Streptomyces
- 2012
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Ingår i: Current Opinion in Microbiology. - : Elsevier BV. - 1879-0364 .- 1369-5274. ; 15:6, s. 737-743
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Tidskriftsartikel (refereegranskat)abstract
- The filamentous bacteria Streptomyces grow by tip extension and through the initiation of new branches, and this apical growth is directed by a polarisome-like complex involving the essential polarity protein DivIVA. New branch sites must be marked de novo and, until recently, there was no understanding of how these new sites are selected. Equally, hyphal branching patterns are affected by environmental conditions, but there was no insight into how polar growth and hyphal branching might be regulated in response to external or internal cues. This review focuses on recent discoveries that reveal the principal mechanism of branch site selection in Streptomyces, and the first mechanism to be identified that regulates polarisome behaviour to modulate polar growth and hyphal branching.
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| 15. |
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| 16. |
- Milone, A. P., et al.
(författare)
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The ACS survey of Galactic globular clusters XII. Photometric binaries along the main sequence
- 2012
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Ingår i: Astronomy & Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 540
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Tidskriftsartikel (refereegranskat)abstract
- Context. The fraction of binary stars is an important ingredient to interpret globular cluster dynamical evolution and their stellar population. Aims. We investigate the properties of main-sequence binaries measured in a uniform photometric sample of 59 Galactic globular clusters that were observed by HST WFC/ACS as a part of the Globular Cluster Treasury project. Methods. We measured the fraction of binaries and the distribution of mass-ratio as a function of radial location within the cluster, from the central core to beyond the half-mass radius. We studied the radial distribution of binary stars, and the distribution of stellar mass ratios. We investigated monovariate relations between the fraction of binaries and the main parameters of their host clusters. Results. We found that in nearly all the clusters, the total fraction of binaries is significantly smaller than the fraction of binaries in the field, with a few exceptions only. Binary stars are significantly more centrally concentrated than single MS stars in most of the clusters studied in this paper. The distribution of the mass ratio is generally flat (for mass-ratio parameter q > 0.5). We found a significant anti-correlation between the binary fraction in a cluster and its absolute luminosity (mass). Some, less significant correlation with the collisional parameter, the central stellar density, and the central velocity dispersion are present. There is no statistically significant relation between the binary fraction and other cluster parameters. We confirm the correlation between the binary fraction and the fraction of blue stragglers in the cluster.
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| 17. |
- Richards, David M., et al.
(författare)
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Mechanistic Basis of Branch-Site Selection in Filamentous Bacteria
- 2012
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Ingår i: PLoS Computational Biology. - : Public Library of Science (PLoS). - 1553-7358. ; 8:3
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Tidskriftsartikel (refereegranskat)abstract
- Many filamentous organisms, such as fungi, grow by tip-extension and by forming new branches behind the tips. A similar growth mode occurs in filamentous bacteria, including the genus Streptomyces, although here our mechanistic understanding has been very limited. The Streptomyces protein DivIVA is a critical determinant of hyphal growth and localizes in foci at hyphal tips and sites of future branch development. However, how such foci form was previously unknown. Here, we show experimentally that DivIVA focus-formation involves a novel mechanism in which new DivIVA foci break off from existing tip-foci, bypassing the need for initial nucleation or de novo branch-site selection. We develop a mathematical model for DivIVA-dependent growth and branching, involving DivIVA focus-formation by tip-focus splitting, focus growth, and the initiation of new branches at a critical focus size. We quantitatively fit our model to the experimentally-measured tip-to-branch and branch-to-branch length distributions. The model predicts a particular bimodal tip-to-branch distribution results from tip-focus splitting, a prediction we confirm experimentally. Our work provides mechanistic understanding of a novel mode of hyphal growth regulation that may be widely employed.
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| 18. |
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| 19. |
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| 20. |
- Weber, H., et al.
(författare)
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The genetic contribution of the NO system at the glutamatergic post-synapse to schizophrenia: Further evidence and meta-analysis
- 2014
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Ingår i: European Neuropsychopharmacology. - : Elsevier BV. - 0924-977X .- 1873-7862. ; 24:1, s. 65-85
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Tidskriftsartikel (refereegranskat)abstract
- NO is a pleiotropic signaling molecule and has an important role in cognition and emotion. In the brain, NO is produced by neuronal nitric oxide synthase (NOS-I, encoded by NOS1) coupled to the NMDA receptor via PDZ. interactions; this protein-protein interaction is disrupted upon binding of NOS1 adapter protein (encoded by NOS1AP) to NOS-I. As both NOS1 and NOS1AP were associated with schizophrenia, we here investigated these genes in greater detail by genotyping new samples and conducting a meta-analysis of our own and published data. In doing so, we confirmed association of both genes with schizophrenia and found evidence for their interaction in increasing risk towards disease. Our strongest finding was the NOS1 promoter SNP rs41279104, yielding an odds ratio of 1.29 in the meta-analysis. As findings from heterologous cell systems have suggested that the risk allele decreases gene expression, we studied the effect of the variant on NOS1 expression in human post-mortem brain samples and found that the risk allele significantly decreases expression of NOS1 in the prefrontal cortex. Bioinformatic analyses suggest that this might be due the replacement of six transcription factor binding sites by two new binding sites as a consequence of proxy SNPs. Taken together, our data argue that genetic variance in NOS1 resulting in lower prefrontal brain expression of this gene contributes to schizophrenia liability, and that NOS1 interacts with NOS1AP in doing so. The NOS1-NOS1AP PDZ interface may thus well constitute a novel target for small molecules in at least some forms of schizophrenia. (C) 2013 Elsevier B.V. and ECNP. All rights reserved.
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| 21. |
- Zakhozhay, Olga, et al.
(författare)
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Radial Velocity Survey for Planets around Young stars (RVSPY) Target characterisation and high-cadence survey
- 2022
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 667
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Tidskriftsartikel (refereegranskat)abstract
- Context. The occurrence rate and period distribution of (giant) planets around young stars is still not as well constrained as for older main-sequence stars. This is mostly due to the intrinsic activity-related complications and the avoidance of young stars in many large planet search programmes. Yet, dynamical restructuring processes in planetary systems may last significantly longer than the actual planet formation phase and may well extend long into the debris disc phase, such that the planet populations around young stars may differ from those observed around main-sequence stars.Aims. We introduce our Radial Velocity Survey for Planets around Young stars (RVSPY), which is closely related to the NaCo-ISPY direct imaging survey, characterise our target stars, and search for substellar companions at orbital separations smaller than a few au from the host star.Methods. We used the FEROS spectrograph, mounted to the MPG/ESO 2.2 m telescope in Chile, to obtain high signal-to-noise spectra and time series of precise radial velocities (RVs) of 111 stars, most of which are surrounded by debris discs. Our target stars have spectral types between early F and late K, a median age of 400 Myr, and a median distance of 45 pc. During the initial reconnaissance phase of our survey, we determined stellar parameters and used high-cadence observations to characterise the intrinsic stellar activity, searched for hot companions with orbital periods of up to 10 days, and derived the detection thresholds for longer-period companions. In our analysis we, have included archival spectroscopic data, spectral energy distribution, and data for photometric time series from the TESS mission.Results. For all target stars we determined their basic stellar parameters and present the results of the high-cadence RV survey and activity characterisation. We have achieved a median single-measurement RV precision of 6 m s−1 and derived the short-term intrinsic RV scatter of our targets (median 23 m s−1), which is mostly caused by stellar activity and decays with an age from >100 m s−1 at <20 Myr to <20 m s−1 at >500 Myr. We analysed time series periodograms of the high-cadence RV data and the shape of the individual cross-correlation functions. We discovered six previously unknown close companions with orbital periods between 10 and 100 days, three of which are low-mass stars, and three are in the brown dwarf mass regime. We detected no hot companion with an orbital period <10 days down to a median mass limit of ~1 MJup for stars younger than 500 Myr, which is still compatible with the established occurrence rate of such companions around main-sequence stars. We found significant RV periodicities between 1.3 and 4.5 days for 14 stars, which are, however, all caused by rotational modulation due to starspots. We also analysed the data for TESS photometric time series and found significant periodicities for most of the stars. For 11 stars, the photometric periods are also clearly detected in the RV data. We also derived stellar rotation periods ranging from 1 to 10 days for 91 stars, mostly from the TESS data. From the intrinsic activity-related short-term RV jitter, we derived the expected mass-detection thresholds for longer-period companions, and selected 84 targets for the longer-term RV monitoring.
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| 22. |
- Zimmer, S, et al.
(författare)
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Cyclodextrin promotes atherosclerosis regression via macrophage reprogramming
- 2016
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Ingår i: Science translational medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6242 .- 1946-6234. ; 8:333, s. 333ra50-
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Tidskriftsartikel (refereegranskat)abstract
- The cyclic oligosaccharide 2-hydroxypropyl-β-cyclodextrin facilitates atheroprotective mechanisms through oxysterol-mediated reprogramming of macrophages.
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| 23. |
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| 24. |
- Bloomfield, Madeleine, et al.
(författare)
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European Autism GEnomics Registry (EAGER): protocol for a multicentre cohort study and registry
- 2024
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Ingår i: BMJ OPEN. - 2044-6055. ; 14:6
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Tidskriftsartikel (refereegranskat)abstract
- Introduction Autism is a common neurodevelopmental condition with a complex genetic aetiology that includes contributions from monogenic and polygenic factors. Many autistic people have unmet healthcare needs that could be served by genomics-informed research and clinical trials. The primary aim of the European Autism GEnomics Registry (EAGER) is to establish a registry of participants with a diagnosis of autism or an associated rare genetic condition who have undergone whole-genome sequencing. The registry can facilitate recruitment for future clinical trials and research studies, based on genetic, clinical and phenotypic profiles, as well as participant preferences. The secondary aim of EAGER is to investigate the association between mental and physical health characteristics and participants' genetic profiles.Methods and analysis EAGER is a European multisite cohort study and registry and is part of the AIMS-2-TRIALS consortium. EAGER was developed with input from the AIMS-2-TRIALS Autism Representatives and representatives from the rare genetic conditions community. 1500 participants with a diagnosis of autism or an associated rare genetic condition will be recruited at 13 sites across 8 countries. Participants will be given a blood or saliva sample for whole-genome sequencing and answer a series of online questionnaires. Participants may also consent to the study to access pre-existing clinical data. Participants will be added to the EAGER registry and data will be shared externally through established AIMS-2-TRIALS mechanisms.Ethics and dissemination To date, EAGER has received full ethical approval for 11 out of the 13 sites in the UK (REC 23/SC/0022), Germany (S-375/2023), Portugal (CE-085/2023), Spain (HCB/2023/0038, PIC-164-22), Sweden (Dnr 2023-06737-01), Ireland (230907) and Italy (CET_62/2023, CEL-IRCCS OASI/24-01-2024/EM01, EM 2024-13/1032 EAGER). Findings will be disseminated via scientific publications and conferences but also beyond to participants and the wider community (eg, the AIMS-2-TRIALS website, stakeholder meetings, newsletters).
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| 25. |
- Camenzind, Tessa, et al.
(författare)
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Arbuscular mycorrhizal fungal and soil microbial communities in African Dark Earths
- 2018
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Ingår i: FEMS Microbiology Ecology. - : Oxford University Press (OUP). - 0168-6496 .- 1574-6941. ; 94:4
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Tidskriftsartikel (refereegranskat)abstract
- The socio-economic values of fertile and carbon-rich Dark Earth soils are well described from the Amazon region. Very recently, Dark Earth soils were also identified in tropical West Africa, with comparable beneficial soil properties and plant growth-promoting effects. The impact of this management technique on soil microbial communities, however, is less well understood, especially with respect to the ecologically relevant group of arbuscular mycorrhizal (AM) fungi. Thus, we tested the hypotheses that (1) improved soil quality in African Dark Earth (AfDE) will increase soil microbial biomass and shift community composition and (2) concurrently increased nutrient availability will negatively affect AM fungal communities. Microbial communities were distinct in AfDE in comparison to adjacent sites, with an increased fungal:bacterial ratio of 71%, a pattern mainly related to shifts in pH. AM fungal abundance and diversity, however, did not differ despite clearly increased soil fertility in AfDE, with 3.7 and 1.7 times greater extractable P and total N content, respectively. The absence of detrimental effects on AM fungi, often seen following applications of inorganic fertilizers, and the enhanced role of saprobic fungi relevant for mineralization and C sequestration support previous assertions of this management type as a sustainable alternative agricultural practice.
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| 26. |
- Douglas, Timothy E. L., et al.
(författare)
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Pectin coatings on titanium alloy scaffolds produced by additive manufacturing : Promotion of human bone marrow stromal cell proliferation
- 2018
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Ingår i: Materials letters (General ed.). - : Elsevier BV. - 0167-577X .- 1873-4979. ; 227, s. 225-228
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Tidskriftsartikel (refereegranskat)abstract
- Ti6Al4V is a popular biomaterial for load-bearing implants for bone contact, which can be fabricated by additive manufacturing technologies. Their long-term success depends on their stable anchoring in surrounding bone, which in turn depends on formation of new bone tissue on the implant surface, for which adhesion and proliferation of bone-forming cells is a pre-requisite. Hence, surface coatings which promote cell adhesion and proliferation are desirable. Here, Ti6Al4V discs prepared by additive manufacturing (EBM) were coated with layers of pectins, calcium-binding polysaccharides derived from citrus (C) and apple (A), which also contained alkaline phosphatase (ALP), the enzyme responsible for mineralization of bone tissue. Adhesion and proliferation of human bone marrow stromal cells (hBMSC) were assessed. Proliferation after 7 days was increased by A-ALP coatings and, in particular, by C-ALP coatings. Cell morphology was similar on coated and uncoated samples. In conclusion, ALP-loaded pectin coatings promote hBMSC adhesion and proliferation.
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| 27. |
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| 28. |
- Filieri, Antonio, et al.
(författare)
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Control Strategies for Self-Adaptive Software Systems
- 2017
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Ingår i: ACM Transactions on Autonomous and Adaptive Systems. - : Association for Computing Machinery (ACM). - 1556-4665 .- 1556-4703. ; 11:4
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Tidskriftsartikel (refereegranskat)abstract
- The pervasiveness and growing complexity of software systems are challenging software engineering to design systems that can adapt their behavior to withstand unpredictable, uncertain, and continuously changing execution environments. Control theoretical adaptation mechanisms have received growing interest from the software engineering community in the last few years for their mathematical grounding, allowing formal guarantees on the behavior of the controlled systems. However, most of these mechanisms are tailored to specific applications and can hardly be generalized into broadly applicable software design and development processes.This article discusses a reference control design process, from goal identification to the verification and validation of the controlled system. A taxonomy of the main control strategies is introduced, analyzing their applicability to software adaptation for both functional and nonfunctional goals. A brief extract on how to deal with uncertainty complements the discussion. Finally, the article highlights a set of open challenges, both for the software engineering and the control theory research communities.
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| 29. |
- Filieri, Antonio, et al.
(författare)
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Software Engineering Meets Control Theory
- 2015
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Ingår i: 2015 10th International Symposium on Software Engineering for Adaptive and Self-Managing Systems. - Piscataway, NJ, USA : IEEE Press. - 9780769555676 ; , s. 71-82
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Konferensbidrag (refereegranskat)abstract
- The software engineering community has proposed numerous approaches for making software self-adaptive. These approaches take inspiration from machine learning and control theory, constructing software that monitors and modifies its own behavior to meet goals. Control theory, in particular, has received considerable attention as it represents a general methodology for creating adaptive systems. Control-theoretical software implementations, however, tend to be ad hoc. While such solutions often work in practice, it is difficult to understand and reason about the desired properties and behavior of the resulting adaptive software and its controller. This paper discusses a control design process for software systems which enables automatic analysis and synthesis of a controller that is guaranteed to have the desired properties and behavior. The paper documents the process and illustrates its use in an example that walks through all necessary steps for self-adaptive controller synthesis.
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| 30. |
- Hempel, Antje, et al.
(författare)
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The Ser/Thr protein kinase AfsK regulates polar growth and hyphal branching in the filamentous bacteria Streptomyces.
- 2012
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Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 109:35, s. 2371-2379
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Tidskriftsartikel (refereegranskat)abstract
- In cells that exhibit apical growth, mechanisms that regulate cell polarity are crucial for determination of cellular shape and for the adaptation of growth to intrinsic and extrinsic cues. Broadly conserved pathways control cell polarity in eukaryotes, but less is known about polarly growing prokaryotes. An evolutionarily ancient form of apical growth is found in the filamentous bacteria Streptomyces, and is directed by a polarisome-like complex involving the essential protein DivIVA. We report here that this bacterial polarization machinery is regulated by a eukaryotic-type Ser/Thr protein kinase, AfsK, which localizes to hyphal tips and phosphorylates DivIVA. During normal growth, AfsK regulates hyphal branching by modulating branch-site selection and some aspect of the underlying polarisome-splitting mechanism that controls branching of Streptomyces hyphae. Further, AfsK is activated by signals generated by the arrest of cell wall synthesis and directly communicates this to the polarisome by hyperphosphorylating DivIVA. Induction of high levels of DivIVA phosphorylation by using a constitutively active mutant AfsK causes disassembly of apical polarisomes, followed by establishment of multiple hyphal branches elsewhere in the cell, revealing a profound impact of this kinase on growth polarity. The function of AfsK is reminiscent of the phoshorylation of polarity proteins and polarisome components by Ser/Thr protein kinases in eukaryotes.
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| 31. |
- Hempel, Elisabeth, et al.
(författare)
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Blue Turns to Gray : Paleogenomic Insights into the Evolutionary History and Extinction of the Blue Antelope (Hippotragus leucophaeus)
- 2022
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Ingår i: Molecular biology and evolution. - : Oxford University Press (OUP). - 0737-4038 .- 1537-1719. ; 39:12
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Tidskriftsartikel (refereegranskat)abstract
- The blue antelope (Hippotragus leucophaeus) is the only large African mammal species to have become extinct in historical times, yet no nuclear genomic information is available for this species. A recent study showed that many alleged blue antelope museum specimens are either roan (Hippotragus equinus) or sable (Hippotragus niger) antelopes, further reducing the possibilities for obtaining genomic information for this extinct species. While the blue antelope has a rich fossil record from South Africa, climatic conditions in the region are generally unfavorable to the preservation of ancient DNA. Nevertheless, we recovered two blue antelope draft genomes, one at 3.4× mean coverage from a historical specimen (∼200 years old) and one at 2.1× mean coverage from a fossil specimen dating to 9,800–9,300 cal years BP, making it currently the oldest paleogenome from Africa. Phylogenomic analyses show that blue and sable antelope are sister species, confirming previous mitogenomic results, and demonstrate ancient gene flow from roan into blue antelope. We show that blue antelope genomic diversity was much lower than in roan and sable antelope, indicative of a low population size since at least the early Holocene. This supports observations from the fossil record documenting major decreases in the abundance of blue antelope after the Pleistocene–Holocene transition. Finally, the persistence of this species throughout the Holocene despite low population size suggests that colonial-era human impact was likely the decisive factor in the blue antelope's extinction.
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| 32. |
- Hempel, Tim, et al.
(författare)
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Molecular mechanism of inhibiting the SARS-CoV-2 cell entry facilitator TMPRSS2 with camostat and nafamostat
- 2021
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Ingår i: Chemical Science. - : Royal Society of Chemistry (RSC). - 2041-6539 .- 2041-6520. ; 12:3, s. 983-992
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Tidskriftsartikel (refereegranskat)abstract
- The entry of the coronavirus SARS-CoV-2 into human lung cells can be inhibited by the approved drugs camostat and nafamostat. Here we elucidate the molecular mechanism of these drugs by combining experiments and simulations. In vitro assays confirm that both drugs inhibit the human protein TMPRSS2, a SARS-Cov-2 spike protein activator. As no experimental structure is available, we provide a model of the TMPRSS2 equilibrium structure and its fluctuations by relaxing an initial homology structure with extensive 330 microseconds of all-atom molecular dynamics (MD) and Markov modeling. Through Markov modeling, we describe the binding process of both drugs and a metabolic product of camostat (GBPA) to TMPRSS2, reaching a Michaelis complex (MC) state, which precedes the formation of a long-lived covalent inhibitory state. We find that nafamostat has a higher MC population than camostat and GBPA, suggesting that nafamostat is more readily available to form the stable covalent enzyme-substrate intermediate, effectively explaining its high potency. This model is backed by our in vitro experiments and consistent with previous virus cell entry assays. Our TMPRSS2-drug structures are made public to guide the design of more potent and specific inhibitors.
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| 33. |
- Hoffmann, Markus, et al.
(författare)
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Camostat mesylate inhibits SARS-CoV-2 activation by TMPRSS2-related proteases and its metabolite GBPA exerts antiviral activity
- 2021
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Ingår i: EBioMedicine. - : Elsevier BV. - 2352-3964. ; 65
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Tidskriftsartikel (refereegranskat)abstract
- Background: Antivirals are needed to combat the COVID-19 pandemic, which is caused by SARS-CoV-2. The clinically-proven protease inhibitor Camostat mesylate inhibits SARS-CoV-2 infection by blocking the virus-activating host cell protease TMPRSS2. However, antiviral activity of Camostat mesylate metabolites and potential viral resistance have not been analyzed. Moreover, antiviral activity of Camostat mesylate in human lung tissue remains to be demonstrated. Methods: We used recombinant TMPRSS2, reporter particles bearing the spike protein of SARS-CoV-2 or authentic SARS-CoV-2 to assess inhibition of TMPRSS2 and viral entry, respectively, by Camostat mesylate and its metabolite GBPA. Findings: We show that several TMPRSS2-related proteases activate SARS-CoV-2 and that two, TMPRSS11D and TMPRSS13, are robustly expressed in the upper respiratory tract. However, entry mediated by these proteases was blocked by Camostat mesylate. The Camostat metabolite GBPA inhibited recombinant TMPRSS2 with reduced efficiency as compared to Camostat mesylate. In contrast, both inhibitors exhibited similar antiviral activity and this correlated with the rapid conversion of Camostat mesylate into GBPA in the presence of serum. Finally, Camostat mesylate and GBPA blocked SARS-CoV-2 spread in human lung tissue ex vivo and the related protease inhibitor Nafamostat mesylate exerted augmented antiviral activity. Interpretation: Our results suggest that SARS-CoV-2 can use TMPRSS2 and closely related proteases for spread in the upper respiratory tract and that spread in the human lung can be blocked by Camostat mesylate and its metabolite GBPA. Funding: NIH, Damon Runyon Foundation, ACS, NYCT, DFG, EU, Berlin Mathematics center MATH+, BMBF, Lower Saxony, Lundbeck Foundation, Novo Nordisk Foundation.
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| 34. |
- Joerger, Markus, et al.
(författare)
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Population pharmacokinetics and pharmacodynamics of doxorubicin and cyclophosphamide in breast cancer patients : a study by the EORTC-PAMM-NDDG
- 2007
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Ingår i: Clinical Pharmacokinetics. - 0312-5963 .- 1179-1926. ; 46:12, s. 1051-1068
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Tidskriftsartikel (refereegranskat)abstract
- Aims: To investigate the population pharmacokinetics and pharmacodynamics of doxorubicin and cyclophosphamide in breast cancer patients. Patients and methods: Sixty-five female patients with early or advanced breast cancer received doxorubicin 60 mg/m(2) over 15 minutes followed by cyclophosphamide 600 mg/m(2) over 15 minutes. The plasma concentration-time data of both drugs were measured, and the relationship between drug pharmacokinetics and neutrophil counts was evaluated using nonlinear mixed-effect modelling. Relationships were explored between drug exposure (the area under the plasma concentration-time curve [AUC]), toxicity and tumour response. Results: Fifty-nine patients had complete pharmacokinetic and toxicity data. In 50 patients with measurable disease, the objective response rate was 60%, with complete responses in 6% of patients. Both doxorubicin and cyclophosphamide pharmacokinetics were associated with neutrophil toxicity. Cyclophosphamide exposure (the AUC) was significantly higher in patients with at least stable disease (n = 44) than in patients with progressive disease (n = 6; 945 mu mol . h/L [95% CI 889, 1001] vs 602 mu mol . h/L [95% CI 379, 825], p = 0.0002). No such correlation was found for doxorubicin. Body surface area was positively correlated with doxorubicin clearance; AST and patient age were negatively correlated with doxorubicin clearance; creatinine clearance was positively correlated with doxorubicinol clearance; and occasional concurrent use of carbamazepine was positively correlated with cyclophosphamide clearance. Conclusions: The proposed inhibitory population pharmacokinetic-pharmacodynamic model adequately described individual neutrophil counts after administration of doxorubicin and cyclophosphamide. In this patient population, exposure to cyclophosphamide, as assessed by the AUC, might have been a predictor of the treatment response, whereas exposure to doxorubicin was not. A prospective study should validate cyclophosphamide exposure as a predictive marker for the treatment response and clinical outcome in this patient group
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| 35. |
- Joerger, Markus, et al.
(författare)
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Population pharmacokinetics and pharmacodynamics of paclitaxel and carboplatin in ovarian cancer patients : a study by the European organization for research and treatment of cancer-pharmacology and molecular mechanisms group and new drug development group.
- 2007
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Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 13:21, s. 6410-6418
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Paclitaxel and carboplatin are frequently used in advanced ovarian cancer following cytoreductive surgery. Threshold models have been used to predict paclitaxel pharmacokinetic-pharmacodynamics, whereas the time above paclitaxel plasma concentration of 0.05 to 0.2 μmol/L (tC > 0.05−0.2) predicts neutropenia. The objective of this study was to build a population pharmacokinetic-pharmacodynamic model of paclitaxel/carboplatin in ovarian cancer patients. Experimental Design: One hundred thirty-nine ovarian cancer patients received paclitaxel (175 mg/m2) over 3 h followed by carboplatin area under the concentration-time curve 5 mg/mL*min over 30 min. Plasma concentration-time data were measured, and data were processed using nonlinear mixed-effect modeling. Semiphysiologic models with linear or sigmoidal maximum response and threshold models were adapted to the data. Results: One hundred five patients had complete pharmacokinetic and toxicity data. In 34 patients with measurable disease, objective response rate was 76%. Neutrophil and thrombocyte counts were adequately described by an inhibitory linear response model. Paclitaxel tC > 0.05 was significantly higher in patients with a complete (91.8 h) or partial (76.3 h) response compared with patients with progressive disease (31.5 h; P = 0.02 and 0.05, respectively). Patients with paclitaxel tC > 0.05 > 61.4 h (mean value) had a longer time to disease progression compared with patients with paclitaxel tC > 0.05 < 61.4 h (89.0 versus 61.9 weeks; P = 0.05). Paclitaxel tC > 0.05 was a good predictor for severe neutropenia (P = 0.01), whereas carboplatin exposure (Cmax and area under the concentration-time curve) was the best predictor for thrombocytopenia (P < 10−4). Conclusions: In this group of patients, paclitaxel tC > 0.05 is a good predictive marker for severe neutropenia and clinical outcome, whereas carboplatin exposure is a good predictive marker for thrombocytopenia.
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| 36. |
- Meister, Anette, et al.
(författare)
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Formation of square lamellae by self-assembly of long-chain bolaphospholipids in water
- 2010
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Ingår i: Soft Matter. - : Royal Society of Chemistry (RSC). - 1744-683X .- 1744-6848. ; 6:6, s. 1317-1324
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Tidskriftsartikel (refereegranskat)abstract
- The self-assembly process of the symmetric single-chain polymethylene-1,omega-bis(phosphocholine) (PC-C34-PC) with a chain length of 34 carbon atoms and two polar phosphocholine headgroups when put into water is exclusively driven by hydrophobic interactions of the long alkyl chains. This process leads to the formation of a dense network of helical nanofibers and the formation of a hydrogel (Meister et al. J. Phys. Chem. B, 2008, 112, 4506). In contrast, the single-chain bolalipids tetra-and hexatriacontane-1,omega-diyl-bis[2-(dimethylammonio)ethylphosphate] (Me2PE-Cn-Me2PE, n = 34, 36) and the partly deuterated analogue Me2PE-C11-(CD2)12-C11-Me2PE (dMe(2)PE-C34-Me2PE) form a different type of stable aggregate. In a first step, the self-assembly of these long-chain bolalipids in water at room temperature leads to the formation of a dense network of nanofibers which eventually form a hydrogel. Within one day, the nanofibers transform into square lamellae that grow up to an edge length of about 100 nm. Nanofibers are linked to one or two (opposite) corners of the squares leading to the appearance of a kite-like structure. After one week, all fibers have been transformed into square lamellae which are apparently stacked and form a gel cake. Within several weeks, a more compact cake is formed by syneresis, i.e. the expulsion of water.
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| 37. |
- Park, Julien H., et al.
(författare)
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The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1
- 2023
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Ingår i: Brain Communications. - : Oxford University Press. - 2632-1297. ; 5:1
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Tidskriftsartikel (refereegranskat)abstract
- Superoxide dismutase-1 is a ubiquitously expressed antioxidant enzyme. Mutations in SOD1 can cause amyotrophic lateral sclerosis, probably via a toxic gain-of-function involving protein aggregation and prion-like mechanisms. Recently, homozygosity for loss-of-function mutations in SOD1 has been reported in patients presenting with infantile-onset motor neuron disease. We explored the bodily effects of superoxide dismutase-1 enzymatic deficiency in eight children homozygous for the p.C112Wfs∗11 truncating mutation. In addition to physical and imaging examinations, we collected blood, urine and skin fibroblast samples. We used a comprehensive panel of clinically established analyses to assess organ function and analysed oxidative stress markers, antioxidant compounds, and the characteristics of the mutant Superoxide dismutase-1. From around 8 months of age, all patients exhibited progressive signs of both upper and lower motor neuron dysfunction, cerebellar, brain stem, and frontal lobe atrophy and elevated plasma neurofilament concentration indicating ongoing axonal damage. The disease progression seemed to slow down over the following years. The p.C112Wfs∗11 gene product is unstable, rapidly degraded and no aggregates were found in fibroblast. Most laboratory tests indicated normal organ integrity and only a few modest deviations were found. The patients displayed anaemia with shortened survival of erythrocytes containing decreased levels of reduced glutathione. A variety of other antioxidants and oxidant damage markers were within normal range. In conclusion, non-neuronal organs in humans show a remarkable tolerance to absence of Superoxide dismutase-1 enzymatic activity. The study highlights the enigmatic specific vulnerability of the motor system to both gain-of-function mutations in SOD1 and loss of the enzyme as in the here depicted infantile superoxide dismutase-1 deficiency syndrome.
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| 38. |
- Perego, Paola, et al.
(författare)
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Cellular pharmacology studies of anticancer agents: recommendations from the EORTC-PAMM group
- 2018
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Ingår i: Cancer Chemotherapy and Pharmacology. - : SPRINGER. - 0344-5704 .- 1432-0843. ; 81:3, s. 427-441
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Forskningsöversikt (refereegranskat)abstract
- An increasing number of manuscripts focus on the in vitro evaluation of established and novel anti-tumor agents in experimental models. Whilst the design of such in vitro assays is inherently flexible, some of these studies lack the minimum information necessary to critically evaluate their relevance or have been carried out under unsuitable conditions. The use of appropriate and robust methods and experimental design has important implications for generating results that are reliable, relevant, and reproducible. The Pharmacology and Molecular Mechanisms (PAMM) group of the European Organization for Research and Treatment of Cancer (EORTC) is the largest group of academic scientists working on drug development and bundle decades of expertise in this field. This position paper addresses all researchers with an interest in the preclinical and cellular pharmacology of anti-tumor agents and aims at generating basic recommendations for the correct use of compounds to be tested for anti-tumor activity using a range of preclinical cellular models of cancer.
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| 39. |
- Peukert, S, et al.
(författare)
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The frequency of occurrence of anti-cardiac receptor autoantibodies and their correlation with clinical manifestation in patients with hypertrophic cardiomyopathy.
- 1999
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Ingår i: Autoimmunity. - 0891-6934. ; 29:4, s. 291-7
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of this study was to investigate the frequency of occurrence of autoantibodies against G-protein coupled cardiovascular receptors and their relation to the clinical manifestation of hypertrophic cardiomyopathy (HCM). Autoantibodies against beta1-receptors, Muscarin-2-receptors, Angiotensin-II-receptor subtype 1 and alpha1-receptors were determined with ELISA in 52 patients with HCM (37 male, 15 female, mean age 55 +/- 15 years) and 40 healthy, age and sex matched controls. The clinical characterization of the HCM-patients included ECG, 24-h Holter, and echocardiography. The results showed that there is no significant difference in the frequency of a single autoantibody between HCM-patients and controls. However, if the number of patients who have autoantibodies against beta1-receptors and/or Muscarin-2-receptors were counted together, there are significantly more autoantibodies in HCM compared to controls (11 vs. 2, p = 0.035). Analysis of clinical data from this pooled group of patients showed that in patients with autoantibodies, heart rate variability (HRV), ultra low frequency (ULF) and very low frequency (VLF) were decreased (HRV by 20%, ULF by 50%, and VLF by 46%, p < 0.008) whereas the QTc-interval was increased by 8% (p < 0.02 each). The ratio of septal to posterior wall thickness was increased by 23% (p = 0.05), and the preejection period was prolonged by 46% in patients with autoantibodies (p < 0.001). These results suggest that the existence of these autoantibodies could be associated with an advanced stage or a severe manifestation of HCM.
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| 40. |
- Saalbach, Gerhard, et al.
(författare)
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Determination of Phosphorylation Sites in the DivIVA Cytoskeletal Protein of Streptomyces coelicolor by Targeted LC-MS/MS
- 2013
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Ingår i: Journal of Proteome Research. - : American Chemical Society (ACS). - 1535-3893 .- 1535-3907. ; 12:9, s. 4187-4192
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Tidskriftsartikel (refereegranskat)abstract
- The filamentous bacterium Streptomyces coelicolor modulates polar growth and branching by phosphorylating the cytoskeletal protein DivIVA. Previous MALDI-TOF analysis of DivIVA showed that a large 7.2 kDa tryptic peptide was multiply phosphorylated. To aid localization of the phosphorylation sites, we introduced additional tryptic cleavage sites into DivIVA, and the resulting phosphopeptides were analyzed by LC-MS/MS. Phosphopeptide isomers could be separated chromatographically, but because of overlapping elution and spectrum quality, site assignment by standard software tools was ambiguous. Because fragment ions carrying the phosphate group are essential for confident localization, large numbers of spectra were collected using targeted LC-MS/MS, and a special script was developed for plotting the elution of site-determining fragments from those spectra under the XIC of the parent ions. Where multiple phosphopeptide isomers were present, the elution of the site-determining y-ions perfectly coincided with the elution of the corresponding phosphopeptide isomer. This method represents a useful tool for user inspection of spectra derived from phosphopeptide isomers and significantly increases confidence when defining phosphorylation sites. In this way, we show that DivIVA is phosphorylated in vivo on five sites in the C-terminal part of the protein (T304, S309, S338, S344, and S355). The data have been deposited to the ProteomeXchange Consortium with identifier PXD00009S.
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| 41. |
- Ziesmer, J., et al.
(författare)
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Vancomycin-Loaded Microneedle Arrays against Methicillin-Resistant Staphylococcus Aureus Skin Infections
- 2021
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Ingår i: Advanced Materials Technologies. - : Wiley. - 2365-709X. ; 6:7, s. 2001307-
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Tidskriftsartikel (refereegranskat)abstract
- Skin and soft tissue infections (SSTIs) caused by methicillin-resistant Staphylococcus aureus (MRSA) are a major healthcare burden, often treated with intravenous injection of the glycopeptide antibiotic vancomycin (VAN). However, low local drug concentration in the skin limits its treatment efficiency, while systemic exposure promotes the development of resistant bacterial strains. Topical administration of VAN on skin is ineffective as its high molecular weight prohibits transdermal penetration. In order to implement a local VAN delivery, microneedle (MN) arrays with a water-insoluble support layer for the controlled administration of VAN into the skin are developed. The utilization of such a support layer results in water-insoluble needle shafts surrounded by drug-loaded water-soluble tips with high drug encapsulation. The developed MN arrays can penetrate the dermal barriers of both porcine and fresh human skin. Permeation studies on porcine skin reveal that the majority of the delivered VAN is retained within the skin. It is shown that the VAN-MN array reduces MRSA growth both in vitro and ex vivo on skin. The developed VAN-MN arrays may be extended to several drugs and may facilitate localized treatment of MRSA-caused skin infections while minimizing adverse systemic effects.
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