| 1. |
- Bodda, C., et al.
(författare)
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HSV1 VP1-2 deubiquitinates STING to block type I interferon expression and promote brain infection
- 2020
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Ingår i: The Journal of experimental medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 217:7
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Tidskriftsartikel (refereegranskat)abstract
- Herpes simplex virus (HSV) is the main cause of viral encephalitis in the Western world, and the type I interferon (IFN) system is important for antiviral control in the brain. Here, we have compared Ifnb induction in mixed murine brain cell cultures by a panel of HSV1 mutants, each devoid of one mechanism to counteract the IFN-stimulating cGAS-STING pathway. We found that a mutant lacking the deubiquitinase (DUB) activity of the VP1-2 protein induced particularly strong expression of Ifnb and IFN-stimulated genes. HSV1 ΔDUB also induced elevated IFN expression in murine and human microglia and exhibited reduced viral replication in the brain. This was associated with increased ubiquitination of STING and elevated phosphorylation of STING, TBK1, and IRF3. VP1-2 associated directly with STING, leading to its deubiquitination. Recruitment of VP1-2 to STING was dependent on K150 of STING, which was ubiquitinated by TRIM32. Thus, the DUB activity of HSV1 VP1-2 is a major viral immune-evasion mechanism in the brain. © 2020 Bodda et al.
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| 2. |
- Hill, M. S., et al.
(författare)
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Reconstruction of Family-Level Phylogenetic Relationships within Demospongiae (Porifera) Using Nuclear Encoded Housekeeping Genes
- 2013
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:1, s. e50437-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Demosponges are challenging for phylogenetic systematics because of their plastic and relatively simple morphologies and many deep divergences between major clades. To improve understanding of the phylogenetic relationships within Demospongiae, we sequenced and analyzed seven nuclear housekeeping genes involved in a variety of cellular functions from a diverse group of sponges. Methodology/Principal Findings: We generated data from each of the four sponge classes (i.e., Calcarea, Demospongiae, Hexactinellida, and Homoscleromorpha), but focused on family-level relationships within demosponges. With data for 21 newly sampled families, our Maximum Likelihood and Bayesian-based approaches recovered previously phylogenetically defined taxa: Keratosap, Myxospongiaep, Spongillidap, Haploscleromorphap (the marine haplosclerids) and Democlaviap. We found conflicting results concerning the relationships of Keratosap and Myxospongiaep to the remaining demosponges, but our results strongly supported a clade of Haploscleromorphap+Spongillidap+Democlaviap. In contrast to hypotheses based on mitochondrial genome and ribosomal data, nuclear housekeeping gene data suggested that freshwater sponges (Spongillidap) are sister to Haploscleromorphap rather than part of Democlaviap. Within Keratosap, we found equivocal results as to the monophyly of Dictyoceratida. Within Myxospongiaep, Chondrosida and Verongida were monophyletic. A well-supported clade within Democlaviap, Tetractinellidap, composed of all sampled members of Astrophorina and Spirophorina (including the only lithistid in our analysis), was consistently revealed as the sister group to all other members of Democlaviap. Within Tetractinellidap, we did not recover monophyletic Astrophorina or Spirophorina. Our results also reaffirmed the monophyly of order Poecilosclerida (excluding Desmacellidae and Raspailiidae), and polyphyly of Hadromerida and Halichondrida. Conclusions/Significance: These results, using an independent nuclear gene set, confirmed many hypotheses based on ribosomal and/or mitochondrial genes, and they also identified clades with low statistical support or clades that conflicted with traditional morphological classification. Our results will serve as a basis for future exploration of these outstanding questions using more taxon- and gene-rich datasets.
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| 3. |
- Caliendo, V, et al.
(författare)
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Transatlantic spread of highly pathogenic avian influenza H5N1 by wild birds from Europe to North America in 2021
- 2022
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Highly pathogenic avian influenza (HPAI) viruses of the A/Goose/Guangdong/1/1996 lineage (GsGd), which threaten the health of poultry, wildlife and humans, are spreading across Asia, Europe, Africa and North America but are currently absent from South America and Oceania. In December 2021, H5N1 HPAI viruses were detected in poultry and a free-living gull in St. John's, Newfoundland and Labrador, Canada. Our phylogenetic analysis showed that these viruses were most closely related to HPAI GsGd viruses circulating in northwestern Europe in spring 2021. Our analysis of wild bird migration suggested that these viruses may have been carried across the Atlantic via Iceland, Greenland/Arctic or pelagic routes. The here documented incursion of HPAI GsGd viruses into North America raises concern for further virus spread across the Americas by wild bird migration.
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| 4. |
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| 5. |
- Schamai, Wladimir, et al.
(författare)
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Execution of UML state machines using modelica
- 2010
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Ingår i: Proceedings of the 3rd International Workshop on Equation-Based Object-Oriented Modeling Languages and Tools, EOOLT 2010 - In Conjunction with MODELS 2010. - : Linköping University Electronic Press. - 9789175198248 ; , s. 1-10
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Konferensbidrag (refereegranskat)abstract
- ModelicaML is a UML profile for the creation of executable models. ModelicaML supports the Model-Based Systems Engineering (MBSE) paradigm and combines the power of the OMG UML standardized graphical notation for systems and software modeling, and the simulation power of Modelica. This addresses the increasing need for precise integrated modeling of products containing both software and hardware. This paper focuses on the implementation of executable UML state machines in ModelicaML and demonstrates that using Modelica as an action language enables the integrated modeling and simulation of continuous-time and reactive or event-based system dynamics. More specifically, this paper highlights issues that are identified in the UML specification and that are experienced with typical executable implementations of UML state machines. The issues identified are resolved and rationales for design decisions taken are discussed.
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| 6. |
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| 7. |
- Donnadieu, P., et al.
(författare)
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Deformation at ambient and high temperature of in situ Laves phases-ferrite composites
- 2014
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Ingår i: Science and Technology of Advanced Materials. - : Informa UK Limited. - 1468-6996 .- 1878-5514. ; 15:3
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Tidskriftsartikel (refereegranskat)abstract
- The mechanical behavior of a Fe80Zr10Cr10 alloy has been studied at ambient and high temperature. This Fe 80Zr10Cr10 alloy, whoose microstructure is formed by alternate lamellae of Laves phase and ferrite, constitutes a very simple example of an in situ CMA phase composite. The role of the Laves phase type was investigated in a previous study while the present work focuses on the influence of the microstructure length scale owing to a series of alloys cast at different cooling rates that display microstructures with Laves phase lamellae width ranging from ∼50 nm to ∼150 nm. Room temperature compression tests have revealed a very high strength (up to 2 GPa) combined with a very high ductility (up to 35%). Both strength and ductility increase with reduction of the lamella width. High temperature compression tests have shown that a high strength (900 MPa) is maintained up to 873 K. Microstructural study of the deformed samples suggests that the confinement of dislocations in the ferrite lamellae is responsible for strengthening at both ambient and high temperature. The microstructure scale in addition to CMA phase structural features stands then as a key parameter for optimization of mechanical properties of CMA in situ composites. © 2014 National Institute for Materials Science.
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| 8. |
- 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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| 9. |
- Mauritsen, Thorsten, et al.
(författare)
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Developments in the MPI-M Earth System Model version 1.2 (MPI-ESM1.2) and Its Response to Increasing CO2
- 2019
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Ingår i: Journal of Advances in Modeling Earth Systems. - 1942-2466. ; 11:4, s. 998-1038
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Tidskriftsartikel (refereegranskat)abstract
- A new release of the Max Planck Institute for Meteorology Earth System Model version 1.2 (MPI-ESM1.2) is presented. The development focused on correcting errors in and improving the physical processes representation, as well as improving the computational performance, versatility, and overall user friendliness. In addition to new radiation and aerosol parameterizations of the atmosphere, several relatively large, but partly compensating, coding errors in the model's cloud, convection, and turbulence parameterizations were corrected. The representation of land processes was refined by introducing a multilayer soil hydrology scheme, extending the land biogeochemistry to include the nitrogen cycle, replacing the soil and litter decomposition model and improving the representation of wildfires. The ocean biogeochemistry now represents cyanobacteria prognostically in order to capture the response of nitrogen fixation to changing climate conditions and further includes improved detritus settling and numerous other refinements. As something new, in addition to limiting drift and minimizing certain biases, the instrumental record warming was explicitly taken into account during the tuning process. To this end, a very high climate sensitivity of around 7 K caused by low-level clouds in the tropics as found in an intermediate model version was addressed, as it was not deemed possible to match observed warming otherwise. As a result, the model has a climate sensitivity to a doubling of CO2 over preindustrial conditions of 2.77 K, maintaining the previously identified highly nonlinear global mean response to increasing CO2 forcing, which nonetheless can be represented by a simple two-layer model.
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| 10. |
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| 11. |
- Parreiras, Lucas S., et al.
(författare)
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Engineering and two-stage evolution of a lignocellulosic hydrolysate-tolerant Saccharomyces cerevisiae strain for anaerobic fermentation of xylose from AFEX pretreated corn stover
- 2014
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:9
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Tidskriftsartikel (refereegranskat)abstract
- The inability of the yeast Saccharomyces cerevisiae to ferment xylose effectively under anaerobic conditions is a major barrier to economical production of lignocellulosic biofuels. Although genetic approaches have enabled engineering of S. cerevisiae to convert xylose efficiently into ethanol in defined lab medium, few strains are able to ferment xylose from lignocellulosic hydrolysates in the absence of oxygen. This limited xylose conversion is believed to result from small molecules generated during biomass pretreatment and hydrolysis, which induce cellular stress and impair metabolism. Here, we describe the development of a xylose-fermenting S. cerevisiae strain with tolerance to a range of pretreated and hydrolyzed lignocellulose, including Ammonia Fiber Expansion (AFEX)-pretreated corn stover hydrolysate (ACSH). We genetically engineered a hydrolysate-resistant yeast strain with bacterial xylose isomerase and then applied two separate stages of aerobic and anaerobic directed evolution. The emergent S. cerevisiae strain rapidly converted xylose from lab medium and ACSH to ethanol under strict anaerobic conditions. Metabolomic, genetic and biochemical analyses suggested that a missense mutation in GRE3, which was acquired during the anaerobic evolution, contributed toward improved xylose conversion by reducing intracellular production of xylitol, an inhibitor of xylose isomerase. These results validate our combinatorial approach, which utilized phenotypic strain selection, rational engineering and directed evolution for the generation of a robust S. cerevisiae strain with the ability to ferment xylose anaerobically from ACSH.
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| 12. |
- Pérez, Lance C., et al.
(författare)
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Information Assurance Education in Two- and Four-Year Institutions
- 2011
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Ingår i: Proceedings of the 2011 ITiCSE Working Group Reports (ITiCSE-WGR’11). - New York, NY, USA : ACM. ; , s. 39-53
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Konferensbidrag (refereegranskat)abstract
- The 2011 ITiCSE working group on information assurance (IA) education examined undergraduate curricula at the two- and four-year levels, both within and outside the United States (US). A broad set of two-year IA degree programs were examined in order to get a sense of similarities and differences between them. A broad set of four-year IA degree programs were also examined to explore their similarities and differences. A comparison between the two-year and four-year degree programs revealed that the common challenge of articulation between two- and four-year programs exists in IA as well. The challenge of articulation was explored in some depth in order to understand what remedies might be available. Finally, a number of IA programs at international institutions were examined in order to gain insight into differences between US and non-US IA programs.
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