Symbolic computation with monotone operators

We consider a class of monotone operators which are appropriate for symbolic representation and manipulation within a computer algebra system. Various structural properties of the class (e.g., closure under taking inverses, resolvents) are investigated as well as the role played by maximal monotonicity within the class. In particular, we show that there is a natural correspondence between our class of monotone operators and the subdifferentials of convex functions belonging to a class of convex functions deemed suitable for symbolic computation of Fenchel conjugates which were previously studied by Bauschke & von Mohrenschildt and by Borwein & Hamilton. A number of illustrative examples utilizing the introduced class of operators are provided including computation of proximity operators, recovery of a convex penalty function associated with the hard thresholding operator, and computation of superexpectations, superdistributions and superquantiles with specialization to risk measures.Comment: 17 pages, 2 figure

Fertility, Living Arrangements, Care and Mobility

There are four main interconnecting themes around which the contributions in this book are based. This introductory chapter aims to establish the broad context for the chapters that follow by discussing each of the themes. It does so by setting these themes within the overarching demographic challenge of the twenty-first century – demographic ageing. Each chapter is introduced in the context of the specific theme to which it primarily relates and there is a summary of the data sets used by the contributors to illustrate the wide range of cross-sectional and longitudinal data analysed

Heparin increases the antibiotic efficacy of colistin

The increasing antibiotic resistance in bacteria is an alarming phenomenon all around the world. Certain strains have developed resistance against multiple antimicrobial molecules, in which cases, the final option is to use a last-resort drug. These drugs, however, are last-resort for a reason: they can pose serious risk on vital organ functions in the patient. To mitigate the risk of severe side-effects and to reduce the rate of bacterial mutation, co-administration with other molecules that increase their efficacy seems to be the only suitable option. This leads to a reduced dose while maintaining the same level of antibiotic activity within the body. In this study, the effect of heparin derivatives on the antibiotic activity of colistin and their interactions were studied by ion mobility, mass spectrometry, and bacterium growth assays. The results show that during the association of colistin and heparin, they retain their structure while higher- stoichiometry complexes can form. When long-chain heparin is co-administered, multiple colistin molecules can associate with it, which increases the antibiotic activity by ~40% relative to the sole administration of colistin.<br

Polysulfate hemmen durch elektrostatische Wechselwirkungen die SARS-CoV-2-Infektion

Wir zeigen, dass negativ geladene Polysulfate durch elektrostatische Wechselwirkungen an das Spike-Protein von SARS-CoV-2 binden. Durch einen Plaquereduktionstest verglichen wir die hemmende Wirkung von Heparin, Pentosanpolysulfat, linearem Polyglycerolsulfat (LPGS) und hyperverzweigtem Polyglycerolsulfat (HPGS) gegengber SARSCoV-2. Dabei ist das synthetische LPGS der vielversprechendste Inhibitor mit IC50=67 μgmL-1 (ca. 1,6 μm) und zeigt eine 60-fach hçhere virushemmende Aktivität als Heparin (IC50=4084 μgmL-1) bei zugleich deutlich geringerer gerinnungshemmender Aktivität. Außerdem konnten wir durch Moleküldynamiksimulationen bestätigen, dass LPGS stärker an das Spike-Protein bindet als Heparin selbst und dass LPGS sogar noch stärker an die Spike-Proteine der neuen N501Yund E484K-Varianten bindet. Unsere Studien belegen, dass die Aufnahme von SARS-CoV-2 in Wirtzellen über elektrostatische Wechselwirkungen blockiert werden kann. Deshalb kann LPGS als vielversprechender Prototyp für das Design weiterer neuartiger viraler Inhibitoren von SARS-CoV-2 herangezogen werden

Polysulfates block SARS-CoV-2 uptake through electrostatic interactions

Here we report that negatively charged polysulfates can bind to the spike protein of SARS-CoV-2 via electrostatic interactions. Using a plaque reduction assay, we compare inhibition of SARS-CoV-2 by heparin, pentosan sulfate, linear polyglycerol sulfate (LPGS) and hyperbranched polyglycerol sulfate (HPGS). Highly sulfated LPGS is the optimal inhibitor, with a half-maximal inhibitory concentration (IC50) of 67 μg/mL (approx.1.6 μM). This synthetic polysulfates exhibit more than 60-fold higher virus inhibitory activity than heparin (IC50: 4084μg/mL), along with much lower anticoagulant activity. Furthermore, in molecular dynamics simulations, we verified that LPGS can bind stronger to the spike protein than heparin, and that LPGS can interact even morewith the spike protein of the new N501Y and E484K variants. Our study demonstrates that the entry of SARS-CoV-2 into host cells can be blocked via electrostatic interaction, therefore LPGS can serve as a blueprint for the design of novel viral inhibitors of SARS-CoV-2

Functionalized fullerene for inhibition of SARS-CoV-2 variants

As virus outbreaks continue to pose a challenge, a nonspecific viral inhibitor can provide significant benefits, especially against respiratory viruses. Polyglycerol sulfates recently emerge as promising agents that mediate interactions between cells and viruses through electrostatics, leading to virus inhibition. Similarly, hydrophobic C60 fullerene can prevent virus infection via interactions with hydrophobic cavities of surface proteins. Here, two strategies are combined to inhibit infection of SARS-CoV-2 variants in vitro. Effective inhibitory concentrations in the millimolar range highlight the significance of bare fullerene's hydrophobic moiety and electrostatic interactions of polysulfates with surface proteins of SARS-CoV-2. Furthermore, microscale thermophoresis measurements support that fullerene linear polyglycerol sulfates interact with the SARS-CoV-2 virus via its spike protein, and highlight importance of electrostatic interactions within it. All-atom molecular dynamics simulations reveal that the fullerene binding site is situated close to the receptor binding domain, within 4 nm of polyglycerol sulfate binding sites, feasibly allowing both portions of the material to interact simultaneously

Validation of GEMS tropospheric NO2 columns and their diurnal variation with ground-based DOAS measurements

Instruments for air quality observations on geostationary satellites provide multiple observations per day and allow for the analysis of the diurnal variation in important air pollutants such as nitrogen dioxide (NO2). The South Korean instrument GEMS (Geostationary Environmental Monitoring Spectrometer), launched in February 2020, is the first geostationary instrument that is able to observe the diurnal variation in NO2. The measurements have a spatial resolution of 3.5 km × 8 km and cover a large part of Asia. This study compares 1 year of tropospheric NO2 vertical column density (VCD) observations from the operational GEMS L2 product, the scientific GEMS IUP-UB (Institute of Environmental Physics at the University of Bremen) product, the operational TROPOspheric Monitoring Instrument (TROPOMI) product, and ground-based differential optical absorption spectroscopy (DOAS) measurements in South Korea. The GEMS L2 tropospheric NO2 VCDs overestimate the ground-based tropospheric NO2 VCDs with a median relative difference of +61 % and a correlation coefficient of 0.76. The median relative difference is −2 % for the GEMS IUP-UB product and −16 % for the TROPOMI product, with correlation coefficients of 0.83 and 0.89, respectively. The scatter in the GEMS products can be reduced when observations are limited to the TROPOMI overpass time. Diurnal variations in tropospheric NO2 VCDs differ by the pollution level of the analyzed site but with good agreement between the GEMS IUP-UB and ground-based observations. Low-pollution sites show weak or almost no diurnal variation. In summer, the polluted sites show a minimum around noon, indicating the large influence of photochemical loss. Most variation is seen in spring and autumn, with increasing NO2 in the morning, a maximum close to noon, and a decrease towards the afternoon. Winter observations show rather flat or slightly decreasing NO2 throughout the day. Winter observations under low-wind-speed conditions at high-pollution sites show enhancements of NO2 throughout the day. This indicates that under calm conditions, dilution and the less effective chemical loss in winter do not balance the accumulating emissions. Diurnal variation observed at a low-pollution site follows seasonal wind patterns. A weekday–weekend effect analysis shows good agreement between the different products. However, the GEMS L2 product, while agreeing with the other data sets on weekdays, shows significantly less reduction on weekends. The influence of the stratospheric contribution and the surface reflectivity product on the satellite tropospheric NO2 VCD products is investigated. While the TM5 model's stratospheric VCDs, used in the TROPOMI product, are too high, resulting in tropospheric NO2 VCDs that are too low and even negative, when used in the GEMS IUP-UB retrieval, the GEMS L2 stratospheric VCD is too low. Surface reflectivity comparisons indicate that the GEMS L2 reflectivity makes a large contribution to the observed overestimation and scatter

Unterstützung kommunalplanerischer Prozesse mit CityGLM-basierter Anbindung Modelica-getriebener Quartierssimulationen

Eine integrale Planung städtischer (Energie-)Systeme bedarf einer planungsbegleitenden Unterstützung durch IT-basierte Planungs- und Simulationswerkzeuge. Die durchgängige Anwendung dieser digitalen Planungshilfsmittel wird allerdings bislang insbesondere durch den sehr hohen Aufwand bei der Spezifizierung und Erfassung benötigter Datengrundlagen sowie eine mangelhafte Interoperabilität zwischen den Systemen gehemmt. Im Rahmen eines Forschungsverbundprojektes wird dieses Problemfeld mittels praxisbezogener Prozessanalysen genauer spezifiziert und die technische und fachliche Integration durch die prozessbezogene Spezifikation relevanter Informationsbedarfe sowie die Entwicklung einer darauf aufbauenden, bidirektionalen Schnittstelle auf Basis des etablierten virtuellen Stadtmodellstandards CityGML verbessert. Als exemplarisches Anwendungsszenario innerhalb kommunaler Planungsprozesse wurde die Ausweisung von Vorranggebieten der Fernwärmenutzung basierend auf einer räumlichen Analyse des Wärmebedarfs für verschiedene Entwicklungsszenarien mittels einer bidirektionalen standard-basierten Koppelung von CityGML und Modelica ausgearbeitet

Exploring mechanisms of lipid nanoparticle-mucus interactions in healthy and cystic fibrosis conditions

Mucus forms the first defense line of human lungs, and as such hampers the efficient delivery of therapeutics to the underlying epithelium. This holds particularly true for genetic cargo such as CRISPR-based gene editing tools which cannot readily surmount the mucosal barrier. While lipid nanoparticles (LNPs) emerge as versatile non-viral gene delivery systems that can help overcome the delivery challenge, many knowledge gaps remain, especially for diseased states such as cystic fibrosis (CF). This study provides fundamental insights into Cas9 mRNA or ribonucleoprotein-loaded LNP-mucus interactions in healthy and diseased states by assessing the impact of the genetic cargo, mucin sialylation, mucin concentration, ionic strength, pH, and polyethylene glycol (PEG) concentration and nature on LNP diffusivity leveraging experimental approaches and Brownian dynamics (BD) simulations. Taken together, this study identifies key mucus and LNP characteristics that are critical to enabling a rational LNP design for transmucosal delivery