a comparison of Venus express ASPERA-4 measurements with 3D hybrid simulations

The thesis deals with the investigation of the plasma environment of Venus using data of the ASPERA-4 (Analyzer of Space Plasmas and Energetic Atoms) experiment onboard the Venus Express (VEX) spacecraft as well as a 3D hybrid code in order to study the solar wind - atmosphere interaction of an unmagnetized planet. (1) Data Analysis: By using data from the ion and electron spectrometers, the shapes and average locations of the plasma boundaries (bow shock, upper and lower boundary of the mantle region) around the planet are determined. Additionally, the variation of the terminator bow shock position is analyzed as a function of the solar wind dynamic pressure and solar EUV flux. It is demonstrated that the shock location is insensitive to the upstream ram pressure and that the changes in the solar EUV radiation are too small over the period of the VEX observations to analyze solar activity dependence.thesi

Die globale Plasmaumgebung der Venus: ein Vergleich von Venus Express ASPERA-4 Messungen mit 3D Hybrid Simulationen

The thesis deals with the investigation of the plasma environment of Venus using data of the ASPERA-4 (Analyzer of Space Plasmas and Energetic Atoms) experiment onboard the Venus Express (VEX) spacecraft as well as a 3D hybrid code in order to study the solar wind-atmosphere interaction of an unmagnetized planet. By using data from the ion and electron spectrometers, the shapes and average locations of the plasma boundaries around the planet are determined. Additionally, the variation of the terminator bow shock position is analyzed as a function of the solar wind dynamic pressure and solar EUV flux. It is demonstrated that the shock location is insensitive to the upstream ram pressure and that the changes in the solar EUV radiation are too small over the period of the VEX observations to analyze solar activity dependence. The results of this data analysis and earlier studies are qualitatively compared with three-dimensional hybrid simulations which are based on VEX observations during low solar activity. But also simulations with PVO input parameters typical for solar maximum conditions are performed and compared with the VEX simulation results. The main focus of this study is the comparison of the plasma and magnetic field measurements provided by VEX with the results of three-dimensional hybrid simulations. The hybrid model is able to produce an adequate picture of the global plasma dynamics and processes at Venus. The positions of the plasma boundaries are well reproduced by the model and the simulated parameters are in fairly good agreement with the values measured by the ASPERA-4 and Magnetometer instruments.In dieser Doktorarbeit wird die globale Plasmaumgebung der Venus mittels der Daten des ASPERA-4 Experiments (Analyzer of Space Plasmas and Energetic Atoms) an Board der Venus Express Raumsonde und eines 3-dimensionalen Hybrid Modells untersucht, um die Sonnenwind-Atmosphären Wechselwirkung eines unmagnetisierten Planeten zu studieren. Die Messungen der Ionen- und Elektronenspektrometer werden zur Bestimmung der Formen und durchschnittlichen Positionen der Plasmagrenzschichten um den Planeten Venus herangezogen. Zusätzlich wird die Abhängigkeit der Position der Bugstoßwelle am Terminator vom Anströmdruck des Sonnenwindes untersucht. Es wird gezeigt, dass die Schockposition vom dynamischen Druck des Sonnenwindes unabhängig ist, und dass die Änderungen der solaren EUV Strahlung über den VEX Beobachtungszeitraum zu klein ist, um die Abhängigkeit von der Sonnenaktivität zu untersuchen. Die Ergebnisse dieser Datenanalyse sowie früherer Studien werden mit 3-dimensionalen Hybrid Simulationsergebnissen verglichen, welche auf VEX Beobachtungen während niedriger Sonnenaktivität beruhen. Außerdem werden auch Simulationen basierend auf PVO Eingabeparametern, die hohe Sonnenaktivität repräsentieren, durchgeführt und mit VEX Simulationsergebnissen verglichen. Der Schwerpunkt dieser Arbeit liegt im Vergleich von Plasma- und Magnetfeldbeobachtungen gemessen an Board der VEX Raumsonde mit den Ergebnissen von 3-dimensionalen Hybrid Simulationen. Das Hybrid Modell ist in der Lage, ein adäquates und angemessenes Bild von der globalen Plasmadynamik und den Plasmaprozessen bei der Venus zu liefern. Die Positionen der Plasmagrenzschichten können vom Modell reproduziert werden und die simulierten Parameter stimmen ziemlich gut mit den gemessenen Werten überein, die vom ASPERA-4 Experiment und dem Magnetometer Instrument beobachtet werden

Multi-scale modeling of drug binding kinetics to predict drug efficacy

Optimizing drug therapies for any disease requires a solid understanding of pharmacokinetics (the drug concentration at a given time point in different body compartments) and pharmacodynamics (the effect a drug has at a given concentration). Mathematical models are frequently used to infer drug concentrations over time based on infrequent sampling and/or in inaccessible body compartments. Models are also used to translate drug action from in vitro to in vivo conditions or from animal models to human patients. Recently, mathematical models that incorporate drug-target binding and subsequent downstream responses have been shown to advance our understanding and increase predictive power of drug efficacy predictions. We here discuss current approaches of modeling drug binding kinetics that aim at improving model-based drug development in the future. This in turn might aid in reducing the large number of failed clinical trials

Microglia protect against brain injury and their selective elimination dysregulates neuronal network activity after stroke

Microglia are the main immune cells of the brain and contribute to common brain diseases. However, it is unclear how microglia influence neuronal activity and survival in the injured brain in vivo. Here we develop a precisely controlled model of brain injury induced by cerebral ischaemia combined with fast in vivo two-photon calcium imaging and selective microglial manipulation. We show that selective elimination of microglia leads to a striking, 60% increase in infarct size, which is reversed by microglial repopulation. Microglia-mediated protection includes reduction of excitotoxic injury, since an absence of microglia leads to dysregulated neuronal calcium responses, calcium overload and increased neuronal death. Furthermore, the incidence of spreading depolarization (SD) is markedly reduced in the absence of microglia. Thus, microglia are involved in changes in neuronal network activity and SD after brain injury in vivo that could have important implications for common brain diseases

All nonadherence is equal but is some more equal than others? Tuberculosis in the digital era

Adherence to treatment for tuberculosis (TB) has been a concern for many decades, resulting in the World Health Organization's recommendation of the direct observation of treatment in the 1990s. Recent advances in digital adherence technologies (DATs) have renewed discussion on how to best address nonadherence, as well as offering important information on dose-by-dose adherence patterns and their variability between countries and settings. Previous studies have largely focussed on percentage thresholds to delineate sufficient adherence, but this is misleading and limited, given the complex and dynamic nature of adherence over the treatment course. Instead, we apply a standardised taxonomy – as adopted by the international adherence community – to dose-by-dose medication-taking data, which divides missed doses into 1) late/noninitiation (starting treatment later than expected/not starting), 2) discontinuation (ending treatment early), and 3) suboptimal implementation (intermittent missed doses). Using this taxonomy, we can consider the implications of different forms of nonadherence for intervention and regimen design. For example, can treatment regimens be adapted to increase the “forgiveness” of common patterns of suboptimal implementation to protect against treatment failure and the development of drug resistance? Is it reasonable to treat all missed doses of treatment as equally problematic and equally common when deploying DATs? Can DAT data be used to indicate the patients that need enhanced levels of support during their treatment course? Critically, we pinpoint key areas where knowledge regarding treatment adherence is sparse and impeding scientific progress

Microglia control the spread of neurotropic virus infection via P2Y12 signalling and recruit monocytes through P2Y12-independent mechanisms

Neurotropic herpesviruses can establish lifelong infection in humans and contribute to severe diseases including encephalitis and neurodegeneration. However, the mechanisms through which the brain's immune system recognizes and controls viral infections propagating across synaptically linked neuronal circuits have remained unclear. Using a well-established model of alphaherpesvirus infection that reaches the brain exclusively via retrograde transsynaptic spread from the periphery, and in vivo two-photon imaging combined with high resolution microscopy, we show that microglia are recruited to and isolate infected neurons within hours. Selective elimination of microglia results in a marked increase in the spread of infection and egress of viral particles into the brain parenchyma, which are associated with diverse neurological symptoms. Microglia recruitment and clearance of infected cells require cell-autonomous P2Y12 signalling in microglia, triggered by nucleotides released from affected neurons. In turn, we identify microglia as key contributors to monocyte recruitment into the inflamed brain, which process is largely independent of P2Y12. P2Y12-positive microglia are also recruited to infected neurons in the human brain during viral encephalitis and both microglial responses and leukocyte numbers correlate with the severity of infection. Thus, our data identify a key role for microglial P2Y12 in defence against neurotropic viruses, whilst P2Y12-independent actions of microglia may contribute to neuroinflammation by facilitating monocyte recruitment to the sites of infection

Perspectives for systems biology in the management of tuberculosis

Standardised management of tuberculosis may soon be replaced by individualised, precision medicine-guided therapies informed with knowledge provided by the field of systems biology. Systems biology is a rapidly expanding field of computational and mathematical analysis and modelling of complex biological systems that can provide insights into mechanisms underlying tuberculosis, identify novel biomarkers, and help to optimise prevention, diagnosis and treatment of disease. These advances are critically important in the context of the evolving epidemic of drug-resistant tuberculosis. Here, we review the available evidence on the role of systems biology approaches - human and mycobacterial genomics and transcriptomics, proteomics, lipidomics/metabolomics, immunophenotyping, systems pharmacology and gut microbiomes - in the management of tuberculosis including prediction of risk for disease progression, severity of mycobacterial virulence and drug resistance, adverse events, comorbidities, response to therapy and treatment outcomes. Application of the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach demonstrated that at present most of the studies provide "very low" certainty of evidence for answering clinically relevant questions. Further studies in large prospective cohorts of patients, including randomised clinical trials, are necessary to assess the applicability of the findings in tuberculosis prevention and more efficient clinical management of patients.Publisher PDFPeer reviewe

All non-adherence is equal, but is some more equal than others? TB in the digital era

Karina Kielmann - ORCID 0000-0001-5519-1658 https://orcid.org/0000-0001-5519-1658Aaron S. Karat - ORCID 0000-0001-9643-664X https://orcid.org/0000-0001-9643-664XReplaced AM with VoR 2020-11-06Adherence to treatment for tuberculosis (TB) has been a concern for many decades, resulting in the World Health Organization’s recommendation of the direct observation of treatment in the 1990s. Recent advances in digital adherence technologies (DATs) have renewed discussion on how to best address non-adherence, as well as offering important information on dose-by-dose adherence patterns and their variability between countries and settings. Previous studies have largely focussed on percentage thresholds to delineate sufficient adherence, but this is misleading and limited, given the complex and dynamic nature of adherence over the treatment course. Instead, we apply a standardised taxonomy- as adopted by the international adherence community- to dose-by-dose medication-taking data, which divides missed doses into a) late/non-initiation (starting treatment later than expected/not starting), b) discontinuation (ending treatment early), and c) suboptimal implementation (intermittent missed doses). Using this taxonomy, we can consider the implications of different forms of non-adherence for intervention and regimen design. For example, can treatment regimens be adapted to increase the ‘forgiveness’ of common patterns of suboptimal implementation to protect against treatment failure and the development of drug resistance? Is it reasonable to treat all missed doses of treatment as equally problematic and equally common when deploying DATs? Can DAT data be used to indicate the patients that need enhanced levels of support during their treatment course? Critically, we pinpoint key areas where knowledge regarding treatment adherence is sparse and impeding scientific progress.https://doi.org/10.1183/23120541.00315-20206pubpub