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Die Autor*innen erörtern Chancen und Herausforderungen der Interaktion im digitalen Raum, exemplifiziert an der digitalen Workshopreihe „Sprachliche Vielfalt mit digitalen Medien fördern, nutzen und gestalten“ (Lehr-Lern-Atelier des Instituts für Sprachen und Mehrsprachigkeit). Die Workshopreihe adressiert den Umgang mit sprachlicher, kultureller und ethnischer Heterogenität und zielt gleichzeitig auf eine Förderung digitalisierungsbezogener Kompetenzen von Lehrkräften ab. Die Autor*innen zeigen auf, wie Selbstlern- und kollaborative Arbeitsphasen sowie innovative Austauschformate – vor dem Hintergrund der Pandemiebedingungen – eine Interaktion zwischen den Teilnehmenden (auch) im digitalen Raum initiieren können. (DIPF/Orig.)

Dissertation, RWTH Aachen University, 2021; Aachen : RWTH Aachen University 1 Online-Ressource : Illustrationen (2021). = Dissertation, RWTH Aachen University, 2021, The Alzheimer’s disease (AD) is one of the best known neurodegenerative diseases. A main hallmark is the accumulation of the extracellular beta amyloid (Aβ) peptides. In addition to the characteristic neurodegeneration, neuroinflammation has become the focus of research in recent years. Therapeutic approaches to influence the inflammatory response require a starting point, which is often found in receptors. One group of these receptors is the family of formyl peptide receptors (FPRs). In order to decipher the exact role of these FPRs in AD, different approaches were used in this study to analyze the development of amyloid beta plaque formation, neuroinflammation and neurodegeneration. Using an AD mouse model (APP/PS1), two with an additional Fpr1 or Fpr2 deficit, these key points were examined. In a second approach, the Fpr2 antagonist WRW4 was administered APP/PS1 mice over a period of 20 weeks. The animals first underwent a Morris water maze (MWM) and were then examined immunohistochemically as well as on molecular biological level. The experiments demonstrated that spatial orientation and memory performance of Alzheimer's mice were additionally impaired by Fpr2 KO as well as Fpr2 inhibition. This could not be determined for Fpr1 KO. A Fpr1 and Fpr2 KO in APP/PS1 seems to reduce neuronal death, whereas Fpr2 inhibition with WRW4 does not induce this positive effect. Furthermore, slightly altered gene expression of neurotrophic factors was detected in Fpr-deficient mice. Alzheimer-induced astrogliosis is partially exacerbated by Fpr KO or inhibition, whereas the characteristic microgliosis tends to be attenuated by Fpr KO. Although the morphology of the cells is still altered, as in AD characteristic, the amount of microglial cells around amyloid plaques is reduced. In addition, gene expression of the anti-inflammatory interleukin 10 (Il-10) is enhanced in Fpr-deficient APP/PS1 mice. Fpr1 KO caused a reduced number of Aβ plaques, whereas a Fpr2 deficit and Fpr2 inhibition only tended to do so. In summary, it is interesting to note that the Fpr1 deficit in particular have a potential positive effect on the progression of AD and could be a suitable starting point for potential therapeutics., Published by RWTH Aachen University, Aachen

Background Bacterial meningitis is still a cause of severe neurological disability. The brain is protected from penetrating pathogens by the blood-brain barrier and the innate immune system. The invading pathogens are recognized by pattern recognition receptors including the G-protein-coupled formyl peptide receptors (FPRs), which are expressed by immune cells of the central nervous system. FPRs show a broad spectrum of ligands, including pro- and anti-inflammatory ones. Here, we investigated the effects of the annexin A1 mimetic peptide Ac2-26 in a mouse model of pneumococcal meningitis. Methods Wildtype (WT) and Fpr1- and Fpr2-deficient mice were intrathecally infected with Streptococcus pneumoniae D39 (type 2). Subsequently, the different mice groups were treated by intraperitoneal injections of Ac2-26 (1 mg/kg body weight) 2, 8, and 24 h post-infection. The extent of inflammation was analyzed in various brain regions by means of immunohistochemistry and real-time reverse transcription polymerase chain reaction (RT-PCR) 30 h post-infection. Results Ac2-26-treated WT mice showed less severe neutrophil infiltration, paralleled by a reduced induction of pro-inflammatory glial cell responses in the hippocampal formation and cortex. While meningitis was ameliorated in Ac2-26-treated Fpr1-deficient mice, this protective effect was not observed in Fpr2-deficient mice. Irrespective of Ac2-26 treatment, inflammation was more severe in Fpr2-deficient compared to Fpr1-deficient mice. Conclusions In summary, this study demonstrates anti-inflammatory properties of Ac2-26 in a model of bacterial meningitis, which are mediated via FPR2, but not FPR1. Ac2-26 and other FPR2 modulators might be promising targets for the development of novel therapies for Streptococcus pneumoniae-induced meningitis.

Additional file 1: Fig. S1. Physical condition of animals is not affected neither in APP/PS1 mice nor by FPR ligands. To analyze the animals physical condition we used the Morris water maze. The average speed [m/s] of the flagged trials were recorded for each animal. There were no differences regarding the condition between the groups (two-way ANOVA with Turkey’s post hoc test). The data represent mean + SEM, n>11. Fig. S2. Illustration of Morris water maze training trials To investigate long-term memory we used the Morris water maze test. To analyze the learning process we used the latency time [s] of the training trials (1-12). Learning curves are separated for a better overview in A) WT group and B) in APP/PS1 mice group. The findings demonstrated that the animals improved their performance over one day (trial 1-6). Data represent mean + SEM; n > 11. Fig. S3. Quantification of amyloid-β 1-42 phagocytosis of microglial cells by flow cytometry. Cells were isolated from adult mice brains 3h after intraperitoneal injection of methoxy-04. Exemplary graphs of each group shows the evaluation of the phagocytosis rate (Q2). Fig. S4. FPR modulation does not affect astrocytes in APP/PS1 mice A) GFAP positive cells/mm² in the hippocampus where increased from WT control to APP/PS1 control mice.B) Also in the cortex we could see the same increased amount of GFAP positive cells in APP/PS1 control mice compared to WT control (n>15) C) Exemplary anti-GFAP staining’s of WT, APP/PS1 and APP/PS1+Boc2 mice in the cortex. D) Relative expression of Gfap mRNA in the hippocampus showed no differences but E) in the cortex we detected an increased Gfap mRNA expression in APP/PS1 control mice (n>6, ). Scale bar c 50 μm. Shown are the mean values of each group with SEM. Two-way ANOVA with turkey test *p

Jedes eingenommene Medikament durchläuft im menschlichen Organismus pharmakologische Prozesse, die zu einer Wirkung führen. Dabei weist jedes Arzneimittel individuelle Eigenschaften auf, die diesen Wirkmechanismus beeinflussen. Medikamente mit geringer Halbwertszeit verlassen den Organismus demzufolge nach kurzer Zeit. Doch sind solche Substanzen trotz kurzer Aufenthaltsdauer im Körper, in der Lage ausreichend und sicher zu wirken, insbesondere bei nur einmaliger Applikation pro Tag? Besteht zudem eine Möglichkeit diese Wirkung und die im Blutplasma erreichten Wirkstoffkonzentrationen theoretisch zu ermitteln, ohne aufwendige Blutuntersuchungen durchführen zu müssen? Diese Zusammenhänge sollen mit einem entwickelten Modell zur Simulation von Wirkstoffkonzentrationsverläufen von Arzneimitteln geprüft werden. Dieses in Form eines Tabellenblatt (Microsoft Excel) vorliegende Modell ermöglicht, die Wirkung eines Medikamentes zu bewerten, indem dessen Wirkstoffkonzentration nach oraler Verabreichung im Blut berechnet und grafisch dargestellt wird. Dazu wurde ein Datensatz von 1023 Arzneimitteln bearbeitet, von denen 22 Medikamente die für eine Simulation notwendigen Kriterien erfüllten. Diese wurden simuliert, hinsichtlich ihrer Wirksamkeit und Sicherheit analysiert und mit klinischen Studienergebnissen verglichen, um die Anwendbarkeit des Modells beurteilen zu können. Bei 18 der 22 analysierten Substanzen stimmten die simulierten Wirkstoffkonzentrationsverläufe mit den Ergebnissen durchgeführter Studien überein. Dadurch konnte den Medikamenten trotz kurzer Halbwertszeit eine ausreichende Wirkung nachgewiesen und die Aussagekraft des Modells positiv bewertet werden. Jedoch wurde festgestellt, dass es bei 11 dieser Arzneimittel bei spezifischen Patientengruppen zu einem nicht ausreichenden Effekt oder Nebenwirkungen durch Unter- oder Überschreitung des therapeutischen Bereiches kommen könnte. Hier wurden die Einnahmeschemata überarbeitet, um den Wirkeffekt zu optimieren. Bei vier der 22 Medikamente bestanden Diskrepanzen zwischen den Ergebnissen der Simulation und Studien, wodurch Defizite des Modells offen gelegt werden konnten. Mit diesem Projekt wurde bewiesen, dass Medikamente trotz kurzer Halbwertszeit fähig sind, effektiv zu wirken. Der Effekt wird jedoch nicht ausschließlich durch die Eliminationszeit beeinflusst, sondern ebenso durch individuelle Patienteneigenschaften, die zu Wirkungsänderungen führen können. Die Dosisanpassung an diese Individualität findet im klinischen Alltag häufig keine Berücksichtigung, sondern erfolgt meist anhand der von den Pharmaherstellern empfohlenen Mengen und anschließender Beobachtung der Dosis-Wirkung-Beziehung. Eine Möglichkeit die Medikamentendosis auf die Bedürfnisse des Patienten abzustimmen, bietet die Medikamentenspiegelbestimmung, die jedoch nur bei ausgewählten Medikamenten routiniert Anwendung findet. Das Simulationsmodell bietet in seiner aktuellen Form einen Ansatzpunkt, um die Wirkung und Sicherheit eines Medikamentes theoretisch abzuschätzen, obwohl Defizite hinsichtlich der Integration der individuellen Patienteneigenschaften bestehen. Durch Weiterentwicklung könnten genauere Simulationen möglich sein und das Modell als Hilfestellung bei der individuellen Dosisfindung dienen., Each taken drug passes through certain pharmacological processes in the human organism, leading to an effect. Though, each drug has individual properties influencing this mechanism of action. Therefore medications with a low half-life are eliminated after a short time. But are these substances despite the short stay in the body able to act effectively, especially when given only once a day? Furthermore is there a possibility to estimate the effect and the blood-plasma concentrations theoretically without doing expensive blood examinations? These correlations should be solved with a designed model for the simulation of the blood concentration of pharmaceuticals. The model, available in a file of the spreadsheet program Microsoft Excel, offers the possibility to evaluate the drug effect by simulating its use. Though the blood concentration is calculated after oral administration and illustrated graphically. A data set of 1023 medications was available for processing and 22 of these fulfil the criteria which are necessary for simulation. The achieved results were tested for efficacy and safety and compared with clinical studies to check the precision of the model. In 18 of the 22 analyzed substances the outcomes of the simulated blood concentrations matched with the results of present studies. So it could be proved, that pharmaceuticals are able to act effective, despite a short half-life. Also the use of the simulation program could be valued positive. However, in 11 of these drugs the efficacy and safety maybe could not be reached because the blood concentrations underrun or exceed the therapeutic window in certain groups of patients. In these cases, dose optimizations were designed. There were discrepancies between the results of the simulation and studies in four of the 22 pharmaceuticals, which offer deficits of the program. This project proved that drugs with short half-lifes are able to act effectively. However, the effect not only depends on the half-life itself, also on the individual characteristics of the patient, which can change the mechanism of action. Often an adaption of these individualities is not considered and the substances are given by the recommended doses of the pharmaceutical industry. The therapeutic drug monitoring provides a way to adapt the dose to the patient, but does not belong to the standard procedure. The current model provides a starting-point to value previously the efficacy and safety of drugs theoretically, although it still has deficits regarding the integration of individual patient characteristics. By further development, more exact simulations could be possible and the model a realistic help in dose-findings.

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