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Abstract
The known Schiff base compound, (E)1‐benzyl‐3‐((4‐methoxyphenyl)imino)‐5‐methylindolin‐2‐one, was prepared as before by reacting 1‐benzyl‐5‐methylindoline‐2,3‐dione with 4‐methoxyaniline. The product was unambiguously characterized using elemental analysis, 1H and 13C‐NMR spectroscopy, and its new single‐crystal X‐ray structural analysis. Molecular orbital calculations were conducted in order to investigate the structures and relative stabilities of the (E) and (Z) isomers of 1‐benzyl‐3‐([4 methoxyphenyl]‐imino)‐5‐methylindolin‐2‐one. Specific attention was paid to the (E) isomer. The available crystallographic experimental data for the latter ensured also validation of the model structures computationally derived at the theoretical B3LYP/6‐31G(d,p) level.
Trotz der kontinuierlichen Weiterentwicklung der präventiven, diagnostischen und therapeutischen Maßnahmen stellt die koronare Herzkrankheit (KHK) und deren Folgen auch zukünftig eine große Herausforderung in der Medizin dar. Es besteht ein kritischer Bedarf für einen nicht-invasiven Biomarker, um Patienten mit dem größten Risiko für ein akutes pathologisches Ereignis bereits vor der klinischen Manifestation zu identifizieren. Ein solcher Biomarker wird auch für die schnelle Diagnosestellung bei symptomatisch auffälligen Patienten benötigt, bei denen die bisher etablierten Marker (Troponin, CK - Kreatinkinase) noch nicht nachweisbar sind. Als potenzieller Kandidat für einen solchen Biomarker könnten zirkulierende Endothelzellen (cEC) in Frage kommen. Obwohl die Rolle der cEC im akuten Myokardinfarkt (MI) noch nicht vollständig geklärt ist, legen die bisherigen Untersuchungen nahe, dass cEC eine differentialdiagnostische Möglichkeit für die Myokardinfarktpatienten in der so genannten ''Twighlight Zone'' - die Zeit zwischen ischämischem Ereignis und Nachweis von Troponin im Blut - sein können. Ziel dieser Untersuchung war daher, eine Einsicht in die komplexe methodische Quantifizierung der cEC und deren potentielle diagnostischen und prognostischen Rolle bei Patienten mit MI zu liefern.
In der vorliegenden Arbeit wurden 31 Patienten mit Myokardinfarkt eingeschlossen, 14 mit ST-Hebungsinfarkt (ST-elevation myocardial infarction/STEMI) und 17 mit nicht ST-Hebungsinfarkt (non ST-elevation myocardial infarction/NSTEMI). Als Kontrolle wurden 12 gesunden Probanden (Blutspender) ohne das Vorliegen einer KHK in der Anamnese gewonnen. Mittels Durchflusszytometrie wurden cEC der Patienten und der Kontrollgruppe bestimmt.
Die Ergebnisse zeigen einen Anstieg der cEC bei Infarktpatienten im Vergleich zur Kontrollgruppe. Dieser Unterschied war zwischen STEMI- und NSTEMI-Gruppe sowie STEMI- und Kontrollgruppe von statistischer Signifikanz. Des Weiteren wurde in Übereinstimmung mit anderen Untersuchungen keine
Korrelation zwischen cEC-Anzahl und den kardialen Enzymen (Troponin und CK) nachgewiesen. Bezüglich der prognostischen Bedeutung der cEC konnte in dieser Arbeit eine signifikante Korrelation der cEC mit dem GRACE-Score (in hospital risk of death and 6-month probability of death) bei den Patienten adjustiert für Alter, BMI und CRP nachgewiesen werden. Diese Studie gibt erste Hinweise darauf, dass cEC als additive Biomarker bei der Diagnose des Myokardinfarktes eingesetzt werden könnten, wobei weitere klinische Studien klären sollten, inwieweit cEC für diagnostische als auch prognostische Zwecke dienen könnten.
Humans are exposed to a plethora of microorganisms that reside on outer and inner body surfaces. These are collectively referred to as the human microbiome. The evolutionary relationship between humans and their microbiome is very complex. It is now widely accepted that these microorganisms are not just passive spectators but play an important role in health. The presence or absence of certain microbes is also linked to various diseases, including inflammatory bowel disease, cardiovascular disease, obesity, cancer, and allergies.
Allergies are several conditions caused by a misguided immune response to foreign antigens that are typically harmless. Common allergic diseases include atopic dermatitis (AD), allergic asthma, hay fever, and anaphylaxis. The incidences of allergic diseases are continuously rising, with up to 40% of the human population thought to be sensitised to environmental antigens. This increased incidence is not simply the result of societies becoming more aware and better at diagnosing these diseases. It is believed that the increases in allergies and sensitisation have environmental causes and are related to Western lifestyles. It is known that the rate of allergies is less frequent in developing countries. They are also more likely to occur in urban than rural areas. The prevailing view of the involvement of bacteria in allergies is described by the hygiene hypothesis. The hypothesis claims that decreased exposure to diverse microbial communities early in life increases the risk of developing allergic diseases. There are numerous examples to support this claim. For example, children born and raised in close contact to farm animals or in the presence of pets, and who are thus in direct and constant contact with a complex microbial environment, are protected from allergic diseases. On the other hand, colonisation or infection with certain bacteria increases allergic disease risks. This seems to contradict the hygiene hypothesis.
It appears that the members of the microbiome have different effects on allergy, and the hygiene hypothesis may not apply to every player in the complex microbial diversity that humans are in contact with. Therefore, a better understanding of the host bacterial interaction is required on the level of bacterial species.
This work studies the interplay between bacteria and the immune system to identify and characterise bacterial components with allergenic properties. In this quest, Staphylococcus aureus (S. aureus) and Staphylococcus epidermidis (S. epidermidis) were investigated for their allergenic properties and involvement in different allergic diseases. In the case of S. aureus, evidence is presented on allergic implications for two different components; serine protease-like proteins (Spls) and superantigens (SAg). Furthermore, experimental support is provided on the allergenic properties of the extracellular serine protease (Esp) from S. epidermidis. We argue that stimulating allergic reactions by staphylococci is an immune evasion mechanism that increases the survival chances of the bacteria within the host.
In chapter 1, an introduction is given to both S. aureus and S. epidermidis and their interactions with the immune system. Also, the bacterial components with allergenic properties and allergic diseases with known bacterial involvement are presented. Finally, the question of why bacteria cause allergy is discussed.
Chapter 2 describes allergic reactions to the Spls of S. aureus in a cohort of cystic fibrosis patients. Chapter 3 focuses on the SAgs of S. aureus. SAgs were discovered more than 30 years ago, but their physiological function is still under discussion. In this chapter, the allergenic properties of SAgs and their possible immunological mechanisms are reviewed, and a possible link between SAgs and allergic diseases is discussed. In chapter 4, the focus shifts to S. epidermidis and its involvement in AD. The human immune response to the Esp from S. epidermidis is characterised in healthy and AD individuals. The allergenic properties of Esp imply a detrimental role of S. epidermidis in AD. Finally, chapter 5 summarises and discusses the results of this thesis. In this section, the pieces are put together, and attention is brought back to the question of why bacteria cause allergies.
Abstract
We investigated four subaerial (paleo)lacustrine landforms at the north‐eastern shoreline of Schweriner See, north‐eastern Germany. These included two beach ridges, one subaerial nearshore bar and a silting up sequence located close to a fossil cliff, which marks the former maximum extent of Schweriner See. We used luminescence profiling with a SUERC portable OSL device (POSL) on all four sediment sequences in combination with sedimentological investigations such as grain size, loss‐on‐ignition and magnetic susceptibility to provide information on the various formations in a lacustrine depositional environment. The POSL reader was used on pre‐treated polymineral samples to gain an insight into luminescence distribution within the individual sediment sequences, but also among the four sequences. POSL proved valuable to understand depositional processes, which were not visible in lithology or sedimentological parameters. With somewhat larger uncertainty this method provides relative chronologies of the sediment sequences. Additionally, we carried out radiocarbon dating and full optical stimulated luminescence (OSL) dating to establish a chronological framework. OSL ages proved to be more reliable to date beach ridges in this setting than radiocarbon samples, which were severely influenced by sediment reworking. This combined approach of sedimentological analyses, luminescence profiling and absolute age determinations revealed details in depositional processes at Schweriner See which otherwise would have remained undetected. Furthermore, it helped to set these subaerial (paleo)lacustrine landforms in a chronological framework.
Modulation der biologischen Wirkung von MikroRNA-1 mittels chemischer Modifikation des RNA-Moleküls
(2021)
In vielen Malignitäten kann eine Dysregulation von miR beobachtet werden. Die reduzierte Expression dieser kleinen, nicht-codierenden RNA resultiert in verlängertem Tumorüberleben, einer gesteigerten Proliferationsrate, verbesserter Angiogenese und Metastasierung von Tumorzellen [1, 2]. Da miR-1 in ihrer Funktion als Tumorsuppressor mehrere onkogene Signal- und Effektorkaskaden supprimieren kann, ist die Erforschung ihres therapeutischen Potenzials von gesteigertem Interesse [1]. Dies zu realisieren eignen sich Prostatakarzinomzellen in besonderem Maße, da dort endogene miR-1 enorm herunterreguliert ist [157].
Die vorliegende Arbeit untersuchte die miR-1 Re-Expressionstherapie zur Hemmung der Tumorprogression auf molekularer Ebene an Prostatakarzinomzellen mit synthetischen miR-1 Molekülen. Darüber hinaus wurde die synthetische miR-1 durch unterschiedliche Substituenten modifiziert, um zu evaluieren ob diese Modifikationen Einfluss auf die biologische Wirkung auf die untersuchten Prostatakarzinomzelllinien haben. Ein weiterer Fokus lag dabei auf der Fragestellung, ob die Position und die chemischen Eigenschaften der Substituenten selbst einen Einfluss auf die miR-1 Effekte ausüben.
Es konnte gezeigt werden, dass die Wiederherstellung der intrazellulären miR-1 Spiegel durch die unmodifizierte, synthetische miR-1 bereits einen hemmenden Effekt auf das Tumorwachstum hatte. Ausserdem deuten die Ergebnisse darauf hin, dass die chemisch synthetisierte und modifizierte miR-1, der unveränderten, synthetischen miR-1 in ihrer tumorsupprimierenden Funktion überlegen sein kann.
Die antiproliferative Wirksamkeit der modifizierten miR-1 Moleküle hing jedoch eher von der Position, als von der Art des modifizierten Nukleotids ab. Es konnte gezeigt werden, dass, unabhängig vom Substituenten, Modifikationen an vermutlich kritischen Positionen sogar ein gesteigertes Tumorwachstum zur Folge hatten. Substituenten an ungünstigen Positionen konnten zu Reduktion der antiproliferativen Effekte von miR-1-Molekülen und somit sogar zu vermehrten Tumorwachstum führen. Dies bietet die Möglichkeit, durch die Auswahl gut charakterisierter miR mit hohem antiproliferativem Potenzial maßgeschneiderte, synthetisch modifizierte miR für die zukünftige, individualisierte Therapie verschiedener Krebsentitäten zu entwickeln.
Background: COVID-19 lead to the adoption of containment measures including temporary closure of dental clinics. Despite the risk of infection transmission, dental emergencies have not ceased during this pandemic and had to be managed also in the lockdown period.
Aim: To analyze the profiles and offered management options of pediatric patients presenting with dental emergencies during a COVID-19 lockdown.
Design: Retrospective analysis of patient records of children seeking emergency dental treatment during a 7-week lockdown period in 2020 in a university pedodontics clinic in Germany, compared to a similar cohort from 2019. Data on patient level, tooth level, and session level were collected. An analysis of the digital records after 6 months follow-up was performed for the patients who received Non-Aerosol Generating Procedures (NAGP) as management for dental emergency in the lockdown period in 2020.
Results: The 2020 cohort consisted of 83 patients, while the 2019 cohort included 46 patients showing 45% higher necessity for emergency treatment in 2020. Most common chief complaint was oral mucosal conditions in 2020 (26.4%), and irreversible pulpitis in 2019 (25.5%). Dental caries (without spontaneous pain) was the second most chief complaint in both cohorts (20.7% and 23.4% respectively). Most interventions in 2020 were Minimally Invasive Treatments such as the hall technique and silver diammine fluoride (20.3%), which were in 2019 not considered, followed by pharmacological treatment (16.9%), which were in 2019 also highly used (35.9%). The 6 months follow up for the NAGP revealed benefit in management of the acute dental problem, by either direct treatment or by postponing the treatment need to a later time period.
Conclusion: The COVID-19 pandemic led to increase in emergency pediatric dental visits and shifted treatment options towards less invasive procedures.
In challenging situations, where aerosols increase the risk of infection transmission, NAPD are a viable option in the management of dental emergencies, especially in pediatric dentistry.
Störungen im Calcium- und Phosphatstoffwechsel bei chronisch Nierenkranken führen zur sogenannten „Chronic Kidney Disease - Mineral and Bone Disorder“ (CKD-MBD). Die CKD- MBD umfasst neben laborchemischen Veränderungen und Knochenerkrankungen vor allem Gefäßverkalkungen. Letztere sind aktive vaskuläre Umbauprozesse und finden sich insbesondere in der Tunica media arterieller Gefäße, mit einer Assoziation zu einer erhöhten kardiovaskulären Mortalität.
Ziel dieser Arbeit war es, vertiefende Einblicke in den Prozess der vaskulären Kalzifikation zu erlangen. Hierbei sollte die Frage geklärt werden, über welche Signalwege das in urämischen Gefäßen überexprimierte TGF-ß1 möglicherweise zur Inhibition vaskulärer Kalzifikation beiträgt und ob eine Beeinflussung möglich ist.
Zur Klärung dieses Sachverhalts wurde ein in vitro Zellkulturmodell (human vascular smooth muscle cells, hVSMCs) durch Zusatz von erhöhtem Calcium- und Phosphat etabliert, ähnlich den laborchemischen Veränderungen bei CKD-MBD. Die kalzifikationsbeeinflussende Rolle von TGF-ß1 sollte geklärt und mit dem SAPK/JNK (stress- activated protein-kinase/ c-Jun N-terminale Kinase) Signalweg eine mögliche Interaktion dieser beiden Signalkaskaden identifiziert werden. Außerdem sollte der Stellenwert der Apoptose sowie der osteogenen Differenzierung im Prozess vaskulärer Kalzifikation analysiert werden.
TGF-ß1 zeigte eine konzentrationsabhängige, kalzifikationsinhibierende Wirkung. TGF-ß1 vermittelte diesen Effekt unter anderem über Phosphorylierung der Proteinkinase SAPK/JNK, die im Zusammenhang mit Apoptose, Zellproliferation und Differenzierungsprozessen steht. Weiterhin konnte bestätigt werden, dass die Apoptose eine wichtige Rolle bei der Initiation der vaskulären Kalzifikation spielt.
Die weiterführende Erforschung der Interaktion des SAPK/JNK Signalwegs mit TGF-ß1 und einem damit verbundenem, potentiellen Therapieansatz bei Patienten mit vaskulärer Kalzifikation sollte in vivo in einem Tiermodell untersucht werden, insbesondere um herauszufinden, ob der Signalweg ohne Beeinträchtigung wichtiger zellulärer Funktionen beeinflusst werden kann. Sowohl TGF-ß1 als auch SAPK/JNK könnten mögliche Targets für neue therapeutische Strategien wie die Entwicklung von sog. „biased ligands“ darstellen, welche selektiv bestimmte Signalwege regulieren können.
Streptococcus pneumoniae has evolved versatile strategies to colonize the nasopharynx of humans. Colonization is facilitated by direct interactions with host cell receptors or via binding to components of the extracellular matrix. In addition, pneumococci hijack host-derived extracellular proteases such as the serine protease plasmin(ogen) for ECM and mucus degradation as well as colonization. S. pneumoniae expresses strain-dependent up to four serine proteases. In this study, we assessed the role of secreted or cell-bound serine proteases HtrA, PrtA, SFP, and CbpG, in adherence assays and in a mouse colonization model. We hypothesized that the redundancy of serine proteases compensates for the deficiency of a single enzyme. Therefore, double and triple mutants were generated in serotype 19F strain EF3030 and serotype 4 strain TIGR4. Strain EF3030 produces only three serine proteases and lacks the SFP encoding gene. In adherence studies using Detroit-562 epithelial cells, we demonstrated that both TIGR4Δcps and 19F mutants without serine proteases or expressing only CbpG, HtrA, or PrtA have a reduced ability to adhere to Detroit-562 cells. Consistent with these results, we show that the mutants of strain 19F, which preferentially colonizes mice, abrogate nasopharyngeal colonization in CD-1 mice after intranasal infection. The bacterial load in the nasopharynx was monitored for 14 days. Importantly, mutants showed significantly lower bacterial numbers in the nasopharynx two days after infection. Similarly, we detected a significantly reduced pneumococcal colonization on days 3, 7, and 14 post-inoculations. To assess the impact of pneumococcal serine proteases on acute infection, we infected mice intranasally with bioluminescent and invasive TIGR4 or isogenic triple mutants expressing only CbpG, HtrA, PrtA, or SFP. We imaged the acute lung infection in real-time and determined the survival of the mice. The TIGR4lux mutant expressing only PrtA showed a significant attenuation and was less virulent in the acute pneumonia model. In conclusion, our results showed that pneumococcal serine proteases contributed significantly to pneumococcal colonization but played only a minor role in pneumonia and invasive diseases. Because colonization is a prerequisite for invasive diseases and transmission, these enzymes could be promising candidates for the development of antimicrobials to reduce pneumococcal transmission.
The pathobiont Streptococcus pneumoniae causes life-threatening diseases, including pneumonia, sepsis, meningitis, or non-invasive infections such as otitis media. Serine proteases are enzymes that have been emerged during evolution as one of the most abundant and functionally diverse group of proteins in eukaryotic and prokaryotic organisms. S. pneumoniae expresses up to four extracellular serine proteases belonging to the category of trypsin-like or subtilisin-like family proteins: HtrA, SFP, PrtA, and CbpG. These serine proteases have recently received increasing attention because of their immunogenicity and pivotal role in the interaction with host proteins. This review is summarizing and focusing on the molecular and functional analysis of pneumococcal serine proteases, thereby discussing their contribution to pathogenesis.
In this study we investigated the synergistic antimicrobial effect of a dual protocol combining cold atmospheric pressure plasma (CAP) and antimicrobial photodynamic therapy (aPDT) against different planktonic bacterial and yeast species including methicillin-sensitive and methicillin-resistant Staphylococcus aureus, Escherichia coli, extended-spectrum β-lactamase-positive Escherichia coli and Candida albicans. A DBD plasma device was used for CAP treatment while for aPDT, toluidine blue O (TBO) was the photosensitizer (PS) of choice and a radiator emitting visible and water-filtered-Infrared A light (VIS-wIRA) was used as irradiation source.
Microbial suspensions were either exposed to CAP treatment alone, aPDT treatment alone or aPDT followed by CAP exposure in a dual treatment protocol. Aliquots from each suspension were plated on agar plates and the number of colonies surviving after each treatment was counted. Under the experimental conditions conducted in this study, combining sub-lethal exposure doses of CAP and aPDT treatment showed significantly higher antimicrobial efficacy (P<0.0001) compared to single treatments against all tested microorganisms suggesting a synergistic effect which yielded at least 3.3 log microbial reduction corresponding to 99.6 % microbial death. In the dual CAP-aPDT approach, aPDT did not interfere with CAP-induced acidification of solution, a crucial feature for CAP antimicrobial efficiency, which further confirms the promising clinical potential of this combination regime.
We believe that the CAP-aPDT dual approach described in this study holds great potential as a successful novel antimicrobial and healing-supporting strategy especially when directed for the management of acute and chronic wounds and possibly other skin and soft tissue infections. The use of a VIS-wIRA light source in treating skin infections is preferential, due to the additional therapeutic effects of wIRA in wound healing. Furthermore, the enhanced antimicrobial effects of aPDT when combined with CAP as shown in this study may grant for a reduction in treatment times and costs as well as improving patient compliance.
Growth, ageing and atherosclerotic plaque development alter the biomechanical forces acting on the vessel wall. However, monitoring the detailed local changes in wall shear stress (WSS) at distinct sites of the murine aortic arch over time has been challenging. Here, we studied the temporal and spatial changes in flow, WSS, oscillatory shear index (OSI) and elastic properties of healthy wildtype (WT, n = 5) and atherosclerotic apolipoprotein E-deficient (Apoe−/−, n = 6) mice during ageing and atherosclerosis using high-resolution 4D flow magnetic resonance imaging (MRI). Spatially resolved 2D projection maps of WSS and OSI of the complete aortic arch were generated, allowing the pixel-wise statistical analysis of inter- and intragroup hemodynamic changes over time and local correlations between WSS, pulse wave velocity (PWV), plaque and vessel wall characteristics. The study revealed converse differences of local hemodynamic profiles in healthy WT and atherosclerotic Apoe−/− mice, and we identified the circumferential WSS as potential marker of plaque size and composition in advanced atherosclerosis and the radial strain as a potential marker for vascular elasticity. Two-dimensional (2D) projection maps of WSS and OSI, including statistical analysis provide a powerful tool to monitor local aortic hemodynamics during ageing and atherosclerosis. The correlation of spatially resolved hemodynamics and plaque characteristics could significantly improve our understanding of the impact of hemodynamics on atherosclerosis, which may be key to understand plaque progression towards vulnerability.
Ausgewählte Lyrik
(2021)
Dieser Beitrag führt in den Stand und den regulatorischen Rahmen der Sektorenkopplung im Status quo ein. Ein Fokus wird dabei auf die Erreichung der Klimaschutzziele gelegt. Zur Systematisierung wurde ein Systembild, welches die wesentlichen Anknüpfungspunkte darstellt, entwickelt und dargestellt. Anhand dessen wird der technisch-systemische Rahmen der Sektorenkopplung erläutert und zentrale ökonomische Aspekte aufzeigt. Daran anknüpfend wird zudem die Begrifflichkeit der "Sektorenkopplung" untersucht. Anschließend wird der regulatorische Rahmen der Sektorenkopplung für die Sektoren Energiewirtschaft, Industrie, Verkehr, Gebäude und Landwirtschaft sowie der Abfallwirtschaft untersucht und dargestellt. Die Betrachtung dieser Sektoren geht davon aus, dass diese zukünftig auf Basis von erneuerbar erzeugtem Strom direkt oder indirekt elektrifiziert und verknüpft werden. Die Darstellung der institutionellen Regelungen im Status quo gibt einen strukturierten Überblick über das bestehende System und zeigt rechtliche Ansatzpunkte bzw. eventuelle Regelungslücken hinsichtlich bestehender und zukünftiger Herausforderungen für das Ziel einer nachhaltigen Sektorenkopplung auf.
Die Messung der endexspiratorischen Ammoniakkonzentration bei Patienten mit terminaler Niereninsuffizienz während der Dialyse stellt eine neue nicht-invasive Methode zur Evaluation des Dialyseerfolges dar.
Ziel dieser Studie ist es die endexspiratorische Ammoniakkonzentration von Patienten mit terminaler Niereninsuffizienz während der Dialyse zu messen, um einen signifikanten Abfall der endexspiratorischen Ammoniakkonzentration während des Dialysevorganges nachzuweisen. Des Weiteren gilt es Einflussfaktoren auf die endexspiratorische Ammoniakkonzentration vor der Dialyse zu finden sowie eine mögliche positive Korrelation zwischen der endexspiratorischen Ammoniakkonzentration und der Harnstoffkonzentration im Blut zu untersuchen.
Insgesamt wurden 45 Dialysepatienten (22 Frauen, 23 Männer) im Alter zwischen
dem 28. und dem 85. Lebensjahren für diese Studie rekrutiert. Es erfolgte eine standardisierte Befragung der Patienten bezüglich ihrer Vorerkrankungen und kardiovaskulären Risikofaktoren. Die restlichen relevanten Diagnosen wurden aus den Krankenunterlagen entnommen. Neben der Messung der endexspiratorischen Ammoniakkonzentration erfolgten laborchemische Bestimmungen der Ammoniakkonzentration im EDTA-Blut ebenfalls vor und nach der Dialyse. Auch weitere Laborparameter, wie Aspartataminotransferase, Alaninaminotransferase, Gamma-Glutamyl-Transferase, Harnstoff, Kreatinin sowie Hämoglobin HbA1c wurden mitbestimmt. Die Analyse der endexspiratorischen Ammoniakkonzentration erfolgte mittels des durchstimmbaren Infrarotdiodenlasers unter der Anwendung der Absorptionsspektroskopie als eine hoch sensitive und selektive Methode zur Bestimmung der organischen Atembestandteile.
Die Ergebnisse dieser Studie zeigen einen signifikanten Abfall der endexspiratorischen Ammoniakkonzentrationen im Verlauf der Dialyse (mediane Werte: von 236,3 ppb
auf 120,6 ppb (p < 0,001)). Beim genaueren Betrachten des individuellen Verlaufs von Dialysepatienten fällt auf, dass 18 Patienten mit einer hohen endexspiratorischen Ammoniakkonzentration vor der Dialyse (über 300 ppb) einen deutlichen Abfall (> 100 ppb) im Verlauf der Behandlung aufweisen. Von den Patienten, bei denen vor der Dialyse ein niedriger Atemammoniakspiegel (< 300 ppb) erfasst wurde, zeigten sich bei fünf Probanden ein deutlichen Abfall, bei elf Probanden ein geringerer Abfall (< 100 ppb), bei vier Probanden keine signifikante Veränderung (±10 ppb) und bei sieben Teilnehmern eine Erhöhung der endexspiratorischen Ammoniakkonzentration während der Dialyse.
Die statistische Analyse ergab weiterhin eine deutlich positive Korrelation zwischen den Ammoniakkonzentrationen im Blut vor der Dialyse mit den Blutammoniakwerten nach der Dialyse und eine mäßig positive Korrelation zwischen den endexspiratorischen Ammoniakkonzentrationen vor der Dialyse mit den Ammoniakspiegel im Atem nach der Dialyse. Eine schwach positive Korrelation wurde zwischen den endexspiratorischen Ammoniakwerten nach der Dialyse mit den Blutammoniakwerten nach der Dialyse gefunden. Die lineare Regressionsanalyse ergab eine signifikante Assoziation von Nephrektomie und Restdiurese mit den endexspiratorischen Ammoniakwerten, welche vor der Dialyse gemessen wurden. Damit wird verdeutlich, das nephrektomierte Patienten und Patienten mit einer höheren Restdiurese einen deutlichen Abfall der endexspiratorischen Ammoniakkonzentrationen während der Dialyse aufzeigten und somit vermehrt von der Dialyse als Behandlung profitieren.
In Anlehnung an die Ergebnisse dieser Studie, dass im Verlauf der Dialyse ein signifikanter Abfall der endexspiratorischen Ammoniakkonzentration vorliegt, wird eine klinische Etablierung der nicht-invasiven Ammoniakkonzentrationsmessung vor und nach der Dialyse als eine gute Möglichkeit der Überwachung einer Dialysesitzung empfohlen. Aus unserer Sicht sollte am besten die Messung nicht offline mittels Sammelns der Atemproben im Tedlar-Beutel, sondern durch direktes Ausatmen in das Messsystem erfolgen, um den Verlust von an der Oberfläche des Beutels haftenden Ammoniaks zu verhindern. Falls jedoch die offline Methode bevorzugt werden sollte, müsste gewährleistet werden, dass die Atemgasproben so schnell wie möglich analysiert werden, um die Messgenauigkeit zu stärken.
Analysis and Reduction of Cellular Heterogeneity in Strain Optimization of Bacillus licheniformis
(2021)
Bacillus species invest substantial resources in inherent cellular processes for pre-adaptation to environmental changes, many of which are dispensable in the controlled environment of industrial bioprocesses. The underlying physiological mechanisms are well characterized in B. subtilis, but only little is known about these processes in the closely related B. licheniformis. Moreover, experimental conditions in previous studies differ from industrial settings in most parameters, foremost in batch cultures or plate-based analysis over fed-batch processes. In this thesis, cellular heterogeneity was analyzed in B. licheniformis in optimized, nutrient-rich media in batch and fed-batch cultivations. Systematic inactivation of genes involved in biofilm formation and synthesis of the flagellar apparatus or global regulators thereof resulted in higher protein production and provided new insights into biofilm formation and cellular heterogeneity in this strain.
Haloalkanes are serious environmental pollutants commonly employed as pesticides, herbicides, and chemical warfare agents. Although haloalkane production is performed mostly in the chemical industry, it also occurs naturally, mostly enzymatically (halide methyltransferases and haloperoxidases). Elimination of toxic haloalkanes is very important and using haloalkane dehalogenases is a promising and environmentally friendly way to achieve this.[53] Therefore, assays are needed for detecting dehalogenase activity either to find new enzymes or to generate laboratory-evolved variants. In this thesis, a new assay for dehalogenase activity was developed based on halide detection. In this assay halides, as dehalogenase products, are oxidized under mild conditions using the vanadium-dependent chloroperoxidase from Curvularia inaequalis, forming hypohalous acids that are detected using aminophenyl fluorescein.[53] This new halide oxidation assay is much more sensitive than previously known assays, with detection limits of 20 nM for bromide and 1 μM for chloride and iodide. Validation of the assay was done by comparison to a well-established GC-MS method in terms of determining the specific activities of two dehalogenases towards five common substrates (Figure 5).
The HOX assay was modified for iodide-specific detection by using two other dyes, o-phenylenediamine (OPD) and 3,3′,5,5′-tetramethylbenzidine (TBM), instead of APF. Also, selective bromide detection in the presence of the common contaminant chloride was achieved by using a bromoperoxidase. Since the assay relies on halide detection, it is possible to use it for other halide-producing enzymes (Section 8.1). For example, the TMB-modified version was used for screening of halide methyltransferase libraries towards various alkyl iodides.[166] Furthermore, the HOX assay was used to identify promiscuous dehalogenase activity of the epoxide hydrolase CorEH from Corynebacterium sp. C12.[105]
Moreover, studies showed that the HOX assay could be used with in-vitro synthesized protein. Selected dehalogenases, DhlA, DhaA, and DmmA, were synthesized in vitro and used in the assay; the product formation was also validated using GC-MS. In conclusion, the HOX assay can be used with purified protein, whole cells, or in vitro synthesized proteins.
The HOX assay application in microfluidic droplets was investigated since an ultra-high-throughput assay for haloalkane dehalogenases is needed. This investigation showed no leakage of reaction components and products in the short term (~24 h), based on tests done on water-in-oil droplets generated by microfluidic chips. Even though 20 μM droplets were not working, 70 μM droplets were successful for assay implementation. Since the Damborsky group in Brno (CZ) and the deMello group in Zürich (CH), have large dehalogenase libraries and more experience in microfluidics, respectively, we collaborated with these groups to finalize implementation of the assay in an ultrahigh-throughput format. Since the studies are ongoing, final results could not yet be shown in this thesis. However, it can be noted that the issue with 20 μm droplets has been sorted out since our collaborators in Brno noticed that the low fluorescence of the droplets is actually caused by excessive accumulation of fluorescein, which is self-quenching, resulting in low fluorescence once the concentration exceeds 1 μM. By lowering the APF concentration they could optimize the maximum amount of fluorescein formed, and a mutant library has now been successfully screened by our collaborators at the ETH. The last topic of the thesis was an investigation of converting an epoxide hydrolase into a haloalkane dehalogenase. These studies focused on increasing the minor dehalogenase activity of two previously identified epoxide hydrolase (Cif) variants. These Cif variants hardly led to soluble proteins, the PROSS algorithm was used to increase soluble expression. New variants of Cif were generated using a 3DM analysis and the PROSS[164] design. The activities of these variants were determined with the newly developed HOX assay in a whole-cell format. Cif23 E153N-H269D and the PROSS D7 E153N-H269D variant, were found being active against 1,2-dibromoethane. Since the determination of enzyme concentration was hard to measure due to the expression/purification problem, specific activities could not be determined. To solve this problem, a HiBiT-tag was added to the selected variants for determining soluble expression. However, the planned studies could not be completed because of a lack of time and will form the basis for a future study.
The EyeFlowCell: Development of a 3D-Printed Dissolution Test Setup for Intravitreal Dosage Forms
(2021)
An in vitro dissolution model, the so-called EyeFlowCell (EFC), was developed to test intravitreal dosage forms, simulating parameters such as the gel-like consistency of the vitreous body. The developed model consists of a stereolithography 3D-printed flow-through cell with a polyacrylamide (PAA) gel as its core. This gel needed to be coated with an agarose sheath because of its low viscosity. Drug release from hydroxypropyl methylcellulose-based implants containing either triamcinolone acetonide or fluorescein sodium was studied in the EFC using a schematic eye movement by the EyeMovementSystem (EyeMoS). For comparison, studies were performed in USP apparatus 4 and USP apparatus 7. Significantly slower drug release was observed in the PAA gel for both model drugs compared with the compendial methods. Drug release from fluorescein sodium-containing model implants was completed after 40 min in USP apparatus 4, whereas drug release in the gel-based EFC lasted 72 h. Drug release from triamcinolone acetonide-containing model implants was completed after 35 min in USP apparatus 4 and after 150 min in USP apparatus 7, whereas this was delayed until 96 h in the EFC. These results suggest that compendial release methods may overestimate the drug release rate in the human vitreous body. Using a gel-based in vitro release system such as the EFC may better predict drug release.
Simple Summary
Recent clinical trials suggest that combination therapies that include either gemcitabine or 5-fluorouracil (5-FU) both give significant survival benefits for pancreatic cancer patients. The tumor level of the nucleoside transporter hENT1 is prognostic in patients treated with adjuvant gemcitabine but not adjuvant 5-FU. This work shows for the first time that hENT1 is only predictive of benefit from gemcitabine over 5-FU in patients with low levels of CDA transcript. A choice between adjuvant 5-FU based combination therapies (such as FOLFIRINOX) and gemcitabine-based therapy (e.g., GemCap) could be made based on a combination of hENT1 protein and CDA mRNA measured in a resected tumor.
Abstract
Gemcitabine or 5-fluorouracil (5-FU) based treatments can be selected for pancreatic cancer. Equilibrative nucleoside transporter 1 (hENT1) predicts adjuvant gemcitabine treatment benefit over 5-FU. Cytidine deaminase (CDA), inside or outside of the cancer cell, will deaminate gemcitabine, altering transporter affinity. ESPAC-3(v2) was a pancreatic cancer trial comparing adjuvant gemcitabine and 5-FU. Tissue microarray sections underwent in situ hybridization and immunohistochemistry. Analysis of both CDA and hENT1 was possible with 277 patients. The transcript did not correlate with protein levels for either marker. High hENT1 protein was prognostic with gemcitabine; median overall survival was 26.0 v 16.8 months (p = 0.006). Low CDA transcript was prognostic regardless of arm; 24.8 v 21.2 months with gemcitabine (p = 0.02) and 26.4 v 14.6 months with 5-FU (p = 0.02). Patients with low hENT1 protein did better with 5-FU, but only if the CDA transcript was low (median survival of 5-FU v gemcitabine; 29.3 v 18.3 months, compared with 14.2 v 14.6 with high CDA). CDA mRNA is an independent prognostic biomarker. When added to hENT1 protein status, it may also provide treatment-specific predictive information and, within the frame of a personalized treatment strategy, guide to either gemcitabine or 5FU for the individual patient.
Although the nose, as a gateway for organism–environment interactions, may have a key role in asthmatic exacerbation, the rhinobiome of exacerbated children with asthma was widely neglected to date. The aim of this study is to understand the microbiome, the microbial immunology, and the proteome of exacerbated children and adolescents with wheeze and asthma. Considering that a certain proportion of wheezers may show a progression to asthma, the comparison of both groups provides important information regarding clinical and phenotype stratification. Thus, deep nasopharyngeal swab specimens, nasal epithelial spheroid (NAEsp) cultures, and blood samples of acute exacerbated wheezers (WH), asthmatics (AB), and healthy controls (HC) were used for culture (n = 146), 16 S-rRNA gene amplicon sequencing (n = 64), and proteomic and cytokine analyses. Interestingly, Proteobacteria were over-represented in WH, whereas Firmicutes and Bacteroidetes were associated with AB. In contrast, Actinobacteria commonly colonized HCs. Moreover, Staphylococcaceae, Enterobacteriaceae, Burkholderiaceae, Xanthobacteraceae, and Sphingomonadaceae were significantly more abundant in AB compared to WH and HC. The α-diversity analyses demonstrated an increase of bacterial abundance levels in atopic AB and a decrease in WH samples. Microbiome profiles of atopic WH differed significantly from atopic AB, whereby atopic samples of WH were more homogeneous than those of non-atopic subjects. The NAEsp bacterial exposure experiments provided a disrupted epithelial cell integrity, a cytokine release, and cohort-specific proteomic differences especially for Moraxella catarrhalis cultures. This comprehensive dataset contributes to a deeper insight into the poorly understood plasticity of the nasal microbiota, and, in particular, may enforce our understanding in the pathogenesis of asthma exacerbation in childhood.
In der vorliegenden retrospektiven, unizentrischen Untersuchung wurden die Daten von 54 Patientinnen, welche zwischen dem 01.01.1990 und dem 31.12.2010 in der Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe der Universitätsmedizin Greifswald aufgrund eines Borderline-Tumors des Ovars behandelt wurden, erfasst und ausgewertet.
Der Beobachtungszeitraum nach Diagnosestellung betrug im Median: 40,5 Monate (Range: 0-231 Monate).
Bei Erstdiagnose waren die Patientinnen im Median: 54 Jahre alt (Range: 23-83 Jahre), wobei sich 29,6% der Patientinnen im prämenopausalen Lebensabschnitt befanden.
18,5% der Patientinnen waren Nulligravida, 20,4% waren Nullipara.
Bei 12 Patientinnen (22,2%) trat vor oder nach der Diagnose „Borderline-Tumor des Ovars“ eine weitere Tumorerkrankung auf. Der häufigste Zweittumor war das Mammakarzinom (6 Patientinnen=11,1%).
Mehr als die Hälfte der Patientinnen (64,8%) gaben Beschwerden an. Am häufigsten wurde über Ober- und/oder Unterbauchschmerzen, eine Zunahme des Leibesumfangs sowie Veränderungen des Körpergewichts berichtet.
Es traten ausschließlich seröse (31/54=57,4%) beziehungsweise muzinöse (23/54=42,6%) Borderline-Tumoren des Ovars auf.
Alle 54 Patientinnen wurden operativ behandelt. 9 Patientinnen (16,7%) wurden initial fertilitätserhaltend operiert. Die 5 während der Erstoperation am häufigsten durchgeführten Maßnahmen waren in absteigender Häufigkeit: bilaterale Salpingo-Oophorektomie (inklusive früher bereits entfernte Adnexe), Hysterektomie (inklusive früher bereits entfernter Uterus), intraoperative Schnellschnittuntersuchung, Appendektomie und Omentektomie.
8 Patientinnen (14,8%) wurden während der Erstoperation entsprechend den Empfehlungen der S3-Leitlinie von 2017 [6] therapiert, wobei eine Zunahme der leitliniengerechten Operationen ab dem Jahr 2000 zu verzeichnen war.
8 Patientinnen (14,8%) erhielten eine adjuvante Chemotherapie. 5 von ihnen im Zeitraum zwischen dem 01.01.1990-31.12.1994.
Innerhalb des Beobachtungszeitraums verstarben 14 Patientinnen (25,9%). Bei keiner von ihnen war ein Borderline-Tumor des Ovars als Todesursache sicher belegt.
Im Kollektiv traten 2 Rezidive nach 9 und 29 Monaten nach Stellung der Erstdiagnose auf.
Clavicle injuries are common, but only few case reports describe combined clavicular injuries (CCI). CCI include combinations between clavicular fractures and acromioclavicular/sternoclavicular joint dislocations (SCJD). We present the first general therapeutic recommendations for CCI based on a new classification and their distribution. A retrospective, epidemiological, big data analysis was based on ICD-10 diagnoses from 2012 to 2014 provided by the German Federal Statistical Office. CCI represent 0.7% of all clavicle-related injuries (n = 814 out of 114,003). SCJD show by far the highest proportion of combination injuries (13.2% of all SCJD were part of CCI) while the proportion of CCI in relation to the other injury entities was significantly less (p < 0.023). CCIs were classified depending on (1) the polarity (monopolar type I, 92.2% versus bipolar type II, 7.8%). Monopolar type I was further differentiated depending on (2) the positional relationship between the combined injuries: Ia two injuries directly at the respective pole versus Ib with an injury at one end plus an additional midshaft clavicle fracture. Type II was further differentiated depending on (3) the injured structures: IIa ligamento-osseous, type IIb purely ligamentous (rarest with 0.6%). According to our classification, the CCI severity increases from type Ia to IIb. CCI are more important than previously believed and seen as an indication for surgery. The exclusion of further, contra-polar injuries in the event of a clavicle injury is clinically relevant and should be focused.
Background and Aims
Gallbladder cancer (GBC) is a neglected disease with substantial geographical variability: Chile shows the highest incidence worldwide, while GBC is relatively rare in Europe. Here, we investigate the causal effects of risk factors considered in current GBC prevention programs as well as C‐reactive protein (CRP) level as a marker of chronic inflammation.
Approach and Results
We applied two‐sample Mendelian randomization (MR) using publicly available data and our own data from a retrospective Chilean and a prospective European study. Causality was assessed by inverse variance weighted (IVW), MR‐Egger regression, and weighted median estimates complemented with sensitivity analyses on potential heterogeneity and pleiotropy, two‐step MR, and mediation analysis. We found evidence for a causal effect of gallstone disease on GBC risk in Chileans (P = 9 × 10−5) and Europeans (P = 9 × 10−5). A genetically elevated body mass index (BMI) increased GBC risk in Chileans (P = 0.03), while higher CRP concentrations increased GBC risk in Europeans (P = 4.1 × 10−6). European results suggest causal effects of BMI on gallstone disease (P = 0.008); public Chilean data were not, however, available to enable assessment of the mediation effects among causal GBC risk factors.
Conclusions
Two risk factors considered in the current Chilean program for GBC prevention are causally linked to GBC risk: gallstones and BMI. For Europeans, BMI showed a causal effect on gallstone risk, which was itself causally linked to GBC risk.
Die Akute Myeloische Leukämie (AML) ist eine klonale Neoplasie der hämatopoetischen Stammzellen, die das Knochenmark, das Blut und andere Organe infiltriert (Döhner and Bloomfield, 2015; Herold, 2015). Patienten mit malignen hämatologischen Erkrankungen haben ein erhöhtes Risiko an einer invasiven Pilzinfektion zu erkranken, dies gilt insbesondere für Patienten mit prolongierter und starker Neutropenie, die bei Patienten nach intensiver Chemotherapie regelhaft auftritt (Rodríguez-Veiga et al., 2019). Von einer schweren Neutropenie spricht man, wenn der Wert der Neutrophilen Granulozyten im Blut 500 Zellen/ μL unterschreitet (Herold, 2015, p.66). Aus diesem Grund gibt es eine starke Empfehlung zur Anwendung einer antimykotischen Prophylaxe bei diesen Patienten (Mellinghoff et al., 2018). Hierfür kommen verschiedene Azol- Antimykotika zum Einsatz. Nach Umstellen des Standards der antimykotischen Prophylaxe bei AML- Patienten nach intensiver Chemotherapie auf Posaconazol, welches auf Grund mehrerer Studien zur Erstlinienanwendung empfohlen wurde, schien die Rate an prolongierter Neutropenie und Thrombozytopenie zuzunehmen (Mellinghoff et al., 2018). Ziel dieser retrospektiven Studie war es Hinweise zu ermitteln, ob dieser Zusammenhang zufällig ist oder ob die Gabe von Posaconazol tatsächlich durch Arzneimittelwechselwirkungen mit den eingesetzten Zytostatika zu einer verlängerten Aplasiedauer führen könnte. Hier untersuchten wir den Einfluss der antimykotischen Medikation und anderer Faktoren auf die Dauer der Aplasie an Patienten mit AML in der Klinik für Hämatologie und Onkologie der Universitätsmedizin Greifswald. Es konnten 83 erwachsene Patienten mit einem medianen Alter von 54 Jahren in die Studie eingeschlossen und 218 Therapiezyklen ausgewertet werden. Es zeigten sich signifikante Assoziationen zwischen der Dauer der Aplasie der Neutrophilen und der Medikation mit Voriconazol oder Posaconazol im Vergleich zu Fluconazol oder keiner antimykotischen Prophylaxe. Insbesondere in den zweiten und dritten Chemotherapie- Zyklen zeigte sich ein erhöhtes Risiko einer prolongierten Aplasie für Neutrophile bei der Anwendung mit Posaconazol oder Voriconazol. Für die Thrombozyten- Regeneration zeigten sich Assoziationen, die zwar nicht signifikant waren, allerdings den gleichen Trend anzeigen. Es erscheint uns möglich, dass hier auf Grund des Interaktionspotenzials von Posaconazol und Voriconazol ein erhöhtes Risiko einer prolongierten Aplasie besteht.
Anaplasma phagocytophilum and Anaplasma ovis–Emerging Pathogens in the German Sheep Population
(2021)
Knowledge on the occurrence of pathogenic tick-borne bacteria Anaplasma phagocytophilum and Anaplasma ovis is scarce in sheep from Germany. In 2020, owners from five flocks reported ill thrift lambs and ewes with tick infestation. Out of 67 affected sheep, 55 animals were clinically examined and hematological values, blood chemistry and fecal examinations were performed to investigate the underlying disease causes. Serological tests (cELISA, IFAT) and qPCR were applied to all affected sheep to rule out A. phagocytophilum and A. ovis as a differential diagnosis. Ticks were collected from selected pastures and tested by qPCR. Most animals (n = 43) suffered from selenium deficiency and endoparasites were detected in each flock. Anaplasma spp. antibodies were determined in 59% of examined sheep. Seventeen animals tested positive for A. phagocytophilum by qPCR from all flocks and A. phagocytophilum was also detected in eight pools of Ixodes ricinus. Anaplasma phagocytophilum isolates from sheep and ticks were genotyped using three genes (16S rRNA, msp4 and groEL). Anaplasma ovis DNA was identified in six animals from one flock. Clinical, hematological and biochemical changes were not significantly associated with Anaplasma spp. infection. The 16S rRNA analysis revealed known variants of A. phagocytophilum, whereas the msp4 and groEL showed new genotypes. Further investigations are necessary to evaluate the dissemination and health impact of both pathogens in the German sheep population particularly in case of comorbidities.
Zink-Transporter 8-Autoantikörper sind auch in Kindern ohne hereditäres Diabetes-Risiko in der Lage, das Erkrankungsrisiko zu stratifizieren, was auf eine ähnliche Pathophysiologie hinweist, und insbesondere in anderweitig als niedrig-risikobehaftet eingestuften und in IA-2A-negativen Individuen diejenigen identifiziert, die manifestieren werden.
ZnT8A sind zudem hilfreich in der Identifizierung eines autoimmun-vermittelten Diabetes mellitus im Erwachsenenalter, insbesondere bei phänotypisch als T2D eingestuften Patient*innen, sodass eine entsprechende Therapie und damit die Prognose sowie das Langzeit-Outcome in diesem Patientenkollektiv positiv beeinflusst werden kann.
Das entsprechend des SNP im kodierenden SLC30A8-Gen getriggerte Reaktionsmuster ist in T1D-Patient*innen und hoch-risikobehafteten Kindern mit überwiegend davon unabhängiger Autoantikörperantwort gegenüber der ZnT8WA-dominierenden Antwort in LADA-Patient*innen deutlich different, was die Hypothese unterschiedlicher Pathomechanismen dieser beiden Diabetesformen unterstützt.
Die zusätzliche Testung von ZnT8QA trägt nicht zu einer zusätzlichen Risikostratifizierung bei, sodass ein kombiniertes ZnT8A-Screening mit einem ZnT8-Arg325-Trp325-Hybridkonstrukt eine deutliche Zeit- und Kostenersparnis ohne Sensitivitätsverlust darstellt.
Abstract
Background
Twenty five‐hydroxy vitamin D (25OHD) levels have been proposed to protect against periodontitis based on in vitro and observational studies but evidence from long‐term randomized controlled trials (RCTs) is lacking. This study tested whether genetically proxied 25OHD is associated with periodontitis using Mendelian randomization (MR).
Methods
Genetic variants strongly associated with 25OHD in a genome‐wide association study (GWAS) of 417,580 participants of European ancestry were used as instrumental variables, and linked to GWAS summary data of 17,353 periodontitis cases and 28,210 controls. In addition to the main analysis using an inverse variance weighted (IVW) model, we applied additional robust methods to control for pleiotropy. We also undertook sensitivity analyses excluding single nucleotide polymorphisms (SNPs) used as instruments with potential pleiotropic effects and used a second 25OHD GWAS for replication. We identified 288 SNPs to be genome‐wide significant for 25OHD, explaining 7.0% of the variance of 25OHD levels and providing ≥90% power to detect an odds ratio (OR) of ≤ 0.97.
Results
MR analysis suggested that a 1 standard deviation increase in natural log‐transformed 25OHD was not associated with periodontitis risk (IVW OR = 1.04; 95% confidence interval (CI): 0.97–1.12; P‐value = 0.297). The robust models, replication, and sensitivity analyses were coherent with the primary analysis.
Conclusions
Collectively, our findings suggest that 25OHD levels are unlikely to have a substantial effect on the risk of periodontitis, but large long‐term RCTs are needed to derive definitive evidence on the causal role of 25OHD in periodontitis.
This thesis focuses on the establishment of biocatalytic cascade reactions for the production and detection of industrially relevant flavor and fragrance compounds for food and cosmetic products. To meet the consumer’s demand for those products to be natural, environmentally friendly biocatalytic manufacturing processes that operate GMO-free must be established. Thus, this thesis presents such pathways for the production of an industrially relevant long-chain hydroxy fatty acid and the important flavor and aroma compound raspberry ketone. Furthermore, a biosensor for aldehyde detection was implemented to facilitate screening for suitable biocatalysts that produce industrially relevant aldehydes that are widely applied in the flavor and fragrance industry.
Methicillin-Resistant Staphylococci and Macrococci at the Interface of Human and Animal Health
(2021)
Zusammenfassung
Im Rahmen immunologischer Erkrankungen, wie Autoimmun- oder inflammatorischer Erkrankungen, Erkrankungen des zentralen Nervensystems oder Krebserkrankungen spielen Peptidasen eine wichtige Rolle [1, 2]. Die Exopeptidasen Membran-Alanyl-Aminopeptidase N (APN/CD13) und Dipeptidylpeptidase IV (DP IV/CD26) sind essentiell für die Regulation vieler biologischer Prozesse, insbesondere für die Autoimmunität und die Inflammation [3-5]. Literaturdaten und Vorarbeiten verschiedener Arbeitsgruppen belegen immunmodulatorische Eigenschaften von Inhibitoren der enzymatischen Aktivität der APN. Sowohl in vitro als auch in verschiedenen Krankheitsmodellen der Maus in vivo, zeigten sich therapeutisch relevante immunsuppressive Effekte dieser Inhibitoren [7, 11]. Mechanistisch liegen diesen positiven Wirkungen unter anderem eine Hemmung der Produktion und Sekretion proinflammatorischer Zytokine, sowie die Verstärkung der Produktion und Sekretion immunsuppressiver Zytokine zu Grunde [5]. Die Inhibitoren scheinen auch einen immunmodulatorischen Einfluss auf den Wnt Signalweg zu haben, der als Signaltransduktionsweg wichtige Aufgaben in der Regulation von Zellmigration, Polarität, interzellulärer Kontakte und für die frühe Embryonalentwicklung übernimmt [47]. Im Rahmen dieser Arbeit wurde sowohl der Einfluss verschiedener Inhibitoren der APN als auch des genetischen CD13-Knockouts in Mäusen auf die Aktivierung verschiedener Mikrogliazellpopulationen und auf die Expression von Komponenten des Wnt Signalweges untersucht. In Abhängigkeit von der Aktivierung war sowohl eine gesteigerte Expression proinflammatorischer Zytokine, als auch eine Hemmung der Komponenten des Wnt Signalweges in BV2 Mikrogliazellen zu beobachten. In BV2 Mikrogliazellen konnten keine signifikanten Einflüsse durch die Inhibitoren A1.002 und IP10.C9 detektiert werden. Lediglich durch den CD13-Antikörper My 7 konnten immunsuppressive Effekte in aktivierten BV2 Mikrgoliazellen beobachtet werden. In CD13-Knockout Mäusen konnte eine signifikante Reduktion der Wnt 10b positiven Mikrogliazellen gezeigt werden. In der Zusammenschau aller Ergebnisse lassen sich regulatorische Zusammenhänge zwischen der Aktivität der Mikrogliazellen, sowie der APN und dem Wnt Signalweg aufzeigen. Daher erscheinen weiterführende Analysen in primären isolierten Mikrogliazellen sinnvoll, um die Bedeutung von Inhibitoren der APN in neuronalen Zellen zu ermitteln. Dabei spielen nicht nur die Inhibitoren selbst, sondern auch deren Inkubationsbedingungen im Verhältnis zur LPS-vermittelten Zellaktivierung eine entscheidende Rolle.
Late to bed, late to rise—Warmer autumn temperatures delay spring phenology by delaying dormancy
(2021)
Abstract
Spring phenology of temperate forest trees has advanced substantially over the last decades due to climate warming, but this advancement is slowing down despite continuous temperature rise. The decline in spring advancement is often attributed to winter warming, which could reduce chilling and thus delay dormancy release. However, mechanistic evidence of a phenological response to warmer winter temperatures is missing. We aimed to understand the contrasting effects of warming on plants leaf phenology and to disentangle temperature effects during different seasons. With a series of monthly experimental warming by ca. 2.4°C from late summer until spring, we quantified phenological responses of forest tree to warming for each month separately, using seedlings of four common European tree species. To reveal the underlying mechanism, we tracked the development of dormancy depth under ambient conditions as well as directly after each experimental warming. In addition, we quantified the temperature response of leaf senescence. As expected, warmer spring temperatures led to earlier leaf‐out. The advancing effect of warming started already in January and increased towards the time of flushing, reaching 2.5 days/°C. Most interestingly, however, warming in October had the opposite effect and delayed spring phenology by 2.4 days/°C on average; despite six months between the warming and the flushing. The switch between the delaying and advancing effect occurred already in December. We conclude that not warmer winters but rather the shortening of winter, i.e., warming in autumn, is a major reason for the decline in spring phenology.
The first Therapeutic ROS and Immunity in Cancer (TRIC) meeting was organized by the excellence research center ZIK plasmatis (with its previous Frontiers in Redox Biochemistry and Medicine (FiRBaM) and Young Professionals’ Workshop in Plasma Medicine (YPWPM) workshop series in Northern Germany) and the excellence research program ONKOTHER-H (Rostock/Greifswald, Germany). The meeting showcased cutting-edge research and liberated discussions on the application of therapeutic ROS and immunology in cancer treatment, primarily focusing on gas plasma technology. The 2-day hybrid meeting took place in Greifswald and online from 15–16 July 2021, facilitating a wide range of participants totaling 66 scientists from 12 countries and 5 continents. The meeting aimed at bringing together researchers from a variety of disciplines, including chemists, biochemists, biologists, engineers, immunologists, physicists, and physicians for interdisciplinary discussions on using therapeutic ROS and medical gas plasma technology in cancer therapy with the four main sessions: “Plasma, Cancer, Immunity”, “Plasma combination therapies”, “Plasma risk assessment and patients studies”, and “Plasma mechanisms and treated liquids in cancer”. This conference report outlines the abstracts of attending scientists submitted to this meeting.
The loss of skin integrity is inevitable in life. Wound healing is a necessary sequence of events to reconstitute the body’s integrity against potentially harmful environmental agents and restore homeostasis. Attempts to improve cutaneous wound healing are therefore as old as humanity itself. Furthermore, nowadays, targeting defective wound healing is of utmost importance in an aging society with underlying diseases such as diabetes and vascular insufficiencies being on the rise. Because chronic wounds’ etiology and specific traits differ, there is widespread polypragmasia in targeting non-healing conditions. Reactive oxygen and nitrogen species (ROS/RNS) are an overarching theme accompanying wound healing and its biological stages. ROS are signaling agents generated by phagocytes to inactivate pathogens. Although ROS/RNS’s central role in the biology of wound healing has long been appreciated, it was only until the recent decade that these agents were explicitly used to target defective wound healing using gas plasma technology. Gas plasma is a physical state of matter and is a partially ionized gas operated at body temperature which generates a plethora of ROS/RNS simultaneously in a spatiotemporally controlled manner. Animal models of wound healing have been vital in driving the development of these wound healing-promoting technologies, and this review summarizes the current knowledge and identifies open ends derived from in vivo wound models under gas plasma therapy. While gas plasma-assisted wound healing in humans has become well established in Europe, veterinary medicine is an emerging field with great potential to improve the lives of suffering animals.
Cold physical plasma is a partially ionized gas expelling many reactive oxygen and nitrogen
species (ROS/RNS). Several plasma devices have been licensed for medical use in dermatology, and
recent experimental studies suggest their putative role in cancer treatment. In cancer therapies with
an immunological dimension, successful antigen presentation and inflammation modulation is a
key hallmark to elicit antitumor immunity. Dendritic cells (DCs) are critical for this task. However,
the inflammatory consequences of DCs following plasma exposure are unknown. To this end,
human monocyte-derived DCs (moDCs) were expanded from isolated human primary monocytes;
exposed to plasma; and their metabolic activity, surface marker expression, and cytokine profiles
were analyzed. As controls, hydrogen peroxide, hypochlorous acid, and peroxynitrite were used.
Among all types of ROS/RNS-mediated treatments, plasma exposure exerted the most notable
increase of activation markers at 24 h such as CD25, CD40, and CD83 known to be crucial for T cell
costimulation. Moreover, the treatments increased interleukin (IL)-1α, IL-6, and IL-23. Altogether,
this study suggests plasma treatment augmenting costimulatory ligand and cytokine expression in
human moDCs, which might exert beneficial effects in the tumor microenvironment.
Für die Hemmung der plasmatischen Gerinnung kommen orale und parenterale Antikoagulantien in Betracht. Bei stationären Patienten spielt das parenteral verabreichte Heparin, vorkommend als höher- und niedermolekulares Heparin, die größte Rolle. Neben Blutungskomplikationen, kann Heparin auch die gefürchtete Nebenwirkung Heparin-induzierte Thrombozytopenie auslösen.
Aufgrund der Bildung von Immunkomplexen durch Bindung von Antikörpern an Komplexe aus PF4 und Heparin, kommt es zu einer Thrombozytenaggregation mit eventuell auftretenden Thromboembolien. Das Risiko für diese Entstehung erhöht sich mit steigender Kettenlänge des Heparins, mit einer zehnfach erhöhten Prävalenz bei UFH gegenüber LMWHs.
Das Protein PF4 ist ein tetrameres Protein aus der Familie der CXC-Chemokine und wird in den α-Granula der Thrombozyten gespeichert. Durch deren positive Ladung zeigt es eine hohe Affinität zu negativ geladenem Heparin, wodurch antigene Komplexe aufgrund der strukturellen Veränderung des PF4s formiert werden.
In dieser Arbeit wurde der Einfluss verschiedener Heparine mit aufsteigender Kettenlänge auf die Struktur von PF4 getestet und untersucht, inwieweit ein Polysaccharid mit einem bestimmten Sulfatierungsgrad in Kombination mit einem Standardheparin die Antigen/Antikörper-Interaktion von PF4/Heparin-Antikörper verändern kann.
Hierfür kamen unterschiedliche Verfahren zum Einsatz. Hauptaugenmerk wurde auf den Zirkulardichroismus gelegt, mit deren Hilfe die Sekundärstruktur und Konformationsänderung von PF4 im Zusammenspiel mit den Heparinen und Polysacchariden untersucht werden kann. Für den Nachweis von antigenen PF4/Heparin-Komplexen wurde der Enzym-gekoppelte Immunologische Test ELISA und der Heparin-induzierte Plättchenakivierungstest (HIPA) angewendet.
Die durch die Standardheparine ausgelöste Änderung der Konfirmation von PF4 lässt sich durch die Zugabe des synthetisch hergestellten Polysaccharids 12mer-3, das 12 Sulfatgruppen hat, hemmen. Dies war nicht mit den anderen synthetischen 12mer-Polysacchariden möglich. Auch zeigte sich keine Interaktion von 12mer-3 auf die Wechselwirkung von PF4 mit 12mer-6, welche durch die geringere Anzahl an Sulfatgruppen des 12mer-3 zu interpretieren ist. Die Bindung von humanen anti-PF4/Heparin-Antikörpern wurde mit ELISA und dem Funktionstest HIPA untersucht. Hier wurden sieben menschliche Seren mit enthaltenen Anti-PF4/Heparin-IgG-Ak verwendet und nach Hinzugabe der synthetischen Polysaccharide die Ak-Bindung an den antigenen PF4/Heparin-Komplexen und die nachfolgende Thrombozytenaggregation getestet.
Das wichtigste Ergebnis dieser Arbeit ist, dass das Polysaccharid 12mer-3die Struktur von PF4 in PF4/Heparin-Komplexen verändert und dadurch die Bindung von PF4/Heparin-Antikörper reduziert. Durch eine gleichzeitige Gabe von Heparin zusammen mit dem Polysaccharid 12mer-3, könnte das Risiko der unerwünschten Arzneimittelwirkung Heparin-induzierte Thrombozytopenie reduziert werden.
Neben der klinischen Wichtigkeit des Ergebnisses, bietet die hier vorliegende Dissertation auch eine Reihe von Ansatzpunkten für weitere Projekte. Zu nennen wäre hier beispielsweise die Testung der Reaktionen von 12mer-3 in Wechselwirkung mit den Standardheparinen UFH, Reviparin und Enoxaparin und 12mer-3 in Kombination mit 12mer-6 im ELISA und im HIPA, um eine Kongruenz hinsichtlich der bereits durchgeführten CD-Messungen zu liefern. Auch wäre es in klinischen Studien interessant herauszufinden, ob die Expression des Antigens auf PF4/Heparin-Komplexe auch in vivo gehemmt werden könnte.
Weiterhin kann unser Ansatz zur Synthese von sichereren Wirkstoffen führen, die an PF4 binden.
Das im deutschen Grundgesetz festgehaltene Ziel der „Herstellung gleichwertiger Lebensverhältnisse“ wird zunehmend auch im präventiven und krankheitsbezogenen Kontext diskutiert. Kinder und Jugendliche haben diesbezüglich speziellen Bedarf. Ihr Gesundheitszustand wirkt sich auf den gesamten Lebensverlauf aus. Es gibt allerdings Regionen, zumeist ländlich geprägt, in denen eine flächendeckende, bedarfsgerechte und wohnortnahe Versorgung mit Pädiater*innen bereits jetzt oder zukünftig gefährdet ist.
Es werden zwei Publikationen mit Ergebnissen aus zwei Expert*innenbefragungen thematisiert. Eine Befragung adressierte zwei Stichproben von Kita-Eltern und verglich diese miteinander. Die andere Befragung bezog Angehörige verschiedener Gesundheitsprofessionen als in der Pädiatrie aktive Leistungserbringer*innen ein. Beide Befragungen waren fokussiert auf die medizinische Versorgungssituation in Mecklenburg-Vorpommern und auf die Akzeptanz gegenüber einer innovativen Versorgungsmöglichkeit in Form von berufsgruppenübergreifender Zusammenarbeit in der ambulanten Pädiatrie.
Als wichtigste Ergebnisse ist zum einen festzuhalten, dass Kinder und Jugendliche in ländlichen Regionen seltener einer für ihre Bedürfnisse ausgebildeten Ärzt*in vorgestellt wurden. Zum anderen nahmen mehr als die Hälfte aller teilnehmenden Experte*innen (54 Prozent der Eltern und 58 Prozent der Leistungserbringer*innen) Probleme in der medizinischen Versorgung der Kinder und Jugendlichen in Mecklenburg-Vorpommern wahr. Gegenüber der berufsgruppenübergreifenden Zusammenarbeit zeigte sich in den Befragungen eine relativ hohe Akzeptanz, so dass in einer der Publikationen neben den Befragungsergebnissen die Entwicklung eines mehrdimensionalen Konzeptes zu ihrer Umsetzung vorgestellt wird.
Darüber hinaus wurden in den letzten Jahren zwei weitere Konzepte innovativer Versorgungsansätze implementiert und evaluiert, die in die Dissertationsarbeit integriert werden. Dies waren Pilotprojekte zu Machbarkeit und Akzeptanz einer telemedizinischen Dringlichkeitseinschätzung in pädiatrischen Notaufnahmen und für eine hausärztlich-pädiatrische Kooperation. Beide Projekte wurden positiv evaluiert. Es gibt Transfer-Strategien und Finanzierungsmöglichkeiten zu einer Ausweitung dieser Versorgungsformen. Die Veröffentlichung der Ergebnisse dieser beiden Konzepte ist derzeit in Vorbereitung.
Ob die Transfer-Strategien für diese Projekte erfolgreich sein werden, entscheidet letztlich der gesundheitspolitische Wille zu langfristigen Veränderungsprozessen.
FAM159B is a so-called adaptor protein. These proteins are essential components in numerous cell signalling pathways. However, little is known regarding FAM159B expression in normal and neoplastic human tissues. The commercially available rabbit polyclonal anti-human FAM159B antibody HPA011778 was initially characterised for its specificity using Western blot analyses and immunocytochemistry and then applied to a large series of formalin-fixed, paraffin-embedded normal and neoplastic human tissue samples. Confirmation of FAM159B’s predicted size and antibody specificity was achieved in BON-1 cells, a neuroendocrine tumour cell line endogenously expressing FAM159B, using targeted siRNA. Immunocytochemical experiments additionally revealed cytoplasmic expression of the adaptor protein. Immunohistochemical staining detected FAM159B expression in neuronal and neuroendocrine tissues such as the cortex, the trigeminal ganglia, dorsal root and intestinal ganglia, the pancreatic islets and the neuroendocrine cells of the bronchopulmonary and gastrointestinal tract, but also in the syncytiotrophoblasts of the placenta. FAM159B was also expressed in many of the 28 tumour entities investigated, with high levels in medullary and anaplastic thyroid carcinomas, parathyroid adenomas, lung and ovarian carcinomas, lymphomas and neuroendocrine tumours of different origins. The antibody HPA011778 can act as a useful tool for basic research and identifying FAM159B expression in tissue samples.
Orthohantaviruses are rodent-borne pathogens distributed all over the world, which do not cause visible disease in their reservoir host. Puumala orthohantavirus (PUUV) causes most human hantavirus disease cases in Europe and is transmitted by the bank vole (Clethrionomys glareolus). Hantaviruses have a tri-segmented genome consisting of the large (L) segment, coding for the RNA-dependent RNA polymerase (RdRP), the medium (M) segment, encoding the glycoproteins, and the small (S) segment. The S-segment contains two major overlapping open reading frames (ORF) coding for the nucleocapsid (N) protein and a non-structural (NSs) protein, a putative type I interferon (IFN-I) antagonist. To date, pathogenesis and reservoir host adaptation of hantaviruses are poorly understood due to missing adequate cell culture and animal models.
In contrast to previous studies, in this work, data from spring and summer 2019 indicated a high vole abundance, a high PUUV prevalence in voles and high human incidence for some endemic regions in Germany, but elsewhere values were low to moderate. Regional and local human health institutions need to be aware about the heterogeneous distribution of human PUUV infection risk.
For a better understanding of virus-host associations, two novel cell lines from bank voles and common voles each were generated and their susceptibility and replication capacities for a variety of zoonotic and non-zoonotic viruses were analyzed. The PUUV strain Vranica/Hällnäs showed efficient replication in a new bank vole kidney cell line, but not in four other cell lines of bank and common voles. Vice versa, Tula orthohantavirus (TULV) replicated in the kidney cell line of common voles, but was hampered in its replication in other cell lines. Several viruses, such as Cowpox virus, Vaccinia virus, Rift Valley fever virus, and Encephalomyocarditis virus 1 replicated in all four cell lines. West Nile virus, Usutu virus, Sindbis virus and Tick-borne encephalitis virus replicated only in a part of the cell lines. These results indicate a tissue or species specific tropism for many of the tested viruses and the potential value of vole cell lines to address such questions in detail.
Using one of these new cell lines, the first German PUUV strains were isolated from bank voles caught in the highly endemic region around Osnabrück. Complete genomes were determined by target-enrichment-mediated high-throughput sequencing from original lung tissue, after isolation and after additional passaging in VeroE6 cells and a bank vole-derived kidney cell line. Different single amino acid substitutions were observed in the RdRP of the two stable PUUV isolates. The PUUV strain isolated on VeroE6 cells showed a lower titer when propagated on bank vole cells compared to VeroE6 cells. Additionally, glycoprotein precursor (GPC)-derived virus-like particles of a German PUUV strain from the same region allowed the generation of monoclonal antibodies that reacted with the isolated PUUV strains.
To investigate the role of PUUV and other vole-borne hantavirus NSs proteins, the evolution of the NSs and N encoding sequences was investigated by a field study in bank voles and the NSs sequences were characterized in vitro for their inhibitory effect on the human interferon-β promoter. Analysis of blood and lung samples of 851 bank voles trapped during 2010-2014 in Baden-Wuerttemberg and North Rhine-Westphalia resulted in detection of 27.8% PUUV-specific antibody positive bank voles, whereas in 22.3% PUUV-specific RNA was detected. In the hantavirus outbreak years 2010 and 2012 PUUV prevalence in bank voles was higher compared to 2011, 2013 and 2014. Sequences of the S segment of all positive bank voles showed amino acid and nucleotide sequence types of the NSs-ORF with temporal and/or local variation, whereas the N-ORF was highly conserved. One sequence type persisted over the whole observation period in both regions. The NSs coding sequence was highly divergent among regional bank vole populations in the outbreak year 2012.
Transfection experiments resulted in the detection of different products of the NSs-ORF of PUUV, TULV, Prospect Hill and Khabarovsk orthohantaviruses, due to translation initiation at different methionine codons along the coding sequence. Using luciferase reporter assays, the NSs proteins of PUUV, TULV, Prospect Hill and Khabarovsk orthohantaviruses showed inhibition of IFN-I induction of up to 70%, whereas Sin Nombre and Andes orthohantavirus NSs proteins showed a reduced effect compared to the other NSs proteins. The first 20 amino acids of the N-terminal region of PUUV NSs were found to be crucial for IFN-I promoter inhibition.
In conclusion, the newly established cell lines, antibodies, reporter assays and PUUV isolates are highly valuable tools for future hantavirus research. The activity of PUUV NSs protein in human cells contributes to our understanding of virus-host interactions and highlights the importance of corresponding future reservoir host studies. Hantavirus surveillance studies showed the necessity for timely information of the potential human PUUV infection risk to public health institutions in endemic areas to initiate appropriate actions.
Im Rahmen dieser Arbeit sollte die Reaktion primärer dermaler Fibroblasten, die für die Versuche aus SKH1-Mäusen isoliert wurden, auf eine Kaltplasma-Behandlung mittels des Argon-betriebenen Plasmajets „kINPen MED“ hinsichtlich ihrer Reaktion auf oxidativen Stress, ihrer interzellulären Kommunikation über Gap Junctions (GJ) und der Organisation ihres Aktin-Zytoskeletts untersucht werden. Die Plasmabehandlung erfolgte dabei stets indirekt, also durch die Behandlung von Zellkulturmedium, in dem die Zellen anschließend inkubiert wurden. Es ergab sich für die angewendeten Versuchsmodalitäten keine signifikante Induktion von Apoptose durch die indirekte Plasmabehandlung von 20 s bis 180 s, wohingegen die metabolische Aktivität der Zellen bei längeren Behandlungszeiten bis 72 h nach der Plasmabehandlung signifikant reduziert wurde. Dies zeigt die von der Behandlungszeit abhängige Beanspruchung der Fibroblasten durch die Plasmabehandlung und gleichzeitig ihre Kompensationsfähigkeit, die die Zellen auch bei 180 s Behandlungszeit vor dem vermehrten Auftreten von Apoptose schützen konnte.
Nach einer Plasmabehandlung konnte die Aktivierung des Nrf2-Signalwegs nachgewiesen werden, der als zellulärer Schutzmechanismus gegen oxidativen Stress fungiert. So wurde sowohl in den Fibroblasten als auch im Primärgewebe eine Translozierung des Nrf2 in den Zellkern gezeigt. Hierbei wurde auch die Aktivierung des Redox-Sensors Keap1 nachgewiesen, der unter physiologischen Bedingungen Nrf2 bindet und dessen Abbau im Proteasom vermittelt.
Ein weiterer Schwerpunkt der Arbeit lag in der Untersuchung der Zell-Zell-Kommunikation, die vor allem über funktionale GJ-Kanäle erfolgt. Dabei wurde in einem SLDT Assay die Zunahme funktionaler GJ-Kanäle in plasmabehandelten Fibroblasten festgestellt. Außerdem ergab sich eine Tendenz zum Anstieg der Gen- und Proteinexpression von Connexin 43, was unter physiologischen Bedingungen in dermalen Fibroblasten während der Frühphase der Wundheilung beschrieben wurde.
Die Plasmabehandlungen induzierten außerdem strukturelle Veränderungen am Aktin-Zytoskelett in den dermalen Fibroblasten. Solche dynamischen Veränderungen des Zytoskeletts sind während der Wundheilung ebenfalls von entscheidender Bedeutung, da sie die interzelluläre Adhäsion und damit die Migration von Fibroblasten ermöglichen.
Die hier beobachteten Veränderungen zeigten sich vor allem bei kürzeren Behandlungs- und Inkubationszeiten, während gleichzeitig keine signifikante Zunahme apoptotischer Zellen festgestellt wurde. Dies legt nahe, dass durch kurze Plasmabehandlungszeiten in primären Fibroblasten ein Hormesis-Effekt induziert wird, also dass die zeitlich begrenzte Aktivierung zellulärer Schutzmechanismen als Reaktion auf den Stress einer Plasmabehandlung (Radikalbildung, UV-Strahlung) günstige, die Wundheilung fördernde Effekte bewirkt.
LPAIV H9N2 and HPAIV H5N8 clade 2.3.4.4 viruses have been frequently isolated from domestic and wild birds in Germany and they are endemic in poultry worldwide. H9N2 is known to donate gene segments to other AIV with high case fatality rate in humans (e.g. H5N1, H7N9). Similarly, H5N8 devastated poultry worldwide since 2014 and has been recently isolated from humans. Therefore, it is important to understand the genetic predisposition for adaptation of H9N2 and H5N8 AIV in poultry and mammals. In the first publication, we focused on the variable hemagglutinin cleavage site (HACS) of European and Non-European H9N2 viruses, since the HACS is a main virulence determinant of AIV in birds. We found a preferential substitution of non-basic amino acids (G, A, N, S, D, K) in the HACS at position 319 of European H9N2 viruses compared to non-European H9N2 viruses. Recombinant viruses carrying different non-basic amino acids in the HACS modulated replication in vitro. While these non-basic amino acids did not affect virulence or transmission in chickens, they modulated virulence and replication in turkeys. Moreover, H9N2 viruses with non-basic amino acids in the HACS were able to replicate in mammalian brain cells for multiple cycles even without trypsin. In the second publication, we addressed the question whether reassortment between two recent German H9N2 and H5N8 clade 2.3.4.4. B viruses is possible and analysed the impact on virus fitness in mammals and birds. We found that H9N2 PB1 and NP segments were not compatible to generate infectious H5N8 viruses and this incompatibility was due to mutations outside the packaging region. However, H9N2 NS alone or in combination with PB2 and PA significantly increased replication of H5N8 in human cells. Moreover, H9N2 PB2, PA and/or NS segments increased virulence of H5N8 in mice. Interestingly, in chickens, reassortment with H9N2 gene segments, particularly NS, partially or fully impaired chicken-to-chicken transmission. These results indicate that the evolution of H9N2/H5N8 reassortants showing high virulence for mammals is unlikely to occur in chickens. In the third publication, we focused on the NS1 protein of different HPAIV H5N8 clade 2.3.4.4 viruses from 2013 to 2019 and studied the impact of its C-terminus (CTE) variation on virus fitness in chickens and ducks. Our findings revealed a preferential selection for a certain NS1 CTE length in 2.3.4.4. H5N8 clade A (237 aa) and B (217 aa) viruses over the common length of 230 aa. Indeed, the NS1 CTE can affect virus virulence and pathogenesis in a species and virus clade dependent manner. In chickens, although there was no impact on virulence, NS1 CTE of H5N8-A and H5N8-B, regardless of the length, have evolved towards higher efficiency to block the IFN response. In ducks, NS1 CTE contributed to efficient transmission, replication and high virulence of H5N8-B. In the fourth publication, we assessed the impact of variable length of NS1 on H5N8 virus replication in human cells and virulence in mice. We showed that NS1 of H5N8-B virus unlike the vast majority of NS1 of AIV, shared preferences for short NS1 similar to human and zoonotic influenza viruses. This virus (i) was able to efficiently block IFN and apoptosis induction which might be the first steps for efficient adaptation to human cells and (ii) without prior adaptation replicated at higher levels and was more virulent in mice than H5N8-A. The virulence of the latter virus increased after shortening the NS1 similar to H5N8-B virus. Therefore, it is conceivable that truncation in NS1 is a determinant for adaptation of H5N8 in mammals irrespective of its impact on virus fitness in poultry. Findings in this dissertation indicated that HA mutations in the European H9N2 and NS1 variations in H5N8 viruses play a role in virus fitness in poultry and/or mammals. These results improve our current understanding for AIV adaptation and are useful to assess the potential of these viruses to infect mammals.
Re-Establishment Techniques and Transplantations of Charophytes to Support Threatened Species
(2021)
Re-establishment of submerged macrophytes and especially charophyte vegetation is a common aim in lake management. If revegetation does not happen spontaneously, transplantations may be a suitable option. Only rarely have transplantations been used as a tool to support threatened submerged macrophytes and, to a much lesser extent, charophytes. Such actions have to consider species-specific life strategies. K-strategists mainly inhabit permanent habitats, are perennial, have low fertility and poor dispersal ability, but are strong competitors and often form dense vegetation. R-strategists are annual species, inhabit shallow water and/or temporary habitats, and are richly fertile. They disperse easily but are weak competitors. While K-strategists easily can be planted as green biomass taken from another site, rare R-strategists often must be reproduced in cultures before they can be planted on-site. In Sweden, several charophyte species are extremely rare and fail to (re)establish, though apparently suitable habitats are available. Limited dispersal and/or lack of diaspore reservoirs are probable explanations. Transplantations are planned to secure the occurrences of these species in the country. This contribution reviews the knowledge on life forms, dispersal, establishment, and transplantations of submerged macrophytes with focus on charophytes and gives recommendations for the Swedish project.
Abstract
The expected signature is an analogue of the Laplace transform for probability measures on rough paths. A key question in the area has been to identify a general condition to ensure that the expected signature uniquely determines the measures. A sufficient condition has recently been given by Chevyrev and Lyons and requires a strong upper bound on the expected signature. While the upper bound was verified for many well‐known processes up to a deterministic time, it was not known whether the required bound holds for random time. In fact, even the simplest case of Brownian motion up to the exit time of a planar disc was open. For this particular case we answer this question using a suitable hyperbolic projection of the expected signature. The projection satisfies a three‐dimensional system of linear PDEs, which (surprisingly) can be solved explicitly, and which allows us to show that the upper bound on the expected signature is not satisfied.
Neutrophils in Tuberculosis: Cell Biology, Cellular Networking and Multitasking in Host Defense
(2021)
Neutrophils readily infiltrate infection foci, phagocytose and usually destroy microbes. In
tuberculosis (TB), a chronic pulmonary infection caused by Mycobacterium tuberculosis (Mtb),
neutrophils harbor bacilli, are abundant in tissue lesions, and their abundances in blood correlate
with poor disease outcomes in patients. The biology of these innate immune cells in TB is complex.
Neutrophils have been assigned host-beneficial as well as deleterious roles. The short lifespan of
neutrophils purified from blood poses challenges to cell biology studies, leaving intracellular
biological processes and the precise consequences of Mtb–neutrophil interactions ill-defined. The
phenotypic heterogeneity of neutrophils, and their propensity to engage in cellular cross-talk and
to exert various functions during homeostasis and disease, have recently been reported, and such
observations are newly emerging in TB. Here, we review the interactions of neutrophils with Mtb,
including subcellular events and cell fate upon infection, and summarize the cross-talks between
neutrophils and lung-residing and -recruited cells. We highlight the roles of neutrophils in TB
pathophysiology, discussing recent findings from distinct models of pulmonary TB, and emphasize
technical advances that could facilitate the discovery of novel neutrophil-related disease
mechanisms and enrich our knowledge of TB pathogenesis
Promiscuous Dehalogenase Activity of the Epoxide Hydrolase CorEH from Corynebacterium sp. C12
(2021)
Haloalkane dehalogenases and epoxide hydrolases are phylogenetically related and structurally homologous enzymes that use nucleophilic aspartate residues for an SN2 attack on their substrates. Despite their mechanistic similarities, no enzymes are known that exhibit both epoxide hydrolase and dehalogenase activity. We screened a subset of epoxide hydrolases, closely related to dehalogenases, for dehalogenase activity and found that the epoxide hydrolase CorEH from Corynebacterium sp. C12 exhibits promiscuous dehalogenase activity. Compared to the hydrolysis of epoxides like cyclohexene oxide (1.41 μmol min–1 mg–1), the dehalogenation of haloalkanes like 1-bromobutane (0.25 nmol min–1 mg–1) is about 5000-fold lower. In addition to the activity with 1-bromobutane, dehalogenase activity was detected with other substrates like 1-bromohexane, 1,2-dibromoethane, 1-iodobutane, and 1-iodohexane. This study shows that dual epoxide hydrolase and dehalogenase activity can be present in one naturally occurring protein scaffold.
Die Dissertation ,Spuren des Religiösen´ im Werk der deutsch-jüdischen Schriftstellerin Barbara Honigmann – eine literaturwissenschaftlich-theologische Werkanalyse – analysiert und interpretiert das literarische Frühwerk der deutsch-jüdischen Schriftstellerin Barbara Honigmann (geb. 12. Februar 1949 in Ostberlin). Die Schriftstellerin verlässt Mitte der achtziger Jahre mit ihrer Familie die ehemalige DDR und findet in Straßburg (Frankreich) eine neue Heimat. In der Dissertation werden der Erzählband Roman von einem Kinde (1986) und die Romane Eine Liebe aus nichts (1991) und Soharas Reise (1996) aus der Sicht verschiedener Fachwissenschaften beleuchtet. Die meisten Texte sind nach ihrer Emigration in Frankreich entstanden. Methodisch werden die Texte nach der Erzähltextanalyse von Sönke Finnern analysiert. Das Judentum und jüdische Religiosität bilden dabei das gemeinsame Zentrum der literarischen Werke Barbara Honigmanns (Hans Otto Horch). In differenzierter Weise werden unterschiedliche jüdisch-theologische Aspekte wie Gottesfrage, Bedeutung der jüdischen Feste, Riten und Exilerfahrung anhand der Werke herausgearbeitet. Aus literaturwissenschaftlicher Sicht wird der Aspekt des exterritorialen Schreibens betont (Andreas Kilcher). Dabei wird die besondere Perspektive als Autorin der sogenannten zweiten Generation nach der Shoah hervorgehoben (Hartmut Steinecke). Georg Langenhorst macht auf die Bedeutung Honigmanns im Kontext des religionspädagogischen Diskurses unter interkultureller und interreligiöser Fragestellung aufmerksam. Die Erzählte Religion bildet das Zentrum der literarisch-theologischen Werkanalyse. Die Kategorie der Grenzerfahrung bzw. der Liminalität rückt dabei in das Zentrum der Verhältnisbestimmung (Victor Turner und Dirk Hohnsträter). Auf der theologischen Ebene werden die jüdischen Konzepte von makom (hebr. Ort), galut (hebr. Exil) und jetzirat (hebr. Schöpfung) herausgearbeitet. Die jüdische Erfahrung von Heimat und Heimatlosigkeit wird hervorgehoben (Yannif Feller). Die Arbeit schließt mit einer Einordnung der Werkinterpretation in den Bereich Literatur und Ritual (Wolfgang Braungart).
Duckweeds (Lemnaceae) are the smallest and fastest-growing angiosperms. This feature, together with high starch production and good nutritional properties, makes them suitable for several applications, including wastewater treatment, bioenergy production, or feed and food supplement. Due to their reduced morphology and great similarity between diverse species, taxonomic identification of duckweeds is a challenging issue even for experts. Among molecular genotyping methods, DNA barcoding is the most useful tool for species identification without a need for cluster analysis. The combination of two plastid barcoding loci is now considered the gold standard for duckweed classification. However, not all species can be defined with confidence by these markers, and a fast identification method able to solve doubtful cases is missing. Here we show the potential of tubulin-based polymorphism (TBP), a molecular marker based on the intron length polymorphisms of β-tubulin loci, in the genomic profiling of the genera Spirodela, Landoltia, and Lemna. Ninety-four clones were analyzed, including at least two representatives of each species of the three genera, with a special focus on the very heterogeneous species Lemna minor. We showed that a single PCR amplification with universal primers, followed by agarose gel analysis, was able to provide distinctive fingerprinting profiles for 10 out of 15 species. Cluster analysis of capillary electrophoresis–TBP data provided good separation for the remaining species, although the relationship between L. minor and Lemna japonica was not fully resolved. However, an accurate comparison of TBP profiles provided evidence for the unexpected existence of intraspecific hybrids between Lemna turionifera and L. minor, as further confirmed by amplified fragment length polymorphism and sequence analysis of a specific β-tubulin locus. Such hybrids could possibly correspond to L. japonica, as originally suggested by E. Landolt. The discovery of interspecific hybrids opens a new perspective to understand the speciation mechanisms in the family of duckweeds.
Ebolaviruses are zoonotic pathogens causing severe hemorrhagic fevers in humans
and non-human primates with high case fatality rates. In recent years, the number and
scope of outbreaks has increased, highlighting the importance of better understanding
the molecular aspects of ebolaviral infection and host cell interactions in order to be able to better control this virus.
To facilitate virus genome replication, transcription and protein expression,
ebolaviruses recruit and interact with specific host factors. These interactions play a key role in viral infection and influence virus survival and disease outcome. Based on a genome-wide siRNA screen, the three host factors CAD, NXF1 and UAP56 were
recently identified to be involved in ebolavirus genome replication and/or transcription
and/or mRNA-translation. However, mechanistical details of how these host factors
affect the ebolavirus lifecycle remained elusive.
In this thesis I analyzed the functional interactions between EBOV and these newly
identified host proteins in order to better understand the virus-host interface. To this
end I used siRNA knockdown as well as overexpression of these host proteins in
combination with different reverse-genetics based lifecycle modelling assays to
investigate the influence of CAD, NXF1 and UAP56 on individual aspects of the EBOV
lifecycle. Using these systems in relation with a host factor knockdown I was able to
show that the provision of pyrimidines by CAD plays an important role for both EBOV
genome replication and transcription, whereas NXF1 is predominantly required for
mRNA transport. I furthermore used immunofluorescence analysis to examine whether
these host factors are recruited by one or more EBOV proteins to inclusion bodies,
which represent physical sites of ebolavirus genome replication. During these
experiments, I was able to show that CAD and NXF1, and possibly also UAP56, are
recruited to EBOV inclusion bodies in order to fulfill their individual function for EBOV RNA synthesis or later steps in protein expression. Additionally, I was able to show that the uptake of NXF1 into NP-induced inclusion bodies is most likely mediated via the C-terminal domain of NP, and that the FG-repeat interaction domains of NXF1 are sufficient for recruitment. Further, my data indicate that RNA interaction of both NXF1 and NP is not required for this process, but rather important for exit of NXF1 from inclusion bodies. I therefore suggest that the viral mRNA is transferred in inclusionbodies from NP to NXF1, which leads to a rapid export of the NXF1 packed viral mRNA into the cytosol for mRNA translation.
The exact mechanism of how these host factors are recruited into inclusion bodies and whether they have similar functions in the lifecycle of other negative-sense RNA viruses still needs to be investigated. Nevertheless, this study increases our understanding of virus-host interaction of ebolaviruses, and thus helps to identify targets for the development of novel therapeutics against these viruses.
The anaerobic pathogen Clostridioides difficile is perfectly equipped to survive and persist inside the mammalian intestine. When facing unfavorable conditions C. difficile is able to form highly resistant endospores. Likewise, biofilms are currently discussed as form of persistence. Here a comprehensive proteomics approach was applied to investigate the molecular processes of C. difficile strain 630Δerm underlying biofilm formation. The comparison of the proteome from two different forms of biofilm-like growth, namely aggregate biofilms and colonies on agar plates, revealed major differences in the formation of cell surface proteins, as well as enzymes of its energy and stress metabolism. For instance, while the obtained data suggest that aggregate biofilm cells express both flagella, type IV pili and enzymes required for biosynthesis of cell-surface polysaccharides, the S-layer protein SlpA and most cell wall proteins (CWPs) encoded adjacent to SlpA were detected in significantly lower amounts in aggregate biofilm cells than in colony biofilms. Moreover, the obtained data suggested that aggregate biofilm cells are rather actively growing cells while colony biofilm cells most likely severely suffer from a lack of reductive equivalents what requires induction of the Wood-Ljungdahl pathway and C. difficile’s V-type ATPase to maintain cell homeostasis. In agreement with this, aggregate biofilm cells, in contrast to colony biofilm cells, neither induced toxin nor spore production. Finally, the data revealed that the sigma factor SigL/RpoN and its dependent regulators are noticeably induced in aggregate biofilms suggesting an important role of SigL/RpoN in aggregate biofilm formation.
Abstract
The article focuses on whether and to which extent heritage bilinguals make use of their heritage language while developing receptive skills in unknown languages which are either related to the majority language or the heritage language. Thirty four adolescent heritage speakers of Russian and Polish and a control group of thirty three German monolinguals were first exposed to a text in Swedish. The monolingual control group was matched with regard to age, educational background, foreign languages learned at school as well as proficiency in English. All participants had to determine the parts of speech of ten items from the text, translate them into German, and extract the main pieces of information from the text. In a second step, the heritage speakers completed a similar task with an unknown Slavic target language (Serbian). The results revealed no bilingual advantage of the heritage speakers over the monolinguals in the Swedish task. Furthermore, they scored lower in the Serbian trial. We treat this as evidence that access to the heritage language as a resource for solving these tasks is limited compared to the majority language and English which might be due to lesser metalinguistic knowledge about structures of the heritage language.
Abstract
Individuals of the marine chelicerate lineage Pycnogonida (sea spiders) show considerable regenerative capabilities after appendage injury or loss. In their natural habitats, especially the long legs of sea spiders are commonly lost and regenerated, as is evidenced by the frequent encounter of specimens with missing or miniature legs. In contrast to this, the collection of individuals with abnormally developed appendages or trunk regions is comparably rare. Here, we studied a remarkable malformation in a postlarval instar of the species Phoxichilidium femoratum (Rathke, 1799) and describe the external morphology and internal organization of the specimen using a combination of fluorescent histochemistry and scanning electron microscopy. The individual completely lacks the last trunk segment with leg pair 4 and the normally penultimate trunk segment bears only a single aberrant appendage resembling an extension of the anteroposterior body axis. Externally, the proximal units of the articulated appendage are unpaired, but further distally a bifurcation into two equally developed leg‐like branches is found. Three‐dimensional reconstruction of the musculature reveals components of two regular leg muscle sets in several of the proximal articles. This confirms interpretation of the entire appendage as a malformed leg and reveals an externally hidden paired organization along its entire proximodistal axis. To explain the origin of this unique malformation, early pioneering studies on the regenerative potential of pycnogonids are evaluated and (a) an injury‐induced partial fusion of the developing limb buds of leg pair 3, as well as (b) irregular leg regeneration following near complete loss of trunk segments 3 and 4 are discussed. Which of the two hypotheses is more realistic remains to be tested by dedicated experimental approaches. These will have to rely on pycnogonid species with established laboratory husbandry in order to overcome the limitations of the few short‐term regeneration studies performed to date.
Abstract
Nervous system development has been intensely studied in insects (especially Drosophila melanogaster), providing detailed insights into the genetic regulatory network governing the formation and maintenance of the neural stem cells (neuroblasts) and the differentiation of their progeny. Despite notable advances over the last two decades, neurogenesis in other arthropod groups remains by comparison less well understood, hampering finer resolution of evolutionary cell type transformations and changes in the genetic regulatory network in some branches of the arthropod tree of life. Although the neurogenic cellular machinery in malacostracan crustaceans is well described morphologically, its genetic molecular characterization is pending. To address this, we established an in situ hybridization protocol for the crayfish Procambarus virginalis and studied embryonic expression patterns of a suite of key genes, encompassing three SoxB group transcription factors, two achaete–scute homologs, a Snail family member, the differentiation determinants Prospero and Brain tumor, and the neuron marker Elav. We document cell type expression patterns with notable similarities to insects and branchiopod crustaceans, lending further support to the homology of hexapod–crustacean neuroblasts and their cell lineages. Remarkably, in the crayfish head region, cell emigration from the neuroectoderm coupled with gene expression data points to a neuroblast‐independent initial phase of brain neurogenesis. Further, SoxB group expression patterns suggest an involvement of Dichaete in segmentation, in concordance with insects. Our target gene set is a promising starting point for further embryonic studies, as well as for the molecular genetic characterization of subregions and cell types in the neurogenic systems in the adult crayfish brain.
Background
Vulnerable groups, e.g. persons with mental illness, neurological deficits or dementia, are often excluded as participants from research projects because obtaining informed consent can be difficult and tedious. This may have the consequence that vulnerable groups benefit less from medical progress. Vulnerable persons are often supported by a legal guardian in one or more demands of their daily life. We examined the attitudes of legal guardians and legally supervised persons towards medical research and the conditions and motivations to participate in studies.
Methods
We conducted a cross-sectional study with standardized surveys of legal guardians and legally supervised persons. Two separate questionnaires were developed for the legal guardians and the supervised persons to asses previous experiences with research projects and the reasons for participation or non-participation. The legal guardians were recruited through various guardianship organizations. The supervised persons were recruited through their legal guardian and from a previous study among psychiatric patients. The data were analysed descriptively.
Results
Alltogether, 82 legal guardians and 20 legally supervised persons could be recruited. Thereof 13 legal guardians (15.6%) and 13 legally supervised persons (65.0%) had previous experience with research projects. The majority of the guardians with experience in research projects had consented the participation of their supervised persons (n = 12 guardians, 60.0%; in total n = 16 approvals). The possible burden on the participating person was given as the most frequent reason not to participate both by the guardians (n = 44, 54.4%) and by the supervised persons (n = 3, 30.0%). The most frequent motivation to provide consent to participate in a research study was the desire to help other patients by gaining new scientific knowledge (guardians: n = 125, 78.1%; supervised persons: n = 10, 66.6%).
Conclusions
Overall, an open attitude towards medical research can be observed both among legal guardians and supervised persons. Perceived risks and no sense recognized in the study are reasons for not participating in medical research projects.
Cold physical plasmas, especially noble gas driven plasma jets, emit considerable amounts of ultraviolet radiation (UV). Given that a noble gas channel is present, even the energetic vacuum UV can reach the treated target. The relevance of UV radiation for antimicrobial effects is generally accepted. It remains to be clarified if this radiation is relevant for other biomedical application of plasmas, e.g., in wound care or cancer remediation. In this work, the role of (vacuum) ultraviolet radiation generated by the argon plasma jet kINPen for cysteine modifications was investigated in aqueous solutions and porcine skin. To differentiate the effects of photons of different wavelength and complete plasma discharge, a micro chamber equipped with a MgF2, Suprasil, or Borosilicate glass window was used. In liquid phase, plasma-derived VUV radiation was effective and led to the formation of cysteine oxidation products and molecule breakdown products, yielding sulfite, sulfate, and hydrogen sulfide. At the boundary layer, the impact of VUV photons led to water molecule photolysis and formation of hydroxyl radicals and hydrogen peroxide. In addition, photolytic cleavage of the weak carbon-sulfur bond initiated the formation of sulfur oxy ions. In the intact skin model, protein thiol modification was rare even if a VUV transparent MgF2 window was used. Presumably, the plasma-derived VUV radiation played a limited role since reactions at the boundary layer are less frequent and the dense biomolecules layers block it effectively, inhibiting significant penetration. This result further emphasizes the safety of physical plasmas in biomedical applications.
On the aqueous phase chemistry of atmospheric-pressure plasma jets for biomedical applications
(2021)
Cold atmospheric-pressure plasmas are candidate biomedical tools proposed for various applications, such as biological decontamination, cancer regression, and promotion of wound healing. Plasmas, which are in the fourth state of matter, can be generated using inert gases (e.g., argon, helium, ambient air) and different source concepts. Together with the applied parameters, the source design defines the chemical-physical characteristics of the resulting plasma, leading in turn to variable biochemical effects on biological matter. The medical effectiveness of cold plasmas has been proven in vitro and in vivo, also in clinical trials for wound healing in patients using two certified plasmas sources, the kINPen MED and the PlasmaDerm. However, molecular mechanisms leading to those effects are unclear. In the same way, it must be studied if the modulation of plasma properties could improve the specificity of biological effects. These findings are needed to define the concept of plasma dose to be optimized in targeting peculiar pathologic conditions. The present thesis consisting of five peer-reviewed publications has investigated these aspects of plasma research.
In the gaseous phase of cold plasmas, various components with biological activity are produced, such as radiation (e.g., vacuum UV, UV) and reactive species (e.g., •O, 1O2, •OH, •NO, •NO2, O3). As most gaseous species are short-lived, liquid compartments surrounding cells and molecular structures could mediate their transformation and/or the production of other aqueous species. For this reason, plasma-induced aqueous chemistry has been mainly investigated in this thesis. The reaction pathways of reactive oxygen and nitrogen species in liquid were analyzed by monitoring the oxidative modifications induced on tyrosine and cysteine, which are biological structures essential in cellular protein functioning. Liquid chromatography and mass spectrometry-based strategies have been elaborated to elucidate structural changes and characterize the oxidative pattern occurring on the tracers after treatment with plasmas.
As a first result, it could be shown that the oxidative pattern induced on tyrosine or cysteine variated qualitatively and quantitatively with the applied conditions, reflecting the action of differently produced/deposited species in liquid. Biologically relevant structures were identified and in part quantified (e.g., cystine, sulfonic acid, sulfinic acid, S-sulfonate, S-nitrosocysteine, nitrotyrosine, nitrosotyrosine). By using isotopically labeled oxygen or nitrogen in the gas plasma, or labeled oxygen in the target liquid, the incorporation of gaseous or aqueous species in the tracer’s structures was monitored via mass spectrometry. With this strategy, the reaction mechanisms involving gaseous oxygen and nitrogen species at the liquid interface were clarified, as well as the de novo production of reactive species in liquid. Short-lived gaseous oxygen species such as atomic and singlet oxygen (•O, 1O2), predominantly formed in conditions with oxygen in the plasma gas, were able to modify the cysteine structures in highly oxidized derivatives, such as cysteine sulfonic acid. Due to their half-life, however, their activity occurred mainly at the interface. Vacuum UV radiation and •O also led to the formation in liquid of hydroxyl radicals (•OH) and hydrogen peroxide (H2O2), due to water photolysis and homolysis. Water-derived species were responsible for the formation of reversible modifications, such as cysteine S-sulfonate, cystine, and cystine sulfoxides. Nitrosative modifications (e.g., S-nitrosocysteine, nitrosotyrosine, nitrotyrosine) could be observed only in conditions with both nitrogen and oxygen in the plasma gas, and further optimization occurred in presence of water molecules in the gas. In this case, the formation and action of peroxynitrite (ONOO-) in generating nitrotyrosine was proven by using a scavenger molecule for ONOO-.
Finally, the cysteine product pattern was applied as a tool to characterize and compare the overall chemistry generated in liquid by different plasma sources and applied parameters. These findings aim to support and contribute to the definition of plasma dose for plasma medicine, through the standardization, control, tuning, and optimization of plasma parameters and plasma liquid chemistry. These results may be applied in the future to improve the specificity and selectivity of the biological effects generated by the described atmospheric-pressure plasma jets.
Fibroblasts contribute to approximately 20% of the non-cardiomyocytic cells in the heart. They play important roles in the myocardial adaption to stretch, inflammation, and other pathophysiological conditions. Fibroblasts are a major source of extracellular matrix (ECM) proteins whose production is regulated by cytokines, such as TNF-α or TGF-β. The resulting myocardial fibrosis is a hallmark of pathological remodeling in dilated cardiomyopathy (DCM). Therefore, in the present study, the secretome and corresponding transcriptome of human cardiac fibroblasts from patients with DCM was investigated under normal conditions and after TNF-α or TGF-β stimulation. Secreted proteins were quantified via mass spectrometry and expression of genes coding for secreted proteins was analyzed via Affymetrix Transcriptome Profiling. Thus, we provide comprehensive proteome and transcriptome data on the human cardiac fibroblast’s secretome. In the secretome of quiescent fibroblasts, 58% of the protein amount belonged to the ECM fraction. Interestingly, cytokines were responsible for 5% of the total protein amount in the secretome and up to 10% in the corresponding transcriptome. Furthermore, cytokine gene expression and secretion were upregulated upon TNF-α stimulation, while collagen secretion levels were elevated after TGF-β treatment. These results suggest that myocardial fibroblasts contribute to pro-fibrotic and to inflammatory processes in response to extracellular stimuli.
Ex vivo- und in vivo-Untersuchungen der Anwendung von nicht-thermischem Plasma zur Blutkoagulation
(2021)
Die steigende Inzidenz und Prävalenz von Vorhofflimmern mit dem gleichzeitig erhöhten Risiko thrombembolischer Ereignisse macht eine Antikoagulation in einer immer größer werdenden Population nötig [1-3]. Das intraoperative Blutungsmanagement stellt bei Patienten, welche eine Antikoagulation erhalten, eine Schwierigkeit dar [4, 5]. Insbesondere für die direkten oralen Antikoagulantien sind Antidote häufig nicht verfügbar oder kostenintensiv [6, 7]. Die aktuell verwendete elektrische Kauterisation geht mit dem Risiko der Bildung von Nekrosen einher, welche unter Umständen zu Nachblutungen, Strikturen oder Perforationen führen können [8, 9]. Dies untermauert den Bedarf an neuen sicheren Techniken zur intraoperativen Hämostase. Eine mögliche Alternative scheint nicht-thermisches Plasma darzustellen [10]. Dies ist ein energiereiches Gas, welches eine Reihe reaktiver Komponenten enthält und eine gewebeschonende Anwendung am Menschen ermöglicht [11].
In der vorliegenden Arbeit wurde demonstriert, dass nicht-thermisches Plasma des gut charakterisierten kINPen MEDs [11] ex vivo eine Blutkoagulation im murinen Blut induzieren kann. Hierbei spielt vor allem die direkte Aktivierung der Thrombozyten eine Rolle. Nachweise der plasmatischen Gerinnung konnten ex vivo nicht gezeigt werden. Während einer murinen Leberteilresektion wurde in der vorliegenden Arbeit in nativen und Rivaroxaban-antikoagulierten Tieren eine suffiziente Blutungskontrolle durch nicht-thermisches Plasma erzielt, welche mit der elektrischen Kauterisation vergleichbar war. Weiterhin war das nicht-thermische Plasma der elektrischen Kauterisation dahingehend überlegen, als dass es zu keiner akuten Schädigung des umliegenden Gewebes und keiner zeitversetzten Nachblutung geführt hat. Die histologischen Analysen der mit nicht-thermischem Plasma behandelten Wunden zeigten die Ausbildung eines Blutkoagulums, welches am ehesten der natürlichen Koagulation entsprach. Nach Inhibition der Thrombozyten-Funktion durch Clopidogrel war das nicht-thermische Plasma in vivo nicht in der Lage, eine suffiziente Hämostase zu induzieren. Daher konnten die Thrombozyten auch in vivo als wichtige Regulatoren der durch nicht-thermisches Plasma vermittelten Hämostase herausgearbeitet werden.
Auf der Basis einer ausführlichen Literaturrecherche wurde weiterhin die Hypothese aufgestellt, dass vor allem Reduktions-Oxidations-Reaktionen an der durch nicht-thermisches Plasma induzierten Blutkoagulation beteiligt sind. In folgenden Arbeiten sollte darauf hingearbeitet werden, den Mechanismus weiter zu verstehen und effizienter zu gestalten, um dieser Methode einen Einsatz in der Zukunft der Medizin zu ermöglichen.
Beta-2-glycoprotein I (β2GPI) is a blood protein and the major antigen in the autoimmune disorder
antiphospholipid syndrome (APS). β2GPI exists mainly in closed or open conformations and
comprises of 11 disulfides distributed across five domains. The terminal Cys288/Cys326 disulfide
bond at domain V has been associated with different cysteine redox states. The role of this disulfide
bond in conformational dynamics of this protein has not been investigated so far. Here, we report
on the enzymatic driven reduction by thioredoxin-1 (recycled by Tris(2-carboxyethyl)phosphine;
TCEP) of β2GPI. Specific reduction was demonstrated by Western blot and mass spectrometry
analyses confirming majority targeting to the fifth domain of β2GPI. Atomic force microscopy images
suggested that reduced β2GPI shows a slightly higher proportion of open conformation and is more
flexible compared to the untreated protein as confirmed by modelling studies. We have determined a
strong increase in the binding of pathogenic APS autoantibodies to reduced β2GPI as demonstrated
by ELISA. Our study is relevant for understanding the effect of β2GPI reduction on the protein
structure and its implications for antibody binding in APS patients.
The soluble blood protein beta2-glycoprotein I (beta2GPI; 326 aa, MW: 48 kDa, 5 domains) is one of the most abundant proteins in human serum and exhibits two main conformational states: the circular or closed conformation, where the first domain (DI) is bound to the last domain (DV) of the protein, and the linear or open conformation. The defined physiological function of beta2GPI is still unknown, though several roles in pro- and anticoagulation as well as oxidative stress protection were discovered. The open form is considered to play a crucial role in the systemic autoimmune disease antiphospholipid syndrome (APS), which is an acquired thrombophilia characterized by recurring thrombotic events and pregnancy morbidity. Beta2GPI constitutes the main antigen for APS autoantibodies which are supposed to bind a cryptic epitope within DI after a conformational change from closed to open form. However, the pathophysiological mechanism of APS is poorly understood. Therefore, investigating the structural dynamics of this protein in relation to its antigenicity is of high interest.
Post-translational modifications (PTM) of a target protein often show an impact on the formation of neoantigens, for instance in the autoimmune-mediated diseases type 1 diabetes mellitus, rheumatoid arthritis, or multiple sclerosis. Such modified antigens may lead to immune tolerance breakdown as they are unknown to the immune system, which therefore could mistakes self for non-self proteins. In this thesis, two frequently occurring PTM were introduced to beta2GPI and their impact on the protein conformation was studied by biophysical tools (i.e. atomic force microscopy (AFM) imaging, transmission electron microscopy (TEM) imaging, dynamic light scattering (DLS), and circular dichroism (CD) spectroscopy). In order to examine immunopathophysiological relevance of these PTM, additional insights were gained from ELISA which was used to examine binding of anti-DI autoantibodies purified from the blood of APS patients to the modified beta2GPI species.
A characteristic feature of beta2GPI is the high content of lysine residues. Previously, opening of beta2GPI was found to be triggered by a drastic shift in pH and salt concentration (pH 11.5 and 1.15 M NaCl), which results in reversible uncharging of the lysine residues. The aim of this study was to investigate the beta2GPI conformation after lysine acetylation as a model system, to elucidate the role of lysine residues on the conformational dynamics of this protein, and to examine anti-DI autoantibody binding to both the untreated as well as acetylated species.
A strategy to permanently open up the closed form under physiological conditions by chemical acetylation of lysine residues utilizing the sensitive acetylation agent acetic acid N-hydroxysuccinimide ester (NHS-Ac) was established. Complete and specific lysine acetylation was verified by quantification of primary amines exerting a fluoraldehyde o-phthaldialdehyde (OPA) reagent assay, as well as by native PAGE and western blot analysis with an anti-acetylated lysine antibody. Beta2GPI acetylation revealed a partial opening of beta2GPI molecules. Compared to untreated, i.e. native beta2GPI which exhibited 93% of the molecules in closed and 7% in open form, complete lysine residue acetylation generated 39% of beta2GPI in closed and 61% in open conformation as shown by AFM high-resolution imaging. pH 11.5-treated beta2GPI was used as a reference in the applied methods and revealed 38% of the protein in closed and 62% in open conformation. Thus, a significant shift in beta2GPI conformation occurred upon lysine residue acetylation as well as basic pH-treatment. The data indicate that lysine residue acetylation destabilizes the closed form, leading to a facilitated opening of the structure. The closed conformation might be predominantly stabilized by electrostatic interactions of lysine residues, which potentially control the conformational dynamics of this glycoprotein. ELISA confirmed that anti-DI autoantibodies do not bind to untreated (closed) beta2GPI. Although acetylated beta2GPI was shown to have a substantial portion of open proteins, no binding of anti-DI autoantibodies to the acetylated species was found either. Hence, acetylated lysine residues may disrupt the immunorelevant epitope in DI which prevents antibody binding. This finding reveals a new hint for epitope organization. However, further detailed epitope mapping has to be performed.
Beta2GPI carries two structural disulfide bonds per domain, whereas an additional disulfide bond Cys288/Cys326 is located at the C-terminus of DV near the putative contact interface of DI and DV in the closed conformation. It was previously shown that beta2GPI is a substrate of thiol oxidoreductases, including human thioredoxin-1 (Trx-1) generating different redox states of disulfide bond Cys288/Cys326, which might serve as a scavenger in oxidative stress protection in the blood stream. In APS patients, anti-DI antibody titers as well as an enhanced risk for thrombotic events are associated with an increase in the oxidized state of the protein. Hitherto, no structural study has been performed in order to prove a correlation of the redox state and the conformation of beta2GPI. Therefore, investigations of beta2GPI conformation in different redox states of disulfide bond Cys288/Cys326 were carried out. In addition, binding of anti-DI autoantibodies to the untreated (native) as well as reduced protein should be explored.
At first, cysteine residues of untreated, i.e. native beta2GPI were confirmed to be completely in oxidized state using Ellman’s reagent assay and the absence of binding of a thiol-specific agent. Statistical analyses of AFM images revealed that untreated beta2GPI was mainly in closed conformation (80% in closed and 20% in open conformation) in the respective system. In this study, an optimized protocol for enzymatic reduction of disulfide bond Cys288/Cys326 was established. The agent TCEP was used to reduce human Trx-1, which in turn enzymatically reduced beta2GPI. To block reoxidation of free thiols and to facilitate product analysis, cysteine residues of reduced beta2GPI were subsequently labeled with the sensitive and thiol-specific reagent 3-(N-maleimidopropionyl) biocytin (MPB), which carries a biotin function. During protocol establishment, complete and specific reduction of disulfide bond Cys288/Cys326 was confirmed utilizing SDS-PAGE, streptavidin western blot, mass spectrometry (MS) analyses, and a biotin quantification assay. Protocol improvements constituted a homogenous system with remarkable decrease of unspecifically reduced beta2GPI. Upon beta2GPI reduction, AFM imaging revealed no significant shift in protein conformation (75% in closed and 25% in open conformation). These results were qualitatively confirmed by TEM imaging. Therefore, reduction of beta2GPI disulfide bond Cys288/Cys326 did not result in a major conformational change of the protein. Upon in vitro reduction, the closed form is still the main conformation and a direct correlation of beta2GPI redox state and conformation must be refused. Furthermore, beta2GPI reduction led to a strong and statistically highly significant increase in anti-DI autoantibody binding compared to untreated beta2GPI. Thus, the reduced form might be the antigenic form of the protein. In contrast to previous knowledge, these findings suggest that anti-DI autoantibodies may also bind to the closed conformation under certain conditions. Hypothetically, reduction of beta2GPI could induce a minor structural change in DV that might facilitate the binding of APS autoantibodies.
Overall, this study reveals that PTM of beta2GPI may lead to a critical level of destabilization of the closed conformation (as in the case of acetylated beta2GPI) or significantly increase the binding of APS autoantibodies (as in the case of reduced beta2GPI), both of which could have a large impact on APS disease. However, further investigations are necessary to put these new findings in the context of APS immunopathophysiology.
The comment on Cristina Lafont’s book includes two main points. (1) Minipublics do not necessarily stand in opposition to political theories that justify electoral democracy and participatory conceptions of deliberative democracy. In contrast to such a view, I argue that minipublics should be combined with electoral and participatory forms of democracy. (2) A deliberative concept of accountability may overcome some of the shortcomings of the traditional, voluntaristic concepts of democratic accountability.
In der DDR wurde im Leistungssport staatlicherseits ein System entwickelt, welches sich unter anderem durch den Einsatz von leistungssteigernden Substanzen auszeichnete. Diese Substanzen zogen häufig schwere somatische Schäden nach sich. Die Sportler*innen wussten in den meisten Fällen nicht, dass sie diese Mittel erhielten und waren häufig minderjährig. Der Alltag der Sportler*innen war meist durch prekäre physische sowie psychische Trainingsbedingungen geprägt. Auf Grund von Schilderungen der Betroffenen, Berichten von Sporthistoriker*innen und Unterlagen des Ministeriums für Staatssicherheit lässt sich vermuten, dass ein erheblicher Teil der Sportler*innen unter psychischen Erkrankungen leidet. Daher sollte die psychische Verfassung überblickshaft dargestellt werden.
Vor diesem Hintergrund wurden Fragebogenpakete an 1200 Proband*innen verschickt, die sich bis zum Erhebungszeitpunkt ratsuchend an die Doping-Opfer-Hilfe e.V. gewendet hatten. Diese Pakete enthielten jeweils 13 Selbstbeurteilungsskalen zur psychischen Symptomatik bzw. Persönlichkeitsmerkmalen. Die Ergebnisse wurden mit einer nach Alter und Geschlecht parallelisierten Stichprobe (N=255) aus der Allgemeinbevölkerung verglichen.
Auf allen untersuchten Skalen konnten signifikante Unterschiede festgestellt werden. Der Großteil der betroffenen Sportlerinnen und Sportler wies eine klinisch-relevante psychische Belastung auf. Exemplarisch hierfür sind eine hohe Punktprävalenz für Posttraumatische Belastungsstörungen (21,1%) und eine klinisch relevante depressive Symptomatik (65,19%).
Vermutlich konnten die negativen Erlebnisse im Kindes- und Jugendalter auf zwei Arten pathogen wirken. Zum einen konnten sie direkt psychische Erkrankungen auslösen und zum anderen fand eine negative Beeinflussung der Entwicklung statt, welche bei den Betroffenen zu einer erhöhten Vulnerabilität gegenüber späteren Stressereignissen führen konnte. Aufgrund des Querschnittsdesigns der Studie müssen potenziell kausale Zusammenhänge jedoch mit Zurückhaltung diskutiert werden. Eine Berücksichtigung der Sportarten bei weiteren Untersuchungen könnte besondere Risikogruppen darstellen.
Abstract
Macroalgae species are fast growing and their polysaccharides are already used as food ingredient due to their properties as hydrocolloids or they have potential high value bioactivity. The degradation of these valuable polysaccharides to access the sugar components has remained mostly unexplored so far. One reason is the high structural complexity of algal polysaccharides, but also the need for suitable enzyme cocktails to obtain oligo‐ and monosaccharides. Among them, there are several rare sugars with high value. Recently, considerable progress was made in the discovery of highly specific carbohydrate‐active enzymes able to decompose complex marine carbohydrates such as carrageenan, laminarin, agar, porphyran and ulvan. This minireview summarizes these achievements and highlights potential applications of the now accessible abundant renewable resource of marine polysaccharides.
Lyssaviruses, the causative agents of rabies, are a long-known threat for animals and humans. To date, terrestrial rabies still accounts for tens of thousands of human deaths annually, notwithstanding ambitious vaccination campaigns targeting susceptible dog and wildlife populations that act as reservoirs for the prototypic rabies virus. Moreover, the continuing discovery of newly emerging virus species in hitherto unconcerned chiropteran hosts and geographic regions drive the expansion of the Lyssavirus genus by unveiling its actual variety, host range and distribution.In this work, the genetic diversity of three distinct lyssaviruses, namely EBLV-1, KBLV and RABV, was elucidated by in-depth genomic analyses to provide further insight into lyssavirus evolution. The generation of full-genome sequences from primarily bat-associated Danish EBLV-1 samples significantly increased the number of available Danish EBLV-1 genome sequences while phylogenetic and phylogeographic analysis revealed a stronger phylogeographic structure for the cluster A1 of the sublineage EBLV-1a than it was postulated in previous studies. In addition, the acquisition of a nearly complete genome sequence for the Kotalahti bat lyssavirus provided the basis for the classification of this putative new lyssavirus species as a recognized member of the genus. Furthermore, phylogenetic analysis revealed the affiliation of KBLV to a group of Myotis-associated lyssaviruses giving a deeper insight into the shared evolutionary history of lyssaviruses co-evolving with particular bat species. Moreover, a deep-sequencing approach was utilized to assess the high genetic diversity of vaccine virus populations, uncovering three independent patterns of single nucleotide variants (SNVs) that became selected in ERA-related vaccine-induced cases. However, no apparent influence of the genetic diversity of vaccine viruses on microevolutionary processes like a potential reversion to virulence or a species-specific adaptation of the vaccine virus strains could be detected, leaving the question for the cause of rabies induction in the affected animals unanswered. Lastly, the successful implementation of a hybridization capturing system for the generation of full-genome sequences and deep-sequencing variant analyses of RABV and KBLV samples was demonstrated for a diagnostic bait set, highlighting the versatility and consistency of this approach to assess the genetic spectrum of known and novel lyssavirus species while setting the basis for its application and optimization in upcoming projects.In conclusion, as shown by the studies in this work, the investigation of lyssavirus genomes at the sub-consensus, full-genome and population level remains crucial to assess the complexity of lyssavirus evolution, as it provides an indispensable source of information to cover the diversity of the genus and understand evolutionary dynamics on a long-term and microevolutionary scale.
Background: There is an urgent need for effective follow-up treatments after acute electroconvulsive therapy (ECT) in depressed patients. Preliminary evidence suggests psychotherapeutic interventions to be a feasible and efficacious follow-up treatment. However, there is a need for research on the long-term usefulness of such psychotherapeutic offers in a naturalistic setting that is more representative of routine clinical practice. Therefore, the aim of the current pilot study was to investigate the effects of a half-open continuous group cognitive behavioral therapy (CBT) with cognitive behavioral analysis system of psychotherapy elements as a follow-up treatment for all ECT patients, regardless of response status after ECT, on reducing depressive symptoms and promoting psychosocial functioning.
Method: Group CBT was designed to support patients during the often-difficult transition from inpatient to outpatient treatment. In a non-controlled pilot trial, patients were offered 15weekly sessions of manualized group CBT (called EffECTiv 2.0). The Montgomery-Åsberg Depression Rating Scale was assessed as primary outcome; the Beck Depression Inventory, WHO Quality of Life Questionnaire–BREF, and the Cognitive Emotion Regulation Questionnaire were assessed as secondary outcomes. Measurements took place before individual group start, after individual group end, and 6months after individual group end.
Results: During group CBT, Post-ECT symptom reduction was not only maintained but there was a tendency toward a further decrease in depression severity. This reduction could be sustained 6months after end of the group, regardless of response status after ECT treatment. Aspects of quality of life and emotion regulation strategies improved during group CBT, and these improvements were maintained 6months after the end of the group.
Conclusion: Even though the interpretability of the results is limited by the small sample and the non-controlled design, they indicate that manualized group CBT with cognitive behavioral analysis system of psychotherapy elements might pose a recommendable follow-up treatment option after acute ECT for depressed patients, regardless of response status after ECT. This approach might not only help to further reduce depressive symptoms and prevent relapse, but also promote long-term psychosocial functioning by improving emotion regulation strategies and psychological quality of life and thus could be considered as a valuable addition to clinical routine after future validation.
Sal (Shorea robusta) forests, a dominant forest type in Nepal, experience different disturbance intensities depending on management regimes. This study compares the impact of disturbance on Nepalese Sal forests, which are managed on three major management regimes: protected area, state-managed forest, and buffer zone community forest. Using a systematic sampling approach, we sampled 20 plots, each covering 500 square meters, and nested plots within each main plot to measure pole and regeneration for each management regime. We recorded forest characteristics including tree species, counts, diameter, height, crown cover, and disturbance indicators. We compared forest attributes such as diversity indices, species richness, and stand structure by management regime using analysis of variance and regression analysis. The forest management regimes were classified into three disturbance levels based on disturbance factor bundles, and the buffer zone community forest was found to have the highest disturbance while the protected forest had the lowest disturbance. Species richness, diversity, evenness, abundance, density and basal area were higher, but regeneration was lower in protected area and state-managed forest compared to the buffer zone community forests. This suggests positive impacts of moderate disturbance on regeneration. The management plan should prioritize the minimization of excessive disturbance to balance forest conservation and provide forest resources to local users.
The early-life microbiome (ELM) interacts with the psychosocial environment, in particular during early-life adversity (ELA), defining life-long health trajectories. The ELM also plays a significant role in the maturation of the immune system. We hypothesised that, in this context, the resilience of the oral microbiomes, despite being composed of diverse and distinct communities, allows them to retain an imprint of the early environment. Using 16S amplicon sequencing on the EpiPath cohort, we demonstrate that ELA leaves an imprint on both the salivary and buccal oral microbiome 24 years after exposure to adversity. Furthermore, the changes in both communities were associated with increased activation, maturation, and senescence of both innate and adaptive immune cells, although the interaction was partly dependent on prior herpesviridae exposure and current smoking. Our data suggest the presence of multiple links between ELA, Immunosenescence, and cytotoxicity that occur through long-term changes in the microbiome.
Glioblastoma multiforme (GBM) is the most common and most aggressive malignant tumor of the central nervous system in adults. The median survival time of patients suffering from GBM is only 14-15 months. Despite a great progress in the technique of resection, radiation therapy, and chemotherapeutic drugs, survival time has not been significantly prolonged. Interestingly, the progression of GBM has been associated with intratumoral immune dysfunction states, and the GBM tissue represents a complex formation of tumor cells itself and diverse non-malignant cells such as endothelial cells, microglia or immunocompetent cells from peripheral blood. In that regard, accumulating evidence supports that Sphingosine 1-phosphate (S1P) acts as a key signal in the cancer extracellular milieu. S1P has been intensively discussed to be an important pro-tumoral molecule, since it is involved in proliferation, migration and invasion of both healthy and malignant cells. An increase in S1P has been associated with proliferation and invasion of GBM and other cancers that display a propensity for brain metastasis. S1P binds to five different cell surface G protein-coupled receptors called S1P receptor 1-5 (S1PR1-5), it has been shown in previous studies that particularly the S1PR1 and 2 are involved in regulating proliferation, metastasis, invasion, vascular angiogenesis and maturation of GBM cells and thus play an important role in tumorigenesis. Therefore, we used S1PR1 (ACT-209905, W146) and S1PR2 modulators/antagonists (Compound 16, JTE013) to investigate the role of these S1P receptor subtypes in the growth of human (prGBM, LN18) and murine (GL261) GBM cells to gain insight into the molecular processes of the pro-tumorigenic S1P signaling cascade in GBM cells. Further, we analyzed the influence of the human monocytic cell line THP-1 on GBM cell growth by co-culture experiments together with simultaneous application of S1PR1/S1PR2 modulators/antagonists to determine the role played by S1PR1 and S1PR2 signaling pathways in the interaction between tumor and immune cells. We found that all tested S1PR1/2 modulators (ACT-209905, W146, Compound 16, JTE013) significantly reduced the viability (Resazurine assay) and vitality (Crystal violet assay) as well as the migration and invasion of prGBM, LN18 and GL261 cells in a concentration dependent manner. The growth inhibitory effect of S1PR1 blocking by ACT-209905 was accompanied by the induction of apoptosis in GBM cells seen by increased caspase 3 activity. When S1PR1 antagonist (ACT-209905, W146) was co-administered with S1PR2 antagonist (Compound 16, JTE013) the inhibitory effect was much stronger compared to the single administration. Further, single and dual application of S1PR1 modulator and S1PR2 antagonist caused a stronger inhibition of GBM cell viability and vitality compared to 100 μM Temozolomide (TMZ) as the standard chemotherapeutic for GBM. These results suggest that both S1PR1 and S1PR2 are involved in the growth of GBM cells and that a simultaneous inhibition of both receptors has synergistic effects. In addition, the influence of THP-1 cells as a model for human monocytes/macrophages on GBM cell growth was analyzed since it has been shown that S1P signaling polarizes macrophages to the pro-tumoral M2 phenotype and S1PR1 has been linked to macrophage activation. Co-culture of GBM cells with THP-1 cells or THP-1 conditioned medium significantly enhanced the viability and vitality as well as the migration and invasion of GBM cells in a cell number dependent manner suggesting that THP-1 cells might secrete to date unknown pro-tumoral molecules which stimulate the pro-invasive growth of GBM cells. Our FACS analyses showed that THP-1 cells express not only the CD11b macrophage marker but also CD163 and CD206 as marker for the pro-tumorigenic M2 phenotype. Interestingly, the concomitant application of the S1PR1 modulator ACT-209905 had a significant inhibitory effect on the THP-1 induced increase of GBM cell growth and migration, which argues for a role of S1PR1 in the pro-tumoral characteristic of THP-1 on GBM cells. Immunoblot analyses further showed that blocking of the S1PR1 pathway leads to a reduced activation of several kinases including p38, AKT1 and ERK1/2 whereas THP-1 cells and THP-1 conditioned medium caused an activation of these kinases. To clarify the role of p38, AKT1 and ERK1/2 in the inhibitory effects of S1PR1 antagonists on GBM proliferation and migration in detail further studies are needed. Beside an impact on growth promoting kinases, S1PR1 blocking by ACT-209905 diminished surface expression (Median Fluorescence Intensity measured by FACS) of the pro-migratory molecules CD54 (ICAM-1) and CD166 (ALCAM), and reduced the percentage of CD62P (P-Selectin) positive GBM cells. In contrast, co-culture with THP-1 cells increased ICAM-1 and P-Selectin content of GBM cells which was reversed by ACT-209905 arguing for a role of ICAM-1 and P-Selectin in the migration of GBM cells. In conclusion, our study suggests a role of S1PR1 and S1PR2 signaling pathways in the growth and progression of GBM, improves our understanding of the complex mechanisms of S1P signaling in GBM cells, and gives at least a partial explanation for the pro-tumorigenic effects that macrophages might have on GBM cells combined with potential underlying mechanisms. Thus, this study argues for a further preclinical and clinical evaluation of a pharmacological modulation of S1PR1 and S1PR2 as a new or adjunctive therapeutic principle in GBM.
Abstract
This work presents the reactivity and dissolution of an as‐polished and electrochemically pre‐treated polycrystalline Au electrode, which is used as a model system. The effect of the electrochemical pre‐treatment in corrosive 0.37 M HCl solutions on the Au surface roughness and dissolution is investigated by varying the number of pre‐treatment steps at 1.16 V against the reversible hydrogen electrode. It is shown that the first 10 s pre‐treatment of the as‐polished Au results in a higher surface roughness and thus higher electrochemically active surface area (ECSA) than that of the as‐polished Au. With the subsequent pre‐treatments, however, the ECSA is gradually decreasing reaching a steady value. The dissolution rate of the pre‐treated Au electrodes upon potential cycling in 0.1 M H2SO4 is determined by in situ inductively coupled plasma mass spectrometry. A non‐linear dependence of Au dissolution amount is found with respect to the number of pre‐treatments. The overall total Au dissolution rate follows a similar trend as ECSA/roughness. However, an important difference in the dissolution behavior is identified with respect to dissolution processes during Au oxidation (anodic dissolution) and Au reduction (cathodic dissolution): the former is more sensitive to the surface roughness. Thus, the ratio between Au anodic and cathodic dissolution amounts decreases substantially with decrease in surface roughness. This finding is explained by the slow and fast dissolution kinetics for anodic and cathodic processes, respectively. Current work further advances our understanding of the complex Au dissolution mechanism.
Organisms often employ ecophysiological strategies to exploit environmental conditions and ensure bio-energetic success. However, the many complexities involved in the differential expression and flexibility of these strategies are rarely fully understood. Therefore, for the first time, using a three-part cross-disciplinary laboratory experimental analysis, we investigated the diversity and plasticity of photoresponsive traits employed by one family of environmentally contrasting, ecologically important phytoflagellates. The results demonstrated an extensive inter-species phenotypic diversity of behavioural, physiological, and compositional photoresponse across the Chlamydomonadaceae, and a multifaceted intra-species phenotypic plasticity, involving a broad range of beneficial photoacclimation strategies, often attributable to environmental predisposition and phylogenetic differentiation. Deceptively diverse and sophisticated strong (population and individual cell) behavioural photoresponses were observed, with divergence from a general preference for low light (and flexibility) dictated by intra-familial differences in typical habitat (salinity and trophy) and phylogeny. Notably, contrasting lower, narrow, and flexible compared with higher, broad, and stable preferences were observed in freshwater vs. brackish and marine species. Complex diversity and plasticity in physiological and compositional photoresponses were also discovered. Metabolic characteristics (such as growth rates, respiratory costs and photosynthetic capacity, efficiency, compensation and saturation points) varied elaborately with species, typical habitat (often varying more in eutrophic species, such as Chlamydomonas reinhardtii), and culture irradiance (adjusting to optimise energy acquisition and suggesting some propensity for low light). Considerable variations in intracellular pigment and biochemical composition were also recorded. Photosynthetic and accessory pigments (such as chlorophyll a, xanthophyll-cycle components, chlorophyll a:b and chlorophyll a:carotenoid ratios, fatty acid content and saturation ratios) varied with phylogeny and typical habitat (to attune photosystem ratios in different trophic conditions and to optimise shade adaptation, photoprotection, and thylakoid architecture, particularly in freshwater environments), and changed with irradiance (as reaction and harvesting centres adjusted to modulate absorption and quantum yield). The complex, concomitant nature of the results also advocated an integrative approach in future investigations. Overall, these nuanced, diverse, and flexible photoresponsive traits will greatly contribute to the functional ecology of these organisms, addressing environmental heterogeneity and potentially shaping individual fitness, spatial and temporal distribution, prevalence, and ecosystem dynamics.
Immunogenität von Hautkrebszellen und dem Modellprotein Ovalbumin nach einer Kaltplasma-Behandlung
(2021)
Eine Behandlung von Tumoren mit physikalischem Kaltplasma zeigt eine erhöhte Toxizität und ein reduziertes Tumorwachstum. Zeitgleich werden während einer Behandlung mit Plasma eine Vielzahl an reaktiven Sauerstoff- und Stickstoffspezies (RONS) generiert, welche Immunzellen stimulieren können. Viele neue Therapieansätze bestreben nicht nur eine Tumortoxizität, sondern auch eine Förderung der körpereigenen, da diese häufig durch Mechanismen der Tumorzellen unterdrückt wird. Zu solchen Therapien zählen checkpoint inhibitoren, Vakzinierungen oder ein adaptiver Zelltransfer mit transgenen oder vor-stimulierten Zellen. Die dadurch geförderte Antitumor-Immunantwort basiert grundlegend auf einem mehrphasigen Prozess. Dieser beginnt mit einer Antigen-unspezifischen frühen Phase, in der das innate Immunsystem aktiviert wird und zu einer Vermehrung und Differenzierung von Antigen-spezifischen CD4+ und CD8+ T-Zellen führt. Da während einer Entzündungsreaktion viele RONS gebildet werden, um Fremdkörper zu eliminieren und Immunzellen zu rekrutieren, ist eine Therapie mit RONS naheliegend. Durch die Anwendung von Kaltplasma können die gebildeten RONS zum Entzündungsgeschehen beitragen und Zellen des innaten und adaptiven Immunsystems stimulieren. Eine veränderte Immunogenität von Tumorzellen sowie eine daraus resultierende direkte Aktivierung von Immunzellen im Kontext einer Antitumor-Immunantwort wurden nach einer Behandlung mit Jet-Plasmen bislang nicht untersucht.
In der vorliegenden Arbeit wurde die Kaltplasma-Behandlung von Hautkrebszellen und eines Modellantigens unter Berücksichtigung einer Antitumor-Immunantwort durch natürliche Killerzellen des innaten Immunsystems sowie adaptive Immunzellen in vitro und in vivo untersucht. Es konnte gezeigt werden, dass eine Behandlung mit Kaltplasma zu einer erhöhten Tumortoxizität führt und das Repertoire der Oberflächenmoleküle auf Tumorzellen verändert. In vivo wurde eine vermehrte Infiltration von Immunzellen in das Tumormikromilieu beobachtet, welche mit einer erhöhten Aktivierung von Lymphozyten und Konzentrationen immunstimulatorischer Zytokine einherging. Durch die zeitgleich reduzierten Tumorgrößen, ist eine durch Immunzellen vermittelte Tumortoxizität als Erklärung naheliegend. In zwei Vakzinierungsstudien konnte die Immunogenität von Plasma-behandelter Tumorzellen und einem Tumorassoziierten Modellantigen bestätigt werden.
Summary
Raised bogs are raised above the regional ground water level and only fed by rain. To be able to be ‘high yet wet’, they have developed intricate self-regulation mechanisms. The most important of these mechanisms in Sphagnum raised bogs is the acrotelm. This upper layer of peat and vegetation shows a distinct gradient from large pores at the top to small ones at the bottom. When the water table drops, water can only flow through small pores and run-off is effectively reduced. Still, the acrotelm has high storativity, which restricts water table fluctuations to this layer. The acrotelm presents a compromise between small pore space to minimise run-off and large pore space to maximise storativity.
These two ‘tasks’ of the acrotelm can also be split in horizontal space. The dry hummocks on the surface of a raised bog have much lower transmissivity and storativity than the wet hollows. These two surface elements can be organised in strikingly regular patterns of elongated strings of hummocks and so-called flarks of hollows arranged perpendicular to the slope. The origin of regular string-flark patterns was studied in chapter 2.
In a simple, heuristic, spatially explicit simulation model, each cell in a square grid is randomly declared either a hummock or a hollow. The grid is on a slope and water is allowed to flow from each cell to its four neighbouring cells until water tables stabilise. Then, every cells changes state based on its water table: if the water table is low, the cell will more likely be a hummock, if it is high a hollow. If the parameter settings are right, this procedure will result in regular striping patters. Chapter 2 was the first study to search the parameter space for settings that result in patterning. Systematic analysis showed that the parameter space in which patterns develop is sharply delineated, indicating positive feedback mechanisms. Once a pattern develops, water tables in the model diverge: the flarks become wetter and the strings become drier. The hummock and hollow cells have combined into higher order units, the strings and flarks, that emerge as more effective in regulating water flow.
Applying the same model for the first time to the dome shape of a raised bog (capther 3), pattern formation appeared to occur on three organisational levels. On the lowest nanotope level, we find strings and flarks, again combined in a string-flark complex, but this complex occurs alongside an all hummock rand and a wet, featureless central plateau. These three mire sites constitute the second, microtope level. On the third, mesotope level we can distinguish different types of bog domes that are defined by different combinations of mire sites. Classical literature on peatland classification used the same approach to classify bog domes, but also other and larger peatland areas. Our modelling shows that the mire sites actually exist as functional units in a self-organising bog and that they are not mere human classification constructs.
To test our ideas on self-regulation and -organisation as well as the modelling results, we studied a patterned raised bog in Tierra del Fuego in terms of its plant cover, its water and its peat (chapter 4). The studied bog is almost completely covered by Sphagnum magellanicum. In northern peatlands the different niches from high and dry hummock to low and wet hollow are filled by different species of Sphagnum, each with their specific growth form. In the studied bog, all niches from dry to wet are occupied by Spagnum magellanicum, showing a wide range in growth form. Yet, we found it has only limited genetic diversity that is not linked to these niches and growth forms.
Detailed measurements were made along a 498 m long transect crossing the bog, including water table measurements (every metre), vegetation relevés (2 × 2 m), hydraulic conductivity just below the water table (n = 246) and hydraulic conductivity in 11 depth profiles to a depth of 2 m (n = 291); the degree of humification of the corresponding peat was assessed in conjunction with the hydraulic conductivity measurements (n = 537). Sphagnum magellanicum moss samples were collected every 2 m along this transect and genotyped (n = 242). In addition, along short, 26 m long transects crossing strings and flarks water table and hydraulic conductivity just below the water table were measured every metre. Sphagnum growth forms were assessed and the vegetation of the entire bog was mapped in 10 × 10 m relevés (n = 3322). The simulation model was applied to a generalised form of the bog.
There was an almost perfect match between plant cover and water tables. As expected, hydraulic conductivity just below the water table was about 7 times lower in the dry than in the wet measurement spots. These observations are valid on the low level of the nanotope: hummocks and hollows or dry and wet spots in general. Other observations only made sense on higher organisational levels like the microtope. For example, the hydraulic conductivity profiles of the string-flark complex show a gentler gradient than those of the plateau and the rand. The peat in the string-flark complex originates on this level of organisation and combines characteristic of both its dry and wet constituents. On the mesotope level, the simulation model produced a good match with the patterns on the actual dome. We analysed the abundant data on different organisational levels ranging from small single plants to the large mire system of fens and domes of which the studied dome is part. We looked for commonalities and discrepancies to help us better understand how the close link between plants, water and peat functions in reality.
The results of all measurements were integrated with information from literature and discussed in the framework of a self-regulating and -organising raised bog. The field measurements considerably sharpened existing theoretical considerations. We identified nineteen hydrological feedback mechanisms. We found that the various mechanisms overlap both in space and time, which means there is redundancy in the self-regulation capacity of the system. Raised bogs, when in a natural state, are among the most resilient ecosystems known; resilience that is provided by feedbacks and back-up systems to these feedbacks.
We used our ideas and insights on self-regulation in Sphagnum raised bogs to look for similar patterns and responses in tropical domed peat swamps (chapter 5). We know that in Sphagnum raised bogs the tasks of the acrotelm can be split in horizontal space. When we looked at undisturbed tropical peat swamps with this new search image, we recognised how hummocks of root material and litter and particularly buttress roots regulate run-off and storage of water. We could identify several additional hydrological feedback loops that mirror the mechanisms found in Sphagnum raised bogs.
This thesis considerably advances our understanding of raised bogs as self-organising systems. The patterns and processes they display on multiple levels can be seen as a form of ecosystem diversity that exists independent of species and genetic diversity.
Forests are key biomes linked to biogeochemical cycles, important species reservoirs and major ecosystem services providers. The observed global climate change in the 20th century has the potential to deeply affect the conservation, functioning and structure of these ecosystems. Expressed as rising average temperatures due to the increase in atmospheric concentration of greenhouse gases such as carbon dioxide, nitrate oxide and methane, pollutants which are mostly product of burning fuel for industrial activities. These long-term changes will be heterogeneous in time and space throughout the globe. For northeastern Germany, predictions indicate that summer temperature and winter precipitation will be at a constant rise, whereas summer precipitation is expected to decrease, conditions will increase the risk of drought conditions. The changes in long-term means will be accompanied by increased frequency of weather extremes. The overall effect of climate change, both its long- and short-term components and their interaction with forest growth is uncertain. Tree
species in the temperate forest are highly adapted to seasonal growth, active in late-spring and summer when temperature thresholds activate primary and secondary growth as well as leaf development, given sufficient water availability. During winter, they become dormant as an strategy to decrease damage by freezing temperatures. These adaptations ultimately determine species distributions as they occur along climate gradients within their ecological
optima. Thus climate change can have a significant effect on species distribution ranges and more locally it can change species abundances. Trees being sessile organisms, possess limited dispersal capacities and rely on their adaptation potential, both genetically through selection over generations and through phenotypic plasticity (e.g. the capacity of adapting to changing conditions within a lifetime).
Tree growth can be explored by dendrochronological methods, that is, by analyzing traits of annual xylem bands as produced by the vascular cambium. These traits are width, wood anatomical properties (e.g. cell wall thickness, lumen diameter), and isotopic composition.
Tree-rings are integrators of environmental conditions and indicators of vitality and productivity of trees and forests. Studying these traits allows to understand the effect of climate on growth and physiological function over decadal to centennial scales in the past and by it inform about future growth performance. However, environmental information is not trivially extracted from tree-rings. Environmental signals in tree-rings are often the result of
complex interactions of lagged meteorological conditions and tree-scale characteristics such as size, canopy status (i.e. social status), competition and stand density, among other factors. For this reason the monitoring of secondary growth as it unfolds, for example through dendrometer monitoring (i.e. record of the stem-radial variations at intra-annual temporal scales) and repeated sampling for the study of xylogenesis, is of major importance to understand climate-growth relationships and bridge the gap between dendroecological analysis atdifferent ecological scales (from single trees to stands to populations). Therefore this thesis contains contributions a) to the understanding of long-term climate shifts and its effect on tree growth for species in the Central European temperate forests through dendrochronological assessments and contributions b) to understanding intra-annual growth dynamics and
its relationship to meteorological conditions through the analysis of monitoring records. In the retrospective analysis chapters (I-III), first an assessment was performed of the climate-growth relationships of important species of these region which indicated that deciduous species’ growth (Fagus sylvatica, Quercus robur and Q. petreae) was influenced mostly by summer water availability. For Pinus sylvestris was late spring temperature. Negative correlations between winter temperatures and growth indices of deciduous species increased over the last decades, possibly linked to less snow cover of the soil leading to root damage causing growth reductions. Scots pine presented the opposite, as positive correlations with winter temperatures became more frequent, indicating that this species’ growth rates might
benefit from an elongation of the vegetation period. Afterwards the effect of stand characteristics in the climate response was explored. The climate signal of solitary oak trees growing in northeastern Germany was compared to oaks in closed stands. Solitary trees
expressed higher growth rates and drought signals, which endanger its conservation as dry conditions are expected to increase in the region. As in the temperate forest crowding effects are variable throughout a tree’s lifetime, as well as other limiting factors (e.g. climate), we subsequently developed a methodology based on analysis of individual tree-ring series rather than chronologies (site means) to disentangle these effects on heterogeneous samples and quantify them. By sampling all present crown classes in a site near Rostock (Germany), we found beech was mostly affected by water availability in the previous summer
and this effect was well represented throughout the population. For oak the main climatic driver of growth was previous October temperature with a low representation throughout the obtained sample. For beech, the main trait governing the variability around the response to the main climate driver of growth was cambial age, and for oak was crown-projection/size. On the prospective analysis chapters (IV-VI), monitoring datasets from the years 2013-2019 were used for the analysis of meteorological forcing of dendrometer series, the effect of a multi-year drought event and for the development of a method to combine continuous dendrometer records with discrete histological observations from xylogenesis analysis. The analysis of meteorological forcing on stem-radial variations indicated all observed species (beech, oak, hornbeam in this case) respond similarly to atmospheric water content whereas
the growth phenology displayed contrasting species differences. These findings indicate high-frequency variations in stem dynamics are similar between species as it reflects transpiration and water transport in the stem, whereas the timing of growth reflects life strategies and
wood anatomical adaptations. Next we evaluated the effect of the consecutive drought years 2018-2019 using dendrometer data (beech, oak, hornbeam and sycamore maple). The increment levels after the onset of drought in 2018 were not reduced for the observed individuals, whereas in 2019 all species showed decreased growth levels, particularly beech. Most likely the water moisture reservoirs were adequately filled in winter and spring before summer 2018, which lead to increased buffer capacity to withstand the harsh conditions for radial growth. However in winter, and the spring before the summer of 2019, there was not sufficient precipitation which lead to less resistance to the second bought of the drought event.
This illustrates the complex lagged meteorological effect on radial growth, which is easily obscured in retrospective dendroecological analysis and emphasizes the pivotal role of soil moisture and soil water storage in tree-growth analysis. As a final contribution, while recognizing the importance of prospective growth monitoring, we developed a software tool to visualize and combine dendrometer stem-radial variations with images of histological events, such as those obtained by microcores for xylogenesis analysis. Growth signals in dendrometers are often of smaller magnitude than variations related to stem-water dynamics. By comparing them with histological images of wood-formation it is possible to accurately assign growth phases to dendrometer series and optimize their assessment. The advancement in methodological approaches to study intra-annual tree growth data is of major importance in the context of permanent ecological monitoring plots and its role in the assessment of the consequences of climate change on forest growth and conservation.
Overall the findings of this thesis indicate that climate change impacts in the temperate forest of Central Europe will be and have been varied depending on the species considered with stand, site and tree-level conditions strongly modulating its consequences and even direction. Deciduous species, particularly beech, will be at risk due to decreased water availability during summer for which beech shows a high sensitivity. While oak seems to
be less prone to drought related growth reductions and it is plausible to consider changes in dominance towards drier sites, it is still at risk if vulnerability thresholds are crossed. Scots pine appears to be favored by the increased temperatures during late winter, although these are naturally found on poor sites or sites either too dry or too wet for other dominant deciduous species to establish. Nevertheless, Scots pine has been planted on a variety of site conditions and especially in northeastern Germany is among the most widespread and economically important forest trees. Furthermore, the individual variability we have found in climate responses indicates that heterogeneous stands contain resilient sub-populations that
could guarantee survivorship of the species after stark changes in climate means. However, it appears that strong enough stressors such as hotter droughts can trigger wide ecosystem changes with more efficiency than shifts in climate means. Due to this intra-annual growth
monitoring is particularly relevant to foretell ecosystem changes and to understand the complex relationships found in climate-growth analysis performed in dendroecological studies, as it permits to mechanistically understand how conditions outside the tree-ring formation
period affects wood formation.
To induce an appropriate immune response, pathogen- or damage-associated molecular
patterns (PAMPs and DAMPs) are sensed by innate immune cells. One of the first
mechanisms after recognition is the assembly of an inflammasome leading to the cleavage of
pro-IL-1β and pro-IL-18 into the active cytokines IL-1β and IL-18, respectively. Hyperinflammatory
conditions and excessive activation of the inflammasome, however, are drivers
of inflammatory and autoimmune diseases. The NLR family pyrin domain-containing 3
(NLRP3) inflammasome is suggested to be involved in the development of gout,
artherosclerosis, type II diabetes, cryopyrin-associated periodic syndrome (CAPS), various
types of cancer, and inflammatory bowel disease (IBD). To tackle these diseases, drugs
interfering with IL-1 signaling are of great value. Anakinra, an IL-1 receptor antagonist,
inhibits binding of both IL-1α and IL-1β. Rilonacept consists of the Fc portion of human IgG1
with two IL-1 receptors grafted onto it. This allows neutralization of IL-1α and IL-1β. The
monoclonal IgG1 antibody Canakinumab specifically blocks IL-1β. Although well tolerated,
patients undergoing a therapy with these drugs are at a higher risk of developing bacterial
respiratory tract infections.
The human upper respiratory tract (URT) is commonly colonized asymptomatically by
bacteria like Staphylococcus aureus and Streptococcus pneumoniae. Only a limited number of
studies have so far addressed the role of the NLRP3 inflammasome during pneumococcal
infections. Imbalances in the immune system enhance the dissemination of these bacteria into
the lungs thereby causing life-threatening infections. Asides from immune-compromising
therapies such as IL-1 inhibition, viral infections are common factors leading to the
development of a secondary, bacterial infection. Influenza A virus infection of C57BL/6J
mice was characterized by a bi-phasic disease progression with a complete remission around
day 16 irrespectively of a previous Streptococcus pneumoniae 19F colonization. At this time
point, low amounts of bacteria were recovered from the lungs of 50% of co-infected mice.
This co-infection model was used for in-depth analyses of the innate immune responses.
Bioactive lipids, such as eicosanoids, are host-derived metabolites, which can heavily impact
the cellular immune response and skew it towards a pro- or anti-inflammatory phenotype.
Eicosanoid analyses revealed increased levels of different hydroxydocosahexaenoic acids
(HDHAs) and hydroxyeicosatetraenoic acids (HETEs) in the lung after single viral infection.
Staphylococcal pneumonia mainly resulted in high expression of 20-HETE. During a coinfection
with S. pneumoniae and influenza A virus (IAV), reduction of HETEs and HDHAs
was measured. Furthermore, ceramide-1-phosphate (C1P) was elevated in the lung, whereas
sphingosine-1-phosphate (S1P) was reduced. The tight control of an inflammatory response
by bioactive lipid mediators might be protective during later stages of an infection.
Cytokine analyses revealed high expression of inflammatory cytokines in lungs and plasma of
single bacteria- and virus infected as well as co-infected mice at early stages of an infection.
In all three infections monocyte chemoattractant protein-1 (MCP-1) dependent monocyte
recruitment was noted. The elevated expression of CC chemokine receptor 2 (CCR2) and
major histocompatibility complex II (MHCII) in the majority of analysed myeloid cells
indicated an activation of these cells. In single virus and co-infections, we further observed a
mainly neutrophil-independent immune response. During pneumococcal pneumonia, an influx
of neutrophils was observed.
Neutrophils, as first recruited responders during an inflammation, can release their granule
contents after activation in order to eliminate extracellular pathogens. However, excessive
neutrophil activation correlates with tissue damage and detrimental outcome of an infection.
As a result of excessive cell death, large amounts of ATP are released into the extracellular
space. Pneumolysin (Ply), a pore-forming toxin and major virulence factor of S. pneumoniae,
is a potent activator of human neutrophils. Stimulation of neutrophils with sublytic
concentrations of Ply readily resulted in the release of resistin and other granule proteins into
the supernatant. Microscale Thermophoresis (MST) analyses revealed that ATP neutralizes
Ply by binding it in the extracellular space. Co-stimulation of neutrophils with both lytic and
sublytic amounts of Ply and physiologically relevant concentrations of ATP resulted in
diminished neutrophil activation. We speculate that during hyper-inflammation (caused by
excessive neutrophil recruitment and activation), tissue injury results in the release of large
amounts of extracellular ATP which, in turn, will bind to Ply. Ultimately, binding of ATP to
Ply inhibits further neutrophil activation and might mitigate immunopathology.
T cells are the key players of the adaptive immune response. They coordinate the activation of other immune cells and kill malignant and virus-infected cells. For full activation T cells require at least two signals. Signal 1 is induced after recognition of MHC/peptide complexes presented on antigen presenting cells (APCs) by the clonotypic TCR (T-cell receptor)/CD3 complex whereas Signal 2 is mediated via the co-stimulatory receptor CD28, which binds to CD80/CD86 molecules that are present on APCs. These signaling events control the activation, proliferation and differentiation of T cells. In addition, triggering of the TCR/CD3 complex induces the activation of the integrin LFA-1 (leukocyte function associated antigen 1) leading to increased ligand binding (affinity regulation) and LFA-1 clustering (avidity regulation). This process is termed “inside-out signaling”. Subsequently, ligand bound LFA-1 transmits a signal into the T cells (“outside-in signaling”) which enhances T-cell interaction with APCs (adhesion), T-cell activation and T-cell proliferation. After triggering of signal transducing receptors, adapter proteins organize the proper processing of membrane proximal and intracellular signals as well as the activation of downstream effector molecules. Adapter proteins are molecules that lack enzymatic or transcriptional activity and are composed of protein-protein and protein-lipid interacting domains/motifs. They organize and assemble macromolecular complexes (signalosomes) in space and time. Here, we review recent findings regarding three cytosolic adapter proteins, ADAP (Adhesion and Degranulation-promoting Adapter Protein), SKAP1 and SKAP2 (Src Kinase Associated Protein 1 and 2) with respect to their role in TCR/CD3-mediated activation, proliferation and integrin regulation.
Abstract
The 10–23 DNAzyme is an artificially developed Mg2+‐dependent catalytic oligonucleotide that can cleave an RNA substrate in a sequence‐specific fashion. In this study, new split 10–23 DNAzymes made of two nonfunctional fragments, one of which carries a boronic acid group at its 5′ end, while the other has a ribonucleotide at its 3′ end, were designed. Herein it is demonstrated that the addition of Mg2+ ions leads to assembly of the fragments, which in turn induces the formation of a new boronate internucleoside linkage that restores the DNAzyme activity. A systematic evaluation identified the best‐performing system. The results highlight key features for efficient control of DNAzyme activity through the formation of boronate linkages.
Ausgewählte Lyrik
(2021)
Jährlich erkranken in Deutschland etwa 10.000 Menschen an einem bösartigen Tumor der Mundhöhle und des Rachens. Diese Tumoren stellen weltweit etwa 4-5% aller Malignome dar. Die Prognose ist trotz sich verändernder Behandlungsmöglichkeiten in den letzten Jahrzehnten weitgehend konstant. Die durchschnittliche Sterblichkeit liegt weltweit für Männer bei etwa 3 - 4 / 100.000 und bei Frauen etwa bei 1,5 - 2 / 100.000.
Der verlässlichste prognostische Marker der Tumorerkrankung ist das Tumorstadium bei Erstdiagnose. Vermutlich entsteht ein großer Anteil der Malignome aus Vorstufen. Daher ist die Früherkennung eine bedeutende Möglichkeit die Morbidität und Letalität dieser Erkrankung zu reduzieren. Die Hauptrisikofaktoren sind Tabak- und Alkoholkonsum.
In Rahmen der epidemiologischen Querschnittsstudie „Study of Health in Pomerania“ wurden von 2008 – 2012 in der Follow-Up-Studie (SHIP-2) und einer zweiten Kohorte SHIP-Trend-0 bei 6078 Probanden die intraorale Schleimhaut untersucht. Zusätzlich wurde eine Reihe von medizinischen, zahnmedizinischen und sozioepidemiologischen Daten bei diesen Probanden aufgenommen. Bei 189 Probanden wurde eine auffällige Schleimhautläsion entdeckt, was einer Punktprävalenz von 3,1% entspricht. Die vorliegende Arbeit basiert auf den Schleimhautläsionen, die bei 102 Probanden fotodokumentiert werden konnten.
In der bevölkerungsrepräsentativen Studienpopulation waren Exophytische Neubildungen (39,6%) die meist prävalenten Schleimhautläsionen, gefolgt von homogenen Leukoplakien (35,8%), Lichen ruber mucosae (6,6%) und Erythroplakien (3,8%). Die Befunde waren vor allem auf der Wangenschleimhaut (31,3%), dem Alveolarfortsatz (24,2%), der Zunge (18,1%) und der Lippe (14,1%) lokalisiert. Alle von uns diagnostizierten Lichen ruber mucosae befielen das Planum buccale.
Hinsichtlich der bekannten Risikofaktoren für orale Plattenepithelkarzinome und deren prämalignen Vorstufen konnte von uns eine erhöhte OR für das Vorliegen einer Leukoplakie bei aktuellem Tabakkonsum von 3,24 nachgewiesen werden. Erhöhter Alkoholkonsum als isolierter Risikofaktor ließ sich nicht nachweisen. Kürzere Schulbildung war ebenfalls mit einem höheren Risiko an einer Schleimhautläsion vergesellschaftet. Die OR betrug 1,84 für Schleimhautläsionen und 3,31 für Exophytische Neubildungen bei einer Schulbildung von weniger als 10 Jahren. Teilnehmer die lange nicht bei zahnärztlichen Untersuchungen waren, wiesen ein erhöhtes Vorkommen von Schleimhautläsionen auf. Es zeigte sich ein erhöhtes Auftreten von Schleimhautläsionen bei Vorliegen einer schweren Parodontitis. Dies ließ sich ebenfalls bei messbarem klinischen Attachmentverlust und einer erhöhten mittleren Sondierungstiefe nachweisen. Studienteilnehmer mit Übergewicht (erhöhter BMI) zeigten ebenfalls ein erhöhtes Risiko für das Vorliegen einer Schleimhautveränderung.
Unsere Daten entsprechen den epidemiologischen Daten der weiteren Prävalenzstudien für Deutschland. Trotz methodischer Einschränkungen kann die vorliegende Studie Hinweise auf die Verteilung der Mundschleimhauterkrankungen in der Bevölkerung Vorpommerns geben. Durch eine Beeinflussung des Risikoverhaltens der Bevölkerung könnte die Letalität deutlich reduziert werden. Konkrete Maßnahmen wären entsprechende Präventionsprogramme der veränderbaren Risikofaktoren.
Results on gray matter alterations in complex regional pain syndrome (CRPS) showed heterogeneous findings. Since CRPS is a rare disease, most studies included only small and heterogeneous samples resulting in a low reliability of findings between studies. We investigated 24 CRPS patients with right upper limb affection in the chronic stage of disease using structural MRI and clinical testing. We focused on gray matter volume (GMV) alterations of the brain in comparison to 33 age matched healthy controls, their association to clinical characteristics (duration of pain syndrome and pain intensity ratings) and sensorimotor performance (finger dexterity and spatiotactile resolution). When applying an explorative whole brain analysis CRPS patients showed lower GMV in the bilateral medial thalamus. No other areas showed a relevant GMV difference for the group comparisons. When applying a region of interest driven approach using anatomical masks of the thalamus, ACC/mPFC, putamen, and insula we found relevant associations of clinical and behavioral data in ACC and insula. Whereas, the GMV in ACC showed negative associations with pain intensity and CRPS duration, the GMV of the left posterior insula was negatively associated with sensorimotor performance of the affected hand side. Overall, our results are in accordance to results of others describing a thalamic reduction of GMV in patients with neuropathic pain and are also in accordance with associations of pain intensity and duration with reduced ACC in general in patients with chronic pain syndromes. Sensorimotor performance seems to be related to posterior insula GMV reduction, which has not been described yet for other patient groups.
Objective
To evaluate the efficacy of tooth splinting (TS) and occlusal adjustment (OA) compared to no TS or OA in patients with periodontitis exhibiting masticatory dysfunction.
Material
The primary outcome criterion was tooth loss (TL), and the secondary outcome parameters were change in probing pocket depth (PPD), change in clinical attachment level (CAL), tooth mobility (TM), and patient‐reported outcome measures (PROMs). Literature search was performed on three electronic databases (from 01/1965 to 04/2021) and focused on clinical studies with at least 12 months follow‐up.
Results
From a total of 1515 publications, 51 articles were identified for full‐text reading, of which 2 retrospective case series on TS with low risk of bias and 1 randomized and 2 prospective studies on OA with unclear risk of bias were included. For TS, synthesis of data showed that in 72 patients, 26 out of 311 teeth (weighted mean incidence of TL 8.4%) and 156 out of 1541 teeth with no TS (weighted mean incidence of TL 10.1%) were lost over 2 years following non‐surgical periodontal therapy. The randomized controlled clinical trial (RCT) indicated CAL gain for teeth with OA compared to no OA. For the effect of OA on TL, PPD, and TM, heterogeneous data were retrieved from the included studies.
Conclusions
Within the limitations of this review and based on a low level of evidence, it is concluded that TS does not improve survival of mobile teeth in patients with advanced periodontitis. OA on teeth with mobility and/or premature contacts may lead to improved CAL, while the effect of OA on the remaining periodontal parameters remains unclear.
Das Werben um Nachwuchs im eigenen medizinischen Fachgebiet ist allen Fächern in der Medizin gemeinsam, ist doch das Fehlen des Nachwuchses in den einzelnen medizinischen Fächern schon länger beschrieben. Als mögliche Ursache für die ausbleibenden Bewerbungen im Fach der Anästhesiologie lassen sich auch in diesem Fach verschiedene mögliche Gründe in der Literatur finden, von inhumanen Arbeitszeiten und Arbeitsbedingungen mit schlechter Bezahlung bis zu einem „problematischen” Rollenbild der Anästhesiologie in der Öffentlichkeit und bei ärztlichen Kollegen*innen anderer Fachrichtungen. Die medizinische Ausbildung und Weiterbildung bis zum Erreichen des Facharztes und damit das Erreichen der letztendlichen Reife zur Ausübung des medizinischen Berufes als Ärztin oder Arzt durchläuft mehrere teils theoretische, teils praktische Schritte und Phasen. Mit dem Abschluss des Medizinstudiums endet die medizinische Ausbildung an der Universität.In der vorliegenden Arbeit soll nun geklärt werden, inwieweit ein Teil das PJ im Wahlfach Anästhesiologie Einfluss hat, die Weiterbildung zur(m) Fachärztin / Facharzt für Anästhesiologie zu wählen bzw. nicht zu wählen. Weiterhin gingen wir der Frage nach, ob der Zeitpunkt der Entscheidungsfindung einen Einfluss auf die Zufriedenheit der Studierenden nahm und inwieweit auch geschlechtsspezifische Unterschiede hier vorliegen. Herauszustellen gilt es, welche Problemfelder im Rahmen der Ausbildung es im Bereich des Faches Anästhesiologie gibt und welche Maßnahmen zur Gewinnung des eigenen Nachwuchses ergriffen werden sollten. Wie schafft das Fach Anästhesiologie, welches als Wahlfach im PJ gewählt werden kann, den Nachwuchs für sich besser zu begeistern?
Gene Expression and Protein Abundance of Hepatic Drug Metabolizing Enzymes in Liver Pathology
(2021)
In einer stetig alternden Gesellschaft mit einem immer größeren Bedarf an
medizinischer Versorgung und mit fortschreitendem Fachärztemangel, stellen
teledermatologische Systeme wie das an der Hautklinik Greifswald entwickelte
System Mobil Skin® und die dazugehörige App mSkin® einen innovativen und
kostensparenden Lösungsansatz dar. Die Etablierung eines solchen Systems
basiert auf der Zufriedenheit seiner Nutzer.
Ziel dieser Studie war es zu überprüfen, wie zufrieden Patienten, Notärzte und
Hautärzte mit dem System im Rahmen der notärztlichen Behandlung in der ZNA
Greifswald waren und welche Faktoren speziell Einfluss auf die Zufriedenheit der
Patienten hatten.
Zu diesem Zweck erfolgte eine retrospektive schriftliche Befragung mit Hilfe von
Fragebögen und auf der Basis zusätzlicher patientenbezogenen Informationen.
Das für die Studie ausgewählte Kollektiv bestand aus allen Patienten, die sich im
Zeitraum vom 01.03.2016 bis 31.12.2018 in der ZNA Greifswald mit einer
Hautkrankheit vorgestellt hatten und dort mit Hilfe der App mSkin® behandelt
wurden, sowie aus den an dieser Behandlung beteiligten Ärzten.
Es nahmen 73 Patienten sowie 13 Ärzte der ZNA Greifswald und 4 Ärzte der
Hautklinik Greifswald an der Befragung teil. Die Zufriedenheit wurde u. a. in Form
eines sog. Zufriedenheitsscores ausgedrückt. Dieser lag bei den Patienten bei
23,85 (von 30), bei den Ärzten der ZNA bei 17,23 (von 30) und bei den Ärzten
der Hautklinik bei 22 (von 30). Zusätzlich wurden Alter, Geschlecht, Diagnose,
Behandlungsverlauf, DLQI-Score und Beschwerdescore der Patienten mit dem
Zufriedenheitsscore sowie mit ausgewählten Zufriedenheitsfragen der Patienten
korreliert. Einen Einfluss auf die Patientenzufriedenheit hatten leicht signifikant
das Alter (p=0,052) und signifikant der DLQI-Score (p=0,025) sowie der
Beschwerdescore (p= 0,045). Die Ergebnisse unterstreichen die im allgemeinen
hohe Akzeptanz und Zufriedenheit mit teledermatologischen Anwendungen
insbesondere auf Patientenseite. Die der Zufriedenheit zugrunde liegenden
Mechanismen bedürfen jedoch weiterer Untersuchungen.
Marine bacteria represent the most diverse organisms in the marine environment. The majority of these microbes is unknown and unculturable. Algae represent the main nutrient source for bacteria. Macro- and microalgae can consist to 70% of polysaccharides. The metabolic degradation of marine polysaccharides is underexplored and thus these mechanisms have to be investigated. These mechanisms are of high importance to generate defined oligosaccharides for the medical and pharmaceutical applications. The specific structure of marine poly- and oligosaccharides show antiviral activities, e.g. carrageenans from red algae are used for the inhibition of human papillomavirus. Another alginate derived marine polysaccharide show inhibition of the replication of the human immunodeficiency virus (HIV). The degradation mechanisms of marine CAZymes and the structure of marine polysaccharides should be further investigated for their high potential of antiviral activities and the creation of new marine drugs.
Many marine bacteria produce membrane extension like membrane vesicles or appendages but the function of these is poorly understood. In order to investigate their function, especially concerning polysaccharide utilization, proteomic analyses of subcellular compartments were performed. Microscopy analyses revealed that, beside MV, P. distincta forms different appendages, vesicle chains (VC) and thin filaments which were dedicated to extracellular polymeric substance. The formation of MV and VC was independent of growth phase or carbon source. The proteomic data showed that transporters end enzymes for the initial degradation of pectin and alginate were highly abundant in these membrane extensions and that there could be a kind of sorting for proteins in the membrane extensions. Additionally, two PUL encoded alkaline phosphatases and other phosphate acquiring enzymes were abundant in the MV and VC fractions. This indicates, that P. distincta constitutively produces enzymes for phosphate uptake, which would be necessary in the phosphate-limiting environment of the Southern Ocean. On the one hand marine bacteria produce membrane extensions in order to create a larger surface in the nutrient limiting marine environment for an increased chance to get in contact to nutrients and on the other hand the results indicate an accumulation of enzymes responsible for uptake and degradation of carbohydrates and phosphates in the MV and VC. Therefore, the membrane extensions act as nutrient traps and this might be beneficial for the bacteria in the diffuse aquatic environment.
The microbial community structure and the metabolism of bacteria in the Southern Ocean are very poorly investigated. The SO is a harsh environment for all organism but nevertheless, the SO is of high importance for the climate in the world due to the high carbon dioxide uptake. In this study water samples from two different sampling sites (S1 and S2) in the SO were investigated. With a metagenomic and metaproteomic approach the key players and the metabolic activity were analyzed. Additionally, the surface water was inoculated with pectin and incubated for several days in order to analyze polysaccharide utilization loci for pectin degradation and to isolate new pectin degraders. 16S-rDNA analyses revealed the bacterial community from the genomic data. Bacteria were separated in particle-associated and free-living bacteria. The overall particle associated bacterial community at both sampling sites was comparable, with Bacteroidetes and Gammaproteobacteria as the abundant phylum. Within the Gammaproteobacteria the Alteromonadaceae and Colwelliaceae were more abundant at S2 than at S1. The free-living bacteria at S1 were dominated by the Alphaproteobacteria, especially the SAR11 clade I. Metagenomic analyses showed that both sampling sites had comparable PUL composition, but taxonomical classification of PULs was differently. The metaproteome data revealed that PUL encoded enzymes were not highly abundant. Only few CAZymes were found, mostly TonB-dependent transporters belonged to the detected PUL proteins. Taxonomical classification of proteins showed differences between the sampling sites. At S2 the genus Colwellia and Arcobacter were highly increased compared to S1. At this location Candidatus Pelagibacter, Planktomarina and Polaribacter were the abundant taxa. The functional classification at both sampling sites was comparable. The only difference was the high abundance of Epsilonproteobacteria at S2 referable to the Arcobacter species. Nevertheless, the notably taxonomical differences could not be explained by the proteomic data and the functional classification, because no specific metabolic function could be highly addressed to these bacteria. These results assumed that different abundance of the key players could be explained by different environmental conditions. The pectin enriched cultured at both sampling sites were investigated for the functional potential of pectin degrading enzymes. No metaproteomic approach could be performed due to less sampling material. Only one PUL for the degradation of rhamnogalacturonan, a component of pectin, was found at S1. In contrast, bacteria grown on pectin could be isolated from these samples. Genome sequencing of five isolates showed that functional potential of pectin degradation is available. Due to the limitations of sequence alignments, it was not possible to detect a PUL responsible for pectin utilization in the metagenomic data. The results show that the polysaccharide degradation mechanism in the Southern Ocean has to be more investigated to get knowledge about the bacterial activity in the ocean’s surface and the carbon turnover in this underexplored environment.
Summary
Outer membrane extensions are common in many marine bacteria. However, the function of these surface enlargements or extracellular compartments is poorly understood. Using a combined approach of microscopy and subproteome analyses, we therefore examined Pseudoalteromonas distincta ANT/505, an Antarctic polysaccharide degrading gamma‐proteobacterium. P. distincta produced outer membrane vesicles (MV) and vesicle chains (VC) on polysaccharide and non‐polysaccharide carbon sources during the exponential and stationary growth phase. Surface structures of carbohydrate‐grown cells were equipped with increased levels of highly substrate‐specific proteins. At the same time, proteins encoded in all other polysaccharide degradation‐related genomic regions were also detected in MV and VC samples under all growth conditions, indicating a basal expression. In addition, two alkaline phosphatases were highly abundant under non‐limiting phosphate conditions. Surface structures may thus allow rapid sensing and fast responses in nutritionally deprived environments. It may also facilitate efficient carbohydrate processing and reduce loss of substrates and enzymes by diffusion as important adaptions to the aquatic ecosystem.
Over thirty years have passed since the first description of ubiquitin-positive structures in the brain of patients suffering from Alzheimer’s disease. Meanwhile, the intracellular accumulation of ubiquitin-modified insoluble protein aggregates has become an indisputable hallmark of neurodegeneration. However, the role of ubiquitin and a fortiori the ubiquitin-proteasome system (UPS) in the pathogenesis of neurodevelopmental disorders (NDD) is much less described. In this article, we review all reported monogenic forms of NDD caused by lesions in genes coding for any component of the UPS including ubiquitin-activating (E1), -conjugating (E2) enzymes, ubiquitin ligases (E3), ubiquitin hydrolases, and ubiquitin-like modifiers as well as proteasome subunits. Strikingly, our analysis revealed that a vast majority of these proteins have a described function in the negative regulation of the innate immune response. In this work, we hypothesize a possible involvement of autoinflammation in NDD pathogenesis. Herein, we discuss the parallels between immune dysregulation and neurodevelopment with the aim at improving our understanding the biology of NDD and providing knowledge required for the design of novel therapeutic strategies.
In der vorliegenden Arbeit wurde der Zusammenhang zwischen der Opazität und der biaxialen Biegefestigkeit von multilayer Zirkoniumdioxiden untersucht. Diese Materialwerte sind für die Indikationseinschätzung der Werkstoffe von großer Bedeutung.
Für die Untersuchung wurden neun Zirkoniumdioxide und als Vergleich ein Lithiumdisilikat ausgewählt. Insgesamt wurden 690 Prüfkörper im CAD/CAM Verfahren und mit einem Sägemikrotom hergestellt. Nachdem die Proben gesintert waren, wurden sie auf ihre Schichtstärke vermessen. Zur Messung wurde ein selbst entworfener und dreidimensional gedruckter Probenhalter eingesetzt. Zur Untersuchung der Probenoberfläche wurde das optische Rauheitsmessgerät Profilm 3D Optical Profiler (Filmetrics, San Diego, CA, USA) eingesetzt. Die Opazität wurde mit Hilfe des Mikrotiterplatten-Lesegerätes Synergy HTX (BioTek Instruments, Winooski, Vermont, Vereinigte Staaten) bestimmt. Für die eingesetzte Universalprüfmaschine Z050 (Zwick/Roell, Ulm, Deutschland) musste zunächst ein Prüfwerkzeug konstruiert und gefertigt werden. Zur Festigkeitsbestimmung wurde ein biaxialer Biegeversuch durchgeführt. Die Messwerte wurden in Form einer Excel-Tabelle gespeichert, auf ihre Normalverteilung überprüft und anschließend mit Hilfe der einfaktoriellen Varianzanalyse (ANOVA) ausgewertet.
Die Ergebnisse zeigen, dass die Rauheiten der Prüfkörper dank der standardisierten Herstellung im selben Größenbereich liegen. Geringe Abweichungen können auf materialspezifische Einflussfaktoren zurückgeführt werden.
Bei den Materialien IPS e.max ZirCAD Prime und Nacera Pearl Q3 ist eine signifikant (p < 0,001) vom Schichtungsgradienten abhängige Änderung der Opazität festzustellen. Zusätzlich zum Opazitätsverlauf weist das Material IPS e.max ZirCAD Prime eine statistisch signifikante (p < 0,001) Änderung der Biegefestigkeit in Abhängigkeit der vertikalen Richtung auf. Bezüglich des Zusammenhanges zwischen der Opazität und der Biegefestigkeit verhalten sich die getesteten multilayer Zirkoniumdioxide ähnlich. Das Material Lithiumdisilikat grenzt sich durch eine geringere Opazität und geringere Biegefestigkeit von den Zirkoniumdioxiden ab. Des Weiteren hebt sich das Material priti Extra Translucent durch eine hohe Biegefestigkeit ab. Von den Firmen Kuraray Noritake Dental, pritidenta und Ivoclar Vivadent wurden jeweils zwei Materialien getestet. Beim Vergleich der beiden Materialien der drei oben genannten Hersteller ist zu erkennen, dass eine größere Biegefestigkeit mit einer größeren Opazität einhergeht. Die Materialien Cercon xt ML und Vita YZ XT Multicolor liegen hinsichtlich ihrer Biegefestigkeit und Opazität im Mittelfeld der getesteten Materialien. Das Material Lava Esthetic befindet sich im oberen Mittelfeld bezüglich der Biegefestigkeit.
Die Ergebnisse lassen schlussfolgern, dass multilayer Zirkoniumdioxide im Hinblick auf die Lichtdurchlässigkeit Lithiumdisilikat unterlegen sind. Der Nachteil einer geringeren Festigkeit von Lithiumdisilikat kann durch eine Erhöhung der Schichtstärke ausgeglichen werden, ohne große Verschlechterung der Lichtdurchlässigkeit hinnehmen zu müssen. Multilayer Zirkoniumdioxide haben ihren Vorteil in der Stabilität, wohingegen Lithiumdisilikat bei ästhetischen Indikationen ein besseres Ergebnis aufweist. Zusammenfassend ist zu sagen, dass multilayer Zirkoniumdioxide den Indikationsbereich zwischen den ästhetischen Lithiumdisilikaten und den stabileren, aber lichtundurchlässigeren Zirkoniumdioxiden schließen.
Verfärbte Stümpfe und die menschliche Wahrnehmung der Farben stellen im klinischen Alltag einen hier nicht berücksichtigten Einflussfaktor dar. In klinischen Studien ist zu klären, inwieweit eine erhöhte Lichtdurchlässigkeit die Ästhetik positiv beeinflussen kann. Des Weiteren spielt die Langzeitfestigkeit für das klinische Überleben einer Restauration eine weitere Rolle, die untersucht werden sollte. Zur genaueren Einschätzung und zum Vergleich der Ergebnisse wäre es interessant, einen direkten Vergleich der Opazitätsmessung mit Hilfe eines Mikrotiterplatten-Lesegerätes und eines Spektralphotometers durchzuführen.
Background: Klebsiella pneumoniae causes severe diseases including sepsis, pneumonia
and wound infections and is differentiated into hypervirulent (hvKp) and classic (cKp) pathotypes.
hvKp isolates are characterized clinically by invasive and multiple site infection and phenotypically
in particular through hypermucoviscosity and increased siderophore production, enabled by the
presence of the respective virulence genes, which are partly carried on plasmids. Methods: Here, we
analyzed two K. pneumoniae isolates of a human patient that caused severe multiple site infection.
By applying both genomic and phenotypic experiments and combining basic science with clinical
approaches, we aimed at characterizing the clinical background as well as the two isolates in-depth.
This also included bioinformatics analysis of a chromosomal virulence plasmid integration event.
Results: Our genomic analysis revealed that the two isolates were clonal and belonged to sequence
type 420, which is not only the first description of this K. pneumoniae subtype in Germany but also
suggests belonging to the hvKp pathotype. The latter was supported by the clinical appearance and
our phenotypic findings revealing increased siderophore production and hypermucoviscosity similar
to an archetypical, hypervirulent K. pneumoniae strain. In addition, our in-depth bioinformatics
analysis suggested the insertion of a hypervirulence plasmid in the bacterial chromosome, mediated
by a new IS5 family sub-group IS903 insertion sequence designated ISKpn74. Conclusion: Our study
contributes not only to the understanding of hvKp and the association between hypervirulence and
clinical outcomes but reveals the chromosomal integration of a virulence plasmid, which might lead
to tremendous public health implications.
Multi-drug resistant (MDR), gram-negative Enterobacteriaceae, such as Escherichia coli (E. coli) limit therapeutic options and increase morbidity, mortality, and treatment costs worldwide. They pose a serious burden on healthcare systems, especially in developing countries like Rwanda. Several studies have shown the effects caused by the global spread of extended-spectrum beta-lactamase (ESBL)-producing E. coli. However, limited data is available on transmission dynamics of these pathogens and the mobile elements they carry in the context of clinical and community locations in Sub-Saharan Africa. Here, we examined 120 ESBL-producing E. coli strains from patients hospitalized in the University Teaching Hospital of Butare (Rwanda), their attending caregivers as well as associated community members and livestock. Based on whole-genome analysis, the genetic diversification and phylogenetics were assessed. Moreover, the content of carried plasmids was characterized and investigated for putative transmission among strains, and for their potential role as drivers for the spread of antibiotic resistance. We show that among the 30 different sequence types (ST) detected were the pandemic clonal lineages ST131, ST648 and ST410, which combine high-level antimicrobial resistance with virulence. In addition to the frequently found resistance genes blaCTX–M–15, tet(34), and aph(6)-Id, we identified csg genes, which are required for curli fiber synthesis and thus biofilm formation. Numerous strains harbored multiple virulence-associated genes (VAGs) including pap (P fimbriae adhesion cluster), fim (type I fimbriae) and chu (Chu heme uptake system). Furthermore, we found phylogenetic relationships among strains from patients and their caregivers or related community members and animals, which indicates transmission of pathogens. Also, we demonstrated the presence and potential transfer of identical/similar ESBL-plasmids in different strains from the Rwandan setting and when compared to an external plasmid. This study highlights the circulation of clinically relevant, pathogenic ESBL-producing E. coli among patients, caregivers and the community in Rwanda. Combining antimicrobial resistance with virulence in addition to the putative exchange of mobile genetic elements among bacterial pathogens poses a significant risk around the world.
AbstractThe efficient operation of a tokamak is limited by several constraints, such as the transition to high confinement or the density limits occurring in both confinement regimes. These particular boundaries of operation are derived in terms of a combination of dimensionless parameters describing interchange-drift-Alfvén turbulence without any free adjustable parameter. The derived boundaries describe the operational space at the separatrix of the ASDEX Upgrade tokamak, which is presented in terms of an electron density and temperature existence diagram. The derived density limits are compared against Greenwald scaling. The power threshold and role of ion heat flux for the transition to high confinement are discussed.