Multiscale Modelling of Malaria-Infected Red Blood Cells

Red blood cells (RBCs) are the type of human cells that are most accessible to biophysical multiscale modelling because they feature a regular molecular cell envelope organization and lack internal organelles. Extensive previous research on how their physical properties are shaped by the actin-spectrin network and other molecular constituents provides a good basis to understand the physical consequences of becoming infected by malaria parasites, which use RBCs to hide from the immune system. After invasion, the malaria parasite rebuilds the RBC-envelope, relying on the self-assembly of parasite proteins released into the cytoplasm. Optical tweezer experiments have shown that infected RBCs (iRBCs) become stiffer. Here, the underlying mechanisms are investigated by quantitative analysis of the flickering spectrum of iRBCs. Extending the membrane Hamiltonian by anchoring points, we find that the parasite stiffens the membrane mostly by introducing more connections between the lipid bilayer and the underlying cytoskeleton. To identify the exact points of attack in the RBC-cytoskeleton, a reaction-diffusion model is developed to investigate the dynamical equilibrium of the RBC-cytoskeleton, allowing us to simulate different scenarios of parasite protein self-assembly and to compare these results with experimental data. The parasite induces protrusions to make the iRBC adhesive, thus increasing residence time in the vasculature and avoiding clearance by the spleen. The number of new transmembrane receptors incorporated into the cell membrane is estimated by quantitative analysis of fluorescence and electron microscopy data. We develop a finite element model aiming to predict the effect of these changes on the movement of iRBCs in hydrodynamic flow. Finally, as an instructive contrast to RBC-mechanics, we investigate the spreading of tissue cells onto micropatterned substrates leading to a complete change in their actin cytoskeleton. A Cellular Potts Model is used to describe this highly dynamic situation. We find that due to its focus on geometrical aspects, it predicts reliably how a family of actin stress fibres is formed, which serves as memory of the spreading process

Evaluation of lung function changes associated with Chlamydiaceae in pigs and calves using impulse oscilloresistometry and the software FAMOS

Deckblatt-Impressum persönlicher Dank Inhaltsverzeichnis Verzeichnis der verwendeten Abkürzungen Einleitung, Aufgabenstellung und Arbeitshypothese Literatur Eigene Untersuchungen Ergebnisse Diskussion Zusammenfassung Summary Literaturverzeichnis Anhang Abbildungs- und Tabellenverzeichnisse Danksagung Lebenslauf Eidesstattliche ErklärungAufgabenstellung: Untersuchungen klinisch gesunder Kälber und Schweine zeigten, dass bei einem Teil der Tiere regelmäßig eine spontane Besiedlung des respiratorischen Systems mit Chlamydien nachgewiesen werden kann. Unklar war, (a) ob es sich hierbei um ein Kolonisations-Phänomen oder um eine klinisch inapparente Infektion handelt und (b) in welchem Ausmaß die Lungenfunktion betroffener Tiere beeinflusst wird. Ziel dieser Untersuchungen war die Evaluierung des Einflusses von Chlamydien auf die Lungenfunktion von Kalb und Schwein. Studiendesign: An 16 klinisch unauffälligen Schweinen im Alter von 5 - 27 Wochen (Körper¬massen von 7 - 100 kg) und 25 klinisch unauffälligen Kälbern im Alter von 2 - 7 Monaten (Körpermassen von 40 - 158 kg) wurden mittels Masterscreen-IOS (VIASYS Healthcare) lungenfunktionsdiagnos¬tische Tests durchgeführt. Jedes Tier wurde über einen Untersuchungs¬zeitraum von sechs Monaten (2. - 7. Lebensmonat) kontrolliert. Der Erreger¬nachweis wurde mittels PCR in Augentupfer-, Na¬sentupfer- und Kottupferproben sowie post mortem in Organproben durchgeführt. Für serologische Untersuchungen wurde beim Schwein ein ELISA und beim Kalb eine KBR angewandt. Zur Datenauswertung wurde nach vorangegangener Validierung die Software FAMOS (Fast Analysis and Monitoring Of Signals) eingesetzt. Sie ermöglicht bei Schweinen und Kälbern eine exaktere Betrachtung der respiratorischen Impedanz in niedrigen Frequenzen, die von der gängigen Messtechnik standardmäßig nicht angeboten wird. Ergebnisse: Bei sechs der 16 untersuchten Schweine wurden folgende chlamydiale Spezies im Lungengewebe nachgewiesen: C. psittaci, C. trachomatis, C. pecorum. Alle 16 Schweine waren serologisch negativ (ELISA). Bei 13 von insgesamt 25 untersuchten Kälbern gelang der Nachweis spontaner Besiedlungen des respi¬rato¬rischen Systems mit folgenden Spezies: C. psittaci und C. pecorum. Sieben der 13 Tiere wiesen außerdem in der serologischen Untersuchung (KBR) Antikörper gegen Chlamydien auf. Die Tiere beider Spezies wurden in Gruppen [Chlamydiennachweis positiv (Chl+); Chlamydiennachweis negativ (Chl-)] klassifiziert und bezüglich ihrer klinischen und lungenfunktionsdiagnostischen Befunde mit folgenden Resultaten verglichen. Schweine: \- signifikant erhöhte Rektaltemperatur bei Tieren mit positivem Chlamydiennachweis \- keine klinisch manifesten Symptome einer respiratorischen Infektion (Fieber, Husten, Nasen- o. Augenausfluss, Atmungsfrequenz) \- keine Beeinträchtigungen der Lungenfunktion Kälber: \- signifikant erhöhte Rektaltemperatur bei Tieren mit positivem Chlamydiennachweis \- keine klinisch manifesten respiratorischen Symptome \- signifikant höhere Werte in den Kenngrößen der Ventilation bei Tieren mit positivem Chlamydiennachweis (Atmungsfrequenz, Atemzugvolumina, Atemminutenvolumina) \- signifikant höhere Strömungswiderstände in den peripheren und zentralen Atemwegen bei Tieren mit positivem Chlamydiennachweis Schlussfolgerungen: Die an Schweinen gewonnenen Untersuchungsergebnisse weisen darauf hin, dass eine klinisch inapparente Besiedlung des respiratorischen Systems mit Chlamydien nicht zwangsläufig mit dem Lungenreifungsprozess interferieren und zu einer Beeinträchtigung der Lungenfunktion führen muss. Bei diesen Tieren, die auch serologisch keinen Hinweis auf eine immunologische Auseinandersetzung mit dem Erreger aufwiesen, sind die mittels PCR geführten Erregernachweise lediglich im Sinne einer Kolonisation der Schleimhäute des respiratorischen Systems ohne funktionelle Konsequenzen zu interpretieren. Bei Kälbern, die neben dem Erregernachweis auch serologische Hinweise für eine immunologische Reaktion auf Chlamydien aufwiesen, muss von dem Vorhandensein einer klinisch inapparenten Infektion ausgegangen werden. In diesem Zusammenhang wurden sowohl morphologisch wie auch funktionell chronisch- obstruktive Veränderungen in den Atemwegen nachgewiesen.Aim: In clinically healthy pigs and calves, Chlamydiaceae can be found quite regularly in samples obtained from the respiratory system. Whether this finding is related to functional and/or pathological changes within the respiratory tract has yet to be defined. Consequently, lung function was evaluated in animals with and without a naturally acquired chlamydial infection. Animals and Methods: Sixteen conventionally raised pigs and 25 calves were examined. Animals did not show clinical signs of respiratory infectious diseases but were partly positive for the presence of Chlamydiaceae within the respiratory tract. Chlamydial DNA was isolated from rectal and nasal swabs as well as from tissue samples using the High Pure PCR Template Preparation Kit (Roche Diagnostics, Mannheim, Germany). According to PCR results, animals of each species were divided into Chlamydiaceae positive or negative groups (Chl- and Chl+). In addition, serology was performed using ELISA in pigs and CFT in calves. In each animal, lung function was evaluated regularly starting at the age of the 2nd month up to the 7th month of life. Variables of ventilation (respiratory rate, tidal volume, minute volume) and respiratory mechanics (airway resistance, respiratory reactance) were measured using the impulse oscillometry system (IOS), a non-invasive technique that has been validated for both species. Statistical analysis was conducted to clarify whether the presence of Chlamydiaceae had any significant influence on lung function. To explore information in the frequency range 1 5 Hz by recalculation of original IOS-data the software FAMOS (Fast Analysis and Monitoring Of Signals) was used, after previous validation. FAMOS allows evaluation of the respiratory impedance at frequencies lower than 5 Hz and facilitates examination of the peripheral respiratory system in calves and pigs for further diagnostic purposes. Results: In six of 16 pigs, at least one of the following chlamydial species was detected by PCR: C. psittaci, C. trachomatis, C. pecorum (old taxonomy). However, all 16 pigs were serologically negative. In 13 of 25 calves, predominantly C. psittaci and C. pecorum were found by PCR. Serologically, a chlamydial infection was confirmed in 7 of the 13 PCR-positive calves. pigs: \- rectal temperature was significantly higher in Chlamydiaceae positive pigs (PCR) \- all 16 pigs were serologically negative (ELISA) \- free of clinical symptoms (fever, cough, nasal or eye secretion) \- no significantly differences in respiratory rate \- no deterioration in lung function calves: \- rectal temperature was significantly higher in Chlamydiaceae positive calves \- 7 of 13 calves with Chlamydiaceae positive results in PCR were also serologically positive (CFT) \- no clinical signs of respiratory illness \- respiratory rate was significantly higher in Chlamydiaceae positive calves \- significantly higher airway resistance (indicating chronic airway obstruction) in Chlamydiaceae positive calves Conclusions: As shown in pigs, the presence of Chlamydiaceae within the respiratory tract alone does not necessarily lead to a deterioration in lung function. As demonstrated in calves (partly serologically positive), the development of chronic airway obstructions may be included in the pathogenesis of a clinically silent, but chronic respiratory chlamydial infection

Airborne VOC measurements on board the Zeppelin NT during the PEGASOS campaigns in 2012 deploying the improved Fast-GC-MSD System

Volatile organic compounds (VOCs) comprise a large number of different species, estimated to 104-106. They are emitted on the Earth’s surface from a variety of biogenic and anthropogenic sources. VOCs are removed by multiple pathways from the atmosphere, by oxidation and finally by dry or wet deposition. Most primary emitted VOCs are non-polar and therefore have a low solubility in water. Oxidation facilitates efficient VOC removal by wet deposition. In the atmosphere the main photochemical VOC oxidation agent is the OH radical. As a consequence the polarity of the VOCs is increased and they can be removed faster. The oxidation of VOCs proceeds in several steps until the VOCs are deposited or are eventually oxidized to carbon dioxide. A downside of the VOCs oxidation process lies in the production of significant amounts ozone if nitrogen oxide is present which is a serious health hazard. Most of the VOC oxidation takes place in lower part of the atmosphere between the altitudes of 100 to 1000 m, which is only sparsely analyzed. Therefore, fast VOCs measurements byGC-MSD on board the Zeppelin NT offered new important insights in the distribution of VOCs. The measurements were performed within the PEAGSOS campaigns in the Netherlands and in Italy in 2012. For the implementation of the GC-MSD system (HCG) on board the Zeppelin it was reconstructed to enhance its performance and to meet aviation requirements. The system was optimized to measure VOCs ranging from C4 to C10 as well asoxygenated VOCs (OVOCs) with a detection limit below 10 ppt. The analyzed VOCs for both parts of the campaigns showed low mean concentration below 5 ppb for all VOCs. Especially, the mixing ratios of the primary emitted VOCs were very low with mean values lower than 200 ppt. Higher concentrations could be observed for the OVOCs with mean concentrations up to 5 ppb. The most abundant OVOCs apart fromformaldehyde were methanol, ethanol, acetone and acetaldehyde

Cyberbullying in Germany – an exploration of prevalence, overlapping with real life bullying and coping strategies

A new phenomenon of violence among pupils has been spreading over Europe in the last few years: Cyberbullying, the repeated and intended hurting of weaker schoolmates via modern communication technologies. This study shows (based on a sample of 1987 pupils), that cyberbullying exists in Germany, although the number of incidents is still rather small. It could also be shown, that the pupils who act as cyberbullies are the same as those who bully others in real life. The same overlap was found to be true for the victims. Cyberbullying can therefore be considered a subcategory of ordinary bullying instead of being considered a whole new phenomenon. The exploration of coping strategies showed, that a common factor structure underlies physical, verbal and cyberbullying. Considering the fact that the findings of the study are based on an online questionnaire with restricted representativeness, the results should however be interpreted carefully

Von Müttern und Töchtern

Die Arbeit beschäftigt sich mit der Darstellung der Geschlechterrollen in schwedischen Generationenromanen. Hierzu wurden Kerstin Ekmans "Kvinnorna och staden"- Tetralogie bestehend aus "Häxringarna", "Springkällan", "Änglahuset" und "En stad av ljus", Marianne Fredrikssons " Anna, Hanna och Johanna" sowie Henning Mankells "Daisy Sisters" untersucht. Mit der Methode der Fraunbildforschung wurden Frauen und die von ihnen eingenommenen Rollen analysiert. Da Darstellung der Frauen nicht von der der Männer zu trennen ist, wurde auch auf die Männerfiguren eingegangen. Auf die konkreten Unterschiede in der Darstellung der Geschlechter wurde ebenso eingegangen wie auf die Frage, inwieweit man die behandelten Werke als feministisch orientiert ansehen kann. Es war interessant festzustellen, dass die von Ekman dargestellten Frauen trotz ihrer Ausübung von sterotyp weiblichen Berufen als unabhängig und stark wahrgenommen werden. Im Gegensatz dazu wuden die von Fredriksson gezeichneten Frauen vom Leser/ der Leserin als unterwürfig und angepasst wahrgenommen. Mankells Frauendarstellung ist ähnlich jener Ekmans wobei er durch die Reduktion auf zwei dominierende Frauentypen- aktive und passive- ähnlich wie Fredriksson pauschalisiert und vereinfacht. Es hat sich gezeigt, dass sowohl Ekmans Romane als auch Mankells Roman in eine feministische Richtung interpretiert werden können, während Fredrikssons Roman durch die unkritische Präsentation von tradtionell- konservativen Geschlechterrollen nicht als feministisch interpretiert werden kann. Das Geschlecht des Autors/ der Autorin ist also nicht ausschlaggebend für die Darstellung der Geschlechter und der ihnen zugeschriebenen Eigenschaften.This diploma thesis occupies itself with the presentation of female figures in swedish generation novels of the 20th century. Therefor were Kerstin Ekmans "Kvinnorna och staden"- tetralogy which containes "Häxringarna", "Springkällan", "Änglahuset" and "En stad av ljus", Marianne Fredrikssons "Anna, Hanna och Johanna" and Henning Mankells "Daisy Sisters" used. Female figures presentation- researching was used as a method for finding out how female figures are described of the different authors. For analyzing the presentation of female figures an their roles it was necessary to analyze male figures as well. So the different gender roles were as well picked up as the question if the novels can be interpreted in a feminist way. Ekmans women seemed to be a lot more independent and stronger than Fredrikssons women. In the analysis Mankells women were principally remindful of Ekmans women. But with his reduction on only two types of women the active one and the passive one, Mankell seemed to simplify and trivialize. It was pointed out that Ekmans novels as well as Mankells novel can be red in a feminst way, whereas Fredrikssons novel definitely is not feminist because of her uncritical presentation of the traditional gender roles

Airborne VOC measurements on board the Zeppelin NT during the PEGASOS campaigns in 2012 deploying the improved Fast-GC-MSD System

Volatile organic compounds (VOCs) comprise a large number of different species, estimated to 104-106. They are emitted on the Earth’s surface from a variety of biogenic and anthropogenic sources. VOCs are removed by multiple pathways from the atmosphere, by oxidation and finally by dry or wet deposition. Most primary emitted VOCs are non-polar and therefore have a low solubility in water. Oxidation facilitates efficient VOC removal by wet deposition. In the atmosphere the main photochemical VOC oxidation agent is the OH radical. As a consequence the polarity of the VOCs is increased and they can be removed faster. The oxidation of VOCs proceeds in several steps until the VOCs are deposited or are eventually oxidized to carbon dioxide. A downside of the VOCs oxidation process lies in the production of significant amounts ozone if nitrogen oxide is present which is a serious health hazard. Most of the VOC oxidation takes place in lower part of the atmosphere between the altitudes of 100 to 1000 m, which is only sparsely analyzed. Therefore, fast VOCs measurements byGC-MSD on board the Zeppelin NT offered new important insights in the distribution of VOCs. The measurements were performed within the PEAGSOS campaigns in the Netherlands and in Italy in 2012. For the implementation of the GC-MSD system (HCG) on board the Zeppelin it was reconstructed to enhance its performance and to meet aviation requirements. The system was optimized to measure VOCs ranging from C4 to C10 as well asoxygenated VOCs (OVOCs) with a detection limit below 10 ppt. The analyzed VOCs for both parts of the campaigns showed low mean concentration below 5 ppb for all VOCs. Especially, the mixing ratios of the primary emitted VOCs were very low with mean values lower than 200 ppt. Higher concentrations could be observed for the OVOCs with mean concentrations up to 5 ppb. The most abundant OVOCs apart fromformaldehyde were methanol, ethanol, acetone and acetaldehyde

The role of hepatic transforming growth factor beta1-stimulated clone 22 D1 (TSC22D1 in the regulation of systemic cholesterol metabolis

Energy storage and consumption of the healthy human body are well geared to the needs under physiological conditions. Any disturbances in this balance can result in metabolic diseases such as obesity. A key feature of metabolic disorders is an abnormal lipid profile, as characterized by elevated serum triglycerides, elevated low density lipoprotein (LDL) cholesterol and reduced high density lipoprotein (HDL) cholesterol. These alterations can increase the risk for the development of type 2 diabetes or atherosclerotic cardiovascular diseases. In this study, the transcriptional co-factor transforming growth factor beta1-stimulated clone 22 D1 (TSC22D1) was identified as novel regulator of systemic cholesterol metabolism. Acute or chronic knockdown of TSC22D1 in livers of wild-type mice resulted in a significant decrease of serum HDL cholesterol and mildly elevated liver cholesterol. These changes are caused by a reduced expression of key genes involved in cholesterol efflux such as Apolipoprotein A1 (ApoA1), or transporters as ATP binding cassette protein A1 (ABCA1), ABCG5 and ABCG8. Interestingly, serum HDL cholesterol could be elevated by overexpression of hepatic TSC22D1 in wild type mice. Moreover, TSC22D1 expression was found to be differentially regulated in mouse models of opposing energy supply. Whereas levels of TSC22D1 transcripts were significantly reduced in states of energy wasting as in cancer cachexia, they were increased by energy surplus as under obese conditions. Along these lines, hepatic TSC22D1 expression was increased in ob/ob mice, which are highly resistant to the development of atherosclerosis due to their elevated HDL levels. Again, TSC22D1 knockdown significantly lowered serum HDL cholesterol and reduced expression of ApoA1, ABCA1, ABCG5 and ABCG8. Intriguingly, plasma concentrations of HDL/ApoA1 inversely correlate with the risk for atherosclerotic cardiovascular disease in humans. Thus, hepatic TSC22D1 transcription factor complex may represent an interesting new target for beneficial manipulation of HDL cholesterol levels

Zur gesellschaftspolitischen Situation der Mayafrauen in Guatemala

Indigene Frauen werden in der guatemaltekischen Gesellschaft dreifach diskriminiert, erstens weil sie zur indigenen Bevölkerung gehören, zweitens weil sie Frauen sind und schlussendlich weil sie vom ökonomischen Standpunkt aus gesehen zumeist arm sind. Die Gründe für die diskriminierende Behandlung der Mayafrauen in Guatemala sind auf verschiedene gesellschaftliche, historische sowie politische Faktoren zurückzuführen. Ein wichtiger Aspekt war die Eroberung und die darauffolgende Kolonisierung durch die Spanier. Die Cosmovisión der Maya, also ihre Denk- und Lebensweise sieht grundsätzlich beide Geschlechter als gleichwertig an. Trotz dieser traditionellen Gleichwertigkeit der Geschlechter wird die Mayafrau aber nicht nur außerhalb sondern auch innerhalb der Gemeinschaft der Maya diskriminiert. Ein wichtiger Punkt um Diskriminierung in allen Aspekten zu beenden, ist, dass sich die Mayafrauen ihrer eigenen Rolle bewusst werden, sie hinterfragen und versuchen sie zu ändern. Es ist notwendig, dass sich jede einzelne Frau mit ihrer Identität und ihrer Selbst- und Fremdwahrnehmung auseinandersetzt, dies habe ich damit begründet, dass es wichtig ist zu wissen, wer man ist und was die eigene Identität ausmacht um als politischer und gesellschaftlicher Akteur wahr- und ernstgenommen zu werden. Auf den Zusammenhang zwischen den Elementen Maya und Feminismus bin ich am Ende meiner Arbeit eingegangen. Dass es bis jetzt noch relativ wenige Mayafrauen gibt, die sich mit Feminismus und feministischen Ideen auseinandersetzten liegt daran, dass die Meinung vorherrscht, dass diese beiden Elemente nicht zusammenpassen würden. Dass sie aber trotz allem Gemeinsamkeiten aufweisen habe ich mit dem Verweis auf die von beiden Bewegungen geforderte Gleichheit belegt.Indigenous women in Guatemala are discriminated against because of three factors: they belong to the indigenous people, they are women and economically seen mostly they are poor. The reasons for that can be found in different social, political and historical factors. Some of the most important factors were the spanish conquest and colonization. Mayan cosmovision, that will say their mode how to see and explain the world, say basically that both sexes are equal. Despite this factor mayan women are also discrimanted against within their own community. To put an end to this, it is necessary that mayan women become aware of their own role to be able to change something. They have to know who they are and how they are seen by other people for being taken seriously as an political and economical factor. Finally I also explained the relation between feminism and mayan cosmovision

Randomized controlled trial of S-1 maintenance therapy in metastatic esophagogastric cancer – the multinational MATEO study

Background: The optimal duration of firstline chemotherapy in metastatic esophagogastric cancer is unknown. In most clinical trials therapy was given until tumour progression or limiting toxicity. Maintenance concepts aiming to prolong the duration of response and maintain quality of life have been established in other tumour types but not in esophagogastric cancer. S-1 is an oral fluoropyrimidine with proven efficacy in metastatic esophagogastric cancer. Methods: The Maintenance Teysuno® (S-1) in esophagogastric cancer (MATEO) trial is a multinational, randomized phase II study that explores the role of S-1 maintenance therapy in Her-2 negative, advanced esophagogastric adenocarcinoma. After a 12-week firstline platinum-fluoropyrimidine-based chemotherapy patients without tumour progression are randomized in a 2:1 allocation to receive S-1 alone or continue with the same regimen as during the primary period. The primary endpoint is overall survival. Secondary endpoints include safety and toxicity, progression-free survival and quality of life. Correlative biomarker analyses focus on the identification of a subgroup of patients with a prolonged benefit from S-1 based maintenance therapy. Discussion: MATEO will be the first trial to define the role of a S-1 based maintenance therapy in patients having received a platinum-based firstline chemotherapy. Trial registration: NCT02128243 (date of registration: 29–04-2014)