Of voyeuristic safari tours and responsible tourism with educational value: Observing moral communication in slum and township tourism in Cape Town and Mumbai

Sightseeing in the poorest quarters of southern hemisphere cities has been observed occurring in Cape Town, Rio de Janeiro, Mumbai and many other cities. The increasing global interest in touring poor urban environments is accompanied by a strong morally charged debate; so far, this debate has not been critically addressed. This article avoids asking if slum tourism is good or bad, but instead seeks a second-order observation, i.e. to investigate under what conditions the social praxis of slum tourism is considered as good or bad, by processing information on esteem or disesteem among tourists and tour providers. Special attention is given to any relation between morality and place, and the thesis posited is that the moral charging of slum tourism is dependent on the presence of specific preconceived notions of slums and poverty. This shall be clarified by means of references to two empirical case studies carried out in (1) Cape Town in 2007 and 2008 and (2) Mumbai in 2009

Modellierung des Bruchverhaltens austenitischer TRIP-Stähle

Das Promotionsthema war die numerische Untersuchung des Einflusses der mechanisch induzierten martensitischen Phasenumwandlung auf das Bruchverhalten hochlegierter TRIP-Stähle. Die Analyse der Spannungsfelder vor einer abstumpfenden Rissspitze hat ergeben, dass die Phasenumwandlung zu höheren rissöffnenden Spannungen führt. Außerdem wurden charakteristische Spannungsverläufe mit Wendepunkten beobachtet. Für duktiles Versagen wurde ein positiver Einfluss der Phasenumwandlung geschlussfolgert, da die umwandlungsinduzierte Verfestigung das Porenwachstum in der Bruchprozesszone erschwert. Dies wurde an Hand mikromechanischer Simulationen der duktilen Rissausbreitung demonstriert. Im Rahmen der Theorie materieller Kräfte konnte eine abschirmende Wirkung des TRIP-Effekts auf die Rissspitze nachgewiesen werden. Durch Phasenumwandlung wird Arbeit dissipiert, die nicht mehr für Rissfortschritt verfügbar ist. Die energetische Triebkraft für Risswachstum wird demzufolge reduziert. Die Rissausbreitung im TRIP-Stahl wurde mit einer Kohäsivzone modelliert. Die Parameter des Kohäsivzonenmodells charakterisieren den Bruchprozess und konnten unter Verwendung experimenteller Daten identifiziert werden. Um zukünftig die Rolle der Phasenumwandlung bei Ermüdungsrisswachstum untersuchen zu können, wurde ein Materialmodell für TRIP-Stähle unter zyklischer Beanspruchung entwickelt. Die erforderlichen Materialparameter wurden mit Hilfe der Daten aus Wechselverformungsversuchen bestimmt.This thesis is focused on the numerical investigation of the fracture behavior of high alloy austenitic TRIP-steels and especially on the effect of mechanically induced martensitic phase transformation. The analysis of stress fields in front of a blunting crack tip has shown that phase transformation leads to higher crack opening stresses. Additionally, characteristic courses of the stress components with inflection points were observed. A positive influence of phase transformation on ductile fracture was concluded, because transformation induced hardening retards void growth in the fracture process zone. This was demonstrated by micromechanical simulations of ductile crack extension. In order to investigate the shielding effect of phase transformation on the crack tip, the theory of material forces was applied. Mechanical work is dissipated due to the TRIP-effect, which is no longer available for crack growth. Hence, the energetic driving force for fracture is reduced. Furthermore, crack extension is modeled with a cohesive zone. The parameters of the cohesive zone model, which characterize the fracture process, are identified based on experimental data. In future work the role of phase transformation during fatigue crack growth should by studied. Therefore, a material model for TRIP-steels under cyclic loading was developed. The associated material parameters were estimated based on the results of cyclic deformation experiments

FUNCTIONAL DISSECTION OF THE HISTONE LYSINE DEMETHYLASE JMJD3

Epigenetic control of developmental genes has emerged as a key mechanism in the acquisition of developmental competence. In particular, patterns of methylation at lysine 4 and 27 of histone H3 have been associated, respectively, with states of gene activation and repression that are developmentally regulated and are thought to underlie the establishment of lineage specific gene expression programs. Recent studies have provided fundamental insight into the problem of lineage specification by comparing global changes in chromatin and transcription between embryonic stem cells (ESCs) and neural stems cells (NSCs), points of departure and arrival for neural commitment, respectively. With these maps of the differentiated state in place, a central task is now to unravel the chromatin dynamics that enable these differentiation transitions between pluripotent ESCs and multipotent NSCs. In particular, the observation that lineage-specific genes repressed in ESCs by Polycomb-mediated histone H3 lysine 27 trimethylation (H3K27me3) are demethylated and derepressed in differentiated cells posited the existence of a H3K27-specific demethylase. In order to gain insight into the epigenetic mechanisms that enable lineage specification, we investigated in the first part of this work the early stages of neural commitment using as a model system the neural differentiation of mouse ESCs. Using a comprehensive expression analysis of JmjC genes, we identified Jmjd3 as a H3K27me3 demethylase that is specifically upregulated at the onset of neural differentiation. This study revealed that Jmjd3 controls the expression of key regulators and markers of neurogenesis and is required for commitment to the neural lineage. In the second part of this work, we have used a genetic loss-of-function approach to characterise the role of Jmjd3 in vivo. Mice lacking Jmjd3 die at birth from respiratory failure. A detailed characterisation of this neurodevelopmental phenotype demonstrated that the defect in respiratory rhythmogenesis upon loss of Jmjd3 is due to an abnormal maturation of the preB\uf6tzinger complex (preB\uf6tC), one of the two principal sites generating respiratory rhythm in mammals

Characterization of the in vivo plaque growth kinetics and synaptic pathology with evaluation of an immunotherapeutic approach in an Alzheimer disease mouse model

Morbus Alzheimer ist die häufigste Form einer Demenzerkrankung und stellt aufgrund der steigenden Lebenserwartung eine sehr große ökonomische und emotionale Belastung für Patienten, deren Familien und die gesamte Gesellschaft dar. Eine Verringerung dieser Belastung erfordert dringend krankheitsmodifizierende Therapien, die bisher nicht zur Verfügung stehen. Als wahrscheinlichste Erklärung für die molekularen Ursachen der Krankheit wurde in der Amyloid-Kaskaden-Hypothese postuliert, dass die Akkumulation und Aggregation des Abeta-Peptids das zentrale Ereignis darstellt. Infolgedessen kommt es zu synaptischen Beeinträchtigungen durch Abeta-Oligomere, Entzündungsreaktionen durch unlösliche Abeta-Aggregate in Form von amyloiden Plaques, progressiven Schädigungen von Synapsen und Neuronen, oxidativem Stress, der Hyperphosphorylierung des Mikrotubuli-assoziierten Proteins Tau und einem Neuronenverlust. Das Abeta-Peptid wird durch sequentielle Spaltung des Amyloid-Vorläuferproteins (APP) durch die beta- und gamma-Sekretase konstitutiv im Gehirn produziert. In der vorliegenden Arbeit wurden die Auswirkungen der Überexpression eines humanen APP mit der schwedischen Mutation auf Synapsen und die Akkumulationskinetik des Abeta-Peptids zu amyloiden Plaques in einem Alzheimer-Mausmodell (Tg2576) untersucht. Die detaillierte Charakterisierung des Mausmodells wurde in einer Therapiestudie umgesetzt, in der eine passive Immunisierung gegen das Abeta-Peptid oder Abeta-Oligomere getestet wurde. Im ersten Teil der Arbeit wurde der Einfluss der Überexpression des APP auf dendritische Spines untersucht, die das postsynaptische Kompartiment glutamaterger Synapsen entlang von Dendriten bilden. Als Reporter-Tiere wurden Mäuse verwendet, die das gelbfluoreszierende Protein YFP in einem Teil der pyramidalen Neuronen des Cortex exprimieren. Mithilfe der in vivo Zwei-Photonen-Mikroskopie wurden die denritischen Spines an den apikalen Dendriten der Schicht II/III und V Neurone im somatosensorischen Cortex analysiert. Die Überexpression des APP führte zu einem differentiellen Effekt, wobei in Schicht II/III Neuronen keine Änderung und in Schicht V Neuronen eine Erhöhung der Dichte dendritischer Spines gemessen wurde. Eine detaillierte Charakterisierung zeigte eine Mehrzahl an stabilen Spines als ursächlich für die erhöhte Spinedichte, während keine zeitliche Änderung der Spinedichte über sechs Wochen detektiert wurde. Auch die Morphologie der dendritischen Spines war unverändert. Diese Ergebnisse deuten auf eine mögliche physiologische Rolle von APP und/oder dessen proteolytische Fragmente an Synapsen. Ein wichtiges neuropathologisches Merkmal von Morbus Alzheimer sind amyloide Plaques, die durch Aggregation des Abeta-Peptids zu Amyloidfibrillen mit einer gekreuzten beta-Faltblattstruktur entstehen. Demzufolge wurde im zweiten Teil der vorliegenden Arbeit mithilfe der in vivo Zwei-Photonen-Mikroskopie, unter der wiederholten Anwendung des spezifischen fluoreszenten Markers Methoxy-X04, die Entstehungs- und Aggregationskinetik amyloider Plaques untersucht. Eine quantitative Auswertung von Plaquegrößen, -wachstumsraten und -dichten in zwei Altersgruppen der frühen und späten amyloiden Pathologie führte zur bisher detailliertesten in vivo Charakterisierung in einem Alzheimer-Mausmodell. Für eine präzise Messung der Plaquedichten wurde ein sehr großes Gehirnvolumen von 3 Kubikmillimeter pro Gruppe untersucht. In einem Langzeitversuch über 15,5 Monate mit einer zeitlichen Auflösung von einer Woche wurde erstmals eine komplette Kinetik des Plaquewachstums in einem Mausmodell beschrieben, die den gleichen Verlauf einer Sigmoid-Funktion aufwies, wie er bereits in vitro und in Alzheimer-Patienten gezeigt wurde. Die Plaquedichte stieg asymptotisch mit dem Alter an und folgte einer exponentiellen, einphasigen Assoziationsfunktion. Neu entstandene Plaques wiesen mit Abstand die kleinste Plaquegröße auf, die mit zunehmendem Alter anstieg. Die lineare Plaquewachstumsrate, gemessen als Zuwachs des Plaqueradius pro Woche, sank mit ansteigendem Alter der Mäuse, was sich in einer negativen Korrelation der Plaquewachstumsrate mit der Plaquedichte widerspiegelte. Sehr große Plaques wurden früh in der Entstehungsphase gebildet und die Größe am Ende der Untersuchung korrelierte mit ihrer Wachstumsrate. In der frühen Phase der Plaqueentwicklung nahmen die Plaques mit einer maximalen Wachstumsrate zu, die nicht durch die Abeta-Konzentration limitiert war. Die Wachstumsraten individueller Plaques waren sehr breit verteilt, was auf einen Einfluss lokaler Faktoren schließen ließ. Dieser Befund wurde gestützt durch den Langzeitversuch, da kein Zusammenhang zwischen den Wachstumsraten benachbarter Plaques detektiert wurde. Die Ergebnisse dieser Studie zeigen ein physiologisches Wachstumsmodell, in dem Plaques sehr langsam über große Zeiträume wachsen bis zum Erreichen eines Äquilibriums. Durch die nachgewiesenen Parallelen zu den Befunden von in vitro Studien und in vivo Ergebnissen von Alzheimer-Patienten stellen die beschriebenen Zusammenhänge eine wertvolle Grundlage für die Translation von Ergebnissen zwischen präklinischer und klinischer Forschung zur Entwicklung von Abeta-senkenden Therapien dar. Im dritten Teil der Arbeit wurden die Effekte einer passiven Immunisierung gegen das Abeta-Peptid oder Abeta-Oligomere untersucht. Nach einer zweimonatigen Antikörper-Behandlung wurden keine Unterschiede in der Plaqueentstehungs- und Plaquewachstumskinetik gemessen. Eine in der Literatur beschriebene Akkumulation von Abeta-Oligomeren konnte durch eine in vivo Visualisierung mit einem hochspezifischen Antikörper gegen diese Molekülspezies nicht bestätigt werden. Lösliche Abeta-Peptide oder Abeta-Aggregate akkumulierten erwartungsgemäß um den amyloiden Kern von Plaques. Am Ende der Immunisierungsstudie wurde die synaptische Pathologie mittels immunhistochemischer Färbung der Prä- und Postsynapsen mit den Markern Synapsin und PSD-95 untersucht. Innerhalb amyloider Plaques wurden sehr niedrige Synapsendichten gemessen, die mit zunehmender Entfernung zum Plaque asymptotisch zu einem Plateau anstiegen. Diese Analyse zeigte erstmals, dass der Einflussbereich der toxischen Wirkung amyloider Plaques für Präsynapsen wesentlich größer ist als für Postsynapsen, was auf eine höhere Sensibilität von Präsynapsen schließen lässt. Abseits von Plaques im Cortex waren die Synapsendichten niedriger im Vergleich zu Wildtyptieren, wie durch den Vergleich der Plateaus gemessen wurde. Beide therapeutischen Antikörper zeigten eine partielle Normalisierung der Synapsendichte. Daraus folgt, dass die Abeta-Oligomere ursächlich für die Synapsenpathologie waren, da eine spezifische Neutralisierung dieser Abeta-Aggregate für einen Therapieeffekt ausreichte. Diese Ergebnisse bestätigen in vivo die toxische Wirkung von Abeta-Oligomeren auf Synapsen und beweisen eine mögliche Neutralisierung dieser löslichen Abeta-Aggregate durch eine passive Immunisierung.Alzheimer’s disease (AD) is the most common form of dementia implying big economical and emotional burden for patients, their families and the whole economy due to a generally rising life expectancy. A reduction of costs and stress urgently requires disease-modifying therapies which are currently still lacking. Maybe the most accurate explanation for the molecular cause of the disease is reflected in the amyloid-cascade hypothesis, postulating the accumulation and aggregation of the Abeta peptide as central pathogenic event. Hence, synaptic pathology caused by Abeta oligomers, inflammatory reactions due to insoluble Abeta aggregates, namely amyloid plaques, progressive damage of synapses and neurons, oxidative stress, hyperphosphorylisation of the microtubule-associated protein tau, and finally neuron loss commonly occur as a result. Moreover, the Abeta peptide is constitutively produced in the brain by sequential cleavage of the amyloid precursor protein (APP) by beta- and gamma-secretase enzymes. In the present work, I studied the effects of human APP overexpression (with a Swedish mutation) on both synapses and the accumulation kinetics of amyloid plaque formation in a mouse model of Alzheimer’s disease (Tg2576). This detailed characterization of the mouse model was then further utilized in a therapeutic study testing the passive immunization against the Abeta-peptide or Abeta oligomers. In the first part of this work, I investigated the effects of APP overexpression on dendritic spines forming the postsynaptic compartment of glutamatergic synapses on dendrites. As reporter animals, mice expressing the yellow-fluorescent protein YFP in a subset of cortical pyramidal neurons were used. Two-photon microscopy enabled the elaborate in vivo analysis of dendritic spines on apical dendrites of layer II/III and V neurons in the somatosensory cortex. Overexpression of APP induced a locally differential effect on the spine density with no changes being observed in layer II/III yet increased spine numbers calculated in layer V neurons. A more detailed characterization revealed a majority of stable spines as responsible for the rise in spine densities; however, no further changes in the spine count were detected over a period of six weeks. Moreover, dendritic spine morphology was also unaltered. Summarized, these results hint to a possible physiological role of APP and/or its proteolytic fragments at the synapse. Amyloid plaques, one of the two characteristic neuropathological hallmarks of AD, are generated by aggregation of the Abeta peptide into amyloid fibrils with a crossed beta-sheet structure. Thus, in the second part of this work, the formation and aggregation kinetics of amyloid plaques were measured by means of in vivo two-photon microscopy and repeated use of the fluorescent marker methoxy-X04. Such extensive quantitative analysis of plaque sizes, plaque growth rates and plaque densities as performed for two different age groups, depicting models for early and late stage AD pathology, allowed the most detailed in vivo characterization so far. For a precise measurement of plaque densities, in each group I analysed large brain volumes of 3 cubic millimeters. Interestingly, the complete range of plaque growth kinetics as imaged in a weekly interval for over 15,5 month showed the same trend like that of a sigmoid function, a finding that accords with in vitro studies and AD patients. Moreover, the plaque densities increased asymptotically with higher age and followed an exponential, one-phase association function. Newly-formed plaques showed by far the smallest plaque size, which also continued to rise upon ageing. In contrast, the linear plaque growth rate, measured as weekly increase in the plaque radius, decreased with increasing age of the animal. This finding was also reflected in a negative correlation between plaque growth rate and plaque density. In addition, huge plaques were produced early in the developmental phase, and the final size they reached at the end of the experiment correlated with the plaque growth rate. In the early phase of plaque formation, the plaques expanded with a maximal growth rate that was not limited by the Abeta concentration. Furthermore, the growth rates of individual plaques were widely distributed assuming the influence of local factors. This finding was supported by the long-term study over 15,5 months showing no correlation between the growth rates of neighbouring plaques. Conclusively, the results of this investigation demonstrate a growth model, in which plaques grow very slowly over longer periods until they reach equilibrium. Thus, both the described relationships and verified parallels to in vitro studies and findings in AD patients shape an important basis for the translation of results between preclinical and clinical research and for the final development of Abeta-lowering therapies. In the third part of this thesis, I analysed the effects of a passive immunization against Abeta peptides or Abeta oligomers. A two-month long antibody treatment did neither affect the plaque formation nor its growth kinetics. Moreover, Abeta oligomer assemblies as described previously in literature were not detected using in vivo visualization with a highly specific antibody against these molecular species. Instead, soluble Abeta peptides or Abeta aggregates accumulated around the plaque core as expected. At the end of the immunization study, the synaptic pathology was analysed by immunohistochemical stainings of pre- and postsynapses using the markers synapsin and PSD-95. Here, very low synapse densities were measured inside amyloid plaques, which increased asymptotically until culmination of a plateau. This analysis showed for the first time that the influenced area of toxic effects of amyloid plaques is higher for presynapses than for postsynapses, suggesting a higher sensitivity of presynapses. Apart from plaques, the synapse densities were lower in AD mice compared to wild-type animals as identified by comparison of the estimated plateaus. Both therapeutic antibodies showed a partial normalization of the synapse density. Thus, Abeta oligomers were likely causative for the synapse pathology since the specific neutralization of Abeta aggregates sufficiently achieved a therapeutic effect. In summary, these findings verify the toxic effect of Abeta oligomers on synapses in vivo and support a possible neutralization of soluble Abeta aggregates by passive immunization

Cortical circuit alterations precede motor impairments in Huntington's disease mice

Huntington's disease (HD) is a devastating hereditary movement disorder, characterized by degeneration of neurons in the striatum and cortex. Studies in human patients and mouse HD models suggest that disturbances of neuronal function in the neocortex play an important role in disease onset and progression. However, the precise nature and time course of cortical alterations in HD have remained elusive. Here, we use chronic in vivo two-photon calcium imaging to longitudinally monitor the activity of identified single neurons in layer 2/3 of the primary motor cortex in awake, behaving R6/2 transgenic HD mice and wildtype littermates. R6/2 mice show age-dependent changes in cortical network function, with an increase in activity that affects a large fraction of cells and occurs rather abruptly within one week, preceeding the onset of motor defects. Furthermore, quantitative proteomics demonstrate a pronounced downregulation of synaptic proteins in the cortex, and histological analyses in R6/2 mice and human HD autopsy cases reveal a reduction in perisomatic inhibitory synaptic contacts on layer 2/3 pyramidal cells. Taken together, our study provides a time-resolved description of cortical network dysfunction in behaving HD mice and points to disturbed excitation/inhibition balance as an important pathomechanism in HD

In vivo imaging reveals sigmoidal growth kinetic of β-amyloid plaques

A major neuropathological hallmark of Alzheimer's disease is the deposition of amyloid plaques in the brains of affected individuals. Amyloid plaques mainly consist of fibrillar β-amyloid, which is a cleavage product of the amyloid precursor protein. The amyloid-cascade-hypothesis postulates Aβ accumulation as the central event in initiating a toxic cascade leading to Alzheimer's disease pathology and, ultimately, loss of cognitive function. We studied the kinetics of β-amyloid deposition in Tg2576 mice, which overexpress human amyloid precursor protein with the Swedish mutation. Utilizing long-term two-photon imaging we were able to observe the entire kinetics of plaque growth in vivo. Essentially, we observed that plaque growth follows a sigmoid-shaped curve comprising a cubic growth phase, followed by saturation. In contrast, plaque density kinetics exhibited an asymptotic progression. Taking into account the fact that a critical concentration of Aβ is required to seed new plaques, we can propose the following kinetic model of β-amyloid deposition in vivo. In the early cubic phase, plaque growth is not limited by Aβ concentration and plaque density increases very fast. During the transition phase, plaque density stabilizes whereas plaque volume increases strongly reflecting a robust growth of the plaques. In the late asymptotic phase, Aβ peptide production becomes rate-limiting for plaque growth. In conclusion, the present study offers a direct link between in vitro and in vivo studies facilitating the translation of Aβ-lowering strategies from laboratory models to patients

Long-term in vivo imaging of fibrillar tau in the retina of P301S transgenic mice.

Tauopathies are widespread neurodegenerative disorders characterised by the intracellular accumulation of hyperphosphorylated tau. Especially in Alzheimer's disease, pathological alterations in the retina are discussed as potential biomarkers to improve early diagnosis of the disease. Using mice expressing human mutant P301S tau, we demonstrate for the first time a straightforward optical approach for the in vivo detection of fibrillar tau in the retina. Longitudinal examinations of individual animals revealed the fate of single cells containing fibrillar tau and the progression of tau pathology over several months. This technique is most suitable to monitor therapeutic interventions aimed at reducing the accumulation of fibrillar tau. In order to evaluate if this approach can be translated to human diagnosis, we tried to detect fibrillar protein aggregates in the post-mortem retinas of patients that had suffered from Alzheimer's disease or Progressive Supranuclear Palsy. Even though we could detect hyperphosphorylated tau, we did not observe any fibrillar tau or Aß aggregates. In contradiction to previous studies, our observations do not support the notion that Aβ or tau in the retina are of diagnostic value in Alzheimer's disease

Cruciform specimens used for determination of the influence of T-stress on fatigue crack growth with overloads on aluminum alloy Al 6061 T651

The publication presents a cruciform specimen for the determination of cyclic crack growth data under biaxial loading. The design of the specimen with slotted loading arms allows good decoupling between the two loading directions. For different initial crack geometries, the solutions for the stress intensity factors KI and KII as well as the crack-parallel T-stress are calculated by linear elastic finite element analysis (FEA) with the program ABAQUS. For two specimens with the same geometry made of aluminum alloy 6061 T651, the crack growth behaviour is measured at different T-stresses at a stress ratio of R=0.7 and overloads. It is shown that the crack retardation after an overload with crack-parallel tensile stress is less than without it. The reason for this behaviour is considered to be the reduced plasticity at the crack tip due to the higher triaxiality of the stress state