Property screening of porous organic molecules

Porous organic molecules have internal pores readily occupied by gases, solvent or other guests. These molecules can form porous molecular materials with possible application in storage and separation. In this thesis, the properties of isolated porous organic molecules are used as a proxy to the bulk or in-solution applications. As a result, software was first developed for the automated and precise structural characterisation of porous organic molecules. This allows one to easily calculate window diameters to study the thermal window size fluctuations and predict guest diffusion in the bulk. A screening of previously reported porous organic molecules for the application of Xe/Kr separation allowed the most promising material, Noria, to be identified. This was possible with a combination of molecular modelling, electronic structure calculations and structural analysis using the developed software. The experimental Xe/Kr selectivity of Noria, not previously considered for this application, was shown to be comparable with the best performing porous materials. Next, eight synthetically realised porous organic cages were studied as possible C60 fullerene encapsulants. The relative orientation of the C60 fullerene in the pore was shown to have little to no effect on the binding energy and the encapsulation of the C60 during cage formation was determined as the likely mechanism of encapsulation. Lastly, a function-led material design approach was developed. An evolutionary algorithm was used to generate possible C60 encapsulants from a database of precursors. The resulting porous organic cages are structurally similar to some recently synthetically realised cages and some found in the literature. In summary, presented in this thesis is software, a methodology and results that can further advance the computational function-led materials discovery for specific applications.Open Acces

Dysfunktion von Signalweginteraktionen in der hippocampalen CA1-Region in einem Mausmodell der Alzheimer-Krankheit

Die Alzheimer-Krankheit gewinnt in unserer alternden Gesellschaft zunehmend an Bedeutung. Schon in frühen Krankheitsstadien zeigen Alzheimer-Patienten Einbußen in der episodischen Gedächtnisleistung sowie eine topographische Desorientiertheit (Walker et al., 2007). Bislang ist nicht bekannt, welche Mechanismen auf hippocampaler Schaltkreis-Ebene zu der eingeschränkten Gedächtnisleistung und kognitiven Dysfunktion bei Alzheimer-Patienten führen. Ziel dieser Dissertationsarbeit war die Identifikation möglicher funktioneller Defizite von synaptischen Schaltkreisen in der hippocampalen CA1-Region des APP/PS1-Mausmodells der Alzheimer-Erkrankung mit zuverlässiger cerebraler Amyloidplaqueablagerung. Hierfür nutzten wir die Technik des Voltage Sensitive Dye Imaging. Zunächst wurde untersucht, ob ein Missverhältnis zwischen Exzitation und Inhibition vorliegt. Ferner gingen wir der Frage nach, inwieweit die räumliche Ausbreitung von Erregung und Inhibition verändert ist. Schließlich untersuchten wir, ob das Zusammenspiel der zwei Hauptinformationszuflüsse (via Schaffer Kollateralen und temporoammonischem Pfad) in der hippocampalen CA1-Region in Anwesenheit von Amyloidplaques gestört ist. In unseren Experimenten konnten wir eine verminderte sowohl vorwärts als auch rückwärts gerichtete Inhibition in Stratum Radiatum und Stratum Oriens der hippocampalen CA1-Region nachweisen. Hieraus resultierte eine Dysbalance zwischen Exzitation und Inhibition. Zudem fanden wir eine gesteigerte räumliche Ausbreitung der Exzitation. Schließlich konnten wir eine gestörte Interaktion zwischen intra- und extrahippocampalem Input von Schaffer Kollateralen und temporoammonischem Pfad in der CA1-Region nachweisen, welche vermutlich auf einer defizitären inhibitorischen Disinhibition beruht und den Verlust eines wichtigen integrativen Mechanismus in dieser für die Gedächtnisbildung entscheidenden Hirnregion darstellt

Computational evaluation of the diffusion mechanisms for C8 aromatics in porous organic cages

The development of adsorption and membrane-based separation technologies toward more energy and cost-efficient processes is a significant engineering problem facing the world today. An example of a process in need of improvement is the separation of C8 aromatics to recover para-xylene, which is the precursor to the widely used monomer terephthalic acid. Molecular simulations were used to investigate whether the separation of C8 aromatics can be carried out by the porous organic cages CC3 and CC13, both of which have been previously used in the fabrication of amorphous thin-film membranes. Metadynamics simulations showed significant differences in the energetic barriers to the diffusion of different C8 aromatics through the porous cages, especially for CC3. These differences imply that meta-xylene and ortho-xylene will take significantly longer to enter or leave the cages. Therefore, it may be possible to use membranes composed of these materials to separate ortho- and meta-xylene from para-xylene by size exclusion. Differences in the C8 aromatics’ diffusion barriers were caused by their different diffusion mechanisms, while the lower selectivity of CC13 was largely down to its more significant pore breathing. These observations will aid the future design of adsorbents and membrane systems with improved separation performance

Porous organic cages for sulfur hexafluoride separation

A series of porous organic cages is examined for the selective adsorption of sulfur hexafluoride (SF6) over nitrogen. Despite lacking any metal sites, a porous cage, CC3, shows the highest SF6/N2 selectivity reported for any material at ambient temperature and pressure, which translates to real separations in a gas breakthrough column. The SF6 uptake of these materials is considerably higher than would be expected from the static pore structures. The location of SF6 within these materials is elucidated by X-ray crystallography, and it is shown that cooperative diffusion and structural rearrangements in these molecular crystals can rationalize their superior SF6/N2 selectivity

Reducing tau aggregates with anle138b delays disease progression in a mouse model of tauopathies.

Pathological tau aggregation leads to filamentous tau inclusions and characterizes neurodegenerative tauopathies such as Alzheimer's disease and frontotemporal dementia and parkinsonism linked to chromosome 17. Tau aggregation coincides with clinical symptoms and is thought to mediate neurodegeneration. Transgenic mice overexpressing mutant human P301S tau exhibit many neuropathological features of human tauopathies including behavioral deficits and increased mortality. Here, we show that the di-phenyl-pyrazole anle138b binds to aggregated tau and inhibits tau aggregation in vitro and in vivo. Furthermore, anle138b treatment effectively ameliorates disease symptoms, increases survival time and improves cognition of tau transgenic PS19 mice. In addition, we found decreased synapse and neuron loss accompanied by a decreased gliosis in the hippocampus. Our results suggest that reducing tau aggregates with anle138b may represent an effective and promising approach for the treatment of human tauopathies