Properties of Nucleosyl Amino Acid-Modified Oligonucleotides

Antisense technology has the potential to evolve into a powerful biomedical tool. By utilizing the unique hybridization behavior of antisense oligonucleotides (ON) the antisense approach facilitates a specific intervention in cellular processes that would be barely feasible by using conventional drugs. However, the tremendous potential that comes with the antisense strategy is paired with the insufficient pharmacokinetic profile of native DNA ONs. Thus, an overall low stability in vivo as well as limited cellular uptake due to the extremely polar DNA structure, represent two of the main obstacles. Consequently, alterations of the native DNA structure are required to obtain applicable, drug-like substances. The reported work focuses on the synthesis and evaluation of modified ONs carrying the nucleosyl amino acid (NAA)-modification, a peptide-like internucleoside structure featuring a free amino group, within their backbone. Part A of this thesis concentrates on the biological stability of partially zwitterionic NAA-modified ONs in the presence of 3'→5'- and 5'→3'-exonucleases as well as human plasma and whole cell lysate. In part B, the hybridization properties of cationic, fully NAA-modified ONs in presence of matched and mismatched counterstrands were analyzed and validated. Finally, part C focuses on the synthesis and evaluation of a chimeric NAA/LNA-gapmer structure with the aim to obtain a selective, high-affinity precursor of an antisense ON.Die Antisense-Technologie hat das Potenzial, sich zu einem leistungsfähigen biomedizinischen Werkzeug zu entwickeln. Durch die Nutzung des einzigartigen Hybridisierungsverhaltens von Antisense-Oligonucleotiden (ON) ermöglicht sie einen gezielten Eingriff in zelluläre Prozesse, der mit herkömmlichen Methoden kaum durchführbar wäre. Das enorme Potenzial, das mit dem Antisense-Ansatz einhergeht, ist jedoch an das unzureichende pharmakokinetische Profil nativer DNA-ON geknüpft. Hierbei stellen eine insgesamt geringe in-vivo-Stabilität sowie eine erschwerte zelluläre Aufnahme aufgrund der polaren DNA-Struktur zwei der Hauptprobleme dar. Folglich sind Veränderungen der nativen DNA-Struktur erforderlich, um applizierbare Substanzen zu erhalten. Daher konzentriert sich die folgende Arbeit auf die Synthese und Evaluierung modifizierter ON, die in ihrem Rückgrat die Nucleosylaminosäure-(NAA)-Modifikation, eine peptidähnliche Internucleosid-Struktur mit einer freien Aminogruppe, tragen. Teil A dieser Arbeit befasst sich mit der biologischen Stabilität von teilweise zwitterionischen NAA-modifizierten ON in Gegenwart von 3'→5'- und 5'→3'-Exonukleasen sowie humanem Plasma und Zelllysat. In Teil B wurden die Hybridisierungseigenschaften von kationischen, vollständig NAA-modifizierten ON analysiert und validiert. Zuletzt befasst sich Teil C mit der Synthese und Untersuchung einer chimären NAA/LNA-Gapmer-Struktur mit dem Ziel, eine selektive, hochaffine Vorstufe eines Antisense-ON zu erhalten

The resistivity switching of iron doped strontium titanate single crystals and thin films

The main objective of this work was to identify and understand the physical mechanisms underlying the phenomenon of the RS in the Fe doped SrTiO3 material. Two basic types of materials were investigated: the single crystals and thin lms. The main reason for this approach was to obtain the information about both: the fundamental physics (single crystals) and the material more suited for the applications (thin lms). The samples with di erent iron concentrations, were modi ed by the temperature, electric eld and chemical gradients. Resulting changes were investigated by a number of techniques that are characteristic to the solid state physics in the macro- and nano- scales. Completed studies have shown that: Crystallographic structure of the starting crystals was in good agreement with the literature. Surprisingly high level of the Fe concentration variation, even for the relatively low Fe doping, was found. Local conductivity in nanoscale showed characteristic conducting stripes, not observed previously. Fe valence state was found to be a mixture of 2+ and 3+, contrary to the most of the reports on similar systems. Moderately high temperature treatment under oxidizing and reducing conditions led to huge chemical modi cation of the crystal surface, including formation of new phases and the decomposition of STO phase. High mobility of the Fe ions above 700 C allowed for signi cant iron migration and preferential atoms localization (close to the extended defects). Especially interesting is that the crystals exposed to the high temperaturę under various conditions undergone transformation and decomposition to other phases. This remains in the contrary to conventional model, where only the oxygen content in the form of SrTiO3 was changing. Moreover, the a nity of the Fe ions to locate close to the extended defects was shown, as an formation of lament like Fe structure. The nanoscale RS behavior was also evident and did not di er signi cantly from the behavior in the undoped STO crystals. It was concluded, that the basic mechanism of RS in Fe doped STO is not in uenced by the iron doping. Similar results can be observed under the electrical stress. The electroformation and subsequent electro-coloration phenomena were investigated. The most prominent results showed: Electrical stimuli led to the I-M transition. I-M transition was connected to changes in the oxygen vacancy concentration and the movement of the oxigen ions along the extended defect network. Evolution of the color front was documented, and compared to the removal of oxygen ions from the material. Total number of the oxygen ions removed from the material during electroreduction experiment was estimated. RS behavior was found and measured both in macro- and nano-scales. Fast reaction of the electrical behavior to the surrounding atmosphere conrmed, that the oxygen can be removed and introduced to the system quite easily. Strong connection between the evolution of the color front and the electrical properties of the samples were shown. Also the fact that the Fe doped STO crystal is in fact 'open' to the removal and introduction of the oxygen ions from the surrounding atmosphere was found. The investigation of the thin lms yielded promising results, especially in the similarities with the single crystal behavior. The most interesting ndings consist of: Many hints that the Fe ions were inhomogeneously distributed in the STO matrix was found. Fe was found to be very mobile and typically was found to migrate away from the surface into the bulk. High susceptibility of the electrical parameters to the electrical stress led to high variation in the measured activation energy values. The RS behavior was con rmed and no clear voltage threshold for the set and reset voltage was found (up to several mV). This results showed many similarities of the STO thin lm and single crystals behavior. It seems possible to maintain good single crystal properties in more applicative thin lms. What is more, the pursue for the 'perfect' or defect-free thin lms is not always necessary, since it can be bene cial for the RS materials to posses slightly di erent structure or defect concentration. Nevertheless, there is still a long way from the basic investigations and prototypes to the commercial applications. It is also important to be more careful measuring the electrical properties of the RS material, since the properties of the investigated material can change during the experiment itself, leading to unreliable results. Outlook Investigation presented in this work showed that the RS is complicated phenomena. The complexity of the RS even increases, when one moves his attention from the macroscale, typically used to describe the properties of the materials, into nanoscale. In many cases, only the nanoscale experiments can provide crucial data necessary for better understanding of the fundamental physics. What is more, the observations in nano-scale clearly shows that the perfect crystals are really not so perfect as one could expect, which is strongly connected to structure defects and inhomogeneity of the dopant. The knowledge of the imperfection and the real state of the materials is not only useful from the fundamental point of view. I strongly believe it is necessary for the future investigation and the development of new technologies. As the case of the STO (and the Fe doped STO) shows, the extended defects, such as dislocations, are crucial for the RS behavior. Therefore a careful investigations, mostly in nanoscale, can provides the ideas and the means to exploit the defects and imperfections for the bene t of new materials with outstanding properties

Computational complexity of the semantics of some natural language constructions

AbstractWe consider an example of a sentence which according to Hintikka's claim essentially requires for its logical form a Henkin quantifier. We show that if Hintikka is right then recognizing the truth value of the sentence in finite models is an NP-complete problem. We discuss also possible conclusions from this observation

Model Informed Drug Development and Precision Dosing for Drug-Drug-Gene-Interactions: Application of Physiologically-Based Pharmacokinetic Modeling

The global demand for pharmaceuticals is continuously growing. As a result, one can observe an increase in adverse drug reactions, which pose a critical risk to patients. The primary triggers for adverse drug reactions are drug-drug- and drug-gene-interactions. Model-informed drug discovery and development as well as model-informed precision dosing can help to mitigate the risks of drug-drug and drug-gene interactions. Thus, this work aimed to improve and to apply physiologically-based pharmacokinetic modeling strategies in the context of model-informed drug discovery and development as well as model-informed precision dosing. For this purpose, best practices for data digitization as an essential step in the development process of most physiologically-based pharmacokinetic models have been established. Moreover, models for zoptarelin doxorubicin and simvastatin were developed and evaluated. The zoptarelin doxorubicin model was used to guide the development process of this drug. In contrast, the simvastatin model was utilized in a drug-drug-gene interaction network to generate 10368 dose recommendations for different interaction scenarios, which were made available in a digital decision support system. In conclusion, the work can be seen as a beacon project to illustrate how physiologically-based pharmacokinetic modeling of drug-drug and drug-gene interactions can be applied in model-informed drug discovery and development as well as in model-informed precision dosing.Der globale Arzneimittelbedarf steigt kontinuierlich an. Infolgedessen kommt es vermehrt zu unerwünschten Arzneimittelwirkungen, die eine Gefahr für Patienten darstellen. Eine wichtige Rolle beim Auftreten unerwünschter Arzneimittelwirkungen spielen Arzneimittel-Arzneimittel- und Arzneimittel-Gen-Wechselwirkungen. Um das Risiko solcher Wechselwirkungen zu minimieren, kann die modellgestützte Arzneimittelentwicklung und Präzisionsdosierung angewendet werden. Das Ziel dieser Arbeit war es, physiologie-basierte pharmakokinetische Modelle zum Zweck der modellgestützten Arzneimittelentwicklung und Präzisionsdosierung einzusetzen. Dafür wurde die Datendigitalisierung als wesentlicher Bestandteil der Entwicklung neuer physiologie-basierter pharmakokinetischer Modelle untersucht. Außerdem wurden Modelle für Zoptarelin Doxorubicin und Simvastatin entwickelt. Das Zoptarelin Doxorubicin Modell wurde verwendet, um die Entwicklung dieses Medikaments zu unterstützen. Mittels des Simvastatin Modells wurden in einem Interaktionsnetzwerk 10368 Dosisempfehlungen für verschiedene Szenarien generiert und in einem digitalen Entscheidungsunterstützungssystem verfügbar gemacht. Zusammenfassend kann die Arbeit als Leuchtturmprojekt gesehen werden, das zeigt, wie die physiologie-basierte pharmakokinetische Modellierung von Arzneimittel-Arzneimittel- und Arzneimittel-Gen-Wechselwirkungen in der modellgestützte Arzneimittelentwicklung und Präzisionsdosierung angewendet werden kann

Stability of ferrous fumarate in medicaments for women : application of Mossbauer spectroscopy

Determination of the iron state (Fe2+ or Fe3+) and content of iron in commercial pharmaceutical products containing ferrous fumarate FeC4H2O4 was made by the Mössbauer spectroscopy and X-ray fluorescence method. Also, influence of thermal treatment on stability of ferrous fumarate in selected medicaments has been investigated. The investigated samples were annealed in definite temperature: 373, 473, and 573 K for 5 h. Room temperature Mössbauer spectra of initial samples gave clear evidence that two phases of iron were presented. The major component was connected with ferrous fumarate with a contribution from 85% to 50%, depending on investigated medicaments. Ferrous fumarate was stable up to annealing temperature 473 K. Above this temperature significant oxidation of Fe2+ to Fe3+ was observed

ДВОРЯНСТВО ЛІВОБЕРЕЖНОЇ УКРАЇНИ І ЛІТЕРАТУРА ДРУГОЇ ПОЛОВИНИ XIX –ПОЧАТКУXX СТ.

В статті розглядається внесок представників дворянських родів Лівобережної України в розвитоклітератури пореформенного періоду. Окреслено основні їх здобутки та подана коротка характеристика літературних розвідок .Стороженка О.П., Ганни Барвінок, Марка Вовчка, СтарицькогоМ.П.. та ін.In the article payment of representatives of the Left-bank nobility is examined in development of literature of poreformennogoperiod.Outlined their basic achievements and short descriptionof literary secret services of .StorozhenkoO. P.,Hanna Barvinok,MarkVovchka, StarickogoM. but insh

Contribution of avoidable causes of death to premature mortality in Poland and selected European countries

Our study, availing the new, agreed by the OECD and Eurostat, lists of preventable and treatable causes of death, seeks to quantify the contribution of avoidable causes to premature mortality and its dynamics in Poland and Central European countries – Czechia, Hungary, Lithuania and Slovenia, in comparison with Sweden serving as a benchmark country in 1999–2017. We calculated age standardised death rates for the broad groups of avoidable causes and more specific ones, which comprised preventable and treatable cancer and diseases of the circulatory system (DCS), preventable injuries and alcohol-related diseases. Deaths from not avoidable causes were also analysed. The analysis of time trends in the death rates and calculation of the Average Annual Percent Change (AAPC) for the overall trend were performed with joint-point models. The contribution of changes in mortality from avoidable causes to increase life expectancy during 1999–2017 and contribution of the difference in mortality from these causes to the difference in life expectancy between five countries and Sweden were based on the decomposition of temporary life expectancy between birth and age 75 [e(0-75)]. For the calculation of life expectancy, we used the classic Chiang method and the decomposition of life expectancy by the death causes and age was conducted with the Arriaga method. The AAPC of death rates from avoidable causes in 1999–2017 was similar in all the countries but Lithuania, where the decline started later. The decline in the death rates from not avoidable causes is much slower than the rates from avoidable causes. Mortality from treatable causes was decreasing faster than from preventable causes in most populations. In 1999–2017, the average rate of mortality decline for preventable cancer was greater among men than among women, while for treatable cancer the sex-related differences were much smaller and in favour of women. As for preventable and treatable death from DCS, their decrease was faster among women than men in all the countries but Sweden. Improvements in mortality from causes that could be avoided through prevention or treatment made substantial positive contributions to the overall change in life expectancy in all the countries. The differences in temporary life expectancy e(0-75) between the analysed Central European countries and Sweden were much smaller in 2017 than in 1999, due to the reduction of the gap in mortality from avoidable causes. Our results show that among men, and to a lesser extent among women, mortality from preventable causes contributes more than mortality from causes that can be effectively treated to shorter life expectancy in the countries of Central Europe than in Sweden. This indicates that in reducing the health gap between the inhabitants of Central Europe and Western Europe, the healthcare system should consider disease prevention even to a greater extent than just treating them

Effect of epoxy and polyurethane coating modification with nanofillers on their resistance to erosive wear

The paper presents investigation results of the effect of epoxy and polyurethane coating modification with three kinds of nanofillers on the resistance to erosive wear. Particles of granulated alundum of grain size 0,6-0,7 mm were used as the abrasive material. They fall freely from the height of 0,94 m and impact the coating surface at an angle of 45°. All polyurethane coatings modified with nanofillers showed higher resistance to erosive wear than the unmodified coatings, regardless of the applied nanofiller. However, the nanofiller modified epoxy coatings showed lower resistance to erosive wear than the unmodified ones