Analysis and Numerics of Stochastic Gradient Flows

In this thesis we study three stochastic partial differential equations (SPDE) that arise as stochastic gradient flows via the fluctuation-dissipation principle. For the first equation we establish a finer regularity statement based on a generalized Taylor expansion which is inspired by the theory of rough paths. The second equation is the thin-film equation with thermal noise which is a singular SPDE. In order to circumvent the issue of dealing with possible renormalization, we discretize the gradient flow structure of the deterministic thin-film equation. Choosing a specific discretization of the metric tensor, we resdiscover a well-known discretization of the thin-film equation introduced by Grün and Rumpf that satisfies a discrete entropy estimate. By proving a stochastic entropy estimate in this discrete setting, we obtain positivity of the scheme in the case of no-slip boundary conditions. Moreover, we analyze the associated rate functional and perform numerical experiments which suggest that the scheme converges. The third equation is the massive $\varphi^4_2$-model on the torus which is also a singular SPDE. In the spirit of Bakry and Émery, we obtain a gradient bound on the Markov semigroup. The proof relies on an $L^2$-estimate for the linearization of the equation. Due to the required renormalization, we use a stopping time argument in order to ensure stochastic integrability of the random constant in the estimate. A postprocessing of this estimate yields an even sharper gradient bound. As a corollary, for large enough mass, we establish a local spectral gap inequality which by ergodicity yields a spectral gap inequality for the $\varphi^4_2$- measure

Fast calculation of real fluid properties for steam turbine CFD analysis with the new IAPWS standard on the spline-based table look-Up method (SBTL)

Workshop byl částečně podpořen projektem CZ.1.07/2.3.00/20.0139. Tento projekt je spolufinancován Evropským sociálním fondem a státním rozpočtem České republiky

4-Arylthieno[2,3-b]pyridine-2-carboxamides Are a New Class of Antiplasmodial Agents

Malaria causes hundreds of thousands of deaths every year, making it one of the most dangerous infectious diseases worldwide. Because the pathogens have developed resistance against most of the established anti-malarial drugs, new antiplasmodial agents are urgently needed. In analogy to similar antiplasmodial ketones, 4-arylthieno[2,3-b]pyridine-2-carboxamides were synthesized by Thorpe-Ziegler reactions. In contrast to the related ketones, these carboxamides are only weak inhibitors of the plasmodial enzyme PfGSK-3 but the compounds nevertheless show strong antiparasitic activity. The most potent representatives inhibit the pathogens with IC50 values in the two-digit nanomolar range and exhibit high selectivity indices (>100)

Continuous Krapcho Dealkoxycarbonylation in API Synthesis

A high pressure and high temperature continuous flow reactor has been used to intensify a Krapcho dealkoxycarbonylation reaction in the context of API synthesis. The reactor enables operation of the reaction above temperatures possible in batch and thus significantly increased conversion rates are achieved. Also a broader choice of solvents is possible by the use of the continuous process. Batch and continuous reaction are compared in terms of operation range and space-time-yield. Despite lower concentrations of the reactants in the continuous process, space-time-yield exceeds that of the batch process by more than an order of magnitude due to the higher reaction rates

1-(Imidazo[1,2-a]pyridin-1-ium-1-yl)-2,3,4-trioxocyclobutan-1-ide

1-(Imidazo[1,2-a]pyridin-1-ium-1-yl)-2,3,4-trioxocyclobutan-1-ide was obtained by reaction of squaric acid with imidazo[1,2-a]pyridine in acetic anhydride

Synthesis and Antiplasmodial Activity of Bisindolylcyclobutenediones

Malaria is one of the most dangerous infectious diseases. Because the causative Plasmodium parasites have developed resistances against virtually all established antimalarial drugs, novel antiplasmodial agents are required. In order to target plasmodial kinases, novel N-unsubstituted bisindolylcyclobutenediones were designed as analogs to the kinase inhibitory bisindolylmaleimides. Molecular docking experiments produced favorable poses of the unsubstituted bisindolylcyclobutenedione in the ATP binding pocket of various plasmodial protein kinases. The synthesis of the title compounds was accomplished by sequential Friedel-Crafts acylation procedures. In vitro screening of the new compounds against transgenic NF54-luc P. falciparum parasites revealed a set of derivatives with submicromolar activity, of which some displayed a reasonable selectivity profile against a human cell line. Although the molecular docking studies suggested the plasmodial protein kinase PfGSK-3 as the putative biological target, the title compounds failed to inhibit the isolated enzyme in vitro. As selective submicromolar antiplasmodial agents, the N-unsubstituted bisindolylcyclobutenediones are promising starting structures in the search for antimalarial drugs, albeit for a rational development, the biological target addressed by these compounds has yet to be identified

(E)-2-(1-Cyano-2-methoxy-2-oxoethylidene)-3,4-dioxo-1- (pyridin-1-ium-1-yl)cyclobutan-1-ide

(E)-2-(1-Cyano-2-methoxy-2-oxoethylidene)-3,4-dioxo-1-(pyridin-1-ium-1-yl)cyclobutan-1-ide was obtained by a three-component reaction of squaric acid dichloride with pyridine and methyl cyanoacetate

7-Bromo-1-methyl-2-phenyl-1H-indole-3-carbonitrile

The title compound was prepared by electrophilic aromatic substitution of 7-bromo-1-methyl-2-phenyl-1H-indole with NCTS (N-cyano-N-phenyl-p-toluenesulfonamide). The structural identity of the title compound was proven by elemental analysis and spectroscopic methods (IR, NMR, APCI-MS). Purity was assessed by two independent HPLC methods

Trypanothione synthetase confers growth, survival advantage and resistance to anti-protozoal drugs in Trypanosoma cruzi

Background: Chagas cardiomyopathy, caused by Trypanosoma cruzi infection, continues to be a neglected illness, and has a major impact on global health. The parasite undergoes several stages of morphological and biochemical changes during its life cycle, and utilizes an elaborated antioxidant network to overcome the oxidants barrier and establish infection in vector and mammalian hosts. Trypanothione synthetase (TryS) catalyzes the biosynthesis of glutathione-spermidine adduct trypanothione (T(SH)2) that is the principal intracellular thiol-redox metabolite in trypanosomatids. Methods and Results: We utilized genetic overexpression (TryShi) and pharmacological inhibition approaches to examine the role of TryS in T. cruzi proliferation, tolerance to oxidative stress and resistance to anti-protozoal drugs. Our data showed the expression and activity of TryS was increased in all morphological stages of TryShi (vs. control) parasites. In comparison to controls, the TryShi epimastigotes (insect stage) recorded shorter doubling time, and both epimastigotes and infective trypomastigotes of TryShi exhibited 36-71% higher resistance to H2O2 (50-1000 M) and heavy metal (1-500 M) toxicity. Treatment with TryS inhibitors (5-30 M) abolished the proliferation and survival advantages against H2O2 pressure in a dose-dependent manner in both TryShi and control parasites. Further, epimastigote and trypomastigote forms of TryShi (vs. control) T. cruzi tolerated higher doses of benznidazole and nifurtimox, the drugs currently administered for acute Chagas disease treatment. Conclusions: TryS is essential for proliferation and survival of T. cruzi under normal and oxidant stress conditions, and provides an advantage to the parasite to develop resistance against currently used antitrypanosomal drugs. TryS indispensability has been chemically validated with inhibitors that may be useful for drug combination therapy against Chagas disease.Fil: Mesias, Andrea Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta. Instituto de Patología Experimental. Universidad Nacional de Salta. Facultad de Ciencias de la Salud. Instituto de Patología Experimental; ArgentinaFil: Sasoni, Natalia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Agrobiotecnología del Litoral. Universidad Nacional del Litoral. Instituto de Agrobiotecnología del Litoral; ArgentinaFil: Arias, Diego Gustavo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Agrobiotecnología del Litoral. Universidad Nacional del Litoral. Instituto de Agrobiotecnología del Litoral; ArgentinaFil: Pérez Brandan, Cecilia María. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta. Instituto de Patología Experimental. Universidad Nacional de Salta. Facultad de Ciencias de la Salud. Instituto de Patología Experimental; ArgentinaFil: Orban, Oliver C. F.. Technische Universitat Carolo Wilhelmina Zu Braunschweig.; AlemaniaFil: Kunick, Conrad. Technische Universitat Carolo Wilhelmina Zu Braunschweig.; AlemaniaFil: Robello, Carlos. Instituto Pasteur de Montevideo; UruguayFil: Comini, Marcelo. Instituto Pasteur de Montevideo; UruguayFil: Garg, Nisha J.. University of Texas Medical Branch; Estados UnidosFil: Zago, María Paola. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta. Instituto de Patología Experimental. Universidad Nacional de Salta. Facultad de Ciencias de la Salud. Instituto de Patología Experimental; Argentin