Towards Enabling Level 3A AI in Avionic Platforms

The role of AI evolves from human assistance over human/machine collaboration towards fully autonomous systems. As the push towards more autonomy subsequently removes the reliance on a human overseeing the system, means of self supervision must be provided to enable safe operations. This work explores dynamic reconfiguration to provide resilience to unforeseen environmental conditions that exceed the systems capabilities, but also against normal faults. We focus on providing the means for this in an ARINC 653 compliant environment, since we target avionics platforms. Scheduling and communication are two major aspects of dynamic reconfiguration. Hence, we discuss multiple respective implementation approaches. The third pillar of reconfiguration, the process of deciding when to reconfigure is also investigated. Combining these yields the building blocks for a self-supervising system

Stabilization of the Cysteine-Rich Conotoxin MrIA by Using a 1,2,3-Triazole as a Disulfide Bond Mimetic

The design of disulfide bond mimetics is an important strategy for optimising cysteine-rich peptides in drug development. Mimetics of the drug lead conotoxin MrIA, in which one disulfide bond is selectively replaced of by a 1,4-disubstituted-1,2,3-triazole bridge, are described. Sequential copper-catalyzed azide–alkyne cycloaddition (CuAAC; click reaction) followed by disulfide formation resulted in the regioselective syntheses of triazole–disulfide hybrid MrIA analogues. Mimetics with a triazole replacing the Cys4–Cys13 disulfide bond retained tertiary structure and full in vitro and in vivo activity as norepinephrine reuptake inhibitors. Importantly, these mimetics are resistant to reduction in the presence of glutathione, thus resulting in improved plasma stability and increased suitability for drug development.NHMRC 1045964 & 107211

ERK and mTORC1 Inhibitors Enhance the Anti-Cancer Capacity of the Octpep-1 Venom-Derived Peptide in Melanoma BRAF(V600E) Mutations

Melanoma is the main cause of skin cancer deaths, with special emphasis in those cases carrying BRAF mutations that trigger the mitogen-activated protein kinases (MAPK) signaling and unrestrained cell proliferation in the absence of mitogens. Current therapies targeting MAPK are hindered by drug resistance and relapse that rely on metabolic rewiring and Akt activation. To identify new drug candidates against melanoma, we investigated the molecular mechanism of action of the Octopus Kaurna-derived peptide, Octpep-1, in human BRAF(V600E) melanoma cells using proteomics and RNAseq coupled with metabolic analysis. Fluorescence microscopy verified that Octpep-1 tagged with fluorescein enters MM96L and NFF cells and distributes preferentially in the perinuclear area of MM96L cells. Proteomics and RNAseq revealed that Octpep-1 targets PI3K/AKT/mTOR signaling in MM96L cells. In addition, Octpep-1 combined with rapamycin (mTORC1 inhibitor) or LY3214996 (ERK1/2 inhibitor) augmented the cytotoxicity against BRAF(V600E) melanoma cells in comparison with the inhibitors or Octpep-1 alone. Octpep-1-treated MM96L cells displayed reduced glycolysis and mitochondrial respiration when combined with LY3214996. Altogether these data support Octpep-1 as an optimal candidate in combination therapies for melanoma BRAF(V600E) mutations

Identifying key amino acid residues that affect alpha-conotoxin AuIB inhibition of alpha3beta4 nicotinic acetylcholine receptors

Background: -Conotoxin AuIB interacts with 34 nAChRs and GABA(B) receptors, but structural determinants of these interactions are unknown. Results: Using alanine scanning mutagenesis and molecular dynamics, we identified residues crucial for AuIB34 nAChR interaction. Conclusion: We identified the key residues that mediate AuIB34 nAChR interaction. Significance: Ability to direct -conotoxin binding to nAChRs or GABA(B) receptors will improve analgesic conopeptides

Reaktionskanäle von Zuckern zu hydrophilen N-Heterocyclen des Imidazol-, Chinoxalin-, Pyridazin-, Benzodiazepin- und Benzothiazepin-Typs sowie NMR-Spektroskopische Charakterisierung neuer Disaccharid-phosphate

Stickstoff-Heterocyclen stellen industrielle Schlüsselprodukte dar und sind speziell im Wirkstoffbereich fundamentale und funktionale Einheiten. Die im Rahmen dieser Arbeit, ausgehend von niedermolekularen Kohlenhydraten entwickelten Reaktionskanäle, erschließen neuartige hydrophile, glycosidisch verknüpfte N-Heterocyclen mit potentiellem pharmakologischem Anwendungsprofil. Ausgehend von technisch einfach zugänglichen Disacchariden wie Isomaltulose, Leucrose, Maltose, Cellobiose und Lactose wurden "Eintopfverfahren" zur Darstellung von Tetrahydroxybutyl-substituierten Imidazolen und Chinoxalinen mit variablem Glycosylierungsmuster erarbeitet. Die zweite verfolgte Synthesestrategie zur Darstellung von N-Heterocyclen ging von a-Glucosyloxymetylfurfural (GMF) aus. Durch Etablierung geeigneter Reaktionssequenzen und Oxidationsverfahren wurde GMF in zahlreiche 1,4-Dicarbonyl-Synthesebausteine übergeführt, welche zum Aufbau von Zucker-substituierten Pyridazinen, Imidazolen, Benzodiazepinen und Benzothiazepinen genutzt wurden. Im zweiten Thema der Arbeit wurden die, vom Bakterium Klebsiella pneumoniae, produzierten Monophosphate verschiedener a-Glucosyl-verknüpfter Disaccharide (z.B. Saccharose, Isomaltulose u.a.) untersucht. Mittels 1- und 2-dimensionaler 1H und 13C-NMR spektroskopischer Methoden wurde bewiesen, das Klebsiella pneumoniae regiospeziefisch die primäre Alkoholfunktion des a-Glucosylrestes phosphoryliert. Desweiteren konnten die Tautomerenverteilungen der Disaccharid-phosphate ermittelt werden

Reducing disaccharides and their 1,2-dicarbonyl intermediates as building blocks for nitrogen heterocycles

The existential importance of a sustainable economy necessitates the utilisation of plant based renewable resources such as lignin and carbohydrates. Carbohydrate utilization as industrial raw materials requires low environmental impact conversions from sugars to high value products. Here we present the conversion of reducing disaccharides into industrially relevant heterocycles of the quinoxaline-, 1,2,4-triazine-, pyrazine- and pyrazolo[3,4-b]quinoxaline- type. Heterocycle formation was facilitated by chemical conversion of reducing sugars into 1,2-dicarbonyl intermediates and their subsequent cyclization with nitrogen bis-nucleophiles. A range of disaccharides was converted into quinoxalines carrying a diverse glycosylation pattern on the polyhydroxy alkyl side chain. All transformations were performed without the need of protecting group chemistry