Mathematisch-Naturwissenschaftliche Fakultät

Chemogenetic G Protein-Ligand Pairs for Causal Investigation of Cellular Biology In Vitro and In Vivo

2026-07-01T00:00:00Z

Chemogenetic G Protein-Ligand Pairs for Causal Investigation of Cellular Biology In Vitro and In Vivo Alenfelder, Judith The targeted pharmacological inhibition of signaling pathways is an appealing experimental approach for deconvoluting signal transduction downstream of G protein-coupled receptors (GPCRs). A powerful and broadly used molecule to pharmacologically inhibit Gq, G11, and G14 heterotrimers with remarkable specificity is the natural depsipeptide FR900359 (FR). FR prevents nucleotide exchange on the Gα subunit and, consequently, its activation, and can, therefore, be used as a tool to study the contribution of Gq family proteins to complex cellular processes. Similar specific inhibitors for other G protein families are urgently needed, as their availability would tremendously advance the field. Despite extensive efforts, developing such molecules has proven extremely challenging, and no suitable cell-permeable compounds have been identified to date.
To overcome this lack of specific inhibitors, we suggest harnessing the specificity of FR by placing the remaining G protein families under its direct pharmacological control. This strategy involves creating artificial FR binding sites to construct a modular "chemogenetics-like" toolkit, from which engineered FR-sensitive G protein subtypes can selectively be chosen. In this thesis, as a first step towards such a toolbox, we aimed to design and validate FR-resistant Gαq isoforms that remain fully functional and can be employed in vivo.
We selected the fruit fly, Drosophila melanogaster, as our experimental model due to its genetical tractability and potential for the detailed dissection of signaling circuits in vivo. We rationally designed Drosophila Gαq (DGq) variants that retain wildtype-like signaling properties and display markedly reduced FR sensitivity. These mutants were characterized in HEK293 cells using a suite of assays covering G protein dissociation, downstream signaling, and whole-cell activation. Several mutants were excluded from further studies due to poor expression, aberrant subcellular localization or residual FR sensitivity. Ultimately, we succeeded in developing DGq proteins combining wild type-like behavior with robust resistance to FR that qualified for proof-of-concept experiments in vivo.
FR exhibits dose-dependent oral lethality in insects, an effect that we exploited to investigate whether lethality is causally linked to Gq inhibition. By ubiquitously overexpressing our DGαq variants, we rescued the FR-induced lethality in Drosophila without any obvious adverse effects, providing direct experimental proof that FR lethality in this model is mediated by Gq inhibition. Encouraged by these results, we introduced analogous mutations to murine Gαq, generating functional mGαq variants refractory to FR inhibition and suited for future application in live mice.
We envision our engineered Drosophila and mouse Gq protein-ligand pairs to serve as versatile chemogenetics-like tools for noninvasive, cell type-specific manipulation of Gq-mediated and -modulated signaling, enabling causal exploration of these pathways in vitro and in vivo.

VISOR: VIsual Seizure Onset Detection PeRsonalized for Epilepsy Patients

2025-06-18T00:00:00Z

VISOR: VIsual Seizure Onset Detection PeRsonalized for Epilepsy Patients Kumar, Uttam; Yu, Ran; Wenzel, Michael; Demidova, Elena Wu, Xintao; Spiliopoulou, Myra; Wang, Can; Kumar, Vipin; Cao, Longbing; Wu, Yanqiu; Yao, Yu; Wu, Zhangkai The onset detection of epileptic seizures from multivariate Electroencephalogram (EEG) data is a challenging task. The variation in seizure patterns across patients and epilepsy types makes it particularly difficult to create a generic solution. Existing approaches indicate low recall due to their inability to capture complex seizure onset patterns. In this paper, we propose VISOR – a novel approach to detect the onset of epileptic seizures based on novel patient profiles and visual, personalized feature representations. VISOR leverages a vision transformer model to learn the spatio-temporal relationships between features, capture individual seizure propagation patterns, and perform seizure onset detection in a heterogeneous multi-patient dataset. Evaluation on a real-world dataset demonstrates that VISOR outperforms state-of-the-art baselines by at least 5% points for seizure onset detection in terms of the F1 score and indicates higher effectiveness for more complex patterns of propagating seizures.

Darstellung von Mehrfachbindungen zwischen Kobalt und den schweren Elementen der Tetrele

2026-06-29T00:00:00Z

Darstellung von Mehrfachbindungen zwischen Kobalt und den schweren Elementen der Tetrele Deckstein, Tobias Die Carbin-Komplexe stellen eine zentrale Klasse organometallischer Verbindungen dar und besitzen, wie ihre schweren Homologe, die Tetrelylidin-Komplexe, eine nahezu lineare M–E–R-Struktur mit sehr kurzen M–E-Bindungslängen (E = Si–Pb, M = Übergangsmetall, R = Substituent). Der metathetische Austausch von M≡C-Bindungen in Carbin‑Komplexen mit Alkine ist ein grundlegendes Prinzip der Alkinmetathese und verläuft über metallacyclobutadienartige Zwischenstufen. Die Dreifachbindungsspaltung von Ditetrelinen RE≡ER (E = Si–Pb, R = Substituent) an Metallzentren ist jedoch deutlich weniger erforscht. Bedingt durch das umgekehrte Verhältnis der Bindungsdissoziationsenergien bei schwereren Tetrel-Elementen |ΔH°(M≡E)| > |ΔH°(E≡E)|) im Vergleich zu Kohlenstoff (|ΔH°(C≡C)| > |ΔH°(M≡C)|), eröffnen sich neue Synthesewege für Tetrelylidin-Komplexe und bietet einen alternativen Zugang zur Synthese von Tetrelylidin-Komplexen jenseits klassischer Synthesemöglichkeiten. Ein bedeutender Fortschritt war die metathetische Austausch von [Mo(⁵-C₅H₅)₂(CO)₂]₂ mit Ditetrelinen RE≡ER (E = Ge–Pb, R = ArDipp; ArDipp = C₆H₃-2,6-(C₆H₃-2,6-ⁱPr₂)) zur Darstellung des Komplexes [Cp(CO)₂Mo≡ER]. In dieser Arbeit wird ein systematischer Ansatz zur effizienten Synthese des kationischen Bis-Germylidin-Komplexes [Co(GeMind)₂(PMe₃)₂][B(ArF)₄] durch die gezielte Spaltung der Ge≡Ge-Bindung mit dem Komplex [Co(PMe₃)₄][B(ArF)₄] vorgestellt. Die Vervollständigung der homologen Reihe von Kobalt-Tetrelylidin-Komplexen gelang zum einem durch eine Kobalt-zentrierte Spaltung der E≡E-Bindung der Ditetreline Ge₂Tbb₂ bzw. Sn₂ArDipp₂ mit [Co(PMe₃)₄]. Zusätzlich wird die Darstellung von Tetrelylidin-Komplexen mittels der klassischen Salz-Eliminierungsmethode durch Reaktionen von Tetrel(II)-Halogeniden mit K[Co(PMe₃)₄] beschrieben. Besonders erwähnenswert ist die Synthese des Silylidyne-Komplexes [Co(SiTbb)(PMe₃)₃], der durch eine bisher einzigartige metathetische Austauschreaktion zwischen Co≡Sn/Co≡Si- oder Co≡Pb/Co≡Si-Bindungen dargestellt wurde. Diese Ergebnisse demonstrieren erstmals einen neuartigen, nicht-Katz-basierten Mechanismus zur gezielten Umwandlung von M≡E-Bindungen. Die vorgestellte Methodik erweitert die Synthesemöglichkeiten für Tetrelylidin-Komplexe des Übergangsmetalls Kobalt mit den schweren Tetrel-Elementen und liefert zudem neue Einblicke in das Reaktionsverhalten und die Bindungseigenschaften von schweren Tetrelylidin-Komplexen des Übergangmetalls Kobalt.

The Galaxy Three-Point Correlation Function: From Theory to Forecasts

2026-06-29T00:00:00Z

The Galaxy Three-Point Correlation Function: From Theory to Forecasts Pugno, Anna (noch nicht zugänglich / not yet accessible)