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Genetic vulnerabilities in acute myeloid leukemia
Get PDFHematopoietic stem cells (HSCs) play a crucial role in maintaining blood system homeostasis through continuous self-renewal and differentiation. However, uncontrolled self-renewal is a hallmark of cancer cells, leading to conditions like acute myeloid leukemia (AML). AML is characterized by myeloid blast cells failing to properly differentiate into functional blood cells. In this study, we investigated three genetic vulnerabilities (PLCG1, LLGL1, H2AFZ) in AML, each of them offering potential new therapeutic interventions for the disease.
The first study identified Phospholipase C gamma 1 (PLCG1)-signaling as a genetic vulnerability in AML-ETO1 (AE)-transformed leukemic stem cells (LSCs). Genetic deletion
of PLCG1 resulted in impaired proliferation and reduced colony formation in vitro and in
delayed disease development in a xenograft model in vivo. Importantly, PLCG1 is dispensable for normal hematopoietic stem and progenitor cell functions. As Ca2+ signaling appeared deregulated in AE- AML, we investigated the effects of pharmacologic Ca2+ inhibition using the clinically approved calcineurin inhibitor ciclosporin A (CsA) as a tractable target downstream of PLCG1. CsA-treated animals showed reduction in total leukemic burden and LSC numbers, suggesting that targeting PLCG1 and calcium signaling may provide a promising therapeutic strategy for AE-positive AMLs.
LLGL1 is a cell fate determinant and polarity regulator that can influence the fine balance between self-renewal and differentiation of HSCs and LSCs. Inactivation of LLGL1 resulted in impaired proliferation of human AML cell lines and murine AML cells in vivo. Transcriptomic analysis revealed decreased expression of HoxA genes and LSC signatures and increased signatures of genes associated with myeloid differentiation in LLGL1- deficient cells. Taken together, our results establish LLGL1 as a specific dependency and putative target in AML.
Histone variants are one of the components that can modulate chromatin structure and function. Among all canonical histones, the H2A family exhibits the highest sequence divergence resulting in the largest number of variants. In the third publication, we identified H2AFZ as a functional vulnerability in AML. Here, inactivation of H2AFZ resulted in impaired AML cell proliferation, reduced colony forming ability and cell cycle activity in vitro and a delay in disease development in vivo. ATAC-sequencing did not reveal any significant changes in chromatin accessibility following H2AFZ inactivation. However, transcriptome analysis revealed upregulation of gene signatures associated with apoptosis and downregulation of gene signatures related to cell cycle, suppression of MYC target genes and DNA repair. Taken together, our results may provide first evidence for a functional role of H2AFZ in models of AML
Quality parameters for the medicinal plant Drosera rotundifolia L.: A new approach with established techniques
Get PDFMonographs of the European Pharmacopoeia (Ph. Eur.) are the basis for quality control of medicinal plants and therefore important to ensure the consistency, quality, safety, and efficacy of phytopharmaceuticals. The traditional medicinal plant sundew (Drosera sp.) has disappeared from therapy due to nature conservation, but can now be cultivated sustainably on rewetted peatland. However, currently there is no valid Ph. Eur. monograph for the quality control of Droserae herba. In this study, sundew material from different species and sources was investigated with the aim of developing quality control methods based on the Ph. Eur. and defining a uniform quality standard for Droserae herba. It was possible to distinguish between sundew species of different quality, using macroscopic, microscopic, and chromatographic methods. Special emphasis was laid on the content of flavonoids and naphthoquinones as important quality parameters as their content differed between the sundew species. The differences in content and toxicity result in the recommendation that only round-leaved sundew (Drosera rotundifolia L.) should be used as a medicinal plant for the production of phytopharmaceuticals in the future
Intrazellulärer Transport lysosomaler Hydrolasen und deren Veränderung in der akuten Pankreatitis
Get PDFDie akute Pankreatitis ist einer der häufigsten gastroenterologischen Erkrankungen, wobei deren Pathogenese auf zellulärer Ebene noch nicht vollständig aufgeklärt ist. Bekannt ist, dass beginnend mit einer hohen cytosolischen Ca2+-Konzentration eine intrazelluläre Aktivierung von Trypsin eintritt, was zu einer Proteasenaktivierung in den pankreatischen Azinuszellen führt. Dies resultiert letztendlich im Tod dieser Zellen und in der Aktivierung des Immunsystems. Wie Trypsin, welches im sekretorischen Kompartiment lokalisiert ist, über das überwiegend lysosomal lokalisierte Cathepsin B aktiviert wird, bleibt jedoch ungeklärt.
Um diese Fragestellung zu untersuchen, wurde über einen pankreasspezifischen Knockout von Rab7 die Fusion von sekretorischen Vesikeln und Lysosomen inhibiert und nachfolgend die subzelluläre Verteilung der Enzyme vor und nach Stimulation der Mäuse mit Caerulein untersucht. Dabei fiel auf, dass bei Fehlen von Rab7 alle untersuchten Cathepsine erhöht exprimiert und verstärkt im sekretorischen Kompartiment lokalisiert vorlagen. Dies hatte jedoch keinen Einfluss auf die Trypsinaktivität oder den Beginn der Erkrankung, was sowohl in isolierten Azinuszellen als auch in vivo gezeigt werden konnte. Zu einem späteren Zeitpunkt nahm die Schwere der akuten Pankreatitis in den knockout Mäusen zu. In einem weiteren Modell erfolgte eine Vorbehandlung von Wildtyp (C57BL/6) Mäusen mit der lysosomotropen Substanz Glycyl-L-Phenylalanin 2-Naphthylamid (GPN). Dabei konnte gezeigt werden, dass auch nach Permeabilisierung der Lysosomen durch Caerulein eine intrazelluläre Trypsinaktivierung und akute Pankreatitis induziert wurde und der pankreatische Schaden im Wesentlichen unverändert zu den Kontrollen war.
Ein zweiter Ansatz fokussierte sich auf den intrazellulären Transport der Cathepsine. Mithilfe eines knockout Mausmodells für CLN8 sollte der Export von lysosomalen Proteinen vom rauen Endoplasmatischen Retikulum in das cis-Golgi Netzwerk inhibiert und Cathepsin B weder das Lysosom noch das sekretorische Kompartiment erreichen und somit nicht für die Aktivierung von Trypsinogen zur Verfügung stehen. In dieser Arbeit konnte allerdings gezeigt werden, dass trotz Deletion von CLN8 Cathepsine im lysosomalen und imsekretorischen Kompartiment lokalisiert sind, Trypsinogen nach Cholecystokinin- bzw. Caerulein-Stimulation intrazellulär aktivierbar sind und eine akute Pankreatitis initiiert werden kann. Das Fehlen von CLN8 führte im Pankreas zu einer vermehrten Bildung von Autophagosomen, zu dysmorphen und dysfunktionalen Mitochondrien und einem erhöhten ER-Stress, wie anhand von elektronenmikroskopischen Aufnahmen, Messung des maximalen mitochondrialen Membranpotentials und der ATP-Synthese sowie Expressionsanalysen der ER-Stress Proteine BIP, ATF6 und CHOP nachgewiesen werden konnte. Expressionsanalysen und Co-Immunopräzipitationen von LC3B sowie dem ER-Phagie regulierenden Rezeptor FAM134B zeigten eine stärkere Expression beider Proteine in CLN8 knockout Mäusen, die sich während der akuten Pankreatitis weiter erhöhte, was darauf hindeutet, dass die ER-Phagie eine wichtige Rolle für die Pathogenese der akuten Pankreatitis bei Defizienz von CLN8 darstellt.
Deletion von CLN8 mittels CRISPR/Cas9 in 266-6 Zellen, einer murinen Azinuszelllinie, bestätigte, dass das Fehlen von CLN8 mit einem erhöhten ER-Stress verbunden ist. Gleichzeitig waren eine verminderte Zellproliferation und Veränderungen der Zellmorphologie in CLN8-defizienten 266-6 nachweisbar.
Zusammengefasst verdeutlichen die Ergebnisse, dass die Initiation der akuten Pankreatitis ohne Lysosomen stattfinden kann. Weder eine Inhibition der Fusion von Zymogengranula und Lysosomen, noch eine Störung der Membranintegrität, hervorgerufen durch die lysosomotrophe Substanz GPN, oder eine Störung des Exports von Cathepsinen aus dem ER verhinderten die Induzierbarkeit der akuten Pankreatitis. Diese Beobachtungen stellen die Notwendigkeit der Fusion von Lysosomen mit Zymogengranula als essenzielle Vorraussetzung für den Beginn der akuten Pankreatitis in Frage. Unsere Beobachtungen lassen im Gegenteil sogar die Vermutung zu, dass Lysosomen in der akuten Pankreatitis eine krankheitsmildernde Funktion haben könnten.Acute pancreatitis is one of the most common gastrointestinal diseases, but its pathophysiology is still unknown. The pathogenesis starts with an increase of the cytosolic Ca2+ concentration leading to an intracellular trypsinogen activation and a cascade-like activation of digestive proteases that finally results in organ injury and cellular death. Several previous studies demonstrate, that the lysosomal enzyme cathepsin B (CTSB) is able to proteolytically activate trypsinogen. However, the underlying mechanisms of the CTSB-mediated trypsinogen activation are still not entirely understood.
To answer this question, we have induced acute pancreatitis by caerulein injections in mice with a pancreas-specific knockout of Rab7, a small GTPase that is implicated in the intracellular transport and fusion of lysosomes with secretory vesicles. Deficiency of Rab7 in the pancreas prevented a subcellular distribution of CTSB from the lysosomal to the secretory compartment but still enabled an intracellular activation of CTSB and trypsinogen followed by the onset of acute pancreatitis. These effects were observed both in isolated acinar cells and in vivo. Loss of pancreatic Rab7 expression even increased the severity of acute pancreatitis during later disease stages (8 hours). In a separate experimental setup, the proper lysosomal function was impaired using the lysosomotropic substance glycyl-L-phenylalanine 2-naphthylamid (GPN) in wild-type (C57BL/6) mice. Despite lysosomal membrane permeabilization trypsinogen activation and acute pancreatitis still occurred and disease severity was similar to control mice.
In a third model, we investigated the effect of a blocked export of cathepsins from the endoplasmatic reticulum to the cis-Golgi network by a knockout model of CLN8 in mice, in isolated acinar cells and 266-6 cells. Upon CCK- or caerulein-stimulation CLN8-deficient acinar cells and mice still developed acute pancreatitis which was transiently milder in the early phase but turned to be more severe at later disease stages. Loss of CLN8 increased autophagosome formation and led to dysmorphic mitochondria with impaired function and ER stress which could be demonstrated by electron microscopy, measurement of the maximal mitochondrial membrane potential, and ATP-synthesis as well as the expression of ER stress markers BIP, ATF6, and CHOP. Analysis of expression and co-immunoprecipitation of LC4B with the ER-phagy regulating receptor FAM134B showed an increased expression of both proteins in CLN8 knockout mice which was further enhanced during acute pancreatitis indicating an important role of ER-phagy in the pathogenesis of acute pancreatitis.
Deletion of CLN8 by CRISPR/Cas9 in 266-6 cells confirmed the association of CLN8 deficiency with higher ER stress, accompanied by reduced cell proliferation and altered cellular morphology.
In summary, our results clearly indicate that the onset of acute pancreatitis seems to be independent of lysosomes. Neither an inhibition of a fusion of lysosomes with secretory vesicles, a distortion of lysosomal membrane integrity by the lysosomotropic substance GPN, nor an impaired transport of cathepsins from the ER to the Golgi prevented the induction of acute pancreatitis. These observations challenge the existing hypothesis that a fusion of lysosomes and zymogen granules is indispensable for the initiation of acute pancreatitis. They rather lead to the assumption that lysosomes are more likely to exert a protective role during acute pancreatitis
Untersuchungen zur Kv7.2/3-Kanalaktivität, Hepatotoxizität und metabolischen Stabilität von Flupirtin und neuartigen Analoga in vitro
Get PDFSpannungsabhängige Kaliumkanäle vom Kv7-Typ stellen ein vielversprechendes Target zur Behandlung von Krankheiten wie Schmerzen, Epilepsie und Multiple Sklerose dar. Umso schwerwiegender ist die Marktrücknahme der Arzneistoffe Flupirtin und Retigabin einzuschätzen, die beiden bis dato einzigen zugelassenen selektiven Kv7-Kanalöffner in Europa. Der Hauptgrund für die Einstellung des Vertriebs der entsprechenden Medikamente waren die substanzspezifischen Nebenwirkungen, d. h. Hepatotoxizität bzw. Gewebeverfärbungen. Potenziell toxische, reaktive (Aza-)Chinondiimin-Intermediate, die durch oxidativen Metabolismus von Flupirtin oder Retigabin entstehen, werden dafür verantwortlich gemacht.
In zwei DFG-geförderten Projekten LI 765/7-1 und BE 1287/6-1 sollten deshalb neuartige Flupirtin-Analoga synthetisiert und charakterisiert werden, um im besten Fall wirkstärkere und sicherere Alternativen zu erhalten. Der Fokus dieser Arbeit liegt auf der Etablierung und Optimierung von in vitro-Assays zur Bestimmung der Kv7.2/3-Kanalaktivität und des hepatotoxischen Potenzials der neuen Substanzen im Arbeitskreis. In Verbindung mit gentechnologisch veränderten HEK-293-Zellen, welche Kv7.2/3-Kanäle überexprimieren, wurden der fluoreszenzbasierte Thallium-Flux- und der Rubidium-Efflux-Assay, bei dem die Rubidiumkonzentration durch Atomabsorptionsspektrometrie ermittelt wird, verwendet, um die Kaliumkanalöffnungsaktivität der Flupirtin-Analoga zu beurteilen. Mittels MTT-Zellviabilitätsassay wurde die Hepatotoxizität mit der humanen Hepatoblastom-Zelllinie HepG2 und der murinen Leberzelllinie TAMH („TGF-α overexpressing mouse hepatocytes“) evaluiert. Dabei wurden die verwendeten Zellen konventionell zweidimensional als Monolayer kultiviert. Darüber hinaus wurden beide Zelllinien in dreidimensionaler Form als sogenannte Sphäroide kultiviert und untersucht, ob diese Technik die leberspezifischen Eigenschaften gegenüber Zellen in Monolayer verbessert und Sphäroide somit ein besseres Modell für die Hepatotoxizitätstestung darstellen. Zudem wurde ein postulierter Stoffwechselweg für die Bildung des Metaboliten 4-Fluorhippursäure aus Flupirtin überprüft. Dafür wurden zwei HPLC-Methoden entwickelt und validiert.
Insgesamt wurden ca. 100 neuartige Flupirtin-Analoga getestet, wobei für die meisten eine geringfügige akute Hepatotoxizität festgestellt werden konnte. Einige der neu synthetisierten Verbindungen wiesen eine bis zu 100-fach höhere Öffnungsaktivität als Flupirtin am Kv7.2/3-Kanal auf. Die Sphäroide der verwendeten Leberzelllinien zeigten zum Teil verbesserte leberspezifische Eigenschaften als die entsprechenden Monolayer. Beim Vergleich des ermittelten hepatotoxischen Potenzials von Flupirtin und Retigabin mittels Monolayer oder Sphäroide konnte jedoch kein relevanter Unterschied identifiziert werden. Der postulierte Mechanismus für die Bildung des Metaboliten 4-Fluorhippursäure aus Flupirtin konnte mit den durchgeführten enzymatischen Experimenten und HPLC bzw. SFC-MS-Analytik bestätigt werden
The underestimated role of plant root nitric oxide emission under low-oxygen stress
Get PDFThe biotic release of nitric oxide (NO), a greenhouse gas, into the atmosphere contributes to climate change. In plants, NO plays a significant role in metabolic and signaling processes. However, little attention has been paid to the plant-borne portion of global NO emissions. Owing to the growing significance of global flooding events caused by climate change, the extent of plant NO emissions has been assessed under low-oxygen conditions for the roots of intact plants. Each examined plant species (tomato, tobacco, and barley) exhibited NO emissions in a highly oxygen-dependent manner. The transfer of data obtained under laboratory conditions to the global area of farmland was used to estimate possible plant NO contribution to greenhouse gas budgets. Plant-derived and stress-induced NO emissions were estimated to account for the equivalent of 1 to 9% of global annual NO emissions from agricultural land. Because several stressors induce NO formation in plants, the actual impact may be even higher
The Association Between Nutritional Risk and Bone Stiffness in Elderly Men and Women in a Population-Based Study in Northeast Germany
Get PDFBackground: The Geriatric Nutritional Risk Index (GNRI) has shown promising potential for identifying individuals at risk for osteoporosis in various patient cohorts. However, data from the general population confirming or refuting the usefulness of the GNRI as a risk factor for osteoporosis are sparse. We therefore aimed to clarify whether the GNRI is associated with the ultrasound-based bone stiffness index and the osteoporotic fracture risk in a sample of elderly men and women from the general population. Methods: Data from 1417 participants in the Study of Health in Pomerania START-2 or TREND-0 aged 65 years or older with quantitative ultrasound measurements at the heel and GNRI values were examined. In cross-sectional linear and logistic regression models, associations between the GNRI and heel stiffness index or ultrasound-based osteoporotic fracture risk were examined. All analyses were repeated after stratification of the study population according to BMI (underweight/normal weight, overweight and obese). Results: In underweight/normal weight individuals, higher, i.e., better, GNRI values had a positive effect on the stiffness index (β-coefficient per standard deviation increase in GNRI = 2.69, standard error = 1.00, p = 0.007). With increasing GNRI values, underweight/normal weight elderly men and women also had higher chances of a low osteoporotic fracture risk (odds ratio 1.42, 95% confidence interval 1.04–1.94, p = 0.026). Corresponding associations in overweight or obese individuals were absent. Conclusions: In elderly men and women with underweight/normal weight, the GNRI is positively associated with the bone stiffness index and the related osteoporotic fracture risk. In this group, the GNRI may prove useful in identifying individuals with an elevated fracture risk
Improved recombinant expression of soluble cathepsin B and L in Escherichia coli
Get PDFCysteine cathepsins such as cathepsin B and L play an important role in numerous diseases like acute pancreatitis or SARS-CoV-2 and therefore have high potential for the development of new therapeutics. To be able to screen for potent and selective inhibitors sufficient amounts of protein are required. Here, we present an easy and efficient protocol for the recombinant expression of soluble and active murine cathepsin B and L. For this, we used the strain E. coli SHuffle® T7 Express which is capable of forming disulfide bridges in the cytoplasm. The enzymes were purified by immobilized nickel ion-affinity chromatography. Using different constructs and media, expression levels were significantly improved and expression yields of 80 ± 2 mg L −1 for procathepsin B, which is 16-fold better than previously reported expression yields for procathepsin B, and 37 ± 2 mg L −1 for procathepsin L, were achieved. After activation with dithiothreitol at slightly acidic pH, in vitro kinetic parameters of both cathepsins were determined using the commonly used synthetic substrates Arg-Arg-AMC or Phe-Arg-AMC. Moreover, to investigate the impact of the short C-terminal propeptide of procathepsin B, it was deleted by site-directed mutagenesis, the shortened target protein was expressed and purified, activated in vitro, and its activity was similar to the variant bearing this C-terminal propeptide.
Key points
• Recombinant gene expression of cathepsin B and L in E. coli SHuffle® T7 Express
• Soluble cathepsin expression with high expression yields
• Investigation of the short C-terminal propeptide of cathepsin
Job satisfaction and working conditions of non-permanent faculty organized in the German communication association: an assessment in the light of recent science policy developments
Get PDFDie vorliegende Untersuchung stellt die erste Welle einer langfristig angelegten Trendstudie dar, die darauf abzielt, die Zufriedenheit des DGPuK-Mittelbaus mit den Arbeitsbedingungen in der Wissenschaft systematisch und evidenzbasiert zu erfassen. Besonderes Augenmerk der Auswertung des Basisteils (spezifischere Teilauswertungen folgen) liegt auf der Wahrnehmung der Arbeitsumstände und deren Einfluss auf die berufliche Zufriedenheit. Die Ergebnisse zeigen, dass die Arbeitszufriedenheit insgesamt moderat ist, eine Karriere in der Wissenschaft aber eher nicht als empfehlenswert wahrgenommen wird. Dabei spielen verschiedene Faktoren, wie Arbeitsbelastung, organisatorische Unterstützung und Karrieremöglichkeiten, eine zentrale Rolle. Es wird deutlich, dass insbesondere die berufliche Unsicherheit und die unklaren Karriereperspektiven als belastend empfunden werden. Die Studie bietet damit wertvolle Einblicke in die aktuelle Situation des Mittelbaus und legt den Grundstein für zukünftige Erhebungswellen, die die Entwicklung der Zufriedenheit im Zeitverlauf abbilden können. Die Erkenntnisse sollen dazu beitragen, gezielte Maßnahmen zur Verbesserung der Arbeitsbedingungen zu entwickeln und eine Datenbasis für das wissenschaftspolitische Engagement der Fachgesellschaft bieten.This study represents the first wave of a long-term trend analysis aimed at systematically assessing job satisfaction among early career scholars (pre- and post-docs) within the German Communication Association (DGPuK). This evaluation focuses on the perception of working conditions and their impact on professional satisfaction. While the working conditions of scholars in academia have long been criticized, recent social media debates have highlighted the problematic working conditions in German academia, especially for early career scholars, and brought them into the focus of public attention. The Act on Fixed-Term Employment Contracts in Academia (Wissenschaftszeitvertragsgesetz, WissZeitVG), introduced in 2007, was intended to protect scholars from systematic exploitation in temporary academic employment contracts. Instead, it has become emblematic of the fixed-term employment problem itself. With each amendment to the law—the first in 2016 and the planned amendment in 2023—the working conditions for scholars appear to worsen, with shorter time frames for completing different phases of qualification. Different studies have examined working conditions in academia in general and evaluated the changes since the introduction of the WissZeitVG. However, since each discipline operates differently, it is crucial to consider the specifics of each field and how scholars within it cope with the changing working environment. This study builds on previous analyses that have examined job satisfaction among early career scholars in German communication and media studies. The most recent study was published in 2014, and much has changed since then. Particularly considering the planned amendment to the WissZeitVG, it seemed only logical to conduct a new study to provide a robust data basis for engaging in discipline-specific science policy. Participants in this study ( N = 243) were recruited between 2023 and 2024 via the email distribution lists of the DGPuK early career network, as well as the DGPuK’s general and group section newsletters. The study targeted all scholars who are members of the newsletter groups and do not hold permanent positions as professors. Designed as a long-term study, the focus of recruitment was on ensuring a long-term comparison of study data; therefore, the results are limited to members of the German Communication Association. The survey results indicate that overall job satisfaction is rated as moderate, with various factors such as workload, lack of organizational support, and uncertain career opportunities playing a central role. Although the number of overtime hours had been declining in previous studies, it is now rising again and remains at a comparatively high level. As in prior studies, most scholars expressed dissatisfaction with the fact that they spend too much time on teaching and administration and too little on more critical tasks such as their own qualification, publications, and acquiring third-party funding. Furthermore, the results indicate that as of 2024, gender differences persist across career stages with the proportion of female researchers decreasing as career levels advance. Regarding contract terms, the findings show that less than half of the respondents work full-time, and the majority are employed in fixed-term contracts, with few prospects for either contract renewal or permanent positions. Therefore, data suggests that the workload, and consequently the perceived performance pressure, are continuing to increase as the working conditions remain insecure. It is particularly noteworthy that many respondents would hesitate to recommend a career in academia. This indicates a sense of uncertainty and skepticism about long-term career prospects, which is exacerbated by the current working conditions and structural framework within the academic system. Professional uncertainty and unclear career prospects are perceived as particularly stressful. In the authors’ opinion, this provides a strong argument for creating more permanent employment opportunities for scholars outside of professorships. These positions should not (just) focus on teaching and administrative tasks but should also allow scholars to conduct research, to maintain competitiveness as a research location
The Journey to a FAIR CORE DATA SET for Diabetes Research in Germany
Get PDFThe German Center for Diabetes Research (DZD) established a core data set (CDS) of clinical parameters relevant for diabetes research in 2021. The CDS is central to the design of current and future DZD studies. Here, we describe the process and outcomes of FAIRifying the initial version of the CDS. We first did a baseline evaluation of the FAIRness using the FAIR Data Maturity Model. The FAIRification process and the results of this assessment led us to convert the CDS into the recommended format for spreadsheets, annotating the parameters with standardized medical codes, licensing the data set, enriching the data set with metadata, and indexing the metadata. The FAIRified version of the CDS is more suitable for data sharing in diabetes research across DZD sites and beyond. It contributes to the reusability of health research studies
Gas-phase thorium molecules from laser ablation
Get PDFLaser ablation is performed on an oxidized, roughly 35-year-old Th232 foil. The produced anionic and cationic molecules are investigated utilizing precision mass measurements by a multireflection time-of-flight mass spectrometer. Molecules with up to three thorium atoms are identified. This includes oxides ThnOx+ containing up to 2n−1 oxygen atoms and further species incorporating carbon or nitrogen. In addition, signals of U+, UO+, and the compound species ThUO2+ are found. Photoexcitation reveals selected molecules' dissociation patterns. The experimental findings are compared to density functional theory calculations