The project on taxonomy and azole resistance in Aspergillus section Flavi aims to investigate the classification and drug resistance patterns of fungal species within this specific section. Aspergillus section Flavi comprises various species known to produce carcinogenic aflatoxins, posing significant risks to human and animal health. The project involves taxonomic studies to accurately identify and classify different species within Aspergillus section Flavi. This classification is essential for understanding the diversity and distribution of these fungi, as well as their specific traits and potential virulence factors. Another crucial aspect of the project is the investigation of azole resistance in Aspergillus section Flavi. Azoles are commonly used antifungal drugs for treating Aspergillus infections. However, reports of azole resistance in certain Aspergillus species have raised concerns. Understanding the mechanisms behind azole resistance is crucial for developing effective treatment strategies and identifying potential targets for drug development. The project involves molecular analysis techniques to detect and characterize genetic mutations or other mechanisms associated with azole resistance in Aspergillus section Flavi. Additionally, it may involve assessing the clinical impact of azole resistance on patient outcomes and exploring potential risk factors for the development and spread of resistant strains. By combining taxonomic studies with investigations into azole resistance, the project aims to enhance our understanding of the diversity, distribution, and drug resistance profiles of Aspergillus species within section Flavi. This knowledge can ultimately contribute to improved diagnostic methods, treatment approaches, and public health strategies to mitigate the impact of these fungal infections.

During development, a cell's fate will become increasingly restricted, facilitated by the combined activity of transcription factors and epigenetic modifiers. Single-cell RNA sequencing has greatly improved our appreciation of the transcriptional dynamics underlying lineage specification. However, we still do not fully comprehend how epigenetic modifiers guide this highly dynamic process, as methods that enable us to accurately concatenate a cell's past and present epigenetic state with its current lineage identity are missing. Here, I propose to investigate the combined dynamics and interdependencies of transcription and the polycomb-group of proteins during the differentiation of mouse embryonic stem cells into gastruloids. First, I aim to deploy a protocol that enables the simultaneous quantification of both layers in the same single cell to disentangle epigenetic from transcriptional heterogeneity. Second, I aim to develop a molecular memory system to record the past epigenetic profiles of single cells. This system will be based on the expression of proteins fused to a bacterial Dcm methylase, which will allow for the timed recording and faithful transmission of historic epigenetic profiles. Combined with quantification of transcription of the same single cell, this will enable us to directly integrate past epigenetic states with the current identity of single cells. The proposed work here will therefore allow us to directly assess the role of epigenetic modifiers on establishing cell fate choice and will have important implications on our understanding of the regulation of mammalian development.

Inheriting one mutant copy of the BRCA1 or BRCA2 gene is associated with a significant increased risk for developing aggressive and difficult to treat breast cancer, the most common cancer type in women worldwide. Despite previous efforts to recapitulate tumorigenesis with the use of mouse models and cancer cell lines, the exact mechanisms that underlie BRCA1 or BRCA2-dependent tumor development remain unclear. Recent advances in stem cell culturing have enabled long-term expansion of in vitro human breast organoids or ‘mini-breasts’. In a novel approach, this state-of-the-art culture technology will be used together with CRISPR/Cas9-mediated gene-editing and human-in-mouse xenografts to prospectively recapitulate early breast cancer development. Results of the study will generate novel fundamental insight into the development of breast cancer, support the development of personalized medicine using laboratory models, and aspires to identify novel breast cancer biomarkers and treatment strategies. The expertise of the laboratory of H. Clevers, who pioneered the organoid methodology and works at the top of the field of stem cell biology, will be combined with the expertise of the research group of J. Visvader and G. Lindeman, world leaders in the field of breast cancer research and experts in the methodology of mammary xenotransplantation. This unique setting forms an excellent envorinment for my postdoctoral research training, allows extensive knowledge exchange and provides opportunities for novel research lines and collaborations.

Understanding the biological mechanisms governing carbon (C) exchanges between terrestrial and atmospheric C pools, and how these exchanges will respond, and feed back, to climate warming, are among the most urgent challenges for climate and ecosystem scientists. Heterotrophic microbes are dominant biochemical engineers in terrestrial ecosystems, governing the flux of C between terrestrial and atmospheric pools. Despite concerns that rising atmospheric temperatures will stimulate the respiratory release of C by heterotrophic microbes, recent work highlights the potential for thermal acclimation to partially ameliorate this positive feedback. The magnitude and efficiency of this physiological response is, however, highly variable, suggesting that the strength of climate-ecosystem C feedbacks will vary across landscapes. The proposed study uses a combination of trait-based and community-scale approaches to explore the relative importance of microbial community composition and climate conditions in governing patterns of acclimation potential across landscapes. Incorporating this microbial physiological information into Earth System Models (ESMs) is essential if we are to predict global patterns in biogeochemical cycling under current, and future climate scenarios. The proposed work incorporates aspects of microbial physiological biology, community ecology and ecosystem ecology to address a critical uncertainty in current climate models. This interdisciplinary project will allow me the opportunity to exchange knowledge with experts in the fields of microbial community ecology and terrestrial ecosystem ecology at NIOO-KNAW. I will also foster an international collaborative network, which will benefit my host organisation and myself. The proposed fellowship will allow me re-enter the European academic system and develop the skills required to initiate my own effective research group following the project.