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Listen to the recordings of previous seminars that have been given by staff from the Crick's partner HEIs
Paola Bonfanti
Reconstitution of a long-lived functional human thymus by postnatal clonogenic stem/progenitor cells
The thymus is a primary lymphoid organ, essential for T cell maturation and selection. There has been long-standing interest in processes underpinning thymus generation and the potential to manipulate it clinically to ensure a healthy population of T cells. The lab has shown that epithelial-mesenchymal hybrid cells, capable of long-term expansion in vitro, can be used to reconstitute an anatomic phenocopy of the native thymus, when combined with thymic interstitial cells and a natural decellularised extracellular matrix (ECM) obtained by whole thymus perfusion. This anatomical human thymus reconstruction is functional, as judged by its capacity to support mature T cell development in vivo after transplantation into humanised immunodeficient mice. These findings establish a basis for dissecting the cellular and molecular crosstalk between stroma, ECM and thymocytes, and offer practical prospects for treating congenital and acquired immunological diseases.
Jernej Ule
How do protein-RNA condensates form and contribute to disease?听
Mutations in many genes encoding RNA-binding proteins (RBPs) cause neurologic diseases, and these tend to be located within intrinsically disordered regions (IDRs). To understand how these mutations act, we employed crosslinking and Immunoprecipitation (CLIP) to obtain maps of in vivo protein-RNA and RNA-RNA interactions. This showed that changes in IDRs can selectively tune the RNA binding properties and functions of an RBP, which are additionally shaped by the arrangements of RNA binding motifs and RNA structure. Taken together, I'll discuss transcriptomic approaches that can unravel the specificity of RBP condensation, and how this opens new doors for understanding signalling, disease and evolution.
Edina Rosta
Computational modelling of phosphate catalytic reactions
Phosphate catalytic enzymes are essential in all living organisms. Here, I will describe atomistic molecular simulations of two phosphate catalytic systems: D-Ala-D-Ala ligase (DDL) and the SARS-CoV-2 helicase. We carried out QM/MM free energy calculations to understand key details about the elusive rate-limiting proton transfer steps of the catalytic reaction of DDL. Our results pinpoint to a key residue that is subsequently also shown to inactivate the enzyme in biochemical assays. Furthermore, we highlight the close structural similarity between the DDL active site and kinase ATP binding sites that are key drug targets against many cancers.
I will also present MD simulation results on the structure and dynamics of the SARS-CoV-2 RNA helicase, NSP13, a key component of the transcription complex of the SARS-CoV-2 virus. We modelled the catalytically competent helicase active site, revealing novel coronaviridae-specific binding pockets.
Unpublished work was shared in this presentation and therefore the recording will be made available at a later date.听
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