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- A multi-pronged approach to targeting myeloproliferative neoplasms
- A new paradigm of machine learning-based structural variant detection
- A whole lot of junk or a treasure trove of discovery?
- Advanced imaging interrogation of pathogen induced NETosis
- Analysing the metabolic interactions in brain cancer
- Atopic dermatitis causes and treatments
- Boosting the efficacy of immunotherapy in lung cancer
- Building a cell history recorder using synthetic biology for longitudinal patient monitoring
- Characterisation of malaria parasite proteins exported into infected liver cells
- Deciphering the heterogeneity of the tissue microenvironment by multiplexed 3D imaging
- Defining the mechanisms of thymic involution and regeneration
- Delineating the molecular and cellular origins of liver cancer to identify therapeutic targets
- Developing computational methods for spatial transcriptomics data
- Developing drugs to block malaria transmission
- Developing models for prevention of hereditary ovarian cancer
- Developing statistical frameworks for analysing next generation sequencing data
- Development and mechanism of action of novel antimalarials
- Development of novel RNA sequencing protocols for gene expression analysis
- Discoveries in red blood cell production and function
- Discovering epigenetic silencing mechanisms in female stem cells
- Discovery and targeting of novel regulators of transcription
- Dissecting host cell invasion by the diarrhoeal pathogen Cryptosporidium
- Dissecting mechanisms of cytokine signalling
- Doublecortin-like kinases, drug targets in cancer and neurological disorders
- Epigenetic biomarkers of tuberculosis infection
- Epigenetics – genome wide multiplexed single-cell CUT&Tag assay development
- Exploiting cell death pathways in regulatory T cells for cancer immunotherapy
- Exploiting the cell death pathway to fight Schistosomiasis
- Finding treatments for chromatin disorders of intellectual disability
- Functional epigenomics in human B cells
- How do nutrition interventions and interruption of malaria infection influence development of immunity in sub-Saharan African children?
- Human lung protective immunity to tuberculosis
- Improving therapy in glioblastoma multiforme by activating complimentary programmed cell death pathways
- Innovating novel diagnostic tools for infectious disease control
- Integrative analysis of single cell RNAseq and ATAC-seq data
- Interaction with Toxoplasma parasites and the brain
- Interactions between tumour cells and their microenvironment in non-small cell lung cancer
- Investigation of a novel cell death protein
- Malaria: going bananas for sex
- Mapping spatial variation in gene and transcript expression across tissues
- Mechanisms of Wnt secretion and transport
- Multi-modal computational investigation of single-cell communication in metastatic cancer
- Nanoparticle delivery of antibody mRNA into cells to treat liver diseases
- Naturally acquired immune response to malaria parasites
- Organoid-based discovery of new drug combinations for bowel cancer
- Organoid-based precision medicine approaches for oral cancer
- Removal of tissue contaminations from RNA-seq data
- Reversing antimalarial resistance in human malaria parasites
- Role of glycosylation in malaria parasite infection of liver cells, red blood cells and mosquitoes
- Screening for novel genetic causes of primary immunodeficiency
- Single-cell ATAC CRISPR screening – Illuminate chromatin accessibility changes in genome wide CRISPR screens
- Spatial single-cell CRISPR screening – All in one screen: Where? Who? What?
- Statistical analysis of single-cell multi-omics data
- Structural and functional analysis of epigenetic multi-protein complexes in genome regulation
- Structural basing for Wnt acylation
- Structure, dynamics and impact of extra-chromosomal DNA in cancer
- Targeted deletion of disease-causing T cells
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- The cellular and molecular calculation of life and death in lymphocyte regulation
- The role of hypoxia in cell death and inflammation
- The role of ribosylation in co-ordinating cell death and inflammation
- Understanding Plasmodium falciparum invasion of red blood cells
- Understanding cellular-cross talk within a tumour microenvironment
- Understanding the genetics of neutrophil maturation
- Understanding the roles of E3 ubiquitin ligases in health and disease
- Unveiling the heterogeneity of small cell lung cancer
- Using combination immunotherapy to tackle heterogeneous brain tumours
- Using intravital microscopy for immunotherapy against brain tumours
- Using nanobodies to understand malaria invasion and transmission
- Using structural biology to understand programmed cell death
- Validation and application of serological markers of previous exposure to malaria
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Jerry Adams-Projects
Researcher:
Determining the structure of the oligomers of Bak and Bax
As we have reviewed recently (Adams and Cory, Cell Death and Differentiation, 2017), the pivotal step in commitment of cells to undergo apoptosis is the formation of oligomers of Bak or Bax that permeabilise the mitochondrial outer membrane, but the structure of these oligomers remains unknown. To gain insights into their structures, we have devised a way to isolate substantial amounts of pure oligomers from mammalian cells, and are attempting to define their structures by both x-ray crystallography and cryoEM.
Clarifying how oligomeric Bak and Bax perforate the mitochondrial outer membrane
Although permeabilisation of the mitochondrial outer membrane (MOM) by oligomers of Bak and Bax is the pivotal event in apoptosis, how the topology of these proteins with respect to the MOM changes on oligomerisation has been unknown. It had been thought that several helices of Bax and Bak penetrate the membrane to initiate pore formation.
However, our studies with Dr Ruth Kluck’s lab at the Institute suggest instead that these helices insert only shallowly into the MOM, in-plane with it, and most likely disrupt its integrity by crowding the outer leaflet and forming proteolipidic pores (Westphal et al, Proc Natl Acad Sci USA 2014).
Defining early steps in activation of Bax
In unstressed cells, Bax is mainly a cytosolic monomer with its membrane anchor (a9) tucked into a surface groove. To perform its apoptotic function, Bax must first dislodge a9, so that it can accumulate on the MOM, but the trigger for this is uncertain. It has been proposed that binding to a novel site remote from the cognate surface groove on Bax provokes release of a9, but this site remains poorly defined.
By structural and mutagenic analysis, we are clarifying how this binding site contributes to Bax activation. Our recent work has identified several mutations in Bax that affect this non-canonical site. Their analysis suggests that engagement of this site controls the translocation of Bax to the mitochondria via the allosteric release of a9 and an altered balance of Bax conformers.