Photoacoustic (PA) imaging is a novel imaging technique that combines the high spatial resolution of ultrasound imaging and the specificity of optical imaging techniques. To achieve good contrast in vivo, PA imaging relies on the optical properties of endogenous molecules. However, many clinically relevant biological species are optically silent, and would require an imaging agent to target them with good specificity while remaining photostable and retaining good bioavailability. Recently, the Tabor group has succeeded in specifically targeting a pDNA delivery nanoparticle to EGFR receptors, overexpressed on the surface of cancer cells, by introducing pendant targeting peptides into the nanoparticle scaffold. Coformulated with lipids and amphiphilic moieties such as PEG and DPPC, these coated nanoparticles have good retention times and their functionalised core remains protected from degradation. Based on the recent synthesis by the Bronstein group of indigo-derived semiconducting polymers (INDT-X) with excellent PA potential, the aim of this project is to formulate EGFR-targeting INDT species within a semiconducting polymer nanoparticle (SPN) scaffold, to produce a safe and performant PA contrast agent for the clinical and pre-clinical imaging of a variety of cancers.

Virtually every decision people make comes with a sense of confidence - a subjective estimate of decision quality. The human capacity for confidence has tremendous social, clinical, and industrial impact. For example, children who can correctly judge their own level of confidence perform better academically. In the elderly, confidence declines faster than other cognitive functions. Clinically, confidence plays a key role in our understanding of various brain-related disorders, including dementia, anxiety, addiction, and depression. In industry, confidence helps people trust algorithms and automated systems, and creates more natural interactions with smartphones and self-driving cars. While the past decade has seen major advances in our scientific understanding of decision confidence, its mechanisms remain poorly understood. This lack of understanding significantly hampers the translation to real-world applications, such as educational programmes and clinical interventions. A major challenge for the immediate future is to fill this gap, by expanding fundamental knowledge on decision confidence and explicitly bridging to technologies, interventions, and clinical practice. CODE aims to address this need. We are an international, interdisciplinary and intersectoral training network that spans fundamental and applied confidence-based research, and bridges between academia, industry, education, and the clinic. By reaching across domains that usually work in silos, CODE will provide critical new insights into decision confidence, and pave the way for important future confidence-based applications. We will train doctoral students to become the interdisciplinary decision confidence experts of the future, who can flexibly apply their knowledge and skills

Antimicrobial resistance (AMR) is an increasing problem pertaining to all bacterial infections, including tuberculosis (TB), caused by infection with Mycobacterium tuberculosis. According to the latest WHO estimates, drug resistant TB lead to around 240 000 deaths in 2016. Unlike most other pathogens, M. tuberculosis does not rely on plasmid-borne resistance. Instead, M. tuberculosis expresses several natural drug resistance machines called efflux pumps, which excrete anti-bacterial drugs that enter the cell. Transcription is the process of copying DNA to RNA, which is subsequently decoded to synthesise proteins. One way of controlling gene expression is by premature termination of transcription, i.e. the process of transcription is initiated but not completed, meaning there is no RNA to decode and hence no protein is expressed. However, premature termination of transcription can be regulated by physical or molecular signals, in which case it is referred to as conditional termination. Recently, several efflux pumps were shown to be regulated by conditional termination in Bacillus subtilis, Enterococcus faecalis and Listeria monocytogenes, and similar mechanisms are likely to be widespread in other bacteria including M. tuberculosis. The aim of this project is to apply very recently developed methods based on Next-generation sequencing to (1) define the abundance of conditional terminators in M. tuberculosis, and (2) determine to what extent natural resistance mechanisms in M. tuberculosis are controlled by such conditional terminators and (3) to what extent anti-TB drugs control overall gene expression in M. tuberculosis. The successful completion of this project will shed light on regulatory aspects of M. tuberculosis's natural drug resistance, and further our understanding of how anti-TB drugs may contribute to and possibly enhance this drug resistance.

I aim to use HIV to study the process of cytoplasmic DNA sensing and HIV innate immune evasion mechanisms. Lentiviruses synthesise DNA outside the nucleus making them an excellent probe for this system. I propose to build on our finding that HIV-1 utlises a series of highly orchestrated cofactor interactions that simultaneously regulate viral DNA synthesis, uncoating, nuclear transport and evasion of DNA sensing. I will take a multidisciplinary approach, combining molecular virology with structu ral investigations, accessed through collaboration, to describe the details of DNA sensing, the downstream pathways activated and the activation of transcriptions factors including NFkB and IRF3. Key goals are to discover how lentiviruses evade or antagonize sensing through cellular cofactor recruitment and viral accessory gene activity but also to understand why viruses fail to evade/antagonize DNA sensing in certain cases. Taking a comparative virology approach we will discover how DNA sensing has protected us from simian viruses and rare HIV variants. Together, this work will reveal the biology of DNA sensing as well as contributing to our understanding of species barriers to infection and HIV/AIDS pathogenesis. Finally, I aim to apply our new knowledge of sensing to understand whether the most effective immune responses against HIV and the most effective drugs used to treat HIV/AIDS gain potency by disturbing innate immune evasion and unleashing the innate immune system for maximum antiviral effect. This new knowledge will be particularly important in a world where we will increasingly depend on global treatment and vaccination of viral infection.