The human gut is home to a wide range of bacteria, and every adult harbours around 100 trillion microbial cells in their intestines belonging to hundreds of bacterial species. This population of bacteria is referred to as the gut microbiota, and these bacteria are thought to undertake numerous beneficial activities. However some of the activities undertaken by the gut microbiota may be involved in the development of colorectal cancer (CRC). Diet, and in particular a high intake of animal fat and red meat, has been identified as a major risk factor for CRC, but it is not yet clear how these dietary factors lead to the development of CRC. It is important for us to understand the causes of diseases like CRC, in order to develop effective treatments or identify ways in which the disease could be prevented altogether. Recent studies have indicated that the gut microbiota may be an important factor in the influence of diet on CRC risk, and in particular the ability of gut microbes to modify components of bile, called bile acids. Bile acids are naturally produced by our bodies to help us digest the fat contained within the food we eat, and a diet rich in fat results in a increased level of bile acid in the intestine. Bile acids are readily converted to different forms by the gut microbiota, and some of these altered bile acids may be carcinogenic and affect the expression of genes thought to be important in the development of CRC. The purpose of this study is to investigate the relationship between the modification of bile acids by gut bacteria and development of CRC, to determine how these microbes may cause this disease. By comparing the gut bacteria of individuals with CRC and those who are healthy, we will be able to identify any association between activities of these microbes and risk of disease. Subsequently we will be able to look at the effect of these bacteria on specific human genes known to be associated with CRC, which will allow us to identify the how gut bacteria may trigger development of CRC.

The project aims to gain a new understanding on the effects of the surface properties on fundamental mechanisms in boiling heat transfer. The insight gained will provide guidelines for designing smart surfaces for more efficient and safer thermal applications. The approach consists in tackling the problem with the most advanced experimental diagnostic and sophisticated numerical simulations. The researcher demonstrates to have a clear foundation to successfully develop the project because of his solid background in two-phase heat transfer, his proficiency in measurement techniques, his strong expertise in nanotechnology and his very good computational skills. MIT and UoB are outfitted respectively with unique and ad-hoc experimental and numerical capabilities to achieve the objectives of the proposal. The fellowship will boost the researcher’s expertise towards a position of excellence by enhancing his experimental skills with cutting-edge techniques and diversifying his profile with numerical techniques and transferable skills valuable for his career prospects. The fellowship will establish a new network between the organizations and increase the internationalization of the researcher aiming to become an independent and mature research leader. The project fits into different pillars of Horizon 2020: 1) Societal Challenges: Secure, clean, and efficient energy. It aims to provide new knowledge to increase the efficiency and enhance the safety of different energy processes (important for reducing the CO2 emissions); 2) Excellence Science: Future and Emerging Technologies. It aims to identify the surface effects on heat transfer mechanisms, which could be exploited for developing new energy technologies; 3) Industrial Leadership: Nanotechnologies, Advanced Materials, Advanced Manufacturing and Processing, and Biotechnology. It involves nanotechnology to engineer the surfaces that could be scaled up to industrial applications.

The proposal aims at the synthesis, characterisation and application of a novel therapeutic nanovaccine (TNVax) that holds multiple modules for targeting glioblastoma multiforme (GBM). The proposed TNVax formulation includes a gold nanocage core encapsulating Temozolamide (TMZ), coated with an extremophilic bacterial polysaccharide, mauran functionalised with anti-PD-L1 antibody and anti-CD133 antibody. The us of NVax nanoparticles (NPs) offers a combinatorial approach in killing GBM cells both by immuno- and chemo- therapeutically. Site-specific delivery of the payload will stimulate the host immune system and channel the immune cells to the target site. Functionalisation of the anti-PD-L1 antibody on drug-encapsulated NPs would significantly alter the immune suppression caused by GBM cells on TNVax delivery. In addition to anti-PD-L1 antibody, the TNVax particles contain tumour specific monoclonal antibody that specifically recognizes CD133 antigen and facilitates strong binding. This approach would enhance the amount of antitumour activity offered by multiple means and thereby leaving a strong immune response against GBM based on antigen-antibody interactions. TNVax NPs will be synthesised and characterised using microscopic and spectroscopic techniques and then subjected to in vitro and in vivo evaluations. In vitro studies will be performed for drug release kinetics and cytotoxicity using immunofluorescence and FACS analysis. Induction of immune response by TNVax NPs will be evaluated using macrophage activation, induction of T-cell activity and cytokine production under in vitro conditions. The pharmacokinetic and pharmacodynamic studies will be carried out and histopathological examinations performed using appropriate murine models induced with GBM cell lines. The potential outcomes of the proposed studies will help patients who suffer from early and advanced GBM by eradicating the disease permanently and leaving good immunological memory.

Malaria continues its reign as one of the largest causes of death in the developing world. Currently, the main therapeutic strategy is drug administration, or chemotherapy. The drug chloroquine is one of the most widely used anti-malarial agents. Chloroquine enters the malarial parasite whilst it resides in red blood cells (erythrocytes). During this period the parasite grows by virtue of digesting the protein rich erythrocyte environment. This digestion occurs within a specific compartment of the parasite, known as the food vacuole. Chloroquine also enters the food vacuole and inhibits a specific pathway involved in digestion of erythrocyte proteins. In turn, this causes a build up of toxic by-products and ultimately leads to death of the parasite. Unfortunately, in many regions worldwide, the malaria parasites have built up a resistance to chloroquine, and many other anti-malarial drugs. There are numerous pathways contributing to resistance in malaria, but the main one associated with chloroquine resistance is caused by mutations in the PfCRT gene. The PfCRT gene produces a protein that resides on the surface of the food vacuole and is thought to confer resistance by altering the amount of chloroquine accumulating in this compartment. It is unclear what this protein does normally in the parasite and what consequences the mutations have on its activity. Our primary aim is to determine how the PfCRT protein contributes to resistance against chloroquine and whether its actions can be overcome. To enable us to reach this objective, we have developed a novel experimental system to directly examine PfCRT activity in isolation. The system will enable us to examine the following key issues: (i) Providing information on which anti-malarial drugs (other than chloroquine) are targeted by PfCRT and therefore succumb to resistance. (ii) Catalogue compounds capable of inhibiting PfCRT, which could potentially restore chloroquine accumulation and overcome resistance. Positive compounds could be used in future chemical programs to develop more potent agents. (iii) Determine whether PfCRT pumps drugs in an energy dependent manner or by simply acting as a pore through which chloroquine can exit the food vacuole. Providing a greater understanding of how PfCRT causes resistance to chloroquine in malaria will significantly enhance future strategies to overcome its unwanted activity and thereby circumvent the resistance to chemotherapy.