The liver flukes O. viverrini and C. sinensis remain a major heath burden throughout eastern Asia. They are recognized as group I carcinogens by the International Agency for Research on Cancer (IARC). Long-term infections lead to Cholangiocarcinoma (CCA), a bile-duct cancer with very poor prognosis. Liver flukes release proteins that exacerbate cancer development, but the proximate mechanisms responsible for cells malignant transformation remain unknown. We have identified viruses associated with these liver flukes and showed that some of these are excreted by parasites. Here, we propose to investigate the role of these viruses in cancer, which may lead to new treatments or preventive therapies for CCA. Our central hypothesis is that viruses of liver flukes can impact host health by modulating host immune response, infecting host cells, and modulating the excretion of parasite virulence factors. We aim to obtain funding from the US National Institutes of Health (NIH) involving the National Cancer Institute (NCI) in response to the funding opportunity announcement (FOA) PAR-23-055 Co-infection and Cancer (R01). This FOA aims to enhance epidemiological and mechanistic investigations focusing on micro- and macro-organisms co-infections with a known oncogenic agent to determine how they contribute to carcinogenesis and identify novel opportunities for prevention and treatment. ParVirCancer involves four partners that have been involved for decades in the study of infectious diseases and public health. All collaborators are leaders in their field with substantial track record and demonstrate complementary expertise - in virology at Institut Pasteur Paris - in liver flukes CCA at Khon Kaen University - in molecular parasitology at George Washington University -, and in proteomics of parasite excretory secretory vesicles at James Cook University. The scientific excellence of the partners, access to biological samples, availability and already developed protocols and access to Biological Safety laboratory and animal experiment infrastructures needed for the project makes them uniquely situated and qualified to conduct this project and develop follow-up therapeutic and preventive applications.

On coastal reefs (0-50 m depth), perhaps more than anywhere in the world, natural and human systems share a history of strong dependence that must be taken into account to maintain, on one side, the long-term human development and well-being, and, on the other side, biodiversity. This biodiversity translates directly into services. Reef fishes support the nutritional and economic needs of people in many poor countries while hosting the major part of marine life on Earth (25%). However world's reefs are severely over-fished or have degraded habitats. Avoiding or escaping this negative spiral and identifying the most vulnerable reef social-ecological systems on Earth are among the major issues that scientists and managers are facing today. The project aims to move beyond the typical over-simplified ‘human impacts’ storyline and focus on uncovering new solutions based on a prospective and integrated modelling approach of reef social-ecological systems at the global scale with three objectives: 1.Quantifying five key services provided by reef fishes: (i) biomass production providing livelihoods, (ii) nutrient cycling that affects productivity, (iii) regulation of the carbon cycle that affects CO2 concentration, (iv) cultural value that sustains well-being tourism activities and (v) nutritional value insuring food security. 2.Determine the conditions (socioeconomic and environmental) under which these ecosystem services are currently maintained or threatened. Based on a global database of fish surveys over more than 5,000 reefs that encompass wide gradients of environments, human influences (fishing impact), and habitats, we will estimate the boundaries or thresholds beyond which these ecosystem services may collapse. 3.Predict the potential futures of these services and social-ecological systems under various global change scenarios. Using multiple integrated scenarios (human demography, economic development and climate change) and predictive models we will simulate the dynamics of shallow reef ecosystems and their ability to deliver services during the next century.

PICPOSS seeks to develop a continuous flow process for the sustainable production of fine chemicals and pharmaceuticals through sensitized photo-oxygenations. Various LED-driven microreactors will be constructed: due to their dimensions, mass, heat and light transfer phenomena are enhanced, thus enabling yields and selectivity to be increased, and safe and photon-efficient conditions to be possible. Contrary to conventionally studies reported in the literature, the sensitizer will not be solubilized in the reaction medium, but supported on silica/polymer beads or inside colloid systems instead. The advantage is to reduce downstream separation processes and to develop a new photochemical synthesis concept. Gas-liquid-solid “slurry Taylor” flows will be generated in flow reactors which can be readily adopted for industrial application using meso-scale continuous equipment. PICPOSS will focus on two benchmark reactions of industrial relevance: the photo-oxygenation of alpha-terpinene, a common essential oil component, and of furfural obtained from hemicelluloses contacting waste from agriculture. PICPOSS combines chemical engineering & process intensification (LGC-Toulouse. K. Loubière), mechanistic photochemistry (ICMR-Reims, N. Hoffmann), solid-supported sensitizer development (IPREM-Pau, S. Lacombe), organic chemistry and trioxane preparation (LCC-Toulouse, O. Dechy-Cabaret), and applied flow photochemistry (JCU-Australia, M. Oelgemoeller). PICPOSS involves four scientific tasks, supported by task 0 (coordination). Task 1 aims at studying benchmark photo-oxygenations in batch reactors. Eco-friendly solvents will be studied and various sensitizers investigated (commercially available, advanced sensitizers synthesized in Task 3). Side reactions (including sensitizer decomposition) will be determined, and analytical conditions for an easy reaction monitoring in microreactors will be established. Task 2 is devoted to the transfer of the benchmark photo-oxygenations to microreactors using solubilized photosensitizers. It also includes the characterization of gas-liquid mass transfer in microreactors and the determination of the incident photon flux. Task 3 concerns the preparation and characterization of various sensitizing materials. Commercial and advanced lab-made sensitizers will be firstly surface-fixed on commercial silica/polymer beads. Then, sensitizing colloids systems (polymer particle, microgel) will be synthetized as they offer higher surface area and/or enable core-functionalization. These materials will be characterized and their stability, photobleaching, turnover frequency and quantum yields of singlet oxygen production will be evaluated. The most efficient and stable sensitizing materials will be tested in batch reactors in view of their implementation in microreactors. In Task 4, photo-oxygenations will be carried out in microreactors using sensitizing materials. For each reaction, a screening of operating conditions will be performed to define an operating domain and to maximize the reaction’s outputs. Experiments will be also implemented in meso-scale flow-equipment to demonstrate proof-of-concept for scale-up. Finally, the performances of the different batch and microreactors will be compared depending on the sensitizing materials. Likewise, the effectiveness of the advanced solid-supported sensitizers will be demonstrated by comparison with their solubilized counterparts. Combining experiments and modelling tools, guidelines will be established to assess the feasibility of flow photochemistry with sensitizing materials, and to address smart scale-up issues. The breakthroughs developed will overcome safety and cost concerns of currently available technologies (batch reactors, energy-demanding mercury lamps), and thus open new opportunities for industrial synthesis of valuable fine chemicals via sensitized photo-oxygenation.

Climate change is threatening marine life worldwide. Coral reefs, which harbor 1/3 of world’s marine biodiversity and provide ecosystem goods and services to > 500 million people worldwide, are expected to experience severe negative impacts due to climate change. The increasing carbon dioxide (CO2) in the atmosphere is driving increased CO2 diffusion into the ocean. Current understanding of the effects of this ‘ocean acidification’ (OA) on marine biodiversity and ecosystem functioning is primarily based on short-term laboratory experiments on individual species. Although many of these experiments suggest dramatic impacts of OA, including the dissolution of carbonate structures and decreased coral calcification rates, short term experiments potentially overestimate such effects because they are too brief for organism acclimatization and/or adaptation to occur. Consequently, there is a pressing need for empirical data documenting the physiology, acclimatization, demographic rates and ecological functioning of coral communities that have been exposed to elevated pCO2 over multiple generations. Natural CO2 seeps have been recently revealed as natural analogues to assess OA effects at the ecosystem level. Studies at CO2 seeps at d’Entrecasteaux Islands in Papua New Guinea have shown coral communities surviving at chronically high pCO2, although these communities are dominated by mound-shaped rather than branching coral species. The CARiOCA project proposes to use this unique site, which has seawater conditions similar to those expected at the end of this century, to identify the phenotypic traits that allow certain coral species to survive and reproduce in seawater naturally enriched in CO2. This will give new insights into the mechanisms that underlie acclimatization and adaptation to climate change. As physiological acclimation is critical in shaping species environmental tolerances this project will, for the first time, link long- and short-term changes in gene expression to changes in organismal physiology and demographic rates, and to shifts in the species composition of coral communities. Coral responses will be investigated at different levels of organization: i) short- and long-term variation in differential gene expression; ii) variation in Symbiodinium communities; iii) variation in coral-associated Symbiodinium and host-associated bacterial communities; iv) colony-level changes in physiology of the coral holobiont; and v) scale-up from changes occurring at molecular and physiological levels to changes in population demographic rates. This approach allows us to establish the specific physiological traits that enable certain species to survive under high CO2 conditions. Our objectives will be achieved via four integrated components: project management (WP #1), fieldwork (WP #2), molecular and microbial analyses (WP #3), and physiological modeling (WP #4). WP #1 will coordinate the project and build a common database to foster the production of joint papers. WP# 2 is dedicated to the acquisition of data during two field expeditions. WP #3 will implement molecular and microbial analyses. WP#4 will coordinate the analyses of the project data and develop and parameterize a ‘scope for growth’ model based on coral physiological energetics. This model will be validated using field observations of coral growth and reproduction from the study locations. CARiOCA will make a significant contribution to the preservation of coral reefs by providing innovative and mechanistic data that resolve, for the first time, whether and how corals acclimatize and/or adapt to OA. These results will allow robust projections of the future biodiversity and ecological functioning of coral reefs by identifying coral species that are likely to dominate coral reefs in a high CO2 world.

A highly effective malaria vaccine against Plasmodium falciparum should help prevent half a million deaths from malaria each year. New vaccine technologies and antigen discovery approaches now make accelerated design and development of a highly effective multi-antigen multi-stage subunit vaccine feasible. Leading malariologists, vaccine researchers and product developers will here collaborate in an exciting programme of antigen discovery science linked to rapid clinical development of new vaccine candidates. Our approach tackles the toughest problems in malaria vaccine design: choice of the best antigens, attaining high immunogenicity, avoiding polymorphic antigens and increasing the durability of vaccine immunogenicity and efficacy. We take advantage of several recent advances in vaccinology and adopt some very new technologies: sequencing malaria peptides eluted from the HLA molecules, parasites expressing multiple transgenes, multi-antigen virus-like particles constructed with new bonding technologies, delayed release microcapsules, and liver-targeted immunisation with vaccine vectors. We enhance our chances of success by using a multi-stage multi-antigen approach, by optimising the magnitude and durability of well-characterised immune responses to key antigens, and using stringent infectious challenges and functional assays as established criteria for progression at each stage. The consortium comprises many of the foremost researchers in this field in Europe with leading groups in the USA, Australia and Africa. We link to EDCTP programmes and harmonise our timeline to fit with the recent roadmaps for malaria vaccine development. We include a major pharma partner and several excellent European biotech companies helping enhance Europe’s leading position in the commercial development of vaccines. This ambitious and exciting programme should have a high chance of success in tackling the major global health problem posed by malaria.