Minister O’Donovan announces funding boost for early career researchers

The origins of structural colour in nature has been traced back over 515 million years. In the plant and animal kingdoms, its presence has been attributed to camouflage, signalling, mimicry, and distraction. As the vibrancy and striking reflection suggest, the mysticism of structural colouration is found in its incredible intricacy, and the ability to create multilayer reflectors, diffracting grating, and scattering features, using naturally high refractive index materials, such as guanine, cellulose, and chitin on the nano and macro scales. Not only do these give rise to the most beautiful and strongest colours observed in nature, the dazzling iridescent shades of such as beetles, butterflies, chameleons, but they can actually be modulated by in a split second to blend in, stand out, or completely disappear. While scientists have agreed on the value of such materials, synthetic analogues with such functionality have not come close to the complexity or responsiveness of hierarchical photonic structures found in nature. This project will combine, self-assembling nano materials, stimuli-responsive polymers, 2 photon-polymerisation, and numerical simulation to yield programmable photonic structures, colour-mixing, angle independent colouration, and image encryption, which represent a new generation of dynamic photonic devices.

Natural killer (NK) cells are a critical component of the anti-tumour response. NK cells are involved in immune surveillance and are highly cytotoxic against tumour cells. A loss of NK cell activity results in increased tumour burden and poor prognosis, as is observed in obesity. Recently, Mucosal Associated Invariant T (MAIT) cells have been highlighted as potent regulators of NK cells. MAIT cells can drive strong NK cell responses via their production of interferon-gamma (IFN-?). Conversely, interleukin-17 (IL-17) production by MAIT cells inhibits NK cells, leading to tumour progression in murine models of disease. In obesity, MAIT cells display defective IFN-? production with a strong IL-17 bias. It is currently unknown if altered MAIT cells in obesity are driving/exacerbating the defective NK cell responses reported. In the proposed study, we aim to elucidate the molecular and metabolic mechanisms via which MAIT cells regulate NK cell responses in the steady state. We will also investigate how “obese” MAIT cells dysregulate NK cells. Finally, we aim to explore if glucagon like peptide-1 (GLP-1), a potent weight therapy, GSK3 inhibitor and ROS scavengers can normalize MAIT-NK cell interactions in people with obesity.

1. establish the primary motor cortex as a novel target for brain stimulation
2. implement closed-loop stimulation aligned to symptom severity

Macrophages are capable of a remarkable array of functions, that differ by tissue and inflammatory status. Most macrophages in the body are tissue-resident and perform homeostatic functions. However, during inflammation monocytes recruited to tissues, differentiate into pro-inflammatory M1 macrophages through exposure to type 1 cytokines. Resolution of inflammation, or exposure to type 2 cytokines, leads to macrophages adopting the anti-inflammatory pro-repair M2 phenotype. My findings indicate that adoption of tissue residency alters their functional capacity to become M1 or M2 activated. To explore this further, we will investigate the disease ANCA-associated vasculitis (AAV), which is characterised by irreversible macrophage-driven damage to the kidney. We will first create a model of macrophage differentiation in the inflamed kidney that will act as framework for understanding how macrophages drive both repair injury. We will next use a model of AAV to show that macrophage differentiation paths can be modified therapeutically, to shift away from inflammatory M1 phenotypes towards adoption of tissue residency that supports resolution of inflammation in autoimmunity. The outputs of this project will provide the basis for development of urinary biomarkers of kidney inflammation and highlight druggable targets in autoimmune kidney disease.

Spreading manure fertilizer in farming is key to recycling the macronutrients of Nitrogen, Phosphorus, and Potassium (‘NPK’), essential for plant growth. The Nitrogen content of manures (e.g., cattle slurry), however, requires significant supplementation from Nitrogen-based chemical fertilizers, an essential component in achieving the high growth yields required to sustain current food production. Nitrogen-based fertilizer is currently produced using natural gas in the Haber- Bosch process contributing ~2-3 % to annual global greenhouse gas emissions. The low Nitrogen content in manures is exacerbated by the Nitrogen loss from ammonia outgassing during storage and land spreading. While this ammonia is not a greenhouse gas it is a very damaging air pollutant that is not only detrimental to human health but has a destabilizing impact on sensitive ecosystems resulting in a loss of biodiversity. The use of acid supplements to halt ammonia losses from manures is an emerging solution. This project proposes the novel use of plasma-produced nitric acid as a slurry additive to lower the climate and air polluting impacts of manures while also enhancing manure Nitrogen content. Plasma technology powered by renewable electricity requires only air and water as a feedstock offering a zero-emissions alternative to the current greenhouse gas emitting Haber-Bosch process.

Are we alone in the Universe? This is one of the most important questions humanity is facing today. For long the only planet thought to potentially harbour alien life was Mars, but with the exploration of the outer Solar System came the realisation that alien life might exist on ocean bearing moons in the outer Solar System. This is the reason why the largest space agencies in the world are currently focusing on exploration of the Jovian moons, like the ESA mission Jupiter Icy Moons Explorer (JUICE). JUICE will study Jupiter and its space environment, with a special focus on the habitability of Jupiter's moons. In September 2024, JUICE will encounter its first science targets as it performs its first swing-by of the Moon. The swing-by will provide an unprecedented opportunity to explore the plasma environment of the Moon and its interaction with the magnetosphere of Earth, with a payload that can provide more detailed and accurate observation than ever before. This will be important not only for our understanding of the Moon - magnetosphere system of Earth, which is crucial for future moon missions, but also for the future moon explorations that JUICE will perform in the Jovian system.

Multiple Myeloma (MM) is an incurable malignancy driven by uncontrolled plasma cell growth. Improved therapeutic targets and combinations are urgently required. Anti-apoptotic BCL-2 family proteins are attractive targets, with inhibitors (venetoclax) already in trial/use. Venetoclax displays highest efficacy in t(11;14) translocated patients. However, it is unclear why translocation of CCND1 induces BCL-2 dependence and confers venetoclax sensitivity. Therefore, we aim to understand the molecular mechanisms determining venetoclax sensitivity, and exploit these mechanisms for broader therapeutic benefit across non-translocated patients. Epigenetic cancer therapies are promising due to the abundance of different modulator compounds which tend to be well- tolerated by patients. To understand reliance on BCL-2 in translocated patients, I will use state-of-the-art epigenetic profiling techniques including CUT&Tag and 4C-seq to compare BCL-2 regulatory mechanisms between t(11,14) and non-t(11,14) MM. Additionally, I will carry out a functional CRISPR screen in venetoclax-resistant MM cells to identify epigenetic regulators whose disruption sensitizes non-translocated cells to venetoclax. Finally, I will perform epigenetic compound treatments and CUT&Tag mapping of epigenetic features in primary patient MM samples as proof-of-concept of epigenetic sensitization to venetoclax treatment. Combining venetoclax with epigenetic modifiers could be an effective strategy for elderly patients that cannot handle aggressive treatment regimes such as chemotherapy.

Premature termination codons (PTC) are responsible for multiple human genetic diseases with no established therapeutic options. PTC suppression during translation has promise for treating genetic disorders, however small molecules promoting PTC read-through have not thrived in clinical trials. RNA therapeutics are an attractive alternative to traditional small molecule approaches as discovery can benefit from intuitive rational design and directed evolution. Transfer RNA (tRNA) molecules have been rationally engineered to decode in-frame PTCs while maintaining amino acid specificity. However, tRNA PTC suppression efficiency and therapeutic delivery are limiting the potential of these therapies. I propose to overcome these limitations by: Investigating RNA delivery vectors consisting of immature or pre-tRNA molecules to increase molecule stability during therapeutic delivery, evaluation of natural RNA modifications in the context of therapeutic delivery for increased thermal stability and resistance to RNA degradation and directed evolution of PTC suppressor tRNA molecules for enhanced suppression activities, while maintaining amino acid fidelity. If successful, this proposal will yield new biomolecules to treat human genetic disease where no current therapeutic exists. It will provide a general platform for discovery of PTC suppressor tRNAs with retained amino acid identity and provide new designs for RNA delivery vectors of small RNA therapeutics.

Gut bacteria synthesise a repertoire of uncharacterised lipids; how are they differentially influencing health and disease and how can they be exploited for health benefits? Although a new and evolving area, certain bacterial lipids are already shown to have important bioactivity e.g., some gut associated bacteria produce diverse inflammatory modulating sphingolipids, others produce novel glycine lipids (our work) which are potent ligands of host Toll-like receptor 2 (TLR2) with both pro-, and anti- inflammatory capacity. AIM: BLOOD will provide extend and improve our knowledge by (1) providing a comprehensive, open- access bacterial lipid database (BacLipidMaps) via liquid-chromatography-mass spectrometry based lipidomics and supporting software (2) establishing the type and range of bacterial lipids in humans across various states of heath and disease by profiling biobanked human plasma and faecal samples and utilising data repositories (such as MetaboLights) for appropriate human lipidomic data and (3) isolating specific bacterial lipids and determining their roles in microbe-microbe and microbe- host interactions via shotgun sequencing, mammalian cell culture and gene expression profiling. BLOOD represents the first large-scale, comprehensive, and qualitative comparison of the lipidome of gut associated bacteria. It will uncover novel
bacterial lipids that may represent an avenue for the development of biomarkers and/or therapeutics of disease.

Wound is one of the most common health issues worldwide. Annually, the cost of wound care has continuously increased to 96.8 billion dollars. As an innovative solution, WOUNDER will establish a novel, cost effective and sustainable CO2-derived  thin film- mesoporous silica nanoparticles (MSNs) platform for wound healing treatment. The green water-based process will be exploited to produce high performance, renewable and low CO2 footprint bio composites composed of poly (propylene carbonate) (PPC), a CO2-based polymer, and stimuli-responsive MSNs. The porosity of incorporated MSNs with different pore- blocking chemistries offers a great versatility to load different therapeutic agents along with their sustained and controlled release, promoting the delivery of multiple therapeutic agents and the healing process. The versatility of the fabrication process will enable the incorporation of low-cost plant-based bioactive compounds and therapeutic agents with differing water-soluble characteristics to obtain multi-functional and programable wound healing materials. These technologies and materials will immediately impact patient outcomes, social wellbeing, and the medical infrastructure, as well as the circular economy and sustainable development of next generation advanced materials, thus contributing to accomplish the objectives of United Nations sustainable development goals 3 and 13 on the improvement of public health and the protection of the planet, respectively.

SMARTFOLD: Development of a smart shape-memory scaffold to support degenerated cartilage and control therapeutic delivery to reduce chronic pain in osteoarthritis

Coronary heart disease (CHD) is one of the leading causes of death globally. In women, the menopause is a major risk factor for CHD, with the decline in oestrogen having a detrimental effect on cardiovascular function. Regular physical activity (PA) can help menopausal women reduce their CHD risk. Digital health interventions are increasingly being used to target PA in a range of chronic health conditions. However, despite the development of multiple digital interventions, it remains unclear how to design engaging and effective digital PA interventions. This proposed research will design, develop and evaluate a digital health intervention for menopausal women at risk of CHD, an underrepresented group in CHD research. Specifically, this research will focus on the development of a ‘just in time adaptive intervention’, which seeks to deliver PA support when most needed, and when it is most likely to be engaged with. This research will engage potential end users in different phases of the development process, integrating their requirements into the intervention. The developed intervention will be evaluated, tested and optimised through a series of trials examining the acceptability and feasibility of the approach. The overall efficacy of the intervention will be evaluated in a pretest-posttest trial.

CDKL5 deficiency disorder (CDD) is a neurodevelopmental disease characterised by early-onset epilepsy, intellectual disability, motor disabilities. There is an urgent and unmet need to develop therapeutic strategies based on the underlying causes of CDD. My approach will target molecules called microRNAs, important controllers of gene activity. Our group has shown that inhibiting certain microRNAs can modify synaptic structures in the brain, improve motor control, and either stop seizures or prevent epilepsy in animal models. This represents an entirely new way to treat CDD. I shall test the idea that specific microRNAs are involved in the key features of CDD and seek evidence that we can alleviate seizures and other behavioural/physiological deficits by their targeting. I will investigate this using the novel CDKL5 exon 6 knockout mouse model. My studies will focus on two microRNAs specifically dysregulated in CDD specifically regulated in CDD. Then rationally design and deliver antisense oligonucleotide inhibitors to these in vivo. I will assess their effects using multi-site recordings of brain activity, single cell sequencing, behavioural assays and histopathology to follow the course and understand the mechanism of disease-modification. Together, my studies will improve our understanding of CDD and drive the development of advanced new precision therapies.

To combat climate change, Ireland has committed to be carbon neutral by 2050. The Irish government’s 2021 Climate Action Plan targets up to 80% electricity generation from renewables by 2030, while the Russia-Ukraine conflict is encouraging EU countries to accelerate plans to end reliance on Russian fossil fuels and switch to renewables. To ensure delivery of decarbonisation aspirations, while maintaining stable and secure system operation, new modelling and analysis approaches are required to assess systems that are predominately based on converter-based renewables, rather than traditional synchronous generator-based thermal plants. Therefore, high-fidelity electromagnetic transient models of the Irish grid for 2030, and beyond, will be developed and validated. Grid stability and innovative technical solutions will be analysed for a comprehensive range of future system conditions and dimensioning events, leading to the development of new robust system management and economic operational rules. Subsequently, the developed control strategies and network configurations will be evaluated through real-time hardware-in-the-loop studies. Novel model-order reduction techniques will be developed to simplify electricity networks, in order to accelerate simulations, and facilitate analysis and control design of complex renewables-dominated converter-based power systems, leading to the development of an open-source, multi-scale, multi-
temporal simulation tool for future power system dynamic studies.