Titulaires de subvention ou de bourse (2024)

Motivation: Cervical cancer is the 4thmost common cancer among women worldwide with majority of cases caused by high-risk human papillomavirus (HPV). It disproportionally affects Indigenous women, immigrants, and the LGBTQ+ population due to disparities in access. Canada is transitioning to HPV testing from traditional pap test for screening because it is more sensitive and amenable to self-collection. However, HPV testing has low specificity which will increase colposcopy referrals. A sensitive and specific test that can be used for both clinician and self-collected samples is needed.

Innovation: Fluorescence Interference Contrast (FLIC) has been shown to amplify the fluorescent signal of a desired biomarker within a biological sample. The technology can increase the signal-to-noise ratio using purposefully designed, semiconductor-manufactured nanostructured surfaces. In addition to its higher sensitivity and specificity, its multiplex capability enables the detection of a panel of biomarkers, including protein and nucleic acid targets.

Objective: We propose to develop a new cervical cancer screening test using FLIC. While FLIC substrates have been shown for uniplex detection of COVID-related biomarkers, our goal is to achieve multiplex detection of both protein (e.g., p16 and Ki67) and nucleic acid (e.g., HPV16 and HPV18) cervical cancer biomarkers using different fluorophores. The fluorescence signal amplified by the FLIC nano architecture will be detected by a multi-colour fluorescence scanner. A microfluidic device with inlets, outlets and mixing chamber using capillary action will be designed to house the FLIC substrate. Validation will be performed on clinical samples of clinical paps and self-collected vagin*l swabs with known disease states ranging from normal to cancer in order establish sensitivity and specificity.

Feasibility/Interdisciplinary team: Preliminary experiments by the bioengineer on the team have demonstrated proof-of-principle for the proposed FLIC technology. A panel of established biomarkers in cervical cancer have been identified by the clinician-scientist on the team who also have access to a biobank of patient samples and is a clinical expert in cervical cancer. Early accurate detection with our proposed test can potentially forego the need for conventional resource-intensive pap, improve access with self-collection, reduce unnecessary colposcopy referrals, and identify early disease amenable to curative treatment.

For a long time, mental health problems were seen as the sole responsibility of individuals, but there is now a better understanding of their social roots as trauma responses to harmful environments. If the sources of the current mental health crisis are systemic, we need systemic solutions such as the potential of higher education to contribute to resilience and trauma integration. This project aims to develop and test a systems-based model for trauma integration that challenges the separation-based paradigm of higher education by developing a resilient, relational and inclusive worldview that fosters well-being. We will create two six-month-long learning communities, one for students and one for professors, meeting monthly to engage in a series of transformative practices such as mindfulness, generative dialogue, somatics, and psycho-spiritual awareness.

We will employ the 40-item Well-Being Assessment created at Harvard University to measure participants’ levels of flourishing before and after the process, as well as focus groups to understand how the practices contributed to their resilience, well-being and connection, while transforming their vision of higher education. We draw on theories and participatory methodologies from four disciplines: education (integral, transformative learning), psychology (depth psychology, positive psychology and trauma theories), spirituality (mindfulness and diverse spiritual practices) and sociology (theory of resonance). The purpose is to synthesize elements of transformation in each of them to create a new and innovative approach that contributes to a regenerative university. This means to replace the normalization of trauma based structures with practices that foster well-being. While psychology and education have a long history of collaboration, the aspect of spirituality in relation to education and trauma healing has only recently started to receive attention. The sociology of resonance explores relational ways of being that can overcome the alienation and acceleration of modern life. It has not yet been explored in relation to the other three disciplines. This action research is high risk since it is novel, complex, inclusive of both students and professors, and it involves a considerable amount of time and work without a guarantee of the desired results. Its efficacy as a new approach for psycho-spiritual transformation and the positive systemic impact on the academia will be markers of high reward.

The roles/expectations of men and women in many African fishing communities are still defined by traditional gender roles: men do the fishing and women sell the catch to local markets. However, women in fish trade are increasingly trapped in a form of transactional sex where local fishermen seek sexual favours to grant sell of their catch – a practice called “sex for fish” or “jaboya” along Lake Victoria. With depleting fish stock and scarce socio-economic opportunities, women in fishing communities are increasingly vulnerable to these practices despite the high prevalence of HIV/AIDS in the region. Unsafe social norms also discourage men and women in these communities from seeking care, social services, and alternative livelihood opportunities.

Objective: This project develops an interdisciplinary ecosystem approach to enhance knowledge and understanding of the core drivers of “sex for fish” and related gender-based violence (GBV) using evidence from Kenya. It will: study and document the core determinants of "sex for fish" and GVB to increase public awareness and advocacy actions; develop training materials to support preventative and response measures by community health workers; and explore sustainable entrepreneurship skills and alternative livelihoods for women at risk of sexual exploitation.

Novelty/significance: Despite the awareness around “sex for fish” and GBV, there is limited research on how and why many fishing communities in Africa are increasingly predisposed to these practices. Existing studies emphasize the lack of entrepreneurship skills and livelihood opportunities for women at risk and survivors of GBV. While such perspectives have been useful in strengthening women’s financial independence, they have challenged male norms of authority in these communities, leading to more incidences of GBV against women. Also, the challenges and solutions to these practices stretch well beyond economic explanations. A complex interplay between social (e.g., structural stigma), economic (e.g., poverty), environmental (e.g., overfishing), and health (e.g., mental health) factors also inform these practices. This project takes an interdisciplinary ecosystem approach (high risk) and gender-based analysis to develop tools that will enhance knowledge, understanding, and response to "sex for fish" and GBV in fishing communities. Given the prevalence of these practices in other African countries, the project holds scalability potential (high reward).

Research Purpose: To promote wholistic wellness among Indigenous early years children and address the health disparities experienced by Indigenous children and youth, particularly in rural and remote areas of Saskatchewan. Using Indigenous research methods and a community-based participatory action research approach, we will co-create an Indigenous-rooted model for constructing physical literacy enriched land-based early learning environments. Our research objectives target multi-level ecological factors (individual, interpersonal, institutional, community and policy) within early learning settings, including educator knowledge and behaviors associated with promoting wellness; revitalized physical environments encouraging children to increase their outdoor/land-based play while exploring relationality with the land; and increased access to family supports to foster intergenerational bonds.

Research Approach: Grounded in the Indigenous philosophies of ceremonial research and ethical space and guided by etuaptmumk (Two-eyed Seeing), the initiative will braid Indigenous ways of knowing, being and doing about wholistic wellness and land-based learning with Western knowledge of physical literacy to create decolonized and physical literacy enriched early learning environments. To assess program effectiveness and child/family/educator experiences, mixed methods (including Indigenous research methods) will guide data collection and analysis. Key to the project will be co-creating culturally-rooted data gathering tools to guide conversational story sharing methods, arts-based methods, and physical literacy enriched land-based environmental scans.

Novelty & Impact: The co-creation of an Indigenous-rooted model assures relevancy to a range of Indigenous cultures and contexts. Although our integrated and community-led team has, over 5 years, created and assessed impacts of culturally-rooted physical literacy enriched early learning settings, our current data collection tools have failed to effectively assess changes in child wellness in a culturally meaningful and sustainable way. Thus, the proposed project outcomes will be tailored to each diverse First Nations and Métis community and early learning setting, ensuring inclusivity, sustainability, and effectiveness in supporting wholistic wellness. By promoting wholistic wellness, the project aims to reduce health disparities and preserve Indigenous sovereignty in early childhood development approaches.

Artificial intelligence (AI) is beginning to transform healthcare, transportation, media, manufacturing, and many other aspects of our daily lives. However, AI tools are notoriously inefficient, requiring large training datasets and gigawatts of power to solve real-world problems. Many of the same problems are regularly solved by humans with brains that require few examples, operate at body temperature, and use only 20 watts of power. Shaped bybillions of years of selection pressures, brains use unknown algorithms to perform highly efficient computations that predict outcomes and make complex decisions in real-time. Identifying and exploiting these algorithms to improve AI is an explicit goal of the field of neuromorphic engineering, which promises to bridge the efficiency gap by integrating brain-based computation with AI, thus creating a superior “NeuroAI”. As we engineer hardware and software to solve problems like brains do, we will see marked improvements in the performance of autonomous vehicles and medical diagnostic tools.

The ethical development of a NeuroAI to benefit society will require an interdisciplinary approach that combines neuroscience, computer science, cognitive science, robotics, and moral philosophy. While most efforts to derive breakthrough algorithms and network architectures from neural cells have relied on the activities of monolayer cultures, the increased complexity of 3D bioengineered neural tissues offers greater physiological relevance. The main objective of our proposed research is to derive computational strategies from the signaling dynamics of tissue-engineered neural building blocks in custom biological circuits that will inform the engineering of NeuroAI. Our approach, informed by ethical analyses of embodied mind, will involve the microfabrication of mesoscale neural building blocks composed of neurospheroids. Then, we will record their electrical activity from conformal multielectrode arrays to isolate algorithms and networking properties. Next, to simulate an embodied nervous system with sensory input, patterned electrical stimulation will be used to entrain recurrent activations. Electrical feedback from the neural building blocks will, in turn, modulate stimulation inputs to form a closed-loop system that learns and adapts. Task-specific goals will be created to evaluate the computational efficiency of the neural building block assemblies. The research program will address a growing need for efficient AI systems.

Why are there different types of muscle fibre? Why are some fibres oblique to the line of action? How does the additional mass of fat that accumulates with obesity, and the additional stiffness that develops during ageing affect the way we move? Musculoskeletal (MSK) simulations that predict human movement based on mathematical models of the neuromusculoskeletal system can reveal causal relationships between musculoskeletal properties and locomotion mechanics and energetics. However, to date, such simulations have used simple muscle models that neglect fibre type composition, geometrical detail and fat. Our ambition is to incorporate more realistic muscle modelsinto predictive simulations of whole-body movement to answer fundamental questions about how the structure and function of muscle shapes movement in humans, and across the animal kingdom.

Until recently it has not been possible to implement realistic muscle models in predictive simulations of movement due to the computational resources and mathematical approaches required to handle their increased complexity. Our research program requires the collective expertise of physiologists and engineers to integrate physiology into the simulations from the single-fibre level through to whole body energetics. Our team is led by pioneers in realistic muscle modelling (models of muscle shape, mass, fat, fibre-type and stiffness) and MSK simulations (rapid and efficient algorithms for predictive MSK simulations). We will challenge the current paradigm for MSK simulations of human and animal movement, incorporating advanced and realistic muscle models into novel MSK simulation frameworks for the first time, enabling these questions about muscle structure and function to be finally addressed.

We will widely disseminate our models and simulations to foster breakthroughs in many related research domains, such as rehabilitation medicine, sports sciences, and comparative biomechanics. Our previous model and simulation developments have been integrated into the open-source MSK simulation package (OpenSim) that has been downloaded 250,000 times by clinicians, sports scientists, physiologists and biomedical engineers. We plan to follow a similar approach here.

Muscle makes up half of our body mass and is critical to mobility, health and pushing the boundaries of human performance. The questions that we will address will rigorously increase our understanding of muscle design and movement across the animal kingdom.

Canada is endowed with nearly 20% of the world's fresh water supply, the third largest on the planet, according to Environment Canada. We have as many as 2million lakes and hundreds of thousands of kilometres of rivers. This is a strategic advantage for a country that accounts for 0.4% of the world's total population. The waste caused by increased urbanisation, agricultural and industrial activity, microplastics, as well as climate change, imposes additional stresses on the hydrological cycle of this water supply. Water is clearly one of Canada’s largest and most precious resources, yet one that we often take for granted. We know alarmingly little about the health of these freshwater bodies, because we lack systematic, scalable, rapid, and automated ways to monitor and take observations of these environments.

In this proposal, we will enable consistent, rapid, and scalable monitoring of water quality in the Great Lakes. We plan to do this by developing both robust robotics navigation technology and cutting-edge water sampling and imaging systems that will enable a team of autonomous robot boats carrying these sensors to make in-situ measurements and data analysis of water quality, and specifically microplastics concentration. Microplastics detection and characterization is currently done manually by biologists, who need to analyze their samples by large spectrometers that are located in labs. This is a very time-consuming process and a bottleneck for understanding the risks affecting freshwater environments, with poorly understood downstream effects on public health. We will develop a novel, portable underwater microplastics sensor, the first of its kind in the world, to enable real-time and in-situ characterization of microplastics in our waters. Our proposed robotic system that carries these sensors will help provide scientific and public health policy insights about water quality in real-time and in a way that easily scales as the number of robots increases. Our team brings together an interdisciplinary group of roboticists, biologists, chemists oceanographers, and researchers with background in public health, who push the boundary of what is possible today in water quality monitoring.

Emerging infectious diseases (EIDs) are a profound threat to human health, a fact underscored by the emergence of the COVID-19 pandemic. Most EIDs originate in wildlife, and bat species are well-established as harboring many zoonotic viruses. Bats are confirmed reservoir hosts for Hendra and Nipah virus, lyssaviruses, Marburg virus, and SARS-like coronaviruses (CoVs). Yet with few exceptions (e.g., lyssaviruses), these otherwise virulent viruses do not cause observable disease in bats. Several identified tolerance mechanisms include constitutive expression of interferons (IFNs) and IFN-stimulated genes (ISGs) and a dampened inflammatory response. However, such findings are limited to a small subset of bat diversity (1400+ species) and bat–virus relationships. The mechanisms by which bats tolerate virulent viruses remain poorly understood, in large part stemming from a lack of integrating field studies of the bat immune response to viruses with in vitro experimental tests.

Relationships between bats and CoVs are of high interest for assessing zoonotic risk. CoVs are RNA viruses that contain at least seven human viruses: two and five in the genera Alphacoronavirus (α-CoV) and Betacoronavirus (β-CoV), respectively. Bat CoVs are highly diverse, and the origins of pathogenic α-CoVs (HCoV-229E, HCoV NL63) and β-CoVs (SARS-CoV, MERS-CoV, SARS-CoV-2) have been ascribed to bats. However, our understanding of bat–CoV interactions remains limited to rare experimental bat systems. To characterize bat–CoV interactions more broadly, coupled field and in vitro studies are critically needed. Our proposed field studies will identify naturally circulating viruses and the wild bat immune response, and experimental interrogation of the antiviral responses in cells and mini-organ (organoid) cultures derived from wild bats will holistically explain the innate immune responses that are observed in our wild-caught bats.

Our goal is to establish an iterative pipeline for characterizing bat–virus relationships in the wild and then in in vitro systems for experimental assessment. Such work will be especially critical for identifying the impacts of intrinsic and extrinsic stressors on bat–virus interactions, as reproductive status, food scarcity, hibernation, and migration have all been speculated to be factors that can disrupt bat tolerance and facilitate shedding infectious virus. Data from our studies will inform policies to mitigate the threats from emerging zoonotic pathogens.

Plus de 400millions d’enfants vivent actuellement dans des zones touchées par des conflits armés. Il existe un besoin urgent et croissant de recherche pour éclairer les efforts visant à comprendre, prévenir et atténuer les conséquences éventuelles de cette violence. La capacité d’apprendre est l’une des plus grandes ressources dont dispose l’être humain. En temps de guerre, cette ressource est considérablement menacée et les premières victimes sont les enfants.

L’objectif du projet de recherche est de mieux comprendre l’impact de la guerre sur la capacité d’apprendre des enfants. Nos objectifs spécifiques sont :

1. de mieux comprendre les interactions entre les caractéristiques psychobiosociales des enfants et leur capacité d’apprendre;
2. d’établir des profils et d’identifier les variables clés pouvant soutenir des actions humanitaires de précision ayant pour but de favoriser l’apprentissage.

Notre projet explorera quatre construits auprès d’enfants déplacés ukrainiens de 8à 10ans (N=240 ♂/♀):

1. apprentissage;
2. stress;
3. vulnérabilités ⇌ protection et
4. santé globale.

Afin de mesurer l’apprentissage, les habiletés des fonctions exécutives (inhibition, mémoire de travail, flexibilité) seront évaluées à l'aide de tâches. Nous recueillerons aussi les résultats scolaires des élèves et ils prendront part à un test standardisé en mathématiques, en sciences et en lecture. Pour évaluer le stress, nous utiliserons des mesures variées comme le cortisol, une échelle de stress perçu et la réponse physiologique en situation. Concernant les vulnérabilités et la protection, nous utiliserons différentes échelles mobilisant des concepts comme le bien-être, la résilience et le coping. Enfin, nous procéderons à une mesure rapide de la santé globale pédiatrique. Afin de mettre en lumière les relations entre les variables, nous effectuerons des analyses par modélisation assistée par intelligence artificielle (IA).

Ce projet inédit est au croisem*nt entre les sciences de l’éducation, de la psychologie et de la pédiatrie et propose des méthodes d’analyse de pointe qui pourraient avoir des répercussions considérables. En effet, dans les contextes aux ressources extrêmement limitées et sous grande tension qui se multiplie, il est aujourd’hui devenu primordial de produire des données probantes permettant la mise en œuvre d’actions humanitaires de précisions pour les médecins, les psychologues et les enseignants soutenant la capacité d’apprendre des enfants.

Work-related musculoskeletal disorders (WRMD) represent a major scourge for the health and safety of workers. The healthcare costs and productivity losses associated solely with injuries to the upper limbs and back are estimated at 3.6billion dollars per year in Canada. These injuries have a significant social cost for workers, including difficulty in performing daily life activities, pain, loss of mobility, forced early retirement, and reduced quality of life. These issues are even more pressing in the current labor shortage context, which will continue to grow due to the aging population.

Primary prevention of musculoskeletal disorders thus needs to be improved in workplaces. Currently, prevention interventions are carried out on a case-by-case basis by safety professionals who provide advice on how to perform tasks safely. However, there are no tools to objectively measure the muscular demands. This prevents practitioners from conducting a quantitative assessment and measuring behavior retention over time. The lack of quantitative feedback for workers can lead to decreased retention and reducing the effectiveness of long-term interventions.

The goal is to prevent musculoskeletal injuries and facilitate the gradual return to work for manual workers who have been injured, using wearable technologies.

The objectives are:

1. To develop and validate intelligent algorithms that provide a quantitative measurement of upper extremity muscular demand in real time using wearables, thus eliminating the need for human analysis intervention.
2. To enhance these algorithms to automatically adjust to individual users' characteristics.
3. To implement these algorithms in a wearable device capable of providing real-time feedback.
4. validate the device’s effectiveness.

The team will consist of users, researchers and HQP from various disciplines (engineering, occupational therapy, physiotherapy, and neurophysiology) that will provide a fresh perspective not typically seen in traditional collaborations.

We are developing a completely new paradigm for real-time monitoring of muscle fatigue through algorithms. This initiative holds promise to significantly impact not just a single community, but multiple strata of society. This project stands to resolve a long-standing societal issue, fundamentally shifting the paradigm in WRMD prevention and rehabilitation. It opens a new area of discovery and changes the direction of thought across multiple disciplines.

Post-traumatic stress disorder (PTSD) is a severe psychiatric condition involving a persistent stress response to a trauma (i.e., a life-threatening event such as military combat, physical/sexual assault, disaster). About 61% of men and 51% of women in the general population experience trauma during their lifetime. A minority develop PTSD (7–8% of the general population) with many more experiencing subthreshold symptoms. Current first-line treatments (exposure therapy; pharmacotherapy) are effective yet suboptimal, leading to a quest for effective alternatives. PTSD service dogs are trained to provide personalized assistance, including an alerting function to warn patients of early signs of PTSD symptoms and a distracting function to prevent escalation.

While canines’ superior olfaction capabilities are the claimed mechanism underlying their ability to perform such functions, there are few controlled experiments of dogs’ abilities in this regard. Those that do exist demonstrate dogs’ abilities to detect stress but in healthy human participants. We have recently conducted the first proof-of-concept study showing that some dogs can learn to detect and discriminate breath samples collected from humans with trauma histories when they are exposed to personalized trauma cues (vs. baseline). Moreover, one dog’s performance was correlated with the human participants’ fear responses, and the other dog’s performance was correlated with the human participants’ shame responses, to the trauma cue. We aim to replicate and extend our initial study by:

1. quantifying the volatiles that dogs are detecting in the human breath samples (e.g., adrenaline- or cortisol-derived) by gas chromatography-mass spectrometry;
2. collecting other aspects of the humans’ responses to the trauma cue exposure (e.g., state PTSD symptoms, state stress, heart rate, galvanic skin response) and examining relations to dog performance; and
3. examining canine detection performance following a longer training period.

This study brings together a psychiatry research team, a canine olfactory learning and psychophysics team and an analytical biochemistry team. The proposed research is both high risk (a highly novel field with only a single proof-of-concept study where there is thus potential for non-replication) and high reward (potential to lead to development of useful training protocols for PTSD service dogs; a future trial of trained PTSD service dogs as an adjunct to first-line PTSD treatment).

Airborne black carbon (BC) pollution is a worldwide contributor to rising global temperatures and an ongoing public health crisis. The World Health Organization estimates BC causes twomillion premature deaths annually. It is the invisible threat in both vehicle exhaust and wildfire smoke, yet public knowledge of its effects remains low. This is partially due to significant obstacles in obtaining scientifically accurate measurements of the BC particulate matter < 2.5µm (PM2.5) which is most harmful to human health. High-fidelity sensors are either expensive and immobile, preventing the necessary density of localized readings, or cannot make direct measurements because they require slow and costly lab analysis. Another challenge is cultural: governments and activists confront an increasingly polarized and skeptical public, and many people do not grasp how directly they are impacted by BC air pollution because particulate < 2.5µm is invisible. Our team integrates art, science, and engineering, proposing to co-create novel BC sensors and deploy them in city streets. This involves the development of a sensor capable of isolating BC particulate integrated into a smart electronic wearable, scaffolded by public art interventions designed to educate and empower citizen scientists to see BC pollution levels and act on their findings.

Our project objectives are:

1. Design a sensor for isolating airborne BC particulate in real-time.
2. Integrate it into wearables logging real-time geolocated BC data.
3. Create a community driven database online to publish findings.
4. Facilitate public art performances in which citizens wear the sensor embedded into eye catching wearables walking through their neighborhood, visibly revealing their lived experience with air pollution.
5. Further knowledge dissemination through workshops, publications and exhibitions.

Our artwork will be collectively produced for the earnest purpose of solving a global issue, high risks in the arts due to the field’s continued Postmodernist emphasis on subjectivity, skepticism, and rejection of sincerity. In engineering it is high risk as this specific use of graphene for BC measurement remains unproven and is high risk in science because of the difficulties involved in public data collection. However, our bold project is high reward because if successful, it will result in simultaneous advancements in engineering, art and science and potentially dramatic public health benefits.

Objectives of the Proposed Research Project

This innovative interdisciplinary project will apply advances in microbiology, mycology and design to create a modular composting toilet. The waterless toilet will utilize designer microbes and mycelium biocomposjtes to convert human waste to valuable soil products. It will offer an ecologically sound alternative for portable chemical toilets, providing a sustainable waste management solution in locations where access to infrastructure is difficult or costly. Combining biodegradable mycelium biocomposites, which are grown rather than manufactured, with engineered microbial communities, has the potential to significantly reduce the amount of time required to convert solid human waste to valuable soil products, contributing to a nutrient cycle that will safely enrich local ecosystems.

Novelty of Research Approach

The proposed interdisciplinary project will engage in novel research in three different areas:

1. It is a novel application of mycelium biocomposites. These materials, which consist of fungal root structures grown on waste cellulose from the agricultural and forestry sectors, have attracted significant research interest in the past decade as sustainable alternatives to petroleum-derived rigid polystyrene foams. The project will contribute new insights on applications that capitalize on the thermal resistance and biodegradability of these materials.
2. The project will also contribute new insights in the field of microbiology, providing information on microbe-fungal interactions as well as mixed microbial communities involved in lignocellulosic and waste stream biomass decomposition.
3. The research will also contribute valuable research on the circular economy through agricultural waste upcycling and point-source treatment of human waste. It upcycles cellulosic byproducts of the forestry and agricultural sectors, adding value to products that might otherwise be considered waste.

Expected Significance

Centralized wastewater treatment plants are capital intensive and account for three percent of global energy demand. The proposed low-cost modular toilet will eliminate the need for energy and chemical inputs, while creating valuable soils that contribute to healthy ecosystems. The high-risk high reward interdisciplinary project has potential to positively impact remote communities across Canada, as well as 2.3billion people who lack access to adequate sanitation globally.

For Canadians to have first access to new vaccines and high-quality biotherapeutics, applied research in biomanufacturing for the development and adoption of innovative technologies is required. Viral medicines include all therapeutic products that involve a virus as a component. This includes vaccines and cell gene therapies for regenerative medicine or cancer treatment. Rapid scale-up manufacturing of novel vectors is challenging and costly; the proposed project is geared toward applying and identifying technologies that enable efficient manufacturing of viral vectors. Lentiviral vectors (LVs) are widely used in clinical applications that involve the delivery of cell function-altering genetic material. Large-scale LV production requires “producing cells” to manufacture harvestable quantities of viral products that may be used for downstream therapies.

While lipids represent crucial structural components of viral envelopes, limited information is available on the composition and roles of lipids in viral products and how they may be affected by variations in biomanufacturing processes. Some evidence has emerged that the lipid composition of viral membranes directly correlates with the biological activity of viral vectors. The impact of lipids on production efficiency in producing cells and on the quantity and efficacy of viroceuticals have not been studied before; this represents an emerging research domain in need of further exploration and development. To accomplish this goal, we've assembled a multidisciplinary team comprising experts in virology, cell biology, biomanufacturing, analytical and medicinal chemistry, as well as lipid analysis. Our aim is to gain a deeper understanding of how cell metabolism influences the composition of lipid envelopes in LVs (Lentiviral Vectors), as well as their efficacy and quality. The proposed project explores a new frontier in LV bio-manufacturing, a venture with potentially profound consequences. This endeavour places its primary emphasis on the following key objectives:

1. development of novel methodology to assess the lipidomic dynamics of LV and LV producing cells during biomanufacturing,
2. investigation of crucial components and the biological impacts of modulating lipid composition on the quality of LV-based viroceuticals.,
3. establishment of efficient methods to improve biomanufacturing and the quality of LV-based therapeutics by manipulating lipid metabolism pathways as well as through lipid modulation.

Les dernières années offrent un aperçu de notre difficulté collective à maintenir un dialogue sur certains sujets sensibles et clivants. La pandémie, la crise climatique, la question LGBTQ+, l’immigration ou la religion sont des questions qui, alimentées par les réseaux socionumériques et des mouvements socio-politiques, nourrissent des points de vue extrêmes et donnent lieu à des polarisations croissantes, conduisant parfois à la violence. Les moments de crise sont propices à ce type de déchirement du tissu social. A terme, le risque majeur est l’érosion d’un pilier démocratique, à savoir notre acceptation du dissensus comme condition du pluralisme politique et la légitimation de formes d’action anti-démocratique.

La plupart des initiatives pour prévenir ces polarisations agissent sur certains aspects de la problématique (sécurité, santé mentale, éducation, régulation du numérique, etc.) et en périphérie des mouvements radicaux. Très peu envisagent un dialogue direct avec et entre ces personnes aux discours extrémistes. D'où le caractère à haut risque et novateur de ce projet de «dialogues extrêmes» dont l'objectif est de replacer et évaluer la délibération, comprise comme un processus à la fois cognitif, comportemental et émotif,en tant qu’approche de prévention de la radicalisation et des polarisations. En mobilisant de façon unique différentes disciplines selon une démarche commune, une méthodologie rigoureuse et un cadre éthique établi, nous testerons plusieurs méthodes de dialogue ayant fait leurs preuves dans d’autres contextes (entretien motivationnel, dialogue transpartisan, approche de contre-discours basés sur le témoignage et l’empathie) au sein des écosystèmes extrémistes au Canada tant en ligne que hors ligne afin de voir les changements qui s’opèrent sur les personnes à court et moyen termes. Porté par une équipe interdisciplinaire d’experts reconnus (science politique, philosophie, psychologie, pédagogie sociale, médecine et communication notamment), ce projet permettra de:

1. produire de nouvelles connaissances et données probantes sur l'extrémisme et la délibération comme outil de prévention,
2. développer de nouvelles approches et méthodes de dialogue pour les milieux de pratique (politique, éducation, services sociaux, communautaire, médias).

A terme, les retombées pourraient être significatives pour les groupes de la population affectées par ces polarisations et plus globalement renforcer la résilience démocratique au Canada.

Metabolism is integral to tissue organization by determining cellular identity and function via mediating intercellular communication through metabolite secretion and uptake. However, the metabolic phenotypes of individual cells and how they contribute to the complex networks within tissues are poorly understood. This presents a significant gap in our knowledge of how cell biology impacts on physiology. While single-cell “omics” technologies are revolutionizing our understanding of tissue organization in health and disease, they are largely restricted to the analysis of nucleic acids. Single-cell metabolomics is considerably more challenging, in part, because metabolite-derived signals from individual cells cannot be amplified. However, because neither DNA sequence nor RNA transcript levels correlate directly with metabolite levels, direct single-cell metabolite measurements are vital to defining cellular states and understanding disease mechanisms.

Significant challenges in robotics, engineering, nano-analytical chemistry, organic chemistry, and biology have hampered previous efforts to bring metabolomics into the single-cell era, making projects in this field inherently risky. This project will take a unique approach to overcome these obstacles and develop a workflow for the measurement of targeted metabolites at single-cell resolution in cancer, neuronal, and immune cells. Combining innovative technologies and expertise from analytical chemistry, the biomedical sciences, and nanotechnology, we propose to develop an integrated platform for single-cell isolation and processing, followed by targeted metabolite detection with attomolar sensitivity. These cutting-edge cell handling, nano-liquid chromatography, and mass spectrometry technologies have yet to be combined and applied to highly accurate biological models. This approach promises to yield transformative insights into metabolic organization, phenotypic heterogeneity, and plasticity at the single-cell level, empowering interdisciplinary studies of cancer, neurosciences, and immunology that would not otherwise be possible. The resulting knowledge will have significant potential to positively impact on the health of the Canadian population given the alarming increase of 76% (1990 to 2019) in early onset cancers and ongoing epidemics of other chronic diseases that disrupt cellular and metabolic networks within tissues.

There are people who believe that computer chips implanted in their bodies are being used to track them, or that Paul McCartney is madly in love with them; that they are the Queen of 182countries, or that they are the chief disciple of the Buddha; that the person they see in the mirror is a stranger, or that they are dead. These are examples of delusions – the pathological beliefs that are characteristic of psychotic illness, notably schizophrenia and psychotic dementia, and that have historically been closely associated with the most severe forms of mental illness. As the psychiatrist and philosopher Karl Jaspers put it: “Since time immemorial delusion has been taken as the basic characteristic of madness. To be mad was to be deluded.”

Unfortunately, the cognitive processes that underpin delusions remain controversial, and the brain networks associated with delusions are unknown. The standard cognitive accounts of delusions appeal to disorders both of perceptual experience, and of thinking or reasoning. In recent years, however, a new approach to delusions has been gaining ground according to which delusions are a disorder of a form of cognition devoted to navigating social life. The most promising version of this hypothesis is that delusions are the disordered outputs of a cognitive system that evolved to detect in social threats. To date, this proposal has been based largely on theoretical considerations; no significant empirical tests of the theory have been attempted. However, empirical confirmation of the social threat model of delusion would take psychosis research in a distinctly new direction. Accordingly, the goal of this project is to investigate the social threat hypothesis of delusion.

The cognitive theory of delusion has been developed by psychologists and philosophers, and the social threat model is rooted in social cognition. Experts on the clinical facts of delusion are psychiatrists who treat patients with schizophrenia and neurologists who treat dementia patients. The optimal behavioural paradigms to explore social threat are those developed by behavioural economics. For this reason, this project requires an interdisciplinary team with all of these disciplines represented. Team members have all of the expertise required to carry out this project successfully and have proven track records in project leadership and publication.

More than half of all Canadian adults rely on social media for their news. Anti-democratic and malicious actors take advantage of social media’s reach to accelerate political extremism, stoke racial hatred, and spread disinformation – undermining democracy and public health.

Combating disinformation, violent extremism, and foreign influence operations is challenging because social media networks are complex and dynamic. The data is varied (e.g., text and images) and highly contextualized in its meaning. Malicious actors circumvent many existing content-based approaches designed to thwart harmful content – requiring novel alternatives.

Graph theory is a computer science and mathematics sub-discipline. It studies networks as dynamic systems, and many of its more theoretical insights remain untapped for studying social media networks. For example, graph burning theory models how influence or contagion spreads through complex networks. Applying this purely theoretical research to social media holds the potential of discovering unforeseen applications in understanding how malicious actors spread harmful content across online ecosystems.

This project brings together, for the first time to our knowledge, graph theorists, conflict experts, and computer scientists to strengthen the resilience of information spaces to harmful content. The team will develop graph theory algorithms tailored to:

1. Strengthen monitoring by calculating the number and position of listening nodes;
2. Increase the effectiveness of “counter-information” messages by modeling information flow through networks;
3. Maximize efforts to disrupt malicious actors by creating tools to identify central nodes in evolving and responsive networks.

The team will use a mixture of theory and simulations to accomplish this. The research builds on our Centre’s unique datasets collected over the last three years – many of which are no longer available on social media platforms (e.g., Russian influence networks in Canada and the Taliban’s social media ecosystem in Afghanistan). We will develop the network monitoring and deployment algorithms by adapting existing graph theory to settings where we can analyze only partial information about an extensive (and changing) network with different types of information that could spread between nodes. This project holds the potential to provide cutting-edge theory and tools for monitoring and protecting Canada’s online ecosystems.

Motivation – Brain surgery: One of the most common brain tumours, glioblastoma multiform, is universally fatal and has a 1-year survival rate of just 25%. Due to the lack of non-invasive therapy options, the standard approach to treatment is surgery followed by chemotherapy. Even with the high mortality rate, studies show that a high degree of resection accuracy is directly correlated to increased survival and quality of life.

Motivation – Spine surgery: By far the most frequent procedure in neurosurgery is the decompression of spinal nerves that are being compressed by a pathological structure (eg. herniated disc, bone spurs, etc.). The number of surgical interventions for these is over 1.2million annually in the US alone, however, the revision rate is high due to the lack of intra-surgical confirmation of decompression.

Ultrasound has become an indispensable tool for intra-surgical guidance. Neuro and spine surgeries, however, are rapidly moving to minimally invasive approaches where the entire operation is performed endoscopically through a small corridor. These approaches are preferred over open surgery due to improved patient outcomes and faster recovery. Consequently, conventional imaging technologies such as ultrasound can no longer be used in these confined surgical corridors. Our interdisciplinary team has recently developed a unique, high-resolution, 3.5mm diameter ultrasound probe specifically for minimally invasive brain and spine surgeries. The small form factor enables this probe to be used in surgeries that are performed through small surgical access routes, which would prevent standard clinical ultrasound technology from being used. The high resolution allows for real-time visualization of tumor and nerve boundaries with extremely high accuracy. This novel imaging platform has recently been approved for preliminary patient imaging studies and has already produced promising, first-of-its kind data during brain tumour resection and spinal decompression surgeries. Initial image data collected suggests that the boundaries between tumors and healthy tissue can be visualized, as well as compressed nerves in and around the spinal cord. The proposed project will focus on refining the imaging technology and validating that our high-resolution imaging probe can quantifiably identify any remaining residual tumor during minimally invasive neurosurgery, as well as objectively confirm nerve decompression during minimally invasive spine surgery.

This NFRF Exploration project, Estamos Aquì (We Are Here), is led by an early career scholar and catalyzes multisectoral and multidisciplinary collaborations to advance strength-based approaches and promote migrant sex workers thriving in Colombia and Peru. Latin America is currently facing its largest recorded mass migration due to the Venezuelan refugee crisis. Over 7.3million Venezuelans, about 20% of the country's population, have been displaced since 2014 due to political turmoil and humanitarian crises. Over 80% of displaced Venezuelans currently reside in neighboring Latin American countries; Colombia hosts more than 2.5million and Peru around 1.5million Venezuelans. Further, South-South migration trajectories in the region are common, namely and gender and sexual minorities and cisgender women. Sex work is a key dimension to assess in migration research as known systemic inequities can lead to engagement in sex work and vulnerability to human-trafficking, particularly for women, girls and sexual and gender minorities. To move beyond a deficit-based model and support transformative action, it is crucial that migration research, especially for those at increased vulnerability, centre community-based experiences of strength and solidarity and culturally responsive solutions. The goal of Estamos Aquí, is to reframe South-South migration research among sex workers in Colombia and Peru from one of scarcity to one of belonging and vibrancy. Guided by Latin American Social Medicine and creative-relational inquiry this project reflects a partnership with community, journalists, key within-country social service providers (e.g. ProFamilia and United Nations International Office of Migration), and academic researchers. Our project employs three high-risk and high-reward strategies:

1. Arts and performance based-methods to collaboratively evidence how migrant sex workers enact agency and autonomy in migration trajectories;
2. Create and disseminate public knowledge campaigns (e.g. photo journalism, graffiti, digital stories) to address pervasive xenophobia; and
3. Co-design culturally situated scalable strategies to support migrant sex worker thriving across health, media, and public policy.

The use of e-cigarettes has rapidly increased particularly among Canadian adolescents and young adults, with an estimated 20% of those aged 15-24 having tried e-cigarettes. Across North America, clinical cases of e-cigarette or vaping associated lung injuries (EVALI) have been reported, with serious health outcomes including hospitalization and death. Diagnosis for these patients included chest radiographs and CT (computed tomography) scans showing reduced lung function, airway obstruction, and gas trapping. EVALI has been linked to hazardous ingredients in e-cigarettes such as nicotine, vitamin E acetate, and tetrahydrocannabinol (THC).

The goal of this project is to investigate the impact of e-cigarette use on respiratory and oral health. We will characterize commercially available vaping fluids (with/without nicotine) to determine the chemical composition of the fluid and vapour, and identify what chemicals are deposited into lung and oral tissues. We will also investigate the properties of the aerosols generated under different vaping conditions. To assess health outcomes, we will expose mice to the two vaping fluids or air (control) and use micro-CT scans to non-invasively monitor changes in lung structure and function over a 6-month exposure period. From the images, we will identify regions of air trapping, airway blockages, and measure lung function. The mice will undergo head CT to investigate anatomical changes in bone in the nasal passages, bone loss as a marker of periodontal disease, and histological assessment of the soft tissue to identify precancerous lesions.

The novelty of this research is the unique combination of chemical and aerosol analysis of vaping fluids with the use of in vivo mouse models to non-invasively monitor over an extended timeframe the changes (if any) to the respiratory system and the oral cavity. Performing the chemical and aerosol studies of vaping fluids alongside the in vivo mouse exposure model will allow for enhanced understanding of the interaction between the chemical and biological systems. We believe these in vivo studies coupled with chemical analysis of vaping fluids are critical for evaluation of vaping products for safety. The impact of this research will be an increased understanding of the ingredients in commercially available e-cigarette fluids and their impact on respiratory and oral health, which would lead to improved product labeling and vital evidence-informed regulation by Health Canada.

There is a critical unmet need for innovative clinical tools to support detection and tracking of neurological diseases. As the prevalence of age-related diseases rises, their burden on individuals, healthcare systems, and society increases. This is exacerbated by the lack of neurologists and other clinicians who specialize in these complex conditions. In parallel, there has been recent universal recognition of the potential for digital technologies to support clinical decision-making by automating disease assessment and monitoring, while remaining highly accurate, objective, and reliable.

The key diagnostic assessment across all neurological diseases is the neurologic examination, which consists of motor and sensory evaluations of body structures and functions. While digitization of gait, balance, posture, hand and arm functions has progressed rapidly, assessment of small face/ mouth structures remains limited. Recent work has demonstrated the promise of video-based face tracking methods in the context of cranial nerve exam (CNE), but video-based technologies for tongue tracking remain limited. However, tongue evaluation is essential for differential diagnosis in stroke, tumors, and neurodegenerative diseases. The location of the tongue inside of the mouth and consequent lack of data have precluded the development of algorithms to detect neuromuscular changes to the tongue across diverse populations.

This innovative, interdisciplinary application aims to develop a tongue function assessment in the context of the CNE in patients with various neuromuscular diagnoses. First, we will develop novel machine learning methods for tongue tracking, using a unique data set collected as part of a large study on the development of a digital CNE. Second, these novel algorithms will be analytically validated in neurotypical adults via the gold standard electromagnetic articulography, and will comprise a diverse sample with respect to age, sex/gender, racial, and anatomic factors. Third, we will clinically validate our method in patients with neuromuscular disorders or stroke, via comparison to CNE by an expert neurologist. Finally, we will develop a digital tool based on these algorithms that will be widely disseminated for clinical and research purposes. The project will result in significant and exciting innovation in the development of a digital CNE that incorporates tongue tracking, which will support automatic and remote digital neurological assessment.

Demand for minerals such as copper, nickel and lithium used for electrification and batteries will rapidly increase as Canada and the world transition to a net-zero carbon energy system. Yet, current supplies of these minerals are insufficient to meet the 2016 Paris Climate targets to reduce greenhouse gas emissions by 2050. Moreover, many current mineral extraction methods have serious negative environmental and social effects, particularly on Indigenous lands, leading to conflict over the unequal distribution of costs and benefits. Responsible sourcing and use of minerals is critical to build both a sustainable society and advance Indigenous mineral governance.

Objectives: Working in collaboration with Indigenous leaders, our diverse team will lay the foundation for transforming Canada’s mineral resource sector. We will identify critical challenges and develop a framework for solutions needed to advance Indigenous governance of mineral resource development on their lands. Our objectives are to:

1. explore and create new regulatory and economic structures that support community-led mineral exploration projects by incorporating Indigenous knowledge and accounting for Canada’s commitment to the United Nations Declaration on the Rights of Indigenous Peoples;
2. generate priorities for innovative technological approaches, from initial mineral exploration to mineral recycling, to prevent negative legacies of the expanding sector on Indigenous lands; and
3. develop frameworks for building resilience in Indigenous communities to anticipated climate changes that could amplify the negative legacies of mineral resource extraction.

Research approach: Drawing on expertise and methodologies in earth sciences, engineering, law, economics, and public policy, we will collectively reimagine the technical, social, environmental, and human rights dimensions of mining in the context of resurgent Indigenous sovereignty. Interdisciplinary collaboration between these fields will enable us to promote innovation and societal change.

Novelty and significance: Mining in Canada continues to be shaped by a colonial, capitalist model that has historically overlooked Indigenous rights and contributed to major environmental disasters. We will challenge this paradigm and set a new standard for Indigenous-led mineral resource stewardship, integrating diverse disciplinary approaches and perspectives to foster a reimagined future for a responsible mineral resource sector in Canada.

Introduction:

The central dogma asserts that DNA is the only hereditary material. However, whether this is true, and whether non-DNA based life may have existed, or could be engineered, are enduring questions. Discoveries in the field of exobiology suggest that primordial biomolecules, including sugars and bases with unique isotopic signatures, are delivered to Earth on a regular basis via meteorites. Moreover, over the past few decades, chemists have synthesized myriad chemically-modified nucleic acids, also known as xenonucleic acids (XNAs), capable of storing, replicating, and evolving genetic information. These developments, coupled with advances in gene editing, now provide a ripe environment to interrogate the possibility of XNA-based life.

My lab engineered an E.coli strain that is auxotrophic for D-ribose (requires exogenous supplementation). Using this, we have evolved bacteria that subsist solely on heavy ribose sugar derivatives. This uniform replacement of ribose with isotopologues is unprecedented, and highlights the remarkable adaptability of life. In this proposal, we will employ the same top-down experimental framework to test if prokaryotes can be evolved to utilize ribose derivatives bearing a single atomic substitution.

Objectives & Approach:

1. Identify types and positions of ribose modifications predicted to be minimally disruptive on a) overall nucleic acid structure (non-local), and b) nucleic-acid-protein interactions (local) using computational modelling techniques.
2. Synthesize candidate xenoriboses using organic chemistry, leveraging team expertise.
3. Perform adaptive laboratory evolution of ribose auxotroph bacteria towards survival on xenoriboses via serial dilution and chemostat methods, testing chemical and genetically-encoded mutagenesis methods. Characterize results using a variety of mass spectrometry methods (e.g. ToF, ICP, NanoSIMS), and RNA-seq.

Novelty & Significance:

This work will contribute to answering one of the three cardinal problems of biology. It has implications for those studying the origin of life here on Earth, and for those looking for it elsewhere. Moreover, XNA-based organisms could be applied as genetic ‘firewalls’ to study pathogens in a lab without risk, and could drive unprecedented medical breakthroughs (e.g. microbiome engineering, synthesis of medically useful XNAs for RNA therapeutics and vaccines).

Microplastics, particles smaller than 5mm in size, are a global environmental concern due to their widespread presence and potential risks to ecosystems and human health. Current microplastic research is hindered by methodological limitations in tracking how microplastics travel through exposed systems. To address these gaps, our interdisciplinary project will merge molecular biology and toxicology with materials design to develop a novel method for DNA-labelling plastics, revolutionizing microplastic research in two key applications: tracking microplastic transport and fate in the physical environment (environmental science) and in biological pathways (toxico*kinetics).

Our project has three objectives:

• Objective 1 – DNA-Labelling of Microplastics: We will create a technique to embed DNA barcodes within biodegradable polymers, enabling unique tagging of microplastics with genetic information. This creates "genetically barcoded" microplastics that can be tagged with crucial encoded information (e.g., time and location of release), allowing precise tracking and identification and improving current limits of detection by orders of magnitude.
• Objective 2 – Environmental Fate and Transport Studies: In landscape-level studies, we will release genetically barcoded microplastics into urban water systems and their transport and fate (e.g., sedimentation) will be tracked over time using DNA sequencing technology. This will enhance our understanding of the temporal dynamics of microplastic interactions with the environment and will inform mitigation strategies.
• Objective 3 – Toxico*kinetics in Fish: Genetically barcoded microplastics will be used to investigate the movement of microplastics through fish. Fish will be exposed to marked microplastics through their diet, and DNA markers in their tissues will precisely determine uptake, transport, and fate, informing potential effects on fish health. This research has direct implications for assessing the risks of microplastic contamination in aquatic ecosystems.

As a result of the inherently novel nature of creating and studying DNA-barcoded plastics, this project carries risks. However, the potential rewards are substantial, offering a transformative understanding of microplastic impacts on the environment, organisms, and human health. Success will position our team at the forefront of microplastic research, paving the way for innovative solutions to address this pressing environmental challenge.

Soft corals exhibit dynamic movements in response to ocean waves and eddies. Notably, they experience vortex-induced vibrations as they interact with vortices shed in their wake. Unraveling this complex fluid-structure interaction is essential for quantifying the hydrodynamic stresses they endure, as well as for understanding their filter feeding mechanics. In an era of increasing hurricane frequency and coral reef upheavals due to climate changes, soft corals exhibit relative success at adapting to changing environments. We seek to understand the role of their flexibility or “softness” in this success.

This interdisciplinary endeavour involves collaboration among mechanical engineers, biologists, and ecologists, with three objectives:

Our methodology combines numerical modeling, flume experiments, and in situ observations. We use finite-element coupled with wake-oscillator models to simulate whole coral colony dynamics. This approach allows us to rapidly identify the effects of geometry, allometry, and flexibility. In flume experiments, we measure the vibration dynamics of freshly collected coral samples, with specific attention to polyp distribution and its correlation with particle capture efficiency. Concurrently, we're pioneering an image-based velocimetry technique. Because a coral colony's frequency response is closely linked to local flow velocity, we build a dataset comprising underwater videos capturing soft corals in diverse flow conditions, alongside acoustic Doppler velocimetry for precise flow measurements. Machine learning algorithms establish a robust correlation between flow velocity and coral motion, offering a transformative tool for coral research.

This research will provide novel insights into the mechanical and hydrodynamic aspects of soft corals, shedding light on their ecological roles within reef ecosystems. Moreover, it will help us predict how changing climate conditions, currents, and storms impact soft corals. Additionally, our innovative flow velocity measurement method will increase accessibility to coral reef monitoring, facilitating data-intensive assessments of coral reefs worldwide.

Severe traumatic injuries affect Canadians of all ages and backgrounds. Hemorrhagic shock remains a leading cause of preventable death for injured patients. Delays to timely resuscitative maneuvers, blood transfusions, and coagulopathy reversal cause increased mortality. Proper care is complex and time-pressured, requiring the trauma team to diagnose and treat injuries simultaneously. This makes trauma care prone to error.

Some die because it takes too long to receive the right blood for transfusion, or because we don’t know which specialized blood products to provide to help stop bleeding. There are blood tests available to help decide how to best to transfuse individual patients, such as viscoelastic hemostatic assays (VHA), but currently they are too difficult to interpret while resuscitating a person who is bleeding out. Ultimately, the cognitive challenges with interpreting VHA and all other relevant critical data in real-time in the trauma bay results is overwhelming. This causes information to be lost and life-saving treatments to be delayed. Machine learning (ML) offers an exciting possibility to analyze multiple sources of data, interpret it, and provide actionable recommendations to the trauma team in real-time.

Aim: To develop and validate an ML program that will analyze patient physiologic data (i.e. vital signs) and electronic medical record (EMR) data (i.e. laboratory values, triage notes) in real-time to provide actionable prompts to the trauma team.

This will be accomplished through the following 3 objectives:

• Objective 1: Create a heuristic ML model that interprets VHA values and proposes a personalized transfusion strategy.
• Objective 2: Add in real-time EMR analysis to the above model (i.e. critical lab values and documentation in EMR) to predict need for transfusion and medical therapies.
• Objective 3: Implement and prospectively validate the ML model in real-time in the trauma bay.

This innovation will leverage artificial intelligence to analyze a patient’s vital signs and blood tests to provide actional recommendations to the trauma team in real-time.It will offload the trauma team’s need to monitor and interpret complicated graphs, allowing for faster time to critical interventions. We expect this to reduce time to transfusion, improve best practices, and ultimately save lives.

Smallholder farmers, many of whom are women, contribute about a third of global food supply. In sub-Saharan Africa (SSA), over sixty percent of the population are smallholder farmers. Climate change risks are highest in SSA, and smallholders are the most threatened because their farming is rainfed. Women in SSA are particularly affected due to sociocultural factors that affect their access to agricultural resources. In Rwanda and Ghana, climate change is causing hunger in farming households due to intense droughts and heatwaves, which are projected to rise in the next few decades. These climate threats are exacerbated by limited adaptive strategies. This proposed interdisciplinary comparative project aims to develop a sustainable gender transformative climate change adaptation framework for improving food security in climate-affected smallholder farming systems in Rwanda and Ghana. The specific objectives of the project are:

1. To assess gendered differences in farmers’ Traditional Ecological Knowledge (TEK) and integrate them into local farming methods through participatory training on agroecology and gender transformative/equitable strategies.
2. To evaluate the impacts of various agroecological practices on crop yield and health.
3. To examine the effects of diverse agroecological farming practices on the resilience of crops to dry spells and heatwaves.

This project will use theoretical concepts from feminist political ecology to achieve research goals. We will use participatory research that engages women and men farmers in knowledge co-production and mobilization. We will also use a gender transformative approach rooted in sustainable, climate-adaptive smallholder farming. Our interdisciplinary research team is well positioned to achieve the project's objectives within a two-year timeframe as it has expertise in gender/feminist-based analyses, social theory, and quantitative and qualitative methods. Our findings will be shared with academic, policy and practitioner communities through journal articles, conference papers, workshops and outreach programs in Rwanda and Ghana.

Overall, this interdisciplinary project will introduce smallholder farmers from four sample districts in two SSA countries, Rwanda and Ghana, to farming practices that can help them adapt to a changing climate in gender equitable ways. The project findings will also provide insights on agroecological practices that enable crops to deal with heatwaves versus dry spells.

PROBLEM AND BACKGROUND:

Congenital heart valve defects are detected in nearly 40,000 infants born in the United States and 1in 80-100Canadian newborns (according to the Heart and Stroke Foundation of Canada) each year. The prevalence of pulmonic valvular stenosis and atresia account for 7-10% and 1% of all congenital heart diseases (CHD), respectively. The heart valve defect can range in severity, with about 25% of cases requiring immediate open-heart surgery to replace the valve or other heart defects. No surgical heart valve prosthesis meets infants' size, flow, and developmental needs. Options include mechanical, bioprosthetic, hom*ograft, or autograft (Ross procedure) valves. However, the most commonly used valves, mechanical and bioprosthetic valves, are designed with adults in mind. Thus, surgeons must alter the structure of the valve in the operating room, effectively altering the hemodynamic profile and minimizing the flow potential. In addition, mechanical and bioprosthetic valves are stagnant, meaning that children often face patient-prosthesis mismatch and multiple operations as a result of their growth. In addition to lack of growth, mechanical valves require life-long anticoagulation medication, and bioprosthetic valves tend to undergo structural valve degeneration.

HYPOTHESIS AND OBJECTIVES:

In response to these challenges, we envision fabricating innovative pediatric pulmonary heart valves with remodeling capability. Such valves will combine state-of-the-art innovations in 3D (bio)printing, functional biomaterials, cardiology, and fluid dynamics. Our team hypothesizes that a 3D (bio)printed heart valve that can be remodeled with optimized biomechanical and hydrodynamic properties will represent a paradigm shift in innovative medical devices for pediatric patients with CHD. We propose three independent specific aims (SAs) to validate our hypothesis:

• SA1. In-depth in vitro assessment of biomechanical and hydrodynamic function of 3D (bio)printed heart valves;
• SA2. Maturation and characterization of living heart valves in a heart valve bioreactor;
• SA3. Combination of 3D (bio)printed heart valves with a minimally invasive transcatheter pulmonary implantation technique.

IMPACT:

The outcomes of this project will have a significant clinical impact in advancing the traditional devices with above-mentioned challenges to fabricate off-the-shelf pediatric pulmonary heart valves that can facilitate translation from bench to bedside.

Global climate change is threatening the ability of natural systems to support and sustain human well-being. With warming, species are predicted to track their preferred climate by moving to higher latitudes, higher elevations, and deeper waters. Given the rapid pace of climate change in the Arctic, these ecosystems are predicted to be hotspots of biodiversity change.

One major challenge facing Arctic communities is lack of accessible, integrated data on the abundance and distribution of species that are important to wildlife and human health. The biting flies are of particular concern for monitoring due to their abundance, importance in ecosystems, and their roles as pests and disease vectors impacting humans and other animals. The potential impact of flies on caribou is concerning to community members of Kitikmeot, Nunavut, as caribou are important from cultural and food security perspectives. Swarms of black flies can negatively impact caribou, driving them to spend time in environments poorer in resources. Northward shifts in fly distributions may thus impact caribou birthing and hunting grounds, human health, and conservation plans.

There are critical needs for collaboration and to integrate knowledge about current and historical distributions of flies and other wildlife species. Respectful sharing and co-analysis of knowledge is essential for understanding temporal trends and inter-relationships of species and predicting the impacts of climate change on wildlife, ecosystem services, human health and nutrition, and cultural practices.

The objectives of this project are to co-design and co-implement a novel program for monitoring fly species composition and for alerting Arctic community groups when species are detected that are new to the region, potentially invasive, or of health concern to humans and wildlife. Our collaborative team will take an inter-disciplinary approach, integrating Inuit and Western Scientific Knowledges and applying community-engaged social science research methods, ecological statistical modeling, and bioinformatics. Respect, inclusivity, reciprocity, sustainability, and a focus on capacity building are among the values that guide this collaboration. We will co-create tools—including maps integrating multiple types of knowledge, predictive models, and a biodiversity dashboard—that will lead to new knowledge and contribute to community capacity for decision making, mitigation, and climate-change adaptation.

This multidisciplinary project brings together advanced materials, microbiology, ecology, and optics to study bacterial colonization of antifouling surfaces. Our goal is to address the critical lack of robust measurements of the interactions between microbes and substrates at the nanoscale by building an assay for quantitative comparisons under well-defined conditions. We will design and test our approach using the bacterium Caulobacter crescentus, a key culprit in aquatic biofouling.

Microbial biofouling has enormous ecological, environmental, economic, and health impacts for Canadians. Biofilms decrease the effectiveness of antimicrobial therapeutics, and biofouling of ship hulls is a major source of species contamination and decreased fuel efficiencies. Eradicating biofilms is difficult and expensive, and climate change is projected to accelerate biofilm formation further. Therefore, using antifouling materials to prevent biofilm formation as much as possible is the dominant strategy. Traditional antifouling coatings use slowly ablating materials and leaching biocides to prevent buildup; however, it has become clear that these approaches can cause significant damage to local ecosystems.

Some bioinspired materials with nanoscale topologies have shown impressive antifouling properties and could be the solution. Still, we lack a standardization for making thorough head-to-head comparisons of bacterial colonization on such surfaces that are needed to build our understanding of bioadhesives and gain predictive power for designing new materials. Specifically, quantitative measurements are needed on the scale of cells and material features. To do so, we will deploy quantitative force spectroscopy methods, namely Atomic Force Microscopy and optical tweezers, to probe the variability of biological systems in a defined and multidimensional matrix of conditions (temperature, pH, organic load, etc.). We will use bacteria that evolved their adhesins to attach to different surfaces under different environmental conditions and establish a set of standardized conditions and quantitative metrics that we and others can deploy to test a variety of cell types, including pathogenic bacteria, nanomaterials, and conditions. These, in turn, will be used for the next phase of our research: rationally designing new materials that combat the dire problem of biofouling by merging the optimization process for obtaining desirable material properties with the characterization.

Air pollution represents one of the largest environmental risk factors to human health, with chronic exposure to high levels of particulate matter (PM2.5) being associated with increased risk to immune-mediated diseases, such as rheumatoid arthritis (RA) and asthma. The incidence of these diseases in Canada is among the highest in the world, and Health Canada estimates that air pollution has severe health and economic consequences on Canada’s population and economy. This is despite Canada having some of the lowest levels of air pollution from traditional sources (e.g. PM2.5, VOC, NO, NO2) in the world. We hypothesize that mixtures of non-traditional pollutants, including from tire and brake-derived chemicals, pesticides, household, and cosmetic products, may be important contributors to the development of immune-mediated diseases. This proposal aims to identify if these emerging and non-traditional pollutants adversely affect asthma and RA and determine whether there are specific chemicals or their atmospheric breakdown products responsible for promoting them.

Dysregulated immune responses, which cause asthma and RA, are driven by a complex set of genetic and environmental factors, such as air pollutants. Our current understanding regarding the health effects of air pollutants stems from studies that investigate individual pollutants from traditional sources usually associated with combustion. However, humans are exposed to tens of thousands of airborne chemicals; yet, only a fraction of these chemicals has been identified. These non-traditional pollutants have unique atmospheric chemistries and their contribution to PM2.5 associated health effects remains unexplored. In collaboration with Environment and Climate Change Canada, the aforementioned chemicals will be used to generate PM2.5 under realistic ambient conditions using an oxidation flow reactor. We will then exploit our expertise in mouse models of asthma and RA to determine the effect of these pollutants on disease severity and progression. Specifically, we will use a Whole-Body Exposure Chamber to chronically expose mice to the generated particles. Disease progression and severity will be measured, and tissues will be harvested to assess inflammation and cellular infiltration.

This proposal may lead to a breakthrough in our understanding of how pollutants derived from atmospherically accurate mixtures of non-traditional pollutants promote the development of immune-mediated diseases.

Long non-coding RNAs (lncRNAs) are a class of molecule that have emerged lately as important regulators of many cellular processes. Human cells express tens of thousands of lncRNAs and some have been shown to be essential in multiple pathways. While some mechanisms are better understood, many long non-coding RNAs seem to function via unknown processes to modulate the different pathways that they are embedded in. There is still a critical gap between the importance of this class of molecule for diverse cellular processes and the very limited structural and biochemical understanding available. Interestingly, a few lncRNAs have been shown to participate in non-genetic function by directly influencing cellular signaling near or at the plasma membrane, in a region of the cell thought to be governed exclusively by proteins, lipids and other small molecules. The participation of lncRNAs in cell signaling as a transducing factors or auxiliary regulatory molecule represents a significant paradigm shift on conceptualizing how signaling pathways are regulated. Investigations in this area are critical to better understand signaling pathways and to open new avenues to intervene pharmacologically to modulate signaling by targeting these lncRNAs.

The PI3K/Akt/mTOR pathway is a growth factor signaling pathway which is central to regulating cellular growth proliferation and motility. Several lncRNAs have been proposed to regulate this signaling pathway either via altering the expression of its protein components, or by directly interacting with the molecular components, protein and lipids, which constitute the PI3K/Akt/mTOR signaling pathway. Given the importance of this pathway in the functioning of healthy human cells, and its involvement in the development of cancer, there is a clear need to better understand how lncRNAs are able to modulate this essential cellular process. We aim to clarify the mechanisms by which lncRNAs are capable of influencing PI3K/Akt signaling through RNA-protein and RNA-lipid interactions combining screening approaches, such as OMAP and CLIP, with in vitro biochemistry. This approach will be conducted in several cancer cell models to obtain an overview of cancer-specific roles of certain lncRNAs. In the long term, we believe that from these insights will emerge

1. a better understanding of the mechanisms of signaling in cancer
2. new targets for cancer therapies
3. new templates for RNA-based technologies to modulate cell behavior.

Objectifs du projet de recherche:

Ambition stratégique : Le projet ambitionne de créer un outil d'évaluation numérique et assisté par l'IA, capable de repérer les difficultés de santé mentale directement dans la langue du locuteur minoritaire et sans passer par la traduction, l'interprétation ou la médiation.

Objectifs clés:

• Développement technologique : Élaborer un outil non invasif spécifiquement conçu pour les langues minoritaires, pour permettre une évaluation psychologique précise et accessible aux communautés minoritaires.
• Synergie interdisciplinaire : Faire converger les expertises de plusieurs domaines (médecine, informatique et linguistique), afin de créer une solution à l’intersection des sciences humaines et des sciences médicales.

Démarche de recherche : En s’appuyant sur une convergence d’expertises, cette recherche adoptera une approche interdisciplinaire pour la conception d’un outil innovant par rapport aux pratiques existantes.

Phases de recherche :

• Collecte de données : Acquisition de données orales dans les communautés minoritaires ciblées pour construire un corpus robuste pour l’apprentissage supervisé de l’IA.
• Développement d’algorithmes : Création d’algorithmes innovants pour l’analyse des marqueurs cognitivo-discursifs de la santé mentale, capables de détecter les signes de détresse ou de troubles directement dans la langue minoritaire.
• Intégration et test : Assemblage des algorithmes au sein d’une plateforme intuitive destinée aux professionnel.les de la santé mentale, et vérification de l’efficacité de l’outil dans divers scénarios appliqués.

Nouveauté et importance attendue des travaux :

Le projet se distingue par son positionnement à l’intersection des technologies langagières et des pratiques cliniques, offrant une solution de rupture par rapport aux pratiques existantes dans l’évaluation de la santé mentale des communautés linguistiques minoritaires.

Rupture méthodologique : L’initiative propose une rupture avec les méthodes conventionnelles en misant sur l’extraction de marqueurs psychologiques à partir de la parole ordinaire, plutôt que de se limiter aux tests standardisés et souvent contraints par les obstacles linguistiques.

Impact potentiel : Ce projet pourrait révolutionner les méthodologies diagnostiques, affiner la détection précoce dans le contexte éducatif et améliorer significativement les processus d’évaluation dans le secteur des ressources humaines, entre autres applications diverses.

Despite all the advances in therapeutics, a significant number of cancers will still progress toward a metastatic disease. Once metastatic, cancer is incurable, and treatments are mostly palliative. The liver is one of the most common cancer metastasis sites, accounting for nearly 25% of all cases. In fact, several cancers exhibit liver-specific tropism, most notably uveal melanoma (UM) and colorectal cancer (CRC). A major issue though is the complete lack of reliable models that can either recreate a metastatic niche or distinguish between events in the primary tumor and metastatic site.

Tumor cells have several mechanisms that allow them to communicate with distant cells in the premetastatic niche. For instance, this communication allows tumor cells to reprogram hepatic stromal cells, such as hepatic stellate cells (HSteCs), which in turn impact the extracellular matrix composition, mechanical properties and architecture. The establishment of this premetastatic niche could depend on the origin of the primary tumor. Moreover, these modifications of the metastatic niche can facilitate the last steps of the metastatic cascade, namely the extravasation and metastatic colonization.

Advances in tissue engineering and biomaterial properties have allowed the development of tissue equivalent constructs for regenerative medicine applications. These approaches, when guided by knowledge derived by oncology and cell biology, can potentially be leveraged to create an engineered hepatic metastatic niche model. Using the self-assembly approach of tissue engineering and hepatic stellate cells, we will create a liver equivalent stroma. Our objectives are:

1. Determine the contribution of tumor cells from different origins on the formation of a premetastatic niche, and
2. Establish a vascularized metastatic niche to recreate the final steps of the metastatic cascade.

Our research approach will combine expertise in tissue engineering, microfluidics, physics, oncology and molecular biology in order to address a critical need for a new generation of fully biomimetic metastatic models. Such models of the premetastatic niche will enable basic researchers to explore new molecular mechanisms involved in metastasis and identify potential therapeutic targets as well as for preclinical translational research in a way that was previously inconceivable.

Intestinal helminths remain one of the most prevalent causes of infectious disease in the world. By virtue of their large, multi-cellular structure, helminths cause significant damage as they migrate through tissues to continue their life cycle. Upon taking residence in the intestine, these parasites secrete a multitude of factors that alter the microbiota and regulate the immune response to prevent their expulsion, but also promote tissue healing to ensure the survival of their obligate hosts. Because of the potent ability of helminth excretory-secretory products (i.e. secretome) to shape their environment, clinical trials involving low-dose, controlled infections have been performed in hopes of dampening pathogenic inflammation associated with diverse autoimmune diseases. Unfortunately, these studies have largely been unsuccessful due, in part, to the confounding effect of the infection itself on host tissues.

To overcome this limitation, isolation and characterization of the helminth secretome has been pursued as a potential source of novel anti-inflammatory therapies. However, the inability to deliver helminth-derived products in a concentrated, tissue-specific fashion has hampered the ability to harness their health-promoting effects. Here we plan to develop smart, ingestible capsules for targeted delivery of purified immunoregulatory helminth-derived products to unique segments of the intestine while simultaneously sampling the tissue microenvironment for high resolution microbial and metabolic analyses. While the challenges associated with this plan involve navigating the incredibly dynamic and individualized intestinal microenvironment, it holds the potential to provide a non-invasive, compact and highly-specific drug delivery and monitoring system. Ultimately, completion of the proposed studies will reveal unprecedented insight into whether an untapped resource of natural products can be used for therapeutic benefit and provide a roadmap for delivering diverse classes of agents and understanding their in situ function.

Advanced drug development methods are being refined by innovative approaches that deliver therapeutics to particular cell types. In parallel, cutting-edge biological research has evolved to encompass the observation and manipulation of specific cell types in living tissues, without resorting to transgenic animals. The aim of this project is to identify short DNA sequences that govern cell-specific gene expression within the rodent and human spinal cord. Such neuronal addresses will serve as tools to visualize neuronal activity with biosensors or control neuronal activity with chemo/optogenetic actuators. These capabilities are crucial in understanding and treating the challenges of chronic pain, spinal cord injury, and motor neuron diseases.

Transcriptional enhancers are DNA sequences that dictate cell and tissue-specificity of gene expression. When active, they are found in genomic regions where chromatin is in an “open” conformation. Enhancers have been used in vivo to drive cell or tissue-specific expression of genes of interest, but never with the aim of treating human spinal cord diseases. Open chromatin regions in human and mouse spinal cords will be identified using single cell-based ATACseq. AI-enhanced bioinformatics will identify candidate neuronal addresses associated with genes of physiological significance for neurons from the dorsal horn (somatosensation/chronic pain), the ventral spinal cord and motor neurons (locomotion/spinal cord injury). Such sequences will be packaged into viral vectors to drive the expression of fluorescent reporter proteins through in vivo infection of rodent spinal cords and in vitro infection of live human spinal cords, followed by cross-referencing against target neuron molecular markers.

In two years, we will identify >30 neuronal addresses. Subsequently, these will undergo rigorous validation of their suitability as tools for imaging or controlling neuronal activity in normal spinal cord and in disease models. This project integrates bioinformatics, harnesses the resources of a provincial AI initiative, the Canadian Neurophotonics Vectorology and Neuronal Imaging cores, as well as the Transplant Québec network of organ donors. More specifically, transformative progress in viral engineering (MEP) will be combined by AI-assisted breakthroughs in epigenetics (MK), creating an interface that is ripe for basic biology discoveries relevant to spinal cord disorders (AK, YdK, RS).

Objectives

Precision medicine offers tremendous potential to secure superior therapeutic outcomes in autoinflammatory diseases. Unlike conventional drug therapy, precision medicine based on the deployment of nucleic acids offers the possibility of precise intervention as well as a permanent cure for pathological events in patients suffering from inflammatory disorders. Nucleic acids, however, are difficult to deploy for therapy since they are unstable in circulation and cannot cross cell-membranes to reach to desired cells and exert their effects. This project will create safe and effective approaches to introduce nucleic acids into immune cells to remedy undesired immune reactions in a host. We aim for implementing RNAi and CRISPR in immune cells so that reactive state of the cells is down-regulated to establish the normal homeostasis in patients.

Approach

Three separate expertise will be amalgamated to realize our objective. The nominated PI will lend his expertise in non-viral nanoparticulate gene delivery systems that are tailed specifically for modification of immune cells. Tailored systems for delivery of cargo to lymphoid cells will be developed and optimized for delivering siRNA, mRNA and Cas9/sgRNA cargo. One co-PI will lend her expertise in immune cell biology to explore novel ways to modulate the aberrant signaling pathways and master regulators in immune cells for a therapeutic effect. One co-PI will lend his clinical expertise in pediatric rheumatology to manage autoinflammatory disorders in order to implement nucleic acid therapy in modifying lymphoid cells in vivo.

Novelty & Expected Significance

The goal of therapy in autoinflammatory disorders is to rapidly control disease activity by suppressing systemic and organ inflammation. IL-1 blockade is available for a few (5) disorders among ~40 different autoinflammatory conditions with no cures for most of the lifelong diseases. Novel approaches are needed to intervene with emerging mediators responsible for aberrant immune activation. We for the first time will explore a precise approach to modulate immune cells by delivering a genetic cargo to transiently or permanent alter specific signaling pathways. This will allow in situ modification of immune cells to restore the normal hemostasis. With the ability to deliver a range of nucleic acid cargo, and modify specific types of lymphoid cells, our approach holds great potential to cure a range of innate and acquired diseases.

Canadians living in remote regions, particularly Indigenous Peoples, have less access to publicly funded health care than other people in Canada. It is reported that Indigenous patients have higher rates of surgery complications after knee and hip replacements. Such complications during or after orthopaedic surgeries are attributed to various failure modes of implant materials and are also associated with patients’ identity factors, such as sex, race, ethnicity, religion, age, and physical disability. Conventional implant materials are very limited and the types of implants are typically standard, which are not customized for individuals. The pandemic and many other restrictions limits the access of patients to orthopaedic surgery and disrupts the researchers’ ability to develop new implant materials based on patients’ identity factors. There is an urgent need to develop a variety of implant materials and improve surgical outcomes for all Canadians, with a focus on Indigenous Peoples and those that live in rural and remote locations.

Our collaborative research brings together the complementary expertise of materials science, orthopaedic surgery, artificial intelligence (AI), and additive manufacturing. Our objective is to identify a group of new implant materials with high strength, fracture-and-fatigue resistance, wear-and-corrosion resistance, biocompatibility, and antibacterial property for best patient fitting based on their identity factors, significantly reducing the rates of complications in orthopaedic surgeries. So far, no approaches have integrated mobile robotics with artificial intelligence (AI) for material development. Our team will develop a mobile robotic system to search for improved properties for hip and keen implants. The robot is expected to be operated autonomously driven by a batched Bayesian search algorithm. Our team will select beneficial compositions and deselect negative ones. This research methodology is expected to be deployed in conventional laboratories for developing new materials and devices for a broad range of applications. The research team engages underrepresented groups and will provide an equal, diverse, and inclusive working environment for highly qualified personnel.

Motivation. Efficient transportation networks, from streets to highways; and buildings, from houses to concert halls and stadia, impact the economy, security, energy, environment, and people health. However, pre-design data are near-impossible to gather, as large-scale experiments involving humans face enormous logistics-, cost-, security-, and ethical difficulties, especially regarding rare but very impactful events, e.g., disasters, accidents.

High-risk, high-reward research question. Do simple motile microorganisms, e.g., bacteria, fungi, search for available space similarly to how humans do it, thus resulting in similar spatial distribution patterns? The answer to this central question directs the project into two distinct but synergetic paths. The “yes” path is suggested by the universality of space searching, which is essential for the survival of all motile organisms, e.g., studies show slime molds replicate the network of various national highways and Japanese railway networks. The “no” path is advocated by the variability of biological species and their space-searching patterns, thus suggesting alternative real-world design geometries, e.g., microfluidics-based experiments showing the efficiency of fungal space searching ‘algorithms’ superior to human-made equivalents.

Goals, approach, and benefits. The project will study the microbial motility in microfluidics

1. with ‘intelligence testing’ geometries, e.g., mazes, to 'harvest' space-searching biological ‘algorithms’, compare them with human equivalents; and, if efficient, ‘reverse engineer’ them into better decision procedures for human movement in confined spaces; and
2. with geometries representing scaled-down versions of traffic networks or building spaces, to mimic people movement in equivalent confining environments, with various densities, speeds, and traffic rules, and if efficient, propose better designs of human networks and habitats.

The project will result in better methodologies for the design of traffic networks and edifices that optimize human density and dynamics, thus minimizing the risk of accidents and emergency preparedness.

Interdisciplinarity, team, and training. The diverse expertise of the research team reflects the deep interdisciplinarity of the project, involving microfluidics, microbiology, urban traffic, and network analysis, which in turn asks for project-driven HQP training in all these areas, with deep exposure to complementary professional perspectives.

Human pluripotent stem cell (hPSC)-derived 3D organoid technologies have immense potential to transform our understanding of brain development and disease pathogenesis. Current approaches, however, limit this potential as they yield structurally unpredictable tissues of heterogenous size and complexity. In this multi-disciplinary project, we will exploit recent advances in micropatterning of hPSC-derived embryonic tissues and bioprinting strategies to establish reproducible architecturally defined 3D models of the developing human brain. We aim to engineer two types of forebrain tissue. First, single ventricular lumens surrounded by NSCs that give rise to standardized neural cell layers, reflecting the architecture of the normal developing brain. The second will harness genetic mutant hPSC lines to recapitulate self-assembled focal tissue aberrations (containing dysplastic NSCs, neurons and astrocytes) that typify developmental cortical malformation syndromes.

To achieve these goals, hPSCs and NSCs will be seeded at high density on 3D printed islands of hydrogel matrices with defined diameters. In these conditions forced spatial constriction will promote self-assembly of developing neural tissues into NSCs surrounding a single lumen (vs multiple lumens in typical organoids), or focal tissue malformations of reproducible size. Brain-mimetic bioinks will subsequently provide a scaffold for more extensive development to establish single lumen tissues with typical neuronal layers found in the in vivo brain. Thus, a major innovation is that we will establish human forebrain tissues of reproducible size and structure which closely recapitulate the architecture of the human brain, and can be produced in high volume.

Standardized brain tissues will transform our ability to model and manipulate human brain development. Drawing on combined expertise, these tissues will be used to precisely model early-stage mechanisms of neurodevelopmental and degenerative disorders. In parallel, they will substantially advance powerful high-throughput analyses, including functional metabolic screening and automated molecular phenotyping following compound or genome editing screens. In the long term, these tissues will streamline patient-specific biomarker and phenotypic screening, and analyses to ascertain the influence of poorly understood components, like non-neural cell types and environmental regulators, on the development of normal and abnormal human brain tissues.

According to the Canadian Interagency Forest Fire Centre, dry conditions, warmer-than-usual temperatures, and fuel buildup have been propelling long and unrelenting wildfire seasons, culminating (over only the last nine months) in burning more than 17.5M hectares (a 650 % increase over the past 10-year average), displacing over 200,000 Canadians and loosing 86 firefighter lives, notwithstanding their far-ranging health consequences. Attributed in large to Canada’s changing climate, the increased frequency and magnitudes of wildfire extremes coupled with our inability to mitigate subsequent risks in recent years, have been demonstrating the urgent need for a paradigm shift in Canada’s wildfire management practices.

Despite being not apparently related, managing the risk of wildfire spread is analogous to controlling power grid cascade (blackout) failures. Notwithstanding their apparent functional and behavioural differences, a forest, when simulated as a network of interconnected (through fire-lines) fuel sources (e.g., vegetation patches and dwellings), resembles a network of interconnected (through transmission-lines) power sources (e.g., generators and substations). Our proposed research will thus harness state-of-the-art blackout risk management research, developed to address emerging sociopolitical threats, to develop a radical approach to wildfire risk mitigation, under climate change-induced stressors.

Our proposal brings together researchers from three disciplines:

1. Wildfire Risk Management;
2. Complex Dynamic Network and Systems Simulation; and
3. Blackout Risk Analysis in Power Grids. To our knowledge, this will be the first time to employ complex dynamic network theory (CDNT) for wildfire spread and behaviour simulations.

CDNT will enable us to identify highly connected vegetation patches and quantify the overall forest connectivity dynamically, in real-time as wildfire continues to spread. Similar to our approach of shutting down specific transmission lines to arrest blackout spread, we will devise Controlled Islanding strategies to guide the implementation of fuel break segments to effectively prevent wildfire spread.

Empowered by leading-edge Constrained Spectral Clustering, our planned open-access national platform is expected to:

1. expand our understanding of wildfire dynamics;
2. optimize firefighting resource management; and
3. ultimately reduce ecological, economic and human losses.

Some medical devices whether sex-specific (IUDs) or universal (surgical mesh, hip replacements) produce harm in women, bad press, and costly legal challenges. However, media and court findings have lacked evidence from rigorous scientific testing to determine when sex differences undermine device safety and/or effectiveness. The challenge is anticipating how sexed bodies adapt to the foreignness of medical devices. We will use surgical mesh as a prototype to develop humanized cellular and tissue models to test sex-specific immune responses to implantable medical devices. Our proposal will integrate sex-focused immunological data with a detailed probing of socially accepted definitions of patient outcomes to better define device failure/success.

Immune systems view implanted devices as foreign. After an initial inflammatory response, the immune system should switch to a healing response; however, over time chronic inflammation can develop, reducing function. The extent to which sex and sex hormones modulate these outcomes within the body varies with devices and implant sites but has yet to be explored. This is an area of high risk. By interrogating the ‘one size fits all’ manufacture of devices it challenges industry and validates sex as a biologic reality. We will develop in vitro culture systems to identify the effects of male and female hormones on male and female immune cell interactions with device materials. We will pair this with histological examination of tissue surrounding explanted devices (from donor programs or animal models) and use multivariate analyses to relate lab outcomes to device properties.

Current evidence of when device design requires consideration of sex is primarily theoretical, arising from understanding of greater female inflammatory potential. The use of surgical mesh as our prototype presents a unique and challenging opportunity to untangle the malfunctions arising from blindness to sex differences from bad luck or physician error currently blamed for mesh failure in females. Even the term failure is contested; if a device corrects a problem, e.g., pelvic mesh diminishing urinary incontinence, but produces concomitant serious side effects, has the device failed? We will identify and account for such instances and relate them to immunological data to redefine failure and suggest changes to the testing and approval processes for implantable medical devices, a high risk endeavor that challenges interests of industry.

La douleur totale en soins palliatifs oncologiques, englobant la douleur physique, psychologique, sociale et spirituelle, représente un défi majeur. Sa gestion souvent sous-optimale conduit à une détérioration de la qualité de vie des patients. Ce projet vise à proposer une approche novatrice combinant deux disciplines très différentes: la pharmacie/ pharmacogénomique et la théologie spirituelle. L'objectif est d'assurer une prise en charge globale et holistique de cette douleur. Les objectifs spécifiques sont les suivants:

1. Documenter les attentes des patients en matière de gestion des symptômes douloureux et l'acceptabilité de cette combinaison d'approches divergentes dans les soins palliatifs au Québec, en utilisant une approche mixte qualitative et quantitative.
2. Évaluer l'efficacité de l'association de la thérapie pharmacogénomique personnalisée aux soins spirituels dans le soulagement de la douleur totale, à travers une étude pilote randomisée contrôlée comprenant deux groupes:
   1. groupe recevant les soins habituels conventionnels, et
   2. groupe recevant des soins individualisés intégrant des tests pharmacogénétiques et des soins spirituels.

Ce projet vise à révolutionner les pratiques actuelles de prise en charge des symptômes douloureux en soins palliatifs, souvent limitées à des approches médicamenteuses ou spirituelles isolées et insuffisantes pour améliorer la qualité de vie des patients. Il aspire à un changement de paradigme significatif en encourageant le dialogue et la complémentarité entre l'anthropologie médicale pharmacologique et l'anthropologie spirituelle. Pour atteindre cet objectif, une équipe pluridisciplinaire internationale d'experts a été formée, en respectant les identités disciplinaires de la pharmacologie/pharmacogénétique et de la théologie/spiritualité. Cette équipe élaborera un modèle anthropologique intégratif qui englobe ces deux disciplines et permet de mieux comprendre les liens possibles entre symptomatologie et profil spirituel. L'approche résultante sera innovante et holistique, prenant en compte la personne malade dans sa globalité au sein des soins palliatifs oncologiques. Elle a un impact direct sur la gestion du plan de soins en intégrant de manière cohérente les dimensions génétiques et spirituelles dans le traitement de la douleur. In fine, ce projet vise à améliorer la qualité des soins et la qualité de vie des patients en fournissant une intervention aussi précoce, personnalisée et ciblée que possible.

The purpose of this research is to continue supporting partnering Indigenous communities through self-determined and sovereign research. A foundational aspect of this effort identified by community partners is the institutional ethics process. We aim to support Indigenous community partners to develop their own ethics protocols and review procedures and challenge institutional ethics boards to require community approval prior to institutional approval. This will bring a variety of mental health benefits, reduce continued harms in Indigenous communities and expand the evidence base for ethical, culturally safe, decolonized, responsive research with Indigenous communities. Self-determined research effectively improves Indigenous health and well-being (Hart et al., 2021; Kipp et al., 2019; Fehring et al., 2019). Previous and current work, as well as existing relationships with Indigenous communities internationally, suggests a wide range of additional mental health benefits of ethical, collaborative research that respects the sovereignty of Indigenous Peoples. While mental health outcomes are realized differently for each community, predicted mental health benefits include: empowerment; increased engagement in research; and/or cultural revitalization. This is a community-led, participatory project that is self-determined with partnering Indigenous communities. Specifically, Indigenous community leadership and the applicants will enter a partnership agreement and a Community Knowledge Committee (CKC) will be formed. CKC objectives are:

1. review the 19 Canada-wide community research ethics protocols;
2. engage Australian Aboriginal ethics boards about successes and challenges;
3. develop communities' ethics protocols; and
4. determine ways in which communities' can engage and challenge the post-secondary institution research ethics boards in requiring community ethics approval prior to consideration of any research that involves them.

This research is high risk as its actions challenge large institutions on their reconciliation plans in a very tangible way. Institutional change is a slow and difficult process, particularly when it involves acknowledgement or respect for external authority. However, this is also high reward work in that community capacity to identify community-driven research ethics protocols will be built as well as Indigenous voices will be heard at the institutional level for the changes that are required to truly act upon reconciliation.

Acute respiratory distress syndrome (ARDS) is a severe inflammatory lung injury that can arise from various triggers, including trauma, burns, or infections (e.g. COVID-19). Most patients with ARDS die, treatment options are limited, and the development of effective therapies has been challenging. Indeed, most novel ARDS therapies fail to replicate between labs or later successfully translate into humans. Inconsistent results within lab research may, in part, stem from the challenges in implementing methods that reduce bias and enhance reproducibility in ‘exploratory’ bench research

To overcome these challenges, we propose an interdisciplinary project that will not only assess barriers to reproducibility in exploratory research, but also pioneer a high-risk, high-reward cell therapy for ARDS. Our innovative approach centers on the use of regulatory T cells (Treg) therapy as an anti-inflammatory ARDS treatment. Tregs mitigate inflammation and promote tissue repair through the secretion of immunosuppressive cytokines and tissue repair factors, respectively. Their function can be further enhanced by expression of chimeric antigen receptors (CARs). CAR-Tregs have yet to be tested in an acute inflammatory condition. Simultaneously, we will assess barriers and enablers to reproducibility practices in exploratory bench research.

We propose an iterative, multifaceted approach:

1. isolate and expand syngeneic or allogeneic Tregs enriched for lung-protective ST2-expressing cells;
2. generate CAR-Tregs that target inflammatory ligands (e.g. tumor necrosis factor-like ligand);
3. evaluate the anti-inflammatory effects of different Tregs in vitro, and efficacy in established mouse models of lung injury.

In parallel, we will assess reproducibility practices throughout the research cycle, from defining the question, experimental design and conduct (e.g. randomization, blinding), to analysis and results reporting. Associated barriers and enablers will be examined using the theoretical domains framework. Semi-structured interviews of team members will be conducted with the aim of real-time evaluation and implementation.

Impact: Our project will assess the feasibility of CAR-Treg therapy in preclinical models of ARDS, potentially introducing a groundbreaking treatment. Furthermore, our research will provide invaluable insights for enhancing reproducibility practices in exploratory laboratory research, benefiting the wider scientific community.

Transcranial Focused Ultrasound (tFUS) potentially offers a non-invasive treatment option for conditions like ischemic stroke, tumor ablation, blood-brain barrier (BBB) opening for local drug delivery, and neuromodulation. However, current methods, such as ExaBlate, rely on Magnetic Resonance Imaging guidance (MRg), which limits their speed, affordability, and availability, especially outside of Canada's three specialized treatment centers (Toronto, Calgary and Montreal). Therefore, there's a pressing need for a more accessible and quicker tFUS solution that aligns with both clinical needs and patient convenience.

This project explicitly aims to go beyond the 'obvious next step' in tFUS research (data collection, application of existing technology) by achieving a technological breakthrough that will significantly expand the clinical applications of tFUS. Indeed, the primary goal of this initiative is to develop a mobile ultrasound-guided tFUS (UTg-tFUS) system suitable for both children and adults. Achieving this requires an interdisciplinary approach that integrates expertise in physiology, engineering, medical imaging, and neurology to address the complexity involved.

This project will focus on two specific applications, leveraging the research team's expertise:

1. pre-surgical neurological function mapping for pediatric patients and
2. early intervention sonothrombolysis for adults with ischemic stroke.

The project is organized around three key sub-objectives, to be pursued collaboratively by Master's and PhD students, in order to:

1. Develop a sparse UTg-tFUS setup, incorporating feedback from patients and clinicians at an early stage;
2. Integrate a method for correcting image distortions in transcranial imaging by locally determining skull characteristics using inverse methods;
3. Develop a mobile UTg-tFUS device capable of real-time operation in both lab and clinical settings, featuring an integrated interface for both imaging and focus control.

Students participating in this project will benefit from a cross-disciplinary educational environment, gaining unique skills at the intersection of mechanical and electrical engineering, medical imaging, neurology, and physiology. The team is optimistic that this innovative approach will pave the way for broader clinical and preclinical applications of tFUS technology, including in remote communities and among populations currently lacking access to MRg-tFUS.

This proposal calls for the development of novel imaging analysis software that will elucidate unexplored physical processes in both the outer reaches of Earth's atmosphere and the cosmos. Studies of these contrasting realms traditionally have little overlap, as ionospheric effects on Galactic radio emissions are generally considered a nuisance to the study of these sources. Our proposed work will leverage ALBATROS, an existing high Arctic radio antenna array led by our team, to study both Galactic radio emissions and the ionosphere through which they propagate.

Radio telescopes are sensitive to the region of Earth's upper atmosphere known as the ionosphere. Rapidly changing structures in the ionosphere distort a radio telescope’s view of the cosmos. ALBATROS is taking the first steps towards observing the cosmic "dark ages,” which occurred before the first stars formed. These observations are performed at low frequencies that are particularly sensitive to distortion from the ionosphere, making the cosmological observations high-risk. However, this challenge also affords a unique opportunity to gain new insights into ionospheric physics and to develop new tools to model and correct these effects.

Although ALBATROS was designed for astronomy, the instrument also naturally functions as a spectral riometer (relative ionospheric opacity meter). ALBATROS is significantly more sensitive than existing riometers and can therefore study solar energetic particle (SEP) events in the upper atmosphere at very low energies. SEP events are of great concern because they create blackout conditions for high frequency radio, precluding the use of aviation communications on transpolar routes and rendering long range early warning radar systems inoperable.ALBATROS is fortuitously co-located with RISR-N, forming the only spectral riometer and incoherent scatter radar pair that can jointly observe within the polar cap.

ALBATROS’s location within the polar cap is unique in that the low plasma densities enable observations at low frequencies. However, ionospheric variability in this region is highly dynamic, and removing these effects is therefore incredibly challenging. This project will forge new connections between astronomers and atmospheric/space scientists to

1. perform studies of high latitude ionosphere that have previously been performed only at mid-latitudes, which have a limited set of instability processes, and
2. deliver the key science of ALBATROS.

The Cervidae (deer family) is one of the few mammalian groups that have demonstrated an extraordinary ability to regenerate appendages, including scar-free wound healing in the antler velvet (skin, surface ectoderm derivatives), and annual antler regrowth (bone, mesodermal derivatives). Establishing in vitro models to better understand the cellular and molecular mechanisms that drive this remarkable regeneration capacity will shed light on how regeneration works. The goal is to harness this knowledge and apply it to less regenerative species, including humans.

Specifically, this project aims to establish induced pluripotent stem cells (iPSCs) from reindeer (Rangifer tarandus) to enable the creation of unlimited cellular sources of lineage-specific progenitors for comparative studies. Reindeer iPSCs (RdiPSCs) will be reprogrammed from somatic cells and differentiated into any cell type in the body. To date, no RdiPSC line has been established, and our team’s preliminary data have already produced RdiPSC-like colonies in our lab. We hypothesize that RdiPSC-derived progenitor cells will retain the robust, reindeer-specific regenerative capability.

• Aim 1 is to characterize RdiPSC self-renewal and its ability to differentiate into multiple lineage progenitors. As reprogramming often results in iPSCs retaining the epigenetic state of the starting cells, we will compare the RdiPSCs derived from various sources, such as those derived from the back skin or from the antler velvet.
• Aim 2 focuses on making appendage-specific progenitors (skin and bone) by employing three-dimensional organoid culture systems. We aim to test the regenerative abilities of RdiPSC-derived appendages by transplant assays and through comparative studies to those appendages derived from human iPSCs.

This project is high-risk, high-reward, as there is no established deer-specific iPSC to study their regenerative capacity. The Cervidae species host diseases like COVID-19 and chronic wasting disease. Natural host cell models can help us study disease pathogenesis and prepare for future pandemics. Additionally, reindeer/caribou are threatened species in Canada, and methods for producing reindeer stem cells will contribute to conservation efforts. We have assembled a strong interdisciplinary team with expertise in stem cell biology, tissue regeneration and veterinary medicine. We have a reindeer research facility and new large animal labs at the Center for Cell Therapy Translation at UCalgary.

Cardiovascular disease (CD) remains the leading cause of death globally, taking more lives than all forms of cancer combined. CD is responsible for one-third and one-fourth of deaths worldwide (18million annually) and in Canada, respectively. CD costs the Canadian economy $22billion yearly in physician services, hospital costs, and decreased productivity.

To reduce morbidity, mortality, and costs of CD, it is essential to perform precise diagnosis in large populations to identify individuals at CD risk. Such diagnosis will enable early treatment and intervention in high-risk individuals to prevent catastrophic events like heart attacks. Precise CD diagnosis hinges on accurate quantifications at the global level in terms of heart function and workload and at the local level in terms of detailed blood fluid dynamics and biomechanics. However, we still lack diagnostic tools that can properly perform these quantifications non-invasively. Additionally, conventional clinical tools should only be used in clinical settings by clinicians. Therefore, performing CD diagnosis within a large population using conventional clinical tools is not currently possible due to the cost and the load it will impose on the already overloaded healthcare system.

In this research, we will develop a new technology to provide precise CD diagnosis and monitoring at both local and global levels, which is not possible using existing diagnostic methods. This high-risk research defies the current paradigm that precise CD diagnosis can only be done in clinics. This project opens a completely new research direction by developing an advanced precise non-invasive ultrasonic diagnostic machine that, in addition to clinics, can be installed in public spaces (e.g., workplaces, parks, community centers, swimming pools, etc.) and can be used by non-experts. Because this risk-free, low-cost, and fast CD diagnosis machine, will not need expert operators, it can also be used on a regular basis for monitoring purposes.

The extensive experience of our team in developing health technologies and providing clinical diagnosis and treatment for CD patients ensures the high clinical impact of this project. The high reward of performing precise CD diagnosis and monitoring in large populations is only possible using our novel interdisciplinary approach that interweaves several disciplines spanning from fluid mechanics to cardiology. The large-scale CD diagnosis can revolutionize cardiovascular health.

Osteoarthritis (OA) is a leading cause of chronic disability, involving the progressive degeneration and inflammation of joint tissues. There are currently no clinically approved treatments that can halt or reverse OA progression. Recent research has uncovered molecular targets associated with OA, and progress has been made in the delivery of potential therapeutics to cartilage. In particular, cationic drug carrier macromolecules have been shown to penetrate cartilage, and the effects of charge density and molecular architecture on uptake are beginning to be understood. However, the effects of these macromolecules on cartilage tissue and the potential for the molecules themselves to serve as therapeutics have not been investigated.

The goal of this project is to determine the potential for cationic macromolecules to play a therapeutic role in strengthening cartilage or slowing its degradation, thereby providing an entirely new approach to OA treatment.

• Aim 1: Prepare and characterize a series of cationic polymers with varying chain lengths, cationic charge densities, and degradation rates. Their uptake into ex vivo articular cartilage and effects on cartilage cells (chondrocytes) will be evaluated.
• Aim 2: Evaluate the effects of select cationic polymers from Aim1 on cartilage tissues. We will examine - through mechanical testing - the possibility that by multivalent binding of polycations to the anionic cartilage extracellular matrix (ECM), mechanical reinforcement may be obtained. We will also examine the potential for the polymers to inhibit cartilage degradation by catabolic enzymes involved in OA.
• Aim 3: Using animal models of OA, cartilage uptake of lead polycations from Aim 1 will be validated in vivo and their localization will be examined (i.e., in cells or within the ECM). In addition, the effects of the polymers on cartilage mechanical properties and degradation will be examined.

This proposal is high risk as the potential for cationic macromolecules to serve as OA therapeutics has not been investigated. However, the reward of success would be significant as the development of OA therapeutics is a major challenge and an unmet need. Even if the macromolecules do not exhibit therapeutic properties, substantial knowledge will be gained regarding cationic polymers as drug carriers. This project will bring together a diverse team with interdisciplinary expertise in polymer chemistry, biomechanics, regenerative medicine, and physiology.

Parkinson's disease (PD) affects over 100,000 Canadians and 10million people worldwide. Excessive neural synchrony in the subthalamic nucleus has been correlated with PD severity and motor impairments including tremor and rigidity. Current treatments lack long-term efficacy or are surgically invasive.

We will develop a novel therapy based on stimulation of the peripheral nerves, building on studies demonstrating that the pathological neural synchrony in PD can be reduced by vibrotactile stimulation. Our unique strategy combines mathematical modelling, clinical research, and new measurement approaches to overcome limitations of prior work based on trial-and-error experimentation and inadequate monitoring that measures key indicators only indirectly.

Our vision is to develop vibrotactile stimulation as a non-invasive, cost-effective treatment for PD. Using readily available off-the-shelf materials, we have built a glove that delivers vibrotactile stimulation to the fingertips. We have access to local field potential recordings in the subthalamic nucleus for 20patients who have received the Medtronic Percept recording battery after deep brain stimulation surgery. Thus, we can directly observe the effects of vibrotactile stimulation on the local field potentials in real time.

Aim 1: We will calibrate dynamic models for optimizing stimulation patterns. This work is enabled by our rare data from patients with neural implants, which will allow us to develop unique insight into the control structures underlying PD pathology. We will use our glove to deliver stimulation to the fingers of our patients while the activity in the subthalamic nucleus is recorded, enabling the important rigorous validation that is lacking in the field.

Aim 2: We will use an interdisciplinary approach combining clinical studies with our deep expertise in mathematical and computer modelling to discover generalizable relationships between stimulation patterns and neural activity. The dynamics of the motor control system are governed by delay differential equations due to processing and signal propagation delays. Our multi-discipline collaboration will enable us to generate the rich datasets we need to refine our models and test our model predictions in the clinic.

Treating PD with vibrotactile stimulation would be a breakthrough with potential to improve the lives ofmillions of people for whom current treatments are ineffective or unaffordable.

OBJECTIVE: The primary goal of this multidisciplinary proposal is to develop an exceptionally precise and specialized system for the detection and categorization of cancer. This will be achieved by applying nanoapertures optical tweezers to extracellular vesicles in liquid biopsy samples.

RESEARCH APPROACH: We will use nanoapertures in metal films to focus a laser beam below the diffraction limit and thereby trap single extracellular vesicles (EVs) from a liquid biopsy sample. Since the trapping signal is sensitive to variations in the refractive index profile, shape and size of the EVs, we will evaluate the platforms capabilities to differentiate between EVs derived from healthy or cancerous cells. To enhance diagnostic specificity, we will employ surface-enhanced Raman spectroscopy on the trapped EV as a fingerprint analysis of the constituents. We will also attempt extraordinary acoustic Raman as an approach to measure low frequency mechanical vibrations and thereby gain insights into the mechanical properties of the EV.

NOVELTY AND SIGNIFICANCE: There is a critical need to develop non-invasive platforms to detect and classify cancer. The potential of EVs to detect and report on cancer is substantial; EVs are abundant in biofluids, exceptionally stable, and easily accessible, making them an excellent biomarker source. Unfortunately, EV analysis is severely limited by available fluorescent labels and their small size requires nanoscale characterization. Commonly used fluorescent labels are limited to the detection of abundant biomarkers and multiple-marker detection is challenging due to steric hindrance. Interrogation of proteins or nucleic acids contained within an EV is also impractical with current analysis platforms. Therefore, approaches that are well suited to small nanoparticles and forgo the need for labels are desired. An unproven yet promising approach would use nanoaperture optical tweezers to trap EVs and characterize their biophysical properties; thus, enabling us to bypass the need for fluorescent labels.

The significance of this novel tweezer-based platform is that it can identify targets where suitable labels have not been identified. The trapping platform has the novelty of working at the single EV level, which provides extreme sensitivity. Furthermore, by forgoing the need for labels, our approach promises to reduce the cost and processing time required in standard biopsy analysis.

Representation matters! It looks difficult to divide CCCXCVIII by CXCIX. However, this daunting task becomes trivial by converting the troublesome Roman numerals to Arabic: CCCXCVIII = 398 and CXCIX = 199, leading to 398/199 = 2. In modern machine learning (ML), Representation Learning (RL) is an emerging technique to uncover hidden structure, facilitating downstream applications based on the “correct representations”. For instance, to recognize a face, modern RL models learn sensible features (noses, eyes, etc.), in contrast to traditional ML that relies on individual pixels. Another example is modern Natural Language Processing, which uses embeddings, a representation that reflects the usage context of phrases, in contrast of “a bag of words” in traditional ML.

In biology and medicine, the omics data (genomics, transcriptomics, proteomics, etc.) contains massive amounts of information; however, it may not be presented “correctly”. Taking DNA as an example, A, C, G, T are too fine-scale without reflecting their functions and interactions. This “default” representation may be analogous to the pixels in of human faces vs. focusing on higher-level objectives such as eyes or noses.

Based on our existing collaborations and preliminary method development, we will learn representations of omics data using large cohorts to unlock discoveries in biology and diseases. Techniques in statistics, computer science, genetics, and biology will be utilized. More specifically, three categories of methods will be employed, first independently and then synergistically:

1. biological a priori knowledge (such as using pathways & regulatory networks) directed structural learning in a white-box approach;
2. standard automatic RL techniques (such as Autoencoders and Attention mechanisms) to reveal hidden dimensions in a black-box style;
3. mathematically inspired (e.g., differential equations) systematic learning behaviour in a grey-box context.

Primary Objective: This proposed research focuses on exploration of bottom-up electrode fabrication using enhanced metal-binding peptides for improved visual function.

Background: Electrodes are critical to the diagnosis, monitoring, and study of human health. Specialized electrodes are required to transmit electrical activity originating from organs such as the brain, or eyes. Vision can be assessed quantitatively via electroretinography via electrodes placed on or near ocular tissue, sending signals to stimulate the retina with high resolution is a challenge. Existing retinal prostheses use electrodes spread across the retina as an electrode array to stimulate nerve cells and generate the perception of an image. The fabrication of flexible electrode arrays is often performed via photolithography containing layers of polymer and metal (e.g., gold, titanium, or platinum), which is the electrode.

This interdisciplinary exploratory research seeks to develop a sustainable approach to generate retinal electrodes for the first time via the metal coordination properties of gold-, titanium- and platinum-binding peptides with the following objectives:

• Objective 1: Elucidate efficient metal capture constructs composed of metal-binding peptide fusion proteins expressed with biopolymer binding motifs.
• Objective 2: Generate functional electrode microarray on digital microfluidic-based deposition of biopolymer inks and metal ion solution.
• Objective 3: Identify high performance electrode based on biocompatibility, function and sensitivity studies with patterned electrodes.
• Objective 4: Examine the socioeconomic barriers to retinal prostheses in Canada.

Summary of Research Approach: Rapid screening of metal-binding and scaffold fusion proteins will be evaluated using cell-free protein expression in the presence of non-canonical amino acids known to mediate metal coordination. Peptides with affinity for hydrogel bioinks composed of cellulose nanocrystals or natural glycosaminoglycans will be tested to generate electrode formation with digital microfluidics. The electrodes with best impedance performance will be evaluated in vitro for compatibility using retinal explant tissues from mice.

Significance of the Work: The biofabrication of electrodes and electric circuits would have significant implications for biosensors, diagnostics, and potential to expand applications with low-cost proteins for applications in microelectronics or bionic implants.

In Canada, individuals with lower levels of income and education live 11.3 fewer years in good health than their more advantaged counterparts. This disparity is most strongly felt by older adults, who as a result experience significantly reduced quality of life and utilize more costly healthcare resources. Fueled by current crises related to food insecurity and affordable housing and the expected doubling of the older adult population by 2060, these social and economic burdens are only expected to worsen. Indeed, the “perfect storm” of social inequality and population aging will be significant and will require practical, innovative strategies to weather.

The conventional biomedical approach to addressing health issues is to treat diseases and conditions after they have emerged. Since illness is common for older adults living in poverty, this strategy merely results in the accumulation of poor health and significantly overburdens primary care. We propose a different approach: by adopting a conceptual framework centred on a salutogenic model of health promotion, our interdisciplinary team featuring NSERC-, SSHRC-, and CIHR-funded experts will identify key resilience factors that are associated with healthy aging trajectories, even under the burden of social inequality. For this, we will employ the largest and most comprehensive health study in Canada, the Canadian Longitudinal Study on Aging (n~50,000), to achieve the following specific aims:

1. Develop an innovative salutogenic health index to examine how resilience varies amongst older adults, especially for inequality indicators such as household income, educational attainment, wealth and neighbourhood deprivation.
2. Estimate the health trajectories of older adults over 9-years using physiological and physical/cognitive function measures and identify resilience factors that are associated with stable health in the face of social inequality.
3. Examine the biological pathways that mediate the protective effects of resilience on the health trajectories of older adults who are experiencing social inequality.

Designed from an interdisciplinary perspective, this work will provide the foundation for novel holistic and multi-faceted approaches to promote healthy aging through resilience for our most vulnerable populations. Importantly, we will generate new tools and knowledge to support future interventions to mitigate the harms of social inequality on older adults.

Research by our team identifies Cree, Saulteaux, and Métis Nations as having the highest prevalence in the world of spinal bulbar muscular atrophy (SBMA), an inherited neuromuscular disorder resulting in muscle weakness and atrophy. Our team’s early explorations suggest that a founder effect resulted in this high prevalence during a period of low genetic diversity, likely around 250years ago. This suggests that high prevalence of SBMA among these Nations is a direct consequence of extractive colonialism, as repeated epidemics devastated Indigenous people.

Our research team has been engaged with people affected by SBMA since 2020. This community of largely Indigenous people reiterates that the most important goal for them is to one day have access to disease-modifying therapies. Barriers to this goal include the need for engagement to ensure any anticipated clinical trials can be done in a culturally safe way, and the currently limited therapeutic pipeline for SBMA. The proposed project addresses these limitations by advancing a high-risk exploration of gene therapies for SBMA with a largely colonially-induced Indigenous SBMA population, for the high-reward of forging culturally safe genetic research protocols and possible therapies for this population.

In Aim 1 we will use qualitative and Indigenous research methods to crystallize priorities from Indigenous communities affected by SBMA, to proactively determine needed elements to ensure safe and ethical participation in anticipated clinical trials. We also seek to address important questions such as perspectives on genetic research, appropriate use of tissue samples, and culturally responsible ways to honour these. In Aim 2, we will apply translational research approaches to develop biomarkers and potential future therapies, with ongoing feedback and engagement with people with lived experience. This will include attempts to bypass the disease mutation using CRISPR activation, and biomarkers correlated to disease states and therapy response.

This interdisciplinary project integrates the efforts of researchers in Indigenous health, population sciences, clinical neurology, genetics, and translational science. Importantly, we also partner with Indigenous people affected by SBMA who have formed a Community Guiding Circle, and a Saulteaux Knowledge Holder from one of the affected communities.

Complex biological networks, such as neural circuits of the brain and ecosystems, are remarkably resilient, preserving their functions in response to perturbations. Patterns of failure accompanying the loss of resilience for both systems - namely seizures or ecological collapses - have widespread consequences for human health and society yet are rarely predictable and seemingly inevitable. Avoiding such failures requires bridging a critical knowledge gap that links resilience to architectural motifs in complex networks, considering their variability in structure and scale. Here, exciting common design features between these two biological networks, such as functional dependencies on diversity, have the potential to advance knowledge in each discipline. Indeed, echoing the established link between ecosystem resilience and biodiversity, our team has recently identified a decline in diversity amongst neurons in brain areas prone to seizures: this suggests that predisposition to seizures is characterized by a progressive decline of the brain’s functional resilience precipitated by diversity loss. These results represent an opportunity to leverage extensive open access neural data combined with modern extensions of ecological theory to determine how diversity supports the resilience of biological function across scales.

Our long-term goal is the identification of common intervention strategies in both systems to improve our ability to prevent instability due to diversity loss. To identify shared motifs vulnerable to failure and extract common architectural features linking diversity and resilience in brain circuits, we will integrate data and theory from ecosystem ecology and neuroscience and implement a hypothesis-testing computational pipeline. Understanding how brain circuits gain resilience from diversity is a paradigm-shifting idea that may transform the way we treat neurological disorders. By leveraging direct measures of network topology and response traits from neural data– a feat that is impossible at ecological scales—we will also rigorously test key hypotheses in ecosystem ecology such as the relative importance of maintaining stability in ecosystem structure vs. function in providing resilience to environmental change. This novel approach will uncover the generality of these mechanisms across scales, and may help to inform functional targets for habitat restoration, a critical conservation strategy in the Anthropocene.

Humans are causing unprecedented biodiversity losses. Iconic species of large mammals (megafauna) are among the most at-risk and their conservation has remained challenging despite their key ecological/cultural roles. Investigating the evolution of a species' genetics and behavior during past climatic/human perturbations is crucial to understanding extinction. While paleogenomics is revolutionizing paleoecology, the lack of modern reference and the limited behavioral data gained from studying fossils’ morphology, restrict the possibility of researching how genetic changes translated into behavioral traits for extinct species. Isotope-based behavior reconstruction could fill this gap. Our overarching goal is to demonstrate, for the first time, how the genetic evolution of an extinct megafauna species relates to behavior characteristics that might have precipitated extinction.

The terminal Pleistocene is an analog to present-day because, during that time, warming and human pressures caused many megafauna extinctions. Horses went extinct in Beringia but survived in Eurasia providing a unique comparative system to study extinction. While Pleistocene Eurasian horse’s genomics and behavior are well-studied, we lack similar knowledge on Beringian horses. First, we will disentangle the ambiguous systematics of Beringian horses during the terminal Pleistocene (~20-11ka) by combining tooth morphometrics, paleogenomics and radiocarbon dating. We will then use sequential stable isotope analysis in tooth enamel/dentine, habitat suitability models built from climate models and spatial statistics to reconstruct the evolution of behavioral traits of Beringian horses during the late Pleistocene (i.e., diet, habitat, mobility). Next, we will associate the evolution of those behavioral traits with paleogenomics to identify genotype-behavior associations and their potential links with the extinction of Beringia horses. The project is high risk, it relies on:

1. dating horse fossils from mixed/poorly-dated stratigraphy to obtain specimens spanning the terminal Pleistocene, and
2. obtaining paleogenomics and isotope-based behavioral reconstruction from those limited/ancient fossils.

If successful, the project will provide a ground-breaking basis to study the drivers of megafauna extinction with high rewards for conservation/de-extinction approaches. The project is highly interdisciplinary bridging the fields of geochemistry, paleontology, paleogenomics, and statistics.

Cardiovascular diseases (CVD) are the leading cause of death worldwide and second leading cause of death in Canada. Indeed, 206 Canadians (60% of them women) die from CVD every day. CVD cost Canada $20.9billion per year. Most CVDs can be prevented/managed. Accurate point of care predictions and early and personalized recommendations for prevention of CVD can help.

In this study, our overall objective is to improve primary prevention of major CVDs by CARDIO-TWIN system, providing accurate and personalized CVD risk score and prevention strategies to the primary care providers and women. Our study aim to develop and evaluate digital twins for identifying major CVDs’ risk score among women using data from those women who had CVDs. This aim will be achieved through two phases.

Phase 1: We will collaborate with our knowledge users to jointly create and assess digital models. In Phase 2, we will compare the predictions with routine care tools. The insights gathered from this preliminary assessment will be instrumental in fine-tuning CARDIO-TWIN and our approach for subsequent phases of the project, laying a solid groundwork for future randomized controlled trials.

Our digital health solution will be delivered in primary care—where women make their first and most frequent contact with the health care system—thus, it can play an important role in early CVD detection and prevention.

CARDIO-TWIN will not only streamline the existing procedures, but also incorporate advanced technology to interpret complex data effectively, guiding personalized prevention strategies based on an individual’s health profile. Moreover, it will promote patient-centred care and foster shared decision making for CVD prevention. Lastly, this high risk, high reward and interdisciplinary project has all the elements in place to succeed: it is feasible, meets the need of patients and clinicians, involves an experienced multidisciplinary team, and proposes a scientifically sound research approach within a reasonable budget.

Plastics are commodity polymers found in every facet of society. Due to their resistance to biological degradation, they have become major pollutants. Recently, however, enzymes capable of breaking down select plastics have been discovered. These plastic degrading enzymes (PDEs) are promising for use in plastics recycling and bioremediation processes. Nonetheless, PDEs are active on only a small subset of plastics. Our proposed project now seeks to address the lack of PDE diversity in two interdisciplinary objectives combining synthetic biology and polymer engineering:

• Designing de novo PDEs by incorporating reactive metal centers into plastic binding proteins.
• Engineering novel plastics with high susceptibility to depolymerization by PDEs.

• In objective 1, the project’s synthetic and chemical biology groups will insert metal chelating unnatural amino acids (UAAs) such as bipyridyl alanine in known plastic binding proteins. These UAAs will be targeted to the proteins’ plastic-binding interfaces to position reactive metal centers next to the plastic surface. As metals are known to catalyze the breakdown of various plastics, including polyesters, polyamides, and polyolefins, we will screen these artificial metalloenzymes for activity again a panel of plastics. Any hits will be retained for optimization by directed evolution.
• In objective 2, the project’s polymer engineering group will develop novel plastic-based materials with enhanced susceptibility to degradation by PDEs. Certain types of plastics, such as polyolefins, are particularly recalcitrant to degradation. Doping of these plastics with easily degraded groups will produce plastics that can be more readily recycled enzymatically. For example, cyclic ketene acetals can be copolymerized with ethylene, incorporating hydrolysable ester groups into the plastic backbone. These will enable enzymatic depolymerization of the resulting material to form monomers that can be purified to a level of quality equivalent to raw materials obtained from the petrochemical industry.

Together, these objectives will provide the plastics industry with new plastics possessing improved recyclability along with the new tools required to recycle them efficiently. By pairing these novel enzymes and materials, we will be able to create high-efficiency plastic depolymerization and recycling processes. Overall, this approach will create a path towards more responsible and sustainable plastic use in modern society.

The embodied experience and expressive intent of our physical movements are key aspects of the diverse ways we negotiate the social and physical world. As machine learning (ML) systems become increasingly present in our daily lives, it is important that we design these systems to be responsive to the qualities of movement that we find salient as human beings.

Human motion data for use in ML are generally composed of sequences of poses, each representing the geometry of the body position at a given time. While there have been important recent advances in predicting and classifying movement based on these data, it is an open question whether these data are sufficient to provide ML systems with a sense of the qualities of movement that we find significant. This is particularly pertinent for body movement, where there is much less data available than in the media of text, image and sound.

Drawing on expertise in our two primary labs, we will form an integrated interdisciplinary team of ML researchers and specialists in dance, theatre and performance to work together on this challenge. We will develop ways to enrich motion data so that it better reflects the qualities of effort, momentum, surprise, awkwardness and gracefulness that give human movement, particularly as practised and studied in the context of dance and theatre, its expressive and aesthetic force.

Throughout the process of enriching motion data and training ML systems on it, we will refine approaches through live sessions where performers in motion capture suits will evaluate how the results align with their embodied experience of their movements and their expressive intent. These sessions will feature rich real-time audio-visual feedback to provide an experiential bridge between ML systems and evaluators.

Recognizing that ML systems, strongly based in statistical methods, tend to privilege normative bodies and movements, our goal is to create a system whose understanding of human movement includes a diverse range of human bodies and abilities; recognizing diverse bodies is critically important both in machine learning and in the study of difference, inclusion and equity in social systems.

Finally, while this is not the explicit focus of our research, our study will lay the groundwork for researchers in clinical and therapeutic contexts where quality of body movement is a valuable diagnostic indicator, modelling innovative research that can be adapted across such disciplines.

Mathematical models of HIV transmission, using computer simulations, are widely used to project what future epidemic trajectories could look like and to help policymakers with decisions about how, when, where and among whom to prioritize interventions to reduce HIV infections. Mathematical models are built on a combination of data and simplifying assumptions about the experiences of communities experiencing disproportionate risks of HIV. However, there has been limited scholarly work on the extent to which the models, and the questions being answered by these models, reflect the lived realities of communities being represented in the models. This is important, as these models are ultimately being used by policymakers to make decisions about communities without including their perspectives on their own lived experiences.

In an era of dwindling funding for HIV interventions, mathematical modeling is increasingly looked towards to answer policy-level questions on where to focus limited resources to prevent the most infections. To date, communities most affected by HIV have not been engaged in this modeling process. This is in part due to the lack of a systematic framework for community-based participatory modeling of HIV epidemics. Building on longstanding relationships between community leaders and academic researchers, and at the request of community, our research study objectives are to:

1. co-develop a framework for participatory community-based HIV modeling with and among gay, bisexual, and other men who have sex with men (GBM) in Kenya.
2. apply the participatory modeling framework to design, parameterize, and analyze a new mathematical model of HIV transmission among GBM in Kenya.

The project brings together community researchers in Kenya, via community-based organizations, with social scientists, medical anthropologists, epidemiologists, and mathematical modelers. The research approach combines the fields of knowledge exchange and mathematical modeling, with focused groups, model-design workshops, and modeling analysis to sequentially address the two objectives. This work fills a methodological gap in HIV modeling, and has the potential to generate better, more robust HIV models to answer policy-level questions that affect the lives of communities most affected by HIV, while also adhering to critical community-based research methodologies that place community voices at the center of research activities from design to dissemination.

En 2019, plus de 7millions de Canadiens souffraient de douleur chronique. Les coûts associés à la prise en charge de cette douleur étaient estimés à plus de 38 milliards de dollars, avec certains patients contraints d'attendre jusqu'à 5 ans pour un traitement adéquat. Pour répondre à cette crise, un groupe d’experts canadiens recommandait le développement d'interventions non-pharmacologiques. Notre projet vise à répondre à cette recommandation en combinant l'hypnose médicale, une approche non-pharmacologique, avec les technologies de la réalité virtuelle, de la neurophysiologie et de l'intelligence artificielle. L’innovation de notre projet consiste à personnaliser l'approche hypnotique selon les caractéristiques individuelles des patients, autant au niveau cérébral que psychologique, afin d’optimiser leur réponse hypnotique. Notre approche est ainsi en phase avec les préceptes de la médecine de précision. Notre équipe est composée de professionnels de divers domaines et de patients partenaires. Notre projet comprend trois phases.

D’abord, nous identifierons le profil hypnotique de chaque patient à partir de leurs caractéristiques psychologiques. Cette première phase du projet s’inscrit dans la trajectoire de nos travaux actuels visant à comprendre les différences inter-individuelles dans l’hypnose. La seconde phase repose sur l’utilisation d’un électro-encéphalogramme portatif dans un contexte d’une procédure de neurofeedback afin d’améliorer et maintenir une réponse hypnotique optimale. Spécifiquement, cette seconde phase permettra aux patients de produire une transe hypnotique profonde et efficace. La troisième phase repose sur l’application de réalité virtuelle associée aux protocoles d’hypnoanalgésie dans le contexte de la gestion de la douleur. Le contenu de la réalité virtuelle et des suggestions hypnotiques seront adaptés au profil de chaque patient afin d’optimiser la réponse de chacun. En combinant l'hypnose, la réalité virtuelle, le neurofeedback et l'intelligence artificielle, nous espérons apporter une avancée novatrice dans le traitement de la douleur chronique à partir d’une approche non-pharmacologique adaptée aux particularités des patients. Les fonds de la subvention Nouvelles Frontières seront essentiels pour réaliser ce projet et jeter les bases d'une nouvelle ère dans la prise en charge de la douleur chronique.

Per- and polyfluoroalkyl substances (PFAS) are synthetic class of chemicals that have been used in industry and consumer products such as non-stick cookware, carpets, firefighting foam since 1940s and since then at least 4,000 PFAS have been introduced to the market. PFAS, which offer characteristics such as heat, stain and water resistance are extremely persistent in the environment due to the presence of carbon-fluorine (C-F) bonds, one of the strongest covalent bonds in organic compounds. PFAS are found in the blood of humans and animals around the world and some chemicals in this class are linked to harmful health effects.

The goal of the proposed research is to develop a novel bioelectrochemical system to achieve complete mineralization of PFAS in a variety of environmental matrices. Novel anode electrode with high porosity, possessing high adsorption capacity for PFAS and high affinity for bacterial attachment will be designed and fabricated. In this electrochemical system, through an innovative design of experiments, we are searching and screening for microbial consortium that their growth and activity are enhanced under electrochemical stimulation and are capable of defluorination of PFAS and further degradation of metabolites, achieving complete mineralization. We hypothesize that we may be able to identify electrogenic bacteria capable of PFAS biodegradation with potential to reduce the energy intensity required for electrochemical oxidation of PFAS.

PFAS are highly persistence and widespread in the environment with serious adverse impacts on human health and the environment, therefore it is crucial to develop cost effective, efficient, practical, and green technologies capable of complete degradation of PFAS. Bioremediation of organic contaminants is a green remediation technology. However, only a few microorganisms have been identified with the ability to break down the C-F bond at a very slow rate. Other technologies that rely on adsorption or advanced oxidation are costly and resource and energy intensive and may not be practical or applicable for variety of environmental matrices. In our research, we aim to construct novel microbial consortia with unique capability of complete mineralization of PFAS using innovative electrochemical biostimulation approach. In our innovative approach, we integrate electrochemistry, microbiology, computer science and chemical engineering to solve PFAS contamination, which is an important environmental issue.

The vision disorder amblyopia is the leading worldwide cause of unilateral visual impairment in children and young adults. Amblyopia causes a loss of 3D vision, reading difficulties, lowered self-esteem, restricted employment opportunities and increased risk for legal blindness. Amblyopia also amplifies disparities in wellbeing because it preferentially affects marginalized socio-economic groups who have restricted access to health care.

Amblyopia can be treated effectively in childhood by patching the non-amblyopic eye. However, poor adherence to treatment is common. This is a critical problem. If amblyopia is not treated successfully in childhood, the vision loss becomes permanent, causing significant health and economic consequences. Improved amblyopia health literacy can improve treatment adherence, but the pressures of publicly funded health care limit the time available for clinicians to provide education.

We propose to integrate the disciplines of vision health, psychology, and social robotics to develop an integrated physical and virtual social robotics infrastructure to promote health literacy, increase wellbeing, and improve amblyopia treatment outcomes. A physical robot embedded within an eye clinic will interact with patients and their families. A complementary gamified virtual robot will support, encourage, and educate children and their caregivers at home where much of the treatment occurs. In year1 we will collect data from patients, caregivers, and clinicians to finalize the robot design, communication style and content, and interaction timing in the clinic and home settings. This work will require cross-disciplinary engineering, psychology, and clinical interactions. In year2 we will compare amblyopia treatment outcomes (amblyopic eye visual acuity) between patient groups randomized to robot interactions or standard care recruited from a busy public eye clinic.

Our project is high risk because the use of social robotics has never been attempted in vision health care and novel research will be required at the interface of engineering, psychology, and vision health. We will develop new methods to integrate real and virtual robot systems into both the clinical and home environment. Robot systems will be adapted to the clinic in terms of usability, power, and intuitive control. The project will provide a first step in introducing social robots to front-line clinical eye care in Canada and beyond.

Introduction: The world uses fossil fuels to meet both energy and material needs. While renewable sources are mitigating our energy dependence, most synthetic materials such as plastics and textiles are still made using petroleum derived building blocks (monomers). Even in a 100% renewables-powered world, new sources for material precursors are needed to fully divest from fossil fuels. Traditional approaches such as recycling and bio-based materials (bioplastics) have had limited impact due to low uptake, land competition, and release of green-house gases from degradation.

Objective: We seek to develop a blueprint for shifting the elemental basis of our materials from fossil-fuel derived carbon to renewable dinitrogen (N2) captured from the air, thereby aligning our materials usage with a NetZero future.

Approach: Our holistic approach will embed the chemistry for turning N2 to materials within a matrix of circular design, lifecycle analysis (LCA), long-term socio-economic assessment, and end-use planning. N2 is not currently used as a monomer because molecules and materials with many N-N bonds are unstable. We have a strategy for making robust, inexpensive, and scalable N-rich materials (50-80% N) starting from NH3 (ammonia, made from N2). Recognizing that N-N bonds can be strengthened if they are part of a 3-dimensional cage, we will make N-rich cages and interconnect them to form materials. We will investigate the properties of these materials in comparison to petroleum-derived plastics. In tandem, we will use LCA and other sustainability metrics to assess the implications of the such a material substitution on the global supply-chain, including possible supply conflicts, such as the competing uses of NH3 as fertilizer or as an energy carrier, and our intended usage as a monomer. To close the material loop we will investigate end-use options, such as their re-introduction into the supply-chain, and specific to this research, assessing how N-rich materials can serve as slow-release fertilizers in both lab and field-based experiments that will evaluate plant responses to various modes of application.

Significance: Our plan of developing petroleum-free and renewable polymers, underpinned by a focus on material circularity and cradle-to-cradle thinking, will help eliminate our dependence on fossil fuels for materials and support the shift to a global materials circular economy where waste and pollution are intentionally designed out of the system.

NASA expects 22 lunar missions by 2026, most in the south polar region. Due to proximity, "operators will face challenges never faced before."

NASA identifies a need for diplomacy and policy development to address coordination challenges with landings, surface operations, radio-frequency interference, and human heritage. It calls for "hybrid technical-policy design work" - before accidents or disputes occur.

The Canadian Space Agency is a partner in NASA's Artemis program and funding Canadarm3 for a lunar orbital station, as well as a rover. In 2024, a Canadian will fly around the Moon.

The proposed project involves interdisciplinary research essential to the success of these programs. Some coordination policy decisions have been made, but require critical testing. For example, NASA proposes "safety zones" to "put the international community on notice that any entry into these areas could cause harmful interference, thus triggering the notice and consultation requirements of Article IX [of the Outer Space Treaty]."

Questions we will ask include:

1. Are safety zones the only viable coordination option? We will explore alternatives, carefully considering the lunar environment and challenges in space domain awareness.
2. Can safety zones include consideration of "trans-boundary" effects? We will assess whether dust lofting could interfere with activities beyond a zone, and whether the "due regard" obligation in the Outer Space Treaty should be interpreted in light of international environmental law, including the precautionary principle.
3. Could safety zones be analogous to "staking claims", as on terrestrial frontiers before mining law? Can we identify a path to rules acceptable to all states active on the Moon?

Other coordination challenges could arise in lunar orbits, Lagrange Points, lunar transfer orbits, and for radio astronomy on the lunar far side.

We will establish sub-projects led by early career scholars and hold all-team workshops with government, industry, and civil society stakeholders. Research output will focus on policy-oriented articles in high-impact peer-reviewed science journals.

The PI and co-PI have a record of building interdisciplinary teams, addressing grand challenges, and delivering cutting-edge research and actionable policy recommendations.

The proposed work will assist CSA, other departments, industry and civil society, to ensure scientifically-informed, safe and sustainable coordination on-and-around the Moon.

More than 11% of Canada's GDP and nearly 50% of provincial budgets are allocated to health care costs, but the country's position among the other 36 OECD members does not reflect this high level of spending. The number of patients needing surgery is rising, and the demand for surgical services is quickly outpacing available resources. This frequently leads to prolonged wait times which have been correlated not only with a high rate of pain and depression, but also with other poor patient health outcomes. The above challenges demonstrate that an immediate implementation of innovative ideas is imperative.

To optimize operating room efficiency and throughput, we propose an AI-driven prescriptive analytics approach which will suggest the best course of action to maximize desired outcomes. Unlike traditional methods that rely on historical data, it helps organizations such as hospitals make informed decisions by considering various constraints, objectives, and uncertainties.

First, we propose to leverage large scale data which includes a significant diversity of patients and surgeries. Second, AI-driven prescriptive analytics will identify important parameters that affect operating room efficiency and throughput and suggest strategies using methods with actionable and explainable outputs. We note here that the prescriptive analytics can continuously analyze and update information to provide the most up-to-date recommendations to the surgical department in hospitals. Third, through an iterative process via quarterly positive deviance seminars, surgical team professionals will meet and agree on the best approach to uptake the AI-driven strategies derived from the previous quarter’s surgeries and transfer them in daily clinical practice. A key element in this high-risk, high-reward multi-disciplinary tri-council project is integration of human factors for decision making, and health economics in the interpretation and actioning of AI outputs.

The proposed project directly addresses NSE challenges in AI to impact health research, considering innovations in social sciences. The challenges associated with operating room efficiency and throughput are shared across other domains increasing the potential impact and reward of the proposed innovations.

Housing affordability is one of the most pressing issues of our time. Numerous efforts have been made to uncover the root causes and address the crisis, yet meaningful change remains elusive. We propose to investigate the housing development approvals process. As housing is tied to land, which in cities is scarce and contested, local governments set up approval processes to ensure that new developments meet community interests. In practice, however, these often become highly political, lengthy negotiations where it is unclear whether what gets approved truly serves the public good.

To open the development approvals black box, we propose leveraging recent breakthroughs in AI, particularly Large Language Models (LLMs), to analyze public records of city council meetings. City council meetings, where housing development decisions are made, are documented in text and video. This data is publicly available but effectively inaccessible due to its large volume and unstructured nature. We propose a computational pipeline that uses LLMs in partnership with human researchers with the goal to identify the key ingredients for successful development applications. To do this, we automate the parsing of Vancouver city council meeting minutes and machine-assisted transcription of video records and identify segments pertaining to housing development decision-making. Then, we employ LLMs for topic modeling to identify patterns, e.g., in the makeup of development proposals or arguments made at public hearings. Finally, we utilize LLMs for conversation-level classification to uncover key players via the analysis of power relationships, revealed in speakers' linguistic style.

By democratizing development approvals, this work has the potential to revolutionize housing supply. More broadly, it will help unlock the power of LLMs for social science research. Text data in social science is ubiquitous, but previously its labor-intensive analysis was limiting its use. LLMs have demonstrated impressive results in processing such data, but raise concerns with regards to cost barriers, transparency, their sensitivity to prompt engineering, and challenges in handling domain-specific terminology or noisy data. By subjecting LLMs to the rigorous test of applying them to a complex, real-world domain, we push the boundaries of their application spectrum and develop solutions that address their limitations.

While needles and syringes are among the common methods to administer vaccines and dermatological medications, they suffer from numerous disadvantages, including unsafe practices, exposure to infections, needle phobia, lack of reusability, and disposal and environmental problems. A safe alternative to deliver vaccines and other immunological products is the needle-free injection method (NFIM), using a high-velocity liquid jet created via a laser pulse exciting the injection drug fluid. Major limitations of this method are severe pain, penetration depth variability, skin hole size variability, skin irritation, etc. Many of these limitations have roots in the jet flow dynamics and they are caused by undesirable jet dispersion, jet widening, jet flow instabilities (e.g. droplet formation), atomization or spray, jet tip deformation, splash, inhom*ogeneous penetration into skin, etc. In this context, our interdisciplinary research project proposes to remove the aforementioned limitations of the NFIMs, via immersing the high-velocity liquid jet into a viscoplastic fluid, filling the space between the liquid drug and the skin (known as the stand-off). This high-risk approach may allow us to use a viscoplastic fluid to properly surround the jet, confining it to a stable cylindrical form that precisely/controllably penetrates into the skin target area, while reducing the jet widening and jet instabilities (break-ups); subsequently, the jet can reach the desired penetration depth, with a precise penetration width/shape. Our specific research objectives, achieved via an interdisciplinary approach, include:

1. examining the effects of filling the stand-off distance with viscoplastic fluids on the jet flow development, possibly stabilizing and controlling the jet;
2. examining the subsequent penetration of the submerged jet into the skin multilayers; and
3. analyzing the skin response to the jet penetration.

These objectives will be achieved via novel experiments and mathematical modeling approaches, relying on the state-of-the-art research methods, while combining interdisciplinary knowledge from a wide range of disciplines, such as fluid mechanics, rheology, viscoplastic mechanics, dermatology, drug delivery, etc.

The 2021 Canadian Census shows that 0.2% of Canadians over 15identify as transgender and the prevalence is rapidly increasing along with social acceptance. Mental health improvement has been associated with gender affirmation surgery (GAS). Here we focus on male-to-female (MTF) transgender patients, and vaginoplasty is the standard of care in GAS for MTF transgender individuals. Most often, penile skin inversion is used to create a neovagin*. However, a keratinized lumen using penile skin implies various complications related to its heterotopic nature.

We have developed a tissue-engineered innovative vagin*l tissue substitute with promising results. Our creative idea is reconstructing functional tissues with vagin*l properties using epithelial cells from the male urethral fossa navicularis (FN). This approach would help circumvent the challenge of providing tissues to MTF GAS. Indeed, this area has been shown to display histological and biochemical properties similar to a female vagin*l mucosa, including its self-lubrication once stimulated by estrogen therapy.

Hypothesis: Extracting epithelial cells from the fossa navicularis will allow tissue engineering of functional vagin*l-like tissues for GAS in MTF transgender patients.

Objectives:

1. Optimization of FN cell extraction to increase the yield and better preserve the stem cells (to limit biopsy size and patient comorbidities) (Months 1-6);
2. Engineering a 3D vagin*l mucosa-like model using human-derived cells from the FN (Months 6-15);
3. Implantation of the human-derived vagin*l mucosa-like model produced using FN cells into a nude mouse model (Months 15-24).

Team: The PI is a urologist and Canadian leader of urogenital tissue engineering; co-PIs include a renowned researcher on skin tissue engineering and stem cells; a urologist specialized in female urology, Collaborators include a GAS specialist who will provide penile tissues, and a professor of anatomy and physiology.

Impact: For MTF transgender individuals, this project will be a significant advancement to provide a more efficient GAS solution with fewer subsequent revisions. Tissue engineering with FN cells will provide an autologous lubricated vagin* that may protect from pathogens for a community with an elevated risk of infection. The success of this project will be a world premiere for the recreation of autologous vagin*l-like tissues from cells originating from the penis of the male patient to carry out MTF GAS.

Osteoarthritis (OA) is the most prevalent chronic health condition in Canada affecting 4million people (1).

• OA will increase to 1 in 4 Canadians by 2040 (2).
• OA is a complex joint disease that reflects intricate interplay of biomechanical, inflammatory, metabolic, and genetic factors affecting multiple tissues leading to degeneration, reduced mobility, and pain. Despite substantial research and financial investments, effective treatments for OA remain elusive. Current therapies for pain management have seen minimal advancements (3–5).
• Joint replacement surgeries are only considered in advanced disease stages (6).
• Elevated friction within the joints amplifies shear stress on the cartilage, prompting the expression of enzymes responsible for cartilage degradation; injections, such as hyaluronic acid, have fallen short due to limited effectiveness and rapid degradation (7).
• Anti-inflammatory steroids commonly used to combat inflammation in OA have substantial clinical limitations due to rapid clearance and associated side effects (8).

We propose a multifunctional injectant to overcome these challenges. Our approach involves the development of innovative injectable nanoparticles that

1. act as hydrodynamic and boundary lubricants strongly adhering to the cartilage surface;
2. behave as reactive oxygen species (ROS, key driver of inflammation (9,10)) scavengers and
3. deliver anti-inflammatory drugs.

An interdisciplinary team of biomaterials and chemical engineers will work with translational scientists, immunologists, and orthopedic surgeons to develop a fit-for-purpose, novel therapeutic approach that dually targets biomechanical and biochemical dysfunction in OA. The innovative nature stems from the unique water-binding properties of phytoglycogen nanoparticles (PhG NPs) conjugated with carbon dots, which combine excellent lubrication and antioxidation properties. Furthermore, near-IR photoluminescence emission of carbon dots will enable monitoring of the biodistribution and retention of injected nanoconjugates. Our objective is to dually reduce joint friction and inflammation through ROS scavenging and improving drug retention and penetration to provide symptom-and disease modifying relief for OA . Additionally, we will correlate sex and other diversity markers in donor tissues with efficacy of the PhG NPs. We propose a novel engineering solution to a refractory disease which will have significant clinical and commercial implications.

The goal of this proposed project is to develop a skin-like pressure sensor system that enables individuals to passively receive continuous BP measurements. Hypertension, a medical condition with diverse underlying causes such as heart disease, stroke, kidney disease, and chronic stress, is noteworthy. Studies also suggest a connection between hypertension and maternal mental depression. The continuous measurement of blood pressure (BP) is essential for understanding how a patient's BP responds to various situations and medications. This ongoing BP measurement can also help identify increased risk factors. To date, continuous BP monitoring is primarily available in intensive care units (ICUs) to closely monitor the hemodynamic status of critically ill patients.

Methodology: Recently, we invented a mechanically flexible nanoelectronic sensor which shows significant advantage over traditional pressure sensors in terms of physical size, sensitivity, temperature stability, low power consumption and cost. This system consists of three key elements:

1. an advanced sensor array system by applying nanobiotechnology, which can be used as the skin-like sphygmomanometer;
2. a body area wireless system and mobile application to enable real-time information exchange between patients and a medical server or doctors;
3. and an intelligent BP measurement system for real-time analysis.

High rewards of this research project are:

1. The proposed skin-like pressure sensor system could significantly benefit patients who cannot afford ICU expenses or do not have access to an ICU.
2. The outcome of the research can lead to a quick diagnosis for people with potential high risk in heart diseases and maternal mental depression.
3. This sensing system will not only provide an accurate diagnosis for individual patient to receive rapid and appropriate treatment, but also provide precisely statistical data to decision maker, and, therefore, realize high-quality, cost-effective health care.

Major high risks of this project include:

1. knowledge is lacking on using the skin-like sphygmomanometers for continuously detecting BP to manage heart diseases and maternal mental health;
2. the challenges in breaking the boundaries of different disciplines may occur because this proposed project is to develop a new diagnostic technique by integrating different disciplinaries.

Dysregulation of gene expression programs drives malignant transformation and cancer progression. Large-scale genetic screening efforts have been made to identify frequent mutations in cancer cells. However, translation of these findings to clinics is limited due to the realization of many layers and complexity in gene expression regulation as well as the cellular heterogeneity of cancer. Single-cell gene expression profiling has revolutionized our view of tumorigenesis and the characterization of populations with stem-like features largely responsible for therapy resistance. Understanding the impact of cancer mutations on gene regulatory mechanisms to define exactly the causal relationships between multiple layers of the networks at the level of single-cell resolution is critical to bringing forward insights into mechanisms of tumorigenesis and innovative therapeutic approaches for cancer treatment. In this project, we will use the Acute Myeloid Leukemia (AML) disease model to evaluate single-cell profiling of genetic, transcriptomic, epigenetics and epitranscriptomic status of primary normal stem/progenitor cells and primary AML patient samples. The main objective is to develop an integrative profiling and analysis platform to measure the molecular activities across multiple layers of gene regulatory networks at a single-cell resolution. To accomplish this goal, we propose 2 aims:

• Aim 1. To establish a cost-effective multiplexed sequencing pipeline through which we obtain 10M+ reads to quantify epigenetic, transcriptomic, and epitranscriptomic activities.
• Aim 2. To customize state-of-the-art machine learning and artificial intelligence models to adjust putative technical biases introduced by sequencing technologies and identify multi-layered gene regulatory programs.

Using a compressive sensing method, we will address prevalent technical challenges in profiling and subsequent computational analysis and probabilistic modelling e.g., sparsity, technical noise, multi-modality, and biological interpretation. For data integration, we will develop an interpretable probabilistic model that takes into account upstream DNA accessibility, baseline expression, splicing and RNA methylation. We will establish a rich catalogue of cell-state-specific causal path diagrams to guide follow-up validation experiments. Our framework will aid systematic survey of transcription factors, epigenetic/epitranscriptomic readers/writers, and target genes.

The placenta is vital for pregnancy, mediating blood, nutrients, and oxygen exchange between fetus and mother. Successful placentation involves angiogenesis, trophoblast invasion, and uterine artery remodelling for increased blood flow. Failure results in placental dysfunction conditions like preeclampsia (PE).

PE affects 2-8% of pregnancies, leading to maternal and fetal morbidity and mortality. It's subdivided into early (≤34weeks) and late (>34weeks), both with similar clinical presentations. Early-PE may result from inadequate placental cell invasion and uterine artery remodelling, impacting placental blood flow. Late-PE is considered to be milder and occurs later in gestation. Both subtypes have been linked to hypoxia or rapid re-oxygenation.

There is a lack of good PE animal models making the evaluation of mechanisms and therapeutics challenging. We aim to create PE subtype-specific cellular models using a unique placenta-on-a-dish tissue model. These models mimic early and late placental development with functional vasculature comprised of fetal endothelial and trophoblast cells in a 3D configuration. Our goals include:

• Aim 1: Develop a late-PE model with varying oxygen conditions

  Our team has created a late-stage placental barrier model using blastocyst-derived placental stem cells (PSC). To study late-PE, we'll expose it to different oxygen levels (3-21%) and hypoxia-reperfusion. We'll assess DNA methylation, gene expression, and cellular function at each oxygen level, comparing to known late-PE changes. We aim to determine which oxygen model aligns with known molecular changes in PE.

• Aim 2: Develop an early-PE model focusing on trophoblast cell invasion

  To mimic early-PE, we'll modify our current model with PSC-derived cytotrophoblasts and a perfusable vasculature. We'll use a stamping biofabrication technique to mimic villus protrusion. Differentiated extravillous trophoblasts (EVT) from PSCs will migrate toward the vasculature. We'll study oxygen's impact on invasion and assess changes in DNA methylation, gene expression, and cell function comparing to known early-PE alterations.

This work is unique, high-risk, and uses a novel system to explore PE through engineering, multiomics, and cell biology. In the short term, these models offer insights into placental development and PE pathogenesis. In the long term, they enable therapeutic strategy testing via high-throughput screening, advancing reproductive medicine.

The WHO has declared air pollution to be the greatest environmental threat to health globally. West African cities record among the highest outdoor particulate matter concentrations in the world. Increases in asthma indices are observed in areas undergoing rapid urbanization, with asthma prevalence among adolescents in Africa one of the highest. The link between exposure to air pollution and asthma is well established implicating inflammation in allergic and non-allergic asthma through differing mechanisms. Exposure to diesel particles, a key air pollution component from road traffic, has been suggested to provoke increased IL-17A production, leading to severe asthma.

Children in Africa are particularly vulnerable to the consequences of untreated disease but have limited access to medications. We propose a study of 860 schoolchildren aged 13-14 years with asthma from Cotonou, Benin, enrolled in a cohort study. The overall goal is to create a personalized air pollution exposure prevention programme, integrating immune biomarker(s).

The cohort study situated across Cotonou represents a wide range of air pollution measures including at the high end of exposures globally. A subset of 300 children will be targeted for individual-level data collection:

1. air pollution exposure assessed through portable measuring devices,
2. concentrations of inflammatory compounds including IL-17A and others related to exacerbations measured in exhalate.

All 860 participants will complete a daily asthma symptom journal and activity questionnaires tracking movements across Cotonou. Environmental air pollution measures will be obtained for several compounds.

We will pursue the following objectives:

1. Integrate individual- and environmental- level air pollution exposure data with activity questionnaire information to develop a predictive model of individual exposure using machine-learning and impute non-measured individual-level data
2. Devise a personalized air pollution exposure prevention programme and test its efficacy via a two-arm randomized controlled behavioral trial in reducing asthma symptom frequency and severity
3. Identify immune biomarker measures from exhalate samples to quantify air pollution exposure and asthma severity considering before, during and after intervention measurements

Identification of biomarkers most affected by air pollution and having greatest impact on asthma will inform preventive efforts also generalizable to Canada.

Proteins are complex macromolecules that influence, among other processes, coagulation and thrombosis (blood clotting). When proteins interact with or are immobilized on biomaterials, their conformation and/or orientation dictates the exposure of functional protein sites and epitopes to the biological environment. It is the availability of these active sites and their spatial location that influences bioactivity, cell recognition, and the resulting biological response. Antithrombotics, including an antithrombin-heparin complex (ATH), can be conjugated to various materials to prevent thrombosis at the surface of blood contacting devices. However, understanding the structural arrangement of antithrombotic proteins on materials is extremely difficult and limits the rational design of sophisticated devices. Therefore, visualizing proteins and their structural/functional characteristics on a surface is of utmost importance for controlling thrombosis, but is nearly impossible with current technologies. Due to their nanoscale size, protein visualization is challenging and largely limited to specialized facilities or indirect methods. Atom probe tomography (APT) is a mass spectrometry tool with 3D sub-nanometer accuracy but has never been fully exploited for protein characterization.

Our objective is to develop strategies to visualize and map proteins on biomaterial surfaces with atomic-scale resolution. Using an interdisciplinary approach that adopts technologies from materials engineering, such as atom probe tomography (APT) and cryo-electron microscopy (cryo-EM) we will develop an approach to map proteins and their functional sites on biomaterial surfaces. Our proposed work will develop strategies to prepare proteins, starting with ATH and extending to other antithrombotics, on/within materials for rapid analysis. We will also explore new labelling techniques to track the exposure of the bioactive sites of the molecules. Ultimately, we will develop methods to advance APT and correlative cryo-EM as a characterization platform for protein analysis on surfaces.

This work will have major implications for our understanding and eventual control of antithrombotic proteins on blood contacting devices such as catheters, stents, vascular grafts, and oxygenators. These advances will provide a clear view of protein functional activity based on structural organization on a surface, leading to improved device design, reduced clotting, and increased quality of life.

Plastic accumulation in our environment is a pressing challenge. Global economic growth has spurred exponentially increasing plastics production with 500million metric tons produced annually, of which about 20% is released into the environment. Instead of degrading naturally, plastics break apart into increasingly smaller pieces. The smallest pieces, termed nanoplastics, are invisible to the naked eye and light microscopes. This makes nanoplastics hard to detect, quantify, and allows them to be absorbed by living things. Indeed, nanoplastics are detected in the blood of ~80% of people. The effects of nanoplastics are just starting to be understood, with potentially catastrophic ecological and health consequences.

Our overall goal is to develop tools to detect nanoplastics and remove them from the environment through three aims:

1. Create protein-based tools to detect and identify nanoplastics

   Hydrophobins are proteins that can bind nanoplastics. We will fluorescently label hydrophobins so they can be detected by fluorescence spectroscopy. We will then use computational approaches to design hydrophobins with improved affinity and selectivity for specific types of plastic, focused on the goal of using these hydrophobins to non-destructively quantify nanoplastic composition in water samples.

2. Develop scaffolds that capture nanoplastics

   Spider silk is renowned for its toughness and biocompatibility. We will use our expertise in silk protein design and production to create silk meshes that are functionalized with hydrophobins. We will develop these meshes to capture and quantify different types of nanoplastic in freshwater and seawater samples.

3. Detect nanoplastics in zebrafish and remediate water

   Fluorescent hydrophobins will be used to quantify the amount and types of nanoplastic absorbed by zebrafish larvae, with direct toxicological correlation to health outcomes. We will also use nanoplastic-binding meshes to remove nanoplastic from water and assess how this affects nanoplastic uptake and health of zebrafish.

This will be the first study that combines two high-potential biomaterials, hydrophobins and silk, to quantify or to remove nanoplastics from water. Although high-risk due the new combination of targeted engineered materials and the unmet challenge of robustly detecting nanoplastics, this multidisciplinary project has great potential to address nanoplastic accumulation, which is a pressing environmental and health concern.

Background: Implant-associated clot formation is an ongoing challenge in the healthcare sector. These complications greatly impair device performance, prolong hospital stays and can lead to life-threatening events such as embolism. Additionally, medical interventions, such as the use of anticoagulants to mitigate these complications, can induce serious issues, such as excessive bleeding. Given these concerns, the development of new biomaterials with superior antifouling properties, along with novel clot detection systems is of immense importance. This emphasis on system advancement is warranted as the available techniques used to assess and monitor thrombosis possess notable limitations. These systems rely on complex reagents and equipment, mostly optical-based equipment, lack precise and real-time measurements, have restrictions on sample size and are mostly incompatible with opaque samples and fluids such as whole blood. These constraints hinder accurate biomaterial thrombogenicity studies, potentially misrepresenting performance in complex biological environments.

Objectives/approaches: Our overarching goal is to explore the integration of microwave sensor technologies for accurate detection, measurement, and assessment of clot formation on biomaterials. This unique sensing approach relies on the interaction between the sensor’s engineered electromagnetic waves and the surface. Consequently, we anticipate that the sensor will detect clot formation independent of sample size, type, and the opacity of the contaminating liquid (i.e., plasma vs. whole blood). Moreover, we aim to take the detection process a step forward and dissect the sequential stages of the clotting profile- spanning protein adhesion to fibrinolysis, all of which are pivotal in understanding biomaterial-induced thrombosis. To achieve this goal, our proposed project consolidates interdisciplinary expertise in biomaterial engineering, thrombosis and microwave circuits and techniques.

Significance: The global medical device market, valued at US$597billion in 2023, is projected to escalate to over US$950billion by 2031. Concurrently, the estimated annual cost for treating device-associated fouling complications in the US alone ranges between US$28.4billion and US$45billion. The outcomes of this research will establish a global hemostatic status for assessing the thrombogenic properties of biomaterials, thereby informing solutions to more effectively evaluate and prevent clot formation.

Context: Influenza viruses have elevated pandemic potential and generate a substantial infection burden globally. Influenza transmission is driven by multiple factors and is also strongly seasonal, yet transmission patterns vary substantially globally particularly between temperate and tropical climates. Understanding the mechanisms behind these seasonal patterns is critical for improving influenza forecasts that allow public health systems to prioritize resources to reduce disease burden.

Paradigm Shift: Currently, models that incorporate climate into disease transmission primarily rely on the use of statistical methods to regress the transmission rate derived from epidemiological data against climate variables. These approaches are insufficient because of spatial biases in the availability of epidemiological data, as well as difficulties in disentangling climate variables. Building on preliminary examples in the field, our approach shifts this paradigm to develop first-principles climate-driven influenza transmission models, in which experimental data guides an explicit framework for modeling how climate variables influence disease transmission factors.

Objectives: We hypothesize that climate variables modulate influenza transmission by impacting the stability of viral proteins critical for cellular infection in emitted droplets. We will study this in a dedicated aerosolization chamber under different climate conditions that capture both tropical and temperate environmental regimes. From these data we will develop empirical relationships between climate variables and transmission, which we will combine with highly resolved near-term weather forecasts and incorporate into epidemiological frameworks to compare with influenza case data globally.

Approaches: Our methodologies draw on the interdisciplinary expertise of the research team in the areas of biophysics, fluid mechanics, virology, climate science, and mathematical disease modeling. Specific approaches include viral infectivity assays, aerosol sampling, and the development of climate and epidemiological models.

Novelty and Significance: Transmission models in which the role of climate is explicitly characterized from first-principles are scarce. Our proposal will pave the way for this to become standard, allowing for an improved understanding of the seasonal transmission patterns of influenza across both tropical and temperate climates and an improved ability for short-term forecasting.

Febrile illnesses are major global causes of mortality and morbidity. Febrile patients are often treated empirically first and targeted therapy begins only after a pathogen is identified. However, conventional pathogen diagnostics have limitations including accessibility, time-to-result and accuracy. In high resource settings, this can delay targeted therapy by 2-3days and in low resource settings, microbiologic diagnoses are often not made. Thus, individuals who need higher level care may not be identified and individuals with mild illness may be mistakenly referred and/or receive unneeded antibiotics leading to extraneous costs. Novel tools for diagnosing and prognosing febrile illnesses are urgently needed.

Here we propose host RNA transcript signatures that overcome the limitations of conventional diagnostics. We will discover and validate host RNA signatures that

1. identify who will develop severe disease and
2. identify the underlying cause of illness including for tropical infections that do not have transcriptomic signatures.

Our long term vision is to incorporate these signatures into tests suitable for rural clinics and tertiary intensive care units.

Our study has three interconnected objectives: 1) Sequence the blood transcriptomes from >1000 patients presenting with febrile illness on the Thai-Myanmar border using long read sequencing and detect splice variants that cannot be identified using short read technologies. We will then identify combinations of RNA transcripts that predict severe outcomes within one month of presentation; 2) Identify new RNA signatures for common and serious tropical infections such as Chikungunya and rickettsia; and 3) Evaluate the performance of diagnostic signatures developed in European populations in patients from the Thai-Myanmar border. These results will inform next steps in the development of novel diagnostic tests.

This is a high-risk idea because transcriptomics is traditionally applied to narrowly-defined illnesses and patient populations. Here, we are developing RNA signatures that predict illness severity irrespective of illness or patient population. This proposal will use advanced transcriptomic and data science methods in conjunction with global health and tropical medicine to generate new knowledge. Though a high-risk idea, this project holds the potential to revolutionize clinical decision making, reduce antibiotic resistance, and ultimately improve patient outcomes around the world.

Our project is focused on a recent exciting discovery of a new cellular molecule—glycosylated RNA (glycoRNA). Glycosylation of proteins has been a recognized cellular chemical modification for a long time, but the discovery of glycoRNA in mammalian cells, apart from some monosaccharide variants of tRNA, was only reported recently, with the first peer-reviewed publication in May 2021 showing RNA modified with complex glycans. The discovery of a new biological molecule opens the door to an unimaginable array of possible new functions and cellular pathways. RNA plays multiple roles in mammalian cells, from structural components to messenger RNAs, to regulatory components such as microRNAs. Moreover, RNAs are known pathogen-associated molecular patterns (PAMPS) and function as inducers of innate immunity—RNA is recognized by several intracellular toll-like receptors such as TLR3, TLR7 and TLR8. RNAs are also proven tools in biotechnology, from siRNAs to the recent SARS-CoV-2 vaccine successes.

GlycoRNAs were found to be mostly small, non-coding RNAs, often associated with the plasma membrane where the glycosylated RNA was exposed to the extracellular space. The main objective of this project is to determine the impact of glycosylation on the response of mammalian cells and organisms to RNA. Firstly, we will use conjugated species to investigate the impact of glycosylation on the innate immune response to different RNAs in cell culture. As glycoRNA studies are in their infancy, very few methods are available to study these difficult to analyze molecules, which hinders advancement in the field. Thus, we will develop analytical methods such as liquid chromatography mass spectrometry and gel electrophoresis-based methods to characterize glycoRNAs, and generate a tool kit to study glycoRNAs in a variety of contexts. If glycoRNAs are to eventually be used for therapeutic purposes, it is critical to know how organisms respond to such molecules.Thus, secondly, we will investigate the impact of glycosylation on the innate immune response to RNA in mice comparing a variety of routes of administration. This high-risk project has the potential for high rewards. The knowledge gained and methods developed will drive progress in glycoRNA research on multiple fronts to unlock the potential of glycoRNAs in therapeutics and in biotechnology.

Many complex organic and inorganic systems have the ability to self-organize and form condensed phases that give rise to emergent properties. Spectacular examples of phase transitions include biomineralization in our body, formation of biomolecular condensates in cells and the creation of impurity phases in alloys during precipitation hardening. Our understanding of the molecular details of the rare events, such as nucleation, that initiate many of these transitions is still very limited. Molecular dynamics (MD) simulations have been used extensively in biochemistry, physics and material sciences to help us understand phase transitions at the microscopic level. Unfortunately, systems of interest are often multicomponent in nature, resulting in complex phase spaces that need to be explored. Moreover, atomistic MD simulations are restricted to the microsecond time scale, which is far from the millisecond or longer time scales of most relevant phase transitions.

Objective: By developing new parallel-in-time integration (PITI) methods and machine learning (ML)-based approaches in collective variable identification, we aim to establish a cross-disciplinary approach that allows for atomic-level characterization of rare events that initiate phase transitions of relevance to biochemistry and materials science.

High Risk: PITI and ML-based collective variable identification methods have shown encouraging results for simple systems, but need to be developed and tested to fully understand their limits and suitability for the investigation of rare events triggering phase transitions. However, these methods open up exciting avenues that we believe to enable breakthroughs in the molecular characterization of the complex phenomena we are interested in.

High Reward: As practitioners working on solving applied problems directly related to human health (e.g, treatment of neurodegenerative diseases) and sustainable development and circular economy (e.g recycling of aluminum alloys), we see the tools developed here as being an essential and missing ingredient needed to accelerate, through predictive modelling, development of new therapeutics and technologies that will impact human life and the environment.

Interdisciplinarity: Conceptual and methodological challenges in our approach require cross-disciplinary teamwork from an erudite group of experts in biochemistry, metallurgy, statistical mechanics and machine learning.

Motivation and background: The microbes populating the human intestine have been described as a "missing organ", reflecting their prior neglect as key determinants of human health and disease. Influencing the state and behaviour of gut microbes can promote health, but the design of manipulation methods has been hampered by the system's complexity. Recent advances in machine-learning (ML) guided experimentation have led to "self-driving lab" (SDL) approaches, in which complex parameter spaces are efficiently searched by iteratively applying ML algorithms to experimental results.

Objective: Use ML-guided SDL experiments to engineer microbial consortia with optimal production levels of intestinally-beneficial molecules.

Research approach:

1. SDL-guided in vitro design of butyrate-producing engineered microbial consortia. Using butyrate as our initial molecular target, we will use automated liquid handling to test the output of intestinal microbial species, where SDL approaches will be used to optimize chemical reactions;microbes will be treated as unusual "reagents" - varying their abundances, nutrient conditions, and the growth environment. Butyrate bioassays will rapidly quantify production levels and we will feed the results into a machine learning algorithm to generate new sets of conditions for testing and iterating until an optimal production level has been achieved.
2. In vitro testing. The best-performing microbial collections will be inserted into small semi-permeable capsules, enabling them to remain together as a consortium while permitting diffusion of the produced butyrate. Organoid or "gut on a chip" models can be created with microbial populations representative of typical human microbiota, enabling us to conduct further ML-guided iteration in these proxy environments.
3. Whole-organism testing. The best engineered microbial consortia from the in vitro tests will be encapsulated and fed to mice and parameters including intestinal barrier function (leaky gut), tissue-specific and systemic inflammation as well as metabolic function will be assessed.

Novelty and significance: The workflow established here will provide a generalizable approach to enable rapid optimization of microbial consortia for a variety of targets, using a new self-driving lab/machine learning approach. Moreover, the application of such an approach will identify new probiotic formulations for optimal gut health benefits.

Female breast cancer is the most diagnosed cancer worldwide and the second leading cause of death in Canadian women. Screening for breast cancer helps to detect it early. For screening, mammograms (MGs) are acquired and subsequently interpreted by radiologists. Radiologists also interpret MGs for diagnosis and follow-up in their routine practice. Advances in artificial intelligence (AI), triggered by deep learning, can automate MG interpretation. However, wide-spread usage of AI in clinic has not been possible due to poor generalizability, lack of prospective evaluation, and concerns about drawbacks arising from designing AI as a supplant than as an aid to the radiologists. Hence, there is a strong need to build trust in AI systems beyond technical improvement. This is challenging due to the lack of availability of large-scale datasets, variance in ground-truth labels, and imbalance caused by very low prevalence of abnormal findings in MGs.

Our objective is to combat those challenges by developing a novel multistage AI-based approach for MG interpretation. The approach is based on self-supervised deep learning (SSDL) and incorporates clinical feedback in its design to build trust. In Stage-I, a pre-trained vision-language model (VLM) will be retrained on large-scale new natural image datasets to improve the image and text embeddings. The Stage-II will include SSDL-based further retraining of the VLM with MG datasets (imaging and reports) to build a domain-specific strong foundation model (FM) that mitigates bias. In the Stage-III, we will leverage the FM through fine-tuning and balanced knowledge distillation using

1. clinical feedback (usability and ethics-based) and
2. labels from MG datasets for two downstream tasks:
   • classification of MG normalcy with high confidence, and generation of detection and segmentation mask for an abnormality. Several MG datasets, collected globally, with variability in demographics, imaging equipment, and labeling methods will be used for large-scale domain-specific training. Models will be tested on prospective local data.
   • Risk and Reward –The proposed multistage approach builds on global data and incorporates clinical feedback. It will improve generalizability, combat imbalance and variation in labelling, mitigate bias, and build trust. The FM can subsequently be applied to other downstream tasks related to MG interpretation, prevent overdiagnosis, and generate socioeconomic benefits by assisting radiologists.

Per- and polyfluoroalkyl substances (PFAS) have strong carbon-fluorine bonds that make them useful in many products, imparting thermal stability and grease- and water-resistance. But due to intensive use and environmental contamination, most people have PFAS in their blood. PFAS have negative impacts on human and ecosystem health. Those resistant to degradation are suspected carcinogens, interfere with immune response and impact metabolic dysfunction. The carbon-fluorine bonds make modifying their structure difficult; human enzymes cannot break these bonds, which prolongs PFAS human contamination for years. Certain PFAS do not breakdown and will exist “forever”. Yet in the human gut, thousands of microbes perform chemically challenging reactions to provide sources of food and energy for growth. We propose to explore the potential of the gut microbiome to breakdown PFAS.

This project will provide novel insights into the role of human gut microbes in environmental chemistry. We will address two objectives:

1. Identify and quantify the transformations of structurally different PFAS catalyzed by dehalogenating and gut microbes under biological conditions.
2. Determine the genetic potential for PFAS transformation using metagenomics and transcriptomics.

Our team will combine their expertise in environmental chemistry, toxicology, microbiology, and ‘omics to solve one of the most pressing environmental challenges of the 21st century. Our approach involves the use of dehalogenating microbes as model organisms. These microbes are known to break carbon-halogen bonds and thermodynamic evidence suggests this includes carbon-fluorine bonds. We will pair this analysis with collected stool samples that mimic the gut microbiome. Transformation products will be identified and quantified using ion, liquid, and gas chromatography and mass spectrometry. We will also employ metagenomics and metatranscriptomic sequencing to determine microbial community structure, their metabolic capacity and active genes.

Novel strategies to mitigate PFAS contamination are urgently needed. This project will involve high risk high reward cultivation experiments that seek to answer whether gut microbes can degrade these forever chemicals, identifying the microbes, genes and enzymes responsible. If successful, we will provide the first evidence that gut microbiota transform PFAS, and whether this transformation has the potential to mitigate or enhance toxicity.

The objective of the research project is to explore new design concepts to create mechanical systems that have the characteristics of artificial intelligence (AI) software implemented in digital computers. These characteristics include the ability to learn (or be designed) in supervised and unsupervised settings, processing physical stimuli through complex mathematical transforms, generalizing learning, as well as the energy-efficient processing of information through massive parallelism.

The research methodology will analyze mechanisms and phenomena in mechanical systems (e.g., solid and fluid mechanics, via stationary-action principles in dynamics and statics) to identify formal equivalences with the constituents of AI software. (An example of such equivalence is the recently identified correspondence between the equilibrium state of a nonlinear metamaterial structure and the fixed points of a recurrent neural network.) These formal equivalences will be leveraged to build and experimentally study smart mechanical systems that respond to external stimuli, in ways that are deeply analogous to how modern AI algorithms process digital information.

The project is novel as it goes far beyond the conventional use of AI in engineering, where a computer is always in the loop to process information in software; here, the goal is to process the information directly within the mechanical system. The current practice in engineering is to divide systems by function; the proposed project challenges this paradigm, as it aims to intimately combine AI functions with other mechanical functions (e.g., load bearing and classification of the loads). The project is deeply interdisciplinary, as it explores the parallels between the AI software and physical phenomena in mechanical systems.

The project could open new areas of discovery in engineering, that would focus on the organic integration of information processing within the physical structure of objects. This could lead to breakthrough technologies that are far more energy efficient, more robust and more capable (examples include MEMS sensor performing AI edge-computing, metamaterials with a stiffness adapting to their load and programmable self-assembling structures). These technologies could have broad and significant societal impacts, by being safer, more efficient or more ecological. Examples include structural integrity monitoring, self-healing structures and wearable medical devices providing biofeedback.

The objective of the research is to identify biosignatures, i.e. unambiguous signatures of life, associated with tungsten (W) metabolism by hyperthermophilic archaea. These organisms thrive in extreme (hot and acidic) environments, such as deep ocean hydrothermal vents, which are potential environments for where life on Earth originated. Uptake of W by these microorganisms and associated biological isotope fractionation could serve as robust biosignatures for early life on Earth and on other planets.

Life on Earth is believed to have emerged in the Archean Eon (4.0-2.5billion years ago). Identifying morphological evidence of early life in the oldest sedimentary rocks can be challenging given their extensive alteration. However, traces of biological activity may be preserved via isotope ratios of certain elements. While the isotope compositions of light elements such as carbon (C) or iron (Fe) have been proven diagnostic of biological signatures, weathering and alteration of ancient rocks can easily modify these isotope compositions.

Tungsten, the heaviest element employed in biological systems, may have predated other essential metals used by modern microbes, as suggested by early tree of life reconstructions. Yet, our understanding of microbial W uptake or isotope fractionation remains limited, hindering its potential use as a biosignature.

Luckily, recent advances in mass spectrometry now enable W isotope measurements with unprecedented levels of precision.

Our research approach will consist of:

1. cultivation of hyperthermophilic archaea to examine metal solubilization, W uptake and associated isotope fractionation;
2. characterization of W-using microorganisms in modern analogues such as hydrothermal vents and hot springs; and
3. constraining abiotic W uptake and isotope fractionation into iron-minerals.

The novelty and success of this research relies on the close collaboration between several disciplines, including microbiology, isotope geochemistry, evolutionary biology and astrobiology. If early life on Earth utilizedW, it stands to reason that early extraterrestrial life forms might follow similar pathways. Research outcomes, therefore, may also influence the scientific planning of future missions to icy-moons and offer insight into longstanding scientific and philosophical debates regarding the emergence of life on Earth and elsewhere.

The human brain dedicates substantial resources to sensing our environment and issuing motor commands to interact with our surroundings. However, while the concept of movement is simple, the functional implementation of movement generation is anything but. To produce coordinated and smooth movements, the brain must learn efficient movement representations starting from infancy. Unfortunately, an estimated 400,000 school-aged children are diagnosed with developmental coordination disorder (DCD), a broad disorder characterized by a child’s difficulty with motor coordination and movement. DCD is currently diagnosed primarily through observations of movements in standardized motor coordination tests (e.g. Bruininks-Oseretsky Test of Motor Proficiency), but its etiology remains unknown. One theory implicates internal model deficits, whereby the internal representations used by the brain to predict how muscle activations produce movements are impaired. Thus, current diagnostic tools are effectively probing these internal models to identify deficits.

We propose to shift this focus by investigating deficits in the motor learning process that generate internal models. We will study motor learning using a reinforcement learning paradigm which is characterized by a trade-off between exploitation of learned movements and exploration of new sensorimotor associations. We hypothesize that pubescent children use risk-taking behaviors as a mechanism to quickly explore new associations in a rapidly changing physical body, and that those with DCD exhibit risk aversion resulting in reduced motor reinforcement. These hypotheses will be tested using unique human-in-the-loop robotic balance platforms to alter the physical laws of natural human movement, combined with domain expertise in clinical DCD, behavioral risk-taking, and computational reinforcement learning. These findings will provide an early diagnostic tool for DCD that relies on observations of the motor learning process rather than the learned movements, and more broadly illuminate behavioral mechanisms of motor learning that suggest controlled risk-taking as an intervention to promote motor learning and recovery.

Finally, we will also investigate sex effects on sensorimotor learning. Sex effects on risk tolerance could have implications on the willingness to explore new sensorimotor associations and the age at which children enter puberty and undergo rapid physical changes is sex dependent.

A common science fiction trope is growing artificial organs in the laboratory to replace damaged tissues. How far are we from making this a reality for patients on transplant waiting lists? Today, large numbers of stem cells can be grown in the laboratory and differentiated into specialized cells such as insulin-producing islets. Clinical trials are evaluating whether stem cell-derived islets could be used to treat type 1 diabetes. Organizing these cells into functional human-scale tissues is another matter. One important hurdle is providing enough nutrients to thebillions of cells in each organ – all of which consume oxygen. If oxygen is provided only at the surface, the thickness of the viable tissue is limited to about one millimeter.

Objectives: In our body, the oxygen supply problem is solved by dense blood vessel networks. Larger arteries branch into smaller vessels down to capillaries where red blood cells release oxygen to nourish our cells. The objective of this project is to design pancreatic tissues which integrate both large and small blood vessels. We will demonstrate that these tissues can be kept alive several weeks.

Approach: We will grow stem cells in bioreactors and differentiate them into insulin-producing cells. The resulting cells, combined with vascular cells, will then be compacted into a dense tissue. Large blood vessel templates will be created within via 3D printing. The printed geometries will be designed based on numerical simulations of oxygen distribution. After removing the 3D printed material, the tissues will be maintained in culture under flow using a custom designed pumping, imaging, and analytical system. We will study how the vascular channels evolve over time. We anticipate that small vessels will form, allowing long-term survival of centimeter-scale tissues.

Novelty and expected significance: This project addresses key limitations in artificial tissue engineering for diabetes and beyond. This technology could be used to study how pancreatic islets interact with blood vessels or how they react to new drugs. This could reduce the need for animal studies in pharmaceutical development for diabetes. These artificial tissues could eventually also be transplanted as long-term treatment for type1 diabetes.

Background & Objectives: Progressive diseases of vital organs affect ~1,000,000 Canadians, costing the health care system >$50billion annually. Canada is a leader in organ transplantation, yet only a fraction of patients on transplant waiting lists ever receive one; this gap will increase over time. Since producing primate organs for xenotransplantation (XT) is not ethically and logistically possible, pigs are viewed as an ideal animal organ donor. In January 2022, a US team replaced the terminally failing heart of a 57-year-old man with a 1-year-old pig heart, which remained functional for 2 months, signalling the start of a new era in medicine. Hence, the long-term objective of our program is to develop an inter-disciplinary Canadian program for basic, experimental, and clinical XT research.

Approach: Transgenic pigs are commonly generated by micromanipulation of oocytes or early embryos, as a result, these methods are extremely inefficient, expensive, time-consuming, and frequently lead to developmental abnormalities in offspring. We have pioneered an innovative approach for generation of transgenic pigs by transplanting genetically modified spermatogonial stem cells (SSCs) into prepubertal pig testes; a procedure which skips one generation, is more efficient, and is less costly than current methods. For this 2-year research proposal, we will employ new genome editing tools to develop transgenic founder pigs by editing in pig SSCs several critical sets of genes related to:

1. hyperacute rejection (e.g., alpha-Gal),
2. classical and chronic rejection (e.g., HLA), and
3. potential transmission of zoonoses to the human host (e.g., PERVs).

These genetically engineered SSCs will be microinjected into recipient pig testes which within ~3months will start producing transgenic sperm for the future production of various lines of transgenic pigs.

Novelty & Significance: The combination of expertise in pig transgenesis, organ transplantation surgery/immunology/pathology, complementary infrastructure, and access to a level-3 facility capable of raising pathogen-free pigs, makes our team uniquely positioned to contribute to this high-risk high-reward effort in regenerative medicine. Our program will:

1. offer innovative solutions for future production of unlimited donor organs for XT,
2. provide new hope for thousands of patients on transplant waiting lists, and
3. potentially savebillions of dollars in cost of treating vital organ failure in Canada.

A healthy gut environment requires an intact intestinal barrier that is supported by cooperative interactions between commensal microbes and immune cells. Unfortunately, when this intestinal barrier is dysfunctional, the immune system reacts strongly leading to excessive inflammation seen in various gastrointestinal (GI) manifestations (e.g. inflammatory bowel disease (IBD), food allergy) with also genetic and environmental factors playing a role. In Canada, over 300,000 people suffer from IBD and an estimated 3million people have one or more food allergies with incidence rates rising at an alarming rate for both. Interferons (IFNs) are a class of potent immunomodulatory proteins best known as being made by our bodies to fight viruses. There are 3 IFN families - type I, II and III, but only the most recently discovered type III IFNs (IFN-lambda, IFN-L) were found to have unique anti-inflammatory properties in various mouse models. This contrasts with the well-studied typeI and II IFNs that promote gut inflammation and damage. In this proposal, we will develop a novel platform for the delivery of IFN-L with an extended half life for the specific treatment of GI inflammation. We hypothesize this selective delivery of IFN-L to the gut will have an advantage over other therapies that aim to broadly inhibit the immune system which leads to significant side effects.

To achieve our main objective, we will use two complementary approaches for creating longer-acting forms of IFN-L, including delivery via self-amplifying RNA or delivery of the altered, glycosylated protein itself. This will be paired with optimization of nanoparticle delivery to the gut. Using animal models, we will confirm the distribution of the nanoparticles, and tailor the expression of IFN-L to determine the optimal dose. We will compare each IFN-L product for how well it promotes gut barrier health and dampens distinct pathways of inflammation.

This project requires an interdisciplinary team with expertise in immunology, gut physiology, biomedical engineering, and glycochemistry to develop this cutting-edge technology to harness the dual function of IFN-L to promote gut health, but also to selectively regulate immune cells contributing to GI inflammation and damage. If successful, our newly developed class of therapies could improve the lives ofmillions of patients suffering from GI diseases around the world.

Background: Chronic kidney disease affects 1 in 10 Canadians, resulting in significant physical and psychological burdens. Hemodialysis (HD), a vital membrane-based therapy, places a strain on patients and costs Canada approximately $310million/year due to the inability of HD membranes to replicate the function of a healthy kidney. The development of HD membranes has, until now, relied on trial-and-error to enhance hemocompatibility and toxin removal. Exploring the physiology and size-selective filtration mechanism of the glomerular basem*nt membrane (GBM) inside the kidney is necessary to create membranes that mimic its function. Our long-term goal is to design an artificial wearable kidney with a hemocompatible membrane. To this end, this project’s objectives are to:

1. investigate and optimize HD performance based on mimicking a 3D model of the GBM under different conditions, and
2. conduct evidence-based synthesis of an innovative biomimetic membrane structure.

Approach: This innovative, high-risk project builds on the latest methods and integrated techniques and pioneers a revolutionary approach by embracing a membrane science perspective, gaining new understanding of the GBM's structure and function and mimicking critical aspects of GBM within an HD membrane, as follows:

1. a novel glomerulus-on-a-chip (human GOAC) composed of human podocytes, humanized GBM, and human glomerular endothelial cells will be constructed;
2. GBM selectivity and function will be explored for different conditions to optimize membrane selectivity;
3. blood transport and interactions will be assessed using synchrotron-based X-ray imaging;
4. biomimetic membranes will be synthesized to offer optimal biocompatibility and performance; and
5. the membranes will be characterized and subjected to ex vivo qualitative and quantitative testing.

Novelty: This project combines several disciplines in a novel way to introduce new technologies to the field of nephrology. It shifts the approach from trial-and-error synthesis to evidence-based synthesis and modeling to optimize membrane hemocompatibility and permselectivity. Significance: The novel membrane and GOAC approach will radically transform HD membrane technology by mimicking the GBM in our nephrons. Successful completion of this project will decrease morbidity and mortality associated with HD, prolong survival of patients, and decrease costs to healthcare systems in Canada and beyond.

Lethal opioid overdoses kill 7500Canadians per year. Even though funded projects supported by Health Canada are aimed at decreasing this dramatic number by providing free and anonymous substance checking technologies, there is still a large proportion of users who decline to use these services running at Supervised Consumption Sites (SCS).

The objective of this high-risk/high benefit project is to identify and lift the barriers to the access of more easily available drug sensing technologies that inform the substance users about the composition and potential dangers of their samples. Such information is relevant to users on site at SCS across Ontario by providing qualitative and quantitative information regarding their samples relevant to decision-making regarding reducing consumption or discarding their sample.

Since June 2023 a pilot project led by the applicants collects data at 10 SCS across Ontario primarily including the quantitative and qualitative analysis of the drugs used as well as certain demographics about the users and the impact of the drug check on their consumption. However, very little information about SCS access and decision making are currently available relevant to how the drug checking service can be fully leveraged to institute drastic changes in the crisis statistics of lethal outcomes.

In collaboration with the SCS, this NFRF Exploration project aims to analyze the collected data on substances, demographics and decision making to provide new solutions including a more accessible service with a higher impact on the population of people who use drugs. The data gathered by the SCS represents a significantly large ensemble of parameters. For the month of September2023 alone 606 substance scans have been performed representing over 203,000 spectra and the demographic data of 600 users. These metrics are ramping up since the installation of the drug checking devices.

Within the NFRF, we will analyze these large data sets using artificial intelligence (AI) methodologies based on deep learning neural networks. We will

1. improve the AI associated with drug identification and the analytics of demographics and drug use and decision making;
2. assess linkages between demographics and SCS drug checking use;
3. assess linkages between demographics, substances and decision-making.

These critical approaches will be used to decipher the intricate parameters that justify the choice of users to use or discard a given substance.

Objectives

1. Determine the mechanism of degradation for a variety of pollutants using the bias-enhanced electrolytic photocatalysis (BEEP) technology, via real-time analysis of the water under treatment using highly sensitive methods.
2. Understand the policy landscape and therefore priority target applications and partnerships for deployment of advanced water treatment processes in British Columbia and elsewhere in Canada.
3. Use this knowledge to optimize the technology and test it in real-world applications (pools, tanks, wastewater, cisterns, leachate ponds, etc.).

Summary of approach

BEEP, a new approach to the destruction of water-borne contaminants using UV light, a small electrical bias, and a nanostructured TiO2 catalyst, has been developed and tested in collaboration with scientists at the University of Victoria. It has shown extraordinary promise in the treatment of a wide variety of contaminants, most recently with its ability to break C-F bonds in polyfluorinated molecules and ions (so-called “forever chemicals”). Coupled with the capacity to render a variety of other contaminants harmless, the technology is very promising for the treatment of wastewater and for keeping closed systems (pools, fish farms, etc) clean. The fact that no chemicals need to be added and that energy consumption is low is a huge advantage over traditional methods.

Novelty. Photocatalysis is a very mature field with tens of thousands of published papers using TiO2 as the catalyst, but practical limitations have held back its application to emerging problems. BEEP uses a unique combination of technological developments that overcome these limitations and opens up a broad range of pollutant targets for attack, including viruses and bacteria, pharmaceuticals, microplastics, aerosolized pathogens, volatile organic compounds, and carcinogenic metal ions.

Expected significance. There is a pressing need for clean methods for destroying air- and water-borne pollutants. The ideal method is one that is highly effective against a broad spectrum of undesirable compounds, is catalytic, avoids the use of added chemicals, and is energy efficient. We have access to just such a method and expect it to be exceptionally useful, but much has yet to be done to understand better how it works (chemistry), to optimize its performance and to apply it in real-life scenarios (civil engineering), and decide where it would be most beneficial to deploy it (law).

Background

Aquaculture is a ~$400billion industry worldwide. With >50% of consumed seafood produced using aquaculture, it is an integral part of the global food supply. Pathogen infection, including aquatic viruses, result in ~$8billion losses yearly and is expected to increase with the climate crisis and the growing population putting more pressure on food supply.

Objectives

We propose an innovative and unexplored method for producing antiviral therapies, using plants as biofactories. Our focus will be on using plants to make long, sequence specific double-stranded (ds) RNA, a potent antiviral which limits viral protein production through the RNA interference (RNAi) pathway. Plant-produced antiviral dsRNA will be delivered either via direct feeding, incorporating dsRNA-containing plants into fish feed, or using isolated dsRNA combined with an all-natural, plant-derived nanoparticle to enhance delivery. The project’s three objectives are to:

1. genetically modify Nicotiana benthamiana plants to produce dsRNA for isolation
2. genetically modify Lemna minor (duckweed) to produce dsRNA for direct feed addition and
3. test the safety, biodistribution and antiviral efficacy of these molecules in the commonly farmed fish, rainbow trout (Oncorhynchus mykiss).

Antiviral efficacy, being a reduction in morbidity and mortality, will be tested in fish infected with viral hemorrhagic septicemia virus, a virus with impactful global threat to fish health.

Novelty and expected significance

Currently there are no fish antiviral therapies used in fish farms, and existing vaccines have low efficacy. This leaves fish farms unprotected and exposed to huge losses due to viral infections. Our proposal could potentially lead to commercialization of a novel antiviral product. The use of plants to produce nucleic acids for therapeutic use in other species is high risk, and the ability to produce an effective antiviral therapy for consumed fish in a socially accepted format would be highly valuable. Current methods of producing RNA for human applications are extremely limited and the cost of manufacturing these molecules makes them prohibitive for fish farms, where the therapy needs to ultimately cost pennies per fish. By combining expertise in plant genetic engineering, aquatic innate immunity, and nanoparticle delivery of nucleic acids, we propose a novel and sustainable approach to improving aquaculture health and strengthening the Canadian food supply.

Spinal cord injury (SCI) is one of the most devastating health conditions with a global rise in incidence, prevalence, and years lived with disability. Rehabilitation interventions are multi-modal, with combinations of pharmacologic, activity-based, technology-based (e.g., exoskeletons and electrical stimulation), assistive (e.g., wheelchairs, bracing) and environmental-based (e.g., accessibility accommodation) approaches. There is considerable variation in rehabilitation outcomes across underrepresented and socioeconomic groups and existing rehabilitation strategies typically rely on best practice interventions based on diagnosis and summary recommendations derived over time and across patient groups, which loses important information pertinent to intersectional groups. A critical gap in SCI rehabilitation is that current rehabilitation practices fail to capture the intersectional needs, strengths, and resources of individuals and community stakeholders.

The central approach of this research project is to integrate computational methods and medical anthropology to advance SCI rehabilitation. We will use a novel algorithmic framework that mimics the deliberate and principled nature of human curiosity while harnessing the power of algorithms to compute complex, far-reaching interactions, allowing clinicians to chart the course of an individual's rehabilitation journey. We will integrate this framework with a mixed-methods approach using medical anthropology techniques to ensure we address the topics and interactions that stakeholders care about.

Our first objective is to thematically construct the web of costs, benefits and interactions using explanatory models in medical anthropology to assess the goals of diverse stakeholders. Our second objective is to develop a curiosity-driven framework that embodies this information. Our third objective is to evaluate the suggested actions of the framework with clinicians, patients, and caregivers.

Integrating medical anthropology with optimal control theory within the field of medicine is a novel departure from recent efforts to employ data-driven machine learning techniques and is likely to offer significant advantages given the paucity of data regarding intersectional effects. The action sequences proposed by the algorithm combined with explanatory models can inform clinicians to accelerate and optimize recovery of patients, resulting in better outcomes for persons with disabilities and aging populations.

Our proposal has two main objectives:

Objective 1: Cardiovascular disease is a major cause of death worldwide. Among the first line therapies in the prevention of cardiovascular disease is prescription of lipid-lowering agents such as ethyl-eicosapentaenoic acid (e-EPA). Interestingly, e-EPA is an analog of eicosapentaenoic acid that is enriched in fish oils, and there is growing evidence that fish oil intake enhances skeletal muscle mass and strength in older adults—a population at risk of skeletal muscle loss. There is also evidence that fish oils can enhance skeletal muscle mitochondrial function, which is important because low skeletal muscle mitochondrial function is linked to several diseased states. However, what is not known is if e-EPA can be repurposed to enhance skeletal muscle mass, strength, and mitochondrial function in older adults. Thus, Objective 1 is to test the hypothesis that administration of e-EPA can be repurposed to promote skeletal muscle anabolism and mitochondrial function in older adults. Given that loss of skeletal muscle mass, strength and mitochondrial function is linked to disability, diabetes, and cancer the findings of our work could open a new avenue of treatment across a range of diseased states.

Objective 2: A major barrier to study skeletal muscle mitochondria is the requirement for skeletal muscle biopsies that are invasive and necessitate specialist expertise. We possess such specialist expertise and will use them to address Objective 1. However, we also have preliminary evidence generated in mice that blood platelet mitochondrial function mimics that of skeletal muscle implying insights into skeletal muscle mitochondrial metabolism could be obtained from a simple blood sample. Thus, Objective 2 is to test the hypothesis that changes in skeletal muscle mitochondrial function induced by e-EPA in Objective 1 will reflect those of blood platelet mitochondria. If we establish that blood platelet mitochondrial function can be used as a surrogate for skeletal muscle mitochondrial function, then we will have discovered a new powerful tool to revolutionize clinical and experimental practice.

To address both objectives, we unite a multidisciplinary team of investigators spanning a range of disciplines (Nutrition, Geology, Kinesiology, Rehabilitation, Neurosciences, Medicine) using novel, cutting-edge quantitative and qualitive techniques.

Transitional age youth (TAY; age 16-30) with chronic health conditions face significant psychosocial challenges during a formative developmental period, including coping with adversity, with anxiety and depression co-occuring in approximately half of this group. Yet, this life phase presents a remarkable opportunity to develop skills and habits that ripple throughout life towards enhanced well-being.

Interventions using contemplative and strengths-based adaptive skills approaches to positive functioning, such as developing coping and resilience abilities, are particularly effective for TAYs with chronic health conditions. However, accessing interventions and supportive environments can be challenging for these youths who require tailored tools that accommodate their lived realities. Virtual Reality interventions (VRIs) demonstrate potential for imbuing adaptive skills such as coping, mindfulness, and compassion towards well-being. Additionally, VR can provide authentic social connection at a time when supportive peer environments are vital and in-person interactions are often unfeasible.

Our aim is to develop a proof of concept VRI that trains adaptive skills and builds resilience towards adversity. Tailored for TAYs with chronic health conditions, we’ll integrate their lived experience in a co-design research process. Leveraging our research team's ability to rapidly develop VR, we will amplify the VRI’s relevance using novel biosensors and AI within its interface. Through feasibility and acceptability testing and collaborator support, we will explore how to extend reach and accessibility of the VRI to TAYs through distribution points such as supported at-home use, and integrated in routine health services.

This interdisciplinary project draws upon knowledge from lived experiences of TAYs and community services providers who inform equitable, relevant insight on the VRI development. Researchers provide theoretical and methodological expertise from cognitive science, psychology, neuroscience, human-centered design, and VR/human-computer interaction.

A VRI can be a gateway for TAYs with chronic health conditions to access early intervention. Using VR could reduce stigma associated with seeking support, empowering TAYs to build skills for future challenges. This research is positioned to facilitate a paradigm shift in how these TAYs develop adaptive skills in a VRI, aiding them in real-world situations and future adversity.

Random or stochastic events play an important role in genetics. Clinically, we observe incomplete penetrance in carriers of pathogenic copy number variants. In zebrafish experiments, we observe incomplete phenotypic penetrance in fish hom*ozygous for mutations in genes of interest. Complex interplay between genetic and environmental factors contribute to incomplete penetrance, but based on epidemiological and experimental data, stochastic genetic or epigenetic variants also modulate phenotypic outcomes. The nature of stochastic events makes direct prediction impossible, hampering individual-level risk prediction, essential for precision medicine.

We recently identified genomic hotspots with highly interconnected genetic networks with transcription factors (TFs) and genes with a very basic genome-regulatory function. We believe these TF-gene networks play an essential role in the most fundamental level of biological regulation. Genetic variation across the entire frequency spectrum in these hotspots increase the risk for autism spectrum disorders, schizophrenia and scoliosis.

We argue that genetic alterations in these TF-gene networks increase the probability of random effects in final biological pathways involved in the most complex human developmental systems like the brain and the upright spine development.

Validation of these hypotheses will provide a paradigm shift in the genomic architecture of complex human disorders. This, in turn, can enable the refinement of animal models and the development of novel genetic risk prediction methods that incorporate different classes of genetic networks and incorporate these stochastic events into their models, essential improvements for precision medicine.

We will leverage well-established zebrafish models and test the hypothesis that zebrafish with high loading of pathogenic variants in TF-gene networks will have higher phenotypic penetrance. Secondly, we will translate the findings in our clinical data with whole genome sequence data, and test whether children with extreme phenotypes without a clinical genetic diagnosis have higher loading of pathogenic variants in TF-gene networks. Finally, we will develop new statistical models to improve risk prediction using the identified genetic networks and validate these models in large clinical datasets. The interdisciplinary research team allows us to test the hypotheses in close conjunction to allow optimal translation from basic science to clinical practice.

Isotopes are used in a broad variety of biomedical applications, including diagnosis and treat of diseases. Naturally occurring isotopes are scarce. Stable isotopes are usually separated from natural minerals and radioactive isotopes must be synthesized in reactors. Both methods employ large specialized sophisticated facilities operated at designated location. Only a few heavy elements can produce radioactive isotopes. Moreover, current methods do not create isotopes in nanoparticles. Shrinking isotopes to nanosized particles opens up new opportunities in developing next generation advanced nanomedicine.

This program introduces an innovative technology to generate nanoisotopes using industrial grade ultrashort laser from a wide range of light elements. We aim to develop a compact affordable system that produces nanoisotope powder on-site in a regular laboratory setting. Through tuning laser-matter interaction, abundant bulk materials will be converted into nanosized particles with desired concentration and type of isotopes. The technology will enable the production of personalized isotope nanomedicine on- demand in a hospital setting from common materials, such as metals, graphite, silicon and their compounds. It will be the first technique to synthesis isotopes from light elements and will be the only one that produces isotopes in the form of nanoparticles.

Nano-isotopes present unique properties, distinct from all other nanoparticles commercially available. The ultra-sensitivity, biocompatibility and new functions of nanoisotopes will translate to advanced nanomedicine with higher detection sensitivity and better efficiency in treatment. It will open up new opportunities in early diagnosis of cancer, cancer nano-immunotherapy and rapid diagnosis of virus/bacterial infection.

Researchers from multiple disciplines in sciences and engineering will work together to develop new knowledge in manufacturing, laser material processing and medical science. The research program proposed has high potential for biomedical technology transfer. It has direct benefits to the Canadian healthcare system and the well-being of Canadians. It also contributes to the growth of Canada’s healthcare innovation and entrepreneurship.

Falls affect 30% of community-dwelling adults aged 65 years and older with high morbidity, mortality and cost. Risk factors are multidimensional including biological, behavioural, socioeconomic, and environmental factors.

Multiple fall risk evaluation tools exist, ranging from self-report based assessments to in-person physical performance testing. In addition to a lack of clarity on which tool to use, existing tools have varying limitations including their time consuming nature, subjective scoring, lack of consideration of multidimensionality, the need for specialized equipment, and a low predictive validity for picking up subtle abnormalities that could promote earlier detection and intervention.

Markerless motion capture (MMC) offers a novel strategy to evaluate subtle abnormalities in key static and dynamic balance tests without the need for markers or hardware. While not currently a part of clinical practice, mmC can be carried out on smart devices making it accessible for testing in rural and remote locations. It also has the potential to incorporate novel as of yet untested movements that could allow for intervention on individuals at earlier stages of fall risk. A standalone virtual fall risk toolkit would need to incorporate other non-MMC based factors (e.g. environmental risks, cognitive status) alongsidemmC.

Accordingly, the proposed research aims to develop a novel virtual fall risk toolkit that combines objectivemmC based testing alongside other key multidimensional fall risk factors. Our research objectives are:

1. To use an interdisciplinary perspective to inform a core outcome set of modifiable, multidimensional contributors of fall risk that can be assessed virtually, including relevant performance based measures.
2. To develop a series ofmmC based performance tests that allows for the objective evaluation of relevant fall risk parameters.
3. To evaluate the novel multidimensional virtual fall risk toolkit in older participants with chronic disease.

If successful, researchers and clinicians would have access to a novel standalone multidimensional virtual toolkit that includes a core outcome set of objectivemmC tests alongside the virtual evaluation of other multidimensional factors. This standalone toolkit could simplify and objectify testing for fall risk and allow for earlier detection of abnormalities. The identification of specific contributors could lead to more tailored intervention strategies than are currently prescribed.

Directed evolution is an incredibly powerful technique that uses repeated cycles of gene diversification and screening of the corresponding proteins to identify biomolecules with new and/or improved properties for use as therapeutics or industrial biocatalysts. A critical component of all directed evolution campaigns is the need to maintain a strict link between genotypes (the amino acid sequence of each mutant gene) and phenotypes (the characteristic(s) of interest exhibited by the corresponding proteins). Given the extremely large mutant libraries that are routinely generated during gene diversification, the required genotype-to-phenotype linkage often renders directed evolution a time-consuming process that requires many sub-culturing steps, the development of specialized screening assays, and/or restricts the throughput of the campaign.

We propose to develop a new screening platform for directed evolution that exploits a liquid micro junction-surface sampling probe (LMJ-SSP) and ambient ionization mass spectrometry to perform on-plate activity assays of libraries of variant proteins. To achieve this, we will combine expertise and techniques from analytical and organic chemistry, microbiology, enzymology, data science, and machine learning. Our platform will use the LMJ-SSP to sample regions in the immediate vicinity of individual bacterial colonies that express and export individual protein variants. By combining the spatiotemporal resolution enabled by the LMJ-SSP with high-resolution mass spectroscopy (MS), our platform will permit the rapid identification of colonies that harbour mutant genes encoding proteins with desirable properties. Since each gene and the corresponding protein are necessarily co-localized in and around the expressing bacteria, this MS-based platform will necessarily maintain the genotype-to-phenotype link while also enabling high-throughput evaluation screening that precludes the need for sub-culturing steps.

Our interdisciplinary team of experts is uniquely suited to develop, validate, and use this platform to make new, valuable biomolecules. Our first aim will be the evolution of an industrially useful biocatalyst that can produce valuable esters and lactones (common moieties in drugs) from affordable precursors. We will also use the described platform to screen variants of known genetically encoded antibiotics for new and improved therapeutic activities to combat the rising tide of antimicrobial resistance.

Opioid use disorder (OUD) is a chronic but treatable medical condition. While opioid agonist treatment has long been the gold standard, retention remains low, with only 16% of individuals being retained after one year in British Columbia. While addressing socio-economic factors that impact the ability to engage in care and adhere to treatment is critical to increasing long-term retention rates, efforts to do in Canada remain largely unsuccessful, as seen by the ongoing overdose epidemic that continues to claim the lives of 20 Canadians daily. However, a unique and urgent opportunity exists to determine the impact of offering incentivized treatment to some of the people most at risk of overdose.

Incentivized treatment is a therapeutic approach that promotes desired behavioural change through positive reinforcement such as cash payments. While considerable evidence supports it as an impactful method for improving engagement and reducing substance use, offering it as part of treatment planning has never been attempted in Canada.

With this funding, we will seek to understand how socioeconomic factors can be mitigated through a health care model that incorporates health incentives into treatment planning. The study will involve offering up to $20 daily to people with severe OUD who are affected by structural vulnerabilities that put them at high risk of overdose. To receive payments, they must engage with an individually tailored treatment plan that is aligned with their personal goals.

Such incentivized treatment planning has never been attempted before and seriously challenges current paradigms. The study will enhance the understanding of the highly complex issues of substance use disorder treatment and social determinants of health and will bring together various disciplines in novel ways. If the study finds there is promise in this planning method, the health impacts could be far-reaching in the midst of one of the worst public health crises ever experienced in Canada. Indeed, it has the potential to contribute to a shift in the treatment model of care for the large and unique community of people who use drugs and presents a critical opportunity to make progress on this hitherto intractable issue. Regardless of the outcome of the study, it will certainly advance current knowledge in significant ways and will transform conventional thinking on the treatment of substance use disorders.

Within residential care, people with advanced dementia often experience minimal social interaction and meaningful engagement. They are often left alone in their rooms spending up to 87% of their days doing nothing and with less than 10 minutes/day engaged in meaningful activity. Green Care Farms (GCFs), innovative small-scale daycare/long term care (LTC) homes, offer a promising strategy to reduce excess disability and increase social and physical interaction through a nature-based approach. GCFs combine agriculture production with health-related, social and educational services. In the Netherlands, a leader in this innovative field of dementia care, GCFs have been found to improve cognitive functioning, emotional and psychological well-being, and sense of belonging.

GCFs prioritize meaningful activities and quality living by embracing a home-like atmosphere which inherently poses some risk. As such, we are challenged to implement GCFs in Canada due to our risk-averse culture and strict LTC regulations. However, we believe that the choice to participate in GCFs, with their higher quality of life and meaningful activities, should rest with the individuals and their caregivers, rather than being dictated by system policies. As such we intend to challenge the status quo in practice and policy in Canada by pushing boundaries and attitudes related to risk tolerance in dementia care, and to explore how GCFs can be implemented within our health, social and agricultural systems. Hence the goal of this study is to co-design and evaluate the implementation of GCFs across a continuum of care for persons with dementia in Canada.

Informed by participatory action research, we will employ a case study approach to investigate and document three distinct instances of GCF implementation across Canada. These case studies will encompass a continuum of contexts, including daycare facilities, LTC homes, and blended GCFs catering to both adolescents and seniors. Additionally, we will consider factors such as profit status and various stages of implementation, ensuring a diverse learning experience and facilitating future dissemination. Presently, we have secured buy-in from 2-3sites. We firmly believe the time is now to challenge the status quo in Canada, shift existing norms and embrace newmodels of person-centered care that create suitable living environments for our dementia population, ultimately improving the quality of life for persons with dementia and caregivers.

Brain diseases are very challenging to treat due to the blood brain barrier and the sensitivity of the organ. For example, glioblastoma multiforme (GBM) has under 5% 5-year survival. Tumour resection extends life, but cancer stem cells inevitably remain leading to recurrence for 87% of patients in 4years. No advancements in therapy have been made for 20 years. The quest to develop innovative therapies for neurological disorders and diseases like GBM has fuelled the rapid evolution of drug discovery, but also the development of novel detection technologies. Among the latest frontiers in this field is the development of selective degradable implantable electronics capable of not only monitoring disease progression, but also releasing therapeutic drugs within the brain.

Driven by the pressing need for such cutting-edge technology and its potential to revolutionize the landscape of neuroscience, this research will create a degradable organic electronic device platform to detect markers of GBM recurrence. Upon detection, the electronic theranostic (e-theranostic) will transmit the signal to a reader, which will trigger a controlled degradation of the device to release drugs in progressive stages. The following aims will enable our interdisciplinary team to accomplish this goal:

1. Validation of patient derived ex vivo models of GBM;
2. Synthesis and implementation of self-immolative substrates and bioresponsive semiconducting polymers for controlled drug release in a sensor prototype;
3. Detection of tumours and achieved controlled degradation in a brain-mimic environment.

This project intertwines drug delivery, degradable materials, microcircuit design, and tissue engineering There are no extant degradable-on-demand electronics for any application. Our combined interdisciplinary approach will tackle crucial scientific questions across multiple fields, impossible to address without engaging all. The research team will be an inclusive environment in which all HQP will acquire experience and advanced technical skills along with the ability to work across disciplines. This research will pave the way for a comprehensive exploration of the development, applications, and impact of selectively degradable implantable electronics and e-theranostics in the broad field of brain drug delivery. It will create a unique synergy to achieve these high-risk, high-reward objectives while further strengthening Canadian core values of innovation and high-quality training.

Importance: One in four North American women will experience at least one pelvic floor disorder in their lifetime. In pelvic organ prolapse (POP), loss of anatomic support allows the bladder, colon, or uterus to descend, collapse the vagin*l wall, and protrude through the vagin*l introitus. Costing the US an estimated $1billion, hundreds of thousands of women undergo surgery for POP each year, with 40% relapsing or still experiencing prolapse symptoms two years after surgery. Tissues that produce and amass structural molecules like collagen have been shown to be compositionally distinct in women with POP, but little is known about the pathogenic processes underlying these changes.

Study Objectives: The overarching goal of this proposal is to identify novel mechanisms through which the vagin*l microbiome contributes to the development of POP. This proposal builds on our recent work showing that enzymes produced by the vagin*l microbiome degrade collagen, elastin, hyaluronan, and chondroitin. We have furthermore shown that microbiome proteases proteolytically activate host proteases and break epithelial barriers. Our objectives are to establish a first-of-its-kind multi-disciplinary study of Canadian POP patients, identify microbiome enzymes enriched in women with POP, and define their capacity to synergize with host enzymes to pathogenically remodel the extracellular matrix (ECM) in structural tissues. We will examine POP tissues with unbiased degradomics and use activity-based probes that deeply profile active proteases. Finally, we will use human organoids to learn how microbiome enzymes access and influence the vagin*l stroma and neighboring support structures like the uterosacral ligament.

Novelty & Expected Outcomes: Leveraging expertise in urogynecological surgery, microbiome science, proteomics, glycomics, activity-based probes, primary cell culture, and human organoids, our team is uniquely positioned to begin unraveling the complexities of ECM remodeling at the host-microbe interface. However, this project goes beyond standard surveys of biological content, and instead aims to capture and validate biological activities. Upon validating the pathogenic effects of poorly understood species and newly discovered enzymes in sophisticated organoid models, our findings will be funneled into rapid activity-based drug discovery platforms to provide new therapeutics that reduce the burden of debilitating prolapse symptoms and costly surgeries.

The rise of antibiotic resistant bacterial infections is one of the most pressing global health challenges facing healthcare systems around the world. To overcome this challenge, new antibiotics with new modes of action are urgently needed. One of the primary challenges hindering the development of new antibiotics is the identification of new cellular targets in bacteria that are not already exploited by currently available antibiotics.

In recent years, the study of antimicrobial proteins (AMPs) has proven to be a fruitful avenue of investigation for the identification of novel ways to kill antibiotic-resistant bacteria. However, traditional approaches for AMP discovery involve a one-at-a-time approach and relies on costly, time-consuming wet lab experimental approaches that suffer from the same rediscovery shortcomings as small molecule antibiotic discovery. For this project, we propose to overcome this challenge by designing and implementing a novel machine learning algorithm for AMP discovery. In doing so, we will rapidly facilitate AMP discovery directly from sequenced genomes, which will therefore allow us to focus our experimental efforts on downstream mode of action studies focused on uncovering new mechanisms of bacterial killing. Central to this approach is a dereplication step that uses Alphafold2-based structure prediction to eliminate AMPs with the same mode of action as currently available antibiotics. Our initial efforts for this two-year project will focus on AMP discovery in the genomes of the closely related human pathogens Salmonella and E. coli due to the abundance of publicly available sequenced genomes for these organisms. In the longer term, we will expand this approach across all pathogenic bacteria and also pathogenic fungi. As such, our specific aims are as follows:

1. Predict the AMP repertoire of ~300,000 Salmonella and E. coli strains using a custom computational AMP discovery pipeline that leverages high-throughput comparative genomics coupled with a novel machine learning algorithm.
2. Elucidate the mechanism of action of newly identified AMPs with potentially novel modes of action using biochemical and structural analyses to determine how they exert their bactericidal activity against priority pathogens.

Collectively, the proposed research seeks to merge the disparate disciplines of computer science with bacteriology and biochemistry to uncover new ways to treat multi-drug resistant bacterial infections.

Diabetic foot ulcers (DFUs) are a debilitating complication of diabetes that will affect up to 25% of people with diabetes, and accounts for 70% of all amputations in Canadian hospitals. The annual cost of DFU-related care in Canada exceeds $574million and is expected to rise due to the growing prevalence of diabetes and an aging population. Advanced wound care technologies are urgently needed to address this socioeconomic burden. Our research aims to develop a sustainable wound dressing using living microalgae to provide photosynthetic oxygenation and immunomodulatory metabolites to resolve chronic inflammation and promote wound closure.

Chronic wounds, such DFUs, fail to progress through the normal stages of wound healing due to chronic hypoxia and inflammation. Consequently, strategies that address chronic inflammation while providing sufficient oxygenation to support tissue formation, have promising potential as wound therapies. Therefore, our team will combine our expertise in biomedical engineering, chemistry, microbiology, genetic engineering, and immunology to develop an advanced wound dressing incorporating genetically modified green algae and arachidonic acid (AA) within an alginate hydrogel scaffold. This dressing will enable adjustable, light-dependent oxygen production to mitigate wound hypoxia. Also, the algae will be genetically engineered to express key metabolic enzymes, such as Cytochrome P450 (CYP) epoxygenases, facilitating the conversion of AA into anti-inflammatory metabolites like epoxyeicosatrienoic acids. The modified algae scaffolds will be tested with in vitro human skin cells and immune cells to evaluate biocompatibility and anti-inflammatory/pro-resolving properties. Moreover, the dressings will be tested in murine diabetic wound models to assess oxygen production, CYP epoxygenase expression, wound closure rates, and vascularization, which will provide crucial insights into the efficacy of our innovative approach.

This novel photosynthetic wound dressing, aimed at in-situ biosynthesis of pro-resolving factors and oxygen, is a high-risk effort and if successful, has the potential to greatly improve chronic wound care, benefiting individuals with DFUs, pressure ulcers, and slow-healing wounds. This sustainable, bioactive dressing utilizes renewable resources without relying on human-derived stem cells or neonatal tissues and will pave the way for in situ production of other therapeutic molecules in future research.

This project will create the design tools to realise lattice materials of the future. It will exploit a combination of disorder, and physically-motivated optimisation methods, to create materials with enhanced physical properties for use across a range of engineering problems, such as in transport, healthcare and future energy systems.

Traditional approaches to lattice creation involve designing a unit cell that is repeated to create a macroscale material. Yet, periodic lattices result in a limited range of properties and are often prone to catastrophic failure under modest defect formation. On the other hand, the addition of disorder to a lattice, has been shown to improve its resilience, increase the isotropy of its response, and offer a larger design space of achievable properties. Indeed, biological materials, such as bone, shell, beak, and wood, have evolved to be intrinsically disordered, and they perform well in variable conditions. This provides a fantastic opportunity to create enhanced materials by exploiting intrinsic disorder.

The PIs aim to address this opportunity by combining their complementary areas of expertise, applied mathematics and materials engineering, to design, build, and test an array of disordered materials, including strut-based systems, minimal-surface-based systems, materials with surface residing features, and multimaterial lattices. They will build computational methods to realize disorder at varying scales in these systems, by appealing to the physics of disordered systems (e.g. interacting heterogeneous particles, coarsening foams), and then to tune their properties while preserving disorder, using e.g. Monte Carlo methods or dynamic objective functions, which mimic the varying conditions found in nature. They will manufacture lattices of interest using additive manufacturing techniques, then evaluate their properties. They will draw upon a network of collaborators to perform advanced acoustic, mechanical and electromagnetic analysis, and then update the design process based on the physical performance of manufactured materials.

The project will create both a new methodology for creating materials with disorder, and an efficient design protocol including supporting software for creating targeted materials, which will be widely distributed. By combining disparate approaches, it will build both foundational ideas and practical technology that will enable the next generation of materials design.

Pulmonary arterial hypertension (PAH) is a devastating disease caused by obliterative remodeling of the lung arterial bed leading to increased vascular resistance and ultimately heart failure and death. To date, there is no available treatment targeting lung arterial remodeling as a key culprit in PAH. Using sc transcriptomics, we have recently identified a disease-specific, aberrant arterial endothelial cell (aAEC) population that is responsible for the occlusive arterial lesions and is characterized by unique expression of a surface protein, TM4SF1. The cell surface nature of this protein and its unique expression on pathological endothelial cells led us target aAEC using CAR NK cells.

Objective: We will use a Chimeric Antigen Receptor (CAR) targeting TM4SF1 to direct Natural Killer (NK) cells against aAECs.

Research approach: Proof-of-principle studies will be performed using the ‘gold standard’ model of PAH induced by a single SQ dose of the VEGF receptor antagonist, SU5416 (SU) together with a 3-week exposure to chronic hypoxia (CH, 10%). This model well-reproduces the complex and obliterative arterial remodeling and the progressive irreversible hemodynamic abnormalities characteristic of severe PAH. A third generation TM4SF1-CAR will be developed taking advantage of already available scFv antibodies targeting TM4SF1. The TM4SF1-CAR will be encoded in a lentiviral vector that will be used to transduce NK cells isolated from healthy rats. Once potency and specificity of CAR-NK cells are verified in vitro, we will assess in vivo efficacy. Expanded CAR-NK cells will be infused in PAH rats at 8weeks, when disease is severe. Control groups will include rats infused with expanded NK cells not transduced with the CAR vector, rats treated with a prostacyclin agonist, trepostinil, and untreated rats. Right heart catheterization and echocardiography will be performed at 8 (baseline) and 12weeks to assess pulmonary hemodynamics and right ventricular function, and histological analysis and immunofluorescence staining of lung sections will be performed at 12weeks to assess arterial remodeling and presence of aAECs.

Novelty and significance: This will be the first time that a CAR therapy will be used to target cancer-like, growth-dysregulated ECs in PAH and if successful, would provide a first-in-class therapy that could readily be translated to a first-in-human clinical trial with the potential to transform the treatment of this deadly disease.

Artificial Neural Networks (ANNs) have demonstrated impressive success in predictions applied to various areas of human life. In particular, deep learning has provided computer-assisted predictions in many aspects, including the recent techniques of generative AI (ChatGPT, DALL-E, Midjourney, etc). However, these successes come at an energy cost that is likely to be unsustainable in the long term, increasing exponentially by an order of magnitude every year or two. While humanity is trying to remove GHG emissions from areas such as transportation, the carbon footprint of the AI, projected in the future, is likely to negate all the efforts in GHG containment we are doing now.

The solution towards sustainable AI is likely to come from the spiking neural networks (SNNs), which model the operation of the actual neurons more closely. The neurons activate only when the threshold is reached and thus are much more energy efficient. In particular, Intel has already been producing the Loihi chip based on the spiking neuron design. Loihi 2chip operates on single-watt power and has thus the ability to bring substantial improvements to the energy efficiency of AI applications.

In spite of the engineering advances in designing hardware, the way of programming the Loihi 2chips could be clearer. Much effort has been dedicated to trying to transfer the lessons from the traditional ANNs to the spiking networks. However, these methods, based on graduate descent, are very difficult to apply and implement in practice. There is currently no consistent way to program the SNNs that can compare in robustness with our understanding of ANN programming.

We suggest employing ideas borrowed from high-energy physics and string theory and also from chemistry (Self-organization) to program SNNs. Although the idea is high risk, the rewards are potentially extremely high. The PIs are experts in various aspects of applied math and neural network applications (PI: V. Putkaradze), with the co-PIs being experts in string theory (T. Gannon and V. Bouchard). We will also connect with one person from chemistry as the co-PI.

Extreme weather events including floods, heat waves, droughts, and storms can exacerbate important drivers of child marriage including landscape degradation and loss of livelihoods, and these events are projected to become more frequent as the global climate changes. There are very limited empirical data on how these events may directly affect child marriage, which was identified as a top research priority by the United Nations. Defined as marriage before the age of18, child marriage is a human rights violation that cuts short girls’ education, harms their reproductive health, and increases rates of domestic violence. The effects of climate change on child marriage could travel through multiple pathways, may vary substantially across geographical locations, and may be heavily influenced by broader socioeconomic and environmental contexts. The lack of empirical evidence limits the ability of researchers, non-governmental organizations, and governments to target interventions to the most vulnerable populations.

Our interdisciplinary team of early-career and established climate scientists, social and environmental epidemiologists, and human and physical geographers will collate over 500 spatially-resolved satellite, environmental, land-use, and demographic datasets spanning 122countries and 29years (1990-2019) to investigate the effects of extreme weather events on incidence of child marriage and to understand how physical environment factors can mitigate or amplify the impacts of extreme weather events on child marriage.

Our proposed study will leverage a diversity of data sources and methods, study a range of geographical regions, and investigate the mechanisms through which extreme weather may impact child marriage. It is high-risk, given its technical, socio-cultural, and data-related challenges. However, the potential rewards are equally high, including a deeper understanding of these critical issues, policy changes, and the opportunity to positively impact the lives ofmillions of vulnerable children globally.

The goal of this research is to determine how nanoplastic pollutants found in our environment, such as in water, food and soil, affect human cells and hence human health.

Even though nanoplastics are found pretty much everywhere in the environment, it is hard to extract enough of them for use in a laboratory. Our first goal will be to create realistic nanoplastics. We will investigate how nanoplastic characteristics such as their shape, their size, what material they are made of, what other molecules are attached to their surface, and how they have “aged” in the environment, affect human cell membranes. And vice versa, how individual components of cell membranes interact with nanoplastics. Instead of using human cells, we will build customisable artificial cell membranes. These are biomimetic models of biological cells that allow us to discover new aspects of cell biology without the complexities and confounding factors associated with using human cells. To build these artificial cells we will use lab-on-a-chip technologies, so that we can build them to be human-sized, on a chip the size of a postage stamp.

The cell membrane surrounds the cell, choreographing access to the cell interior, and hence allowing or denying the access of drugs to the cell. We will build artificial cells to mimic different aspects of drug behaviour in humans. For example, we will mimic how an orally administered drug moves from the intestine into the intestinal cells and then into the bloodstream, and to mimic how cell membranes degrade during diseases such as cancer. We will then be able to determine the effect that nanoplastics have on the efficacy of a range of drugs to treat cancer.

There is currently heightened global interest in the impact of plastics on the environment, and how they degrade to create nanoplastics that can harm human health. Although it is well-known that particles from plastic waste are found in all organs of the human body, including the placenta and the bloodstream, little is known about how they affect human cell membranes. Learning how plastics disrupt this protective barrier will allow us to understand how nanoplastics are toxic to human life, what effect they might have on human health, and how to design consumer products that do not cause long-term nanoplastic pollution.

Trafficking of proteins through the endoplasmic reticulum (ER) is fundamental to cellular function, with ~1/3 of eukaryotic proteins passing through the ER before secretion. Disruption of the ER folding pathway is implicated in a wide range of diseases including Alzheimer’s and Parkinson’s diseases, Type 2 diabetes and cancer.

Despite the importance of ER protein trafficking to cellular function, many aspects remain poorly understood. Recent single-particle tracking experiments indicate active flow through ER tubules. However, it is unclear if this is a universal feature of ER transport, or situation and location dependent. Additionally, the mechanism through which this flow is generated, the dynamics of proteins at junctions between ER tubules, which is important for protein sorting, and the response of protein transport properties to external cues are unknown.

The objective of this research project is to determine how hydrodynamic interactions and chaperone clustering effect protein transport through the ER.

Hydrodynamic interactions (HI) strongly influence particle motion at the nanoscale, yet the role they play in ER protein trafficking has not been explored. HI significantly impact association and self-assembly processes by correlating motion of particles over long distances. Their impact can be magnified near surfaces, making them particularly important in confined geometries like ER tubules and sheets. HI are directly coupled to chaperone (BiP) clustering in response to perturbations such as Ca+2 depletion. The formation of higher-order aggregates alters the microrheolegy in the ER affecting the transport of proteins through the ER lumen.

HI in the ER have thus far remained understudied due to the difficulty of measuring correlated particle motion within the ER, and the limitations of accurately modeling long-range hydrodynamic interactions on the ER network. In this research project, we seek to overcome these challenges by combining genetically encoded multimeric nanoparticles (GEMs), which can measure transport properties at targeted cellular locations, with a reduced-order surrogate model trained on reactive Stokesian dynamics simulations to correlate transport properties to underlying macromolecular heterogeneity. The work will provide a novel tool to probe dynamic cellular heterogeneity and answer fundamental questions about protein trafficking in the ER.

Chronic pain is a major global health problem with an economic burden greater than diabetes, heart disease and cancer combined. Despite the enormity of the problem, effective treatment remains elusive. A critical issue is that treatments target generic symptoms, not mechanisms, sometimes with harmful consequences (e.g. opioids, surgery). Identification of the molecular mechanisms driving the development of chronic pain is a new frontier that could provide new targets for personalized treatment.

Immune dysregulation is a plausible molecular mechanism underpinning the development of chronic pain, yet this field is in its infancy and evidence is scarce. We will utilize a novel multiomic strategy, developed by members of our team, and capitalize on data from the UPWaRD prospective longitudinal cohort study of the transition from acute to chronic pain, to identify a common signature of immune dysregulation in those who develop chronic pain. Our objectives are to:

1. identify differences in the proteomic profiles of individuals who do, and do not, recover from acute pain to determine common hallmark genes and pathways of immune disruption driving chronic pain,
2. conduct targeted assessment of key tryptophan/kynurenine pathway proteins and metabolites to determine if a common immune signature underpins chronic pain and
3. examine the role of sex differences in immune control during development of chronic pain.

Global proteomic strategies will be applied. Using our innovative approach, semi-and relative quantitative targeted mass spectrometry methods will be applied to substantiate the proteomic and metabolomic changes in human serum from i) individuals with acute pain who do, and do not, develop chronic pain at 3- and 6-months follow-up and ii) pain-free age- and sex-matched controls.

Novelty: No study has undertaken multiomic profiling of individuals in the transition from acute to chronic pain and studies exploring biological mechanisms of chronic pain neglect the presence of sexual dimorphism. This study will be the first to apply a novel multiomic strategy to identify the immune signature of chronic pain.

Significance: Chronic pain is poorly understood and poorly treated. Through a collaborative interdisciplinary effort by a diverse team, we will uncover molecular mechanisms underpinning the transition from acute to chronic pain providing a step toward personalized biomarkers and new therapeutic targets.

Musculoskeletal disorders (MSDs) are one of the most common work-related injuries, often causing people to leave jobs they love. MSDs affect a wide range of occupations, including physically demanding roles like fieldwork, athletics, and playing musical instruments, as well as sedentary ones like office work and driving. Fixing improper task biomechanics is essential in MSD prevention programs, typically involving supervised training sessions led by licensed physical therapists. Nevertheless, this manual training approach has limitations in effectiveness and scalability. First, determining the best movement patterns can vary based on an individual's anatomical attributes, posing challenges even for experienced therapists. Secondly, everyone has a unique optimal learning style to learn and master ideal movements, based on their cognitive and physical characteristics, which is challenging to discern through manual observations. Thirdly, giving correction guidance in current sessions, where therapists use their bodies as a reference, can be less clear, as their bodily characteristics may differ from those of the trainees. Last but not least, relying on trained therapists can be costly, as multiple sessions are required over an extended period to settle down ideal task movement.

To tackle these challenges, this interdisciplinary study leverages various knowledge and technology domains, including wearable sensing, neurocognition, biomechanics, reinforcement learning (RL), neurocognitive science, and augmented reality (AR). The goal is to develop an automated adaptive task biomechanics correction training that guides trainees toward personalized optimal task movements with intuitive correction guidance, considering their optimal learning styles. The system incorporates two meta-RL agents that quickly understand each trainee's optimal movements and learning preferences by collecting real-time information and feedback during training using computer vision and wearable brain sensing techniques. Corrective instructions are conveyed through an AR device (e.g., mirror), along with vocal guidance. To assess system effectiveness, a training program based on this approach will be compared to an existing therapist-driven program, involving at least 50 construction laborers performing tasks with heavy material handling. This system can revolutionize musculoskeletal health across various applications, offering effective and scalable solutions to address and prevent MSDs.

Current therapies for cystic fibrosis (CF) are notably constrained in their effectiveness, particularly for patients afflicted with nonsense mutations that introduce premature termination codons in the CFTR gene, leading to truncated and non-functional CFTR proteins. These mutations disrupt the genetic code, resulting in truncated, dysfunctional proteins. Our research project is poised to pioneer a novel approach that leverages anti-codon-engineered transfer RNAs (ACE-tRNAs) encapsulated within lipid nanoparticles (LNPs) for treating CF caused by such nonsense mutations. While natural tRNAs with modified anticodons have been explored for their suppressive potential against these mutations, their clinical performance has proven suboptimal in both efficacy and safety profiles.

On the other hand, the viability of LNP-mediated RNA delivery as a therapeutic modality has been recently validated by the FDA's approval of Onpattro, an LNP-encapsulated siRNA drug designed for liver-related genetic disorders. However, the application of RNA-based therapeutics to pulmonary diseases remains a largely untapped frontier, primarily due to challenges associated with mucus barriers and mucociliary clearance in the lungs.

Capitalizing on our lab's recent advancements in surmounting these pulmonary delivery obstacles—evidenced by successful LNP-facilitated mRNA delivery and CRISPR/Cas9 gene editing in lung tissues, we hypothesize that ACE-tRNAs can be effectively optimized for pulmonary delivery via inhalable LNPs. This would provide a precision-targeted therapeutic option for CF patients afflicted with nonsense mutations. To achieve this, we will employ a combinatorial approach to engineer both ACE-tRNAs and LNPs, targeting prevalent nonsense mutations in CFTR genes. Subsequently, we will evaluate the therapeutic efficacy and safety of tRNA LNPs using in vitro models that closely mimic the lung tissue of CF patients harbouring these mutations. This research is pioneering in its focus on a hitherto untreatable subset of CF patients, offering them a renewed prospect for an enhanced quality of life. It is the first initiative to synergize ACE-tRNAs with LNPs for pulmonary delivery, a strategy with the potential to revolutionize not only CF treatment but also gene therapies for other hereditary diseases. If successful, this research could serve as a landmark in genetic medicine, opening new therapeutic avenues and potentially extending the lifespan of affected individuals.

This project aims to explore the scale to which sand mining leads to the existence of malaria mosquito breeding sites and provide detection methods and mitigation plans. Sand and gravel make up the most extracted group of materials worldwide, even exceeding fossil fuels. They are key ingredients for modern civilization as it goes into concrete, asphalt, and glass. Africa faces the highest projected demand for sand within the next 100 years due to population growth and urbanisation. Simultaneously, mosquito-borne diseases (MBD) such as malaria, dengue, and zika are the largest contributor to vector-borne diseases, with 93% of the world’s malaria cases occurring in Africa. A critical preventive measure for diminishing the spread of vector-borne diseases is adequate housing built from e.g., concrete and cement, but today half of the urban Africans still live in unimproved houses. Meanwhile, by 2050 the African population will rise from 1billion to 2.4billion. Given the growing population in Africa, the acute need for sand and gravel is higher than ever, if MBD preventions are to be implemented through housing development.

Current mining practices of sand and gravel extraction introduces a hitherto overlooked problem, which this project aims to uncover and provide solutions for: Artisanal extraction of sand and gravel in rivers leaves behind a scarred landscape with extensive amounts of small ponds of standing water. This introduces the acute paradox this project aims to explore and thereby contest current disease prevention paradigms: while attempting to mitigate malaria prevalence through the mining of sand and gravel to improve housing conditions, the mining practices unwillingly creates new breeding ground for malaria mosquitos, thus increasing the risk of malaria spreading.

This project focuses on Rwanda, the country in Africa with the second largest population density. We will use an environmental DNA (eDNA) detection system, to target the three mosquitos known to carry malaria in sand mining environments in Rwanda to develop better mining strategies and detection methods to prevent the spread of malaria in and around mining sites. The high risk-high gain focus on providing the first documentation to link the hitherto overlooked connection between the mining of sand for housing and the prevalence of malaria mosquitoes, to ultimately contribute to combat one of the most pervasive and deadliest diseases on the continent.

There are structural barriers within academic institutions that limit the research and training potential of Indigenous faculty, staff, and students engaging in science and technology fields. Indigenous researchers face institutional limitations, including a lack of interdisciplinary structures that enable robust collaboration, science and technology capacity within Indigenous studies units, and financial support required to sustain and grow existing Indigenous science, technology, and society programming.

The proposed interdisciplinary project “Supporting Indigenous Governance through Indigenous Science, Technology, and Society (ISTS)” explores a unique Indigenous-led research and training agenda. Our goal is to sustain and expand the subfield of ISTS by facilitating an innovative and leading-edge teaching and research collaboration across faculties and disciplines. The project will support the expansion of an ISTS research and training network and creation of physical lab space where Indigenous and partnered science, social science, and humanities researchers can study, collaborate, and create. We will:

1. build an ISTS Research and Training Facility;
2. establish Student and Community Fellowships in ISTS research;
3. bolster an ISTS research network through the establishment of an ISTS Colloquium Series; and
4. secure formal partnerships with aligned programs to enhance training and expand the program globally.

We foreground the critical and decolonizing theoretical framework of ISTS that is currently being developed by Indigenous scholars to answer calls for Indigenous governance of research about and affecting Indigenous peoples. The methodology considers the risks and promises posed by science and technology fields for Indigenous peoples; and disrupts barriers between the academy and the rest of society in support of environmental and health-related wellbeing. ISTS trains Indigenous and other learners to consider how scientific knowledge production, the institutionalization of science and technology fields, ethical policies, and national science policy programs have been co-produced with (settler) colonial nation-states. ISTS reframes Indigenous peoples not as subjects of scientific research, but, crucially, as producers of them. If further developed, shared and adopted, ISTS could significantly reshape the research landscape of academia both in Canada and globally.

OBJECTIVE: Aortic aneurysm is a major health risk with no pharmacological treatment. It is a focal dilation of the aorta, with thinning of the aortic wall due to cell loss and degradation of the extracellular matrix (ECM). It is asymptomatic and can remain undetected, but if untreated, can rupture causing blood loss, paralysis, or death. Currently, with no pharmacological treatment, surgical repair is the only option but only in very severe cases given its risk factors. Hence, there is a dire need for novel approaches to treat aortic aneurysm. We aim to engineer hydrogel biomaterials, enriched with vascular cells and/or drugs, which will be implanted on the aneurysmal aorta as a localized and targeted delivery vehicle, to inhibit further degeneration and to promote regeneration of the aortic wall.

RESEARCH APPROACH: Collagens are abundant ECM protein and interact with cell surface receptors (integrins) and other ECM proteins (laminin, fibronectin) that promote cell proliferation, differentiation, and migration. Collagen-based drug delivery biomaterials are attractive tools in clinical applications because of their biocompatibility and biodegradability.

• Collagen-based hydrogel does not trigger an inflammatory response in animals.
• We routinely isolate and culture primary vascular smooth muscle cell (SMC), and fibroblasts (FB). We have established 3 different models of aortic aneurysm in mice, and have identified proteins that protect against (TIMP3) or worsen aneurysm (ADAM17).
• Our team has the expertise to modify the composition of the hydrogel biomaterial to achieve optimal compliance, curvature and density to serve as a delivery platform (for cells and drugs).
• Aortic aneurysm will be induced in mice and confirmed by Echo-ultrasound. Mice with comparable aneurysm size will be randomly divided into groups to have hydrogel biomaterial implanted on the adventitia of aneurysmal region, to deliver:
  1. FB or SMCs.
  2. FB or SMCs overexpressing TIMP3 (GFP-tagged).
  3. ADAM17-inhibitor (Pfizer), or recombinant TIMP3, slow-release formula.
  4. Control groups: no hydrogel, non-enriched hydrogel.
• Aneurysm growth will be monitored by echo-ultrasound. Aortic wall will be analyzed for structure, cellular, and molecular remodeling.

NOVELTY & SIGNIFICANCE: There is NO PHARMACOLOGICAL TREATMENT for aortic aneurysm. Findings from this project will lead to discovery of a minimally invasive approach in treating patients with aortic aneurysm.

Here a bioengineer (Prof. Mahshid), a biophysicist (Prof. Reisner) and a psychiatric researcher (Prof. Turecki) will join forces to develop a nanotechnology tool that exploits analysis of single extracellular vesicles to yield a simultaneously single-cell resolved and patient specific view of depressive order. Our end goal is to harness this information for improved evaluation and ultimately prediction of how a given patient will respond to antidepressive treatment. This addresses an extremely challenging problem in psychiatry: patient response to antidepressant drugs is highly variable and poorly understood, necessitating stressful and time-consuming treatment with different compounds to find an optimum drug choice and dose. This highly interdisciplinary project combines expertise drawn from engineering (bioengineering), natural science (physics) and biomedicine (psychiatry) to use nanotechnology tools to tackle a critical health problem that is also a non-traditional application area for diagnostic technologies.

This project is high risk as it brings new disciplines together with different perspectives to solve a major current health challenge: specifically, combining multiple novel nanotechnology and biological approaches with the end goal of gaining single cell insight into the complex biology of depressive disorder. This project is high reward as our tool may lead to enhanced treatment of depression, a common but extremely debilitating and dangerous condition that leads to heightened suicide risk. In detail, our approach exploits extracellular vesicles (EV), nanoscale lipid bilayer particles secreted by all cells, including cells in the central nervous system. EVs package biomolecules (like RNA) from the secreting cell and are a key means of cell-to-cell communication. EVs can cross the blood-brain barrier enabling sampling via routine blood collection, yielding access to otherwise inaccessible brain biology. Remarkably, as each EV originates from a given cell, EVs potentially yield single-celled resolved information on complex interacting cell populations in the brain, dysregulation of which underlies neurological conditions like depression. Our tool will exploit nanofluidic confinement to specifically isolate single brain derived EVs in nanoscale compartments, chemically process them and then obtain an electrical readout of encapsulated molecules from a single EV, providing a molecular and single cell resolved view of depression.

Effective integration of synthetic biology with gene- and cell-therapy has the potential to unlock curative interventions for many of the most serious human diseases. Cells, tissues, and even entire organs can be envisaged with augmented functionality. For example, in partnership with regenerative medicine groups, we are engineering synthetic gene circuits in stem cells that will make them ischemia-resistant when differentiated into many cell types. It is possible to envisage cells, tissues and even entire organs that are engineered in vivo using viral vector delivery (imagine ‘infarct-proof’ hearts and ‘stroke-proof’ brains!). However, despite the explosion of tools in synthetic biology, meaningful deployment in therapeutic applications is almost non-existent. Several major barriers hamper advancement, and chief among these is immunogenicity of synthetic components.

Gene and cell-based therapies that contain synthetic proteins display non-self-peptides and get recognised and destroyed by cytotoxic cd8+ T-cells. Viral vector-based gene therapies can also be similarly impeded by these and neutralising antibodies. Autoimmune diseases, such as type I diabetes, can occur when endogenous proteins are mistakenly recognised as non-self. Even stem cell derived replacement beta cells are destroyed by autoantigenic T cells. Protein replacement via gene therapy for monogenic diseases can be hampered by cytotoxic T cells interpreting corrected proteins as non-self. Currently, there is no solution to the immunogenicity problem for gene therapy applications and the current solution for cell-based therapies has serious safety concerns.

Here we present a safe strategy for ‘immunocloaking’ of synthetic and autoantigen proteins in both gene and cell therapy contexts. The strategy has three main aims: One. development of ‘CloakVAE’, a highly novel generative deep learning model for immunogenic protein epitope removal. Two. development of an innovative in vitro testing platform that allows statistically robust evaluation of immunogenicity across a representative sample of the entire human population. Three. deployment of the model and testing platform toward immuno-cloaking proteins of high value in gene and cell therapy development: AAV capsid proteins, CRISPR/Cas proteins, and synthetic myoglobins. Development of these pipelines and proteins would unlock the vast therapeutic capabilities of synthetic biology in gene and cell therapy development.

Improving indoor air quality (IAQ) can greatly ameliorate respiratory and cardiovascular health. Housing is a universal right, but different populations have different opportunities and challenges with respect to IAQ. We propose to examine potential improvements of IAQ in two case study locations (one remote Indigenous, one urban non-Indigenous) through the use of laboratory studies, home monitoring tools, and information campaigns delivered in co-designed modalities. In both communities we will identify concerns and attitudes toward IAQ, monitor IAQ in residences selected by community-led teams, and provide real-time visualization for participants. We will work with community residents and property managers to develop tools for address and redress of identified IAQ concerns with homebuilders and local through to federal government bodies.

A subset of this project will be to investigate chemical interactions between environmental tobacco smoke (ETS) and mold. Smoking rates in the participating Indigenous community exceed 70% and over 50% of homes are contaminated by mold. Guided by and with sampling from community members and a team member who is a former band councilor, we will test the hypothesis that ETS-mold interactions lead to exposure risks greater than the sum of their parts using lab-based measurements to evaluate the chemistry and resulting toxicity of ETS-mold interactions. We will co-create information campaigns with community members in multiple modalities.

High risk: The project centres novel interdisciplinary approaches. The team includes experts in IAQ, exposure risk assessment, toxicology, and science and policy communication. Each stage of the study will be designed with input from researchers spanning the breadth of community and university-based expertise. This novel transdisciplinary approach will break down barriers between conventionally siloed research fields and will serve as a model for future research teams and projects.

High reward: This project has the potential for broad impact and reach. The tools created may inform actions by individuals, home builders, and various levels of government to improve IAQ and Canadians’ health. Both participating communities will benefit directly from this work, and results can be applied to other remote Indigenous and urban communities. Results from these two distinct communities may lead to a better understanding of – and action toward meeting – the housing and IAQ needs of all Canadians.

The COVID-19 pandemic led many seniors (>65 years) to rethink their long-term housing preferences, given the disproportionate impact on those living in long-term care homes. The increase in frequency of extreme climate events and the higher risk of heat-related death, also led many seniors to reconsider how and where they may live comfortably and safely for as long as possible (i.e., age-in-place). Since the proportion of ageing population in Canada is expected to significantly increase, developing viable solutions to facilitate aging-in-place and ensure physical, mental and emotional well-being of older adults is paramount. The rapid proliferation of connected devices inside Canadian homes led to new applications that can be beneficial. However, the feasibility of using existing “smart home” devices and scaling up the deployment of these applications is still a challenge.

The goal of the proposed project is to research aging-in-place with everyday technologies associated with "smart homes". How can these smart technologies be leveraged to enhance the comfort, health, safety and well-being of senior occupants without the need for additional infrastructure?

This project will investigate the potential of smart thermostats with motion detectors and simple wearables to document, understand, and communicate activities of daily living (ADL) of senior occupants. We will also investigate the differences in the thermal comfort preferences of older occupants relative to other age groups. Identifying these differences will provide insight into how older adults experience thermal comfort, and how this comfort relates to well-being and safety, especially during extreme climate events. This research will test the proposed methods within a representative sample of homes with older occupants, from diverse backgrounds, locations, and sexes, while respecting their autonomy and agency. Our approach is unique because it focuses on the point of view of the older adult occupant. This means taking seriously how they wish to age-comfortably-in-place. The project team includes building engineers with expertise in smart home technologies, health researchers focusing on the psychological and cognitive processes in adulthood and healthy aging, and social scientists researching the social and cultural experiences of aging with technologies. We are committed to exploring these matters from integrated an anti-ageist perspective that places older occupants at the centre.

The goal of this project is to change the direction of thought in academic research through developing and amplifying intersectional strategies and practices across different social movements for just and sustainable futures. More specifically, the project focuses on practices of consciousness change with community organizers across the Americas to:

1. support the development of new intersectional strategies;
2. synthesize in a novel way interdisciplinary debates between Indigenous, systems thinking, and critical scholarship about the role of consciousness in social change; and
3. radically challenge the accepted paradigm of top-down technocratic approaches to just transitions that fail to centre the voices of front-line communities.

The research approach follows three steps. First, assemble a core interdisciplinary research team made up of scholars and activists that are not commonly combined to review literature on the role consciousness plays in advancing just transitions, based on contributions from different fields in the humanities, sciences, social sciences, and engineering. Second, select 4-6 community organizers from different geographical locations across the Americas to co-create knowledge by traveling to, and spending several weeks participating in, a social movement different from their own, to learn about the practices and strategies used there. Community organizers will be interviewed before and after their stay to better understand which practices might contribute new perspectives on their own movement-building work. Third, the results from Step1 (interdisciplinary synthesis of literature debates) and Step2 (interviews and notes from community organizer experiences) will be analyzed and compared to propose a new framework for advancing just transitions through intersectional consciousness change practices that can be amplified and scaled up across vastly different social movements and literatures.

While the project is high risk, bringing together disparate academic and non-academic forms of knowledge, it has tremendous potential for high impact by:

1. deepening interdisciplinary conversations between Indigenous, systems, and critical scholars as they pertain to theories and practices of consciousness change in the context of just transitions;
2. impacting unique communities, with lessons for others, by expanding the repertoire of intersectional consciousness change practices that can be used for social change.

Rationale: The climate crisis and our polluted environment is the existential threat to human health right now. Pregnancy is a period vulnerable to lifestyle and environmental exposures. Physical activity and air pollution each impact the health of the mother and fetus - physical activity for the better, air pollution for the worse. Their combined effects have not been examined during pregnancy. Elevated breathing rates associated with physical activity increase the volume of pollutants entering the respiratory tract. Therefore, physical activity could catalyze the negative effects of air pollution.

Inhaled dose of pollutants (IDoAP), the product of inspired air (i.e., minute ventilation (V̇E)) and air pollutant concentrations, quantifies the volume of pollutants effectively entering the respiratory tree. IDoAP is currently not available or validated as an objective assessment of air pollution exposure in pregnant people but is essential to understand the combined health impacts of physical activity in a polluted environment.

Objective & aims: To introduce IDoAP as a novel air pollution exposure assessment method of air pollution exposure that accounts for physical (in)activity to environmental health research in pregnant people.

RESPIRE aims to:

1. generate and validate algorithms to estimate V̇E for the calculation of IDoAP in pregnant individuals with data collected in the real world as opposed to the laboratory;
2. evaluate the effect of assessment methods and temporal aggregations of air pollution on IDoAP in pregnancy; and to
3. determine the effects of IDoAP of air pollutants on respiratory, cardiovascular, and mental health in pregnant people.

Methods: In Canada, Switzerland and Spain we will collect air pollution exposure and physical activity levels of pregnant individuals throughout pregnancy. To test the impact of measurement methods on IDoAP, we will use wearable and stationary monitoring, GPS tracking, and questionnaire data to determine individualized air pollution exposures and physical activity levels (aims1 & 2). Self-perceived and objectively assessed respiratory, cardiovascular, and mental health markers will be collected in every measurement period to determine the acute and short-term effects of IDoAP on health (aim 3).

Novelty: Expanded research tools and understanding of the combined effects of air pollution and physical activity in pregnant individuals.

In 2022, the Canadian Cancer Society projected the number of Canadians newly diagnosed with cancer will exceed 230,000 per year. It is crucial to continue advancement in early detection and treatment of cancer to reduce the health burden on Canadians and relieve strain on our healthcare system. Theranostic radiopharmaceuticals are being hailed as the key to early detection and treatment.

Theranostic radiopharmaceuticals are constructed by joining a disease-targeting biomolecule to a theranostic pair of radionuclides. Theranostic pairs are chemically similar isotopes in which one isotope emits positrons or gamma photons for diagnostic imaging and the other emits alpha- or beta-particles, or Auger electrons for targeted radiotherapy. Canadian researchers are making tremendous advancements in developing new theranostic pairs such as [212Pb]/[203Pb] and [225Ac]/ [111In], however, the success of these constructs is limited by disease-targeting biomolecule efficiently delivering the isotopes to the diseased tissue. Nanomedicines, built from nanomaterials, have demonstrated their utility as drug delivery constructs due to the small size and large functional surface area positively influencing cell permeability, disease-targeting precision, and toxicity profiles.

Cyclic peptide nanotubes (cPNTs) are bioorganic nanomaterials that outperform carbon nanotube counterparts with respect to aqueous solubility, surface functionalization, natural biodegradability, and low toxicity. Additionally, they have therapeutic tendencies by inherently inserting into viral membranes horizontally to trigger cell death. cPNTs are composed of flat cyclic peptide monomers stacked like a tower of blocks stabilized by intermolecular hydrogen bond formation. Our objective is to explore the theranostic potential of disease targeted cPNTs by merging peptide and chelator characteristics into a novel [Pb] chelator that functions as a universal cPNT endcap to transform any cPNT into a theranostic radiopharmaceutical.

To achieve this, a team composed chemists, oncologists, and radiologists will collaborate to:

1. identify disease targets with the highest clinical relevance to benefit Canadians;
2. design prototype "arrowhead" chelators and test universal compatibility;
3. assess targeted breast cancer therapy outcomes of this new technology in vitro and in vivo assays. This technology has the potential to amplify nanotheranostics and improve targeted radiotherapy in clinical settings.

Objective: Despite the improvements in therapeutic options for patients with breast cancer, high-risk patients or patients who have completed their initial treatment often live with a constant fear of developing breast cancer or if their cancer will recur. Current screening tools of mammography and imaging of metastatic disease are inadequate and need to be improved. We hypothesize that the diagnostic utility of liquid biopsies (blood tests) can be leveraged by evaluating three components:

1. quantification of cytokine/immune markers (peripheral immunomics),
2. Raman spectroscopy (RS) - a molecular imaging technique that measures the vibrational properties of a tissue to accurately detect a wide range of biological matter, including the presence of cancer; and
3. circulating tumor DNA (ctDNA) to improve the detection of recurrent breast cancer.

Methodology: Our team has previously used RS to detect cancer and COVID-19 infection using biofluids. Therefore, we are proposing to collect plasma samples in two contexts:

1. at the time of initial diagnosis, and
2. to detect recurrence amongst patients who have completed their initial treatment plan.

At diagnosis, we will combine peripheral immunomics by performing multiplex flow cytometry and chemokine profiling and use optical spectroscopy to develop a platform for diagnostic test development using label-free and/or ligand-based interrogation, to rapidly provide a reading at the time of sample acquisition. To detect recurrence, we will also perform whole exome and targeted next-generation sequencing to detect ctDNA. Ensemble learning mechanisms and tabular neural networks will integrate ctDNA, peripheral cytokine and immune cell components, RS features, and clinical parameters, to identify a robust tool with the highest lead-time to detection of breast cancer recurrence, and predictor of disease-free survival.

Impact: Many patients suffer from much anxiety either at the time of diagnosis or post-treatment due to fear of early breast cancer recurrence. Patients need better tools to improve cancer detection. RS can be used as a rapid first-line test in the doctor’s office. Using artificial intelligence to combine ctDNA, immune profiling, and RS, to integrate the tumor, host response, and spectral features of each patient’s tumor, is a novel and comprehensive approach that has great potential to be the first blood test for breast cancer detection in the clinic.

Rapid climate change is a major global threat that requires urgent attention. Large scale reduction in CO2 emissions, and atmospheric levels through carbon capture and storage (CCS) are critical. Buildings represent our largest energy sink (heating, cooling, lighting) and consume about 32% (32.4 PWh) of total energy globally (about 25% of total CO2 emissions).

Increasing building energy efficiency and adding means for CCS are important goals. This proposal aims to develop large scale, ‘milli-fluidic’ layers for the culture of mineralizing micro-algae (coccolithophores), designed for building facades and other large urban surfaces. These fluidic layers will modulate solar transmission and also enable photosynthetic carbon capture. Coccolithophores are capable of efficient biomass generation, and long term carbon sequestration through CaCO3 shell formation.

Globally, phytoplankton perform about half of total photosynthesis. Oceans are a major CO2 sink through the biological carbon pump, having both organic and inorganic (CaCO3) mechanisms. There is great interest in mineralizing phytoplankton for global CCS, such as adding nutrients to ocean regions to promote growth, but also with a risk of ecosystem disruption.

Incorporating micro-algae culture onto buildings can enable CCS in urban environments, but previous attempts have been complex and expensive. Recently the Hatton group has developed fluidic layers for building facades, to enable dynamic control of solar transmission. This proposal aims to enable E. Huxleyi culture in these layers, for direct air carbon capture (DAC) (with gas-permeable polymer sheets) and dynamic shading. The fluidic layers will be relatively thin (1-3 cm) but potentially cover large areas (10^2 m2) of a building.

Specific aims:

1. Optimize the fluidic layer design, through materials (gas permeability, non-fouling, UV-resistance), fluidic distribution and fabrication.
2. Micro-algae growth optimization as a function of flow, media, light exposure, and temperature variations.
3. Characterize biomineralized shell formation (rates, morphology) and overall carbon capture.
4. Measure dynamic shading, and estimate building performance through simulation.

Our team is diverse and interdisciplinary:

• B. Hatton (fluidic devices, microbiology);
• P. Lee (polymer science);
• D.G. Allen (micro-algae culture);
• P. McGinn (marine micro-algae);
• E. Sone (biomineralization); and
• A. Jakubiec (architecture, energy simulation).

The health and well-being of Indigenous populations around the globe are closely tied to autonomy, land rights, and access to resources. In Peninsular Malaysia, some communities of the Indigenous peoples (Orang Asli) are leaving the government settlements where they have lived for decades, and re-establishing a traditional way of life in the remote hinterlands of the Peninsula. These ‘breakaway’ dynamics represent a rare opportunity to pursue research on the strategies Indigenous peoples employ to seek autonomy and freedom and gain access to the traditional resources that lie at the foundation of their material and spiritual lives. These dynamics may also make the Orang Asli healthier by enabling them to pursue more traditional foodways, engage in increased physical activity, and experience lower stress. To examine and test these ideas, the proposed research leverages long-standing partnerships with ‘breakaway’ communities.

The research adopts a mixed-methods approach, using methodologies from anthropology, political science, and the health sciences, while also centering Indigenous ways of knowing. Detailed histories of breakaway events and data on demography, social networks, and cooperation will be recorded through focus groups and interviews. Health clinics will be conducted with consenting communities, during which data on biomarkers of cardiometabolic health and stress will be collected. Combined, this rich body of information will contribute to a better understanding of the dynamics of Indigenous self-empowerment and its impact on their health. Given the uniqueness of the ‘breakaway’ situation among the Malaysian Orang Asli, this represents an extraordinary and rare opportunity for discovery. Taken together, the project seeks to describe an Indigenous ‘anarchist history’ that is happening in the present moment.

Compared to centralized piped water systems that are compromised due to aging, urban growth, and climate change, small-scale, decentralized, water systems are adaptable, energy efficient, and affordable. Rainwater harvesting (RWH) is one such decentralized technology with growing global reach. In 2019, the government of Mexico City partnered with a social enterprise, Isla Urbana, to install 10,000 RWH systems annually in low-income neighbourhoods. Recently, Isla Urbana began a program to translate their experiences with RWH to First Nations communities in Canada. Despite their technical adaptability to local contexts and affordability, the uptake of RWH systems has been lower than expected. Our fieldwork reveals that users often have concerns about rainwater quality, limiting its use. This research aims to understand the influence of water quality perception on adoption, develop tools to enable users to understand their own water quality, and develop approaches for distributed water treatment. These elements can break down the barriers towards adoption and long-term use of RWH.

Creative dialogues with RWH end-users, systematic literature reviews, and statistical analysis of RWH adoption data will be used to study the relationship between water quality, water costs, and technology adoption. Based on the observations, field studies will be completed to track rainwater usage and water quality. Custom distributed instrumentation will enable monitoring of the interfacing between end-users and the RWH systems. In addition, custom water testing kits will be implemented to enable users to track their own water quality. These tools will then be used together to evaluate the impacts of water quality measures, such as UV treatment, on the adoption of RWH. Finally, the outcomes will be used to make policy recommendations to Isla Urbana and the Mexico City government for future RWH systems.

This research provides HQP with hands-on interdisciplinary training in engineering design, community-based research, and policy evaluations. Besides their research, HQP will lead interdisciplinary research communication and whitepaper discussions with international collaborators and community members, which contributes to developing strong leadership and global fluency of the HQP. The project develops a cross-disciplinary framework for human-centered design of decentralized water technologies and supports training of cross-disciplinary water leaders for sustainable development.