Award Recipients: 2020 Exploration

Background: Epilepsy is a severe neurological condition characterized by frequent seizures.  80% of seizure occurrences follow the circadian rhythms (endogenous biological cycles of 24h) and vary between individuals with seizure rates fluctuating over time. Patients with frontal lobe epilepsy have more seizures during sleep than those with temporal lobe epilepsy, whereas generalized seizures occur mostly out of sleep. Such rhythms afford a novel therapeutic window (chronotherapy) where the drug dose can be adjusted to match with the times of highest seizure occurrence and susceptibility. Instead of the equally-divided doses during a 24h interval, differential dosing (e.g., lower doses during the day and higher doses during the night) could maximize efficacy. Targeted differential dosing directly into the cerebrospinal fluid using an implantable infusion system and intracranial implantation of drug-loaded capsules suffer from the need for multiple surgeries. Delayed or extended-release oral anti-epileptic drug (AED) formulations are available; however, at best, they only release a constant amount over time. Patient compliance is also a challenge for multiple and equally divided doses over a 24 h period.

Objective: We challenge conventional wisdom and enter into a new realm of AED delivery by designing core-shell oral tablets/capsules such that a single capsule taken once every 24h can deliver variable amounts of the drug matching the seizure peak in a patient-specific manner. In this game-changing approach, the capsule releases sub-therapeutic amounts of the drug during the day but releases an increased amount in the night where seizure occurrence and frequency is maximum. The tablet can be designed to release the increased dose of the drug linearly, exponentially, or in a pulsatile (defined amplitude and frequency) manner.

Research approach: We will use advanced microfabrication methods to print variable shapes of the drug-loaded core in an FDA-approved erodible polymer to precisely match the prescribed differential dose. The drug core will be enclosed in a shell of the same polymer. Following oral administration, the shell uniformly erodes (akin to ice cube melting) exposing the variable-shape drug core.

Significance: Once the patient's seizure peak time and the required dose are determined, the AED capsule can be designed, printed, and dispensed in a span of 3h, allowing us to enter the realm of personalized medicine unique to each patient.  

Atherosclerosis, stroke and peripheral artery disease are the leading causes of morbidity and mortality, responsible for >45,000 deaths in Canada each year. Drug-eluting stents are the standard treatment, however current drugs are extremely cytotoxic, leading to endothelial dysfunction and necessitating prolonged anti-platelet therapy. A common pathogenic mechanism in restenosis involves the directional migration of smooth muscle cells (SMCs) into the intimal layer. We are pursuing a high risk project to specifically target SMC migration, while sparing endothelial repair. The approach will preserve arterial function, preventing inflammation and thrombosis, outcomes which are highly desirable in the post-COVID-19 cardiovascular patient population. This is a paradigm shift in therapeutic approach, and will be undertaken by an interdisciplinary team. The PI's cell biology lab has rationally designed a small peptide with a natural sequence, which engages N-cadherin to stabilize SMC adhesion and stop migration. The peptide is not cytotoxic and does not impair endothelial cell migration. We will work with a co-PI who has extensive biomedical engineering expertise in drug delivery and cardiovascular polymeric biomaterials, having resorbable, anti-inflammatory, and wound healing characteristics. To translate our discoveries to the clinic, an interventional cardiologist who is an end-user for this technology will be a co-applicant, and we have established collaborations within the biomedical materials industry (an international company based in Germany, and a Toronto based biomedical technology company with 20 years of experience in applying biomaterials to drug eluting balloons and stents). Our research approach is to develop peptide coated nanoparticles embedded in a fast releasing-polymeric biomaterial coating, apply onto angioplasty balloons, and demonstrate the delivery and effectiveness of N-cadherin peptides at the site of atherosclerosis using in vivo animal models. The overarching hypotheses driving this work are:

1) Administration of synthetic N-cadherin binding peptides at defined doses will arrest directional smooth muscle cell migration and spare endothelial cell repair. 2) Custom-designed nanoparticles which allow N-cadherin binding peptide release for weeks, enabling targeted drug delivery via coated angioplasty balloons at sites of arterial injury and restenosis.

Pain poses the largest health-related burden in society. Although the biological and psychological aspects of pain have received substantial attention, little is known about the psychosocial and sociocultural attributes that affect pain. Specifically, understanding the changing relationship between the individual and the body shapes the pain experience has yet to be explored.

For example, transgender people often report incongruence between their sex assigned at birth and their gender-i.e., gender dysphoria. The body image, in this scenario, is a complex construct of the perceived appearance of the self. Transgender people often report dissatisfaction of their body image. In transgender men, undergoing mastectomy is associated with marked improvement in body image - i.e., gender affirming.

Women undergo prophylactic mastectomy surgery for the prevention of breast cancer. In contrast to transgender men who report improved body image and less pain after the procedure, this surgery can cause dissatisfaction with post-operative body image in women undergoing prophylactic treatment - i.e., gender disconfirming, and up to 68% develop persistent post-mastectomy pain.

Drawing from the chronic pain literature, patients with body perception disturbances, in particular distorted body images, tend to report higher pain and not respond to traditional treatment paradigms. For example, body image and anxiety are significantly correlated with pain-related disability post-mastectomy. Therefore, there is a link between body image and pain persistence. However, the relationship between gender dysphoria, body image and pain has yet to be explored.

The objective of this study is to investigate whether pain perception changes with body image changes in those undergoing simple mastectomy in cisgender women and transgender men. Specifically, we aim to identify individual factors that can impact the development of post-mastectomy persistent pain. This proposal is timely, important and novel in that it will explicitly model the contribution of sociocultural and psychological aspects of gender identity on the pain experience.

The significance of this research is its potential to identify new understandings of pain that may lead to novel therapeutic interventions that are supportive of gender identity. This framework emphasizes the need to address body image dissatisfaction to reduce the vulnerability to developing post-mastectomy persistent pain.

The holy grail of regenerative medicine is the activation of endogenous adult stem cells from the inside of the body to rebuild lost cells and tissues with drug treatments. Although most current treatments attempting to restore vision use cells grown in culture and transplanted to the eye, the discovery that adult  mouse and human eyes contain retinal stem cells at the periphery of the eye in the ciliary marginal zone has opened up the holy grail approach in the retina of the mammalian eye. However, the adult mammalian retinal stem cells are completely quiescent. In the last few years, two chemical factors (BMPs and sFRP2) were shown to be secreted in the early postnatal period to suppress the proliferation of retinal stem cells in vitro and presumably for the rest of adult life in vivo. Most interesting, new data suggest that administering short acting antagonists of the BMPs and sFRP2 inhibitory factors into the eye can relieve the inhibition in vivo and allow endogenous retinal stem cells to start to proliferate. FGF2 and insulin were shown to be positive factors for retinal stem cell proliferation. In vivo injection of BMP and sFRP2 antagonists into the adult mouse retina indcue retinal stem cell proliferation (and the migration of their progeny to the retina and their differentiation into photoreceptors). However, the antagonists injected into the eye were cleared relatively rapidly from the eye, and retinal stem cell proliferation appeared to end within 24 hours after injection. To achieve much longer adult retinal stem cell stimulation and production of many more photoreceptor progeny in the peripheral retina, a stem cell biologist and a chemical engineer will take advantage of novel innovative protein affinity release strategies. We first will design a controlled release strategy for the proteins of interest and then test the strategy in vitro for bioactivity, and in vivo for activation of the resident retinal stem cells in the adult mouse eye, and the promotion of their migration and differentiation to photoreceptor  - the critical cells required to restore vision in many blinding diseases. Most important, we propose to test our long release strategies in adult human retinal organoids made from human pluripotent cells, to investigate if  the newly produced cells can migrate into the peripheral retina and  differeniate into human photoreceptors (in both wild type human retinal organoids and in organoids with degeneration of host photoreceptors).

A ventriculostomy is performed to access the cerbrospinal fluid (CSF) pathways in situations where CSF circulation is blocked and creates a dangerous increase in intracranial pressure (ICP), harming the brain. The procedure requires drilling a hole in the skull, opening the membranes and guiding an external ventricular drain (EVD) catheter through the brain into the ventricle to drain the fluid, thereby restoring a normal ICP. The surgeon uses anatomical landmarks on the patient to locate the ideal point and trajectory for EVD placement. Given the technical challenges in a typical ventriculostomy where acutely raised ICP mandates immediate placement of an EVD in an ICU setting, accurate targeting of the ventricle can be difficult and is hence associated with up to 40% placement error with resultant increased morbidity.

We will develop a novel, low-cost and portable imaging system that will improve surgical accuracy of ventriculostomy using a combination of transcranial ultrasound (TUS) for real time catheter and brain imaging, and augmented reality (AR) to visualize the target anatomy. The system will be: (1) portable such that it can be used in the OR, ICU, and on clinical wards; (2) low-cost (running on a tablet), i.e. easily affordable for ICUs and ERs across Canada and globally; (3) work with and without preoperative images. When available, images are automatically registered to the patient for use with guidance, or if unavailable (e.g. remote regions) a customized human head atlas will be registered to the patient, using TUS; (4) use AR imaging to best guide the operator; and, (5) be ergonomically designed such that the surgeon can operate without breaking the surgical workflow, looking away from the site, or needing to reposition any equipment.

As per the criteria our proposal is high-risk as we will be using low-cost consumer-grade components (tablet, low-cost US probe) to establish surgical-grade anatomical accuracy and precision required in this field. If successful, implementation of our system will be highly-rewarding as increased accuracy and portability will reduce morbidity, and enable regions with minimal imaging resources to easily access the ventricular space in any emergency. Our interdisciplinary team consists of engineers, computer scientists, surgeons and designers.  We will develop an ergonomic solution for the surgeon, which will have a major impact on the ease of execution and accuracy of ventriculostomy.

The incidence rate of melanoma is increasing faster than any other type of cancer worldwide. Early detection and treatment are crucial for reducing morbidity and mortality rates. However, existing diagnostic approaches are limited by their invasiveness, resolution, and accuracy, which result in a large number of unnecessary biopsies. The diagnosis and the possible ensuing treatment are also separated by up to months, which increases the financial, physical, and mental burdens of tens of thousands of Canadian impacted by this disease.

The overall goal of this NFRF application is to develop a one-stop theranostic (i.e., therapy+diagnostics) platform for precise in-situ detection and elimination of early-stage melanoma. To achieve this goal, we propose a new approach that interfaces ultrafast imaging, nanomaterials, microtechnology, and pharmaceutical sciences. In particular, theranostic nanoplatforms (NPFs) will be painlessly administered into melanoma and the surrounding dermal tissue by a microneedle array. Then, thermostimulation will be applied to the targeted area. An ultrafast microscope, developed from the world's fastest camera, will monitor the transient skin-surface temperature distribution indicated by the NPFs' lifetimes during temperature recovery, whose rate will determine the lesion's type. In the case of melanoma, near-infrared therapeutic light, spatiotemporally modulated by a high-speed spatial light modulator according to the lesion's characteristics, will be applied for temperature-regulated photothermal therapy. The procedure will be validated first in clinically-relevant melanoma mouse models.

The proposed approach will explore a novel one-stop paradigm for detection and treatments of melanoma complementary to existing diagnostic and surgical procedures. The theranostic NPFs are biocompatible and without noble metals. The painless microneedle administration can precisely deliver these NPFs based on customized prescriptions without the aid of medical professionals. The synergy of NPF synthesis with ultrafast imaging will enable real-time wide-field thermometry with a high spatiotemporal resolution and sensitivity, contributing to detect melanoma at the earliest possible stage. The ability to flexibly adjust spatiotemporal exposure will maximize therapeutic efficiency while minimizing side effects. Altogether, the proposed project will greatly benefit melanoma patients as a convenient, precise, and personalized theranostic platform.

Singlet oxygen is the primary cytotoxic agent used to destroy cancer cells using the clinically approved technique, photodynamic therapy (PDT). PDT uses a photosensitizer drug whereby once administered to the patient, light is directed at the cancerous site to produce singlet oxygen. Although the requirement of light aids in reducing toxicity to healthy cells, light does not penetrate tissues more than a few millimeters, and as a result, invasive incisions and fibre optics are needed for delivery. Moreover, once delivered, light is scattered and attenuated by blood, thereby limiting production of singlet oxygen to the outer lining of organs, thereby diminishing its cytotoxicity. Thus, despite the proven ability of singlet oxygen to effectively kill various types of cancer, clinical practice of PDT remains mostly to superficial cancerous lesions.

The goal of the proposed project is to produce singlet oxygen without the input of light, site-specifically at cancerous tissue. To achieve this, singlet oxygen will be produced from a photosensitizer via chemiluminescence resonance energy transfer (CRET) whereby the luminescence is generated using a small molecule dioxetane scaffold. Our first objective will be to synthesize derivatives of the dioxetane scaffold to contain photosensitizers that have their absorption overlapping with the chemiluminescence wavelengths to permit efficient CRET, then evaluate their ability to produce singlet oxygen via CRET. To site specifically trigger CRET production of singlet oxygen at only cancerous tissues, we will synthetically amend on the dioxetane scaffold, substrates for overexpressed enzymes found in cancer cells relative to their healthy tissue, such that CRET is "masked" in healthy tissues but produced in cancer cells by enzymatic action. Our lead compounds pharmacokinetic, biodistribution and toxicity profiles will then be evaluated in vivo, and if necessary, the compounds will be formulated into an appropriate drug delivery vehicle (e.g. liposomes). Once formulation is optimised, the efficacy of our compounds will be assessed in murine cancer models.

The production of singlet oxygen to selectively kill cancer cells in vivo without the use of light has not been reported. If effective ablation of cancers can be achieved using the proposed "darkdynamic" therapy, we would revolutionize the use of singlet oxygen as an effective cytotoxic agent for a variety of malignancies, beyond what is achievable by PDT.

Coupling renewably generated electricity with waste chemicals to generate value-added products has potentially transformative benefits for society by curbing emissions and mitigating climate change. Two waste chemicals are of particular interest: carbon dioxide (CO2) is a potent greenhouse gas that contributes significantly to global warming, while excess ammonia (NH3) emissions from agricultural livestock production depletes nitrogen from the soil and has harmful health effects on human and aquatic life. Thus, we aim to develop an electrolyzer capable of converting CO2 into fuels (methane and ethanol) and NH3 into fertilizer (ammonium nitrate) for the dual benefit of alleviating the harmful effects of these waste chemicals and closing the carbon and nitrogen cycles.

Our electrolyzer will use nanostructured Cu as the cathode electrocatalyst. Cu is regarded as the best electrocatalyst for CO2 reduction, producing methane and ethanol with high selectivity. In contrast, the most active electrocatalyst Pt for NH3 oxidation produces N2 instead of the more agriculturally beneficial nitrate. Ni-based hydroxide/oxide materials were recently reported to produce nitrate, however these materials are much less active compared to Pt. Using these Ni-based materials as a departure point, there is a significant opportunity in exploring alloys and multimetal systems to exploit the effect of metal additives on improving the activity of Ni-based electrocatalysts. Metal alloying is a well-known method for modulating electrocatalyst performance and is thus far under-explored for NH3 oxidation.

Our interdisciplinary team will leverage expertise from chemical and materials engineering, chemical sciences, and agricultural/food biotechnology to address the challenges of each component in electrolyzer design. We will (1) interface directly with OMAFRA to carry out techno-economic analyses of NH3 oxidation, (2) utilize hollow fiber ion-exchange membranes to concentrate waste ammonia directly from anaerobic digester wastewater, (3) carry out synthesis, characterization, and electrochemical benchmarking of the Ni alloy electrocatalyst, and (4) use first-principles modelling to improve intrinsic Ni alloy electrocatalyst activity. Ultimately, this project will direct nitrogen back into the soil and provide value-added products while decreasing the impact of the pollutants CO2 and NH3 on the environment using a renewable electrochemical process.

In this work, we intend to develop novel in-glass radiating structures (antennas)and arrays that remain invisible and will be compatible with all display screens in the future. This idea can be incorporated in cell phone screens, tablets, desktop screens as well as vehicular and residential windows (smart windows) for 6th generation wireless communications.

The project aims to integrate radiation structures and arrays that will utilize state of the art laser techniques (i.e. femtosecond lasers - FSL) and state of the art radiating mechanisms (i.e. dielectric resonator antenna arrays - DRAA) to obtain in-glass radiating structures at THz frequencies for 6G and beyond compatible devices. The main requirement is to maintain close to 100% glass transparency and acceptable radiation efficiencies. Thus, the first stage will be to create proper FSL induced grooves and waveguides within the glass (i.e. Corning Gorilla glass among other commercial grades used in electronic screens) and load the waveguides to obtain slow waves that will generate sub-THz based waves that can excite custom made photodetectors (PD). An array of PD will be designed to excite an in-glass embedded DRAA operating at sub-THz frequencies (i.e. in the range of 140 - 250 GHz). Such embedded DRAA will then be able to radiate and receive THz signals for wireless communications. The transparent in-glass excited radiator systems (TIGERS) will be also used to create multiple-input-multiple-output (MIMO) mm-wave antenna systems with high reliability, excellent transparency and low cost.

This is a novel idea/approach that has never been demonstrated or examined (and thus considered very challenging with high risk) and requires experts from the radio-frequency (RF) and photonics domains (bridging the gap between the two domains) to perform the joint co-design. Challenges in the slow-wave optical waveguides, PD design at sub-THz and DRAA embedded in glass need to be overcome. Several prototypes will be provided for the slow-wave waveguides and the integrated antenna systems that are excited by the optical sources via the utilization of the PD array. Rectangular DRA arrays will be created using the FSL writing technique within the 150-250 µm thick glass and loading it with high dielectric constant materials. The project will develop several kinds of TIGERS at THz frequencies with DRAA arrays with efficiencies higher than 60%, bandwidth of at least 15GHz and gain of at least 30dBi.

Objective

There is a tremendous potential in genetically modifying immune cells to secure specific therapeutic outcomes. Unlike the drug therapy, immune cells offer the possibility of continuous surveillance and intervention against disease causing agents, whether host derived (e.g., malignant cells) or exogenous (e.g., viral infections). Immune cells, however, are the hardest cells to genetically modify and typically require some type of activation before they are able to accept genetic elements for phenotypic modulation. This project has the single minded focus to create a safe and effective approach to modify immune cells with safe, non-viral systems. We seek `gene-activating matrices' that can be implanted in a host and deliver nucleic acid cargo, while activating the immune cells to accept the cargo.

Research Approach

Three separate expertise will be amalgamated to realize the specific objective outlined above. 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 lymphoid cells will be developed and optimized for delivering pDNA, siRNA and mRNA based cargo. One co-PI will lend her expertise in immune cell biology to explore novel ways to stimulate a range of immune (T/NK/B-cell progenitor) cells to accept exogenous genetic cargo. One co-PI will lend his expertise in fabricating biocompatible scaffolds where the immune stimulatory mechanisms and gene delivery systems will be incorporated for modification of lymphoid cells in vivo.

Novelty and Expected Significance

It is now well established that (i) various cells of the immune system do not get transfected with exogenous nucleic acids and (ii) synthetic approaches are needed to activate the cells for modification. These approaches are suitable for ex vivo modification of the cells, and can not be translated to a living host. We, for the first time, will explore a possible approach to activate immune cells in situ while delivering a genetic cargo with an integrated, implantable scaffold. This will allow in situ modification of therapeutically important cells without the need to harvest, expand and modify them ex vivo. With the ability to deliver a range of nucleic acid cargo, and possibility of modifying specific types of lymphoid cells, the application of the proposed intervention will be diverse to impact a range of innate and acquired diseases.

New generations of astronomical surveys are poised to produce unprecedented volumes of data, whose analysis remains a colossal challenge for traditional statistical models. In particular, the automated detection of anomalous patterns in these surveys could lead to the identification of new astronomical phenomena. Recent efforts in this direction have been mostly focused on the supervised classification of prespecified rare events, such as gravitational lensing or stellar streams. This proposal describes the development of unsupervised anomaly detection methods that can realistically identify a wide range of previously unknown anomalous patterns in large astronomical datasets.

A key characteristic of our approach is in our choice of data representation: so far machine learning applications in astronomy have been mostly limited to the use of convolutional networks on image and volumetric data. However, often a more natural approach is to represent a collection of celestial objects such as planets, stars, and galaxies as a point-set. We adopt the latter representation, which can also benefit from the recent advances in deep learning and computer vision on the modeling side. In particular, such models are extensively applied for prediction with the point-cloud output of LiDAR sensors in autonomous vehicles.

While the long-term goal of our program is to develop models capable of dealing with the complexities of various publicly accessible astronomical surveys (e.g., Gaia, LSST, and WFIRST), within this Exploration project, we plan to focus on the specific case of Gaia dataset. Gaia is a space mission that has produced the largest and most precise 3D catalog of approximately 1.7 billion astronomical objects in the Milky Way. Two defining challenges of this project are the massive size of the dataset, as well as the diversity of potential anomalies,  appearing at different scales, or within different families of celestial objects. We address these challenges through an interdisciplinary effort that systematically builds around a notion of anomaly in astronomical surveys and in particular the Gaia dataset. While we plan to evaluate our approach using planted outliers and realistic simulations, the high-risk outcome of this proposal involves our ability to identify entirely new classes of astronomical phenomena in our own Galaxy. The tools and techniques developed could mark the beginning of a holistic approach to anomaly detection in astronomy at large. 

The widespread antibiotic resistance has been acknowledged as the biggest threat to global health and economy in the coming decades. The bacterial pathogen Pseudomonas aeruginosa grows in cystic fibrosis (CF) airways as biofilms, representing one of the most common causes of drug-resistant infections. This project aims to directly address the global crisis of rapid emergency of antibiotic resistant pathogens by developing an inhalable metal-ion releasing therapeutic particle for effective eradication of persistent P. aeruginosa biofilms in CF lung microenvironment. It drives a new interdisciplinary frontier by bridging uncharted innovations in material science, bioengineering, and microbiology to mitigate the potential high risks of causing lung damages and triggering bacterial virulence and resistance. Our expertise in antibiotic resistance mechanisms, customizable drug delivery biomaterials and biomimetic mammalian-microbe co-culture techniques will enable the mechanistical study of the effects of our novel therapy on biofilms in the lung environment. This knowledge will guide the precision control of ion component, releasing dynamics and synergy with antibiotics to safely destroy life-threatening antibiotic-resistant infections with three specific objectives:

1. Establish an innovative drug delivery platform: Based on our unique metal-ion releasing glass particle design, we will create a platform to orchestrate the controlled delivery of metal ions with distinct bactericidal and antibiofilm mechanisms. We will refine the platform formulations within a statistical design space for optimal activities to destroy biofilms.

2. Create an in vitro model of P. aeruginosa infections in CF: An engineered lung epithelial tissue with polymer to mimic the thick mucus layer that simulates CF airways will be combined with advance bioprinting co-culture techniques to sustain extended P. aeruginosa biofilm growth. This groundbreaking model will allow simultaneous real-time investigations of host and bacterial responses to therapies.

3. Develop a breakthrough antibacterial technology: We will compare biofilm eradication efficiency and host cells viability of CF cell-P. aeruginosa co-cultures subjected to various combinations of glass nanoparticles and antibiotics. This information will inform optimization of biofilm eradication treatments at lower and safer dosages and eliminates the development of drug-elicited resistance and bacterial cytotoxicity on the host.

Electron transfer is an essential component of energy generation and utilization in all living systems, from plant photosynthesis through to enzymatic based energy production. Indeed, the intriguing redox properties of enzymes have sparked intense worldwide research into their use as a means of sustainable energy production and utilization.  Recent breakthroughs have demonstrated that redox active enzymes offer enormous potential for clean energy production, thereby providing a biomimetic alternative to the existing fossil fuel energy paradigm. Similarly, new enzymatic routes towards carbon dioxide scrubbing are being developed to mitigate climate change.  Crucially, it is electron transfer energetics and rates that underpin the chemical activity of redox active enzymes in all such applications.  Thus, immense technological gains could be attained through a deeper quantum resolved exploration of their underlying electron transfer dynamics.  While ground breaking advances have been made towards understanding the structural properties of enzymes, via sophisticated synchrotron and nuclear magnetic resonance techniques, their quantum derived electron transfer dynamics remain sparsely explored at the single-molecule level.  In this project we will investigate the multi-step electron transfer processes present in single enzymes, thereby enabling the nucleation of a wider effort to map natural catalytic and photosynthetic electron transfer pathways at the macro-molecular scale.   In this regard, hydrogenase and galactose oxidase shall act as model systems which will yield important new insights regarding: (1) the relative energetic offsets between electron transfer sites in the reaction pathway; (2) the quantum mechanical coupling associated with inter-site transfer; and (3) the quantum based Franck-Condon factors of both shuttling and catalytically active electron transfer sites.   This will be achieved though state-of-the-art atomic force microscopy measurements and quantum theory analyses, yielding an unprecedented exploration into the quantum energetics underpinning the electron transfer activity of single enzymes.   More broadly, the results of this exploratory work are expected to inform the design of new sustainable energy technologies based on biomimetic engineering.  This, in turn, will aid the global effort to combat climate change.

The application of electromagnetic fields (EMF) and alternative forms of energies in medicine faces a new era. The historically inconclusive results in EMF research have begun to become more consistent and are rapidly developing in recent publications, due to the increased consensus on instruments and international collaborations. Current research indicates an apparent detrimental effect of EMF on biological cells in high doses, but a stimulatory impact in low doses in the form of extremely low-frequency MEF (ELF-EMF).

Natural killer (NK) cells are potent cytotoxic effector cells for cancer immunotherapy. In particular, the transfer of the cells into patients presents promising potential. A critical challenge is that it takes >3 weeks of culture to generate a sufficient number of NK cells with potent cytotoxic activity. Shortening this time is critical for the development of prompt NK cell-mediated immunotherapy, and thus tremendous efforts have been dedicated towards this improvement.

Taking a multidisciplinary approach that combines physics and immunology, we will formally test the effect of ELF-EMF and acoustic energies (AEs) on the anti-tumor functions and proliferation of NK cells. This involves developing innovative test-beds, which use Electromagnetic Metamaterial principles for greater wave exposure control. In addition, we will apply the technology to efficiently produce effective NK cells for immunotherapy.

High risk: The application of EMF/AE in medicine has been considered quasi-science because the findings were often not reproducible. So far, no formal evaluation of the effect of MEF/AE on NK cells has been performed. The study for the application of EMF/AE in medicine faces difficulties acquiring funding from CIHR, which supports ideas in established fields.

High reward: EMF/AE may be an option for non-invasive therapy that can be combined with current treatments. The potential hormetic effect of EMF/AE in low doses on NK cell stimulation and proliferation will benefit NK cell-mediated immunotherapy by enhancing its economic and health impacts. The formal evaluation of the effects of EMF/AE on immune cells will provide us with the insight necessary for the application of the wave energies on cancer therapy and prompt us to study the underlying molecular mechanisms.

Resource conflicts and legal uncertainties have dominated the political landscape over the last decade. From Standing Rock to the TransMountain pipeline, conflicts over extraction and its infrastructures have intensified, catalyzing a fierce Indigenous resurgence. As we conceived this project, Wet'suwet'en hereditary leaders were blocking a pipeline company from accessing their lands, inspiring solidarity actions that blocked rail lines, ports, highways, and political offices. The situation dramatically demonstrated that when corporate interests thrust contested projects onto Indigenous homelands - even with governmental approvals - they must contend with Indigenous governing authority.

We offer a transformative way forward: a fundamentally new set of relations based on different underlying assumptions about law and land. It is a vision that insists the future is not foreclosed, but pregnant with potential for renewed relations of jurisdiction and infrastructure. If anything, the new COVID-19 reality has only made this more obvious. Will we rebuild? Should we rebuild? Or, even more importantly, what should we build anew?

The ground-breaking 2019 Yellowhead Red Paper documents how Indigenous-led consent processes based on fulfilling responsibilities are already having the effect of restoring Indigenous jurisdiction and reclaiming Indigenous lands and waterways, foodways and lifeways. We propose to systematically document, support, expand and evaluate this work to determine which strategies and approaches have the most success. How can remaking the material systems that sustain collective life enact Indigenous jurisdiction? What does infrastructure resilience look like for Indigenous communities emerging out of COVID-19 in an era of ongoing climate crisis? How can the "just transition" to sustainable economies be imagined and infrastructured to foreground Indigenous governance systems?

Our project offers an agenda for fundamentally re-making our socio-technical systems; for both conceptualizing and building infrastructure otherwise. If infrastructures of extraction constitute the `spine' of the settler colonial nation (LaDuke and Cowen 2020), we propose a vital new central nervous system: communities energized by a completely different conception of what `critical infrastructure' entails. We will offer conceptual visions and concrete material practices and structures that foster renewed relations for prosperous, caring and just collective futures.

Chronic wasting disease (CWD) is a prion disease affecting deer, moose, elk and reindeer in North America, Europe and South Korea. As all prion diseases, it is fatal and infectious, characterized by spongiform neurodegeneration and accumulation of protein aggregates in the brain. These consist of a misfolded form of the host's cellular prion protein, designated PrPSc. which transmits disease among and between species. Prion disease are known in humans (e.g. Creutzfeldt-Jakob disease/CJD) and animals, e.g. bovine spongiform encephalopathy (BSE) or `mad cow disease' in cattle which was transmissible to humans. Neither therapeutic nor prophylactic treatment exists.

CWD is the only prion disease affecting both free-ranging and farmed animals, is spreading out-of-control, and is potentially zoonotic. Solutions to such complex challenges require interdisciplinary research and the availability of relevant infection models. Current models are mostly limited to transgenic mice.

Prion-infected cultured cells are widely used to study cellular response or anti-prion compounds. There is no cell model for CWD prion propagation, and we hypothesize that differentiated reindeer stem cells will sustain stable CWD prion replication. We propose in aim 1 to establish induced pluripotent stem cells (iPSCs) from reindeer fibroblasts, and develop protocols for reindeer in vitro fertilization (IVF) to generate embryonic stem cell cultures. Aim 2 focuses on differentiation into neuronal or glial cells and infection with CWD prions. Aim 3 is dedicated to single cell RNA-seq analysis to study responses to prion infection, to gain knowledge about molecular pathogenesis of CWD in a cell model derived from a natural host.

We have assembled a strong, first-of-its-kind interdisciplinary team, with expertise in stem cell biology, cervid reproductive physiology and prion biology to generate the proposed cell models. Our innovative approach is supported by unrestricted access to reindeer, housed by our faculty for research purposes.

This project will generate ground-breaking and impactful outcomes beneficial for multiple fields of research. It pioneers the generation of a multi-purpose CWD cell model derived from a natural cervid host. Reindeer stem cells will be used for stem cell research. Reindeer/caribou are threatened species in Canada, and protocols for reindeer IVF may be beneficial for conservation medicine.

Understanding the mechanistic aspects governing cell transport of molecular cargo is key to the development of potent nanomedicines. However, the polydispersity and large structural diversity of cell surface biomacromolecules responsible for these events have typically hindered these studies. An important class of such molecules, glycosaminoglycans (GAGs), are ubiquitous to the cell membrane and key "gate keepers" of signaling, trafficking and uptake events. They are also attractive therapeutic targets since their unique albeit complex expression profiles represent the "signature" associated with the onset and progression of many diseases, including cancer and Alzheimer's disease. However, due to their structural diversity, the development of specific GAG binding partners has been limited by the requirements for adaptable probes. Moreover, understanding the generated high-dimensional data requires complex statistical modeling.

To address these shortcomings, we propose a new research methodology based on DNA nanostructures as versatile scaffolds to arrange GAG-binding ligands in programmed patterns. Their unparalleled addressability will be used to independently study the effect of structural parameters such as ligand identity, number, valency, and 3D presentation on their mode of entry into cells with varying GAG expression patterns. Towards this goal, we will build a library of constructs and use machine learning to find which structural features predict high affinity and specific GAG binding as well as cell entry pathways. Moreover, we will use dimension reduction methods to assess patterns in the binding and entry mechanisms of these nanostructures.

We expect this study will provide a comprehensive set of design rules that will enable the rational design of novel nanoscale probes and therapeutics with programmable cell interactions. By conducting these analyses on a library of structures in the context of diseased and healthy cells associated with differential GAG expression patterns, we hope to gain detailed information on the parameters linking ligand 3D structure to subsequent GAG binding and uptake. This project will also pave the way for the design of nucleic acid structures capable of targeting cells based on GAG surface expression. This would represent a crucial step for the development of effective targeted therapies for a myriad of diseases including cancer and Alzheimer's disease.

Microplastics (MPs) have been detected everywhere on the planet- from highly urbanized areas to the depth of the Arctic Ocean. MPs have been found to impact human and environmental health and can leach additives with potential effects ranging from carcinogenicity to endocrine disruption. Yet, despite scientific and regulatory attention, MPs and their additives continue to be a challenge for environmental and human health risk management: Existing efforts have failed to effectively identify specific local emission sources that would allow for targeted emission reduction measures. The main hurdle for developing mitigative measures is the lack of methodological "tools" that can effectively distinguish MPs from different products, producers and applications. With the proposed research we aim to develop these missing tools.

Using a combination of state-of-the-art analytical instrumentation, advanced forensic fingerprinting, and the latest computational pattern recognition we aim to develop methods to identify MP sources. This will be achieved by applying advanced statistical fingerprinting to interpret a comprehensive suite of analytical data on MP composition, additives, trace metals and carbon isotope ratios. Using machine learning to identify the patterns that make plastic fingerprints unique will allow us to identify what combination of information is needed to discern MPs from different product categories, entry points into the environment, or even specific plastic producers. This ambitious endeavor is made possible by bringing together international experts on chemical analysis and data science.

The knowledge generated through this project will benefit scientists, regulators, and consumers. Product-specific information on MP and additive emissions can inform consumer choices leading to a potential reduction in emissions and consumer exposure. The identification of producers or product types that contribute to local MP loads can inform targeted mitigative regulatory action and potential cost-recovery from polluters. Moreover, localized information on sources for specific MPs and additives can help inform the design of wastewater treatment techniques to increase removal efficiencies for these contaminants.

The immense potential benefits from this research have been recognized by partners from academia, industry, and regulators. Our collaboration with these partners will ensure effective dissemination and potential translation of the research into policy.

Cold physical plasma has the potential to revolutionize precision medicine in cancer and infection control. We propose a new therapeutic method based on tailored plasma redox stimulation applied to primary and secondary bone cancer metastasis control and infection control in bone tissue. Both are to date unsolved health issues with high impact on patients' wellbeing. Because current therapeutic options are limited in success and applicability, there is a great need to find novel methods. Demographic development in the ageing population will intensify this situation in the coming years.

Plasma, an electrically activated gas, consists of reactive oxygen and nitrogen species (RONS), electric fields, and photons. Plasma treatment induces highly reactive chemistry and novel cold plasma sources can be applied to human tissue. Recent medical plasma devices are certified for wound healing. Empirical observations in plasma-medicine, however, lack fundamental understanding of the biochemical processes that lead to a successful plasma-based therapy.

Our mixed gender research team combines multi-national expertise in physics, biophysical engineering, biochemistry and the medical fields of cancer research and microbiology. The project is based on the following findings: A) Plasma can be tailored to generate a precise RONS composition; B) Plasma can kill multidrug resistant pathogens and has been observed to lead to tumour volume reduction in palliative cancer care; C) Exogenous supply of a redox-burst mimics metabolic functions of the body and triggers immune responses, gene expression that differs between healthy and malignant cells, and selective killing of antibiotic-resistant bacteria.

The project will 1) design a test platform that combines tailored plasma reactivity, a highly reproducible circular bone tissue model, and co-cultured invading cells 2) measure and 3) control the reactivity induced in the tissue model by plasma 4) study ways to control metastasis formation on cell lines and patient derived cells from male and female patients 5) study control of bone infection.

The project's findings will identify which redox stimulation activates which molecular pathways. The to be designed plasma and tissue model will allow to study fundamental RONS triggered biological mechanisms with so far unmet precision. The project will lead the way to novel therapies founded on specific biochemical hypotheses derived from our plasma-bone tissue model.

Cranial sutures are soft connective tissue joining skull bones allowing for cranial growth and development. Sutures biologically respond to mechanical stimulus, facilitating local bone growth and remodeling, through complex cellular and molecular pathways studied together in the field of mechanobiology. Numerous craniofacial disorders effect a significant portion of the population around the world and commonly require invasive procedures for correction. For instance, premature fusion of a cranial suture, known as craniosynostosis, effects nearly 1:2000 births worldwide, leading to increased intracranial pressures and abnormal cranial shapes requiring correction through invasive surgical procedures. Due to a lack of sophisticated planning tools incorporating predictions of expected growth resulting from a change in mechanical environment at suture sites, clinicians must rely largely on evidence from limited case studies and their own experience when forming corrective procedures for craniofacial disorders. This, in turn, frequently leads to post-treatment reactionary measures and/or undesirable outcomes. The proposed high-risk/high-reward project aims to develop a novel mechanobiological model linking suture site mechanics to resulting bone growth and remodeling. Firstly, we will conduct in vivo experiments using a rodent model to study growth and development at suture sites under normal and mechanically stimulated conditions. Using novel advanced imaging techniques and biological analysis, we will establish a fundamental understanding of bone apposition and resorption at suture sites under a range of mechanical conditions at cellular and macroscopic structural levels. In our second research thrust, we will develop computational 4-dimensional mechanical models to mimic loading conditions under normal and constrained growth over time. Results from mechanical simulations and in vivo experiments will be correlated to establish a fundamental mechanobiological relationship for cranial sutures for a range of mechanical stimuli. Our vastly interdisciplinary project will combine mechanical modeling, biological, advanced imaging, and computational biology methods in a high-risk/high-reward program to greatly advance our foundational knowledge of cranial growth and development. Our findings will be leveraged in future work with craniofacial surgeons and computing scientists to develop vital prediction and planning tools to improve health-care delivery to patients.

Stroke is the third leading cause of death in Canada and the number of Canadians living with stroke will almost double in the next 20 years.  Middle cerebral artery (MCA) stroke, one of the more devastating strokes that occur in humans, has an especially high morbidity and mortality, associated with malignant edema. Decompressive craniotomy is a surgical procedure that can reduce elevated intracranial pressure to decrease MCA mortality, but there are currently no therapies that will reverse or repair the damage caused by stroke.  While many therapeutic strategies have been developed, they are not clinically applicable due to the lack of safe and effective routes of delivery.  This proposal leverages the expertise of an interdisciplinary team of neurobiologists, biomedical engineers and neurosurgeons to develop a local drug delivery system to specifically target in situ the stroke lesion site for regeneration that limit adverse systemic effects on other organs.

The discovery of ischemia-activated pericytes that can be reprogrammed into induced-neural stem cells shortly after stroke in both rodents and humans offers a revolutionary regenerative therapy to produce neurons from non-neuronal cells locally at the lesion site.  We have defined the molecular mechanisms that are essential to the regulation of neural stem cells reprogramming/differentiation. Importantly, these signaling pathways can be targeted by pharmacological strategies to facilitate the generation of local neurons from ischemia-activated pericytes. We propose to use an "open" opportunity, a surgical decompressive craniotomy procedure, to bioengineer a specialized drug-releasing duraplasty, a biocellulose biomaterial that can be placed directly onto the brain at the time of surgery to enhance in vivo cellular reprogramming/differentiation and promote post-stroke recovery.  We will use two rodent stroke models that closely mimic the human stroke to perform proof of concept experiments.

This is a high-risk project in that while duraplasties have been used in clinics as part of a standard decompressive craniotomy procedure, they have never been attempted to deliver therapeutic drugs to improve post-stroke functional recoveries. The successful implementation of the preclinical work could lead to the high rewards in developing a clinically applicable and compatible biomaterial-guided local drug delivering system to enhance post-stroke regeneration and recovery.

It has been known for more than a century that living cells emit ultra-weak light (UWL). However, it is still not clear what role this UWL plays nor how it is generated in the first place, although energy metabolic processes seem to be involved. Models and experiments show that neurons are capable of guiding light and, thus, it has been suggested that the UWL may be involved in neuronal communication. In light of this, our objective is to determine the properties of the UWL in brain tissue of tadpoles using detection techniques from quantum information science.

The main challenge of detecting UWL is that it requires highly sensitive detectors. A similar requirement in quantum communication, has led to the development of state-of-the-art superconducting nanowire single-photon detectors (SNSPDs). Such detectors, with close to unity efficiency and less than one erroneous (dark) count per second, are ideally suited for UWL detection and notably can be tailored to operate over a much broader wavelength range than any standard detector platform. For this project, we will develop tailored SNSPDs compatible with multimode fibre inputs. Using these, there are several key properties of the UWL, which we aim to measure and correlate with potential sources. The spectral information allows us to rule out or identify potential source molecules, such as reactive oxygen species, and processes. The optical fibre-based collection yields spatial information, which allows us to determine active regions e.g. where mitochondria, light-sensitive opsins or light-guiding axons are present. Finally, we choose tadpoles from the frog Xenopus as our model because of the ability to observe embriogenesis from a single-cell embryo to a fully developed tadpole brain over a span of only four days and, thus, correlate the UWL emission with specific developmental stages.

Unlocking the origin of the UWL will solve a long-standing research question and, thus, spur further interest and guide research in this field. Further studies will expand this research into the role of UWL including how it may be transported through tissue and interact with light-sensitive receptors. The goal is to establish if UWL serves a communication purpose in our brains and nervous systems. The ultimate conjecture to be tested is if quantum phenomena, such as entanglement, play a role in our brain biology e.g. being at the origin of our consciousness. Such research questions are highly exploratory and unique.

Cellular imaging deep within a living organism opens a window on the most basic unit of life - the cell - where diseases originate and whose replacement via cell therapy promises to treat a spectrum of diseases and debilitating conditions. The promise is immense: repair a broken heart, restore mobility, or treat the mind. Yet, that promise remains outside the clinical realm, as we currently cannot look inside the body non-invasively to assess treatment efficacy. We do not have the tools to track cell survival and migration, and monitor their growth and integration over time. In essence, we are limited in our ability to optimize the cell therapy platform itself for human translation.

The overall objective of our proposed research is to create a clinical cell imaging platform based on magnetic resonance imaging (MRI) to guide stem cell therapy in humans for a broad range of tissue regeneration targets. This platform uses a novel MRI approach for visualizing stem cells deep in the body. Unlike previous cell imaging methods, our platform furnishes a large signal contrast only in cells that remain alive, sustains the signal through repeated cell division, and maps cell distribution with high resolution. Uniquely, contrast from cells can be recalled on demand any time after cell transplantation. In this proposal, we bring together molecular biology and MR physics to establish new capabilities that take our platform to the clinical level. We propose stem cell innovations and novel cellular MRI capabilities to achieve the following: (1) genetically engineered stem cells able to regenerate tissue and impart an MRI-visible contrast over their lifetime, (2) broadened cellular MRI platform to include different stem cell treatment paradigms, and (3) feasibility for tracking key targets - heart, brain, liver, and cartilage.

We offer the first deep-tissue, in-vivo cell imaging platform compatible with stem cell therapy across key tissue targets. No other competing technology offers comparable sensitivity, repeatable imaging, and on-demand signal recall across the lifetime of therapeutic cells. Scientifically, our platform will inform pre-clinical cell therapy research, allowing one to begin solving questions pertaining to cell survival, integration, and need for additional regeneration strategies. Clinically, our platform will permit long-term patient monitoring, truly a first, to ensure continued normal transplant function and to allow early intervention.

The rapidly changing climate has driven hundreds of governments around the world to declare states of emergency in 2019. However, in comparison to the declarations of public health emergency due to the ongoing COVID-19 pandemic which have led to immediate lockdowns, the declarations of climate emergency are largely symbolic gestures. The reasons for no real actions towards climate emergency are multifold, including but not limited to: 1) lack of awareness of both opportunities and challenges of future climate change at local scales; 2) lack of sustainable technologies towards changing climate conditions or poor understanding of the economic feasibility of potential technologies; and 3) lack of effective policies and societal engagement to facilitate the implementation of new technologies. Turning the symbolic declarations of climate emergency into real actions requires a systematic framework to address these issues.

This project will bring an interdisciplinary team of researchers in the areas of climate change modeling, big data analytics, environmental economics, sustainability, and public policy to develop a systematic modeling and analysis framework for identifying and promoting immediate and effective climate actions at local scales. Compared to existing frameworks or methodologies which are either focused on high-level policy analysis or large-scale impact assessment, our framework will be targeted for individual economic sectors within regional and local communities where real and immediate actions are needed. The proposed framework can be used to 1) quantify the socioeconomic benefits and/or impacts of future climate change at local scales, 2) identify economically-feasible technologies and solutions for climate mitigation and adaptation from both near-term and long-term perspectives, and 3) promote immediate actions through effective policies and societal engagement. We will focus on the smallest province in Canada, Prince Edward Island (PEI), as a case study to develop the proposed framework. Based on the research team's well-established climate monitoring networks and collaborative partnerships with local policy makers and stakeholders in PEI, we will carry out various experiments through a prototyping approach to test and improve the proposed framework. If successful, we hope to scale this framework up to other provinces and jurisdictions across Canada to support a nation-wide transition from climate emergency declarations to real actions.

This vanguard proposal assesses, for the first time, the feasibility and socioeconomic impact of a time-based approach to the treatment of intracranial hemorrhage (ICH) emphasizing hyperacute(<8hrs) intervention with a new minimally invasive surgical (MIS) technique. Specific Aim (SA) 1: To determine safety, feasibility, and technical effectiveness of hyperacute MIS. Mortality and functional outcome will be secondarily assessed. SA 2: To determine the cost effectiveness of hyperacute MIS evacuation compared to best medical management (MM). SA 3: Implement an AI algorithm for acute automatic ICH detection, delineation and prognostication. Study design: A single center, prospective safety, and feasibility study of hyperacute MIS. Study population: A convenience sample of 20 patients; randomized 3:1 to MIS or best MM. Significance and Novelty: ICH is an orphan disease. No effective therapy improves outcome or reduces mortality. ICH accounts for more disability-adjusted life-years lost than ischemic stroke with dire clinical consequences and a 39% mortality.  Half of deaths occur <48hrs, and most survivors are left with serious long-term disability. ICH expansion (HE) is an independent predictor of neurological deterioration and mortality due to mass effect and toxicity of retained blood products. HE is a time-dependent phenomenon occurring in ~38% and ≤16% of patients ≤3hrs and >3hrs from ICH onset respectively. Early ICH extraction removes the causes of poor outcome and MIS reduces iatrogenic brain injury compared to craniotomy.  ICH detection, patient selection, prognostication and early stroke team notification is enabled by AI. Several single center studies demonstrate feasibility of hyperacute craniotomy for ICH but this has never been implemented in larger trials or tested with MIS. Meta-analysis shows MIS <24hrs is 2.8x more likely to achieve good outcome than craniotomy. A systematic hyperacute MIS approach would be a Canadian first, fortifying leadership in ICH imaging and intervention. The proposal offers a multi-disciplinary approach (Radiology, Neurosurgery, Health Economics and Computer Science) to ICH with the primary goal of improving outcomes in a devastating disease. No study has tested hyperacute MIS feasibility, time-dependency and ICH outcome, or the socioeconomic impact of this novel intervention. A positive study would be paradigm shifting for ICH converting a traditional "watch and wait" model to aggressive time-based intervention. 

The discovery of microbes drawing metabolic energy not from the Sun, but from the chemistry of water-rock reactions revolutionized thinking about the intersection of life-water-energy on our planet in the late 1970s. Since that time investigations of "rock-hosted life" (microbes inhabiting the subsurface in water-filled fractures) have identified new species, but to date no program to our knowledge has tackled a detailed understanding of the energetics sustaining the subsurface biosphere on a planetary scale from the novel interdisciplinary perspectives of hydrogeochemistry (NPI) and astroparticle and underground physics (Co-PI).

THE CHALLENGE: Water-rock reactions supporting such chemolithotrophic ("rock-eating") life by producing electron donors and acceptors in the subsurface have been identified, from serpentinization, to radiolysis (subsurface radiation breaking apart H2O molecules and minerals). Constraining the governing controls on these reactions however is a major challenge limiting our ability to predict rates of energetic availability (e.g. habitability), biomass quantities and levels of microbial activity, and the distribution and preservation of life in the deep earth. Key parameters includes the distribution, transport and age of deep groundwaters that host microbial ecosystems, the controls of mineral and elemental distributions (O, F, U, Th, K) that drive the reactions, and the controls on α, ß, ? radiation flux that define this Radiogenic (rather than Photosynthesis based) biome.

THE OPPORTUNITY: Oddly, to date, subsurface biosphere studies have not engaged the scientists who, for the purposes of exploring dark matter, low energy particle physics and neutrinos have established the world's subsurface research laboratories. This proposal will challenge existing paradigms by integrating the physics of deep earth radiochemistry with the study of the habitability of deep fracture fluids, some of which have residence times of more than a billion years. This program will quantify the radiogenic energy of the deep subsurface by integrating specific site elemental, noble gas and fluid geochemistry with global datasets and models of α, ß, ? flux in order to develop predictive capability to identify where and for how long microbial communities may be sustained by radiogenic energy in the subsurface biosphere. Once developed such models can also inform planetary and astrobiology mission planning for planets and moons elsewhere in the solar system.

Rationale: The lack of large-scale communication between researchers around the world limits the ability to complete practice-changing randomized controlled trials (RCTs). Researchers compete for shrinking research dollars and, if successful in obtaining funding, conduct small trials that may not be completed or were underpowered to start. A fundamental paradigm shift from a culture of siloed competition to one of widespread collaboration is needed. However, getting hundreds of international researchers in a room to prioritize research questions, develop protocols and strategize funding is impractical, expensive and too episodic. We propose a novel web-based application that will bring the connectivity of social media and existing resources together on a secure platform to strengthen research networks and support communities of researchers to develop research together. Our bold and innovative approach challenges the current paradigm of how researchers think about, plan and collaborate on research.

Objectives: 1. To develop, test and implement a web-based application among a structured online community of Canadian and international venous thromboembolism (VTE) researchers. 2. To evaluate the effectiveness of the web-based application using social network analysis.

Research Approach: Using VTE research as a 'proof of concept' test case, the web-based application and a related Shared Protocol Development tool will be custom built. Our team includes VTE researchers and leaders, health technology experts, a business entrepreneur, a social network researcher and a patient partner to build a product that is effective, sustainable and adaptable to users' needs. Our project is supported by technology from a Canadian company that specializes in secure communication.

Testing will occur in focus groups of VTE researchers and a patient partner, followed by feedback from members of CanVECTOR (Canadian VTE Research Network) and INVENT (International VTE Research Network). We will use social network analysis to examine how end users' social networks are created, shaped or shifted. We will report the proportion of protocols that have included SPIRIT RCT guidelines, VTE core data elements, and sex and gender considerations,  compared to historical protocols.

Significance: By incorporating social media and resources in a novel secure web-based application, we will disrupt traditional practices to revolutionize how future research is developed around the world.

There is an urgent need for generalizable ways to repair or replace the function of damaged or mutated genes. For example, the thousands of "orphan diseases" (OD) affect small numbers of people individually, but hundreds of millions in total. Two-thirds are genetic, but potentially curative gene therapies must be developed anew for each, delivering different gene functions to a different spectrum of cell types - an obstacle for current cell-type specific approaches.

Consequently, cures for OD are unattractive to industry, and can be tremendously expensive without achieving economic viability. For example, mutations in the SMN1 gene in Spinal Muscular Atrophy (SMA) cause loss of motor neurons, with outcomes ranging from muscle weakness and loss of the ability to walk later in life, through death within a few months of birth. At more than two million dollars US per treatment, Zolgensma (the gene therapy for SMA) is currently the most expensive drug in the world, excluding all but the wealthiest patients. Another "million dollar drug" gene therapy with a Canadian connection is Glybera - abandoned by the manufacturer with only 31 patients ever having been treated, despite being the most expensive drug of its time.

Therapies that are both accessible and economically sustainable will require not just incremental improvements, but a complete paradigm shift away from existing viral and non-viral delivery strategies. Our objective is a single common validated platform, able to make repairs or deliver replacement functions to any cell in the body, and flexibly customizable to the needs of individual patients. Working with cultured cells, organoids, and molecular biology techniques with which we have extensive experience, and guided by our expertise in biosafety, we will construct prototypes of our new platform and demonstrate their effectiveness with a range of genes including SMN1. Details will be provided in the confidential body of the proposal.

As an exploration of new territory at the intersection of basic science, biomedical engineering and health research, with the potential for "game-changing" rewards, the proposed research exemplifies the interdisciplinary innovation that the NFRF-E program was founded to enable. Filling the gaps between conventional funding mechanisms, this unique opportunity will provide critical foundational data essential for subsequent translation into a clinically tool with broad applications across many OD and beyond.

Identifying and countering the side effects of a new drug during its developmental phase is critical to achieving clinical success.  Side effects due to off target interactions are a major cause of failures in clinical trials.  At the cellular level, drugs target, and interact with, protein(s) to induce perturbations in their interaction network.  However, knowledge of drug-protein interactions within the cell is typically incomplete and, when available, limited to that of the intended protein target.    This knowledge gap is greater if a drug is repurposed for another disease, and different protein interactions are targeted.  A systematic methodology to identify on- and off- target protein interactions would therefore represent a major advance in the process of development or repurposing of a clinical drug.  This would lead to higher efficacy in clinical trials and rapid characterization of lead candidates, important factors for improving public health as a whole.

Here we pioneer a highly inter-disciplinary approach, combining expertise in analytical chemistry, cellular proteomics and quantitative network modelling to design and validate a widely applicable method that reveals the interaction landscape of a given drug (CHEMO-ID).  In CHEMO-ID, a two-part biosensor is generated inside living cells. The first part involves genetic code expansion technology to encode a chemically reactive moiety into a customized biotin ligase gene.  The second part is the drug of interest, synthetically modified with complementary reactivity to the biotin ligase.  When present together in cells, both parts chemically combine to form a chimeric drug-biotin-ligase, which will then report on the local protein environment of the derivatized drug by biotinylating proximal proteins.  Biotinylated proteins are then identified by mass spectrometric analysis, and with this technique, both transient and stable associations with the drug are detectable with high sensitivity.

In this proposal we will: 1) as proof-of-concept, implement CHEMO-ID with prototypical drugs that have well-established protein targets; 2) discover and validate novel targets for drugs; and 3) develop a statistical model that will allow us to compare CHEMO-ID interaction networks with previous experimental data, and with predictive data from structure based algorithms, so we can perform CHEMO-ID with a variety of drugs.  The CHEMO-ID  technology has the potential to revolutionize drug development.

In recent decades, human populations have been shifting from rural to urban areas, and most individuals now live in urban centers. The expansion of cities and anthropogenic activities is an immense source of various airborne contaminants. However, urban forests are associated with important ecosystem services such as climate mitigation and reduced environmental exposure. Yet it is unclear if features of urban forests promote respiratory health or exacerbate auto-immune diseases. The urban microbiome is another important component involved in urban population health, especially since anthropogenic activities have substantial impacts on plant microbiota which can in turn remediate air pollutants. Nearly one-quarter of Canadians suffer from respiratory disorders such as asthma and rhinitis, estimated to represent public health costs of more than $4 billion per year by 2030. Alterations in human gut microbiota during the first three-years of life have been reported in infants that later developed asthma and allergies. Although much hope has been put into this window of opportunity hypothesis, during which changes in gut microbiota can result in immune dysregulation, we propose that urban environmental allergens and microbiota disseminated by urban forests are stronger determinants of population health. To reduce the development of auto-immune diseases in urban population, city planning strategies must integrate a mechanistic understanding of how urban forests influence public health through their impact on air contaminants, allergens, and microorganisms. Our main objective is to identify the mechanisms by which urban allergens and microbiota contribute to educating the human immune system in order to improve city planning and reduce the costs of autoimmune diseases in urban populations. In a latitudinal and longitudinal gradient of Canadian cities, we will: 1) measure city-specific forestry indicators such as biomass, crown volumes, leaf area, pollen emission using advanced ground based and 3D remote sensing approaches; 2) identify and quantify leaf bacterial, fungal, and viral organisms emitted by urban forests in the air and on pollen; 3) assess relationships between these indicators, urban microbiomes, and human health to challenge the "window of opportunity" hypothesis and reduce the exacerbation of autoimmune diseases in cities. Finally, using machine learning, we will create an end-user tool to quantify the health value of city-planning scenarios.

Plastics, which are so widely used in our economy, have become an increasingly critical environmental pollution challenge. The wide use of single-use protective masks and face shields during the COVID-19 pandemic has further increased the immediacy of plastic pollution. The problem is that synthetic plastics are widely used and highly wasteful but difficult to degrade in natural environments. Unlike naturally occurring biopolymers, synthetic plastics can take thousands of years to decompose in water or soil environments. Macro-sized plastics are relatively easy to collect and can be recycled where economical - but microplastics are difficult to collect and treat. Microplastics can readily escape from the wastewater treatment systems and pose a direct threat to aquatic microorganisms and environments. The objectives of the proposed research are to investigate and develop innovative ways to resolve the problem of microplastics pollution, to help enable a sustainable and circular economy. We propose a combination of membrane, photo- and bio-catalytic treatments as a promising approach for accelerating the degradation process for microplastic particles that can be recovered from wastewater or natural environments. The novelties of this project include the utilization of (a) recent advances of nanotechnology and photochemistry to fabricate active membranes for effective collection and degradation and (b) advanced microbial technology to generate suitable bacterial strains to further degrade the microplastics and to produce other useful materials such as fully biodegradable bioplastics. This will involve enrichment culture using photo-degraded particles as feedstock, construction of metagenomic libraries, and use of the isolated metagenomic DNA for genome engineering of Pseudomonas putida for conversion of the microplastics particles to a broad range of bioplastics. Furthermore, we will analyze the sources and types of microplastics, identifying the best areas to employ the developed technologies. As far as we know, the photo and bio-degradation techniques have not been used together for treating microplastics; thus this interdisciplinary research is innovative and presents a high-risk and high-reward endeavor, which will significantly enhance the leading role of Canada on controlling plastic pollution. The developed technology is anticipated to be commercializable and can be integrated into a circular bioeconomy framework.

Nuclear technology can satisfy growing energy demands, while providing efficient, low-carbon energy to combat climate change. Small Modular Reactors (SMRs) are scaled-down, flexible models of traditional nuclear plants, that seek improvements in performance and reduced costs by moving production to factory settings; there is massive interest at International, Federal and Provincial levels (ON, SK, NB). SMRs can address both on-grid and remote (northern community; mining) needs.  To achieve improved safety by operating at atmospheric pressure, many SMR vendors will rely on molten salts for transport of thermal energy generated by nuclear fission. Materials performance in molten salt environments is poorly studied, with the dynamic effects of radiation fields completely unexplored; due to both technical challenges and risks.

This project will enable simultaneous molten salt corrosion and irradiation studies by designing a molten salt cell that can be mounted on the existing proton accelerator at our institution, and building a working prototype.  This is a challenging and complex task; we are at an early / exploratory stage.  If successful, the prototype will be followed by a CFI submission to build a full-scale facility.  This will enable first-of-a-kind experiments evaluating materials in molten salts in the presence of radiation; a breakthrough for implementation of SMR technology globally. The facility will allow rapid screening of candidate materials for SMRs, as well as long-term aging studies.

The team brings together two core required disciplines: radiation damage / accelerator technology, and corrosion / electrochemistry. For this first-in-world system we need material selection experiments and significant design effort. Two major concerns will be: (i) sample integrity; the material to be tested is <100 µm thick for proton passage, yet acts as a barrier to separate cell from beamline; (ii) high temperatures (550°C+).

The potential impact is very significant: there are ~50 SMR designs concepts globally. SMRs will have a huge international market (thousands of SMRs) which, due to its strong existing nuclear sector, Canada is well positioned to lead. The Canadian nuclear industry, Ontario Power Generation, Canadian Nuclear Laboratories, and Bruce Power are all partnering to develop SMR technology in Canada. With the only facility capable of doing representative molten-salt experiments, the facility will be critical to success of SMRs in Canada.

People living with dementia (PLWD) have the right to full inclusion in their community. Despite existing efforts, stigmatization remains entrenched and PLWD are excluded from full participation. Existing dementia-friendly community research and practice has usually focused on high priority places (e.g. banks, rec centres); however, reliance on family, friends, and neighbourhood support (for groceries, care needs, etc.) during COVID-19 highlights a need for inclusive practices at all community levels from individuals to policy.

RISK & REWARD: To create a dementia-inclusive community, action is required at multiple scales (the individual, relationships, physical environment, public/private services, policy, planning). The need for coordination across scales is a major challenge that requires an interdisciplinary, multi-scalar, participatory approach that brings together PLWD, family/friends, community stakeholders (policy makers, municipal staff, rec providers, etc.) and researchers from diverse disciplines (planning, policy, health sciences, recreation, tech). The payoff will be an inclusive community plan that recognizes PLWD as citizens of their communities, addresses stigma and creates interdependent networks among community members.

GOAL: To use participatory action research (PAR) to identify specific actions needed at multiple scales based on the needs of PLWD. Specifically, to:

1-Identify barriers/facilitators to inclusion from the perspective of PLWD and family/friends, and envision a dementia-inclusive community

2-Co-create tools/networks with PLWD, family/friends, and community stakeholders to address barriers to inclusion/participation from person to policy levels

3-Integrate learnings from #1,2 to inform a multi-scalar framework for development of dementia-inclusive communities.

APPROACH: PLWD and care partners will be co-researchers, driving project goals, methods, and analysis. Centering their experiences increases the likelihood of identifying actions with high impact on the lives of PLWD and families/friends. We will also partner with community members and stakeholders to identify actions needed to create an inclusive environment in diverse Canadian neighbourhoods. Methods and tools will be chosen over the course of the project in line with PAR. We anticipate outputs will include tools for action at multiple scales. Combined, we will have a dementia-inclusive community framework to expand inclusive communities across Canada.

Around the world, there is a critical need for cost-effective and sustainable battery technologies for electric transportation and renewable energy storage. This urgency has led to a research wave on novel batteries made of low-cost, high-abundance and safe components. One element of interest is aluminum because it offers the above advantages, and very high theoretical volumetric and gravimetric capacities because of its three-electron redox chemistry. We have developed batteries made of aluminum anode, graphitic cathode and abundant, low-cost and environmentally friendly electrolytes that deliver superior performance compared with state-of-the art aluminum batteries. However, considering the very high theoretical capacities of aluminum, there is a great potential to further increase the capacity by several folds by using alternative cathode materials made of other elements.

The proposed multidisciplinary collaborative research will utilize an innovative modelling-experimental framework for material discovery combining thermo-electrochemical hierarchical modelling of batteries with state-of-the-art material synthesis processes and characterization techniques. The modelling component builds on the multi-scale hierarchical methodology that covers relevant physical domains, time and length scales for metal-ion batteries. The hierarchical computational approach leverages state-of-the-art machine learning algorithms to integrate simulations from atomistic models of the nanostructured electrodes with Density Functional Theory (DFT) and Molecular Dynamics (MD) into reduced-order thermo-electrochemical models of the macroscale battery architecture. We will apply this framework to investigate cathode candidates from three material groups (transition metal oxides, metal sulfides and metal selenides) with particular emphasis on hybrid nanostructures of these materials that favour the battery intercalation process, such as layered nanostructures with superior electrochemical, cycling and thermal stability.

This work ushers in novel solutions in the Canadian energy storage industry and enables the long-term objective of developing post Li-ion batteries to address materials sustainability. Combination of hierarchical modelling, artificial intelligence and materials syntheses enables investigating numerous scenarios that would not be possible otherwise; hence, enabling next generation Al batteries for sustainable electric transportation and renewable energy storage.

Rationale: Employed in industries including mining, recycling and food processing, sensor-based production line sorting is a real-time technique offering increased productivity and significant economic benefits while simultaneously reducing environmental footprints. Within a mining context, current sensor-based ore sorting techniques have key limitations that restrict the sorting of lighter elements and compounds early in the mining cycle where it is most effective. Attempts to address this deficiency by using laser induced breakdown spectroscopy (LIBS) have achieved only limited success.

High Risk: In LIBS, a high energy laser pulse ablates the collected sample (a rock) and the emission from the resulting plasma is analyzed to identify the density of desired elemental components or their proxy compounds. One of the biggest unsolved difficulties in LIBS is the poorly understood time-dependent plasma leading to background noise and a rapidly varying emission from the constituents. This, in turn, prevents an accurate and reliable determination of the densities. A second major difficulty is the unknown validity and applicability of the required calibration procedures across several measurement conditions, severely restricting application in actual production line environments.

Interdisciplinary: Combining the unique skillsets of optical physics and mining engineering, we will address the critical disadvantages of LIBS by using time-resolved plasma absorption spectroscopy.

Feasibility: Leveraging the capabilities of femtosecond frequency combs, dual frequency comb spectroscopy (DFCS) has emerged as a broadband spectroscopy tool with high spectral resolution, time-resolved capability, and superb sensitivity. Recent work using DCFS has shown promise for determining the density concentrations of multiple elemental compounds from ablated material. We will adapt this approach for ore analysis.

High Reward: Several formidable challenges must be overcome, including technical issues as well as fundamental scientific concerns. Yet, if successful, this novel technology would offer a rapid and custom calibration standard for LIBS suitable for on-site analysis and could potentially be employed directly as an ore sorting sensor in an active mining and processing environment. It would increase sorting accuracy, reduce the amount of material that must be processed, and decrease the environmental footprint, while having a significant impact on mine economics

The penetration of renewable sources into energy markets requires the development of efficient energy conversion processes and novel materials such as catalytic materials. Catalyst design is a highly complex, multiscale and multiphase field. Conventionally, catalysts are selected based on heuristics or trial-error expensive and time-consuming procedures. An efficient systematic method that can accurately predict near-optimal catalysts can accelerate catalyst design, provide new insights on the performance of new catalysts for particular applications, and boost the development of new sustainable chemical processes and emerging renewable energy systems. To date, an optimization framework for catalyst design is not available. The key, high-risk factor for optimization is the overly expensive computational costs due to the large number of discrete decisions, each corresponding to a particular combination of chemical elements under consideration. In a computational environment, the search for the elementary reaction mechanisms (ERM) requires expensive quantum mechanics (QM) calculations to find the optimal electronic configuration. QM calculations must be repeated multiple times using different initial electronic configurations until the lowest energy path is found, thereby increasing the already taxing computational costs. Since emerging catalysts are composed of multiple elements, the search for ERM using QM for each catalytic material becomes an overly challenging (almost prohibitive) computational task. We will take an interdisciplinary approach, combining combinatorics and optimization theory, machine learning and chemical engineering to develop an optimization-based framework to find ERM of near-optimal catalysts for renewable energy conversion systems, e.g. CO2 conversion. ERM for a small set of catalysts involving multiple elements will be obtained first using QM; this data will be used to develop an active machine learning algorithm. The optimization algorithm will use the information from the learning algorithm to predict new catalysts with improved properties, e.g. maximize CO2 conversion while keeping selectivity for by-products at minimum threshold. This unique approach requires special optimization techniques that enable simultaneous consideration of integer (combinatoric) decisions, on-demand machine learning predictions and QM calculations. The proposed framework has not been considered before and can transform and accelerate catalyst design.

Suicide is the second leading cause of death worldwide among individuals between the ages of 15 and 29. It is known that a total of 90% of people who die from this preventable event have a diagnosed mental health condition. Recent data showed that, in Ontario, over 67.4% of people who died from suicide saw their primary care physician prior to their deaths. Moreover, suicide risk assessments were reportedly conducted in 87.1% of the physician visits. For individuals who committed suicide, 39.8% were classified by their clinicians as having no risk, and an additional 50% were deemed low risk. Unfortunately, these results clearly indicate that the clinical assessment of suicidal behaviour largely fails to predict suicide.

In this sense, our group has set forth to develop better tools for personalized risk assessments. Recent cross-sectional studies showed that machine learning algorithms, coupled with clinical data, are very effective at predicting suicide attempts at the individual level. Importantly, automated risk calculations can create alert notices to clinicians, patients, and their families. What is not known is whether such individualized predictions can be made in a timely fashion so as to inform health care decisions. Thus, there is a need to test a promising new technology that incorporates different sets of data into user-friendly risk calculators.

To achieve this aim, this project will be conducted in a centre that receives 900 referrals per year and has 500 active clients aged between 16 and 25. Our specific hypothesis is that a multi-scale signature will establish a personalized predictive model for the risk of suicide attempts among transition age youth (16 to 25 years of age). Predicting suicide attempts, and thereby establishing timely preventive strategies, would be a major milestone in public health. Our approach will help to reduce direct costs (estimated to be $ 829 million/year) and indirect costs (estimated to be $ 2.1 billion/year) associated with suicidal behaviour and will ultimately strengthen the Canadian healthcare system. This proposal includes a multidisciplinary team from engineering and health sciences who will share their complementary expertise in conducting this project, and in addressing the ethical, legal and societal impact that we may encounter.

The plasticity of early childhood development represents great opportunity to promote lifelong health, but also great risk of enduring detriments in cases of adverse childhood experiences (ACEs). While the neuropsychological impact of ACEs is increasingly examined, there is a dearth of evidence regarding effects on less-apparent downstream connections to other systems, including immunity. Like the brain, the developing immune system is plastic, and experiences during the sensitive window of childhood can have profound and lasting consequences. Associated with dysregulated immunity, allergic diseases are increasing in childhood and represent a leading cause of morbidity, yet contributing mechanisms remain elusive. As with the negative effects of ACEs on brain development and self-regulation, it is evident that the developing immune system is also jeopardized, and yet this study would be the first to directly examine mechanistic associations with allergy. Current estimates of allergy in North American children (40%) and rates of ACEs, including child abuse (27-32%) and severe household dysfunction (49%), underscore the scale and significance of each problem. Establishing mechanistic links between childhood adversity and allergy demands an interdisciplinary and novel design. Linking sociology and psychology with immunology and physiology is rare and requires a unique team with a transdisciplinary approach. Our team is well-positioned to apply a social-immunological framework, bringing together researchers from otherwise disparate fields with expertise in allergy and immunology, and psychosocial determinants of child mental and physical health, supported by both established and early career experts in sociology, diversity, proteomics, and physiology.

Toward a mechanistic assessment linking ACEs and allergy, we will integrate physiological and psychosocial measures to:

1. Characterize the association between ACEs and allergy;

2. Assess how various psychosocial risk and resiliency factors act as mediators/moderators; and

3. Examine the modulatory role of lifestyle/environment including the immune-microbiome axis.

If successful, this study will be the first to establish mechanistic links between ACEs and allergies. Our novel approach integrating and developing from the interface of unconventionally linked disciplines could lead to a paradigm shift in our understanding and approach to curtailing the pressing and lifelong health burdens of allergic diseases.

During early development the anterior pole of an embryo is a blank expanse of homogeneous ectoderm. However, voltage sensitive dyes reveal a pattern of membrane potential in which the future eyes are easily identified.  Cells destined to form the eyes in a Xenopus (frog) embryo are characterized by hyperpolarization of their cell membranes compared to surrounding cells.  Decreasing the membrane potential of these cells can interfere with eye development. Manipulating membrane potential of other cells can induce well-formed eyes in other parts of the body. 

What is the mechanism for establishing patterns of voltage among groups of cells?  Ion channels set the membrane potential in individual cells by controlling the transfer of charged particles across the cell membranes but groups of cells are directly electrically coupled by channels known as gap junctions that allow the flow of ions and small molecules from one cell to another.  Cells linked by open gap junctions have the same membrane potential.  Surrounding cells with closed gap junctions provide a distinct electrical boundary.

We propose to develop the first optogenetic tools to control gap junctions.  These tools will be designed for use in Xenopus embryos, a model system for the study of development and bioelectricity.  From libraries of small proteins (affibodies), phage display will be used to select proteins that bind specific regions of the gap junctions which will, when bound, interfere with activity.  Addition of a photoswitchable domain to the binder will allow control of gap junction function with light.

These tools will allow, for the first time, the manipulation of patterns of membrane voltage in groups of developing cells.  If we use light to close gap junctions in cells along the midline of a developing eye, will the frog grow two small eyes instead of one?  Such questions are currently impossible to answer. By characterizing changes in gene expression and anatomy that result from changes in patterns of coupled cells we will transform our understanding of intercellular communication networks within tissue.

The spatial and temporal precision afforded by photocontrol will allow unprecedented control of morphogenesis in developing Xenopus embryos.  What we learn in the frog may lay the foundation for future therapies to correct birth defects and regenerate organs.

CRISPR-mediated gene editing technology has revolutionized biology, biomedicine, and biotechnology. All CRISPR systems are based on guide RNAs (gRNAs) that direct Cas nucleases to specific loci in the genome. However, current delivery systems for CRISPR enzymes by viral transduction or transfection do not work efficiently for many important primary cell types and lack the spatial precision needed to target specific cells in heterotypic mixtures. Compared to non-specific biological vector systems, we propose to develop and employ a laser-mediated cell perforation approach, called plasmonic nanoparticle-assisted optoporation, for precise and efficient delivery of CRISPR enzymes at a single cell level. The optoporation as a membrane disruption-mediated delivery system is able to initiate a transient perforation in the membrane of nanoparticle-targeted cells by using ultrashort laser pulses, thereby leading to the internalization of genetic materials without affecting the viability of the cells. Our novel optoporation technology will be combined with different CRISPR enzymes to allow the efficient and selective modification of single cells in small culture volumes. To improve delivery of gene editing enzyme complexes, we will focus on a recently described CRISPR nuclease called CasΦ, which is much smaller than Cas9 and other conventional nucleases, and therefore more amenable to optoporation-based delivery. We will develop state-of-the-art technology for site-specific markerless gene editing of primary cells and organoids, and it can be scaled to many individual samples in a parallelized manner. The optimized optoporation approach will enable an efficient introduction of recombinant gRNA-Cas ribonucleoprotein complexes for the isolation of clonal gene-edited populations and screening applications in powerful arrayed CRISPR library formats. The laser optoporation-based gene editing system will have transformative and groundbreaking applications in array-based genetic screens and cell-based engineering of primary human cells for a broad range of therapeutic applications. These applications will include the targeted modification of discrete cell types within multicellular organoid and tissue model systems, the markerless genetic modification of rare primary cell types for cell-based therapies, and multi-parametric high content CRISPR screens in genome-wide array formats. 

With the commercialization of 5G, the world is crossing the Rubicon, marching towards a future where the physical and the virtual become one, where wireless technologies transcend convenience and productivity, fusing into the very existence of every human being.

Powering this deep transformation are novel technologies in communications and sensing for wireless systems with pervasive and powerful devices. These systems involve a massive number of antenna units or devices densely populated along continuous geometric configurations. For example, future Smart Cities demand seamless communications among radio-configurable fabrics with thousands of antennas along city infrastructures, ubiquitous wearable devices, and a myriad of drones.

The analysis of such systems with massive spatial dimension calls for a new theoretical framework. Current theories for the spatial domain, built upon discrete mathematics, are intrinsically awkward for large scale or multi-scale systems. Inspired by the success in mechanics and biology of modeling large populations of objects through continuous mathematics, we propose to develop a new mathematical foundation to model and exploit the spatial domain of wireless communications, upon continuous mathematics, in particular differential geometry and partial differential equations.

This presents numerous challenges. New connections need to be made between communication measures and mathematical objects. New mathematical concepts need to be developed. New mathematical operations need to be invented. The consistency of these concepts and operations needs to be proved. Once this mathematical foundation has been laid, more challenges will appear. Can the resulting differential and integral equations be solved? If so, how should the solutions be interpreted in the design of wireless communications systems?

Current theoretical framework based on discrete mathematics has become an impenetrable obstacle for the design of future intelligent and ultra-dense wireless systems. This proposal aims at creating a new mathematical framework through continuous mathematics to deal with the massive spatial dimension of future networks. Success of the proposed research will define the key performance indicators, enable rigorous analysis, and lead to new powerful solutions to the integration of the physical and virtual worlds. It will open a new research field and have groundbreaking impacts on all aspects of wireless communications.

Brain-derived neurotrophic factor (BDNF) is a key molecule controlling brain development and plasticity. It is essential for nervous system function and is reduced in neurodegenerative and psychiatric conditions such as Alzheimer's disease and depression. Increasing brain BDNF levels improves these conditions in animal models and human subjects. However, BDNF cannot be easily delivered to the brain therapeutically, as it does not cross the blood brain barrier. The objective of this research is to develop an effective way of delivering BDNF or BDNF inducers across the blood brain barrier. This would provide major therapeutic benefits for a variety of neurological and psychiatric disorders.

Scientists have attempted for decades to modify BDNF for transport across the blood brain barrier, with little success. Instead, we propose to use red blood cell membranes studded with targeting molecules as delivery vessels to carry BDNF or BDNF inducers across the blood brain barrier. We have developed red blood cells that can be loaded with such cargo.  Targeting molecules embedded in the red blood cell membrane are selected to direct the loaded red blood cells to specific tissues. Targeting molecules include viral proteins and molecules that bind to endothelial cell transporters. We have embedded viral proteins such as the covid spike protein in our membranes . Other molecules, such as neurotropic viral proteins or antibodies to blood brain barrier transporters like the transferrin receptor, will be embedded in the red blood cell membrane to provide a novel and targeted approach. Red blood cells loaded with BDNF and including membrane-embedded targeting molecules will be tested in vitro for their ability to deliver cargo across (1) blood brain barrier endothelial cells and (2) novel blood-brain-barrier constructs differentiated from human induced pluripotent stem cells (iPSCs). iPSCs will be used from both healthy and Alzheimer's disease subjects.

Red blood cells can also be loaded with peripheral molecules known to cross the blood brain barrier and upregulate brain BDNF, such as FNDC5/irisin, osteocalcin or lactate. Directing loaded red blood cells to the blood brain barrier will allow targeted delivery of high amounts of these normally circulating molecules to a location where they can efficiently cross into the brain. Focused ultrasound can also be used to create transient holes in the blood brain barrier through which loaded red blood cells can enter.

Timing is everything for embryonic cells to decide their fates. Problems in the coordinated timing of genetic expression lead to malformations, e.g. congenital scoliosis. It is thus crucial to understand the laws of developmental timing, to better understand such diseases. But there is still no clear way to understand  how laws of (macroscopic) phenomena at the organism level are (microscopically) encoded by the genome. Theoretical progress to go beyond molecular biology mechanisms  would have major fundamental impact while paving the way for applications in synthetic biology.

Summary of the approach

Vertebrae formation is controlled by multiple genetic oscillators, emerging  at the embryo level into a macroscopic segmentation clock. Waves of genetic expressions propagate from a growing tail bud and stabilize into a pattern encoding future vertebrae position. While the process is conserved between species, its precise modalities are extremely variable. Different species display different wave patterns, implicating different genes and pathways. Because of this, it has not proved possible to fully understand this process by focusing on the microscopic (molecular, cellular) details. We propose to break this traditional logic to focus on the macroscopic description, using a physics inspired approach, to establish the laws of developmental timing.

Research objectives

Spatio-temporal segmentation oscillations can be routinely observed experimentally in multiple model organisms. Multiple handles and controls (microfluidic devices, cellular reaggregates) will allow us to quantitatively probe and perturb the system just like a traditional experimental system in physics. We will  :

1. experimentally conduct a cross-species study to map the phenotypic space, focusing on the description of the wave patterns in embryos and in reaggregates, and their response to targeted perturbations.

2. quantify the phenotypes and their non-linear variations, to extract the principal non-linear modes in the phenotypic space.  Theoretical focus will be on coarse-grained or macro observables  and will include scaling properties of tissues, phase response curves and coupling functions between cellular oscillators.

3. leverage cutting edge theoretical and numerical techniques, such as evolutionary algorithms, neural differential equations, and physics based approach for coupled oscillators to build the geometric laws of developmental timing 

Nanoparticle-enabled RNA delivery holds tremendous promise to silence pathological gene expression in a variety of diseases, especially cancers. The recent FDA approval of Onpattro, a lipid nanoparticle-based siRNA drug for the treatment of polyneuropathies, demonstrates the clinical feasibility and success of this strategy. However, effective siRNA delivery and cellular internalization in extrahepatic tissues remains substantial barriers in the field of nanomedicine. Most nanoparticles rely on their long blood circulation to passively extravasate and accumulate in the tumour interstitium over a period of days (a.k.a., EPR effect), but this strategy is unsuitable for RNA delivery vehicles since it negatively impacts the bioavailability and therapeutic efficacy of siRNA drugs.

Recently we discovered that the inclusion of a non-toxic EDTA-lipid into a lipid nanoparticles (LNP) leads to an impressive 10-fold enhancement in cellular internalization and rapid in vivo tumour accumulation compared with conventional delivery vehicles. Our nanoparticles, named `express-LNP', offer unprecedented advantages for siRNA delivery by combining a favorable pharmacokinetic profile (~6 hour blood half-life) with rapid and efficient delivery to cancer cells. Further modifying these express-LNP with ionizable lipids, we have achieved 90% siRNA encapsulation efficiency and demonstrated effective gene silencing with in vitro knockdown assays.

Express-LNP unite the highly desirable features for high siRNA loading with the rapid and efficient delivery to tumour cells in vitro and in vivo. Therefore, they hold tremendous promise as a siRNA delivery platform to improve cancer management with novel RNA therapeutic targets.

Prostate cancer (PCa) poses significant clinical burden as the second most common malignancy in men and the third most common cause of cancer-related death worldwide. While localized PCa can be curative, the 5-year survival rate for patients presenting with metastatic disease is as low as 30%. Through genome-wide as well as targeted functional genomic screens, we identified hundreds of protein-coding and noncoding RNAs that confer essentiality of prostate cancer cells. These essential genes are potential therapeutic targets, but only a handful can be targeted by traditional strategies such as small molecule inhibitors. In this proposal, we will use the express-LNP platform to target selected essential genes and test the efficacy in vitro and in vivo. 

Major Depressive Disorder (MDD) and Bipolar Disorder (BD) are leading causes of disability worldwide. Longitudinal studies show that relapse is very common and clinical remission is seldom accompanied by functional recovery. Such functional impairment is associated with an economic burden to the individual (job loss, disability) and to the society (emergency, medical costs). Despite multiple "first-line" medications being available, the reality is that the treatment choice is still largely based on "trial-and-error". One of the reasons behind the limited progress in drug development in mood disorders is due to the lack of understanding of the exact effect of the action of antidepressants and mood stabilizers in the brain. To overcome this gap, the field needs to understand which specific medication is more likely to help the individual in front of us. A major barrier to targeted treatments is the lack of access to live neuronal tissue from patients. In this sense, a promising avenue to pursue is the generation of patient-specific 3D brain tissues in vitro. Human pluripotent stem cell (hPSC)-derived 3D- cultures- also called organoids or spheroids -recapitulate complex developmental processes, cell-cell interactions, microenvironments, tissue architectures, and extended temporal dynamics that are inaccessible in traditional in vitro cultures. In the proposed study, experts in the areas of psychiatry and molecular biology will generate brain organoids from individuals with bipolar and unipolar depression and will map the genome-wide changes in gene expression (RNAseq and single-cell RNAseq) and proteins (mass spectrometry) of individuals with BD and MDD. We will treat the organoids with first-line treatments for BD and MDD, such as mood stabilizers (e.g. lithium) and antidepressants (e.g. citalopram, duloxetine) to assess which medications best reverse the pathogenic molecular (gene/protein) profiles. Then, using this biological information, we will treat the same patients with the medication that most effectively reversed the pathogenic profiles. If this high-risk, high-reward project succeeds, it will provide a strong rationale for future clinical trials that will dramatically change the current practice in the field of mood disorders, reducing the direct and indirect costs associated with failed treatments in these major mental disorders.

Hospitalised children undergo an average of approximately 7 painful procedures a day in Canada, often requiring pharmacological intervention to reduce pain and anxiety. Several potential anxiolytic agents are available, differing in adverse event profile, duration and degree of pain and distress reduction, and route of administration (intravenous, oral, intramuscular, intranasal). This variation has contributed to a lack of consensus on the optimal agent among clinicians and a request for more clinical research in this area.

However, a direct comparison of all paediatric anxiolytic options requires an unfeasibly large sample size and has inherent difficulties comparing treatments with diverse profiles. Our novel proposal builds on the current clinical evidence and combines evidence synthesis methods, decision analysis, health economics and biostatistics to design a viable research program that will reduce clinical uncertainty in a cost-effective and timely manner. We will use methods from decision analysis, known as Value of Information (VoI) methods, to target research towards gaps in the current body of evidence that restrict clinicians' ability to select the optimal anxiolytic. Specifically, this project will:

(i) synthesize information from published research on clinical outcomes (i.e. pain and distress reduction, adverse effects) and costs for the different therapeutic interventions to understand how clinical choices for anxiolytics are made.

(ii) Employ VoI methods to assess what, if any, additional research should be carried out to guide clinical decision-making.

(iii) Undertake a pilot study to assess the feasibility of our proposed research strategy.

To date, these elegant design methods have been chiefly presented in theoretical terms and have not been translated effectively into clinical research. A key reason for this is the difference between determining statistical significance, usually required in clinical research, and supporting decision making using decision analysis. Thus, this project will leverage the team's interdisciplinary expertise to overcome this hurdle and successfully translate VoI into clinical research. This has the potential to improve efficiency and reduce costs across diverse disease areas by designing research that supports clinical decision-making. This project will also inform a key clinical question; what is the optimal anxiolytic agent and route for use in children?

The United Nations predicts that the world population will reach 11 billion by 2100. Feeding this many people, and doing it in a sustainable and environmentally responsible way, is a global challenge that requires significant attention. Grains and oil-seeds are critical to feeding the world and contribute approximately $10 billion to Canada's GDP, but harvesting them is challenging due to the plants natural tendency to disperse their mature seeds through a process called seed "shattering". Once shattering occurs, the seeds fall to the ground and cannot be harvested, so farmers must balance between avoiding shattering and harvesting immature plants, which results in losses of up to 50% of the crop.

The standard approach to solve this problem is to breed plants that do not shatter. While this has been effective for some crops (e.g. wheat), it has proved challenging for others (e.g. canola) and may limit the ability to select for other important traits to increase the nutritional quality or resistance to varying climates and diseases. Instead, we propose a novel, harvesting technology that consists of a spray-on netting material to physically prevent shattering until the optimal time to harvest mature crops. This netting will be a water-based spray that solidifies into a net-like material that is nontoxic, biodegradable, and easily separated from the grain after harvest. This game-changing technology will shift the paradigm for increasing crop yield from a genetic problem to an engineering solution.

To create this material, there are several research challenges that must be addressed that require a unique combination of expertise from agronomy, synthetic chemistry, and chemical engineering. First, the spray-on netting must be easy for farmers to deploy using standard tractors and spray booms. Second, the spray system must reliably generate a net-like structure: either from a polymer-stabilized, low-density foam that forms a liquid network between bubbles, or using a polymer additive to spray long liquid strands that overlap into a network. Finally, a polymer must be synthesized with strict performance requirements while also being safe for the environment and human consumption. For example, the polymer must provide the interfacial and rheological properties necessary to generate a net-like structure from the spray, as well as be soluble in water, rapidly cure (solidify) in sunlight, and produce a mechanically robust solid netting.

Demand for pilots in Canada is projected to exceed training capacity by 2030. Recruiting, training, and retaining pilots will be significant issues. Further, only 6% of pilots are female, and to succeed most women in aviation are taught to learn, think and act like men. Competency-base education (CBE) for aviation, with protocols developed to account for gender based physiological, psychological, and communication differences, is expected to allow professionals to achieve licensure more quickly and at a higher standard by aligning instruction with contextualized training and facilitating faster development of the required knowledge, skills, and attitudes. Data to guide CBE development and model-based assessment tools for aviators are lacking. Regulatory vision requirements for pilots affect recruitment pools and pilot retention. Undoubtedly, vision provides critical sensory input when flying an aircraft so the dearth of evidence supporting these requirements is surprising. Existing criteria for assessing vision are generic and do not consider whether standards align with professional practice requirements. Remediation of these deficiencies is critical for aviation of the future.

The overarching aim of the proposed interdisciplinary research is to develop a novel scientific approach to pilot training and assessment as well as evidence based vision requirements (EBVR) that will dramatically change flight education practice, guide regulatory standards and help mitigate the aviation gender gap. We will use flight simulation, gaze behaviour, cognitive task analysis, consensus modeling, computational modeling and artificial intelligence methods to develop objective metrics for pilot competency at different stages of training (i.e., novice, intermediate, expert). We will also investigate the effects of visual function on gaze behaviour and pilot performance for different levels of task difficulty and pilot expertise. The approach is highly innovative: in Canada there are no known flight simulators used to study pilot training or visual standards and no other research of this kind is being done. The development of competency metrics and EBVR for aviation represents a significant high-risk departure from the status quo with potentially high-impact. We will draw on the team's unique collective multidisciplinary expertise in the fields of aviation, vision science, gaze behaviour, skill learning, kinesiology and human factors engineering to accomplish this.    

This project will design, implement, and evaluate a new programming language for the live coding of dance and movement. The language will allow researchers, artists, and learners to explore the movement of virtual dancers (eg. 3D representations of human bodies) in algorithmic ways. The language will be available in a zero-installation, web browser environment, and as such, will represent an expansion of the ways in which we can engage both with algorithms, and with concepts of motion.

Existing research on live coding has produced new domain-specific languages oriented to the nimble exploration of specific types of creative expression, such as music and generative visuals. These languages have provided significant educational and artistic opportunities around those types of expression, as well as more generally with respect to code literacy. Focusing on the choreography of three dimensional objects (ie. virtual "dancers"), we hope to take advantage of the high salience of dance and motion to provide additional, meaningful ways for people to engage with algorithms, and with movement.

This work brings together research on choreographic scores and notation systems with research in programming language design, in the specific context of live and creative coding. The risk in this work stems from the difference between these two traditions of representation: Choreographic notations tend towards the concrete and representational, making motion legible in advance;  Programming languages tend towards the abstract, describing chains of computational effects or actions rather than their results. To meet the danger of producing a new language that is either excessively descriptive of motion or excessively abstracted from it, we will iteratively design our language starting from complex representations of motion. The primary types in our language will be functions that produce complex motion, and our language will provide economical, live-coding-ready notations for composing and transforming these functions.

The method for this project involves four components: (1) design of a choreographic language; (2) implementation of the language, both as a standalone environment and as a library for integration into other web-based environments; (3) creation and curation of 3D models and motion data (gathered with motion capture techniques) as a key resource activating the language; and (4) evaluation of the language in various artistic performance and educational settings. 

"sugar is part of our culture/it's in our history, it's our identity/we should be proud of our industry /cause sugar made us free."

The lyrics of this 1982 Barbadian calypso lament the decline of the sugar industry, gesture towards the centrality of sugar in shaping modern diets and global economies, and call attention to the historical and affective dimensions of sugar. This narration of history erases Barbados' infamous position as the world's first Black slave society in the 17th-19th centuries and its contemporary notoriety as the `amputation capital of the world' for its high incidence of diabetes-related amputations. Caribbean historians have linked this growing epidemic of diabetes not merely to the prominence of sugar within citizens' diets, but to its connection with the emotional, physical and nutritional brutality of slavery. Yet, the dehumanizing work of the race and gender categories of slavery and its impact on the uneven distribution of diabetes among Black Barbadian women has yet to be confronted within public health research. As the COVID-19 pandemic exposes the legacies of coloniality and the vulnerabilities which inhere in the region's reliance on tourism and services, imported food, and women's unpaid care work, these issues become more urgent.

We thus propose to: 1) identify how socio-historical factors like slavery, sugar production, and coloniality affect the racialized and gendered systems and risk factors related to type 2 diabetes in Barbados; 2) produce socio-historically informed (e.g., gender-based) public health policy recommendations on diabetes management and care and; 3) foster community engagement and knowledge production on the historical and gendered dimensions of diabetes in Barbados.

Our interdisciplinary approach combines feminist theory, social science, historical and arts-based methodologies. Guided by a transnational feminist framework, we will conduct archival research on sugarcane production, gender, race and slavery that will co-inform 100 in-depth interviews with type 2 diabetes adult patients, caregivers and medical professionals. Next, we will work closely with local visual artists to share aspects of the research and co-create an arts exhibit that explores the gendered, embodied and historical complexity of diabetes in Barbados. This project promises generative insights across a range of disciplinary fields and will have transnational implications on this global epidemic across the Black diaspora.

Congestive heart failure (CHF) is a disease that reduces the pumping power of the heart, resulting in a lower quality of life and significantly increasing morbidity and mortality rates in patients. Patients with severe CHF have typically a mortality rate up to 50% within five years. Furthermore, it is anticipated that as a result of the increase in life expectancy, the number of patients with CHF will be constantly increasing in the next decades. Patients with severe CHF typically require transplants but the number of donors is significantly low leading to a long waiting period during which the state of the patient keeps deteriorating. An alternate solution is the use of engineered heart assist devices. However, despite some recent developments, most of devices are limited to left ventricle assist devices and have significant limitations mostly due to the required invasive surgical procedure or their inability to deliver a realistic pulsed cardiac flowrate. The main objective of this proposal is to develop a new innovative non-invasive heart assist device capable of reproducing realistic flow conditions in heart cavities. The new innovative concept is based on a stent-activated membrane arrangement inserted using a transcatheter approach inside the left and/or right ventricles in order to reproduce a pulsatile flow at different heart rates accommodating patient needs in terms of cardiac output. This original proposed design is expected to lead to minimal hemolysis, one major limitation of current existing designs. The team has already performed some preliminary measurements on a working custom-made prototype with very positive preliminary results. In this proposal, advanced experimental and numerical approaches will be used. In silico simulations will be performed in order to optimize the design and simulate patient-specific conditions. The simulations will be validated and complemented by in vitro measurements on a custom made heart duplicator to evaluate the hemodynamic performance of the system under realistic conditions. The results of this proposal have the potential to represent a game-changer in the treatment of patients with congestive heart failure. 

Excessive inflammation has profound system-wide effects on the health of humans and animals. Inflammatory responses in the gut can be induced by opportunistic bacterial pathogens that secrete toxins and displace other gut microbiota. The pathogens Clostridium difficile, C. perfringens take an enormous toll on human patients and agricultural animals. Although human patients can be effectively treated with antibiotic drugs, resistant pathogens continue to arise. This is more problematic with food animals where prophylactic antibiotic use is increasingly prohibited. Probiotics have been employed to compete with pathogens but these have limited ability to target pathogenic microbes and resolve inflammation.

The objective of this project is to develop effective whole cell biotherapeutics that can be deployed to control opportunistic pathogens and the pathologies that they induce. The research approach will focus on the application of synthetic biology to perform smart microbial engineering to achieve probiotic organisms expressing surface receptor nanobodies capable of detecting opportunistic pathogens. Additionally, we will explore novel metabolic engineering approaches to exploit the yeast secretory system to allow delivery of anti-inflammatory cytokines and anti-microbial peptides to assist in clearing pathogens and resolving inflammation and tissue damage triggered by the pathogen.

A sub-clinical challenge model in chickens will be used to assess the effectiveness of the engineered probiotic to mitigate the growth-suppressive effects of necrotic enteritis (NE) induced by the opportunistic pathogen C. perfringens. The effectiveness of the probiotic in relation to antibiotic drug treatment will be initially screened in a pilot study testing a number of different probiotics and doses for promoting resistance to NE-induced growth depression.  From the pilot study, the most promising candidates will be tested under simulated commercial conditions.  Growth, feed efficiency, pathogen load, and indices of systemic inflammation will be used to assess the efficacy of the engineered probiotic.

This project will lead the way to generating first-in-class smart biotherapeutics to serve as effective treatments for pathogen induced inflammatory syndromes and serve as a platform to advance the development of engineered probiotics.

Recuperating the devastation of the Capitalocene is urgent given growing recognition of ecological challenges and climate-related risks around the globe. Women and children who are targets of annihilation through capitalism and colonialism, specifically, BIPOC (Black, Indigenous and people of colour), understand the value of non-hegemonic knowledges/practices to heal ruined places. The challenge is in recognizing their unconventional ways of knowing and doing as legitimate healing alternatives to the technological "fixes" that damaged blasted landscapes.

This research will congregate a diverse team of scholars, students, Indigenous activists, Elders, knowledge keepers and healers to lead an interdisciplinary project that draws from and contributes to education, anthropology, biology and the arts. Our approach is to codesign recuperative practices in "blasted landscapes" in Canada and Ecuador in an urgent effort to address the damage of extractive capitalism and exploitative investments. Our sites- built on the dispossession and enslavement of BIPOC-are connected through capitalist, extractive industries that have left the environments forever changed.

The ecological devastation of these sites is the point of departure for this project. We ask: How are women and children who identify as BIPOC staging unconventional relations with the land to regenerate "blasted landscapes"? And how are they activating alternative modes of belonging in the process? How can we approach blasted landscapes as sites for imagining other futures?

Our objectives are: (1) codevelop interdisciplinary research methods to serve Indigenous and other racialized women and children  as a commitment to social and political change; (2) collaborate with these communities to engage in regenerative practices within blasted landscapes; (3) generate insights and knowledge from the margins of social and scientific norms as the basis for addressing environmental risks in the context of settler colonial nations and a vampirish extractive capitalism; (4) foster collaboration across sites where resistances and solidarities are forming against the destructive forces of global capitalism and its colonial webs of inequity and ecological devastation; (5) codevelop materials with communities to disseminate our learning.

Age-related macular degeneration (AMD) affects ~1.4 million Canadians (a number projected to grow as Canada's population ages) and accounts for ~90% of new cases of legal blindness. The "dry" form of AMD is currently untreatable, while the more advanced "wet" form (10% of cases) is only treatable by chronic monthly injections of anti-vascularization drugs that are expensive, uncomfortable for patients, and time-consuming for doctors. Developing a therapeutic that could stop AMD progression at an early stage, or avoid its onset entirely, would thus have significant societal, health, and economic benefits. Although AMD is traditionally understood as a disease of the retinal pigment epithelial cells, recent research suggests that age-related liquefaction of the vitreous humour is critical to AMD onset. We hypothesize that by combining (1) early detection of vitreal liquefaction and (2) new polymer-based therapeutics that "re-gel" the vitreous, AMD can be delayed or prevented.

In this project, a diverse team of engineers, psychologists, ophthalmologists, and economists aims to develop and validate a new strategy for vitreal restoration. Vitreal liquefaction is linked to (1) the loss of chondroitin sulfate-rich type IX collagen, which exposes type II collagen to drive fibril aggregation, and (2) oxidative degradation accelerated by the reduced antioxidant potential of the vitreous upon aging. We will fabricate new long-lasting therapeutics based on zwitterionic polymers that mimic the high water binding capacity of chondroitin sulfate by grafting (1) the WYRGRL peptide that binds to the α1 chain of type II collagen (to prevent fibril aggregation) and (2) glutathione, a endogenous antioxidant (to prevent oxidative degradation). By monitoring changes in the elasticity of the vitreous humour via ultrasound, we aim to identify when intervention is required. In parallel, we will assess the potential for adoption of the therapy from the perspectives of patients (who would need to agree to therapy prior to substantial vision loss) and health systems (who would need to fund screening/early therapy to save on future costs), with the results directly informing therapeutic design.

Success would enable a paradigm shift in treating AMD and other ocular diseases linked to the vitreous (e.g. cataracts, diabetic retinopathy) away from the current emphasis on management toward a focus on prevention, preserving vision while potentially reducing long-term treatment costs.

In a growing digital, mobile, and technological era, expectations of processing times and volumes of data are increasing exponentially, as are energy demands. The key to addressing this challenge is to do more with less, thus innovations in faster and lower power electronics are needed. In recent years, materials based on molecular (e.g. nanomagnets) or two-dimensional (e.g. graphene) systems have shown tremendous magnetic/conducting properties. If these properties can be triggered or harnessed through the application of a small amount of energy, it is possible to drastically cut the energy consumption related to data processing and storage. Spin electronics (i.e. spintronics) is an emerging field that offers such a solution and are ideal candidates in the quest for superior next generation nanoelectronic devices that reduce power consumption while increasing memory and processing capabilities. Such devices take advantage of the spin degree of freedom of electrons and/or holes, and their ability to interact with orbital moments. In these devices, spin polarization can be controlled via spin-orbit coupling or through the use of magnetic layers as spin-polarizers or analyzers. Alternatively, spin waves can be used to carry spin current. The development of novel spintronic materials and innovative circuit architectures that take full advantage of spintronic phenomena, materials and devices is expected to yield pioneering spintronic applications (e.g. 3D spintronic embodiments for high-density memory and storage devices, development of artificial neurons and synapses for artificial intelligence based on spintronic devices, quantum engineering/computing).

This research proposal targets new materials by design: compounds created to exploit key attributes of organic and inorganic paramagnetic materials and their implement into molecular electronics. While rational design permits access to novel materials with new functionalities that combine magnetic, optical and transport properties, a further challenge is the dependence of physical properties on solid-state packing. Through crystal engineering and device design we will address this while amplifying spintronic interactions. Overall, this proposal breaks the conventions of spintronic design and development, introducing unprecedented organic radicals and multicentric-multimetallic materials into innovative device architectures thereby disrupting current paradigms in spintronic materials and applications.

Very little work has focused on the 30% of autistic people who have limited ability to communicate using speech. Not being able to share their thoughts and desires is arguably the most significant barrier these individuals face, severely limiting their participation in educational, social, and employment settings. Studies estimate that a lack of effective autism interventions could cost Canada $30 billion annually. Unfortunately, the most common communication interventions, involving training on the use of speech or picture-based communication systems, have not been shown to be effective for most minimally verbal individuals. This project seeks to explore novel, practical, and evidence-based assistive communication technology that will plug this critical gap thereby enabling fluent communication for minimally verbal autistic individuals and enhanced socioeconomic outcomes.

There are several novel factors that differentiate this work from previous technology-based communication intervention systems. First, through our community partnerships we will engage minimally autistic individuals as direct collaborators in the design of the proposed technology. Autistic people have traditionally not been invited to collaborate in the design and interpretation of research about autism. As a result, their lived experience has been absent from efforts to understand and intervene in autism, an oversight that has had serious negative consequences on the way people with autism are viewed and treated. Second, our effort is different from previous attempts since it recognizes that for many autistic individuals, communication issues stem from sensory, motor, attentional, and self-regulatory challenges and not from a lack of cognitive abilities. We will exploit Augmented and Mixed Reality (AR/MR) technology in combination with wearable sensors to provide these sensory-motor supports, which in turn would facilitate more fluent communication. The implementation of these supports will be shaped by insights from our autistic collaborators, their caregivers, professional therapists as well as by latest advances in autism science and sensory-motor interventions.

Through our technology, minimally verbal autistic people will be able to access age-appropriate education and will be better integrated in society. The adverse socioeconomic impact of autism will be mitigated through the significantly increased likelihood of these individuals and their caregivers joining the workforce.

Large-scale livestock production has increased food security, while also leading to unintended environmental consequences, including widespread algal blooms, drinking water contamination, and increased emission of greenhouse gases (GHG). In the past, crop and livestock production were integrated, allowing most livestock to be fed by local crops, and livestock manure to be applied directly to nearby cropland. Under current management practices, however, there is a frequent spatial decoupling of crops and livestock, leading to hot spots of manure production that contribute to: (1) runoff polluting nearby waterways, and (2) release of GHGs. The use of bioreactors to convert excess manure to energy would decrease such pollution, while increasing renewable energy production. While bioreactor technology is not new, their widespread implementation is still limited due to logistical, economic and policy constraints.

Our overall goal is to evaluate the feasibility of widespread use of bioreactors to improve water quality and reduce GHG emissions from a technological, economic, and policy perspective. We ask: (1) what are the environmental and economic trade-offs associated with transporting manure for spreading on cropland, (2) what are the optimal sizes and locations of bioreactors to process excess manure, (3) what are the policies that would encourage the use of biogas reactors and their full integration into the energy system? Specifically, we will use a spatial optimization approach to evaluate the economic and environmental feasibility of manure transportation and biogas reactors in Ontario. Using this model as an input, we will analyze the socio-economic implications of such integrative solutions to food-water-energy challenges.     

The significance of our work lies in developing a solution for a water quality challenge while also contributing to energy sustainability.  The novelty lies in bringing together widely different fields -- nutrient management and water quality with economics, energy systems and climate policy to address a critical need at the food-water-energy systems nexus. This is high risk due to challenges in addressing these questions at such a large spatial scale, from both a technological and policy perspective. Billions of dollars are spent each year to address water pollution - our project is high reward since it offers a solution pathway that would be economically viable, while contributing to energy sustainability.      

In Canada and globally, pharmaceuticals receive widespread attention as contaminants of emerging concern (CEC): pharmaceutical ingredients and excreted drug metabolites increasingly find their way into the environment, posing risks to ecosystems and human health. Wastewater discharge is a critical vector, because many drugs are not fully eliminated in wastewater treatment facilities (WWTF), even under optimal operating conditions. This project aims to transform the wastewater sector by deploying genetic engineering as a novel drug removal technology designed to function as a mega liver.

Drugs are broken down and absorbed in the human liver through cytochrome P450s enzymes. These enzymes are studied during the drug development process and, consequently, the specific P450 enzymes responsible for metabolic disposition of each approved drug are known. We hypothesize that exposing wastewater to these enzymes, ex vivo, will continue the job that the liver was unable to complete. Therefore, we want to upgrade wastewater microorganisms with CYP3A4, a key P450 enzyme involved in the metabolism of 60% of small-molecule pharmaceuticals. For our proof-of-concept, we will transpose the cDNA for human CYP3A4 into C. reinhardtii, a model microalga that readily facilitates gene transfer and occurs in wastewater environments. We will use fluorescents to trace expression of functional CYP3A4 in the engineered algae, characterize the tolerance and growth of our modified C. reinhardtii under representative conditions, and we will perform biodegradation experiments with the steroid estrogen 17α-EE2 and the antidepressant venlafaxine, two CEC's that are metabolized by CYP3A4. In partnership with select Ontario WWTF, we will tackle practical design considerations: upscaling and acclimation of the technology in existing infrastructure will be assessed by metabolic fingerprinting of in-situ and engineered microbial communities.

Our project pushes boundaries in wastewater technology by enhancing current bioaugmentation with targeted genetics, merging the fields of medical biotechnology and civil and environmental engineering. Our technology for drug removal promises a low-cost alternative to other tertiary treatment technologies (UV/ozonation), which require expensive infrastructure upgrades. As such, we will produce practical and sustainable Canadian-made technology ready for deployment globally.

In bone, the process of remodeling involves coordinated resorption and formation, carried out by transient cellular populations known as Basic Multicellular Units (BMUs) which replace focal packets of tissue. BMUs represent the fundamental quanta of bone physiology and their cumulative activities determine skeletal health through regulation of bone quantity, repair of microdamage and modulation of material properties.  Osteoporosis (OP), which afflicts millions and costs billions worldwide, is ultimately the result of imbalance summed across a multitude of individual BMUs. As such, modulation of remodeling presents a key strategy for preventing and treating OP. If BMUs can be reduced in number and size, slowed in their progression and spatially constrained to avoid coalescence into larger pores then the balance can be tipped in favor of bone formation. Traditional anti-resorptive OP treatments have the negative side-effect of eliminating remodeling whereas anabolic treatment is limited in duration and faces effect reversal after withdrawal. Directly observing and tracking the impact of these treatments on individual BMUs would represent a step-change in the study of OP and create a novel platform for optimization of existing treatments and the development of novel interventions. To date, study of BMUs has rarely been performed in situ (3D) and their activity has never been dynamically tracked over time (4D). Further, study of BMUs has been largely siloed within separate disciplines (e.g, biomedicine, pharmacy, engineering, mathematics). Unified computational models present an important step toward integrating what we know about BMUs and creating a virtual platform for studying treatment regimens; however, such modeling is limited by the lack of 3D and 4D data. Our team will overcome these limitations through a collaborative multidisciplinary approach which unifies expertise in bone biology, OP pharmaceuticals, animal models, synchrotron imaging and computational modeling. Ultimately, our vision is the development of holistic and predictive models - a virtual physiology of bone - to serve as a platform for understanding the etiology of OP and the improvement of treatment regimens. Our proximate goals include: 1) Direct observation of the impact of existing OP treatments on BMU activity within rabbit OP models using in vivo synchrotron imaging; and 2) Synthesis of these novel data into computational models of BMU regulation.

Cancer is the second leading cause of death in Canada but little is known about Canadian cancer disparities despite numerous international studies reporting disparities in cancer incidence and outcomes for people of African ancestry. These disparities reflect the interplay of social determinants of health, the environment and genetics. For example, American Black women have lower breast cancer incidence rates and lifetime risks than White women but higher breast cancer mortality rates. As North American Blacks often reside in low-income neighborhoods near polluting industries, these disparities may be due to an interplay of high environmental contaminants exposure and an ancestral genetic susceptibility. As the lack of Canadian cancer disparity data may be shortening the lifespan of marginalized communities, we will study a Black Nova Scotian community (Shelburne) who have an inordinately high incidence and family history of various cancers. This requires a high-risk framework incorporating natural and social sciences to determine if environmental, biological, genetic, socio-economic and lifestyle factors are associated with the high cancer incidence and mortality in Shelburne.

Research Objectives & Methods

1. Identify geographical hotspots of cancer incidence and deaths in partnership with Atlantic PATH, who investigate the link between genetics, environment, lifestyle and chronic diseases. The demographic and socioeconomic profile of Shelburne residents will be determined using questionnaires and cancer registries.

2. Create a biorepository and determine environmental exposures in Shelburne residents using biological samples (urine) to assess heavy metal and carcinogen levels.

3. Identify genetic changes that may explain an ancestral cancer susceptibility using whole genome sequencing of saliva samples.

Novelty & Expected Significance

Our first of its kind, interdisciplinary mixed-methods study will provide novel pioneering data on Canadian cancer disparities and positively impact the quality of life of a Black community. Identifying a genetic basis for cancer susceptibility in Shelburne will clarify the complex interactions between social determinants of health and genetics and yield large dividends in the short (locally) and long-term (nationally). We will create a framework for transformative and racially-inclusive biomedical research and translational medicine to help address racial and socioeconomic disparities in Canadian health outcomes.

Video games: a global phenomenon which, in Canada, are a multi-billion dollar industry. Almost 2/3 of Canadians from all age groups play games, evenly split between males and females. That means 23 million people play games in Canada alone. Videogames are clearly part of our lives and our culture.

Games are economically and culturally significant, but also technically significant. This technological significance is particularly true when looking at early computer/video games in the 1980s and earlier; these games were running on platforms constrained in ways that would be inconceivable to modern computer scientists. Even the simplest retrogame can be a programmatic and algorithmic tour de force under the hood. What's more, many of the techniques that were used still have modern applications, but we have to be able to find them, uncover them, and understand them in context.

We will construct a software-based Framework for Analysis of Games (FrAG) to assist with the technical analysis of early videogames including, for example, reverse engineering of their binary computer code. Our framework will allow us to ask and answer questions across large corpuses of these games, and to see patterns of human activity captured in these digital artefacts. We will be applying FrAG first to Atari 2600 games, then to the Fairchild Channel F (the design of which was notably led by a Black engineer) to gain an understanding of these games' implementation that is informed both technically and archaeologically.

Archaeologically, our work on videogames falls within the scope of contemporary archaeology, and more specifically the developing area of "archaeogaming". While computational techniques are routinely used in archaeology, they are overwhelmingly applied to traditional archaeology; digital artefacts have seen relatively little archaeological study, in part because of the level of technical knowledge required to understand them, an issue this archaeology/computer science collaboration addresses.

Our interdisciplinary approach benefits computer science, where software "archaeology" is not a practice involving actual archaeologists with expertise understanding how humans create and interact with technology; our work will result in new methods to study and understand the aging software that our society relies upon. Our work also benefits archaeology, in developing the study of digital artefacts and illustrating how they can be studied at scale.

The Theban Necropolis is a UNESCO World Heritage site comprised of tombs and temples near Luxor, Egypt. The tombs are often shallow excavations with entrances at the base of cliffs. The tombs hold evidence of rock mass collapses during construction through to recent deterioration leading to potential instabilities.

Climatic variations are known to cause rock to deteriorate, however, there is debate about the exact influence on crack growth rates. Due to lack of detailed observations and experiments on long-term crack growth in rock, since such experiments span many months or even years, current numerical tools are not capable of capturing the influences of climate change on crack growth. This leads to challenges in determining when instabilities will develop and problems designing preservation strategies.

To address these challenges, we propose to utilize machine learning (ML) to aid in analyzing existing climate data and crack growth indicators to predict instability. A ML algorithm will be trained on current measurements (weather & crack movement), then on historic climate & photographs of crack growth. Ancient climate records and models (Nile sedimentation, tomb flooding & collapses) could be used to back analyze the influence on crack growth with time. With the expertise of geotechnical engineering, geology, archaeology, data and climate science, the objectives below can be met:

1)  Align global climate change models with ancient Egyptian records and specifically local, observations and measurements made of the site, to develop an accurate timeline of significant events.

2) Develop and validate an ML algorithm that captures the climatic influence on long-term crack rates to pin-point the key input variables that lead to crack development.

3) Back-analyze selected sites of interest to understand the prevailing conditions that lead to the current state of stability and therefore develop guidelines for preserving the stability into the future.

The novelty of this research is in the combination of machine learning with archaeology and geological engineering. Machine learning in both fields is in its infancy, however, such techniques allow for nuanced behaviors to be extracted from large and complex data sets as in this project. Understanding the current measurements, past influences and applying it to predict future instabilities will help to identify key areas for protection and aid in preserving this UNESCO site for generations to come.

Anterior cruciate ligament (ACL) injury is a common knee injury, often disproportionately affecting otherwise young, healthy and active individuals. ACL-injury is associated with up to 90% risk of developing post-traumatic osteoarthritis (PTOA) later in life. The disease etiology includes a cascading chain of events affecting the whole joint, including changing bone mechanics. Importantly, PTOA has no treatments. We propose to change the trajectory of early bone changes using off-label pharmaceutical intervention. This will utilize a team led by a mechanical engineer and an endocrinologist who will combine their technical skills to monitor bone mechanics through modeling and advanced imaging with a novel pharmaceutical treatment and comprehensive clinical assessments. Halting early bone changes may result in a new treatment leading to improvements in patient quality of life, reduced health care costs, and increased number of pain-free years, contributing to lasting economic benefits.

Current clinical indications for PTOA often occur at the onset of pain and cartilage degradation, which is beyond the period to reverse the cascade of negative joint adaptations. We know that major bone changes occur in the first 4-6 months after an injury, leaving a short window of time to intervene. A promising approach for early intervention is to use anti-resorptive drugs known as bisphosphonates (BPs). Recent randomized control trials have shown limited benefits of the use of BPs for middle- to old-age patients with long-term knee OA, however, their application in the specific post-injury acute phase is a novel strategy that has never been tested. A short and limited time-course of anti-resorptive treatments will alter the bone outcome and consequently the disease progression affecting all the tissues in the joint in PTOA.

Our proposal to apply a well-established osteoporosis treatment to PTOA requires a unique combination of engineering skills for modeling and imaging with clinical skills for patient safety and efficacy. We propose to recruit a small cohort of patients with an acute ACL-injury and test the intervention using a simple, single 20-minute intravenous dose of zoledronic acid (effectiveness of up to a year). Follow-up imaging visits, clinical assessment and bone strength using finite element techniques will provide critical evidence of significantly reduced alteration in joint structural changes in one year and a new treatment option for PTOA.

Schistosomiasis affects over 200 million people worldwide with more than 90% of the global burden in African settings. Children and the impoverished are disproportionately affected, and chronic infection leads to significant morbidity and mortality. Current World Health Organization (WHO) strategies aim to curb schistosomiasis morbidity through Mass Drug Administration (MDA) when infection prevalence exceeds specified thresholds, and while MDA alleviates morbidity, there is growing concern for the development of antimicrobial resistance (AMR). Because there are few drugs that effectively treat schistosomiasis, AMR in these settings would be catastrophic. Schistosomiasis-related morbidity is compounded by the low sensitivity of diagnostic laboratory tests used to identify regions in need of MDA. The WHO has highlighted this as one of the most pressing public health issues of our time.

This project aims to develop, validate, and implement a rapid, automated, cost-effective point-of-contact diagnostic test for schistosomiasis to enable African public health programs to more precisely guide MDA strategies. We aim to use point-of-contact schistosomiasis diagnostics to rapidly identify regions where MDA is appropriate, and further identify lower-prevalence settings where individual test-and-treat strategies are recommended.

Our approach is first, to further develop and validate mobile phone microscopes with the capability to diagnose urinary schistosomiasis. Second, we aim to integrate Artificial Intelligence (AI) technology for the automated diagnoses of urinary schistosomiasis. Third, we aim to field validate a combined approach of mobile phone microscopy for the automated diagnosis of urinary schistosomiasis coupled with existing, inexpensive rapid diagnostic tools for gastrointestinal schistosomiasis.  This will allow for a simple, inexpensive, comprehensive and rapid schistosomiasis screening platform tailored to low-resource settings.

A successful platform could be integrated into routine public health screening and treatment programs in African settings to efficiently screen large geographic regions and to guide public health approaches on MDA implementation. The goal of such a program is to judiciously use anthelminthic agents in MDA campaigns with the goal of decreasing the potential for AMR, and to lower costs by more effectively utilizing limited public health and laboratory resources.

BACKGROUND

Neurodegeneration (NDG) is the primary driver of disability in multiple sclerosis (MS) and there is an urgent need to identify its underlying mechanisms, since current disease-modifying therapies target the immune response in MS without affecting NDG. RNA-binding protein (RBP) aggregation is widely associated with NDG in Alzheimer's and Parkinson's diseases, but its role in MS is unknown. Heterogeneous nuclear ribonuclear protein A1 (A1) is an RBP associated with NDG in MS and its animal models, and somatic A1 mutations identified in MS patients show altered A1 aggregation in tissue culture. Our team of computational modelers and molecular neurobiologists will design and screen A1-specific aggregation-disrupting peptides with the long-term goal of developing novel aggregation- and NDG-mitigating therapies with potential to inhibit disability and improve the lives of persons with MS.

HYPOTHESIS

Inhibiting A1 aggregation with computationally-designed and experimentally-validated A1-specific molecules will reduce NDG in MS.

APPROACH

We will apply innovative cross-disciplinary tools: optogenetics with live cell imaging, next-generation DNA sequencing, bioinformatics, molecular modelling, computational biophysics, and molecule engineering, to perturb pathogenic aggregation of A1. We will:

1. Identify a MS-associated A1 somatic mutation profile using next-generation sequencing of MS brains and measure the kinetics of mutant vs. wild-type A1 aggregation in primary neurons using optogenetics paired with live-cell imaging, and assay NDG by cell viability, stress granule formation, and neurite loss.

2. Computationally simulate the protein:protein interactions driving aggregation in the wild-type and mutant A1 proteins with molecular modeling.

3. Develop novel aggregation-disrupting molecule libraries against A1 with evolution-based ancestral reconstruction methods and structure-based screening, followed by validation with optogenetics.

OUTCOMES

Short-term: We will improve our understanding of A1 aggregation in NDG and demonstrate that A1 is a viable therapeutic target. Our in silico approach using mutation profiling to model A1 self-association overcomes a major challenge in modelling protein aggregation.

Long-term: Disrupting aberrant A1 aggregation and providing a computational pipeline for aggregation-disrupting peptides establishes a new therapeutic paradigm to inhibit NDG, and particularly to mitigate its associated disability in MS.

Imagine being able to understand the human brain cell by cell and seeing how we learn and how diseases progress in real-time. This depends on our ability to image the brain very precisely but also to interpret the information we collect. Quantitative high-throughput brain imaging is essential to make transformative progress in our understanding of the molecular mechanisms underlying neurodegenerative disorders. The complexity of the associated analysis task has been multiplied by recent technological developments increasing among others, the measurement accuracy and the volume of collected data. In order to capture all the richness contained in ultra-precise images, it is becoming increasingly important to transform how we analyse them to detect new and rare events in real time on multiple devices. Contemporary astronomy exists in just such a context: new telescopes bringing fainter objects and a wealth of new rare events into view.

This proposal brings together very separate fields to bear on the problem of quantitative imaging for the discovery of new structures: namely neuroscience, astrophysics, machine learning (ML) and optical microscopy.

The similarity in structure and noise properties of image data in optical microscopy of the brain and wide-field astronomy surveys provides a unique opportunity to develop innovative ML approaches for quantitative analysis and anomaly detection. We will leverage complementary measurements from both fields (e.g. spectral data in astronomy and time sequences in microscopy) to obtain data pairs that can be decomposed into a set of potentially related subproblems, and develop efficient algorithms that can share information between them. We will develop image analysis strategies relying on deep multi-task learning and generative adversarial networks to combine very different data types and modalities, learn across platforms, and discover new structures. Additionally, we will explore how ML techniques developed in astronomy (e.g. astronomical alert brokers) can be applied to the detection of rare events in neuroscience (e.g. sparse coding). The Co-PIs have extensive experience in both the data and machine learning contexts of their respective subfields, astronomy and optical microscopy. The analysis strategies developed in the project will be combined to not only improve performance in known tasks, but may lead to serendipitous discovery of new phenomena that cannot be detected with current state-of-the-art approaches.

Adverse childhood experiences (ACEs) refer to traumatic exposures before age 18 such as domestic abuse, violence, mental illness, substance abuse and poverty. ACEs can lead to disrupted neural, social and emotional development, and are associated with later high-risk behaviors, mental illness and physical health issues. An individual's ACEs are typically identified as they experience later life consequences.

Recent research has linked oral health problems (e.g., excessive teeth loss, caries) to ACEs in adults. Tooth formation and mineralization begin during fetal development, and tooth eruption completes at age 2.5 years. Analysis of children's primary teeth may yield information about early-life stressors and maternal adverse behaviours during pregnancy (e.g., smoking, substance use).This creates potential opportunities for early intervention.

The proposed study will assess the association between structural anomalies in children's teeth and ACEs. Exfoliated teeth will be collected from 50 children aged 6-10 years old in Toronto, Ontario. To detect structural anomalies (e.g., malformed enamel structure, tooth decay), the team will visually assess the tooth defects using innovative imaging technologies. Specifically, the Canary System (PTR-LUM) Enhanced Truncated Correlation-Photothermal Coherence Tomography (eTC-PCT) will create depth-resolved tomographic 3D reconstructions of tooth defects, and Microcomputed Tomography (MicroCT) will detect and quantify differences in mineral densities in hard tissues. To learn about ACEs, dental history and other relevant variables (e.g., child diet), the children and their mothers will be interviewed and dental records will be reviewed.

If an association between child tooth structure and ACEs is shown, next steps will be to repeat the study with a larger sample and then evaluate if the primary tooth structural abnormalities linked to ACEs can be detected during routine dental visits. Risks are that while the technologies are innovative for dental caries detection and treatment monitoring, they will not be sensitive to the structural anomalies linked to ACEs, and that ACEs will be under-reported by mothers.

This collaboration between dentistry, engineering, psychiatry, and health services research is timely because of increased rates of domestic violence, child abuse and other ACEs during COVID-19. As such, calls are growing to medical specialists to focus on prevention and early intervention for childhood adversity

The Problem: Why can we not effectively treat brain injury? Because we have not identified the molecular mechanisms leading to electrical failure and constriction of blood vessels in brain tissue which are caused by a process termed SPREADING DEPOLARIZATION (SD). Consequently, we lack molecular targets and biomarkers to help neurons survive from losing blood flow. So when you arrive in the emergency room with a stroke, a traumatic brain injury (TBI) or sudden cardiac arrest (SCA), there is no therapeutic drug to help you recover. Within 2 min of severe ischemia (lost blood flow), SD propagates like a wave through the brain at ~3 mm/min. More SDs arise over hours in adjacent tissue, causing more injury. This time period represents a THERAPEUTIC WINDOW to inhibit SD, a golden time to reduce impending brain damage. Yet we still do not know the molecular mechanisms underlying SD. Most clinicians think that the basic science of early brain injury is accurately documented in their textbooks. In fact, what they learn is poorly understood and inaccurate dogma.

Novelty and expected significance of this work: Our challenge to the conventional wisdom is original and justified, motivated by the continuing failure by neuroscientists and industry to develop drugs that reduce brain injury. SD arises within 1 to 2 minutes of lost blood flow and so is key to understanding destructive downstream pathways. Here, we propose and pursue new molecular targets for drug therapy. 1) Ischemic brain tissue releases one or more small biomolecules (an SD activator, SDa) which promotes SD ignition in the stressed brain tissue. The SDa does this by binding to what is normally a membrane pump, converting it into an open channel. Once SD is started the SDa is continually released, thereby driving SD and the brain cell injury that arises in its wake. To prove that this sequence is correct requires an inter-disciplinary team of 3 groups: Dr. Andrew`s neuroscience lab (record SD; collect rodent brain samples), Dr. Sivilotti and colleagues in Emergency Medicine (collect human cerebral spinal fluid containing the SDa), and Dr. Whiteheads Chemistry lab (identify the SDa and associated biomarkers).

High-reward objective: Both identifying the channel that drives SD as well as characterizing the SDa will allow us to target the SDa to block its release. This will halt ischemic SD, thereby protecting human brain cells that would normally die from stroke, head trauma, or sudden cardiac arrest.

The HIV pandemic remains one of the world's most intractable public health problems. Methods for pinpointing the sexual networks of HIV spread based on linking highly similar HIV genetic sequences are gaining considerable popularity in the field of HIV molecular epidemiology. Although this approach can identify previously unlinked transmissions, these data are often analyzed at great distance from those most directly affected by HIV epidemics. These remote analyses often mean new knowledge is removed from the lived experiences, economic, political and policy realities that could greatly inform the ethical application of network-derived information in "real world" programs. Do these new powerful techniques for identifying transmission patterns represent a major breakthrough to effectively tackle HIV epidemics, or do they signify the emergence of a highly intrusive surveillance regime in HIV science? We have analyzed several hundred HIV sequences within a large sex worker prevention program and noted several large, mixed transmission networks. Here we unpack the ethical implications of this rapidly growing new research area by directly engaging communities of male and female sex worker (M/FSW) activists living in Nairobi, Kenya in a critical knowledge exchange process with our study team. This will answer how, or if, these data can be ethically used to inform existing programs. Drawing upon a community based participatory approach employed by feminist and postcolonial scholars, our multidisciplinary team of basic and social scientists, policy makers, and local community health activists will 1) work through lay technical summaries of the molecular data to explore the possibilities and limitations of employing network interventions, 2) co-design and test, under carefully controlled conditions, a targeted pilot intervention that combines molecular network data with community knowledge and 3) critically assess and identify the emergent ethical issues, advantages and disadvantages of the tested intervention (when compared to conventional approaches). Opening up a critical and engaged dialogue with a vibrant local activist community, will offer insight into the potential uses and anticipated abuses of using such information to sharpen the focus of HIV epidemic prevention. The outcome of this process holds major importance to the development of policy frameworks that will guide the next generation of the global response. 

Depression is the leading cause of disability with more than 12% of Canadians affected during their lifetime. A significant proportion of this disability is due to deficits in emotional and higher-order thinking skills (metacognition), a third of Canadians with depression remain treatment-resistant with first-line treatments. Recent demonstration of rapid acting antidepressant effects of sub-anesthetic ketamine represents a breakthrough. However, several aspects of treatment response, including impact on metacognition and real-life functioning /disability remain unclear, and digital simulations to model real-life behavior in depression do not exist. We will develop a novel digital paradigm, which includes cognitive tasks combined with computational models of behaviour, and augmented/virtual reality scenarios accompanied by digital phenotyping of behavior. 

This pilot project will compare subjects with treatment-resistant depression before and after IV ketamine infusions on a digital paradigm to examine treatment response with following objectives: 1. Understand impact on metacognition; 2. Delineate personalized digital phenotype profiles; 3. Develop computational assays of treatment response.

The digital paradigm will include subjective measures (e.g. rating scales and questionnaires); objective measures (e.g. Electroencephalography and probabilistic learning tasks), and custom-designed virtual scenarios to assess metacognition and real-life behavior. Physiological and psychological responses will be analyzed with digital signal processing techniques employing biostatistical/machine learning algorithms accompanied by hierarchical Bayesian models of learning under uncertainty.

This is a high-risk/high-reward project to develop a novel digital paradigm for depression and demonstrate utility with rapid acting antidepressant-ketamine. It is a multidisciplinary initiative with investigators from psychiatry, anesthesia, biomedical engineering and data analysis, computational modelling, neuropsychology and philosophy. Dissecting ketamine's rapid antidepressant effect using the novel digital paradigm will enable deeper insights into aberrant perception, self-knowledge and self-realization, and real-life functioning in depression. Demonstration of the utility of the digital paradigm in developing computational assays and digital phenotypes of antidepressant treatment response has transformative potential to improve outcomes for Canadians with depression.

Colorectal cancer (CRC) is one of the leading causes of cancer-associated mortality in the world. Anastomotic leak (AL) is a major complication in digestive surgery and increases mortality and morbidity after the operation, in addition to decreasing quality of life. AL is also linked to an increased risk of cancer recurrence. Recent findings suggest that the gut microbiota is involved in AL development and may serve as a marker for it. High complexity gut metagenomics, however, represents a challenge to understanding the relationship between gut microbiota and AL, and the integration of data from a large number of patients for medical prediction remains a daunting task.

We propose to establish artificial intelligence (AI) algorithms (data-mining and machine learning) to predict AL risk, cancer recurrence and microbiota restitution by integrating high-resolution microbiome output with clinical data, tumor characteristics, and perioperative imaging. This will be accomplished by computing data derived from an ongoing clinical study with collection of fecal samples at multiple timepoints. Follow-up experimentation in human microbiota-associated animal (HMA) models will be deployed to identify underlying mechanisms using fecal microbiota transplantation. HMA models will be used to validate AI-generated microbiota profiles associated with AL and CRC recurrence, providing an unprecedented insight into the role of specific bacterial species in the healing of injured bowel and its link with oncological prognosis.

The project brings together a team composed of leading researchers and surgeons with established expertise in CRC, microbiome biology and AI, offering training and development opportunities in a multidisciplinary environment while promoting principles of equity, diversity, and inclusion. The proposed integrative AI system and follow-up experimentation is a highly innovative approach that may improve the identification of CRC patients at high risk of developing AL. While our proposal focuses on colorectal anastomosis, improving intestinal wound and anastomotic solidity through microbiome prediction will ultimately be relevant to an to a number of important traumatic intestinal interventions, including J-pouch surgeries, stricturoplasties, biopsies, and gastroduodenal surgery, among others. As such, the project could potentially improve patients' quality of life and substantially decrease hospital stays.

Global meat consumption has grown by 58% in the past 20 years. Economic development in Asia and increased consumption in the West is expected to further increase demand for meat. Livestock production to meet this insatiable demand is unsustainable due to high water consumption, greenhouse gas emission (15% of global emissions), accelerated soil erosion and pollution of waterbodies. The industry accounts for 70% of land suitable for agriculture and almost 30% of agricultural water consumption.

Current methods for meat production are wasteful and inefficient. It takes about 2-3 years to bring beef from farm to fork and consumes significant amount of nutrition and water, most of which do not directly contribute to meat production. Cultivated meat is an environmentally friendly and ethically appealing alternative as it decreases water consumption and greenhouse gas emission. Cultivated meat can decrease greenhouse gas emissions by 78-96%, land use by 99%, and water consumption by 82-96% in this sector.

Recently, tissue culture methods developed for regenerative medicine have been repurposed for growing meat aggregates (minced meat type granules) to address this environmental challenge. Nevertheless, research in this area is in infancy and a number of challenges including ability to produce at scale, dense tissues that are thick and fibrous with the full complement of cell types present in animal tissues have not been overcome in a scalable or sustainable manner.

In this project, we will build on our recent advances in biofabrication to develop scalable production methods to form thick, fibrous and dense animal tissues composed of both muscle and fat cells. We will also develop techniques to tune the fat composition of these tissues from lean to high-fat meat. Using bioprinting approaches we will develop the ability to incorporate fat rich and muscle rich regions that mimic the marbling in meat. We will also develop strategies to incorporate biophysical stimuli on these tissues in a scalable fashion to develop macrostructures such as muscle fibers that mimic the natural meat texture. An important component of the research will be the genomic and proteomic analysis of the tissues formed and their similarity to natural meat. We will also investigate the influence of serum free media on the viability and functionality of the cells during growth and differentiation. Finally, we will analyse all the bioprocesses developed for scalability and sustainability.

Text-intensive research in social sciences relies on the retrieval, organization, conceptualization and summarization of large amounts of text, with the aim to obtain insights on social science research questions. Typically social science researchers can only read and annotate limited amounts of text, hence the amount of text data must be constrained by limiting the scope of the research question. Furthermore, retrieval of relevant text data is carried out by key term searches, which risks missing relevant documents using unanticipated vocabulary, and including irrelevant documents simply because they happen to include the search terms. Text types that are of relevance to social science include parliamentary debate records, court decisions, news, and, more recently, social media data. This project introduces a novel methodological paradigm in social science research that employs natural language processing (NLP) and visual analytics (VA), to enable social scientists, to retrieve and make sense of large document collections. From a computer science perspective, the transition from laboratory evaluations to addressing real-world problems and the close interdisciplinary collaboration will advance the state of the art of the design of VA systems aiming for usability by social scientists, enabling them to analyze much larger document sets than has been feasible so far. To support interactivity, deep language models will be used to represent the semantics of text.  

Two interrelated projects focusing on immigration will serve as use cases. The first project will examine shifting views and social constructions of refugees to Canada through federal court decisions, parliamentary debates, news and social media from the 21st century. The second project will examine how COVID-19 is impacting the successful integration of immigrants and refugees in Canada. More specifically, we will be focusing on immigrants and refugees' socioeconomic and health challenges during the pandemic (e.g., accessing health care, mental health, post-migration lifestyle changes). Overall, we will introduce and formally evaluate a novel methodology for text-intensive social science research supported by novel VA. Risks include the adequacy of computing resources for the required NLP, the ability to capture nuances in the text relevant to the social science research questions, and the achievement of sufficiently usable VA designs that social scientists can learn and use.

Debate rages as Kingston struggles with the legacy of its most famous resident, John A. Macdonald, and his actions against Indigenous peoples whose lands and children were taken. Like communities worldwide, the city is at a historic juncture confronting legacies of racism and dispossession: the ousting of the Mississauga by the British; slave-owning by Loyalist leaders; high rates of incarceration of black and Indigenous persons in Kingston's prisons; and ongoing racialized patterns of poverty, undereducation and poor health. As patience dwindles and tensions mount, questions about heritage are high-risk and exceedingly difficult to solve. Yet success promises high rewards in the quest for justice and equality.

We propose a timely interdisciplinary investigation into how Kingston should confront the cultural narratives of its past. `Heritage' is often understood as the conservation of old buildings; it can seem hostile to economic development or progress, culturally exclusive or chauvinistic. Yet, as our Kingston case study demonstrates, heritage cannot be reduced to the built form of settler inhabitants; it comprises tangible and intangible cultural artefacts, places and practices, and includes a range of narratives and perspectives. Heritage provides a context of meaning, calling for stewardship of nonmarket value, `therapeutic landscapes', ancestral lands, or commemorative sites. Paired with Indigenous cultural resurgence and the inclusion of racialized perspectives, it is a vital social determinant of health.

The challenge of cultural heritage thus demands a novel, multipronged approach. Our group of scholars, both settler and Indigenous, in Philosophy, Politics, Law, Public Health and the Arts is a prodigious powerhouse. Key to our work is engagement with Anishinaabe, Haudenosaunee and racialized communities to formulate questions and share knowledge to 1) Critically investigate and subvert monument culture with new, decolonizing narratives to integrate different dimensions of heritage; 2) Redefine and analyse the public health impact of colonial culture that effaces the experience and knowledge of oppressed people; 3) Provide counter-narratives to white hegemonic discourse with community-engaged art practices. In uniting conceptual investigation, healthcare practice and cultural resurgence, we will forge new understandings of heritage, safeguard and revitalize sources of value, and improve the wellbeing of disadvantaged persons.

Proteome analysis is central to our understanding of biological processes and their dynamic nature, as well as to gain deeper insights into human health. Indeed, a typical human cell contains thousands of unique proteins that carry critical biological functions. Many of these proteins are thought to exist in post-translationally modified forms and to vary immensely in abundance. Despite the obvious importance of protein analysis, no techniques currently exist that allow the determination of protein sequences at the single molecule level.

Currently, mass spectrometry is the method of choice for protein sequencing, but it is constrained in terms of detection limit and dynamic range. Inspired by the revolutionary advances brought forward by nanopore nucleic acid sequencing, a protein sequencing technique that could read the exact sequence of individual proteins would be highly disruptive and bring a revolution to proteomics.

Here, we propose to exploit solid-state nanopores (ssNPs) to enable single molecule protein sequencing. ssNPs are molecular-sized holes in thin solid-state membranes that have emerged as a versatile tool to electrically detect single molecules. While nanopores have transformed DNA sequencing, numerous challenges remain to sequence a protein: (i) the charge distribution of amino acids is not uniform, complicating electrophoresis-driven translocation; (ii) the folded structure of proteins needs to be disrupted to thread them through a pore; and (iii) 20 distinct amino acids need to be differentiated. To tackle the critical hurdle of controlling protein motion through nanopores, we will use protein unfoldases as molecular motors, such as ClpX, positioned within nanoscale distance from a ssNP by a nanoporous membrane to unfold proteins and control their unidirectional movement through the ssNP.

We will use the unique and highly complementary expertise of our interdisciplinary team in unfoldase biochemistry and in nanopore biophysics, to offer original solutions to these problems. The project will involve: (1) Integration of ssNPs and protein unfoldases; (2) Characterization of this unique enzyme-assisted protein translocation system; and (3) Application of the novel system for protein fingerprinting by tagging specific residues, which would bring important advantages for applications such as biomarker detection for disease diagnosis. These results will represent a critical step towards single-molecule sequencing of full-length proteins.

Molecular imaging facilitates the non-invasive visualization of biological functions at a sub-cellular level. Within this field, the most sensitive methods for detecting molecular changes in living patients are single photon emission computed tomography (SPECT) and positron emission tomography (PET). Recently, PET has been used to classify and characterize dementias. High infrastructure costs limits PET to large population areas; thus, patients not located near major research centres may have trouble accessing these tests. Furthermore, rural residents cannot readily be recruited into large dementia research studies, such as the Alzheimer's Disease Neuroimaging Initiative (ADNI). This excludes an important cohort from these seminal studies. These issues result in a significant disparity in health care delivery between those in rural areas and their urban counterparts.

To address this problem, we propose to investigate the barriers faced by rural Canadians who want to access molecular imaging for dementia studies or diagnosis. Our first study objective will examine sociodemographic and health system factors limiting access to PET. By systematically investigating these inequities, we can provide a foundation to work upon improving these shortcomings. Our second objective will explore mechanisms to improve the "supply side" of PET by facilitating a shift to SPECT. Due to lower operating costs, SPECT is more widespread than PET and those in more remote locations may face less challenges when trying to access this technology. Both PET and SPECT rely upon injection of radiolabeled molecules to generate an emission signal. There are currently no SPECT agents available to image neurodegenerative diseases such as dementia. As such, we propose to develop suitable radiopharmaceuticals to visualize pathological protein targets associated with dementia. These include Tc-99m and I-123 radiolabeled probes targeting ß-amyloid (few preclinical candidates reported) and tau (no viable candidates reported).

Given the high diagnostic value of PET and SPECT imaging, equal access to leading edge techniques must be a goal for any universal health care system. Shedding light upon factors impacting access will facilitate future efforts to improve rural health care delivery. Furthermore, developing new SPECT imaging agents will increase access to nuclear medicine use for the diagnosis of neurodegenerative diseases in rural and remote areas of Canada. 

In a game-changing 2017 discovery, gravitational waves (GWs) were observed in concert with light for the first time. A burst of gamma-rays was observed within seconds of a GW signal from the merger of two neutron stars, but the glow of the resulting "kilonovae" explosion was not detected until nine hours later.

Understanding the complete evolution of kilonovae will unlock new insights into some of the most important outstanding questions about our Universe, including the structure of extremely dense matter and the origin of heavy elements like gold. However, this requires rapid, successful telescope follow-up of GW candidate events.

Successful identification of kilonovae is an extraordinary challenge. Progress has been made with new wide-field telescopes, however, astronomers have faced the major impediment of "false" GW candidates caused by noise, sometimes even for events with low estimated false alarm rates (FARs). In 2019, ~50% of GW alerts with a potential kilonova were retracted, often after costly telescope time was invested in follow-up.

We will employ a novel machine learning (ML) approach to leverage information reported by LIGO-Virgo to distinguish between true signals and noise events. Our algorithm will use the coherence between GW detectors encoded in the skymap, the estimated FAR, and the detectors that registered the event, to gauge the probability that the event is astrophysical versus due to or influenced by detector noise.

This truly interdisciplinary work will benefit all fields that use ML by improving our understanding of artificial intelligence (AI) decision making with complex architecture. We will also deliver a complete risk-reward assessment pipeline that will incorporate factors such as the range of available telescope assets.

This project is very high risk. The rate of compact object mergers that are expected to produce a kilonova is uncertain. It's possible there will be no detections of `electromagnetically bright' GW events during the next observing run. Even if there is a nearby neutron star merger, it could be that the signal is initially outside of the view of any telescopes.

However, despite the risk, this project is extremely high reward. In addition to advancing AI methods, we will enable Canadian telescope assets located around the world to swiftly slew toward a true astrophysical GW signal, reject noise events, and unlock the potential for new cosmic discoveries led by Canadian astronomers.

Atmospheric chemistry and art conservation science are both, in part, the study of how light and pollutants interact with surfaces: in the case of atmospheric chemistry, the surfaces include particulate matter, buildings and other urban surfaces, and the interactions occur over days to weeks; in the case of conservation science as practised in museum and gallery contexts, the surfaces are cultural heritage objects themselves, and the interactions occur over decades to centuries. Despite these commonalities, the atmospheric chemistry and conservation science communities have largely operated independently. Our team, which transcends these traditional disciplinary boundaries, proposes to apply concepts and strategies from atmospheric chemistry to provide novel insights and solutions for three topics of fundamental importance for the conservation of cultural heritage.

First, using highly sensitive instrumentation for gas-phase pollutant and surface corrosion detection, we will compare the results of material aging studies conducted under near-ambient conditions to those conducted under more extreme temperature and lighting conditions, and thereby enable conservation professionals to evaluate and address potential biases associated with commonly used accelerated aging protocols for prediction of cultural heritage object degradation.

Second, using custom-built reactors from the heterogeneous atmospheric chemistry field, we will obtain quantitative reaction parameters for pollutant gas-surface pairs relevant to museum storage environments (e.g. volatile organic acids and paints/varnishes), and implement these data in air quality models that will enable conservation professionals to bridge the gap between measured pollutant concentrations and risk of damage to enclosed objects.

Third, using instrumentation for stable and reproducible particle generation and custom-built exposure chambers, we will quantify particulate matter deposition to painting materials as a function of material type, relative humidity, and pre-existing surface soiling; in the process, we will generate a library of particle-exposed surfaces with which to systematically test and refine surface cleaning strategies for paintings.

Ultimately, these three projects will enable us to better anticipate, arrest, and ameliorate damage to cultural heritage objects, and serve as a model for future collaborations between atmospheric chemists and heritage scientists.

Virtual reality (VR) technology, now available for the mass market, offers profound opportunities to improve the creation, generation, and sharing of stories, a key component of human culture. However, the development of VR environments and delivery systems has been driven by engineers in response to the demand of the commercial gaming market. This development model is extremely successful from a commercial perspective, with VR headsets entering classrooms and living rooms, but vulnerable to significant critiques. Few people have the tools to work with VR, leading to little relevance outside of the context of the commercial entertainment industry, and many people lack the means to acquire or the ability to use VR technology.

The next phase of VR development will include haptic technology, which will further entrench these two critiques. Haptic technology engages the sense of touch, which can lead to better immersion, realism, and experiences in VR. Haptics is especially  seductive as more people live their lives globally and remotely, and when events like the COVID-19 pandemic severely reduce our ability to hug a friend or hold a loved one's hand. However, haptic experiences are already challenging for experts to create and deploy. Without intervention now, VR will further become a means of communication for only the wealthy and powerful.

We propose to retarget development of VR environments and their interfaces to be guided by social justice so that voices from marginalized communities can tell their stories to broad audiences. We will 1) design a new haptic VR story driven by community partners to develop guidelines for incorporating social justice into haptic VR experiences, 2) explore ways to deploy this experience in an accessible format (e.g., with commodity or low-cost devices), and 3) produce tools by which marginalized communities can continue to tell and experience VR stories. The result will be a guiding example of how to design future VR experiences to be accessible for marginalized creators and audiences, and initial infrastructure to enable other communities to tell their stories.

While the proposed project is high-risk - requiring a highly interdisciplinary team and directly challenging existing norms for the creation of VR content - it is high-impact. This work will enable more people to deliver on the promises of VR and haptics, and could radically redirect VR technology to include more diverse communities.

Rationale: Every six days in Canada a woman is murdered as a result of intimate partner violence (IPV). There are no educational opportunities for medical students to learn how to identify IPV, communicate with victims and perpetrators of IPV, or access resources in their early training. There is a critical need for focused collaboration, research, and education to protect the health and well-being of all Canadians. Our interdisciplinary team proposes to employ novel research methodology to develop an IPV educational program and to learn how to identify and assist those in violent intimate relationships.

Objectives (OB): OB1: Develop a multi-modal IPV educational program for medical students. OB2: Develop and validate a new IPV screening tool for identifying perpetrators of IPV using non-accusatory language. OB3: Measure respondent and health care provider (HCP) comfort with the new screening tool. OB4: Determine the prevalence of likely IPV perpetrators presenting to hand clinics and general fracture clinics. OB5: Develop streamlined access to IPV resources.

Approach: OB1: Mixed-methods qualitative and quantitative assessment of our novel multi-modal IPV educational platform for medical students. OB2 and OB3: Multicentre, cross-sectional survey of adults with hand or lower extremity fractures. Those with hand fractures are believed to include a higher prevalence of IPV perpetrators compared to those with lower extremity fractures. We have developed a new screening tool to help identify perpetrators of IPV, where each question will be assessed for fit, using the Item Response Theory and the Rasch model, including checks for Differential Item Functioning by age and gender. OB4: Sex- and gender-based analysis will be performed between the hand and lower extremity fracture groups. OB5: Collaboration with women's shelters, counseling programs, and police to identify and remove barriers for accessing resources.

Novelty and Significance: IPV is a global health issue which has been magnified by the COVID-19 pandemic isolation requirements. This interdisciplinary research concurrently addresses critical social, technological, and health-related knowledge gaps by developing and validating: 1. an educational program for HCPs, 2. an identification tool for perpetrators of IPV, and 3. improved dissemination of IPV knowledge and resources. Our goal is to break the cycle of violence and reduce physical, emotional, and psychosocial consequences of IPV in Canada.

The Sociability of Sleep is an interdisciplinary research-creation initiative that aims to generate new knowledge and empathies for sleep conditions. Many people suffer from sleep ailments-unable to sleep well, enough, at the "right" times, etc.  Yet complaining about problems like fatigue remains stigmatized. Responsibility for good sleep is framed as an individual responsibility to manage, even as sleep is known to be vital to our well-being, and issues often stem from underlying physiological (e.g. neurological) conditions. Thus the inability to sleep well is not merely a matter of behavioural or lifestyle failings such as poor sleep hygiene. Such popular rhetoric highlights key limits to how we approach sleep problems and their care: they are significantly underdiagnosed, with long delays to treatment, and outcomes are an individual's responsibility and even an individual experiment. Dealing with chronic sleep problems becomes an isolating burden, lived as a private and invisible experience. This is how we have come to commonly think of sleep.

Our team goal is to explore exceptional and everyday experiences of sleep and its problems, and through collaboration between artists, scientists and media studies scholars, to generate novel sleep situations. Our aim is to make perceptible, and thus actionable, our key intuition: that sleep is much more social than it might seem. In sleep, we become radically vulnerable in a way that requires social forms of care. An individual is an expert of their somatic experience of sleep, and yet access to our sleeping selves relies on other's perceptions: human and technological. Our autonomy is dispossessed in sleep. Yet, artistic experiments show how sleep's undermining of the self-possessed subject requires us to look beyond individual resolutions to these problems and treat sleep as a collective concern. Thus sleep exists at a critical threshold-between public and private, individual and collective, body and environment-that allows us to reimagine novel social relations of sleep equity. We aim to 1) develop interdisciplinary approaches to sleep research taking advantage of the tools, methods, and insights of arts, humanities and social sciences; 2) think critically about biometric sleep tracking and monitoring technologies; and 3) identify, analyse and produce artistic interventions into sleep in design, media and performance to see how they might enrich normative treatment of sleep conditions.

COVID-19 has fundamentally altered nearly every aspect of youths' relational lives; new norms regarding physical and social intimacy and access to public and private spaces affect family, peer, and sexual connections. The challenge of navigating this new terrain coincides with adolescence, a developmental period when choices regarding risk and well-being are already fraught and complicated. Though decisions around how to connect, date, and love continue to be influenced by factors including gender, race, sexual cultures, community, and space, pandemic logics cause a profound shift: behaviors that once sparked alarm are now endorsed as low risk (e.g., sexting); practices that were up for debate are now decidedly off-limits (e.g., sleepovers); and what were idealized as innocuous romantic gestures are now the height of danger (e.g., kissing). Changing policies and regulations (e.g., wearing masks, keeping distance, forming pods) influence sexual and intimate possibilities in new and unanticipated ways. Our multi-method, multi-disciplinary, and multi-site research will examine how COVID-19 is redefining risk and re-forming youth sexuality. Our focus will be Australia, Canada, and the United States, liberal democracies with comparable discourses and debates surrounding youth sexuality, but starkly different experiences of and responses to the pandemic. We will gather qualitative and quantitative data to foreground the perspectives of youth, parents, and health educators as we (1) compare experiences across geographic, temporal, political and social locations and (2) explore changing notions of sexual safety, risk, pleasure, and coercion. COVID-19 has also fundamentally altered the possibilities of social research. We will develop new synchronous and asynchronous participatory research methods that enable collaborative data collection and analysis regarding stigmatized topics to create conversation and community at a time that prohibits physical proximity. We will use results to develop site-specific and transnational briefings, videos, podcasts, and other resources to help sex educators, parents and youth navigate social norms, health risks, and sexual relationships during (and, eventually, in the wake of) a pandemic. Our international and interdisciplinary team brings together scholars in education, psychology, public health, social work, sociology, and youth studies with expertise in participatory methods, sexuality, and global health research.

Plants acquire their essential mineral elements from the soil. Crop productivity and resiliency rely on the acquisition and distribution of mineral nutrients to both plant vegetative and reproductive organs. Many studies have provided important insights into the mechanistic basis for nutrient uptake in crop plants, however, mostly have verified the broad localization of nutrients at the organ level (e.g. shoot and root); the challenge is to now map the distribution of mineral elements in living plants, at the cellular level and in real-time.

The overall goal of this research is to establish the real-time changes in the translocation and distribution of mineral nutrient elements, at the cellular to whole-plant levels, under nutrient-limited conditions. We will phenotype genetic mapping populations for several important crop species, to identify genomic regions involved in nutrient accumulation and redistribution under nutrient-stress conditions, by the integrated use of interdisciplinary technologies, including plant biology, plasma physics for nutrient imaging, and computational science.

Our interdisciplinary team will image plants using an advanced X-ray fluorescence (XRF) platform, integrated with laser wakefield technologies that produce synchrotron quality X-rays in the laboratory, for real-time imaging of mineral elements in living plants at the tissue and cellular levels. The efficacy of the XRF technique with laser wakefield-produced synchrotron light will enable us to, for the first time, bring these advanced imaging approaches directly to plant research labs. This will facilitate cutting edge plant research greatly enhancing our understanding of plant mineral acquisition, distribution, and homeostasis that underly increased nutrient acquisition efficiency.

New information on mineral nutrient absorption, translocation, and storage will be translated to improving both crop yield and food nutritional quality, while reducing fertilizer inputs. This will lead to reduced production costs and improved environmental sustainability for agriculture. This research will also contribute to the interdisciplinary training of HQP, advancing the use of new technology in agricultural research in Canada. The findings from this research will be pivotal to developing national and international collaborations that have a great impact on global food security to provide sufficient and highly nutritious foods for Canada and the world.

Pandemics not only impact physical health but pose long term challenges for public health, community mental health, and the built environment. This project brings together architects, cultural psychiatrists, interior designers, critical race theorists and public health scholars to address and unsettle dominant responses to such COVID-19 challenges including the impact of racism, stigma, and exclusion on individuals, communities and neighbourhoods.

This shared virtual reality (VR) project builds on the team's experience at the forefront of community-driven public health and art-based responses during the HIV epidemic, SARS outbreak, COVID-19 pandemic and #Blacklivesmatter movement. Despite the growing popularity of VR in architecture and therapy, applications remain centred on individual use. This project explores new models for community-led VR experiences. With the team's expertise in 3D scanning and architectural VR environments, co-creation VR workshops will utilize 3D scanned buildings to reimagine impacted neighbourhoods and communities through a social justice lens "beyond imagination". Here, "beyond" is threefold: 1) build on clinical research which has demonstrated positive emotional and therapeutic responses to VR simulations extending beyond the benefits of imagination alone; 2) use speculative fiction, experiential learning and reflection, and mindfulness processes to create realities beyond what is presently known allowing for collective healing, recovery, and empowerment; 3) facilitate grassroots empowerment and community resilience through collaborative re-envisioning.

Bringing together diverse disciplines and practices, we aim to develop models of therapeutic VR co-creation through bi-monthly community resilience workshops, prioritizing communities and neighbourhoods disproportionately impacted by COVID-19. Evaluating impact through an intersectional lens not only offers models of support within a single community but enables cross-community solidarity. Through VR envisioning this project explores not only how communities are perceived, but how they perceive themselves. In providing them with the platform to virtually envision their own communities and neighbourhoods as a collaborative process, this technology can potentially further identify collective systemic barriers caused by COVID-19, redress the impact of spatial exclusion on psychosocial and mental health, and support community-led engagement with city planning.

DNA nanotechnology relies on the molecular recognition properties of DNA to produce complex architectures through self-assembly. DNA nanostructures allow scientists to organize functional materials with unprecedented precision, finding important applications in materials science and biology. DNA materials also possess unique dynamic properties, which led to their use in logic circuits, biosensing and drug delivery. Progress in the field has been formidable; yet, missing is the ability to translate this powerful technology from the bench to the market and to clinical settings. At the core of this bottleneck is our current inability to mass produce DNA nanomaterials with tailored structures and well-defined molecular properties.

Automated, solid-phase methods have revolutionized the covalent synthesis of peptides and DNA (pioneered by Merrifield in the 60' and Letsinger in the 70's, respectively). Similar automated methods have not yet been reported for self-assembled - non-covalent - systems. Here we propose to develop a solid-phase based automated synthesis of DNA nanomaterials by combining concepts of chemistry, engineering and data science toward assembling the materials of the future, produced in a high-throughput manner. Toward these goals we will study the kinetics and thermodynamics of step-by-step supramolecular assembly as a function of DNA sequence and multivalency; engineer microfluidic methods for controlled and automated delivery of building blocks; seek chemical protection and deprotection of growing self-assembled structures with optimal yield per synthesis cycle; search for isolation of newly rendered DNA nanomaterials, explore post-synthetic chemical and enzymatic ligation methods toward welding the self-assembled blocks and develop the algorithms for sequence characterization and validation. We will subsequently scale up the methods toward high-throughput syntheses including use of smart software to control robotics to execute the synthesis.

Through the convergence of expertise in chemical synthesis, DNA nanomaterials, biophysics, data science and robotics, we will develop a new generation of DNA-based nanomaterials via a "Dial-a-DNA nanosystem" approach, with immediate applications in biosensing, plasmonics and drug delivery. Much like the work of Merrifield and Letsinger led decades later to the birth of the Biotechnology industry, our proposed work holds the promise to be a game changer in Nanoscience in as-of-yet unpredictable ways.

Transient electronics brings new applications in healthy monitoring (e.g., wound healing, tissue engineering) because they can interact with the human body without leaving a permanent mark and eliminate removal surgeries. Realizing such electronics remains an outstanding challenge of power sources due to limitations of biodegradable/stretchable materials and device configuration. The proposed research aims to enable a fully biodegradable battery in vivo with desirable biocompatibility/stretchability for biomedical implants.

The approaches of the proposed research are:

� Technological aspects: (i) Building blocks of natural proteins will be applied to develop biodegradable/stretchable materials. Design on these proteins allows tunability of electronic, mechanical, and transient properties. Special emphasis will be placed on proteins from agricultural resources to ensure renewability and environmental friendliness. (ii) Battery configuration will be designed based on these materials as electrodes. These materials contain or are modified to contain active sites for electrochemical redox reactions, while aqueous electrolyte will be applied that is compatible with human environment. Thus, a biodegradable battery will be ready for mechanism investigation.

� Biomedical aspects: (i) A detailed investigation will be done to identify practical requirements of such transient electronics for device design including the attainable current and voltage. (ii) Biodegradable battery will also be correlated with bioprocess (phagocytosis, metabolization, bioabsorption, etc.) to further boost the electrical functions, such as wireless communication, stimulation, sending, etc. (iii) Such battery will also be integrated with active components to demonstrate its applications in the sensitive health monitoring system.

Enable proposed technologies is highly challenging but rewarding as success of this research will significantly benefit human healthcare and environment, as well as reducing associated hospital costs. This multidisciplinary research combined fundamental chemical, agricultural and biomedical science in terms of material and device exploration and new mechanisms understanding for practical clinical applications. The novelty of this research lies in innovative ideas of integrating electronic devices with biomedical applications through the concept of degradability. The proposed project will position Canada as a global leader in biodegradable medical power devices.

Background: Global warming is a world-wide phenomenon where changes in one part of the world are linked to those in other parts. This is analogous to the situation in psychiatric disorders where different symptoms, like changes in movements, emotion and cognition, are coupled despite being mediated by different regions or networks. However, unlike global warming as source of climate change, we do not know the brain's global source of symptom coupling beyond its neural activity in specific regions/networks. Global neuronal activity can be measured with Global signal (GS) in fMRI. Often considered an artifact and  eliminated from the data, recent data show that GS displays an electrophysiological basis and is represented at different degrees in different regions/networks, GS topography. Linking GS topography to symptom coupling and clinical diagnosis in psychiatric disorders is the focus of our project.

Research question, goal, and interdisciplinary character: How can we bridge the gap between global and regional-network neuronal activity in the brain as key to account for symptom coupling and diagnosis in psychiatric disorders? Recent studies demonstrated changes in GS topography in single  disorders like schizophrenia (SCH), bipolar disorder (BD), major depressive disorder (MDD), and anxiety disorders (AD). The goal of our project is to extend these studies by comparing GS topography between different psychiatric disorders in order to (i) account for symptom coupling; and (ii) yield novel diagnostic markers. For that, we use available large-scale psychiatric fMRI brain imaging data sets, deep learning, and brain stimulation with  exploratory repetitive transcranial magnetic stimulation (rTMS). This requires interdisciplinary collaboration between neuroscience, computer science, and clinical psychiatry.

Novel paradigm, High risk, high reward: The project challenges the common paradigm that psychiatric symptoms are (i)  isolated from each other; and (ii) mediated by specific regions/networks. Instead, reflecting high risk, we probe the assumption that symptoms and their coupling are mediated by the local-regional representation of the brain's global activity as measured by GS topography. This will lead to a novel view and understanding of the neural basis of psychopathological symptoms. That, reflecting high reward, paves the way for use of GS topography as precise diagnostic and more effective therapeutic marker in psychiatric disorders. 

Retinoblastoma is an eye cancer affecting young children that presents with a white reflex (leukocoria) visible to parents, often in photographs. Leukocoria occurs when light reflects from an eye tumor when the eye is illuminated coaxially. Prompt detection of this sign brings children to care before the cancer is a risk to life.

Leukocoria may be observed in "red-reflex screening" recommended for neonatal and childhood screening tests, or in flash photographs. It can occur from cancer or other causes of blindness and eye abnormalities (including eye malformations, retinal exudates, or retinal detachment). Leukocoria often occurs in eyes without any abnormality (pseudo-leukocoria), causing anxiety to the family until the suspicion of cancer is ruled out by an eye doctor. True leukocoria is distinguished from pseudo-leukocoria only after a complete eye examination, which is challenging in toddlers.

We propose that 3D light propagation simulations of the eye will enable us to understand the features of true leukocoria vs pseudo-leukocoria ultimately improving the diagnosis of retinoblastoma and other causes of blindness in children.

We will generate anatomically accurate digital 3D models of normal and abnormal eyes with retinoblastoma, using MRI images and clinical photographs obtained at diagnosis. We will assign known and measurable optical properties (refractive index, spectral reflectance, opacity) to eye tissues in the 3D model. We will then run multiple Monte Carlo simulations with the model, generating images as seen through a virtual camera. The images generated will be validated by comparing them to photos of leukocoria provided by the family or obtained in the eye clinic at the time of diagnosis, to adjust the 3D model.

Once we achieve a comparable model, we can simulate different eye diseases or alter clinical and physiological variables (such as the site and size of tumor and pupil diameter) of eyes with cancer to determine variations in the characteristics of leukocoria. We can also study normal red-reflexes and pseudo leukocoria, including simulating healthy eyes of different ethnicities, to determine why pseudo-leukocoria is more prevalent in dark-eyed, dark-skinned ethnic groups, thereby encouraging equitable care to ethnic minorities.

In summary, the proposed 3D model will be a foundation to develop and validate precise and equitable screening tests to detect eye cancer and other blinding eye diseases in children, with a global impact.

This project aims to find new materials and procedures to establish effective plant microbiomes for plant health and food production. Like the human gut microbiome, plants are also living with a multitude of microorganisms. Especially, the plant root surface area, called the rhizosphere, is the most critical interface and contains an astonishing number and variety of microorganisms that is different from the surrounding soil. The rhizosphere microbiome is critical for plant health by affecting its growth, development, nutrient acquisition, and tolerance to stresses. Thus, beneficial microorganisms are extremely valuable for agriculture and the environmental protection by reducing harmful synthetic pesticides and fertilizer usage. Some soil bacteria are being used for agriculture, however the interfacial molecular interactions between plant roots and beneficial bacteria is not known. As such, conventional application methods are rather primitive. Therefore, in this project we seek new materials and procedures that can facilitate effective and long-lasting colonization of roots by beneficial bacteria.

To this end, we will study 1. spatio-temporal bacterial colonization on roots by a scanning electron microscope, 2. genomic profiles of colonizing microorganisms by a laser dissection microscope and DNA sequencing, and 3. plant root-bacteria surface interaction at the single-cell level using atomic force microscopy to obtain mechanistic insights into the nature of bacteria binding.

Outcome of this study will guide the development of new materials and application methods for effective bacterial colonization on roots. The overarching hypothesis of this project is `an innovative inoculation method using a biofilm-promoting matrix leads to optimum interaction of plant roots and bacteria by providing a suitable microenvironment'.

This study requires interdisciplinary expertise (i.e. molecular biology, physiology, physical and chemical sciences, material science and nanotechnology) and highly specialized equipment. Thus, usually it will not and can not be conducted due to the high risk associated with novelty and technical difficulties. However, the outcome of this project has significant potential to drastically change the usage of beneficial bacteria and modernize the biotechnological usage of beneficial bacteria for effective farming which is critical for future food production. 

Annually in Canada, there are approximately 2000 partial hand amputations that result in the loss of a thumb. In an uninjured hand, the thumb provides 40% of global hand function. Thumb amputation imposes a tremendous reduction in hand function. Partial hand amputations have a greater incidence among individuals in rural areas and with lower socioeconomic status; demographic factors that impact prosthetic options.  Currently there are passive, body-powered and myoelectric (ME) thumb prosthetic devices available. Prosthetic devices for partial hand amputations are often abandoned due to their limited capabilities and lack of sensory feedback. While advances in thumb prosthetic technology have been made with modern ME design allowing for intuitive patient-controlled motion, their high cost, need for intensive training can be barriers for patients with limited funds and/or remote from specialized prosthetic centres. Prosthetic devices for partial hand amputations are often abandoned due to their limited capabilities. Currently there are no available thumb prosthetics that restore sensory function. To address these barriers, our team of engineers and clinicians will design a low-cost sensate prosthetic thumb with haptic feedback. We will combine distributed sensing via capacitive dielectric elastomers and quasi-distributed fiber optic sensing with an embedded array of multiplexed Bragg gratings to measure pressure and temperature. This sensing redundancy and synergy along with novel data fusion techniques will curtail the challenging nature of developing a cost-effective and widely accessible proprioceptive prosthetic thumb that is compliant and biologically inert. Dielectric elastomers have the advantage of being able to operate as both sensors and actuators, simplifying hardware requirements and allowing for easy integration. Alternatively, piezoelectric actuators and microfluidic technologies will be incorporated in the design to provide high quality vibro-tactile and thermal feedback. The smart thumb prototype will be developed using a phased process of laboratory experiments and end-user engagement. Iterative laboratory experiments will test and validate the design under various normal and shear stresses and heat fluxes applied to different zones on the thumb pad. The final prototype will be evaluated at two amputee rehabilitation programs. Patients will participate in interviews to assess usability, acceptability and perceived impact of the prosthetic.

Objective

Emphysema and chronic obstructive pulmonary disease (COPD) are characterized by a permanent enlargement of distal air spaces associated with destruction of alveolar walls. Investigators are trying to "build" bioengineered lungs by recellularizing decellularized scaffolds obtained from donated lungs unsuitable for transplantation. However, lungs are complex structures with complicated geometry, numerous specialized cell types, and unique extracellular matrix (ECM). As such, current bioengineered lungs are a valuable research tool, but have not and perhaps will not be able to generate transplantable organs.

Research proposal

The proposed project is by means of gaining structure in the diseased lung parenchyma where loss of lung scaffolds took place. We observed that Gelfoam may be a special scaffold for the lung since the sponge pores exhibit similar structure to alveoli. Gelfoam, a hemostatic sponge commonly used in surgery, is inexpensive; causes little tissue reaction; and can dissolve in soft tissue overtime, potentially leaving functional tissue in its place. We have obtained preliminary data showing alveolar-like structure built on the biogelfoam sponges in healthy rats. We will use gelfoam sponge as a lung scaffold material alone and supplemented with human lung bud organoids or human induced-pluripotent stem cell-derived alveolar epithelial type II cells (AECII), as progenitors, to explore the possibility of sponge-based tissue engineering for lung regeneration in pigs.

The project is high-risk given many unknown factors including timing of angiogenesis migrating into the gelfoam sponge, precision delivery of sponge to injured sites, and cell seeding conditions. However, our team has expertise to handle the technical challenge at our state-of-art facilities.

Novelty and expected significance of the work

If our approach works in pigs, the techniques will be tested in humans with lung diseases. If successful, the impact would be dramatic, obviating the need for lung transplantation in many patients with end-stage disease (~300 lung transplants/year in Canada and another 200 on waiting list, Canadian Health Institute 2017), and help treat many patients who die with severe lung injury (patients with severe lung diseases who die per year account for ~5% of all deaths in Canada among those aged 40 and older). Also, an estimated 11% Canadians aged 35 to 79 have COPD. More than 830,000 Canadians are believed to be living with COPD.

Education is the right of every child, and music offers one of its most enjoyable, beneficial, and interdisciplinary components. Beyond its intrinsic value, music education has been associated with increased academic achievement, attentional focus and interpersonal skills (eg, cooperation and empathy). Sadly, access to music education favours children of higher socioeconomic status, a situation exacerbated by strained school resources. Eminent American music educator Robert Cutietta (2017, p. 261) notes that such unequal music education may be reformed only when "some disruptive force comes in to alter how music is taught".

Responding to Cutietta in a Canadian context, Access to Music Education (AMusE) is a multidisciplinary team of researchers and stakeholders taking a dynamic systems evidence-based management (EBMgt) approach in exploring music education reform. We aim to (1) identify inequalities in the current Canadian K-16 music education system, (2) analyze their causes, and (3) recommend an integrative solution including exploiting the role of technology.

Adopting a mixed-methods research design, AMusE will acquire data from survey, focus group, and interviews  of  stakeholders (e.g., decision makers, music-specialist and teachers, parents, and students) across representative geographical jurisdictions. Analyses will be conducted on content of, budgets for, and policies governing music programs, and stakeholder attitudes to traditional vs. non-traditional music education, instrumental vs vocal music, and role of classroom teachers. We will test the hypothesis that funding is disproportionately distributed to programs that align with a Western, colonial approach to music education. Additional data analysis will examine how music-education-as-usual may raise sociocultural and economic barriers preventing the most vulnerable youth (e.g., rural, Indigenous, special needs) from benefits of music in their schools.

This project is high risk because an evidence-based integrative solution to equalizing access may challenge a music education system rooted in both European colonialist traditions and heightened value of instrumental over vocal training. Yet, AMusE is well poised for high rewards based on its unique interdisciplinary lens, new diverse data, and dynamic systems framework as the foundation for equalizing access to music education that can offer profound positive implications for Canadian children, families, institutions, and society.

Lung cancer is the deadliest cancer in North America, killing more individuals than any other cancers. Immune checkpoint inhibitors (ICIs) are a major breakthrough in the treatment of lung cancer. Despite the overall efficacy of ICIs, only about 20-30% of patients showing a significant and durable clinical response. Hence, the development of reproducible biomarkers that can precisely stratify lung cancer patients to ICIs remains an unmet clinical need. In this regard, understanding the tumor immune microenvironment (TIME) promises to be the key for ICIs. The TIME plays a crucial role in modulating the local immune environment and dissecting its spatial architecture.

The overall objective of our project is to dissect the TIME of lung cancer and to develop robust and reproducible multimodal biomarkers to improve the response of ICIs of lung cancer patients.To achieve this goal, we will leverage a cohort of patients treated with ICIs from which we have identified good and poor responders with available pre-treatment tissue and radiological images. By using Hyperion imaging mass cytometry (IMC), a technology enabling highly-multiplexed immunostaining at the single-cell level, we will get insights into the TIME with a high level of granularity through an optimized 36-markers antibody panel that includes immune lineage markers, co-stimulation/inhibition markers expressed on T cells, myeloid cells and tumor cells and markers that depict the tumor-stroma interface. Additionally, we will leverage pre- and post-treatment CT scans of these patients to extract imaging features using a conventional pipeline based on region of interest. Through the expertise of the applicants, we will use a multidisciplinary approach using artificial intelligence and machine learning based methods to define population dynamics, cell-cell interactions and activation states that are associated with clinical response. The application of IMC to this unique cohort will facilitate the discrimination of highly complex TIME with a high degree of spatial resolution. We will then use this unique set of data to design a multimodal AI-based biomarker indicative of ICIs response by integrating TIME with radiomics features.

This project will make a very significant contribution to the emerging field of immunooncology by generating a unique set of data with an unachieved level of details of TIME architecture, which will help to develop a novel, robust and clinically implementable AI-based biomarker.

Several Sustainable Development Goals (SDGs) call for a shift from fossil fuels to renewable energy. Achieving this ambitious target requires bridging the development of alternative technologies with renewable energy system (RES) and policy.

Among renewables, solar fuels, in particular hydrogen (H2), are considered promising. Developing affordable, safe and efficient technologies for clean H2 production is the overarching objective of our project, together with analyzing the technology development process and their integration into RES in terms of innovation life-cycle, logistics, infrastructure, safety and energy policy requirements.

Quantum dots (QDs) are semiconductor nanocrystals whose size, shape and composition allow for unique optoelectronic properties, making them promising photocatalysts for H2 evolution. However, while QDs are promising building blocks in photocatalytic devices, several major challenges (efficiency, safety, stability and cost) remain to be fully addressed, limiting opportunities for wider dissemination. A deeper understanding of molecular adsorption and reaction kinetics on QD surfaces holds the promise of improving their performance, in particular by optimizing structure vs. properties. Our objectives include identifying preferential molecular adsorption sites on the surface, detailed reaction pathways for water splitting and the role of defects in catalysis. To address these challenges, by investigating model semiconductor substrates we will elucidate the mechanisms of water splitting reactions. We will then use insights obtained from these systems to design and realize devices based on QDs (made of the same semiconductors as in the models) with improved photocatalytic performance.

The proposed research is inherently risky, as it involves translating fundamental knowledge to improve a material's performance in an operating device on one hand and developing daring energy policies on renewables on the other. Each step is risky, from identifying model surfaces, difficulty translating results from model systems to QDs and the challenges of incorporating these materials into devices. In combination, they could lead to breakthrough advances such as cost-competitive water splitting and low-cost devices for energy conversion. The outcome of this project will provide crucial data for research on policies related to sustainable development, focusing on the transition towards a post-carbon society based on renewables.

Challenges like staying within planetary boundaries, and meeting the Sustainable Development Goals (SDG) will be achieved mostly through cities. Cities today use more than 75 percent of the world's energy (contributing to the world's growing greenhouse gas emissions). Cities, and the people in them, consume the bulk of material resources. This energy demand and material use and associated impacts are on track to double by 2050.

Responding to these urban imperatives, governments plan to spend more than $100 trillion on urban infrastructure between now and 2050; optimizing this investment to help the environment and quality of life, as well as the economy, is critical.

The objective of this research is to establish the means for cities (urban areas) to measure and move toward greater sustainability. Through a systems approach that looks at biophysical and socioeconomic indicators the research would ground-truth and anchor initiatives such as circular economy, public health, green infrastructure and urban resilience.

This proposal brings together more than a dozen academic disciplines in 20+ countries since working with cities demands a broad and inter-disciplinary approach. Bringing together this many researchers introduces risk, however this is critical to better understand and influence the complexities of urban areas. Another risk associated with the approach is its design to require minimal ongoing financial input. This helps with sustainability, but requires sustained commitment from partners.

The work will investigate how cities individually and collectively impact ecosystems, how healthy they and their residents are, how these impacts are growing, and quantify how improved urban infrastructure can reduce these impacts and bring about more sustainable cities.

Through collaboration with partners and academics around the world, this research program plans to develop a framework to quantify sustainability in all of the world's larger cities (starting with the largest 200 cities). A metric as common as `GDP', but far more fulsome in its measure, will be established. More than 75 existing metrics support the assessments, with some 35 international partner agencies. The initiative will be loosely coordinated (i.e. initiated) from Canada, but will be fully autonomous in participating communities.

Work is already influencing urban finance, e.g., supporting Canada's Infrastructure Bank, and similar agencies around the world. Potential impact is large.

This unique Indigenous-led research initiative has gathered together a team of leading Indigenous and non-Indigenous thinkers committed to using Two Eyed Seeing and regulation theory to conceptually frame understandings of the ways that neoliberal restructuring acts on cities and urban centres. Two Eyed Seeing is a decolonizing practice that stresses a weaving back and forth between separate but parallel ways of knowing (knowledge systems). Regulation theory emphasizes the importance of considering local, social spaces of economic development, and supports the view that successful participation in the global economy is a highly localized process in which economic structures, values, cultures, institutions and histories contribute to success or failure. Researchers will explore the ongoing consequences of neoliberal restructuring in cities and urban centres through targeting three grand challenges: (i) sustainability to understand how social and economic well-being is sustained over time through addressing complex and interrelated issues of poverty, inequality, and exclusion; (ii) inclusiveness to identify the conditions which facilitate/constrain equitable access and participation in opportunities for shared prosperity for marginalized peoples and communities; and (iii) resilience to facilitate resilient cities with diverse opportunities for protection against social, economic and environmental shocks. The research team's objective is to work closely with and for communities. Using an interpretive qualitative methodology, they will (i) identify and explore localized power structures, marginalized voices and communities, (ii) design interventions and (iii) implement effective mechanisms for action to respond to and act on localized grand challenges and wicked problems in three Canadian cities: Ottawa, Saskatoon and Vancouver. This research is novel and promises high reward through co-creating interventions and co-generating actions that trigger social and economic transformation, with and by, marginalized communities on their own terms. It will facilitate community-based learning and competency building that links research outcomes directly to local action focused on empowerment. Challenging powerful neoliberal forces and facilitating the resistance of marginalized communities, however, is inherently risky and can lead to tensions, conflicts and challenges for the research team, communities and sociopolitical economies of Ottawa, Saskatoon and Vancouver.

The capability of rapidly healing wounds is perhaps the most fascinating technology ever staged in science fiction. In modern medicine, wound healing remains a very complex and delicate process, where the main goal is to achieve a fast regeneration matched to an aesthetically satisfactory appearance. In particular, reducing the healing time and minimizing tissue scarring are the most important considerations. In view of minimally-invasive clinical interventions, laser-assisted wound healing is emerging as an appealing concept in surgical medicine, holding the promise of suture-free surgeries. Recently, nanoparticle-assisted, low-dose photothermal therapies, have drawn significant attention due to their ability to facilitate wound healing with dramatically low laser power requirements. However, these therapies are still in their infancy and have yet to be employed in a clinical setting. The main reason is that the rapid temperature increase, due to optical absorption and the concomitant heat generation, can cause significant photothermal tissue damage. As such, cutting-edge diagnostic tools are indispensable in order to monitor temperature changes and prevent the occurrence of tissue damage. The goal of this interdisciplinary, high risk/high reward, project is to develop an innovative technique combining nano-heating and nanotherapeutics with non-invasive terahertz diagnostic tools. Specifically, we will study (i) how nanoparticle design and synthesis can ultimately improve targeted heat deposition within tissues. In parallel, we will investigate (ii) how to circumvent common issues (e.g. infection, carbonization and blood coagulation) by functionalizing drugs to nanoparticle surfaces using thermosensitive linkages. Finally, we will develop (iii) the first real-time terahertz three-dimensional imaging system to monitor temperature variations and photothermal damage during the wound healing process. Such a platform will offer an unprecedented method for the healing of delicate tissues, such as corneas, blood vessels, and nerves. Our discoveries will boost fundamental research in laser-assisted regenerative nanomedicine to gain a stronger foothold within clinical settings and have the potential to revolutionize topical surgical practices related to the treatment of wounds as well as cancers. The commercialization of the resulting technology will ultimately lead to breakthroughs for the Canadian industry while improving the health of millions of Canadians.  

This project will explore how Art History Conservation and Computing -particularly the area of Human-Computer Interaction (HCI)- can expand and enrich interactions with museum collections. We believe that bringing artifacts to life using digital technology can form social counter-measures in response to the pandemic's lockdown. This is particularly timely research as we are redesigning Canada for the new normal where people will remain advised to keep physical distancing. We want to develop digital fabrication methods (e.g. 3D scanning/printing, laser-cutting, e-textiles) to create connections between people, their past and the future.

Objects are archive of knowledge, culture and skill just as books are objects that contain information and inspiration. In this project, we aim to think of how museums can function like libraries, and artifacts can be accessible to the public similar to books that can be picked up or mailed. Even post-pandemic, borrowable museum collections can reach people for whom a physical visit to the museum is difficult, including people with disabilities, those living in remote areas, and older populations. In this sense, we aim to break some barriers facing inclusion and diversity and build bridges between cultures as a metaphor for global circumstances.

Our motivation is to develop digital fabrication methods that resemble, complement or augment traditional art and crafting techniques, exploring various methods and materials (textiles, ceramics, wood, paper, etc) to create interactive museum objects that connect individuals and foster historical inquiry through physical objects. If we can find new ways of embedding interactive technology within existing materials, we can reinvent things around us. Apart from typical rigid sensors, emissive displays and motor actuators, interactive objects can be designed using soft circuits of connected e-textiles and capacitive sensing fabrics, and shape-changing threads and colour-changing pigments, as output modalities. Equipped with such capabilities, we can leverage the nuanced and complex ways in which humans interact with and manipulate physical objects.

This project also has the potential to offer new insights for art history and practice. We will draw on case studies in art conservation relating to performance, replicas, authenticity, and engagement. Through this New Frontiers Research Fund (NFRF) we aim to explore ways to reach this ambitious vision and explore the challenges. 

One key land features in Canada is seasonal cycles of freeze and thaw (FT), acting as a controller for a range of environmental processes, from vegetation growth to movement of water and solute in soil, to land-atmospheric interactions. Considering the human utilization of land, FT cycles matter to agriculture; but they also determine soil stability and expected lifespan of the built environment, and therefore matter to human activities such as infrastructure construction and operation, mining, and transportation. Due to these impacts, FT has been a key driver shaping culture in northern Indigenous communities. Having said that, climate change has generated unprecedented changes on FT cycles across Canada, where the rate of warming is twice the global average. Existing scientific methodologies, however, are not able to fully reproduce, predict and project the evolving links between hydroclimate variables, landscape characteristics and FT conditions. In addition, a holistic understanding of the impacts of changing FT conditions on human activities and northern communities is currently lacking. Building improved tools for projecting FT, and coming up with new assessments that can form a woven understanding of the impacts of changing FT on socio-economic activities are two essential steps to prepare Canada for challenges and opportunities of the thawing north. The aim of this study is to explore recent and future changes in Canada's FT cycles and their impact on agriculture, infrastructure, and society above 55°N.  Using various sources of data support and formal statistical dependence models, we provide - for the first time - a synoptic, pan Nordic projections of future changes in the FT cycles throughout the 21st century. Through community engagements, we verify our findings with traditional ecological knowledge. By merging computer models and laboratory setups, we present an integrated assessment of the impacts of changing FT on agriculture, soil, and infrastructure. We also explore what the compounding pressures of changing natural and socio-economic landscapes mean to the the people of north. By merging quantitative western knowledge with traditional Indigenous knowledge and co-creating new forms of inquiries with members of Indigenous communities, we present new insights for future development in the thawing north that not only support economic growth; but also values and preserves the precious environmental and cultural landscapes above 55°N.        

Rapid advances in artificial intelligence are driving the adoption of robotics and automation in transport and logistics,  providing new solutions to highway systems,  passenger transport, last-mile  delivery,  and  automated  warehouses. For  the foreseeable future, humans will remain indispensable to supervise and manage such fleets because we are transitioning from systems that are generally already in use; technology gaps prevent us from performing all of the required functions autonomously; and particularly in visible, safety-critical applications, society's trust in decentralized technology will be earned gradually. However, integrating increasingly sophisticated AI techniques leads to increasingly opaque robot control programs. Furthermore, human supervisors' cognitive capacities are challenged (and eventually exceeded) as the size of autonomous fleets grows. The difficulty of ensuring operational performance is compounded when incoming information is scattered,  delayed,  asynchronous,  or unreliable. These factors lead to increased pressure on human supervisors' cognitive resources and their ability to maintain situational awareness, detect problems, and make successful decisions. Our aim in this project is to develop a novel framework for the supervision of AI-driven multi-vehicle systems, deployed across domains such as transportation and logistics. We believe that deployment of human-in-the-loop AI systems will have a large positive impact on society, but its adoption will ultimately be determined by the level of trust that people put in these systems. This framework strives to avoid both human and system breaking points, by providing techniques that ensure resilient fleet operation as we progressively transition to higher levels of automation. This proposal is at the intersection between engineering (AI, robotics), natural sciences (cognitive neuroscience), and social sciences (psychology). This project addresses fundamental issues arising from the fact that human supervisory control is needed to enhance the trustworthiness of AI systems, but automation becomes less transparent as it increases. We propose a novel approach to this problem that is based on co-optimization of automation and human performance.  Overall, this project addresses fundamental gaps for the adoption of large-scale autonomous systems through a supervisory control system that takes advantage of the human strengths and acknowledges the need to gain society's trust.

Microplastics pollution has grown to become a world-wide crisis.  The inevitable consequence of dramatically increased plastic use, microscopic plastic particles and fibres contaminate natural marine, terrestrial and atmospheric ecosystems. To date, limited studies conducted in Europe, Asia and the Middle East have detected atmospheric microplastics, but no Canadian data yet exists. No systematic scientific study has characterized the health effects of microplastics in the inhalable and respirable ranges (PM 10 and PM 2.5 microns, respectively). Here we propose a program of NFRF research with the goals of (1) detecting and characterizing inhalable and respirable microplastics in indoor and outdoor air seasonally, and (2) exploring their potential adverse effects on health. To address this research challenge, we will assemble a unique interdisciplinary team forging a close collaborative interaction of leading groups in the fields of Aerobiology, Analytical and Atmospheric Chemistry, System Biology and Immunology.

We will collect seasonal outdoor and indoor aerosol particles with different sizes using Compact Multistage Cascade Impactors (CCI) and characterize microplastics in these samples using advanced methods of micro-Raman Spectroscopy and interferometric backscattering microscopy, backed by high-throughput image processing. With an in-depth understanding of the physical characteristics of inhalable and respirable microplastics including length, diameter, polymer type, surface chemistry, and concentration, we will use metagenomics shotgun sequencing to determine the range of microorganisms carried on the surfaces of microplastics. This work will shed new light on the extent to which microplastics act as a vector for transporting microbes. We will conduct animal studies to investigate the immunological and toxicological consequences of inhalation of these microplastics. As a control, we will prepare samples of known microplastics and shapes ranging from flakes and microbeads to microfibers spiked in sterile air, and compare their health impacts to those determined for environmental samples. Our success in this research will support ongoing national and provincial strategic initiatives underway in Canada, in line with the EU and UN environment programmes. The information and insight we gather will inform internationally integrated strategies for the control and mitigation of microplastics pollution with respect to their impact on health and well-being.

Central sensitization (CS) is a pain condition in which the central nervous system amplifies nociceptive

signals and fails to suppress noise signals. This results in chronic pain which has a tremendous negative

impact on people's lives and the healthcare system. Currently, CS is diagnosed based on subjective, self-reported

criteria, resulting in misdiagnosis and mechanism-agnostic therapies.

CS is thought to arise from maladaptive central nervous system plasticity. A positive feedback cycle of

nociception and pathophysiology originates in skeletal muscle. Maladaptive neuroplasticity can occur

through several mechanisms and at numerous sites on the pain pathway, including: skeletal muscle,

afferent neurons, the dorsal horn and the brain. However, to date, these potential maladaptations have not

been examined in an integrated fashion; thus, a significant knowledge gap exists in understanding the

dynamic and functional relationship between neuromuscular components.

We propose to exploit advances in machine learning (ML) to examine CS-induced neuroplasticity in a

systematic, integrated and dynamic fashion. We will utilize known positive (experimentally induced CS) and

negative (e.g., exercise) regulators of CS, in healthy and pain populations, to identify pain signatures using

ML clustering techniques. Experimentally induced CS in healthy will allow us to examine the conversion of

a normal functioning system to a centrally sensitized one. ML feature extraction from CS patient data will

allow us to identify neuroplastic features that are clinically meaningful. Neuroplastic/pain signatures will be

clustered using multiple-levels pain pathway data fusion, including skeletal muscle (ultrasound imaging,

EMG), the spinal cord (dorsal and ventral horn behaviour), and the brain (fMRI). ML will be used to detect

CS-related anomalies at each level- and in the functional relationships between levels (e.g., maladaptive

pattern recognition).

Our team is ideally positioned to undertake this research using our expertise in biomedical engineering,

neurophysiology, advanced imaging, ML, and clinical research. We anticipate this research will have a far-reaching

impact on basic understanding in pain, clinical practice, therapeutic discovery, and, ultimately, the

quality of life of hundreds of thousands of Canadians.

Cancer and many of its common treatments are associated with neurotoxicity, resulting in both acute and delayed-onset cognitive impairment (CI). One unfortunate consequence of these life-saving anti-cancer therapies has been colloquially termed "Chemo-Brain" (CB) and remains a significant source of decreased quality of life among the increasing rate of cancer survivors. Without predictive and early-detection diagnostic tools, clinicians cannot anticipate which patients are most at-risk of developing chemo brain, thus delaying the administration of adjuvant therapies to mitigate CI. To date, it is unclear why certain patients, experience cancer therapy related CI and which factors determine their severity. In recent years, fMRI has been used to identify resting brain networks that are predictive of cognitive outcome following cancer therapy which primarily include right-hemispheric cortical regions of interest (ROIs). These predictive ROIs are located primarily within superficial (and therefore accessible) regions of the brain, which invites exciting new possibilities for novel diagnostic imaging strategies. Indeed, similar diagnostic predictions can likely be made with quantitative electroencephalography (QEEG) and related machine-learning-based strategies that identify brain electrical networks (i.e., electomes) - techniques which are less invasive, cheaper, and more accessible than fMRI. As electomes have previously been used to predict susceptibility to other neuropsychiatric disorders, their successful use to detect risk of CB in combination with the higher temporal resolution of QEEG would reveal significantly more functional detail of the changing brain. Even more intriguing is the possibility of detecting early signs of CB as light emissions associated with molecular mechanisms of cell stress in the brain. Anti-cancer therapies are known to disrupt cell functioning which result in reactive oxygen species (ROS) which are cell stress molecules that have been postulated to be involved in CB induction. These ROS expressions are often paired with the release of biologically-generated light: biophotons. Therefore, measurements of biophotons may represent the earliest possible non-invasive diagnostic imaging strategy. Our goal is to create an early diagnostic tool using these biophotons, electomes and neuropsychological assessments to detect both risk and the early expression of CB for improved diagnostics of CI associated with cancer therapy.

Gravitational waves are ripples in spacetime produced by colliding neutron stars or black holes. In less than five years, gravitational wave (GW) astronomy has evolved from a ground-breaking first detection in 2015 to a quickly growing GW event catalog that has already exceeded 67 discovered and candidate events.  The two four km long Advanced LIGO detectors in the U.S., the most sensitive GW detectors in the world, have registered the GW signals of 12 binary black hole and two binary neutron star mergers. These discoveries have constrained models for hyper-dense matter, provided new insight into the physics of relativistic jets (charged matter moving close to the speed of light), fundamentally changed our understanding of the origin of heavy elements, and independently measured the rate of expansion of the Universe.

The detection sensitivity is fundamentally limited by the rate at which mechanical vibrations are damped in the highly reflective (HR) coatings on fused silica mirrors. The next generation of  detectors requires an improvement in mechanical loss of at least an order of magnitude in the most sensitive (10-1000 Hz) GW frequency range. Low mechanical loss materials are also urgently needed in many other nanoscale applications, for instance in optomechanical resonators and in quantum information components.

Discovering new materials that meet these design challenges is a high risk project that requires a deep fundamental understanding of the origin of dissipation in amorphous solids, high-throughput synthesis techniques to create candidate materials, and equally efficient characterization of absorption and mechanical loss. Our unique approach of combining highly interdisciplinary expertise in Physics and Chemistry under one roof will result in a feedback loop that accelerates the search for the optimal material chemistry, composition and process conditions. We will establish a "materials-by-design" framework that optimally synergizes thin film fabrication with atomistic simulations identifying the operative mechanisms of internal friction and predicting mechanical loss that will be measured in a novel optical cryostat. The novel HR materials created in this high reward project will open the door to ground-breaking discoveries such as tests of general relativity in extreme spacetime curvature,  a census of all stellar-mass black holes in the visible Universe, and a resolution of conflicting measurements of the expansion of the Universe.

Sepsis is a life-threatening response to infection that requires management in intensive care. Although sex-dependent influences have been demonstrated in various medical conditions, these have not been evaluated in sepsis. Moreover, for intravenous fluids and antibiotics (the two cornerstones of sepsis therapy) there is a remarkable lack of robust and reliable data evaluating how biological sex influences the effectiveness of these treatments. In order to address this knowledge gap, we propose a vanguard multicenter preclinical study to assess the sex-dependent responses to early versus late antibiotic therapy in a mouse model of sepsis. Only twelve multicenter preclinical studies have ever been conducted, none in sepsis and none in Canada. Similar to clinical multicenter trials, a multicenter preclinical study would ensure efficient conduct, be methodologically rigorous, and directly assess reproducibility by incorporating necessary factors of heterogeneity (e.g. site, technician, treatment, sex). However, establishing and executing a consistent protocol are two of the greatest challenges facing multicenter preclinical study teams. These challenges highlight the importance of collaboration across professional and organizational boundaries to ensure various stakeholders (e.g. research technicians, lab animal veterinarians, site investigators) are "on the same page" or, in other words, have shared mental models (SMMs). SMMs positively predict team functioning and performance in a range of contexts but have never been examined in preclinical, laboratory-based collaborations. The primary objectives of our proposed project are to a) assess the feasibility of a multicenter preclinical study to evaluate the sex-dependent response to antibiotic therapy in sepsis and b) examine where mental model convergences and divergences are occurring in team members' conceptions of their tasks and roles. Three laboratories and associated stakeholders will co-develop and carry out a common protocol. Comprehensive analysis of outcomes will be stratified according to biological sex. Our project represents a paradigm shift in clinical translation and vigorous understanding of disease and discoveries.  It will also be a unique opportunity for Canada to establish itself as a leader in the new field of preclinical multicenter studies through an interdisciplinary approach of biomedical, social, and management sciences.

Background: Inflammatory and immune-mediated diseases include cardiovascular diseases (myocardial infraction, stroke, thrombosis), sepsis, diabetes, multiple sclerosis, kidney diseases and immune-rejection of transplants. Collectively, these affect 1 in 3 Canadians and cost Canadian economy >$100 billion/year. That challenge emphasizes the need for improved prevention and treatment methods. In this project, we are addressing this unmet clinical need by developing an effective therapeutic approach that can be applied systemically to rapidly repair the endothelial glycocalyx to reverse endothelial dysfunction and pathogenesis in these inflammatory diseases.

The endothelium lies at the interface between the circulating blood and tissues of all organs and glycocalyx is the most prominent structure on the endothelium that serves as a protective shield. Endothelial dysfunction and glycocalyx shedding perpetuate the inflammation and recruitment of immune cells leading to organ damage. Rapidly rebuilding the damage glycocalyx in vivo is anticipated to prevent activation of the immune system and preserve organ homeostasis. Thus, we hypothesize that engineering and rapidly rebuilding of vascular endothelial glycocalyx using immunomodulating polymer conjugates can prevent inflammation and immune-mediated damage of organs. Localizing molecules onto endothelium and repair the damaged glycocalyx is an enormous challenge but will open a new era in the treatment.

Objectives:

1. Development of novel methods to localize immune-supressive polymer conjugates on endothelium in vivo in order to rebuild and repair the glycocalyx.  Novel conjugated and endothelium targeting approaches will be developed to rapidly rebuild the damaged glycocalyx and its functional properties in vivo and in mice models. 

2. Proof-of-concept investigation on glycocalyx therapy in animal models of inflammatory and immune-mediated diseases. Using mouse models of sepsis, acute kidney injury, organ transplantation and multiple sclerosis, we shall screen the lead candidates on their efficacy.

Significance and Novelty: The proposed rapid endothelial glycocalyx repair and immunomodulation approach is first of its kind. This will realize a novel approach with broad applicability as a treatment for diverse disease conditions with significant therapeutic potential. The potential for improving the health of Canadians suffering from inflammatory and immune-mediated disease conditions is wide ranging. 

About 5 million scholarly papers were published in 2019 - that is about 14,000 new papers everyday. That is a lot of information to filter and process, for researchers, scientific journalists, and the general public. While most of those papers build on and expand the existing scientific consensus, others challenge it. The goal of our project is to provide a better understanding of how scientific consensus forms, using large scale data on scholarly documents authored by researchers. It also aims at providing tools to map how existing and new studies are situated in the scientific ecosystem, from the margin to the core, in real time and with an historical perspective. The project will develop algorithms that will help distinguish studies that will remain at the fringe of science from those that hold the potential to become mainstream. Understanding and mapping scientific consensus is of crucial importance to counter misinformation-the current COVID-19 pandemic is making this issue quite explicit. Indeed, while only a small proportion of scientific studies make their way to the general public through traditional and new media, the mediatization of controversial studies, or fraudulent ones, have lasting negative impact. Much research has been devoted to its spread, and the roots of this phenomenon lies not only in science. But how can we improve the way studies are mediatized and avoid hype and spin of preliminary or controversial ones? Journalists face an unprecedented crisis, and misleading information has never traveled so easily. This is not a new phenomenon: even when driven by an honest quest for knowledge, science suffers the influence of lobbies or private interests, with effects on the consensus building on topics such as tobacco, asbestos or climate science, for example. Taking these considerations into account, we plan on providing an open, free and user-friendly tool for journalists and the public to see where marginal science stands relatively to the scientific consensus. While marginal science cannot be considered to be a synonym for "bad" science, it needs to be communicated with more caution. Science breakthroughs often emerge from the margins. Such a tool could prove useful for communication practitioners, educators, policymakers and health care practitioners. Also, the theoretical work behind this project will contribute to the fields of science sociology, science communication, information science, science policy and knowledge mobilization.

Gene therapy is poised to revolutionize treatment for rare diseases. At present, nearly all gene therapy uses adeno associated viruses (AAVs) as the main delivery vehicle because of their relatively large packaging size, trophism for multiple target organs, and low immune exposure in the pediatric population. Several gene therapy programs are currently in clinical trial, and one therapy (Zolgensma) has proven successful for spinal muscular atrophy.

The major barrier that has emerged in clinical trials of AAV based gene therapy is liver trophism and toxicity. AAVs are taken up and expressed at several fold higher levels in the liver than in other target organs. For non-liver disease treatments, this causes a relative reduction in available drug, which necessitates very high doses, and which leads to AAV mediated liver injury. The significance of this problem is highlighted by the recent report of two deaths due to liver toxicity in the AAV8 based gene therapy trial for X-linked myotubular myopathy.

The goal of this proposal is to identify and translate a therapy that enables AAV to evade liver sequestration. Our hypothesis is that a single drug can selectively reduce AAV entry into the liver but not alter entry to other organs, which will lead to increased systemic concentration and availability, lower overall dosing, and prevention of dose limiting liver toxicity.

To identify a viable therapeutic for circumventing liver exposure, we established a novel drug discovery pipeline. The initiation point of the pipeline is a high throughput drug screen in HepG2 organoids, a validated ex vivo model of human liver amenable to large scale screening. Our primary outcome will be the amount of AAV8 able to enter HepG2 organoids, as determined using high content confocal imaging and a fluorescent AAV8. "Hits" that prevent AAV8 uptake will be validated on iPS cell derived hepatocytes vs myocytes, and then translated to a murine model. Specifically, we will test AAV8 based gene therapy for XLMTM, and determine if hits from our screen can prevent mouse liver uptake, eliminate liver toxicity and enable lower overall dosing to treat disease.

Our proposal represents a novel approach to solving this essential issue in gene therapy. Successful completion will represent a paradigm shifting advance in the field. It will lead to dramatic changes in dosing and safety, greatly broadening the reach and impact of gene therapy, which is currently limited by this key barrier.

Deep learning has revolutionized several areas of machine learning and data science, though its use in the application of earth observation data to solving environmental problems, mitigating hazards, and addressing associated social impacts is just beginning. This comes when the volume of earth observation data from satellites and autonomous instruments is growing at an unprecedented rate, the diversity of sensor types is broadening, and sensor spatial and temporal resolutions are improving. It also comes when the Canadian Arctic is experiencing emerging sea ice conditions that are increasingly variable on diurnal, seasonal, and inter-annual time scales. Annual average air temperature in the Arctic is increasing, and is projected to continue increasing, but the response of sea ice and marine conditions to warming remains uncertain. Examples include the increased flow of old, thick ice into Canadian waterways, due to the intermittent seasonal breakdown of ice arches further north that used to block the ice; the formation of rougher ice due to later than normal freeze-up, when wind speeds are greater; and unpredictable hazards such as thin ice, cracks, and melt holes during early spring melt. Variable conditions impede the safe use of sea ice as a platform for travel and subsistence activities, and impact the ability of Arctic Indigenous users to maintain traditional activities. This project will bring together researchers and collaborators from a diverse set of fields including remote sensing, artificial intelligence, social sciences, and transport, to foster the development of deep learning, in particular the emerging field of tensor methods, for the dynamic mapping of Arctic sea ice conditions at the local scale. Deep learning provides promising tools for identification and mapping features that represent hazards or challenges to local users of sea ice. The methodology is grounded in the need to improve the Arctic sea ice observational capacity at the local scale, and promote climate resilience at the community level, while addressing challenges relating to managing and aggregating high volumes of earth observation data effectively. Stakeholders in the Canadian Arctic will be involved in the research design and co-production of new knowledge on sea ice observation. Outcomes will be delivered in map-product and info-graphic formats designed to guide Indigenous livelihood activities, including safe travel, domain awareness, and subsistence.      

Within the discipline of architecture, digital design and fabrication software platforms are developed by a small number of companies, offering software solutions that are compiled within inaccessible source codes and secured by cloud infrastructures. By targeting businesses exclusively, and evading open source frameworks that would typically allow a user access to the inner workings of the interface, digital tools not only become unattainable but also serve to hinder any creative and innovative explorations.

This is further intensified in northern communities where additional barriers exist due to the overreliance on southern markets, the lack of technical skill and limited access to digital technologies.  To initiate a shift, this research brings forth a transdisciplinary team to develop a novel platform for cognitive human-robot interaction and collaboration, through community-centered outreach and design-build activities. More specifically, the research is developed in three interconnected streams. First, with the development of a portable and modular cable-driven parallel robot (CDPR) as an innovative and alternative method for large scale fabrication and assembly. Second, to develop a brain-machine interface to capture subtle changes in a person's cognitive and emotional states in real time to allow for direct control of the CDPR, thus eliminating the technical need for traditional offline programming. Third, to develop a community-based material production model through the development of suitable building assemblies solely out of renewable energy and locally-sourced raw materials.

The risk of the research lies in its attempt to merge traditional methods of making with digital fabrication in communities that may not share the same techno-enthusiasm as their southern counterparts. Its success is therefore dependent on a framework rooted in traditional ideals yet responding to current demands. In return, the investigation has the potential to drastically transform current methods of construction, through a novel CDPR platform and brain-machine interface that historically has yet to be explored. It has the potential to deploy new materials through emerging technologies; to improve rural and northern health by directly confronting the housing crisis in remote communities; to address the technological challenges in Northern Ontario and to engage in community-centered research that benefits all northern communities, including Indigenous and Francophone.

Neuroendocrine neoplasms (NENs) are heterogeneous tumors that arise throughout the body. More than 20 types exist, ~50% patients develop non-curable metastatic disease, and survival varies from months to years. NEN diversity is poorly understood at the molecular level and hence difficult to treat. Currently, primary tumor site, grade (activity), and stage (spread) are the best predictors of survival. However, pathologic classification is subjective and slow due to site-specific morphology and immunohistochemistry-based evaluation schemes, compromising diagnosis and clinical management. Thus, there is a major need for a bold new approach to advance molecular knowledge of NEN diversity.

Post-transcriptional gene regulatory (PTGR) networks coordinate gene expression to meet cellular needs. These networks involve complex interactions between microRNAs (miRNAs), RNA-binding proteins (RBPs), and RNAs. When perturbed, these networks likely drive or mediate tumor aggressiveness and potentially serve as unconventional disease biomarkers. Graph neural network (GNN) models are increasingly used in the field of computer science for understanding and classifying data with rich relational information, such as social networks.  Conceptually, this approach may prove versatile enough to efficiently and effectively study PTGR networks. In graph data structures, RBPs, miRNAs, and RNAs can be viewed as nodes, and relationships between nodes, such as miRNA or RBP co-expression, as edges. By analogy, we will explore molecular social networks.

We hypothesize that NEN diversity is reflected in pathologic type-specific PTGR perturbations. We will test this hypothesis through two aims to (i) define PTGR networks in variably aggressive NEN cell lines using RNA-seq and specialized miRNA- and RBP-targeting approaches, and (ii) develop and validate a universal NEN classifier using GNNs and RNA profiles from NEN cell lines and archived tissues. Our proposal is feasible because we have developed key methods for profiling RNAs, predicting miRNA target sites, defining RNA targets of RBPs, and selecting molecular features for cancer classification.

Our team has expertise in pathology, RNA biology, and computer science. Our proposal is high risk because it uses novel biomarkers and approaches to reimagine cancer classification. It is high reward because more accurate knowledge of tumor behavior, and even treatment response given relevant data, will improve NEN clinical outcomes.

With an incidence of 3-5 % of pregnancies, placental disorders such as preeclampsia (PE) can progress to life-threatening complications during pregnancy and life-long cardiovascular and developmental complications for mother and child. The pathophysiology of the disease remains unclear but cell fragments released by the placenta, known as extracellular vesicles (EVs), may provide clues as to how this arises. Placental EVs contain protein and genetic biomarker cargo, making them a prime target for understanding their role in maternal-fetal disorders. As EVs are released by every cell in the body, the main challenge in this area of research is how to discriminate EVs from maternal or placental sources. Recent efforts in nanoscale flow cytometry may allow us to do so, which would facilitate highly novel datasets that describe how the placenta is negatively affecting maternal systems and development of early detection assays for pregnancy disorders.

Hypothesis: Placental EVs are elevated in preeclampsia and contain pathogenic biomarkers which can be used as a "fluid biopsy" for early detection of PE and other pregnancy disorders.

Our objectives include validation of our techniques to enumerate placental EVs from patient plasma samples, isolation of placenta EVs from PE and normal pregnancies, determination of the protein and mRNA/miRNA content of placental EVs and to determine their functional impact on host vasculature.

There is a degree of uncertainty in this proposal as we will need to assess which markers can be used to reliably and robustly detect and isolate EVs of placental origin. However, we believe the potential rewards outweigh these risks as the generation of these highly novel datasets may provide crucial steps in further understanding the pathophysiology of PE and transform PE research. Moreover, differences observed between placental EVs from PE and normal pregnancies suggest a rapid development of non-invasive, early detection assays for PE in expecting mothers, potentially offering a short interdisciplinary turn-around from basic research to a reliable clinical assay.

While our initial focus is on PE, this technology can be readily applied to other maternal-fetal disorders (e.g. growth restriction, diabetes). Ultimately, these techniques will enable other developmental biologists to further understand embryology and human development without posing any invasive risk to mother or child.

Rapid urbanization has exacerbated the vulnerability of densely populated cities, which is home to half of the world's population. The severe effects of climate change are evident, with excessive rainfall, heat waves, and other extreme weather events occurring at higher frequencies. For instance, by 2100, it is estimated that assets of up to 20% of global GDP ($14.2 trillion USD) would be inundated by tidal and storm surges, with an elevated risk of water-borne diseases. Also, as demonstrated by the extreme heat wave in Quebec in 2016 that claimed 280 lives, excessive heat, intensified by common impervious materials such as concrete and asphalt, elevates mortality in vulnerable groups such as the elderly and marginalized communities. To alleviate the susceptibility of cities to such extreme weather, green infrastructure such as green roofs and vegetation areas is increasingly implemented. In particular, the transpiration by plants and trees is integral for the minimization of flood damage and cooling of surfaces. Despite the promise, the difficulty of retrofitting to cities of dense layouts by creating such additional areas and facilities as well as their high construction and maintenance cost remain a major hurdle to implementation of this infrastructure.

Our interdisciplinary team of experts from forestry, chemical/civil engineering, and public health will work towards a paradigm shift to transform buildings into artificial trees that provide effective flood control and surface cooling with the goal of building extreme-weather-resilient cities. This interdisciplinary team is equipped to develop a triple-layered film that will mimic the three functionalities of trees to foster conditions for transpiration: absorption (roots), conduction (stem), and evaporation of water (leaves). Attached to building walls and roofs, this film will transform cities into a forest of artificial trees. Based on measurements of water removal rate and surface cooling in both lab and building scales, we will apply a spatial microsimulation model to assess the potential impact of this artificial tree on reducing flood damage and health risks by heat waves. Our proposed research allows for retrofitting existing city infrastructure into artificial trees at a minimal cost, and addresses public health concerns by preventing the spread of water-borne diseases, eliminating the risk of sewer overflow, and protecting vulnerable groups from excessive heat.

Transcription factors (TFs) are notoriously difficult to target for drug development due to challenges in designing specific inactivating molecules. Successfully targeted TFs include nuclear receptors, which naturally bind small molecules. We have shown that the pure antiestrogen fulvestrant, used in breast cancer treatment, induces SUMOylation of estrogen receptor alpha (ERa), transforming it into a transcriptional repressor driving chromatin closure at target genes. We have identified PIAS 1, 2 and 4 as SUMO E3 ligases active on ERa bound to fulvestrant and shown that the main determinant of ERa SUMOylation is a conformation specific to fulvestrant that results in PIAS recruitment. Finally, overexpression of a de-SUMOylase led to loss of both SUMO and Ubi modified forms of ERa, suggesting a positive cross-talk between these modifications.

Our main goal in this Exploration project is to test whether targeting SUMO E3 ligases to TFs inactivates them in a similar manner as for ERa bound to fulvestrant. Ultimately, our objective is to develop "PROTAC" equivalents, i.e. ligands that recruit SUMO E3 ligases to targeted TFs. Our specific aims are the following:

- To provide a proof of principle, we will fuse SUMO E3 ligases to constitutively active forms of ERa occurring during tumor progression, and test whether this inactivates these mutant forms in a dominant negative manner.

- We will test the general application of this concept to other TFs that are also tumorigenesis drivers, such as Myc or mutated TP53, by fusing them to SUMO E3 ligases as above. 

- We will initiate the design of "PROTAC" drugs targeting SUMO E3 ligases by screening in silico for molecules that can interact with SUMO E3 ligases or using fragment-based screens. Such ligands will be ultimately linked to ER ligands to determine whether they mimic fusion of SUMO E3 ligases.

SUMO PROTAC drugs may be particularly efficient as TF inhibitors since they may (i) inactivate their target in a dominant negative manner, leading to chromatin compaction at target genes (ii) cross-talk with ubiquitination to induce accelerated TF degradation, depleting the pool of active drivers, and (iii) target simultaneously several PIAS proteins, a multi-gene family of conserved and essential E3 ligases, precluding escape mechanisms. This innovative project fits the "high risk - high reward" concept as it may yield a novel strategy to inactivate TFs driving diverse pathologies.

Climate change is driving the expansion of marine low oxygen environments (oxygen minimum zones; OMZs), with cascading impacts on the microbial ecosystems that govern food webs and global climate. Understanding microbial ecosystems in existing OMZs is therefore key to predicting how climate change will transform the world's oceans in the future.

A critical knowledge gap in OMZ microbial ecology is the identity and metabolic repertoire of nucleus-bearing microbes, or protists, along with their symbiotic interactions with prokaryotes (Bacteria and Archaea). Protists encompass most of the genetic diversity across eukaryotes, and they strongly influence prokaryotic populations in virtually every environment, yet they are vastly understudied. Our overarching objective is to use high-throughput methods to improve our understanding of protists in marine OMZs, which may improve models of how OMZ expansion will affect marine life, biogeochemical cycles, and climate.

We will use SPLiT-seq - a novel, high-throughput sequencing technology - to resolve single-cell gene expression profiles from heterogeneous populations of anaerobic protists collected from Saanich Inlet, a seasonally anoxic OMZ model near Victoria, BC. Transcriptome sequencing will generate hundreds of thousands of gene sequences from multiple unexplored eukaryotic lineages, which can be leveraged to determine the evolutionary affinities of OMZ protists, the identities of their associated prokaryotes, and the genetic bases of their adaptation to life in anoxia. Furthermore, we will employ recently developed microfluidics chips in combination with Lund University's MAX-IV synchrotron to produce novel insights into the metabolism of anaerobic protists, and the precise chemical context(s) of their interactions with other microbes.

Altogether, our study will disrupt conventional understanding of OMZ ecosystems by providing unprecedented insights into protist genomics, and how protists affect microbial responses to ocean deoxygenation. This is critical for the management of food security, and understanding broader short- and long-term impacts of climate change. Additionally, OMZs may resemble the Proterozoic oceans in which eukaryotes originated, in conjunction with symbiotic prokaryotes. The novel combination of single-cell genomics and chemical ecology of OMZ protists therefore has great potential to illuminate the genetic and chemical interactions that shaped the origin of eukaryotic cells.

The objective of this proposal is to develop and assess a strategy to selectively target anti-diabetic therapies to adipose tissue using magnetic nanoparticles (MNPs).

In obesity, excess white adipose tissue accumulates to the detriment of metabolic health and is a substantial burden on the health of Canadians and national resources. Adipose tissue function is critical for the maintenance of metabolic homeostasis and adipocytes have been targeted for therapeutic improvement of metabolic health in patients with obesity. The potent insulin sensitizing effects of thiazolidinediones (TZDs), such as rosiglitazone, are largely mediated by their effects on adipose tissue. However, meta-analyses of several clinical trials in 2007 showed TZDs also induced cardiovascular complications and had detrimental effects on bone health due to off-target effects on kidney and bone.

This finding has decimated the use of TZDs to treat type 2 diabetes.

We hypothesize MNPs can be utilized as a drug carrier for adipose tissue-targeting of anti-diabetic agents for the treatment of metabolic disease. To test this hypothesis we will use biocompatible, FDA-approved MNPs bound with rosiglitazone (rosi-MNPs) in combination with an external or implanted magnetic field, to concentrate rosiglitazone in subcutaneous white adipose tissue. Previously, we established binding and release profiles for rosiglitazone adsorbed to lipid-coated MNPs and characterized toxicity of rosi-MNPs in an adipocyte cell line. Rosiglitazone retains its biological activity when adsorbed to MNPs and can be concentrated to a specific adipose tissue depot with an implanted magnet, as shown with radio-labelling and live-animal imaging. Armed with this validated tool, we now aim to assess the effect of adipose tissue-targeted rosi-MNPs on lipid/carbohydrate metabolism and thermogenesis in mouse models of diet-induced obesity, while monitoring rosi-MNP biodistribution and pharmacokinetics. The long-term effects of rosi-MNPs on kidney function and bone health will be evaluated.

While MNPs have been shown to be an effective strategy for tissue-specific drug delivery, the novelty of this project will be using MNPs in the context of obesity and metabolic disease. This proof of concept validation for adipose tissue-targeted drug delivery using rosiglitazone is significant to Canadians, as it will be translated to a myriad of adipose-specific molecular targets for the treatment of diabetes or obesity.

Objectives: This proposal will investigate the application of allometric scaling laws to the relationship between measures of population health status, health system performance and the size of population settlements.

Specifically, the objectives are to:

1. Characterize the allometric scaling of health status of populations, in particular Maternal, Newborn and Child Health (MNCH) indicators of access, coverage and outcomes, as related to the size of human settlements and their population density;

2. Determine the consistency of scaling coefficients of health indicators across multiple countries, over a much broader continuum of human settlement sizes (from mega-cities to villages) and over time;

3. Explore how scaling theory can support a novel understanding of the performance of public health systems, health programs and interventions, and, importantly, the failure of international development strategies.

Research Approach:

Researchers in the fields of theoretical physics, economics and geography have proposed that human settlements (i.e: villages, cities) follow scaling principles that have been described in other complex systems observed in nature. The urban scaling theory proposed by these researchers hypothesizes that many indicators of human development, economic production, energy needs and infrastructure follow universal power-law scaling functions that can be predicted by population size. While some indicators increase in direct proportion with increases in settlement size (linear scaling), others see larger increases than the increases in settlement size (super-linear scaling), and others smaller (sub-linear scaling). Previous research has concentrated predominantly on a narrow fraction of the continuum of human settlements, composed of large urban areas and focused on infrastructure and socio-economic indicators; therefore it is important to understand how scaling-theory applies to health outcomes, health infrastructure and health behaviour, especially in Low and Middle-Income Countries (LMICs) and to smaller settlement sizes (i.e: villages, towns).

Expected Significance:

This research could revolutionize health policy, decision-making, financing and systems management. We also believe that scaling theory can be used to restructure existing health research frameworks catalyzing a re-evaluation of previous knowledge by incorporating the role of population settlement size on health status and health system performance.